Pyrazolopyrimidine derivatives as NLRP3 inhibitors

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of diseases, disorders or conditions associated with NLRP3, including diseases, disorders or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS). JPEG2026514121000054.jpg2770[wherein L, X, Y, R 7 , 8 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the specification]

Description

[Technical Field]

[0001] Field of Invention The present invention relates to heterocyclic compounds that are inhibitors of the NLRP3 inflammasome, agents containing them, and the use thereof for treating NLRP3-related diseases, disorders, and / or conditions, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases, and obesity with certain additional risk factors for cardiovascular disease.

[0002] Background of the Invention 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 have no effective treatments. The incidence of neurodegenerative diseases is expected to double in the next few decades, particularly impacting 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 features of neurodegenerative diseases is the aggregation of certain proteins into oligomers or fibrils. These structural changes lead to neurotoxicity, inflammation, and neurodegeneration. Although the clinical manifestations of these diseases are heterogeneous, they often share common underlying mechanisms and pathophysiology. See BNDugger and DWDickson, “Pathology of Neurodegenerative Diseases,” Cold Spring Harbor Perspect Biol. 9(7):a028035 (2017). In fact, systemic activation of the innate immune system, the first line of host defense against pathogens and tissue damage, and subsequent neuroinflammation, play a crucial role in the onset 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 extrinsic and endogenous invaders targeting the central nervous system (CNS), representing a protective response in the brain. However, excessive inflammatory responses are harmful to the CNS. See LILabzin, MTHeneka and E. Latz, “Innate Immunity and Neurodegeneration,” Annu Rev Med 69:437-449 (2018).

[0004] Microglia, the bone marrow cells of the central nervous system (CNS), play a major role in 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 host- or environmentally-derived danger-associated molecular patterns (DAMPS). See RMRansohoff, MABrown, “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 oligomeric domain-like receptors (NLRs). See P. Broz and VMDixit, “Inflammasomes: mechanism of assembly, regulation and signaling,” Nat Rev Immunol 16(7):407-20 (2016). PRR binding activates various inflammatory signaling pathways to eliminate infection and repair damaged tissue. The ongoing inflammation seen in various neurodegenerative diseases may be maintained by inflammasomes, which are important innate immune sensors that signal danger. Several different inflammasomes exist, all defined by the PRRs they contain. Among the NLR family of PRRs, NLRs (NLRP1, NLRP3, 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 inflammasome (containing a nucleotide-binding domain (NOD), a leucine-rich repeat-containing domain (LRR), and a pyrine-containing domain 3) has been a 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 main components: a pattern recognition receptor (PRR) protein (NLRP3), an apoptosis-related speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD) that functions as a central adapter protein, and caspase-1, an inflammatory caspase. See Kelley et al. (2019). NLRP3 comprises three domains: an amino-terminal pyrine domain (PYD), a central NACHT domain with ATPase activity crucial for NLRP3 self-association and oligomerization, and a carboxy-terminal LRR domain. See Broz and Dixit (2016).

[0006] Activation of the NLRP3 inflammasome involves a two-step process. The 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 TSXiao, “Post-translational regulation of inflammasomes,” Cell Mol Immunol 14(1):65-79 (2017). This initial trigger is followed by a second "activation" signal (β-amyloid, α-synuclein and other protein-based invaders, ATP, crystals, nucleic acids, toxins), which induces conformational changes in various inflammasome components, subsequently leading to the oligomerization and nucleation of monomeric NLRP3, resulting in the formation and activation of the NLRP3 inflammasome. See A. Lu, VG 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 via caspase-1-dependent proteolytic cleavage of several proteins, including pro-interleukin (pro-IL)-18 and pro-IL-1β, to their mature inflammatory cytokines, IL-18 and IL-1β. See Kelley et al. (2019). Caspase-1 can also cleave gasdermin D (GSDMD), which can initiate a specific type of cell death called pyroptosis, which facilitates the insertion of GSDMD into the cell membrane, forming a pore and releasing a soluble intracellular fraction that promotes the inflammatory response.See SLFink and BT 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 "classical" NLRP3 inflammasome activation pathway, "non-classical" NLRP3 activation pathways have been described in the literature. The non-classical pathway involves activation of caspase-4 / 5 (or its mouse ortholog, caspase-11) by cytosolic LPS, induction of pyroptosis via GSDMD cleavage, and release of high-mobility box 1 protein (HMGB1), leading to IL-1β production. See M. Lamkanfi and VMDixit, “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 generation of biologically active forms of the pro-inflammatory cytokines IL-1β and IL-18, which initiate inflammatory signaling cascades contributing to neuroinflammation, nerve injury, and cell death. See SM Allan, PJ Tyrrell and NJ 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 LMBooshehri and HMHoffman, “CAPS and NLRP3,” J Clin Immunol 39(3):277-286(2019). This is a rare hereditary autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation, 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 multiorgan inflammatory disease (NOMID / CINCA). Intermediate forms of CAPS are called Muckle-Wells syndrome (MWS). Familial cold autoinflammatory syndrome (FCAS) is a milder form of CAPS caused by cold. See Booshehri and Hoffman (2019). Current anti-IL-1 therapies (anakinra, lilonacept, canakinumab) have proven successful in treating CAPS, but clinical experience over the past decade has shown that some CAPS patients become less responsive over time and require higher or more frequent doses or a switch in therapy.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 See “Juvenile idiopathic arthritis and autoinflammatory syndromes,” BMC Pharmacol Toxicol 14:40 (2013).

[0009] Beyond neurodegenerative diseases, hyperactivation of the NLRP3 inflammasome results in systemic, chronic, low-grade inflammation, a major feature of obesity and insulin resistance. Obesity, characterized by excessive accumulation of body fat, is recognized as a cause of numerous health complications. It is now recognized that obesity is associated with the development of low-grade metabolic inflammation in peripheral tissues and the brain, particularly in the hypothalamus, the brain region responsible for regulating appetite and satiety (Sonnefeld et al., “Is human obesity an inflammatory disease of the hypothalamus?” Eur J Endocrinol. 188(3):R37-R45(2023)).

[0010] The persistent inflammation characteristic of obesity is induced throughout the proliferating tissue (Hotamisligil and Erbay “Nutrient sensing and inflammation in metabolic diseases” Nat Rev Immunol.(12):923-34(2008); Odegaard and Chawla “Mechanisms of macrophage activation in obesity-induced insulin resistance” Nat Clin Pract Endocrinol Metab.(11):619-26(2008)). Excessive fat accumulation is accompanied by the development of adipocytes and promotes macrophage infiltration into tissue (Weisberg et al., “Obesity is associated with macrophage accumulation in adipose tissue” J Clin Invest.112(12):1796-808(2003)). Increased tissue inflammation has cytokine properties and contributes to the progression of diabetes (Olefsky and Glass “Macrophages, inflammation, and insulin resistance” Annu Rev Physiol.72:219-46(2010); Shoelson et al. “Obesity, inflammation, and insulin resistance” Gastroenterology 132(6):2169-80(2007)).In addition, IL-1β is thought to be involved in the progression of obesity-related insulin resistance (Jager et al., “Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression” Endocrinology 148(1):241-51(2007); Netea et al., “Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance” Nat Med.12(6):650-6(2006); Zorrilla et al., “Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency” Proc Natl Acad Sci US A.104(26):11097-102(2007)). Furthermore, overeating leads to stimulation of caspase-1 in adipose tissue in experimental animals (Stienstra et al., “The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity” Cell Metab. 12(6):593-605 (2010)).

[0011] Microglia and astrocytes, glial cells that reside in the brain, can predispose individuals to excessive weight gain by disrupting the hypothalamic energy homeostasis system (Yoo et al., “Tanycyte ablation in the arcuate nucleus and median eminence increases obesity susceptibility by increasing body fat content in male mice” Glia 68(10):1987-2000(2020); Douglass et al., “Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance” Cell Metab.35(9):1613-1629.e8(2023); Sonnefeld et al., “Is human obesity an inflammatory disease of the hypothalamus?” Eur J Endocrinol.188(3):R37-R45(2023)). This is a predisposition. This is because gliosis occurs rapidly before actual weight gain. This inflammation disrupts local signaling of insulin and leptin, leading to dysfunction in the regulation of energy homeostasis and ultimately weight gain.Although not yet fully understood, the mechanism by which this gliosis response occurs involves the transfer of dietary saturated fatty acids into the cerebrospinal fluid (Melo et al., “Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α” Cell Rep.30(7):2180-2194.e8(2020)), which promotes inflammatory activation of hypothalamic microglia, likely via a Toll-like receptor 4-dependent mechanism (Milanski et al., “Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity” 29(2):359-70(2009); Valdearcos et al., “Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function” Cell Rep.9(6):2124-38(2014); Folick et al., “Metabolic factors in the regulation of hypothalamic innate immune responses in obesity” 54(4):393-402(2022)). Dysregulated hypothalamic circuits alter interactions between neurons and non-neuronals, contributing to the establishment of inflammatory processes. Interventions that inhibit this gliosis response have shown a reduction in excessive weight gain (Valdearcos et al., Cell Rep.9(6):2124-38(2014); Douglass et al., Cell Metab.35(9):1613-1629.e8(2023)).NLRP3 deficiency has been reported to inhibit the progression of obesity-related insulin resistance (Stienstra et al., Cell Metab. 12(6):593-605(2010)).

[0012] Several small molecule inhibitors that block the NLRP3 inflammasome pathway have recently been reported. These include the prototype NLRP3 inhibitor MCC-950. See RCColl, JRHill, CJDay, et al., “MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition,” Nat Chem Biol 15(6):556-559(2019); RCColl, AARobertson, JJChae, 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, oridonine, tranilast, INF-39, glybride, 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 demonstrate the NLRP3 inflammasome as a viable drug target for developing therapeutic drugs for human diseases. See SECorcoran, R. Halai and MACooper, “Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950,” Pharmacol Rev 73(3):968-1000 (2021).

[0013] Inhibitors of the NLRP3 inflammasome pathway are expected to be useful in treating neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases; treating CAPS associated with heterozygous gain-of-function mutations in the NLRP3 gene; and treating obesity with certain additional risk factors for cardiovascular disease.

[0014] WO2023 / 032987 discloses the following 6-aminopyrazolopyrimidine derivatives as compounds that have inhibitory activity against NLRP3. [ka]

[0015] WO2024 / 048519 discloses the following 6-aminopyrazolopyrimidine derivatives as compounds that have inhibitory activity against NLRP3. [ka]

[0016] US9,688,681 discloses heterocyclic compounds for controlling animal pests, comprising the following three compounds: [ka] [Overview of the project]

[0017] The present invention provides heterocyclic compounds, pharmaceutically acceptable salts thereof, solvates thereof, or hydrates thereof. The present invention also provides pharmaceuticals containing pyrazolopyrimidone derivatives and their use for treating NLRP3-related diseases, disorders, and / or conditions, including Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, as well as other neurodegenerative disorders.

[0018] One aspect of the present invention is, [1] A compound of formula (I), or a pharmaceutically acceptable salt thereof: [Chemical formula] [Wherein, L is O or a bond; X is N or CR 4 ; Y is N or CR 5 ; R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted 4- to 6-membered heterocyclic group, provided that when L is a bond, the 4- to 6-membered heterocyclic group is a 4- to 6-membered non-aromatic heterocyclic group bonded to the pyrazolopyrimidone ring by a carbon-carbon bond; R ' 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-8 cycloalkyl group; R 3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, or a halogen atom; and R 4 , R 5 , R 6 , R 7 and R 8 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, a halogen atom, a hydroxy group, an optionally substituted C 1-6 alkoxy group, an optionally substituted 5- or 6-membered heterocyclic group, a cyano group, an amino group, or a nitro group; However, it excludes (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidin-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidin-4-one, and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6-(trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidin-4-one. (Hereinafter, it may be referred to as "Compound (I)".) To provide.

[0019] Another aspect of the present invention provides the following [2] to

[33] .

[0020] [2] L is O or a bond; X is N or CR 4 and; Y is N or CR 5 and; R 1 is (1) (a) a halogen atom, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be halogenated, (d) a di-C 1-6 alkylamino group, (e) a C 7-16 aralkyloxy group, (f) a 5- or 6-membered aromatic heterocyclic group, (g) a 5- or 6-membered non-aromatic heterocyclic group, [[ID=4i6]](h) a carboxy group, (i) a 4- to 6-membered non-aromatic heterocyclyloxy group, and (j) a cyano group and is optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group, (2) (a) a C 1-6 alkyl group, (b) a C 1-6 alkoxy group, (c) a halogen atom, (d) cyano group, and (e) Formula: -(CH2) a -O-(CH2) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups, (3)(a) Halogen atoms, and (b) C 1-6 Alkoxy group C may be substituted with one to three substituents selected from the following. 6-14 Aryl group, (4)(a) Halogen atom, (b)(i) Halogen atoms and (ii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups. 1-6 alkyl group, (c) C 1-6 Alkoxy groups, and (d) Together with the 5- or 6-membered aromatic heterocyclic group to which they are bonded, they form an 8- to 10-membered condensed heterocyclic group, formula: -(CH2) a -O-(CH2) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) A 5- or 6-membered aromatic heterocyclic group which may be substituted with one to three substituents selected from, or (5)(a) Oxo group, (b) C 1-6 alkyl group, (c) Halogen atoms, and (d) C 1-6 Alkoxy group A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following: and; R 2 but, (1) A hydrogen atom, or (2) C 1-6alkyl group and; R 3 but, (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and; R 4 and R 8 However, they each act independently. (1) Hydrogen atom, (2)(i) Halogen atom, (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy group C may be substituted with one to four substituents selected from the following. 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atoms, (5) Hydroxyl group, (6) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group, (7) A 5- or 6-membered aromatic heterocyclic group, (8) Cyano group and; R 5 and R 7 However, they each act independently. (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) Halogen atoms, or (4) C 3-8 Cycloalkyl groups and R 6 but, (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms3-8 a cycloalkyl group, (4) C 2-6 an alkenyl group, (5) a halogen atom, (6) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (7) a 5- or 6-membered aromatic heterocyclic group, (8) an amino group, or (9) a nitro group and is the compound defined in [1] above or a pharmaceutically acceptable salt thereof.

[0021] [3] L is O or a bond; X is CR 4 and is Y is CR 5 and is R 1 is a C 1-6 alkyl group which may be substituted with an alkoxy group which may be halogenated, 1-6 and is R 2 is a hydrogen atom; R 3 is a hydrogen atom; R 4 and R 8 are each independently (1) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, or (2) a halogen atom <983>and is R 5 and R 7 are both hydrogen atoms; and R 6 is (1) a C 3-8 cycloalkyl group which may be substituted with 1 to 3 halogen atoms, (2) a halogen atom, or (3) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms and is The compound defined in [1] or a pharmaceutically acceptable salt thereof.

[0022] [4] L is O; X is N or CR 4 and; Y is N or CR 5 and; R 1 is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 6-14 aryl group, or an optionally substituted 4- to 6-membered heterocyclic group; R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl group; R 3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or a halogen atom; R 4 and R 8 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, a halogen atom, a hydroxy group, an optionally substituted C 1-6 alkoxy group, an optionally substituted 5- or 6-membered heterocyclic group, or a cyano group; R 5 and R 7 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, or a halogen atom; and R 6 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 2-6 alkenyl group, a halogen atom, an optionally substituted C 1-6 alkoxy group, or an optionally substituted 5- or 6-membered heterocyclic group, The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0023] [5] L is O; X is N or CR 4 and; Y is N or CR 5 and; R 1 but, (1)(a) Halogen atom, (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy group, (d) G-C 1-6 Alkylamino group, and (e) C 7-16 Aralkyloxy group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2)(a) C 1-6 Alkoxy group, (b) cyano group, and (c) Formula: -(CH2) a -O-(CH2) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups, (3) C 6-14 Aryl group, or (4) 4- to 6-membered non-aromatic heterocyclic groups and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 3 but, (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2)(i) Halogen atom, (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy group C may be substituted with one to four substituents selected from the following. 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atom, (5) Hydroxyl group, (6) C 1-6 Alkoxy group, (7) A 5- or 6-membered aromatic heterocyclic group, (8) Cyano group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and R 6 but, (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) C 2-6 Alkenyl group, (5) Halogen atom, (6) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group, or (7) 5- or 6-membered aromatic heterocyclic groups That is, The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0024] [6] L is O; X, CR 4 and; Y, CR 5 and; R 1 However, 1 to 3 C 1-6 C may be substituted with an alkoxy group. 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, they each act independently (1) C which may be substituted with one to three halogen atoms 1-6 Alkyl alkyl group, or (2) Halogen atom and; R 5 and R 7 However, both are hydrogen atoms; and R 6 but, (1) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (2) Halogen atoms, or (3) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group That is, The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0025] [7] L is O; X, CR 4 and; Y, CR 5 and; R 1 However, C 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both are C 1-6 It is an alkyl group; R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 It is a cycloalkyl group. The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0026] [8] L is a combination; X is N or CR 4 and; Y is N or CR 5 and; R 1 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered non-aromatic heterocyclic group; R 2 However, a hydrogen atom, or a substituted C 1-6 It is an alkyl group; R 3 However, hydrogen atoms may be substituted C 1-6 It is an alkyl group or halogen atom; R 4 and R 8 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 An alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, or a cyano group; R 5 and R 7 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6Alkyl alkyl groups, halogen atoms, or optionally substituted C 3-8 It is a cycloalkyl group; and R 6 However, hydrogen atoms may be substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, an amino group, or a nitro group. The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0027] [9] L is a combination; X, CR 4 and; Y, CR 5 and; R 1 but, (1)(a) Halogen atom, (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy group, (d) C 7-16 Aralkyloxy group, (e) A 5- or 6-membered aromatic heterocyclic group, (f) A 5- or 6-membered non-aromatic heterocyclic group, (g) Carboxy group, (h) 4- to 6-membered non-aromatic heterocyclyloxy groups, and (i) cyano group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2)(a) C 1-6 alkyl group, (b) C 1-6 Alkoxy group, (c) Halogen atoms, and (d) cyano group C may be substituted with one to three substituents selected from the following. 3-8Cycloalkyl groups, (3)(a) Halogen atoms, and (b) C 1-6 Alkoxy group C may be substituted with one to three substituents selected from the following. 6-14 Aryl group, or (4)(a) Oxo group, (b) C 1-6 alkyl group, (c) Halogen atoms, and (d) C 1-6 Alkoxy group A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following: and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 3 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with 1 to 4 halogen atoms 1-6 alkyl group, (3) Halogen atoms, (4) Hydroxyl group, or (5) C 1-6 Alkoxy group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) Halogen atoms, or (4) C 3-8 Cycloalkyl groups and R 6 but, (1) Hydrogen atom, (2) C 1-6 alkyl group (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atom, (5) an amino group, or (6) Nitro group That is, The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0028]

[10] L is a combination; X, CR 4 and; Y, CR 5 and; R 1 However, C may be halogenated. 1-6 C may be substituted with an alkoxy group. 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both C atoms may be substituted with one to three halogen atoms. 1-6 It is an alkyl group; R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 It is a cycloalkyl group. The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0029]

[11] The compound is: 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[2-bromo-4-(difluoromethoxy)-6-methylphenyl]-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl]-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-[(difluoromethoxy)methyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; and 2-[4-Cyclopropyl-2-(difluoromethyl)-6-methylphenyl]-6-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one Selected from, The compound as defined in [1] above, or a pharmaceutically acceptable salt thereof.

[0030]

[12] A method for treating a disease, disorder or condition in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt defined in [1] above, wherein the disease, disorder or condition is related to NLRP3.

[0031]

[13] A method for treating a disease, disorder or condition in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt defined in [1] above, wherein the disease, disorder or condition is associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

[0032]

[14] A method for treating cryopyrin-associated periodic syndromes (CAPS) in a subject, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt defined in [1] above to the subject.

[0033]

[15] The method according to

[14] , wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0034]

[16] A method for treating a neurodegenerative disease, disorder or condition in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt defined in [1] above.

[0035]

[17] A method for treating Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or prion disease in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt defined in [1] above.

[0036]

[18] A pharmaceutical product comprising a compound or a pharmaceutically acceptable salt as defined in [1] above.

[0037]

[19] The pharmaceutical product described in

[18] above, which is a treatment agent for a disease, disorder or condition associated with NLRP3.

[0038]

[20] The pharmaceutical product described in

[18] above, which is a treatment agent for a disease, disorder or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

[0039]

[21] The pharmaceutical product described in

[18] above, which is a treatment for cryopyrin-associated periodic syndromes (CAPS).

[0040]

[22] The pharmaceutical product according to

[21] , wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0041]

[23] A compound or pharmaceutically acceptable salt as defined in [1] above, for use as a medicine.

[0042]

[24] Compounds or pharmaceutically acceptable salts as defined in [1] above, for use in the treatment of diseases, disorders or conditions associated with NLRP3.

[0043]

[25] The compounds or pharmaceutically acceptable salts defined in [1] above for use in the treatment of diseases, disorders or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene.

[0044]

[26] The compounds defined in [1] above or pharmaceutically acceptable salts thereof, for use in the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0045]

[27] The cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS), and is a compound or pharmaceutically acceptable salt as defined in

[26] above.

[0046]

[28] Use of the compounds or pharmaceutically acceptable salts defined in [1] above for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NLRP3.

[0047]

[29] Use of the compound or pharmaceutically acceptable salt defined in [1] above for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

[0048]

[30] Use of the compounds or pharmaceutically acceptable salts defined in [1] above for the manufacture of a medicament for the treatment of cryopyrin-associated periodic syndromes (CAPS).

[0049]

[31] The use according to

[30] , wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0050]

[32] A combination comprising the compound or pharmaceutically acceptable salt defined in [1] above, and at least one additional pharmacologically active agent (hereinafter sometimes referred to as the "pharmacologically active compound").

[0051]

[33] The combination described in

[32] , wherein the additional pharmacologically active agent is selected from the group consisting of beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, vitamin E, anti-amyloid antibodies, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. [Detailed description of the invention]

[0052] Unless otherwise indicated, this disclosure uses the definitions provided below.

[0053] "Substituted" means a chemical substituent or part (e.g., C 1-6 When used in relation to alkyl groups, it means that one or more hydrogen atoms in the substituent or moiety are replaced by one or more non-hydrogen atoms or groups, provided that the valence requirements are met and the substitution results in a chemically stable compound.

[0054] When used in relation to a measurable numerical variable, "approximately" or "about" refers to the indicated value of that variable and all values ​​of the variable that are within the experimental error of the indicated value or within ±10 percent of the indicated value, whichever is greater.

[0055] "Alkyl" refers to a linear and branched saturated hydrocarbon group that generally has a specified number of carbon atoms (for example, C 1-3 Alkyl refers to an alkyl group having 1 to 3 (i.e., 1, 2, or 3) carbon atoms. 1-4 Alkyl refers to an alkyl group having 1 to 4 carbon atoms (i.e., 1, 2, 3, or 4 carbon atoms). 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). 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), penta-1-yl, penta-2-yl, penta-3-yl, 3-methylbuta-1-yl, 3-methylbuta-2-yl, 2-methylbuta-2-yl, 2,2,2-trimethylethanol-1-yl, and n-hexyl.

[0056] "Alkanediyl" refers to a divalent alkyl group (alkyl is defined above) that generally has a specified number of carbon atoms (for example, C 1-4 An alkanediyl refers to an alkanediyl group having 1 to 4 carbon atoms (i.e., 1, 2, 3, or 4 carbon atoms). 1-6 Alkanediyl refers to an alkanediyl group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). 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, and isobutane-1,2-diyl.

[0057] "Alkenyl" refers to a linear and branched hydrocarbon group having one or more carbon-carbon double bonds and generally a specified number of carbon atoms (for example, C 2-6An alkenyl refers to an alkenyl group having 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6). 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-butadiene-1-yl, and 1,3-butadiene-2-yl.

[0058] "Alkynnyl" refers to a linear or branched hydrocarbon group having one or more carbon-carbon triple bonds and generally possessing a specified number of carbon atoms (for example, C 2-6 Alkynyl refers to an alkynyl group having 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6). Examples of alkynyl groups include ethynyl, 1-propyne-1-yl, 2-propyne-1-yl, 1-butyne-1-yl, 3-butyne-1-yl, 3-butyne-2-yl, and 2-butyne-1-yl.

[0059] "Alkoxy" refers to a linear and branched saturated hydrocarbon group that generally has a specified number of carbon atoms bonded via oxygen atoms (for example, C 1-4 An alkoxy refers to an alkoxy group having 1 to 4 carbon atoms (i.e., 1, 2, 3, or 4 carbon atoms). 1-6 Alkoxy refers to an alkoxy group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, penta-1-yloxy, penta-2-yloxy, penta-3-yloxy, 3-methylbuta-1-yloxy, 3-methylbuta-2-yloxy, 2-methylbuta-2-yloxy, 2,2,2-trimethylethanol-1-yloxy, and n-hexoxy.

[0060] "Alkyl-carbonyl" and "alkylsulfonyl" refer to alkyl groups as defined above, which are bonded via carbonyl (C(O)) or sulfonyl (SO2) groups and generally have a specified number of carbon atoms (for example, C 1-6 Alkyl-carbonyl refers to an alkyl-carbonyl group that has 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6) excluding the carbonyl portion. 1-6 Alkylsulfonyl refers to an alkylsulfonyl group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). Examples of alkyl-carbonyl groups include methylcarbonyl (acetyl), ethylcarbonyl, i-propylcarbonyl (propanoyl), n-propylcarbonyl, and 2-methylpropanoyl. Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, i-propylsulfonyl, and n-propylsulfonyl.

[0061] "Alkylamino," which includes a monoalkylamino group or a dialkylamino group, refers to the alkyl group defined above, which is bonded via at least one amino group and generally has a specified number of carbon atoms (for example, C 1-6 Alkylamino refers to a monoalkylamino group or dialkylamino group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). Examples of monoalkylamino or dialkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, and N-ethyl-N-methylamino.

[0062] "Alkyl-carbamoyl" including a monoalkyl-carbamoyl group or a dialkyl-carbamoyl group refers to the alkyl group defined above, which is bonded via a carbamoyl (CONH2) group and generally has a specified number of carbon atoms (for example, C 1-6Alkyl-carbamoyl refers to a monoalkyl-carbamoyl group or dialkyl-carbamoyl group having 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6) (excluding the carbamoyl portion), etc. Examples of monoalkyl-carbamoyl or dialkyl-carbamoyl groups include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0063] "Alkyl-carbonylamino" refers to the alkyl-carbonyl defined above, which is bonded via an amino moiety and generally has a specified number of carbon atoms (for example, C 1-6 Alkyl-carbonylamino refers to an alkyl-carbonylamino group having 1 to 6 carbon atoms (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) and ethylcarbonylamino.

[0064] "Alkoxy-carbonyl" refers to an alkoxy group defined above, which is bonded via a carbonyl (C(O)) group and generally has a specified number of carbon atoms (for example, C 1-6 An alkoxy-carbonyl group refers to an alkoxy-carbonyl group (excluding the carbonyl portion) that has 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5, or 6). 1-6 Examples of alkoxy-carbonyl groups include methoxycarbonyl and ethoxycarbonyl.

[0065] "Halo," "halogen," and "halogeno" are sometimes used interchangeably and refer to fluoro, chloro, bromo, and iodine.

[0066] "Haloalkyl," "haloalkenyl," and "haloalkynyl" refer to alkyl, alkenyl, and alkynyl groups (alkyl, alkenyl, and alkynyl are defined above) that are substituted with one or more halogen atoms and generally have 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, and 1-chloro-1-methylethyl.

[0067] "Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups that generally have a specified number of carbon atoms constituting a ring (for example, C 3-8 A cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members. 3-10 A cycloalkyl group refers to a cycloalkyl group having 3 to 10 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members. Bicyclic hydrocarbon groups may include separated rings (two rings that do not share carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (two rings that share a bond between two carbon atoms and two common carbon atoms), and bridging rings (two rings that share two carbon atoms but do not share a common bond). Cycloalkyl groups can be bonded via any ring atom, provided that such bond does not violate the valence requirements, and may optionally contain one or more nonhydrogen substituents, as shown, provided that such substitutions do not violate the valence requirements.

[0068] Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of condensed 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, and bicyclo[4.4.0]decanyl. Examples of crosslinked 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, and bicyclo[4.3.3]dodecanyl. Examples of spirocycloalkyl groups include spiro[3.3]heptanyl, spiro[2.4]heptanyl, spiro[3.4]octanyl, spiro[2.5]octanyl, and spiro[3.5]nonanyl. Examples of separated bicyclic cycloalkyl groups include those derived from bi(cyclobutane), cyclobutanecyclopentane, bi(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, and bi(cyclohexane).

[0069] "Cycloalkanediyl" refers to a divalent cycloalkyl group (cycloalkyl is defined above) that generally has a specified number of carbon atoms (for example, C 3-8A cycloalkanediyl refers to a cycloalkanediyl group having 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8). Examples of cycloalkanediyl groups include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, and cyclobutane-1,2-diyl.

[0070] "Cycloalkylidene" refers to a divalent monocyclic cycloalkyl group (cycloalkyl is defined above) that is bonded through a single carbon atom of the group and generally has a specified number of carbon atoms forming the ring (e.g., C 3-8 A cycloalkylidene refers to a cycloalkylidene group having 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members. Examples of cycloalkylidene groups include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.

[0071] "Cycloalkenyl" refers to a partially unsaturated monocyclic and bicyclic hydrocarbon group that generally has a specified number of carbon atoms constituting a ring (for example, C 3-8 A cycloalkenyl refers to a cycloalkenyl group having 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members, etc. Similar to cycloalkyl groups, bicyclic cycloalkenyl groups may include separated rings, spiro rings, fused rings, or bridging rings. Similarly, cycloalkenyl groups can be bonded via any ring atom and, where indicated, may optionally contain one or more nonhydrogen substituents, provided that such bonding 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, and bicyclo[2.2.1]hepta-2-enyl.

[0072] "Cycloalkyl-carbonyl" or "cycloalkylsulfonyl" refers to the cycloalkyl group defined above, which is bonded via a carbonyl (C(O)) group or a sulfonyl (SO2) group, and generally has a specified number of carbon atoms (for example, C 3-8 A cycloalkyl-carbonyl group refers to a cycloalkyl-carbonyl group that, excluding the carbonyl portion, has 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members of a cycloalkyl group. 3-8 A cycloalkylsulfonyl group refers to a cycloalkylsulfonyl group having 3 to 8 carbon atoms (i.e., 3, 4, 5, 6, 7, or 8) as ring members of a cycloalkyl group. Examples of cycloalkylcarbonyl groups include cyclopropylcarbonyl, cyclobutylcarbonyl, and cyclopentylcarbonyl. Examples of cycloalkylsulfonyl groups include cyclopropylsulfonyl, cyclobutylsulfonyl, and cyclopentylsulfonyl.

[0073] "Aryl" refers to completely unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons having at least one aromatic ring, where both monocyclic and polycyclic aryl groups generally have a specified number of carbon atoms constituting their ring members (for example, C 6-14 The term "aryl" refers to an aryl group having 6 to 14 carbon atoms as ring members (e.g.). This group can be bonded via any ring atom and, if shown, may optionally contain one or more non-hydrogen substituents, provided that such bonding or substitution does not violate valence requirements. Examples of aryl groups include phenyl, biphenyl, cyclobutabenzenyl, indenyl, naphthyl, benzocycloheptanyl, biphenylenyl, fluorenyl, and groups derived from cycloheptatriene cations.

[0074] Examples of "acyl groups" include formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group, and phosphono group, each of which is "C 1-6 Alkyl alkyl group, C 2-6Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 It optionally has one or two substituents selected from an aralkyl group, a 5-14 member aromatic heterocyclic group, and a 3-14 member non-aromatic heterocyclic group, each of which is a halogen atom, and optionally halogenated C 1-6 "It optionally has 1 to 3 substituents selected from alkoxy groups, hydroxyl groups, nitro groups, cyano groups, amino groups, and carbamoyl groups." Examples of "acyl groups" also include hydrocarbon-sulfonyl groups, heterocyclylsulfonyl groups, hydrocarbon-sulfinyl groups, and heterocyclylsulfinyl groups. Here, hydrocarbon-sulfonyl groups mean sulfonyl groups to which hydrocarbon groups are attached, heterocyclylsulfonyl groups mean sulfonyl groups to which heterocyclic groups are attached, hydrocarbon-sulfinyl groups mean sulfinyl groups to which hydrocarbon groups are attached, and heterocyclylsulfinyl groups mean sulfinyl groups to which heterocyclic groups are attached.

[0075] Preferred examples of "acyl groups" include formyl groups, carboxyl groups, and C 1~6 Alkyl-carbonyl group, C 2~6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3~10 Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3~10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6~14 Aryl-carbonyl group, C 7~16 Aralkyl-carbonyl group, 5-14 member aromatic heterocyclylcarbonyl group, 3-14 member non-aromatic heterocyclylcarbonyl group, C 1~6 Alkoxy-carbonyl group, C 6~14 Aryloxycarbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7~16Aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl groups, mono- or di-C 1~6 Alkyl-carbamoyl group, mono- or di-C 2~6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3~10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6~14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7~16 Aralkyl-carbamoyl group, 5-14 member 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 group (e.g., diallylthiocarbamoyl), mono- or di-C 3~10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6~14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7~16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5-14 member aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1~6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1~6 Alkyl sulfonyl group, C 6~14 Aryl sulfonyl groups, phosphono groups, and mono- or di-C groups 1~6 Examples include alkylphosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0076] "Aralkyl" refers to an alkyl group as defined above, in which one of its hydrogen atoms is substituted by an aryl group as defined above, and which generally has a specified number of carbon atoms (for example, C 7-16 Aralkyl refers to an aralkyl group having 7 to 16 carbon atoms. Examples of aralkyl groups include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0077] "Aralkyloxy" refers to a hydroxyl group in which its hydrogen atom is substituted by an aralkyl group as defined above, and which generally has a specified number of carbon atoms (for example, C 7-16 Aalkyloxy refers to an aralkyloxy group having 7 to 16 carbon atoms. Examples of aralkyloxy groups include benzyloxy, phenethyloxy, naphthylmethoxy, and phenylpropyloxy.

[0078] "Aralkyloxy-carbonyl" refers to the aralkyloxy group defined above, which is bonded via a carbonyl (C(O)) group and generally has a specified number of carbon atoms (for example, C 7-16 Aalkyloxycarbonyl refers to an aralkyloxycarbonyl group having 7 to 16 carbon atoms (excluding the carbonyl portion). Examples of aralkyloxycarbonyl groups include benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl, and phenylpropyloxycarbonyl.

[0079] "Arylene" refers to a divalent aryl group (aryl is defined above), and generally has a specified number of carbon atoms that constitute its ring members (for example, C 6-14 Arylene refers to an arylene group having 6 to 14 carbon atoms as ring members, etc. An example of an arylene group is o-phenylene (i.e., benzene-1,2-diyl).

[0080] The terms "heterocyclic," "heterocyclic formula," and "heterocyclyl" are sometimes used interchangeably and refer to saturated or partially unsaturated monocyclic or bicyclic groups having a ring atom 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 A heterocyclyl refers to a heterocyclyl group having 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6) and, for example, 1 to 4 heteroatoms (i.e., 1, 2, 3, or 4) as ring members, while a 5- or 6-membered heterocyclic group refers to a heterocyclyl group having a total of 5 or 6 atoms (carbons and heteroatoms) as ring members. Similar to bicyclic cycloalkyl groups, bicyclic heterocyclyl groups can include separated rings, spiro rings, fused rings, and bridging rings. Heterocyclyl groups can be bonded via any ring atom 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 heterocyclyl groups include oxyranil, thyranil, aziridinil (e.g., aziridin-1-yl and aziridin-2-yl), oxetanil, thietanil, azetidinil, tetrahydrofuranil, tetrahydrothienyl, pyrrolidinil, tetrahydropyranil, tetrahydrothiopyranil, piperidinil, 1,4-dioxanil, 1,4-oxathianil, morpholinil, 1,4-dithianil, piperazinil, 1,4-azathanil, oxepanil, thiepanil, azepanil, 1,4-dioxepanil, 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.

[0081] A "heterocyclic-diyl" group refers to a heterocyclyl group (heterocyclyl as defined above) that is bonded via two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (e.g., C 2-6 A heterocyclic diyl group refers to a heterocyclic diyl group having 2 to 6 carbon atoms (i.e., 2, 3, 4, 5, or 6) and, for example, 1 to 4 heteroatoms (i.e., 1, 2, 3, or 4) as ring members. Examples of heterocyclic diyl groups include polyvalent analogs of the above heterocyclic groups, such as morpholine-3,4-diyl, pyrrolidine-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, and 1-piperazinyl-6-ylidene.

[0082] "Heteroaromatic," "aromatic heterocyclyl / heterocyclic," and "heteroaryl" are sometimes used interchangeably and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, where each group has a ring atom composed of one or more heteroatoms independently selected from carbon atoms and nitrogen, oxygen, and sulfur. Both monocyclic and polycyclic groups generally have a number of carbon atoms designated as ring members (e.g., C 1-9A heteroaryl group may include any bicyclic group in which any of the monocyclic or heterocyclic groups described above is fused to a benzene ring, having 1 to 9 carbon atoms (i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and, for example, 1 to 4 heteroatoms (i.e., 1, 2, 3, or 4) as ring members. The heteroaryl group may be bonded via any ring atom (or ring atom of the fused ring), and may optionally contain one or more nonhydrogen substituents, as shown, 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., pyrrole-1-yl, pyrrole-2-yl, and pyrrole-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, pyridadinyl, pyrimidinyl, and pyrazinyl.

[0083] Examples of heteroaryl groups also include bicyclic groups, such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[c]thienyl, 1H-indolyl, 3H-indolyl, isoindolyl, 1H-isoindolyl, indolinyl, isoindolyl, 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, and 3H-imidazo[4,5-b]pyridinyl. Dinyl, 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-prinyl, indolidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrozolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridadinyl, imidazo[1,2-c]pyrimidinyl, quinolyl, isoquinolyl, sinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,6-naphthilidinyl, 1,7-naphthilidinyl, 1,8-naphthilidinyl, 1,5-naphthilidinyl, 2,6-naphthilidinyl, 2,7-naphthilidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrimidinyl, pyrido[3,4-b]pyrimidinyl, pyridido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrimidinyl, pyridido[4,5-d]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3-b] Pyrazinyl, 2,3-dihydrobenzo[b][1,4]dioxynyl, 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,Examples include [2-a]pyrimidinyl, 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidinyl, 2,3,6,7-tetrahydro-1H-prinyl, 5H-pyrrolo[2,3-b]pyradinyl, imidazo[1,2-a]pyradinyl, imidazo[1,2-b]pyridazinyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyradinyl.

[0084] A "heteroarylene" refers to a heteroaryl group (heteroaryl is defined above) that is bonded via two ring atoms of the group. They generally have a specified number of carbon atoms in their ring(s) (for example, C 3-5 A heteroarylene refers to a heteroarylene group having 3 to 5 carbon atoms and, for example, 1 to 4 heteroatoms (i.e., 1, 2, 3, or 4) as ring members. Examples of heteroarylene groups include polyvalent analogs of the heteroaryl group mentioned above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, and pyrazole-3,4-diyl.

[0085] "Non-aromatic heterocyclic / heterocyclyl" ("including 3-8 member non-aromatic heterocyclic groups") refers to heterocyclic groups other than the heteroaryl groups mentioned above. Preferred examples of "non-aromatic heterocyclic groups" include azilidinyl, oxyranil, thyranil, azetidinil, oxetanil, thietanil, tetrahydrothienyl, tetrahydrofuranil, pyrrolinil, pyrrolidinyl, imidazolinil, imidazolidinyl, oxazolinil, oxazolidinyl, pyrazolinil, pyrazolidinyl, thiazolinil, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydro monocyclic non-aromatic heterocyclic groups of 3 to 8 members, such as loisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranil, tetrahydrothiopyranil, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azokanyl, and diazokanyl, and

[0086] Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hexa Examples include 9-14 member condensed polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups such as hydrophenothiazinyl, hexahydrophenoxadinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0087] In this specification, an example of a "nitrogen-containing heterocyclic group" is a "heterocyclic group" that contains at least one nitrogen atom as a ring constituent atom.

[0088] In this specification, examples of "arbitrarily substituted heterocyclic groups" include heterocyclic groups having optionally selected substituents (multiple substituents) from substituent A listed below.

[0089] "Oxo" refers to oxygen (=O) that is double-bonded.

[0090] Examples of "substituents" (including "heterosubstituteds") 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 hydroxyl groups, optionally substituted sulfanyl (SH) groups, and optionally substituted silyl groups.

[0091] Examples of "hydrocarbon groups" (including "hydrocarbon groups" in "arbitrarily substituted hydrocarbon groups") include C 1-6 Alkyl alkyl 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 group, and C 7-16 An example is the aralkyl group.

[0092] A "heterosubstituted" refers to a substituent that contains at least one heteroatom. Examples of heterosubstituted groups include halogen atoms, cyano groups, nitro groups, heterocyclyl groups, heteroaryl groups, heterosubstituted groups (halo-alkyl, amino-alkyl, cyano-alkyl, alkoxy-alkyl, etc.), cycloalkyl groups substituted with heterosubstituted groups (e.g., halo-cycloalkyl, cyano-cycloalkyl, hydroxy-cycloalkyl, etc.), and arbitrarily substituted alkoxy groups.

[0093] Examples of "arbitrarily substituted hydrocarbon groups" include hydrocarbon groups having optionally selected substituents (multiple substituents are possible) from the following substituent A.

[0094] [Substituent A] (1) Halogen atom, (2) Nitro group, (3) Cyano group, (4) Oxo group, (5) Hydroxyl group, (6) C halogenated by optional choice 1-6 Alkoxy group, (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8)C 7-16 Aralkyloxy group (e.g., benzyloxy), (9) 5-14 member aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3-14 member non-aromatic heterocyclyloxy groups (e.g., morpholinyloxy, piperidinyloxy), (11)C 1-6 Alkyl-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) 5-14 member aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) 3-14 member non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) C halogenated by choice 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, trifluoromethyl sulfonyloxy), (19)C 1-6 C optionally substituted with alkyl groups 6-14 Aryl sulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) C halogenated by choice 1-6 Alkylthio group, (21) 5-14 member aromatic heterocyclic group, (22) 3-14 member non-aromatic heterocyclic group, (23) Formyl group, (24) Carboxy group, (25) C which can be halogenated by choice 1-6 Alkyl-carbonyl group, (26)C 6-14 Aryl-carbonyl group, (27) 5-14 member aromatic heterocyclyl carbonyl group, (28) 3-14 member non-aromatic heterocyclylcarbonyl group, (29)C 1-6 Alkoxy-carbonyl group, (30)C 6-14 Aryloxycarbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 Aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) Carbamoyl group, (33) Thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl group, (35)C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) 5-14 member aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3-14 member non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) C which is optionally halogenated 1-6 Alkyl sulfonyl group, (39)C 6-14 Aryl sulfonyl group, (40) 5-14 member aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) C which is optionally halogenated 1-6 Alkyl sulfinyl group, (42)C 6-14 Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl), (43) 5-14 member 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 group (e.g., phenylamino), (47) Aromatic heterocyclylamino groups with 5 to 14 members (e.g., pyridylamino), (48)C 7-16 Aralkylamino group (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 group (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 Aralkyloxycarbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with alkyl groups 6-14Aryl sulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) C which is optionally halogenated 1-6 alkyl group, (58)C 2-6 Alkenyl group, (59)C 2-6 Alkynyl group, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl group, (62)C 6-14 Aryl group, and (63) Formula:-(CH2) a -O-(CH2) b A base represented by the formula - (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4).

[0095] The number of substituents in the "arbitrarily substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0096] A "leaving group" refers to any group that leaves a molecule during fragmentation processes, including substitution, elimination, and addition-elimination reactions. Leaving groups can be nucleofugal (leaving along with the electron pair that originally functioned as a bond between the leaving group and the molecule) or electrofugal (leaving without an electron pair). The ability of a nucleofugal leaving group to leave depends on the strength of the base, with the strongest base producing the weakest leaving group. Common nucleofugal leaving groups include nitrogen (e.g., from diazonium salts); alkylsulfonates (e.g., mesylate); fluoroalkylsulfonates (e.g., triflate, hexaflate, nonaflate, and toresylate); and sulfonates, including arylsulfonates (e.g., tosylate, brosylate, crosylate, and nosylate). Other examples include carbonates, halide ions, carboxylate anions, phenolate ions, and alkoxides. Some stronger bases, for example, NH2 - and OH - These can be made into better leaving groups by treating them with acid. Common electron-leaving leaving groups include protons, CO2, and metals.

[0097] An "opposite enantiomer" refers to a molecule that is an incompatible mirror image of a reference molecule, and can be obtained by inverting all the chiral centers of the reference molecule. For example, if the reference molecule has an S absolute stereochemistry, its opposite enantiomer will have an R absolute stereochemistry. Similarly, if the reference molecule has an S,S absolute stereochemistry, its opposite enantiomer will have an R,R stereochemistry, and so on.

[0098] The "stereoisomers" of a compound having a given stereochemical configuration refer to any diastereoisomer, including its opposite enantiomer and its geometric isomer (Z / E). For example, if a compound has an S,R,Z stereochemical configuration, its stereoisomers may include its opposite enantiomer with an R,S,Z configuration, as well as its diastereoisomers with 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, the "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

[0099] "Substantially pure stereoisomers" and their variations refer to samples containing compounds with a specific stereochemical configuration, where such compounds constitute at least about 95% of the sample.

[0100] "Pure stereoisomers" and their variations refer to samples containing compounds with a specific stereochemical configuration, where such compounds constitute at least about 99.5% of the sample.

[0101] "Target" refers to mammals, including humans.

[0102] A "pharmaceutically acceptable" substance refers to a substance that is suitable for administration to a target individual.

[0103] "To treat" means to reverse, alleviate, inhibit or prevent the progression of a disease, disorder, or condition to which such term applies, or to reverse, alleviate, inhibit or prevent the progression of one or more symptoms of such disease, disorder, or condition.

[0104] "Treatment" refers to the act of "taking action" as defined immediately before.

[0105] "Drugs," "active pharmaceutical ingredients," and "pharmaceutical active ingredients" refer to compounds that can be used to treat subjects requiring treatment (for example, compounds of formula (I), including sub-concept compounds and compounds specifically named herein, or their pharmaceutically acceptable salts, solvates, or hydrates).

[0106] The "effective dose" or "therapeutic effective dose" of a drug refers to the amount of drug that can be used to treat a subject, and this amount may depend, in particular, on the subject's weight and age, as well as the route of administration.

[0107] "Excipient" refers to any diluent or vehicle for a drug.

[0108] A "pharmaceutical product" refers to a combination of one or more active pharmaceutical ingredients and one or more excipients. In some cases, such a combination may also be called a "formulation" or "pharmaceutical composition."

[0109] "Drug product," "medicinal dosage form," "dosage form," and "final dosage form" refer to a pharmaceutical composition or medicine suitable for treating a target requiring treatment, and generally may take the form of tablets, capsules, powders or granules in individual packets, liquids or suspensions, patches, films, etc.

[0110] "NLRP3-related disease, disorder, or condition" and similar phrases refer to diseases, disorders, or conditions in which inhibition of the NLRP3 inflammasome pathway may provide therapeutic or prophylactic benefits.

[0111] In this specification, the following abbreviations may be used: Ac (acetyl); Ac2O (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]undeca-7-ene); DCC (1,3-Dicyclohexylcarbodiimide); DCE (1,1-Dichloroethane); DCM (Dichloromethane); DEA (Diethylamine); DIAD (Diisopropyl azodicarboxylic acid); DIPEA (N,N-Diisopropylethylamine, Hünig base); DMA (N,N-Dimethylacetamide); DMAP (4-Dimethylaminopyridine); DME (1,2-Dimethoxyethane); DMF (N,N-Dimethylformamide); DMP (Des-Martin periodinane); DMSO (Dimethyl sulfoxide); dppf (1,1'-Bis(diphenylphosphino)ferrocene); DTT (Dithiothreitol); EC 50(Effective concentration at half of the maximum response); EDA (Ethoxylated dodecyl alcohol, Brj(registered trademark) 35); EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide); EDTA (Ethylenediaminetetraacetic acid); ee (Enantiomer excess); ELS (Evaporative light scattering); eq (Equivalent); Et (Ethyl); Et3N (Triethylamine); .'' (Ethyl acetate); EtOH (Ethanol); FA (Formic acid); HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridine-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]triazole-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-leaf toxide); NMM (N-methylmorpholine); NMP (1-methyl-pyrrolidine-2-one); OTf (triflate); PE (petroleum ether); Ph (phenyl); pEC 50 (-log 10 (EC 50 ), here, EC 50 The value is given in moles (M); pIC 50 (-log 10 (I C 50 ), here, IC 50(The values ​​are given in moles (M)); PMB (p-methoxybenzyl); Pr (propyl); c-Pr (cyclopropyl), i-Pr (isopropyl); PTFE (polytetrafluoroethylene); PyBOP ((benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate); PyBroP (registered trademark) (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-trioxatriphosfinan 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)).

[0112] As described below, this disclosure relates to the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof (collectively referred to herein as compound (I)). This disclosure also relates to materials and methods for preparing the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, pharmaceuticals containing them, and the use of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof (optionally in combination with other pharmacological 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.

[0113] The definitions of each variable in equation (I) are explained in detail below.

[0114] L is either O or a bond.

[0115] In one embodiment, L is preferably O.

[0116] In another embodiment, L is preferably a bond.

[0117] X is N or CR 4 And here, R 4 It is defined as follows:

[0118] X is preferably CR 4 And here, R 4 It is defined as follows:

[0119] Y is N or CR 5 And here, R 5 It is defined as follows:

[0120] Y is preferably CR 5 And here, R 5 It is defined as follows:

[0121] R 1 C may be substituted 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered heterocyclic group, wherein when L is bonded, the 4- to 6-membered heterocyclic group is bonded to the pyrazolopyrimidone ring by a carbon-carbon bond.

[0122] As one embodiment, R 1 Preferably, C may be substituted. 1-6 It is an alkyl group.

[0123] As another embodiment, R 1 Preferably, (1)(a) Halogen atoms (e.g., fluorine atoms), (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy groups (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy), (d) G-C 1-6 Alkylamino group (e.g., dimethylamino), (e) C 7-16 Aralkyloxy group (e.g., benzyloxy), (f) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (g) 5- or 6-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazolidinyl), (h) Carboxylic group, and (i) 4- to 6-membered non-aromatic heterocyclyloxy groups (e.g., oxetanyloxy), and (j) cyano group C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl), (2)(a) C 1-6 Alkyl groups (e.g., methyl), (b) C 1-6 Alkoxy groups (e.g., methoxy), (c) Halogen atoms (e.g., fluorine atoms), (d) cyano group, and (e) Formula: -(CH2) a -O-(CH2) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) (e.g., -CH2OCH2-) C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (3)(a) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (b) C 1-6 Alkoxy groups (e.g., methoxy) C may be substituted with one to three substituents selected from the following. 6-14 Aryl group (e.g., phenyl), (4)(a) Halogen atoms (e.g., fluorine atoms), (b)(i) Halogen atoms (e.g., fluorine atoms, and (ii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy). 1-6 Alkyl groups (e.g., methyl, ethyl), (c) C 1-6 Alkoxy groups (e.g., methoxy), and (d) Together with the 5- or 6-membered aromatic heterocyclic group to which they are bonded, they form an 8- to 10-membered condensed heterocyclic group, formula: -(CH2) a -O-(CH2) b - A group represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) (e.g., -(CH2)2OCH2-, -(CH2)2O-, -(CH2)3O-) A 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl) which may be substituted with one to three substituents selected from the above, provided that when L is bonded, the 5- or 6-membered aromatic heterocyclic group is bonded to the pyrazolopyrimidone ring by a carbon-carbon bond, or (5)(a) Oxo group, (b) C 1-6 Alkyl groups (e.g., methyl), and (c) Halogen atoms (e.g., fluorine atoms), and (d) C 1-6 Alkoxy groups (e.g., methoxy) A 4- to 6-membered non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, morpholinyl, dihydropyridyl, piperidyl, dioxanyl) which may be substituted with one to three substituents selected from the above, wherein when L is bonded, the 5- or 6-membered non-aromatic heterocyclic group is bonded to the pyrazolopyrimidone ring by a carbon-carbon bond.

[0124] R 1 C may more preferably be halogenated. 1-6 C may be substituted with an alkoxy group (e.g., methoxy, difluoromethoxy). 1-6 It is an alkyl group (e.g., methyl, ethyl). 1 is more, C 1-6 It is an alkyl group (e.g., methyl).

[0125] R 2 C is a hydrogen atom, which may be substituted. 1-6 Alkyl alkyl group, or optionally substituted C 3-8 It is a cycloalkyl group.

[0126] R 2 Preferably, this is a hydrogen atom, or a substituted C 1-6 It is an alkyl group.

[0127] R 2 more, (1) A hydrogen atom, or (2) C 1-6 Alkyl group (e.g., methyl) That is the case.

[0128] R 2 This is, in particular, a hydrogen atom.

[0129] R 3 C is a hydrogen atom, which may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 It is a cycloalkyl group or a halogen atom.

[0130] R 3 Preferably, a hydrogen atom, or a substituted C 1-6 It is an alkyl group or a halogen atom.

[0131] R 3 is more (1) Hydrogen atom, (2) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (3) Halogen atoms (e.g., chlorine atom) That is the case.

[0132] R 3 This is, in particular, a hydrogen atom.

[0133] R 4 and R 8 These are, independently, a hydrogen atom and a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, hydroxyl group, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, a cyano group, an amino group, or a nitro group.

[0134] R 4 and R 8 Preferably, each of these is independently a hydrogen atom, or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 The group is an alkoxy group, or a substituted or otherwise substituted 5- or 6-membered heterocyclic group (preferably a substituted or otherwise substituted 5- or 6-membered aromatic heterocyclic group).

[0135] As one embodiment, R 4 and R 8 More preferably, each of the C elements may be independently substituted. 1-6It is an alkyl group or a halogen atom.

[0136] As another embodiment, R 4 and R 8 More preferably, independently (1) Hydrogen atom, (2)(i) Halogen atoms (e.g., fluorine atoms), (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C may be substituted with 1 to 4, preferably 1 to 3, substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl), (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (4) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (5) Hydroxyl group, (6) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy, ethoxy), or (7) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (8) Cyano group That is the case.

[0137] R 4 and R 8 More preferably, independently (1) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine atom, bromine atom) That is the case.

[0138] More preferably, R 4 and R 8 One of them is C 1-6(1) C 1-6 (2) an alkyl group (e.g., methyl), or a halogen atom (e.g., a fluorine atom, a bromine atom). 4 and R 8 Most preferably, both C 1-6 It is an alkyl group (e.g., methyl).

[0139] R 5 and R 7 These are, independently, a hydrogen atom and a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, hydroxyl group, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, a cyano group, an amino group, or a nitro group.

[0140] R 5 and R 7 Preferably, each of these is independently a hydrogen atom, or a substituted C atom. 1-6 It is an alkyl group or a halogen atom.

[0141] R 5 and R 7 More preferably, independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl), (3) Halogen atoms (e.g., bromine atoms, fluorine atoms), (4) C 3-8 Cycloalkyl groups That is the case.

[0142] R 5 and R 7 Particularly preferably, both are hydrogen atoms.

[0143] R 6C is a hydrogen atom, which may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, hydroxyl group, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, a cyano group, an amino group, or a nitro group.

[0144] R 6 Preferably, a hydrogen atom, or a substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 The group is an alkoxy group, or a substituted or otherwise substituted 5- or 6-membered heterocyclic group (preferably a substituted or otherwise substituted 5- or 6-membered aromatic heterocyclic group).

[0145] As one embodiment, R 6 C may be substituted more preferably. 3-8 It is a cycloalkyl group or a halogen atom.

[0146] As another embodiment, R 6 is more (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (4) C 2-6 Alkenyl group (e.g., vinyl), (5) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (6) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6Alkoxy groups (e.g., methoxy, ethoxy), or (7) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (8) an amino group, or (9) Nitro group That is the case.

[0147] R 6 To be even more (1) C which may be substituted with one to three halogen atoms (fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (2) Halogen atoms (e.g., bromine atoms), or (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) That is the case. R 6 Most preferably, C 3-8 These are cycloalkyl groups (e.g., cyclopropyl).

[0148] Preferred embodiments of the compound of formula (I) include the following compounds:

[0149] [Compound A] L is either O or a bond; X is N or CR 4 and; Y is N or CR 5 and; R 1 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered heterocyclic group, wherein when L is bonded, the 4- to 6-membered heterocyclic group is a 4- to 6-membered non-aromatic heterocyclic group bonded to the pyrazolopyrimidone ring by a carbon-carbon bond; R 2 However, a hydrogen atom, or a substituted C 1-6 It is an alkyl group; R 3 However, hydrogen atoms may be substituted C 1-6 It is an alkyl group or halogen atom; R 4 and R 8 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 The group is an alkoxy group, a substituted or otherwise 5- or 6-membered heterocyclic group (preferably a substituted or otherwise 5- or 6-membered aromatic heterocyclic group), or a cyano group; R 5 and R 7 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl group, halogen atom, or C 3-8 It is a cycloalkyl group; and R 6 However, hydrogen atoms may be substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise 5- or 6-membered heterocyclic group (preferably a substituted or otherwise 5- or 6-membered aromatic heterocyclic group), an amino group, or a nitro group; However, the following are excluded: (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6-(trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one.

[0150] [Compound B] L is either O or a bond; X is N or CR 4and; Y is N or CR 5 and; R 1 but, (1)(a) Halogen atoms (e.g., fluorine atoms), (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy groups (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy), (d) G-C 1-6 Alkylamino group (e.g., dimethylamino), (e) C 7-16 Aralkyloxy group (e.g., benzyloxy), (f) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (g) 5- or 6-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazolidinyl), (h) Carboxy group, (i) 4- to 6-membered non-aromatic heterocyclyloxy groups (e.g., oxetanyloxy), and (j) cyano group C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl), (2)(a) C 1-6 Alkyl groups (e.g., methyl), (b) C 1-6 Alkoxy groups (e.g., methoxy), (c) Halogen atoms (e.g., fluorine atoms), (d) cyano group, and (e) Formula: -(CH2) a -O-(CH2) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) (e.g., -CH2OCH2-) C may be substituted with one to three substituents selected from the following.3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (3)(a) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (b) C 1-6 Alkoxy groups (e.g., methoxy) C may be substituted with one to three substituents selected from the following. 6-14 Aryl group (e.g., phenyl), (4)(a) Halogen atoms (e.g., fluorine atoms), (b)(i) Halogen atoms (e.g., fluorine atoms) and (ii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy). 1-6 Alkyl groups (e.g., methyl, ethyl), (c) C 1-6 Alkoxy groups (e.g., methoxy), and (d) Together with the 5- or 6-membered aromatic heterocyclic group to which they are bonded, they form an 8- to 10-membered condensed heterocyclic group, formula: -(CH2) a -O-(CH2) b - A group represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) (e.g., -(CH2)2OCH2-, -(CH2)2O-, -(CH2)3O-) A 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl), which may be substituted with one to three substituents selected from the above, or (5)(a) Oxo group, (b) C 1-6 Alkyl groups (e.g., methyl), (c) Halogen atoms (e.g., fluorine atoms), and (d) C 1-6 Alkoxy groups (e.g., methoxy) A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following (e.g., oxetanyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, morpholinyl, dihydropyridyl, piperidyl, dioxanyl) and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 Alkyl group (e.g., methyl) and; R 3 but, (1) Hydrogen atom, (2) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (3) Halogen atoms (e.g., chlorine atom) and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2)(i) Halogen atoms (e.g., fluorine atoms), (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C may be substituted with 1 to 4, preferably 1 to 3, substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl), (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (4) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (5) Hydroxyl group, (6) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy, ethoxy), (7) A 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl), or (8) Cyano group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl), (3) Halogen atoms (e.g., bromine atoms, fluorine atoms), (4) C 3-8 Cycloalkyl groups and R 6 but, (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (4) C 2-6 Alkenyl group (e.g., vinyl), (5) Halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom), (6) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy, ethoxy), (7) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (8) an amino group, or (9) Nitro group and; However, the following are excluded: (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6-(trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one.

[0151] [Compound C] L is either O or a bond; X, CR 4 and; Y, CR 5 and; R 1 However, C may be halogenated. 1-6 C may be substituted with an alkoxy group (e.g., methoxy, difluoromethoxy). 1-6 Alkyl groups (e.g., methyl, ethyl); R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, they each act independently (1) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine atom, bromine atom) (preferably, R 4 and R 8 One of the C atoms may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1-6 (1) C 1-6 (1) an alkyl group (e.g., methyl), or (2) a halogen atom (e.g., a fluorine atom, a bromine atom). and; R 5 and R 7 However, both are hydrogen atoms; and R 6 but, (1) C which may be substituted with one to three halogen atoms (fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (2) Halogen atoms (e.g., bromine atoms), or (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) That is the case.

[0152] [Compound D] L is O; X, CR 4 and; Y, CR 5 and; R 1 However, 1 to 3 C 1-6 C may be substituted with an alkoxy group (e.g., methoxy). 1-6 Alkyl groups (e.g., methyl, ethyl); R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, they each act independently (1) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl group (e.g., methyl), or (2) Halogen atoms (e.g., fluorine atom, bromine atom) (preferably, R 4 and R 8 One of them is C 1-6 C is an alkyl group (e.g., methyl), and the other may be substituted with (1) one to three halogen atoms (e.g., fluorine atoms). 1-6 (1) an alkyl group (e.g., methyl), or (2) a halogen atom (e.g., a fluorine atom, a bromine atom). and; R 5 and R 7 However, both are hydrogen atoms; and R 6 but, (1) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (2) Halogen atoms (e.g., bromine atoms), or (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy groups (e.g., methoxy) That is the case.

[0153] [Compound G] L is O; X, CR 4 and; Y, CR 5 and; R 1 However, C 1-6 It is an alkyl group (e.g., methyl); R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both are C 1-6 It is an alkyl group (e.g., methyl); R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 These are cycloalkyl groups (e.g., cyclopropyl).

[0154] [Compound H] L is a combination; X is N or CR 4 and; Y is N or CR 5 and; R 1 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered non-aromatic heterocyclic group; R 2 However, a hydrogen atom, or a substituted C 1-6 It is an alkyl group; R 3 However, hydrogen atoms may be substituted C 1-6 It is an alkyl group or halogen atom; R 4 and R 8However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 The group is an alkoxy group, a substituted or otherwise 5- or 6-membered heterocyclic group (preferably a substituted or otherwise 5- or 6-membered aromatic heterocyclic group), or a cyano group; R 5 and R 7 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, halogen atoms, or optionally substituted C 3-8 It is a cycloalkyl group; and R 6 However, hydrogen atoms may be substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise 5- or 6-membered heterocyclic group (preferably a substituted or otherwise 5- or 6-membered aromatic heterocyclic group), an amino group, or a nitro group; However, the following are excluded: (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6-(trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one.

[0155] [Compound I] L is a combination; X, CR 4 and; Y, CR 5 and; R 1 but, (1)(a) Halogen atoms (e.g., fluorine atoms), (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy groups (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy), (d) C 7-16 Aralkyloxy group (e.g., benzyloxy), (e) 5- or 6-membered aromatic heterocyclic groups (e.g., pyrazolyl), (f) 5- or 6-membered non-aromatic heterocyclic groups (e.g., tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazolidinyl), (g) Carboxy group, (h) 4- to 6-membered non-aromatic heterocyclyloxy groups (e.g., oxetanyloxy), and (i) cyano group C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, neopentyl), (2)(a) C 1-6 Alkyl groups (e.g., methyl), (b) C 1-6 Alkoxy groups (e.g., methoxy), (c) Halogen atoms (e.g., fluorine atoms), and (d) cyano group C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclohexyl), (3)(a) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (b) C 1-6 Alkoxy groups (e.g., methoxy) C may be substituted with one to three substituents selected from the following. 6-14 Aryl group (e.g., phenyl), or (4)(a) Oxo group, (b) C 1-6 Alkyl groups (e.g., methyl), (c) Halogen atoms (e.g., fluorine atoms), and (d) C 1-6 Alkoxy groups (e.g., methoxy) A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following (e.g., oxetanyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, morpholinyl, dihydropyridyl, piperidyl, dioxanyl) and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 Alkyl group (e.g., methyl) and; R 3 but, (1) A hydrogen atom, or (2) C 1-6 Alkyl group (e.g., methyl) and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with 1 to 4, preferably 1 to 3, halogen atoms (e.g., fluorine atoms). 1-6 Alkyl groups (e.g., methyl, ethyl), (3) Halogen atoms (e.g., fluorine atoms, chlorine atoms), (4) Hydroxyl group, or (5) C 1-6 Alkoxy groups (e.g., ethoxy) and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methyl), (3) Halogen atoms (e.g., bromine atoms), or (4) C 3-8 Cycloalkyl groups and R6 but, (1) Hydrogen atom, (2) C 1-6 Alkyl (e.g., methyl, (3) C which may be substituted with one to three halogen atoms (e.g., fluorine atoms) 3-8 Cycloalkyl groups (e.g., cyclopropyl), (4) Halogen atoms (e.g., chlorine atom, bromine atom), (5) an amino group, or (6) Nitro group That is the case.

[0156] [Compound J] L is a combination; X, CR 4 and; Y, CR 5 and; R 1 However, C may be halogenated. 1-6 C may be substituted with an alkoxy group (e.g., methoxy, difluoromethoxy). 1-6 It is an alkyl group (e.g., methyl); R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both C atoms may be substituted with one to three halogen atoms (e.g., fluorine atoms). 1-6 It is an alkyl group (e.g., methyl); R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 Cycloalkyl groups (e.g., cyclopropyl) That is the case.

[0157] Specific examples of compounds of formula (I) include the compounds of Examples 1 to 326.

[0158] The preferred compounds of formula (I) are: 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 24); 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 39); 2-[2-bromo-4-(difluoromethoxy)-6-methylphenyl]-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 142); 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 146); 2-[4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl]-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 186); 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-[(difluoromethoxy)methyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 224); 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 235); and 2-[4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl]-6-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (Example 321); That is the case.

[0159] The compounds of formula (I) include those specifically named in the embodiments and examples described in the preceding paragraphs, and these compounds may exist as salts, complexes, solvates, hydrates, and liquid crystals. Similarly, the salts of the compounds of formula (I) may exist as complexes, solvates, hydrates, and liquid crystals.

[0160] Compounds of formula (I) can form pharmaceutically acceptable complexes, salts, solvates, and hydrates. These salts include acid addition salts (including diacides) and basic salts. Examples of 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 alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. Examples of such salts include acetate, adipine, aspartate, benzoate, besilate, bicarbonate, carbonate, bisulfate, sulfate, borate, cansilate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, gluconate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethion. Examples include salts, lactates, malates, maleates, malons, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, saccharates, stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, and xinofoate salts.

[0161] Pharmaceutically acceptable basic salts include salts derived from bases, including metal cations such as alkali or alkaline earth metal cations, and amines. Suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Suitable amines include arginine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine, lysine, N-methylglucamine, olamine, 2-amino-2-hydroxymethylpropane-1,3-diol, and procaine. For a discussion of useful acid addition salts and basic salts, see SMBerge et al., J. Pharm. Sci. (1977) 66:1-19. Also see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

[0162] pharmaceutically acceptable salts can be prepared using a variety of methods. For example, the compound of formula (I) may be reacted with a suitable acid or base to obtain the desired salt. Alternatively, a precursor of the compound of formula (I) may be reacted with an acid or base to remove an acid- or base-unstable protecting group, or to open the lactone or lactam group of the precursor. In addition, a salt of the compound of formula (I) may be converted to another salt (or free form) by treatment with a suitable acid or base, or by contact with an ion-exchange resin. If the salt precipitates from the solution after the reaction, it may be recovered by filtration or by evaporation to isolate the salt. The degree of ionization of the salt can vary from completely ionized to almost unionized.

[0163] Compounds of formula (I) can exist in a range of solid states, from perfectly amorphous to perfectly crystalline. The term "amorphous" refers to a state in which a substance does not have long-range order at the molecular level and can exhibit solid or liquid physical properties depending on the temperature. Typically, such substances do not yield a distinctive X-ray diffraction pattern and exhibit solid properties, but are more formally described as liquids. Upon heating, a change occurs from solid to liquid properties, typically characterized by a phase transition, usually a second-order phase transition ("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 yields a distinctive X-ray diffraction pattern with distinct peaks. Such substances also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is characterized by a phase transition, typically a first-order phase transition ("melting point").

[0164] The compound of formula (I) may exist in both non-solvated and solvated forms. The term "solvate" refers to a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules other than water (e.g., ethanol). The term "hydrate" means a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent can be isotope-substituted (e.g., D2O, acetone-d6, DMSO-d6).

[0165] The currently accepted classification system for solvates and hydrates of organic compounds distinguishes between segregated sites, channels, and metal ion-coordinated solvates and hydrates. See, for example, KRMorris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). Segregated site hydrates and solvates are those in which solvent (e.g., water) molecules are segregated by intervening organic compound molecules, preventing direct contact between them. In channel solvates, solvent molecules reside in lattice channels, where they are adjacent to other solvent molecules. In metal ion-coordinated solvates, solvent molecules are bound to metal ions.

[0166] When the solvent or water is tightly bound, the complex exhibits clearly defined stoichiometric properties 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 becomes dependent on humidity and dry conditions. In such cases, non-stoichiometric properties are generally observed.

[0167] 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 are typically defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, although they may also be complexes of neutral molecules and salts. 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.

[0168] The compound of formula (I) may exist in an intermediate state (intermediate phase or liquid crystal) when subjected to appropriate conditions. The intermediate state lies between the true crystalline state and the true liquid state (either melted or dissolved). 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 that have the potential to form a lyotropic intermediate phase are described as "amphiphilic," and the polar ionic moiety (e.g., -COO-Na) + ,-COO-K + , -SO3-Na + ) or polar nonionic moiety (-NN +This includes molecules containing (CH3)3, etc. See, for example, N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th ed, 1970).

[0169] Each compound of formula (I) may exist as a polymorph, stereoisomer, tautomer, or a combination thereof, may be isotope-labeled, may be obtained from the administration of a prodrug, or may form metabolites after administration.

[0170] A “prodrug” refers to a compound that has little or no pharmacological activity but can be converted in vivo into a compound with desired pharmacological activity through metabolism. Prodrugs may be prepared by replacing the appropriate functional group present in a pharmacologically active compound with a “pro-part,” as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether, or amide derivatives of the compound of formula (I) having a carboxylic acid, hydroxyl, or amino functional group, respectively. For a detailed discussion of prodrugs, see, for example, T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” ACS Symposium Series 14 (1975) and E. Roche ed., Bioreversible Carriers in Drug Design (1987).

[0171] "Metabolites" refer to compounds that are formed in vivo when a pharmacologically active compound is administered. Examples include hydroxymethyl, hydroxy, secondary amino, primary amino, phenol, and carboxylic acid derivatives of the compound of formula (I) having methyl, alkoxy, tertiary amino, secondary amino, phenyl, and amide groups, respectively.

[0172] Compounds of formula (I) may exist as stereoisomers arising from the presence of one or more chiral centers, one or more double bonds, or both. These stereoisomers may be pure, substantially pure, or a mixture. Such stereoisomers may also arise from acid addition salts or base salts in which the counterion is optically active (e.g., when the counterion is a D-lactate or L-lysine).

[0173] Compounds of formula (I) may exist as tautomers, which are isomers resulting from tautomerization. Examples of tautomer isomers include imine-enamine, keto-enol, oxime-nitroso, and amide-imido acid tautomerisms.

[0174] The compound of formula (I) may exhibit two or more types of isomers.

[0175] Geometric (cis / trans) isomers can be separated by conventional techniques such as chromatography and fractional crystallization.

[0176] Conventional techniques for preparing or isolating compounds with specific stereochemical configurations include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as 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 mixture of diastereoisomers may be separated by chromatography, fractional crystallization, etc., and the appropriate diastereoisomers may be converted into compounds with the required stereochemical configuration. For further consideration of techniques for separating stereoisomers, see ELEEliel and SHWilen, Stereochemistry of Organic Compounds (1994).

[0177] Compounds of formula (I) may have isotopic forms in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass than that normally found in nature. Suitable isotopes to include in compounds of formula (I) are, for example, isotopes of hydrogen, e.g., 2 H and 3 H; an isotope of carbon, for example, 11 C, 13 C, and 14 C; an isotope of nitrogen, for example, 13 N and 15 N; an isotope of oxygen, for example, 15 O, 17 O, and 18 O; an isotope of sulfur, for example, 35 S; an isotope of fluorine, for example, 18 F; an isotope of chlorine, for example, 36 Cl; and isotopes of iodine, for example, 123 I and 125 I is one example. Isotope variants (e.g., deuterium, 2 By using H), certain therapeutic effects may be obtained due to increased metabolic stability (e.g., increased half-life in vivo or reduced required dose). In addition, certain isotopes of the disclosed compounds may have radioactive isotopes (e.g., tritium, 3 H, or 14 C) may be incorporated, which may be useful for studying the tissue distribution of drugs and / or substrates. 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds may be prepared by a process similar to those described elsewhere in this disclosure, using a suitable isotope-labeling reagent instead of an unlabeled reagent.

[0178] Compound (I) may be prepared using the following techniques. Some methods and examples omit details of general reactions, including oxidation and reduction, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, grinding, crystallization, etc.), and analytical procedures, which are known to those skilled in organic chemistry. Details of such reactions and techniques can be found in several publications, including Richard Larock, *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 reaction schemes omit small amounts of products resulting from chemical transformations (e.g., alcohols from ester hydrolysis, CO2 from diacid decarboxylation, etc.). In addition, in some cases, reaction intermediates may be used in subsequent steps without isolation or purification (i.e., in situ).

[0179] In the following methods and examples, certain compounds may be prepared using protecting groups to prevent undesirable chemical reactions outside the reaction site. Protecting groups may also be used to enhance the solubility of the compound or to otherwise modify its physical properties. For a discussion of protecting group strategies, a description of materials and methods for attaching 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 TW. Greene and PG. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0180] In general, the chemical transformations described throughout this specification may be carried out using substantially stoichiometric amounts of reactants, but in certain reactions, advantages may be obtained by using one or more excess reactants. In addition, many of the reactions disclosed throughout this specification may be carried out at approximately room temperature (RT) and ambient pressure, but depending on the reaction kinetics, yield, etc., some reactions may be carried out under increased pressure, or at higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78°C to 0°C). All references to stoichiometric ranges, temperature ranges, pH ranges, etc. in this disclosure and claims include the indicated endpoints, whether or not the word “range” is explicitly used.

[0181] Many chemical transformations may also involve the use of one or more miscible solvents, which can affect the reaction rate and yield. Depending on the properties of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, nonpolar solvents, or a combination of several. Typical 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-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)ethanol, 2-(2 Examples include (-butoxy-ethoxy)-ethanol); 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-methylpyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydrothiophene-1,1-dioxide); and phosphorus-containing solvents (e.g., hexamethyl phosphate triamide).

[0182] In the following scheme, substituent identifiers (e.g., X, L, R) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , and R 8 ) is as defined above for formula (I). As previously mentioned, some of the starting materials and intermediates may contain protecting groups, which are removed before the final product. In such cases, the substituent identifiers refer to the parts defined in formula (I) and those parts that have appropriate protecting groups. For example, the starting materials or intermediates in the synthetic method may include potentially reactive (secondary) amines. In such cases, the amine may include parts that have, or do not have, a Boc group or a Cbz group bonded to the amine.

[0183] The method for producing the compound of the present invention is described below.

[0184] The raw material compounds and reagents used in the following manufacturing methods, as well as the compounds obtained in each step, may each be in the form of salts. Examples of such salts include salts similar to those of the compounds of the present invention. If the compounds obtained in each step are in free form, they can be converted to the desired salt by methods known to the contrary.

[0185] If the compounds obtained in each step are in a free form, they can be converted to the desired salt by methods known to the present day. If the compounds obtained in each step are salts, they can be converted to the desired free form or other salts by methods known to the present day.

[0186] The compounds obtained in each step can be used directly in the next reaction, either as a reaction mixture or as a crude product. Alternatively, the compounds obtained in each step can be isolated and / or purified from the reaction mixture by separation means known by themselves, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and column chromatography.

[0187] If the raw materials and reagents used in each step are commercially available, those commercially available products can also be used directly.

[0188] In each step of the reaction, 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.

[0189] In each step of the reaction, the reaction temperature varies depending on the reagents and solvents used, but unless otherwise specified, it is usually -78°C to 300°C, preferably -78°C to 150°C.

[0190] In each step of the reaction, the pressure varies depending on the reagents and solvents used, but unless otherwise specified, it is usually between 1 atmosphere and 20 atmospheres, preferably between 1 atmosphere and 3 atmospheres.

[0191] A microwave synthesis apparatus, such as a Biotage Initiator, may be used for the reactions in each step. The reaction temperature varies depending on the reagents and solvents used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time varies depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0192] In each step of the reaction, the amount of reagent used varies depending on the reagent and solvent used, but unless otherwise specified, it is 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 solvent.

[0193] Unless otherwise specified, the reactions in each step are carried out without a solvent, or by dissolving or suspending the starting compounds in a suitable solvent. Examples of solvents 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: such as dichloromethane and carbon tetrachloride. Nitriles: such as acetonitrile, Sulfoxides: Dimethyl sulfoxide, etc. Aromatic organic bases: such as pyridine, Anhydrous compounds: such as acetic anhydride, Organic acids: Formic acid, acetic acid, trifluoroacetic acid, etc. Inorganic acids: hydrochloric acid, sulfuric acid, etc. Esters: such as ethyl acetate, Ketones: such as acetone and methyl ethyl ketone. water.

[0194] The above solvents may also be used as a mixture of two or more solvents in appropriate proportions.

[0195] When a base is used in the reaction at each step, examples include the bases described in the examples, and the following bases. 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: such as sodium hydride, Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. Organolithium compounds: such as n-butyllithium.

[0196] When an acid or acid catalyst is used in the reaction at each step, examples include the acids and acid catalysts described in the examples, as well as the following acids and acid catalysts. 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.

[0197] Unless otherwise specified, the reactions in each step are based on known methods, e.g., Jikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (LFTietze, 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 This is carried out according to the method described in Kiyoshi Tomioka, Kagakudojin; Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or according to the method described in the examples.

[0198] In each step, the functional group protection or deprotection reaction is carried out by methods known in themselves, such as those described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter GMWuts); “Protecting Groups 3rd Ed”, Thieme, 2004 (PJ Kocienski); or by the methods described in the examples.

[0199] Examples of protecting groups for hydroxyl groups of alcohols and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, methyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate esters; sulfonic acid ester-type protecting groups such as methanesulfonic acid esters; and carbonate ester-type protecting groups such as tert-butyl carbonate.

[0200] Examples of protecting groups for the carbonyl group of aldehydes include acetal-type protecting groups such as dimethyl acetal, and cyclic acetal-type protecting groups such as 1,3-dioxane.

[0201] 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-dioxolane and 1,3-dioxane, oxime-type protecting groups such as O-methyloxime, and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0202] Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl esters, and amide-type protecting groups such as N,N-dimethylamide.

[0203] Examples of thiol protecting groups include ether-type protecting groups such as benzylthioether, and ester-type protecting groups such as thioacetic acid esters, thiocarbonates, and thiocarbamates.

[0204] 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.

[0205] The protecting group can be removed by known methods, such as using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or by reduction methods.

[0206] When reduction reactions are carried out in each step, examples of reducing agents that can be used include metal hydrides, such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, triacetoxyborotetramethylammonium hydride, boranes, such as boranetetrahydrofuran complexes, Raney nickel, Raney cobalt, hydrogen, formic acid, triethylsilane, iron, and zinc. When reducing carbon-carbon double or triple bonds, methods using catalysts, such as palladium-carbon or Lindlar catalysts, may be used.

[0207] Examples of oxidizing agents used when oxidation reactions are carried out in each step of the process include: peroxides, such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide, perchlorates, such as tetrabutylammonium perchlorate, chlorates, such as sodium chlorate, chlorites, such as sodium chlorite, periodates, such as sodium periodate, hypervalent iodine reagents, such as iodosylbenzene, and manganese. Examples of reagents include nitrate-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).

[0208] When radical reactions are carried out in each step, examples of radical initiators 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; and benzoyl peroxide. Examples of radical reagents used include tributylstanan, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0209] When Wittig reactions are carried out at each step, examples of Wittig reagents used include alkylidene phosphoranes. Alkylidene phosphoranes can be prepared by known methods, for example, by reacting a phosphonium salt with a strong base.

[0210] When the Horner-Emmons reaction is carried out in each step, examples of reagents used include phosphonoacetates, such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate, and bases, such as alkali metal hydrides and organolithium compounds.

[0211] When the Friedel-Crafts reaction is carried out at each step, a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.) is used as the reagent. Alternatively, organic or inorganic acids can be used instead of Lewis acids, and acid anhydrides such as acetic anhydride can be used instead of acid chlorides.

[0212] When aromatic nucleophilic substitution reactions are carried out in each step, nucleophiles (e.g., amines, imidazoles, alcohols, etc.) and bases (e.g., inorganic bases, organic bases, etc.) are used as reagents.

[0213] When a nucleophilic addition reaction, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion is carried out in each step, examples of bases used to generate the carbanion include organolithium, metal alkoxides, inorganic bases, and organic bases.

[0214] When performing a Grignard reaction in each step, examples of Grignard reagents used include aryl magnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. Grignard reagents can be prepared by known methods, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0215] When the Kneefenagel condensation reaction is carried out 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, a metal alkoxide, or an inorganic base) are used as reagents.

[0216] When the Vilsmeier-Haack reaction is performed at each step, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide) are used as reagents.

[0217] When carrying out azidation reactions of alcohols, alkyl halides, or sulfonates in each step, examples of azidating agents used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when azidating alcohols, methods using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) or methods using trimethylsilyl azide and Lewis acid are used.

[0218] When reductive amination or reductive alkylation reactions are carried out in each step, examples of reducing agents used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, and formic acid. When the substrate is an amine compound, examples of carbonyl compounds used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0219] When the Mitsunobu reaction is carried out in each step, cyanomethylenethryalkylphosphoranes (e.g., cyanomethylenethrymethylphosphoran, cyanomethylenethrybutylphosphoran), or azodicarboxylates (e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and phosphines (e.g., triphenylphosphine, tri-n-butylphosphine) are used as reagents.

[0220] When esterification, amidation, or urea formation reactions are carried out in each step, examples of reagents used include acyl halides, such as acid chlorides and acid bromides, and activated carboxylic acids, such as anhydrides, activated esters, and sulfates; esters are particularly used in amidation reactions. Examples of carboxylic acid activators 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-triazine-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), carbonate condensing agents, such as 1,1-carbonyldiimidazole (CDI), diphenyl phosphate azide (DPPA), benzotriazole-1-yloxytrisdimethylaminophosphonium salt (BOP reagent), 2-chloro-1-methylpyridinium iodide (Mukoyama reagent), thionyl chloride, lower alkylhaloates, such as ethyl chloroformate, and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Examples include hexafluorophosphate (HATU), sulfuric acid, and combinations thereof. When using carbodiimide coupling agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be added to the reaction system. Examples of reagents used to convert esters to their corresponding carboxamides include ammonia.

[0221] When coupling reactions are carried out in each step, examples of metal catalysts that can be used include palladium compounds, such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O), and 1,1'-bis(diphenylphosphine)ferrocenepalladium(II) chloride; nickel compounds, such as tetrakis(triphenylphosphine)nickel(O); rhodium compounds, such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds, such as copper oxide and copper(I) iodide; and platinum compounds. Furthermore, bases may be added to the reaction system, and examples of such bases include inorganic bases and metal alkoxides.

[0222] When thiocarbonylation reactions are carried out in each step, phosphorus pentasulfide is usually used as the thiocarbonylating agent. Alternatively, instead of phosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (for example, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson's Reagent)) can also be used.

[0223] When carrying out the Wahl-Ziegler reaction at each step, examples of halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and sulfuryl chloride. Furthermore, the reaction can be accelerated by adding heat, light, or radical initiators such as benzoyl peroxide and azobisisobutyronitrile to the reaction system.

[0224] When halogenation of the hydroxyl group is carried out in each step, examples of halogenating agents used 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 can be used to produce alkyl halides by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method can also be used to produce alkyl halides through two steps, which include converting an alcohol to a corresponding sulfonate and then reacting the sulfonate with lithium bromide, lithium chloride, or sodium iodide.

[0225] When carrying out the Albuzov reaction at each step, examples of reagents used include alkyl halides, such as ethyl bromoacetate, and phosphites, such as triethyl phosphite and tri(isopropyl) phosphite.

[0226] When sulfonate esterification reactions are carried out in each step, examples of sulfonating agents that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and p-toluenesulfonic anhydride.

[0227] When hydrolysis reactions are carried out in each step, an acid or base is used as a reagent. For acid hydrolysis of tert-butyl esters, formic acid, triethylsilane, etc. may be added to reductively trap the by-product tert-butyl cation. For hydrolysis of cyano groups, potassium carbonate, sodium hydroxide, etc., can be used as bases. Furthermore, an oxidizing agent may be added to the reaction system, such as hydrogen peroxide.

[0228] When a dehydration reaction is carried out in each step, examples of dehydrating agents that can be used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphate.

[0229] When the Chan-Lam reaction is carried out at each step, examples of metal catalysts used include copper compounds such as copper(I) bromide, copper(I) iodide, and copper(II) acetate. Furthermore, a base may be added to the reaction system, such as organic bases.

[0230] When the Ullmann reaction is carried out at each step, examples of metal catalysts used include copper compounds such as copper(I) bromide, copper(I) iodide, and copper(II) acetate, and examples of ligands include N,N,N',N'-tetramethylethylenediamine. Furthermore, a base may be added to the reaction system, and examples of such bases include organic bases and inorganic bases.

[0231] When alkylation reactions are carried out in each step, examples of bases that can be used include potassium carbonate, tripotassium phosphate, triethylamine, N,N-diisopropylethylamine, pyridine, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and n-butyllithium. Furthermore, inorganic salts may be added to the reaction system, examples of which include lithium bromide.

[0232] When a deoxofluorination reaction is carried out at each step, examples of fluorinating agents used include bis(2-methoxyethyl)aminosulfur trifluoride, diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, N,N-diethyl-S,S-difluorosulfiriminium tetrafluoroborate, and difluoro-4-morpholinylsulfonium tetrafluoroborate.

[0233] When performing the Hoffmann rearrangement reaction at each step, examples of reagents used include lead tetraacetate and iodobenzene diacetate.

[0234] When a thiourea formation reaction or thiocarbamate reaction is carried out at each step, examples of reagents used include thiophosgene, and examples of bases include organic bases and sodium hydride.

[0235] When cyclopropanation reactions are carried out in each step, examples of reagents used include diiodomethane, dibromomethane, dibromodifluoromethane, dibromofluoromethane, (trifluoromethyl)trimethylsilane, (bromodifluoromethyl)trimethylsilane, (dibromofluoromethyl)trimethylsilane, carbon tetrafluoride, and sodium trifluoroacetate.

[0236] Compound (I) and intermediates for producing compound (I) are convertible functional groups (e.g., carboxyl group, amino group, hydroxyl group, carbonyl group, mercapto group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group, C 7-16 Araloxy-carbonyl group, sulfo group, sulfide group, halogen atom, C that can be optionally halogenated. 1-6 Compounds having alkylsulfonyloxy groups, cyano groups, aminocarbonyl groups, boryl groups, etc., can be produced by transforming such functional groups according to known methods or similar methods.

[0237] The carboxyl group can be converted by reactions such as esterification, reduction, amidation, and conversion to an optionally protected amino group.

[0238] The amino group can be converted by reactions such as amidation, sulfonylation, nitrosation, alkylation, arylation, and imidation.

[0239] Hydroxyl groups can be converted by reactions such as esterification, carbamoylation, sulfonylation, alkylation, fluorination, arylation, oxidation, and halogenation.

[0240] Carbonyl groups can be transformed by reactions such as reduction, oxidation, fluorination, iminomination (including oxime and hydrazone), (thio)ketalization, alkylidenamination, and thiocarbonylation.

[0241] Mercapto groups can be converted by reactions such as alkylation and oxidation.

[0242] C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group, and C 7-16 The aralkyloxy-carbonyl group can be converted by reactions such as reduction and hydrolysis.

[0243] The sulfo group can be converted by reactions such as sulfonamidation and reduction.

[0244] Sulfide groups can be converted by reactions such as oxidation.

[0245] Halogen atoms can be transformed, for example, by various nucleophilic substitution reactions and various coupling reactions.

[0246] C is optionally halogenated. 1-6 Alkylsulfonyloxy groups can be transformed, for example, by various nucleophilic substitution reactions and various coupling reactions.

[0247] The cyano group can be converted by reactions such as reduction and hydrolysis.

[0248] The aminocarbonyl group can be converted by reactions such as dehydration and reduction.

[0249] The boryl group can be converted, for example, by oxidation, various coupling reactions, and other means.

[0250] In each of the above reactions, if the compound is obtained in its free form, it can be converted to a salt according to conventional methods. If it is obtained as a salt, it can be converted to its free form or other salts according to conventional methods.

[0251] The transformation of these functional groups can be carried out according to known methods, such as those described in Comprehensive Organic Transformations, Second Edition, Wiley-VCH, Richard C. Larock.

[0252] Compound (I) obtained in each reaction scheme can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, and chromatography. Furthermore, each starting compound used in each reaction scheme can be isolated and purified by means similar to the known separation and purification methods described above. The starting compounds may also be used directly in the next step as a reaction mixture without isolation.

[0253] If compound (I) contains isomers, such as optical isomers, stereoisomers, positional isomers, and rotational isomers, then such isomers and mixtures thereof are also included in compound (I). For example, if compound (I) contains optical isomers, then optical isomers separated from a racemate are also included in 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.), or optical resolution (e.g., fractional recrystallization, chiral column chromatography, diastereomerization, etc.).

[0254] 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 within compound (I). The crystals may be produced according to crystallization methods known in themselves.

[0255] Compound (I) may be a solvate (e.g., a hydrate) or a non-solvate (e.g., a nonhydrate), and both are included in compound (I).

[0256] Isotopes (for example, 3 H, 14 C, 35 S, 125 Compounds labeled with (I, etc.) are also included in compound (I).

[0257] 1 H 2 The deuterium conversion form that is converted to H(D) is also included in compound (I).

[0258] 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.

[0259] Compound (I) of the present invention can be synthesized according to the manufacturing method described below.

[0260] Unless otherwise specified, the variables in the reaction scheme equations are as defined above.

[0261] Compounds (Ia) and (Ib), where L is O, can be prepared from compounds (1), (2), and (3) according to the following scheme 1. In the scheme, R is a substituted C 1-6 Alkyl alkyl group, or optionally substituted C 3-8 It is a cycloalkyl group, where PG is a protecting group for the hydroxyl group and LG is a leaving group. Examples of hydroxyl protecting groups include methoxymethylene group, benzyl group, 4-methoxybenzyl group, and methyl group. Examples of leaving groups include halogen atoms and optionally halogenated C. 1-6 Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl), possibly halogenated C 1-6Alkyl sulfonyl oxy (e.g., methanesulfonyl oxy, ethanesulfonyl oxy, trifluoromethanesulfonyl oxy), C 1-6 C may be substituted with alkyl. 6-14 Examples include aryl sulfonyl oxy compounds (e.g., benzenesulfonyl oxy, toluenesulfonyl oxy).

[0262] Scheme 1 [ka]

[0263] Compound (Ia) is compound (1) with the corresponding alcohol (R 1 It can be produced by subjecting compound (2) to an aromatic nucleophilic substitution reaction with -OH, subjecting compound (2) to a deprotection reaction, or subjecting compound (3) to a hydrolysis reaction.

[0264] Compound (Ib) can be produced by subjecting compound (Ia) to an alkylation reaction.

[0265] Compounds (1), (2), and (3) used in Scheme 1 above can be produced from compound (4) according to Scheme 2 below. In the scheme, PG is a protecting group for the hydroxyl group, and LG 1 LG 2 and LG 3 This is a leaving group. Examples of protecting groups for the hydroxyl group include, for example, the methoxymethylene group, benzyl group, 4-methoxybenzyl group, and methyl group. Examples of leaving groups include, for example, halogen atoms and optionally halogenated C 1-6 Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl), possibly halogenated C 1-6 Alkyl sulfonyl oxy (e.g., methanesulfonyl oxy, ethanesulfonyl oxy, trifluoromethanesulfonyl oxy), C 1-6 C may be substituted with alkyl. 6-14Examples include aryl sulfonyl oxy compounds (e.g., benzenesulfonyl oxy, toluenesulfonyl oxy).

[0266] Scheme 2 [ka]

[0267] Compounds (4) and (6) are commercially available or can be manufactured according to methods known to the public.

[0268] Compound (5) can be produced by subjecting compound (4) to a protective reaction.

[0269] Compound (7) can be produced by subjecting compound (5) to an aromatic nucleophilic substitution reaction with compound (6).

[0270] Compound (8) can be produced by subjecting compound (7) to an acid-mediated cyclization reaction. Examples of acids that can be used include p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.

[0271] Compound (1) can be produced by subjecting compound (8) to a hydrolysis reaction.

[0272] Compound (9) can be produced by subjecting compound (8) to an aromatic nucleophilic substitution reaction with the corresponding alcohol (PG-OH).

[0273] Compound (2) is compound (9) with the corresponding alcohol (R 1 It can be produced by subjecting it to an aromatic nucleophilic substitution reaction with -OH.

[0274] Compound (10) is compound (4) with the corresponding alcohol (R 1 It can be produced by subjecting it to an aromatic nucleophilic substitution reaction with -OH.

[0275] Compound (11) is subjected to a protective reaction of compound (10), or compound (5) is subjected to the corresponding alcohol (R 1 It can be produced by subjecting it to an aromatic nucleophilic substitution reaction with -OH).

[0276] Compound (12) can be produced by subjecting compound (11) to an aromatic nucleophilic substitution reaction with compound (6).

[0277] Compound (3) can be produced by subjecting compound (12) to an acid-mediated cyclization reaction. Examples of acids that can be used include p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.

[0278] Compounds (Ic) and (Id), in which L is a bond in compound (I), can be produced from compound (1), compound (13), or compound (14) according to the following scheme 3.

[0279] Scheme 3 [ka]

[0280] Compound (Ic) is used in the coupling reaction of compound (1) and compound (13) as an oxidizing agent and the corresponding aldehyde (R 1 It can be produced by subjecting it to a cyclization reaction with -CHO) or by subjecting compound (14) to a cyclization reaction using a base. Examples of oxidizing agents that can be used include iodine. Examples of bases that can be used include sodium hydroxide, potassium hydroxide, potassium tert-butoxide.

[0281] Compound (Id) can be produced by subjecting compound (Ic) to an alkylation reaction.

[0282] Compounds (13) and (14) can be prepared from compound (15) according to the following scheme 4. In the scheme, Z is a dihydroxyboryl group, a pinacolboryl group (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), or a halogen atom. In the scheme, LG 1 and LG 2 This is a leaving group. Examples of leaving groups include, for example, halogen atoms and C, which may be halogenated. 1-6 Alkyl sulfonyl (e.g., methanesulfonyl, ethanesulfonyl), possibly halogenated C 1-6 Alkyl sulfonyl oxy (e.g., methanesulfonyl oxy, ethanesulfonyl oxy, trifluoromethanesulfonyl oxy), C 1-6 C may be substituted with alkyl. 6-14 Examples include aryl sulfonyl oxy compounds (e.g., benzenesulfonyl oxy, toluenesulfonyl oxy).

[0283] Scheme 4 [ka]

[0284] Compounds (15), (16), and (19) are commercially available or can be manufactured according to methods known to the present day.

[0285] Compound (17) can be produced by subjecting compound (15) to a Chan-Lam reaction with the corresponding arylboronic acid ester or boronic acid (16), a Ullmann reaction with the corresponding arylhalide (16), or an aromatic nucleophilic substitution reaction with the corresponding arylhalide (16). Alternatively, compound (17) can also be produced by subjecting compound (24) to a deprotection reaction.

[0286] Compound (18) can be produced by subjecting compound (17) to an amidation reaction.

[0287] Compound (14) can be produced by subjecting compound (18) to a hydrolysis reaction using hydrogen peroxide and a base. Alternatively, compound (14) can also be produced by subjecting compound (13) to an amidation reaction.

[0288] Compound (13) can be produced by subjecting compound (17) to a hydrolysis reaction using hydrogen peroxide and a base. Alternatively, compound (13) can also be produced by subjecting compound (25) to a deprotection reaction.

[0289] Compound (20) can be produced by subjecting compound (15) to an aromatic nucleophilic substitution reaction with compound (19).

[0290] Compound (21) can be produced by subjecting compound (20) to a protective reaction.

[0291] Compound (22) can be produced by subjecting compound (21) to a reduction reaction.

[0292] Compound (23) can be produced by subjecting compound (22) to a Sandmeyer reaction.

[0293] Compound (24) can be produced by subjecting compound (23) to a coupling reaction with the corresponding boronic acid ester or boronic acid.

[0294] Compound (25) can be produced by subjecting compound (24) to a hydrolysis reaction using hydrogen peroxide and a base.

[0295] Compound (13) can also be prepared from compounds (26) and (6) according to the following scheme 5. In the scheme, R' and R'' are alkyl groups, and Z is a dihydroxyboryl group, a pinacolboryl group (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), or a halogen atom.

[0296] Scheme 5 [ka]

[0297] Compounds (26) and (30) are commercially available or can be manufactured according to methods known to the public.

[0298] Compound (27) can be produced by subjecting compound (26) to a Chan-Lam reaction with the corresponding arylboronic acid ester or boronic acid (16), a Ullmann reaction with the corresponding arylhalide (16), or an aromatic nucleophilic substitution reaction with the corresponding arylhalide (16).

[0299] Compound (28) can be produced by subjecting compound (27) to an amidation reaction.

[0300] Compound (13) can be produced by subjecting compound (28) to a reduction reaction. Alternatively, compound (13) can be produced by subjecting compound (31) to a cyclization reaction using a base. Examples of bases that can be used include sodium hydroxide.

[0301] Compound (29) can be produced by subjecting compound (6) to an amidation reaction. Compound (31) can be produced by reacting compound (29) with compound (30).

[0302] 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 at pH, solution stability, and permeability, to select an appropriate dosage form and route of administration. Compounds intended for pharmaceutical use may be administered as crystalline or amorphous products, or obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, evaporative drying, microwave drying, or high-frequency drying.

[0303] Compound (I) may be administered alone, in combination with other compounds, or in combination with one or more pharmacologically active substances other than compound (I). When compound (I) is administered in combination with pharmacologically active substances ("combination drug"), the timing of administration of compound (I) and the combination drug is not limited, and compound (I) or its pharmaceutical composition, or the combination drug or its pharmaceutical composition, may be administered to the subject simultaneously or at different times. The dose of the combination drug may be determined according to clinically used doses and may be appropriately selected depending on the subject, route of administration, disease, combination, etc.

[0304] The combination of compound (I) and the concomitant drug is not particularly limited; it is sufficient that compound (I) and the concomitant drug are combined at the time of administration. Examples of such combinations of administration include: (1) Administration of a single formulation obtained by simultaneously processing compound (I) and the concomitant drug; (2) Simultaneous administration of two formulations of compound (I) and the concomitant drug, manufactured separately, via the same route of administration; (3) Time-staggered administration of two formulations of compound (I) and the concomitant drug, manufactured separately, via the same route of administration; (4) Simultaneous administration of two formulations of compound (I) and the concomitant drug, manufactured separately, via different routes of administration; (5) Time-staggered administration of two formulations of compound (I) and the concomitant drug, manufactured separately, via different routes of administration (for example, administration of compound (I) and the concomitant drug in that order, or in the reverse order).

[0305] The dosage of concomitant medications may be appropriately determined based on the dosage used in the clinical situation. The mixing ratio of compound (I) and concomitant medications may be appropriately determined depending on the patient, route of administration, target disease, symptoms, combination, etc.

[0306] 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 entire formulation.

[0307] The amount 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 entire formulation.

[0308] The content of additives such as carriers used in combination with compound (I) and the concomitant drug 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.

[0309] Even when compound (I) and the concomitant drug are formulated separately, the same content may be used.

[0310] Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) with one or more pharmaceutically acceptable excipients. The selection of excipients depends, in particular, on the mode of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form. Useful pharmaceutical compositions and methods for preparing them can be found, for example, in ARGennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000).

[0311] Compound (I) may be administered orally. Oral administration may include swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration may include mucosal administration (e.g., buccal, sublingual, or superlingual administration) in which the compound enters the bloodstream through the oral mucosa.

[0312] Formulations suitable for oral administration include solids, semi-solids, and liquid systems, such as tablets; soft or hard capsules containing multiple particles or nanoparticles, liquids, or powders; licks (which may be filled with liquid); chewables; gels; rapidly dispersible dosage forms; films; vaginal suppositories; sprays; and buccal or mucosal adhesive patches. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules (e.g., those made from gelatin or hydroxypropyl methylcellulose) and typically comprise a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers, suspending agents, or both. Liquid formulations may also be prepared by reconstitution of solids (e.g., from sachets).

[0313] Compound (I) is also known as Liang and Chen, Expert Opinion. It can be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Therapeutic Patents (2001) 11(6):981-986.

[0314] In the case of tablet dosage forms, the active pharmaceutical ingredient (API) may constitute about 1% to about 80% by weight of the dosage form, or more typically about 5% to about 60% by weight of the dosage form, depending on the dose. In addition to the API, the tablet may contain one or more disintegrants, binders, diluents, surfactants, flow enhancers, lubricants, antioxidants, colorants, flavoring agents, preservatives, and taste enhancers. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, C 1-6Examples include alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will constitute about 1% to 25% by weight, or about 5% to 20% by weight, of the dosage form.

[0315] Binders are generally used to give tablet formulations cohesiveness. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, 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.

[0316] The tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and flow enhancers, such as silicon dioxide and talc. If present, the surfactants may constitute about 0.2% to about 5% by weight of the tablet, and the flow enhancers may constitute about 0.2% to about 1% by weight of the tablet.

[0317] The tablets may also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant may constitute about 0.25% to about 10% by weight, or about 0.5% to about 3% by weight, of the tablet.

[0318] Tablet blends may be compressed directly or by roller compression to form tablets. Alternatively, the tablet blend or a portion of the blend may be wet-granulated, dry-granulated, or melt-granulated, melt-set, or extruded before tableting. If desired, one or more components may be separated by sieving, grinding, or both before blending. The final dosage form may contain one or more layers, may be coated or uncoated, or may be encapsulated. Exemplary tablets 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 discussions on blending, granulation, grinding, sieving, tableting, and coating, as well as descriptions of alternative techniques for preparing drug products, see ARGennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); HALieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and DK Parikh & C.K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

[0319] Consumable oral film formulations for use in humans or animals are flexible, water-soluble, or water-swellable thin film formulations that may be rapidly soluble or mucosal-adhesive. In addition to APIs, typical film formulations include one or more film-forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film components may include antioxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulants, cooling agents, co-solvents (including oils), softeners, bulking agents, defoamers, surfactants, and flavoring agents. Some components of a formulation may perform two or more functions.

[0320] In addition to the drug requirements, the amount of API in the film may depend on its solubility. If water-soluble, the API will typically constitute about 1% to 80% by weight of the non-solvent component (solute) in the film, or about 20% to 50% by weight of the solute in the film. Less soluble APIs may constitute a larger proportion of the composition, typically up to about 88% by weight of the non-solvent component in the film.

[0321] The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrophilic colloids, and typically constitutes about 0.01% to about 99% or about 30% to about 80% by weight of the film.

[0322] The film formulation is typically prepared by evaporative drying of a thin aqueous film 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), freeze-drying equipment, or vacuum oven.

[0323] Suitable solid dosage forms for oral administration include immediate-release and controlled-release formulations. Controlled-release formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations. For a general overview of suitable controlled-release formulations, see U.S. Patent No. 6,106,864. For details on other useful release techniques, such as high-energy dispersion and osmotic and coated particles, see Verma et al., Pharmaceutical Technology On-line (2001) 25(2):1-14.

[0324] Compound (I) may also be administered directly into the bloodstream, muscle, or viscera of the target. Suitable techniques for parenteral administration include intravenous, intra-arterial, intraperitoneal, subarachnoid, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrabursal, and subcutaneous administration. Suitable devices for parenteral administration include needled (including microneedle) syringes, needleless syringes, and infusion devices.

[0325] Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., pH about 3 to about 9). However, for some applications, compound (I) may be more appropriately formulated as a sterile non-aqueous solution or as a dry form used with a suitable vehicle, such as sterile pyrogenicity-removed water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily achieved using standard pharmaceutical techniques.

[0326] The solubility of compounds used in the preparation of parenteral solutions can be increased using appropriate formulation techniques, such as the incorporation of dissolution enhancers. Formulations for parenteral administration may be formulated to be immediate-release or release-modulated. Release-modulated formulations include delayed-release, sustained-release, pulsed-release, controlled-release, targeted-release, and programmed-release formulations. Thus, compound (I) can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implantable depot that results in the release modification of the active compound. Examples of such formulations include drug-coated stents, as well as semi-solids and suspensions containing drug-supported poly(DL-lactic acid-glycolic acid) copolymer (PGLA) microspheres.

[0327] Compound (I) may also be administered topically, intradermally, or transdermally to the skin or mucous membranes. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, bandages, 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).

[0328] Other means of local administration include electroporation, iontophoresis, sonication, ultrasound, and microneedle or needle-free methods (e.g., Powderject). (TM) and Bioject (TM) Delivery by injection is one example. Locally administered formulations may be formulated to be immediately released or release-adjusted as described above.

[0329] 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 contain API alone, a powder blend of API with a diluent such as lactose, or mixed component particles containing API with phospholipids such as phosphatidylcholine. When used intranasally, the powder may contain a bioadhesive, such as chitosan or cyclodextrin. Aerosol sprays may be produced from a solution or suspension using a pressurized vessel, pump, sprayer, atomizer, or nebulizer, the solution or suspension comprising the API, one or more agents (e.g., EtOH with or without water) for dispersing, solubilizing, or spreading the release of the API, one or more solvents (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) acting as propellants, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Electrohydrodynamic atomizers may be used to produce a fine mist.

[0330] Prior to use in dry powder or suspension formulations, drug products are typically ground to a particle size suitable for inhalation delivery (typically, 90% of particles, based on volume, have a maximum dimension of 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.

[0331] Capsules, blisters, and cartridges (e.g., made from gelatin or hydroxypropyl methylcellulose) for use in inhalers or injectors may be formulated to contain an active compound, a suitable powder base such as lactose or starch, and a powder mixture of performance modifiers such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0332] Solution formulations suitable for use in atomizers that generate fine mist using electrohydrodynamics may contain approximately 1 μg to 20 mg of API per operation, and the operation volume may vary from approximately 1 μL to 100 μL. Typical formulations may contain one or more compounds (I), propylene glycol, sterile water, EtOH, and NaCl. Glycerol and polyethylene glycol are examples of alternative solvents that can be used instead of propylene glycol.

[0333] Formulations for inhalation, intranasal administration, or both may be formulated to be immediately released or release-modulated, for example, using PGLA. Such formulations intended for inhalation / intranasal administration may be supplemented with appropriate flavorings, such as menthol and levomenthol, or appropriate sweeteners, such as saccharin or sodium saccharin.

[0334] For dry powder inhalers and aerosols, the dosage unit is determined by utilizing a valve that delivers a measured amount. This unit is typically defined as a measured dose or "puff" containing approximately 10 μg to 1000 μg of API. The overall daily dose is typically in the range of approximately 100 μg to 10 mg, which may be administered as a single dose or, more commonly, as divided doses throughout the day.

[0335] The active compound may be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate. Formulations for rectal or vaginal administration may be formulated to be immediately released and / or release-controlled as described above.

[0336] Compound (I) may be administered directly to the eye or ear, typically in the form of a finely divided suspension or solution droplets in pH-adjusted isotonic sterile saline. Other formulations suitable for administration to the eye and ear include ointments, gels, biodegradable implants (e.g., absorbent gel sponges, collagen), non-biodegradable implants (e.g., silicone), wafers, lenses, and microparticles or vesicle systems such as niosomes or liposomes. The formulations may contain one or more polymers and preservatives, such as benzalkonium chloride. Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers (e.g., gelan rubber). Such formulations may also be delivered by iontophoresis. Formulations for administration to the eye or ear may be formulated to be immediately released or release-adjusted as described above.

[0337] Compound (I) may be combined with soluble macromolecular entities such as cyclodextrins and their derivatives, as well as polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, flavor, bioavailability, or stability. For example, API-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complex formation with API, cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. α-, β-, and γ-cyclodextrins are commonly used for these purposes. See, for example, WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0338] As described above, one or more compounds of formula (I), including the compounds specifically named above, as well as their pharmaceutically active complexes, salts, solvates, and hydrates, may be used to treat various diseases, conditions, and disorders, either with each other or with one or more other pharmaceutically active compounds. In such cases, the compounds may be provided in combination in single dosage forms as described above, or in the form of a kit suitable for simultaneous administration of the compositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which contains compound (I), and (2) a device for holding the two pharmaceutical compositions separately (e.g., a divided bottle or a divided foil packet). An example of such a kit is a standard blister pack used for packaging 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 separate dosing intervals, or for dosing different pharmaceutical compositions relative to each other. To assist patient compliance, the kit typically includes instructions for administration and may further provide memory aids.

[0339] When administered to human patients, the total daily dose of the claimed and disclosed compounds typically ranges from approximately 0.1 mg to approximately 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of approximately 1 mg to approximately 3000 mg, while intravenous administration may require only a total daily dose of approximately 0.1 mg to approximately 300 mg. The total daily dose may be administered as a single dose or in divided doses, and may deviate from the typical ranges shown above at the discretion of the physician. These doses are based on an average human subject weighing approximately 60 kg to approximately 70 kg, but a physician should be able to determine an appropriate dose even for patients whose weight falls outside this range (e.g., infants).

[0340] As described above, compound (I) may be used to treat diseases, disorders, and / or conditions associated with NLRP3, namely, diseases, disorders, and / or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene, such as cryopyrin-associated periodic syndromes (CAPS), which are characterized by inhibition of the NLRP3 inflammasome pathway. These may include neonatal-onset multiorgan inflammatory disease (NOMID / CINCA), Mackle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

[0341] 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 impairment) associated with one or more medical conditions, including frontotemporal dementia, Lewy body dementia, vascular disease, traumatic brain injury, use of substances or pharmaceuticals, HIV infection, prion diseases, Parkinson's disease, and Huntington's disease. Compound (I) may also be used to treat severe or mild neurocognitive impairment associated with depression, schizophrenia, bipolar disorder, and autism. Furthermore, Compound (I) may also be used to treat obesity with certain additional risk factors for cardiovascular disease.

[0342] The compounds described and disclosed in the claims may be combined with one or more other pharmacologically active compounds or therapies to treat one or more disorders, diseases, and / or conditions exhibiting inhibition of the NLRP3 inflammasome pathway. Such combinations may result in significant therapeutic benefits, including reduced side effects, improved treatment capacity for underserved patient populations, or synergistic activity. For example, compounds of formula (I), including the compounds specifically named above, as well as 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. Examples of such compounds or therapies include β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., Apazon, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, sodium meclofenamate, 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.

[0343] In addition to drugs used to improve cognition, compound (I) may be combined with sedatives, hypnotics, anxiolytics, antipsychotics, tranquilizers, and other pharmaceuticals 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, isocarboxazide, lamotrigine, levomilunacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine It may be used in combination with one or more pharmacologically active agents (antidepressants) for treating depression, and / or one or more pharmacologically active agents (atypical or typical antipsychotics) for treating schizophrenia, including paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, bilazodone, and vortioxetine and ziprasidone.

[0344] Similarly, compound (I) may be combined with one or more pharmaceutically active agents (anxiolytics) for treating anxiety disorders, 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.

[0345] Compound (I) may also be used in combination with one or more pharmaceutically active agents (antiepileptic or anticonvulsant) for treating epilepsy, including acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxycarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, thiagabine, topiramate, vigabatrin, and zonisamide. [Examples]

[0346] The present invention will be described in detail with reference to the following examples, experimental examples, and formulation examples, but these should not be interpreted as limiting, and modifications are possible within the scope of the present invention.

[0347] In the following examples, "room temperature" generally means approximately 10°C to approximately 35°C. Unless otherwise specified, the ratios given for mixed solvents are volume ratios. Unless otherwise specified, % means weight percentage.

[0348] Unless otherwise specified, elution by column chromatography in the examples was performed under observation by TLC (thin-layer chromatography). For TLC observation, a Merck 60F TLC plate was used. 254 Using this method, the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector was used for detection.

[0349] In silica gel column chromatography, the notation NH indicates the use of aminopropylsilane-linked silica gel, and the notation diol indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane-linked silica gel.

[0350] For many of the compounds in the following examples, 11H nuclear magnetic resonance (NMR) spectra were obtained. Characteristic chemical shifts (δ) are shown in parts per million from tetramethylsilane to low magnetic fields, using conventional abbreviations representing the major peaks, including s (singlet), d (doublet), t (triplet), q (quadruplet), m (multilet), and br (broad). The following abbreviations are used for common solvents: CDCl3 (deuterated chloroform), DMSO-d6 (deuterated dimethyl sulfoxide). 1 For 1H NMR analysis, software such as ACD / SpecManager (product name) was used. Peaks with very gentle proton peaks, such as those of hydroxyl groups and amino groups, may not be displayed.

[0351] MS was measured using LC / MS. ESI or APCI was used as the ionization method. The data shown are the actual measured values. Generally, molecular ion peaks are observed, but fragment ions may also be observed. For example, in the case of compounds with a tert-butoxycarbonyl group, the peak after the elimination of the tert-butoxycarbonyl or tert-butyl group may be observed as a fragment ion. In the case of compounds with a hydroxyl group, the peak after the elimination of H2O may be observed as a fragment ion. In the case of salts, the free molecular ion peak or fragment ion peak is generally observed.

[0352] Where indicated, the intermediate preparations and example compounds are purified by HPLC. Tables 1-3 show the columns, mobile phases, and gradients used for some HPLC separations.

[0353] [Table 1]

[0354] [Table 2]

[0355] [Table 3]

[0356] In the preparations and examples, supercritical fluid chromatography (SFC) can be used to separate the enantiomers. Table 4 shows the apparatus, materials, and conditions used for some SFC separations.

[0357] [Table 4]

[0358] The following abbreviations are used in the examples. MS: Mass Spectrum M: Molar concentration CDCl3: Deuterated chloroform DMSO-d6: Deuterated Dimethyl Sulfoxide 1 1H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatography Mass Spectrometer ESI: Electrospray ionization; APCI: Atmospheric pressure chemical ionization Ar: Argon CaCl2: Calcium chloride DAST: (Diethylamino) sulfur trifluoride DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide æ:ethyl acetate EtOH: Ethanol HCl: Hydrogen chloride IPE: Diisopropyl ether K3PO4: Potassium triphosphate mCPBA: m-chloroperbenzoic acid MeOH: methanol MgSO4: Magnesium sulfate NaOEt: Sodium ethoxide NaHCO3: Sodium bicarbonate NaOH: Sodium hydroxide NaOMe: Sodium Methoxyde Na2SO4: Sodium sulfate Na2S2O3: Sodium thiosulfate NBS: N-bromosuccinimide NH4Cl: Ammonium chloride PTSA: p-toluenesulfonic acid TEA: Triethylamine t-BuOH:tert-butanol TFA: Trifluoroacetic acid THF: Tetrahydrofuran

[0359] Example 24

[0360] 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0361] A) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(methylsulfanyl)pyrimidine

[0362] PTSA acid monohydrate (0.043 g) was added at room temperature to a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (1.02 g) and ethane-1,2-diol (0.767 mL) in toluene (30 mL). The mixture was heated under reflux for 10 hours using a Dean-Stark apparatus. The mixture was neutralized at room temperature with saturated aqueous sodium bicarbonate and extracted with SiO2. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2 / hexane) to obtain the title compound (1.200 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.56 (3H, s), 3.94-4.09 (2H, m), 4.13-4.26 (2H, m), 6.18 (1H, s).

[0363] B) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(Methanesulfonyl)pyrimidine

[0364] A mixture of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-(methylsulfanyl)pyrimidine (200 mg) and mCPBA (442 mg) in DMF (3 mL) was stirred at room temperature for 12 hours. An additional 220 mg of mCPBA was added to the mixture. The mixture was stirred at room temperature for 1.5 hours. Water and an aqueous sodium thiosulfate solution were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (123 mg). 1 H NMR (400 MHz, DMSO-d6) δ 3.43 (3H, s), 4.04-4.13 (2H, m), 4.21-4.29 (2H, m), 6.31 (1H, s).

[0365] C) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-ethoxypyrimidine

[0366] 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(methanesulfonyl)pyrimidine (50 mg) was dissolved in THF (2 mL) and 20% sodium ethoxide-EtOH (59.7 mg) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Water was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water 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 obtain the title compound (32.6 mg). MS: [M+H] + 264.9.

[0367] D) 2-(4-bromo-2-fluoro-6-methylphenyl)-4-chloro-6-ethoxy-2H-pyrazolo[3,4-d]pyrimidine

[0368] A solution of sodium nitrite (0.558 g) in water (15 mL) was slowly added at 0°C to a solution of 4-bromo-2-fluoro-6-methylaniline (1.5 g) in 6M HCl (20 mL). After stirring at 0°C for 20 minutes, tin(II) chloride (4.18 g) in 6M HCl (30 mL) was added to the mixture. The mixture was stirred at 0°C for 30 minutes. An 8M aqueous NaOH solution was added to the mixture at 0°C. The mixture was extracted with ELISA. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale brown solid (1.450 g). This solid (83 mg) and TEA (0.158 mL) were added at room temperature to a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-ethoxypyrimidine (100 mg) in THF (1.0 mL). The mixture was stirred overnight at 60°C. The mixture was poured into water and extracted with toluene. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Toluene (2 mL) and PTSA monohydrate (3.59 mg) were added to the residue at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with toluene. 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 (toluene / hexane) to obtain the title compound (130 mg). MS: [M+H] + 384.9.

[0369] E) 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0370] A solution of 2-(4-bromo-2-fluoro-6-methylphenyl)-4-chloro-6-ethoxy-2H-pyrazolo[3,4-d]pyrimidine (337 mg) in THF (10 mL) was mixed with 8 M NaOH aqueous solution (2 mL). The mixture was stirred overnight at room temperature. HCl and 6 M HCl aqueous solution (3 mL) were added to the mixture. Saturated hydrated NAHCO3 was then added to the mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (300 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.1 Hz), 2.12 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 7.60 (1H, s), 7.73 (1H, d, J = 9.2 Hz), 8.75 (1H, s), 11.85 (1H, s).

[0371] Example 39

[0372] 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0373] A mixture of 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (240 mg), cyclopropylboronic acid (168 mg), K3PO4 (416 mg), palladium(II) acetate (29.3 mg), and tricyclohexylphosphine (73.3 mg) in toluene (5 mL) and water (1 mL) was stirred overnight at 100°C under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added to the mixture. 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 (ethyl acetate / hexane) to obtain the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.75-0.83 (2H, m), 0.99-1.06 (2H, m), 1.34 (3H, t, J = 7.1 Hz), 1.95-2.05 (1H, m), 2.06 (3H, s), 4.40 (2H, q, J = 7.1 Hz), 6.99-7.03 (2H, m), 8.67 (1H, s), 11.80 (1H, s).

[0374] Example 142

[0375] 2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0376] A) 2-Bromo-4-(difluoromethoxy)-6-methylaniline

[0377] NBS (1.752 g) was gradually added at 0°C to a solution of 4-(difluoromethoxy)-2-methylaniline (1.55 g) in DMF (30 mL). The mixture was stirred at 0°C for 1 hour under a dry atmosphere (CaCl2 tube). The mixture was quenched at 0°C with saturated aqueous NaHCO3 and 1M Na2S2O3 aqueous solution, and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.450 g). MS: [M+H] + 252.0.

[0378] B) (2-bromo-4-(difluoromethoxy)-6-methylphenyl)hydrazine

[0379] A solution of sodium nitrite (0.437 g) in water (15 mL) was added dropwise to a solution of 2-bromo-4-(difluoromethoxy)-6-methylaniline (1.45 g) in a 6 M aqueous HCl solution (35 mL) at 0°C. After stirring at 0°C for 20 minutes, a 6 M aqueous HCl solution of tin(II) chloride (3.27 g) (10 mL) was added to the reaction mixture. The mixture was stirred at 0°C for 30 minutes. An 8 M aqueous NaOH solution was added to bring the pH of the solution to the basic range. HCl and Celite were added to the mixture. The precipitate was filtered through a Celite pad and washed with HCl. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (1.060 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.38 (3H, s), 4.17 (2H, br s), 5.55 (1H, s), 6.83-7.41 (3H, m).

[0380] C) 4-(2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)hydrazineyl)-6-chloro-5-(1,3-dioxolan-2-yl)-2-ethoxypyrimidine

[0381] (2-bromo-4-(difluoromethoxy)-6-methylphenyl)hydrazine hydrochloride (4 g) was added at room temperature to a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-ethoxypyrimidine (3.84 g) and TEA (9.18 mL) in THF (130 mL). The mixture was stirred under Ar at 70°C for 5 hours. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.89 g). MS: [M+H] + 495.0.

[0382] D) 2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0383] TFA (24.18 mL) was added dropwise at 0°C to a solution of 4-(2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)hydrazineyl)-6-chloro-5-(1,3-dioxolan-2-yl)-2-ethoxypyrimidine (3.89 g) in THF (75 mL). After stirring at 0°C for 5 minutes, the mixture was stirred at room temperature under Ar for 1.5 hours. The mixture was poured into 2M aqueous NaOH (157 mL), and saturated hydrated NaHCO3 was added to the mixture at 0°C. The mixture was extracted with HCl / THF (2:1). The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (2.71 g). MS: [M+H] + 414.9.

[0384] E) 2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0385] 2-(2-bromo-4-(difluoromethoxy)-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (3.0 g) was dissolved in hot ELISA (74 mL). Hexane (41 mL) was added to the mixture at 70°C. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with hexane, and dried under vacuum to obtain the title compound (2.21 g). 1H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 2.05 (3H, s), 4.41 (2H, q, J = 7.0 Hz), 7.34 (1H, d, J = 2.3 Hz), 7.40 (1H, t, J = 73.9 Hz), 7.56 (1H, d, J = 2.6 Hz), 8.67 (1H, s), 11.83 (1H, s).

[0386] Example 146-1

[0387] 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0388] A) (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride

[0389] A mixture of sodium nitrite (18.97 g) and water (400 mL) was added dropwise to a mixture of 4-bromo-2,6-dimethylaniline (50 g) and 6M aqueous HCl (1000 mL) at 0°C. After stirring at 0°C for 30 minutes, a mixture of tin(II) chloride (142 g) and 6M aqueous HCl (200 mL) was added to the reaction mixture. The mixture was stirred at 0°C for 30 minutes. The precipitate was filtered off and washed with ice-cold 2M aqueous HCl (300 mL × 2) and ice-cold IPE (300 mL × 3), and then dried under vacuum to obtain the title compound (55.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.38 (6H, s), 6.42-6.94 (1H, m), 7.32 (2H, s), 9.73 (3H, br s).

[0390] B) 2,4,6-Trichloro-5-(1,3-Dioxolan-2-yl)pyrimidine

[0391] PTSA monohydrate (2.371 g) was added at room temperature to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (52.7 g) and ethane-1,2-diol (41.8 mL) in toluene (500 mL). The mixture was stirred at 20°C for 1 hour while removing the resulting water using a Dean-Stark trap. The mixture was poured into saturated aqueous NaHCO3 at room temperature and extracted with siRNA. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was suspended in IPE, the precipitate was filtered, washed with IPE, and dried under vacuum to obtain the title compound (39.4 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.98-4.11 (2H, m), 4.17-4.28 (2H, m), 6.22 (1H, s).

[0392] C) 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazineyl)-2,6-dichloro-5-(1,3-dioxolan-2-yl)pyrimidine

[0393] (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (40.7 g) and MeOH (250 mL) were mixed with 2,4,6-trichloro-5-(1,3-dioxolan-2-yl)pyrimidine (39.4 g) at 0°C. TEA (64.5 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 2 hours. The resulting solid was filtered, washed with MeOH (100 mL) and hexane (100 mL), and dried under vacuum to obtain the title compound (50.5 g). This product was subjected to the next reaction without further purification. MS: [M+H] + 432.9.

[0394] D) 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0395] TFA (22.18 mL) was added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(1,3-dioxolan-2-yl)pyrimidine (50 g) and toluene (500 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was added dropwise to a mixture of K3PO4 (68 g) and water (230 mL) at 0°C and extracted with ELISA / THF. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. To a mixture of the residue and THF (dry) (400 mL), 4M aqueous NaOH (101 mL) was added at room temperature. The mixture was stirred at 60°C for 20 minutes. The mixture was acidified with 2M aqueous HCl (180 mL) at 0°C and extracted with ELISA. The organic layer was separated, washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The mixture was filtered through a silica gel pad using HCl, and the filtrate was concentrated under reduced pressure. The resulting solid was filtered, washed with HCl and IPE, and dried under vacuum to obtain the title compound (23.10 g). MS: [M+H] + 353.0.

[0396] E) 2-(4-bromo-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0397] 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (23.1 g) and THF (dry) (230 mL) were mixed with a 28% NaOMe solution in MeOH (37.8 g) at room temperature. The mixture was stirred at 70°C for 8 hours. The mixture was poured into saturated aqueous NH4Cl at 0°C and extracted with siRNA. The organic layer was separated, washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The mixture was filtered with siRNA through a two-layer pad of basic silica gel and silica gel. The filtrate was concentrated under reduced pressure, and the resulting solid was filtered using IPE, washed with XXX, and dried under vacuum to obtain the title compound (21.40 g). MS: [M+H] + 349.0

[0398] F) 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0399] To a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (5.0 g), toluene (100 mL), and water (20 mL), cyclopropylboronic acid (3.69 g), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.467 g), and K3PO4 (4.56 g) were added at room temperature. The mixture was stirred at 100°C for 3 hours under Ar. To a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (15.0 g), toluene (300 mL), and water (60 mL), cyclopropylboronic acid (11.1 g), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (1.40 g), and K3PO4 (13.7 g) were added at room temperature. The mixture was stirred at 100°C for 3 hours under Ar. The two reaction mixtures were poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over Na2SO4. The mixture was filtered through a basic silica gel pad using ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (15.5 g). The solid was dissolved in ethyl acetate (800 mL) and filtered to remove the powder. The filtrate was concentrated under reduced pressure. The solid was dissolved in siRNA (400 mL) at 70°C. The mixture was stirred overnight at room temperature. The precipitate was filtered, washed with hexane, and dried under vacuum to obtain the title compound (12.00 g). 1H NMR (400 MHz, DMSO-d6) δ 0.69-0.78 (2H, m), 0.91-1.02 (2H, m), 1.88-1.99 (7H, m), 3.93 (3H, s), 6.94 (2H, s), 8.55 (1H, s), 11.83 (1H, s).

[0400] Example 146-2

[0401] 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0402] A) 2,4-Dichloro-6-[2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazinyl]-5-(1,3-dioxolan-2-yl)pyrimidine

[0403] To a solution of (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride (11.0 g) in MeOH (60 mL), 2,4,6-trichloro-5-(1,3-dioxolan-2-yl)pyrimidine (11.0 g) was added at 0°C. TEA (18.0 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 3 hours. The reaction mixture was filtered, and the filter cake was washed with MeOH (15 mL) and hexane (15 mL) to obtain the title compound (12.3 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.47-0.62 (2H, m), 0.74-0.88 (2H, m), 1.67-1.78 (1H, m), 2.31 (6H, s), 3.92-3.99 (2H, m), 4.19-4.27 (2H, m), 5.94 (1H, s), 6.60 (2H, s), 6.89 (1H, d, J = 3.2 Hz), 8.86 (1H, d, J = 3.2 Hz).

[0404] B) 4,6-Dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine

[0405] 4M HCl-MTBE (123 mL) was added dropwise at 0°C under an N2 atmosphere to a solution of 2,4-dichloro-6-[2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazinyl]-5-(1,3-dioxolan-2-yl)pyrimidine (12.3 g) in THF (120 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was added dropwise at 0°C to saturated aqueous NaHCO3 (200 mL), and then extracted with siRNA (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel column chromatography (siRNA / petroleum ether) to obtain the title compound (7.4 g). MS: [M+H] + 333.1.

[0406] C) 6-Chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0407] A solution of compound 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (7.4 g) in THF (74 mL) was mixed with 4 M NaOH aqueous solution (19.4 mL) at 20°C. The mixture was stirred at 60°C for 1 hour. The mixture was acidified with 2 M HCl aqueous solution (40 mL) at 0°C and extracted with HCl (100 mL × 3). The organic layer was separated, washed with saturated aqueous NaHCO3 (100 mL) and saline solution (100 mL), and dried over Na2SO4. The mixture was filtered through a silica gel pad using HCl, and the filtrate was concentrated under vacuum to obtain the title compound (7 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.70-0.77 (2H, m), 0.95-1.02 (2H, m), 1.89-1.97 (7H, m), 6.96 (2H, s), 8.76 (1H, s), 12.85 (1H, s).

[0408] D) 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0409] A solution of 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (7 g) in THF (70 mL) was added to a 30% NaOMe solution in methanol (12.0 g). The mixture was stirred at 70°C for 8 hours. The reaction mixture was quenched at 0°C with saturated aqueous NH4Cl (100 mL), and then extracted with siRNA (100 mL × 3). The combined organic layers were washed with saline (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (6.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.69-0.76 (2H, m), 0.94-1.01 (2H, m), 1.87-1.96 (7H, m), 3.93 (3H, s), 6.94 (2H, s), 8.55 (1H, s), 11.82 (1H, br s).

[0410] E) 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (45.8 g) was dissolved in HCl (1470 mL) at 70°C. The solution was filtered. The filtrate (suspension) was heated at 70°C. To the clear solution, heptane (400 mL) was added dropwise at 65-70°C. Seed crystals were added to the mixture and stirred at 66°C for 40 minutes. Heptane (600 mL) was added dropwise to the suspension at 65°C. The suspension was gradually cooled to room temperature. The precipitate was filtered, washed with a mixture of HCl / heptane (v / v = 1 / 1, 400 mL), and dried to obtain the title compound (34.1 g). 1H NMR (400 MHz, DMSO-d6) δ 0.65-0.81 (2H, m), 0.90-1.08 (2H, m), 1.89-1.97 (7H, m), 3.94 (3H, s), 6.94 (2H, s), 8.56 (1H, s), 11.84 (1H, s).

[0411] Example 186

[0412] 2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0413] A) 1-(difluoromethyl)-3-fluoro-2-nitrobenzene

[0414] DAST (2.81 mL) was added at 0°C to a solution of 3-fluoro-2-nitrobenzaldehyde (1.2 g) in toluene (20 mL). The mixture was stirred at room temperature under N2 for 2 hours. The mixture was quenched with water at 0°C and extracted with siRNA. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (1.120 g). 1 H NMR (400 MHz, CDCl3) δ 6.81-7.18 (1H, m), 7.43 (1H, t, J = 8.9 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.66 (1H, td, J = 8.2, 4.9 Hz).

[0415] B) 4-Bromo-2-(difluoromethyl)-6-fluoroaniline

[0416] A mixture of 1-(difluoromethyl)-3-fluoro-2-nitrobenzene (9.5 g) and Pd-C (wetted with 10% 55% water, 2.351 g) in EtOH (50 mL) was hydrogenated at room temperature under balloon pressure for 16 hours. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in DMF (dry) (100 mL) at 0°C. NBS (9.28 g) was added. The mixture was stirred at 0°C for 1 hour under N2. Water (100 mL) was then added, and the resulting mixture was extracted with SiO2 (100 mL x 2). The combined organic solvents were washed with water and saline solution and dried over anhydrous Na2SO4. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography (SiO2 / hexane) to obtain the title compound (10 g). MS: [M+H] + 240.0.

[0417] C) 4-Cyclopropyl-2-(difluoromethyl)-6-fluoroaniline

[0418] A mixture of 4-bromo-2-(difluoromethyl)-6-fluoroaniline (10 g), cyclopropylboronic acid (5.37 g), dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.815 g), and K3PO4 (17.69 g) in toluene (100 mL) and water (20 mL) was stirred at 100°C for 3 hours under N2. Insoluble matter was filtered off and washed with phosphate. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (7.60 g). MS: [M+H] + 202.0.

[0419] D) (4-Cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)hydrazine

[0420] To a stirred suspension of 4-cyclopropyl-2-(difluoromethyl)-6-fluoroaniline (1 g) in 36 mL of 6 M aqueous HCl solution, sodium nitrite (0.377 g) in 18 mL of water was added dropwise at 0°C. After stirring at 0°C for 30 minutes, CH3CN (24 mL) was added. To the stirred mixture (solution), tin(II) chloride (2.83 g) in 18 mL of 6 M aqueous HCl solution was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The resulting mixture was quenched at 0°C with 42 mL of 8 M aqueous NaOH solution and diluted with saline and THF (90 mL). Insoluble matter was filtered off, and the filtrate was extracted with THF. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude material (1 g) was used in the next reaction without further purification. 1 H NMR (300 MHz, DMSO-d6) 0.51-0.68 (2H, m), 0.82-0.95 (2H, m), 1.81-1.96 (1H, m), 4.40 (2H, s), 6.39 (1H, br d, J = 3.0 Hz), 6.85-6.93 (1H, m), 7.03 (1H, s), 7.53-8.02 (1H, m).

[0421] E) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(methylthio)pyrimidine

[0422] PTSA monohydrate (0.128 g) was added at room temperature to a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (3 g) and ethylene glycol (2.256 mL) in toluene (100 mL). The mixture was refluxed for 3 hours while removing the resulting water using a Dean-Stark trap. The mixture was neutralized at room temperature with saturated aqueous NaHCO3 and extracted with SiO2. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2 / hexane) to obtain the title compound (3.37 g). MS: [M+H] + 266.9.

[0423] F) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(methylsulfonyl)pyrimidine

[0424] m-CPBA (25.00 g) was added at 0°C to a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-(methylthio)pyrimidine (12.9 g) in DME (150 mL). The mixture was stirred overnight at room temperature. The resulting solid was filtered using DME, washed with DME, and dried under vacuum to obtain the title compound (9.00 g). MS: [M+H] + 298.9.

[0425] G) 4,6-Dichloro-5-(1,3-Dioxolan-2-yl)-2-(2-Methoxyethoxy)pyrimidine

[0426] 2-methoxyethanol (22.82 mL) was stirred in DME (70 mL), to which 60% NaH (3.70 g) was added gradually at 0°C. The mixture was stirred at room temperature for 30 minutes, and then, using a dropping funnel, 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-(methylsulfonyl)pyrimidine (8.66 g) was added dropwise to the mixture in DME (70 mL) at 0°C. The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (3.94 g). MS: [M+H] + 295.1.

[0427] H) 4-Chloro-6-(2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)hydrazineyl)-5-(1,3-dioxolan-2-yl)-2-(2-methoxyethoxy)pyrimidine

[0428] To a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-(2-methoxyethoxy)pyrimidine (1.467 g) in THF (dry) (40 mL), (4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)hydrazine (1.075 g) and Et3N (2.425 mL) were added at room temperature. The mixture was stirred at 65°C for 16 hours, treated with water, and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.020 g). MS: [M+H] + 475.2.

[0429] I) 2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0430] To a solution of 4-chloro-6-(2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)hydrazineyl)-5-(1,3-dioxolan-2-yl)-2-(2-methoxyethoxy)pyrimidine (976.6 mg) in THF (dry) (30 mL), TFA (7.92 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was basicized with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (763 mg). MS: [M+H] + 395.2.

[0431] J) 2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0432] 2-(4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl)-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (793.3 mg) was dissolved in hot ethyl acetate (12 mL) at 75°C. To the solution, heptane (3 mL) was added dropwise at 50°C (oil bath) and the mixture was stirred at 50°C for 5 minutes. Heptane (3 mL) was added to the suspension and the suspension was stirred at 50°C for 1 minute. An additional heptane (6 mL) was added and the oil bath was removed. After the addition of heptane (6 mL), the suspension was stirred at room temperature for 12 hours. After the addition of heptane (14 mL), the suspension was cooled to 0°C. The suspension was stirred for 10 minutes, the white crystals were filtered off, washed with heptane / ethyl acetate (5:1), and dried to obtain the title compound (679 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.84-0.90 (2H, m), 1.04-1.15 (2H, m), 2.13-2.21 (1H, m), 3.31 (3H, s), 3.64-3.71 (2H, m), 4.46-4.53 (2H, m), 6.88 (1H, t, J = 56.0 Hz), 7.39-7.44 (2H, m), 8.80 (1H, s), 11.96 (1H, s).

[0433] Example 224

[0434] 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-((difluoromethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0435] A) 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

[0436] To a solution of 5-amino-1H-pyrazole-4-carbonitrile (5.10 g) in pyridine (100 mL), (4-bromo-2,6-dimethylphenyl)boronic acid (9.0 g) and copper(II) acetate (7.14 g) were added at room temperature. The mixture was vigorously stirred at 90°C for 3 hours under open air. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over Na2SO4. The mixture was filtered through silica gel and Celite pads using ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (2.500 g). MS: [M+H] + 291.0.

[0437] B) 3-amino-1-(4-cyclopropyl-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

[0438] Cyclopropylboronic acid (2.213 g), K3PO4 (9.11 g), and dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.392 g) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (2.50 g) in toluene (50 mL) and water (10.00 mL). The mixture was stirred at 100°C for 1 hour under Ar. The mixture was poured into water and extracted with SiO2. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2 / hexane) to obtain the title compound (2.160 g). MS: [M+H] + 253.1.

[0439] C) 3-amino-1-(4-cyclopropyl-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide

[0440] 30% hydrogen peroxide solution (31.5 mL) was added dropwise to a mixture of 3-amino-1-(4-cyclopropyl-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (5.18 g) and K2CO3 (8.51 g, 61.59 mmol) in DMSO (150 mL) while maintaining the reaction temperature in a water bath. The mixture was stirred at room temperature for 1.5 hours. The mixture was quenched at room temperature with water and saturated aqueous NH4Cl, and extracted with HCl and THF. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting solid was triturated with HCl / IPE / hexane to obtain the title compound (4.91 g). MS: [M+H] + 271.2.

[0441] D) 1-(4-cyclopropyl-2,6-dimethylphenyl)-3-(2-(difluoromethoxy)acetamide)-1H-pyrazole-4-carboxamide

[0442] Oxalyl chloride (1.907 mL) and 4 drops of DMF were added at 0°C to a mixture of 2-(difluoromethoxy)acetic acid (2.497 g) in THF (40 mL). The mixture was stirred at room temperature for 1 hour. The resulting solution was then added dropwise over 1 hour using a dropping funnel to a mixture of 3-amino-1-(4-cyclopropyl-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (3.8243 g) and DIEA (9.88 mL) in THF (130 mL) at -5°C. The mixture was stirred at -5°C for 10 minutes and then stirred at room temperature for 16 hours. The mixture was poured into water, the precipitate was filtered, washed with water, and dried to obtain the title compound (4.83 g). MS: [M+H] + 379.2.

[0443] E) 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-((difluoromethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0444] A 2M aqueous solution of Na2CO3 (128 mL) was added to a mixture of 1-(4-cyclopropyl-2,6-dimethylphenyl)-3-(2-(difluoromethoxy)acetamide)-1H-pyrazole-4-carboxamide (4.83 g) in EtOH (300 mL). The mixture was stirred at 80°C for 16 hours, and the EtOH was removed under reduced pressure. An aqueous solution of NH4Cl was added to the residue, and the mixture was extracted with HCl. The organic phase was separated, washed with saturated aqueous NH4Cl and saline solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (3.77 g). MS: [M+H] + 361.2.

[0445] F) 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-((difluoromethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0446] 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-((difluoromethoxy)methyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (4.3872 g) was dissolved in SiO2 (55 mL) at 75-77°C. Then, heptane (38 mL) was added dropwise to the mixture at 75-77°C. Next, a seed crystal was added to the mixture. The mixture was stirred at the same temperature under N2 for 1 hour. Then, the mixture was gradually cooled to room temperature and stirred overnight under N2. An additional heptane (17 mL) was added to the mixture at room temperature. The mixture was stirred at room temperature for 1 hour, then cooled to 0°C and stirred for a further 1 hour. The resulting solid was filtered, washed with cold SiO2 / heptane (1:2, 20 mL × 2), and dried under heat (65°C) under vacuum for 1 hour to obtain the title compound (3.96 g). 1H NMR (400 MHz, DMSO-d6) δ 0.69-0.77 (2H, m), 0.95-1.03 (2H, m), 1.88-1.99 (7H, m), 4.80 (2H, s), 6.64-7.07 (3H, m), 8.70 (1H, s), 12.01 (1H, s).

[0447] Example 235

[0448] 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0449] A) 2-Bromo-1,3-dimethyl-5-vinylbenzene

[0450] Potassium tert-butoxide (6.3 g) was added at 0°C to a mixture of methyltriphenylphosphonium bromide (20.0 g) in THF (150 mL). After stirring at 0°C for 30 minutes, 4-bromo-3,5-dimethylbenzaldehyde (10 g) in THF (100 mL) was added to the reaction mixture. The mixture was stirred at room temperature under N2 for 1 hour. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (9.50 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.35 (6H, s), 5.28 (1H, dd, J = 11.1, 1.1 Hz), 5.85 (1H, dd, J = 17.6, 1.1 Hz), 6.64 (1H, dd, J = 17.6, 11.1 Hz), 7.27 (2H, s).

[0451] B) 2-Bromo-5-(2-Bromo-1-fluoroethyl)-1,3-dimethylbenzene

[0452] NBS (16.02 g) was added at 0°C to a solution of 2-bromo-1,3-dimethyl-5-vinylbenzene (9.50 g) in CH2Cl2 (100 mL). After stirring at 0°C for 5 minutes, triethylamine hydrofluoric acid (22.01 mL) was added to the reaction mixture. The mixture was stirred overnight at room temperature under N2. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 and water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (9.90 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.38 (6H, s), 3.82-4.01 (2H, m), 5.60-5.87 (1H, m), 7.27 (2H, s).

[0453] C) 2-Bromo-5-(1-fluorovinyl)-1,3-dimethylbenzene

[0454] A solution of 2-bromo-5-(2-bromo-1-fluoroethyl)-1,3-dimethylbenzene (9.90 g) and potassium tert-butoxide (5.38 g) in THF (200 mL) was refluxed for 1 hour. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with HCl. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (HCl / hexane) to obtain the title compound (7.10 g). 1 H NMR (300 MHz, DMSO-d6) δ 2.38 (6H, s), 4.88-5.05 (1H, m), 5.21-5.57 (1H, m), 7.42 (2H, s).

[0455] D) 2-Bromo-5-(1-fluorocyclopropyl)-1,3-dimethylbenzene

[0456] Zinc (5.99 g) was added at room temperature to a solution of chloromethyl benzoate (15.64 g), 5,10,15,20-tetraphenyl-21H,23H-porphyrin iron monolith (2.151 g), and sodium iodide (13.74 g) in THF (500 mL). After stirring at room temperature for 5 minutes, 2-bromo-5-(1-fluorovinyl)-1,3-dimethylbenzene (7.0 g) was added to the reaction mixture. The mixture was stirred overnight at 60°C under Ar. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (siRNA / hexane) to obtain the title compound (5.50 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.06-1.22 (2H, m), 1.39-1.51 (2H, m), 2.37 (6H, s), 7.09 (2H, s).

[0457] E) Di-tert-butyl 1-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazine-1,2-dicarboxylate

[0458] n-BuLi (2.3 M in hexane) (1.770 mL) was added at -78°C to a solution of 2-bromo-5-(1-fluorocyclopropyl)-1,3-dimethylbenzene (450 mg) in THF (5 mL). After stirring at -78°C for 1 hour, di-tert-butyl (Z)-diazene-1,2-dicarboxylate (469 mg) was added to the reaction mixture. The mixture was stirred under N2 at -78°C for 2 hours. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (210 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.80 - 0.93 (m, 2 H) 1.09 - 1.13 (m, 2 H) 1.35 - 1.42 (m, 18 H) 2.24 - 2.32 (m, 6 H) 6.88 - 7.03 (m, 2 H) 9.34 - 9.43(m, 1H).

[0459] F) (4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazine hydrochloride

[0460] A 4M HCl solution in SiO2 (3 mL) was added to a solution of di-tert-butyl 1-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazine-1,2-dicarboxylate (200 mg) in SiO2 (5 mL) at room temperature. The mixture was stirred overnight at 50°C under N2. The precipitate was filtered to obtain the title compound (93 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.06-1.15 (2H, m), 1.38-1.49 (2H, m), 2.39 (6H, s), 6.59-6.89 (1H, m), 7.01 (2H, s), 9.6G2 (3H, br s).

[0461] G) 4,6-Dichloro-5-(1,3-Dioxolann-2-yl)-2-methoxypyrimidine

[0462] NaOMe (ca. 5 M in MeOH) (0.962 mL) was added at -78°C to a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-(methylsulfonyl)pyrimidine (1.37 g) in THF (60.0 mL). The mixture was stirred at -78°C for 30 minutes under N2. The mixture was quenched with water at -78°C and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (0.941 g). MS: [M+H] + 251.0.

[0463] H) 4-Chloro-5-(1,3-dioxolan-2-yl)-6-(2-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazineyl)-2-methoxypyrimidine

[0464] DIPEA (0.2 mL) was added at room temperature to a solution of 4,6-dichloro-5-(1,3-dioxolan-2-yl)-2-methoxypyrimidine (80 mg) and (4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazine hydrochloride (90 mg) in THF (5 mL). The mixture was stirred at 50°C for 3 hours under N2. The mixture was poured into saturated aqueous NH4Cl at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (45.0 mg). MS: [M+H] + 409.0.

[0465] I) 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0466] TFA (0.5 mL) was added at room temperature to a solution of 4-chloro-5-(1,3-dioxolan-2-yl)-6-(2-(4-(1-fluorocyclopropyl)-2,6-dimethylphenyl)hydrazinyl)-2-methoxypyrimidine (45 mg) in THF (1.5 mL). The mixture was stirred at room temperature under N2 for 3 hours. The mixture was poured into saturated aqueous NaHCO3 at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (28.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.16-1.28 (2H, m), 1.44-1.59 (2H, m), 1.99 (6H, s), 3.93 (3H, s), 7.16 (2H, s), 8.61 (1H, s), 11.86 (1H, br s).

[0467] Example 321

[0468] 2-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-6-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0469] A) 1-(difluoromethyl)-2-fluoro-3-methyl-5-nitrobenzene

[0470] DAST (5.77 mL) was added dropwise at 0°C to a solution of 2-fluoro-3-methyl-5-nitrobenzaldehyde (5.33 g) in anhydrous toluene (60 mL). The mixture was stirred at room temperature under N2 for 2 hours. The mixture was quenched at 0°C with water and saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3, water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (5.52 g). 1 H NMR (400 MHz, CDCl3) δ 2.43 (3H, d, J = 1.8 Hz), 6.76-7.08 (1H, m), 8.21-8.28 (1H, m), 8.32-8.39 (1H, m).

[0471] B) 3-amino-1-(2-(difluoromethyl)-6-methyl-4-nitrophenyl)-1H-pyrazole-4-carbonitrile

[0472] A mixture of 1-(difluoromethyl)-2-fluoro-3-methyl-5-nitrobenzene (5.52 g), 3-amino-1H-pyrazole-4-carbonitrile (2.91 g), and K2CO3 (4.46 g) in DMSO (25 mL) was stirred overnight at room temperature under a dry atmosphere. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and filtered through a short pad of silica gel using ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was washed with IPE, collected, and dried under vacuum to obtain the title compound (6.83 g). MS: [MH] - 291.9.

[0473] C) tert-butyl (tert-butoxycarbonyl)(4-cyano-1-(2-(difluoromethyl)-6-methyl-4-nitrophenyl)-1H-pyrazole-3-yl)carbamate

[0474] Di-tert-butyl dicarbonate (11.90 mL) was added at room temperature to a mixture of 3-amino-1-(2-(difluoromethyl)-6-methyl-4-nitrophenyl)-1H-pyrazole-4-carbonitrile (6.83 g), TEA (6.49 mL), and DMAP (0.285 g) in anhydrous THF (50 mL). The mixture was stirred at 70°C for 1.5 hours. The mixture was quenched with water at room temperature and extracted with siRNA / THF. The organic layer was separated, washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered through a short pad of silica gel, and concentrated under reduced pressure. The residue was washed with IPE, collected, and dried to obtain the title compound (8.46 g). MS: [M+Na] + 516.2.

[0475] D) tert-butyl (1-(4-amino-2-(difluoromethyl)-6-methylphenyl)-4-cyano-1H-pyrazole-3-yl)(tert-butoxycarbonyl)carbamate

[0476] 8.46 g of tert-butyl(tert-butoxycarbonyl)(4-cyano-1-(2-(difluoromethyl)-6-methyl-4-nitrophenyl)-1H-pyrazole-3-yl)carbamate was dissolved in 61 mL of THF and 56 mL of MeOH in a heated water bath (ca. 70°C). Then, 5.64 g of 1% Pt / C, STAF-1M (wetted with water) was gradually added to the mixture, and the entire mixture was hydrogenated at room temperature under balloon pressure for 3.5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.96 g). MS: [MH] - 462.2.

[0477] E) tert-butyl (tert-butoxycarbonyl)(4-cyano-1-(2-(difluoromethyl)-4-iodo-6-methylphenyl)-1H-pyrazole-3-yl)carbamate

[0478] n-amyl nitrite (3.51 mL) was added at 0°C to a mixture of tert-butyl (1-(4-amino-2-(difluoromethyl)-6-methylphenyl)-4-cyano-1H-pyrazole-3-yl)(tert-butoxycarbonyl)carbamate (7.96 g) in anhydrous CH3CN (70 mL), followed by the addition of copper(I) iodide (4.91 g) and diiodomethane (6.93 mL). After removing the ice bath, the system was filled with N2 and the mixture was stirred for 10 minutes. The mixture was then stirred under N2 at 58-63°C for 2 hours. The mixture was quenched at 0°C with saturated aqueous NH4Cl and diluted with ELISA. Insoluble matter was filtered off, the organic layer was separated, washed with water and brine, and dried over MgSO4. Silica gel was then added to the mixture, and the whole was concentrated under reduced pressure. The crude mixture supported on a silica gel was purified by silica gel column chromatography (siRNA / hexane) and concentrated. The residue was washed with IPE, collected, and dried under vacuum to obtain the title compound (7.23 g). MS: [M+Na] + 597.1.

[0479] F) tert-butyl (tert-butoxycarbonyl)(4-cyano-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-3-yl)carbamate

[0480] 0.564 mL of 3M K3PO4 aqueous solution was added at room temperature to a mixture of tert-butyl (tert-butoxycarbonyl)(4-cyano-1-(2-(difluoromethyl)-4-iodo-6-methylphenyl)-1H-pyrazole-3-yl)carbamate (243 mg), cyclopropylboronic acid (109 mg), and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) (19.30 mg) in toluene (2.0 mL), DME (2.0 mL), and water (0.2 mL). The mixture was stirred at 100°C for 1 hour under N2. The mixture was partitioned into ELISA and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ELISA / hexane) to obtain the title compound (200 mg). MS: [M+Na] + 511.2.

[0481] G) tert-butyl (4-carbamoyl-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-3-yl)carbamate

[0482] 35% H2O2 water (18.47 mL) was added dropwise to a mixture of tert-butyl (tert-butoxycarbonyl)(4-cyano-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-3-yl)carbamate (6.44 g) and K2CO3 (7.29 g) in DMSO (55 mL) while maintaining the reaction temperature in a water bath. An additional DMSO (35 mL) was then added. The mixture was stirred at room temperature for 90 minutes. Water was added to the mixture, the resulting precipitate was collected, dissolved in THF, and concentrated under reduced pressure to obtain the title compound. This product was used in the next reaction without further purification. MS: [MH] - 405.1.

[0483] H) 3-amino-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-4-carboxamide

[0484] A 6M aqueous solution (30 mL) of tert-butyl (4-carbamoyl-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-3-yl)carbamate (5.36 g) was added at room temperature to a suspension in CH3CN (60 mL). The mixture was stirred at 40°C for 1.5 hours, then neutralized with an 8M aqueous solution of NaOH (23 mL) at 0°C. The mixture was partitioned into toluene and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized from THF / IPE to obtain the title compound (3.49 g). MS: [M+H] + 307.0.

[0485] I) 2-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-6-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

[0486] 600 mg of 3-amino-1-(4-cyclopropyl-2-(difluoromethyl)-6-methylphenyl)-1H-pyrazole-4-carboxamide was dissolved in 11 mL of THF, to which 0.546 mL of 2-methoxyacetyl chloride was added at room temperature. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. 769 mg of potassium tert-butoxide was added to the solution of the above-obtained residue in 23 mL of t-BuOH at room temperature. The mixture was stirred at 90°C for 2 hours under N2. The mixture was quenched with water at room temperature and extracted with siRNA. The organic layer was separated, washed with saturated aqueous NH4Cl and brine, and dried over Na2SO4. The first aqueous phase was acidified with 1 M aqueous HCl and extracted with siRNA. The organic layer was separated, washed with brine, and dried over Na2SO4. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (siRNA / hexane) and concentrated to obtain the title compound (595 mg). The product (595 mg) was dissolved in siRNA (45 mL) at 70°C (oil bath temp.). When heptane (55 mL) was added dropwise to the mixture at 70°C (oil bath temp.), a white precipitate was formed. After stirring at the same temperature under N2 for 1 hour, the mixture was cooled to room temperature, stirred overnight under N2, and then stirred at 0°C for 20 minutes. The resulting precipitate was collected, washed with cold siRNA / heptane (v / v = 1 / 1), and dried under vacuum with heating to obtain the title compound (489 mg). The product (489 mg) was dissolved in siRNA (40 mL) at 70°C (oil bath temp.). When heptane (40 mL) was added dropwise to the mixture at 70°C (oil bath temp.), a white precipitate was formed. The mixture was stirred at the same temperature for 1 hour under N2, then cooled to room temperature, stirred overnight under N2, and then stirred at 0°C for 20 minutes. The resulting precipitate was collected, washed with cold dimethylheptane (v / v = 1 / 1), and dried under vacuum with heating to obtain the title compound (433 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.78-0.85 (2H, m), 1.03-1.10 (2H, m), 1.97 (3H, s), 2.06-2.15 (1H, m), 3.38 (3H, s), 4.32 (2H, s), 6.40-6.72 (1H, m), 7.32 (1H, s), 7.35 (1H, s), 8.76 (1H, s), 11.79 (1H, s).

[0487] The example compounds are shown in Tables 5-1 to 5-30. MS in the tables refers to measured values. The compounds in Examples 1-326 in the following tables were prepared according to the methods described in the above examples, or similar methods.

[0488] [Table 5-1]

[0489] [Table 5-2]

[0490] [Table 5-3]

[0491] [Table 5-4]

[0492] [Table 5-5]

[0493] [Table 5-6]

[0494] [Table 5-7]

[0495] Table 5-8

[0496] Table 5-9

[0497] Table 5-10

[0498] Table 5-11

[0499] Table 5-12

[0500] Table 5-13

[0501] Table 5-14

[0502] Table 5-15

[0503] Table 5-16

[0504] Table 5-17

[0505] Table 5-18

[0506] Table 5-19

[0507] Table 5-20

[0508] Table 5-21

[0509] Table 5-22

[0510] Table 5-23

[0511] Table 5-24

[0512] Table 5-25

[0513] Table 5-26

[0514] Table 5-27

[0515] [Table 5-28]

[0516] [Table 5-29]

[0517] [Table 5-30]

[0518] biological activity

[0519] The biological activity of the compound of Equation 1 in relation to NLRP3 was determined using the following in vitro method.

[0520] IL-1β TR-FRET assay (inhibition rates reported at 300 nM, 6 μM, or 10 μM)

[0521] Monocyte THP-1 cells (ATCC:TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the donor's instructions. RPMI was supplemented with 10% heat-inactivated fetal bovine serum (Corning catalog number 35-010-CV). Cells were differentiated into macrophages by adding 25 ng / mL of IFN-γ (PeproTech, catalog number AF-300-02-100UG) for 24 hours at 37°C / 5% CO2. The medium was replaced with fresh medium without FBS, and the cells were treated with 50 ng / mL of LPS (priming step) (LPS-EK:Invivogen, catalog number tlrl-peklps). Cells were seeded at a rate of 20,000 cells per well in a 384-well flat-bottom cell culture plate (FALCON, catalog no. 353962) and incubated at 37°C / 5%CO2 for 24 hours. The compound was serially diluted with DMSO (half log or 5-fold dilution), and finally diluted in FBS-free medium. The compound was added to the cells in the 384-well plate (at a 1:3 ratio), and the plate was 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 with a plate shaker for 1 minute. The supernatant was mixed with HTRF antibody (human IL1β kit, Cisbio, 62HIL1BPEH) in an assay plate (Greiner Bio-One, catalog number 784075), and the assay plate was incubated in a shading box at room temperature for 16-24 hours. The HTRF signal was measured using EnVision (Perkinelmer) according to the manufacturer's instructions.

[0522] TNF-α assay (IC) 50 (Reported as)

[0523] Monocyte THP-1 cells (ATCC:TIB-202) were maintained in RPMI medium (Life Technologies, catalog number A10491-01) according to the donor'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 of IFN-γ for 24 hours at 37°C / 5%CO2. The medium was replaced with fresh medium without FBS. Cells were seeded at a rate of 40,000 cells per well in a 384-well flat-bottom cell culture plate (Costar 3764) containing the compound (added at a ratio of 1:1000) in a serial dilution series of 1:3.16 in DMSO, and incubated at 37°C / 5%CO2 for 30 minutes. The NF-κB pathway was activated by adding 600 ng / mL of LPS, and cells were incubated for 3 hours at 37°C / 5% CO2. At the end of the incubation period, the supernatant (40 μL) was removed, and TNF-α was monitored using ELISA (Human TNF-α ELISA, R&D Systems, catalog number DY201) according to the manufacturer's instructions. 100% inhibition was determined using the positive control TPCA-1.

[0524] Data Interpretation The inhibition rates at 300 nM, 6 μM, or 10 μM in the IL-1β TR-FRET assay were calculated using the following formula: Inhibition rate (%) = [1 - (HTRF signal test -HTRF signal Low ) / (HTRF signal High -HTRF signal Low )] × 100. Here, the HTRF signal test This is the HTRF signal of the well to which the test compound was added. Low This is the HTRF signal of a well doped with 3 μM MCC-950. High This is the HTRF signal from the well to which DMSO was added.

[0525] IC of TNF-α assay 50 The value is Y = [bottom + (top - bottom)] / (1 + 10 ∧ [(Log IC 50 The percentage of inhibition relative to the inhibitor concentration was calculated from a plot of the percentage of inhibition relative to the inhibitor concentration by fitting a logistic curve according to the formula [-X)·Hill Slope] (wherein Y is the percentage inhibition at inhibitor concentration X, the "bottom" is the lowest inhibition value, i.e., 0%, the "peak" is the maximum inhibition value, i.e., 100%, and the "Hill Slope" represents the slope of the sigmoid curve between the "bottom" value and the "peak" value). Curve fitting was performed using internally developed software.

[0526] Table 6 lists the in vitro biological assay data (IL-1β and TNF-α assays) for the compounds shown in the examples. These assays are described in the section titled "Biological Activity" above.

[0527] [Table 6-1]

[0528] [Table 6-2]

[0529] [Table 6-3]

[0530] [Table 6-4]

[0531] [Table 6-5]

[0532] [Table 6-6]

[0533] [Table 6-7]

[0534] These results demonstrate that the compounds of the present invention suppress IL-1β production. It was also confirmed that the compounds are more selective to IL-1β than to TNF-α. These findings indicate that the compounds inhibit the targeted NLRP3 inflammasome activation pathway with little to no interference to the NF-κB-dependent priming pathway. Given the diversity of pro-inflammatory factors, often with opposing functions, specific inhibition of the NLRP3 inflammasome pathway is necessary to achieve the most desired outcomes without disrupting tissue repair processes.

[0535] The following in vitro assay can be used to evaluate the ability of the compound of Formula 1 to reach the central nervous system (CNS) across the blood-brain barrier.

[0536] Multidrug resistance protein 1 (MDR1) substrate screening assay

[0537] Method 1

[0538] Human MDR1-expressing Madeine-Darby Canine Kidney (MDCK) cells were cultured, and a transcellular transport test was performed. The cells were placed in a Transwell 96-well permeable support with a polycarbonate membrane (Corning Life Sciences, Lowell, MA) (pore size 0.4 μm, surface area 0.143 cm²). 2Cells were cultured in ). Cells were pretreated with Hanks' Balanced Salt Solution (HBSS) at 37°C for 10 minutes. Then, transcellular transport was initiated by adding HBSS containing 1 or 10 μmol / L of each test compound to the apical compartment (75 μL) or the bay-lateral compartment (250 μL). The assay was terminated by separating each assay plate after 1 hour. Aliquots (25 μL) from the opposite compartment were mixed with acetonitrile. After centrifugation, the compound concentration in the supernatant was measured by LC-MS / MS and a Unison UK-C18HT column (3.0 μm, 2.0 × 2 mm). The apparent permeability (Papp) in the recipient well was determined, and the Papp and efflux ratio (ER) for the membrane permeability test were calculated from a two-point standard curve (concentrations corresponding to 10 and 100 nm / sec) using the following formula: Papp = (y-intercept of RR,STD100 and R,STD10) / (slope of R,STD100 and R,STD10) Here, R is the ratio of the peak area of ​​the test compound to the peak area of ​​the internal standard, and R,STD10 and R,STD100 are the ratios of the peak areas of the standard samples corresponding to 10 and 100 nm / sec, respectively, to the peak area of ​​the internal standard. ER=Papp,BtoA / Papp,AtoB Here, Papp,AtoB and Papp,BtoA represent the apparent transmittance from the apical to the basal direction and from the basal to the apical direction, respectively.

[0539] Method 2

[0540] 1.Cell culture

[0541] MDR1-MDCK I cells were seeded at 2.5 × 10⁵ cells / mL onto polyethylene membrane (PET) in a 96-well Corning insert system and cultured for 4–7 days to form a confluent cell monolayer.

[0542] 2. Experimental Procedure

[0543] For the control compound, the transport buffer used in this study was HBSS containing 10.0 mM HEPES at pH 7.40 ± 0.05. For the test compound, the transport buffer used in this study was HBSS containing 10.0 mM HEPES and 1% BSA at pH 7.40 ± 0.05. The test compounds were tested bidirectionally and overlappingly at 1.00 μM. Digoxin was tested bidirectionally and overlappingly at 10.0 μM, while nadolol and metoprolol were tested bidirectionally and overlappingly at 2.00 μM from direction A to direction B. The final DMSO concentration was adjusted to less than 1%. The plates were incubated in a CO2 incubator at 37 ± 1°C, 5% CO2, and saturated humidity for 1 hour without shaking. All samples, after mixing with acetonitrile containing the internal standard, were centrifuged at 3220 × g for 10 minutes. For all samples, 150 μL of supernatant was diluted with 150 μL of ultrapure water and subjected to LC-MS / MS analysis. Furthermore, the efflux ratio of each compound was determined. Test compounds and reference compounds were quantified by LC-MS / MS analysis based on the analyte / IS peak area ratio. Following the transport assay, the integrity of the cell monolayer was assessed using a Lucifer yellow exclusion assay. Buffer was removed from both the apical and bay-solar chambers. 75 μL of transport buffer containing 100 μM Lucifer yellow was added to the apical chamber, and 250 μL of transport buffer was added to the bay-solar chamber. The plates were incubated at 37°C, 5% CO2, and 95% relative humidity for 30 minutes without shaking. After 30 minutes of incubation, a 20 μL Lucifer yellow sample was taken from the apical side, followed by the addition of 60 μL of Transport Buffer. Subsequently, an 80 μL Lucifer yellow sample was taken from the bay-solar side. The relative fluorescence units (RFU) of Lucifer yellow were measured at 425 / 528 nm (excitation / fluorescence) using a microplate reader.

[0544] 3. Data Analysis

[0545] The apparent transmittance coefficient Papp (cm / s) was calculated using the following formula: Papp = (dCr / dt) × Vr / (A × C0) Here, dCr / dt is the cumulative concentration of the compound in the receptor chamber as a function of time (μM / s); Vr is the volume of solution in the receptor chamber (0.075 mL on the apical side, 0.25 mL on the nasolateral side); and A is the surface area for transport, i.e., the area of ​​the single layer, 0.0804 cm². 2 C0 is the initial concentration (μM) in the donor chamber. The efflux ratio was calculated using the following formula: Emission ratio=Papp(BA) / Papp(AB) The recovery rate was calculated using the following formula: Solution recovery rate % = 100 × [(Vr × Cr) + (Vd × Cd)] / (Vd × C0) Here, Vd is the volume of the donor chamber (0.075 mL on the apical side, 0.25 mL on the bay-lateral side); Cd and Cr are the final concentrations of the transport compound in the donor and recipient chambers, respectively. The percentage of Lucifer yellow in the bay lateral well was calculated using the following formula:

number

[0546] Breast cancer resistance protein (BCRP) substrate screening assay

[0547] Human BCRP-expressing MDCKII cells were cultured, and a cell-to-cell transport test was performed. The cells were placed in a Transwell 96-well permeable support with a polycarbonate membrane (Corning Life Sciences, Lowell, MA) (pore size 0.4 μm, surface area 0.143 cm²). 2 Cells were cultured in ). Cells were pretreated with M199 at 37°C for 10 minutes. Then, transcellular transport was initiated by adding M199 containing 1 μmol / L of each test compound to the apical compartment (75 μL) or the bay-solar compartment (250 μL). The assay was terminated by separating each assay plate after 1 hour. Aliquots (25 μL) from the opposite compartment were mixed with acetonitrile. After centrifugation, the compound concentrations in the supernatant were measured by LC-MS / MS and Unison UK-C18 HT column (3.0 μm, 2.0 × 20 mm). The apparent permeability (Papp) in the recipient well was determined, and the Papp and efflux ratio (ER) for the membrane permeability test were calculated from a two-point standard curve (concentrations corresponding to 10 and 100 nm / sec) using the following formula: Papp = (y-intercept of RR,STD100 and R,STD10) / (slope of R,STD100 and R,STD10) Here, R is the ratio of the peak area of ​​the test compound to the peak area of ​​the internal standard, and R,STD10 and R,STD100 are the ratios of the peak areas of the standard samples corresponding to 10 and 100 nm / sec, respectively, to the peak area of ​​the internal standard. ER=Papp,BtoA / Papp,AtoB Here, Papp,AtoB and Papp,BtoA represent the apparent transmittance from the apical to the basal direction and from the basal to the apical direction, respectively.

[0548] Formulation Example 1 (Capsule Manufacturing) 1) Compound from Example 1: 30 mg 2) Crystalline cellulose 10 mg 3) Lactose 19mg 4) Magnesium stearate 1 mg Total 60mg Mix 1), 2), 3), and 4) and fill into gelatin capsules.

[0549] Formulation Example 2 (Tablet Manufacturing) 1) Compound from Example 1, 30g 2) Lactose 50g 3) Cornstarch 15g 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1g Total 1000 tablets, 140g The total amounts 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.

[0550] As used herein and in the appended claims, singular articles such as "a," "an," and "the" can refer to a single object or to multiple objects, unless the context clearly indicates otherwise. For example, "compound (a References to compositions containing "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 determined by reference to the appended claims and includes the entire scope equivalent to such claims. All disclosures of papers and references cited herein, including patents, patent applications and publications, are incorporated herein by reference in their entirety for all purposes.

Claims

1. Compounds of formula (I), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, L is either O or a bond; X is N or CR 4 and; Y is N or CR 5 and; R 1 C may be substituted 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered heterocyclic group, wherein when L is bonded, the 4- to 6-membered heterocyclic group is a 4- to 6-membered non-aromatic heterocyclic group bonded to the pyrazolopyrimidone ring by a carbon-carbon bond; R 2 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 3-8 cycloalkyl group; R 3 C is a hydrogen atom, which may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 It is a cycloalkyl group or a halogen atom; and R 4 , R 5 , R 6 , R 7 and R 8 These are, independently, a hydrogen atom and a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, hydroxyl group, possibly substituted C 1-6 The group is an alkoxy group, or a substituted 5- or 6-membered heterocyclic group, a cyano group, an amino group, or a nitro group; However, this excludes (1) 2,5-dihydro-6-methyl-5-(1-methylethyl)-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, (2) 5-ethyl-2,5-dihydro-6-methyl-2-(3-pyridinyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one, and (3) 5-ethyl-2,5-dihydro-2-(3-pyridinyl)-6-(trifluoromethyl)-4H-pyrazolo[3,4-d]pyrimidine-4-one.

2. L is either O or a bond; X is N or CR 4 and; Y is N or CR 5 and; R 1 but, (1)(a) Halogen atom, (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy group, (d) G-C 1-6 Alkylamino group, (e) C 7-16 Aralkyloxy group, (f) A 5- or 6-membered aromatic heterocyclic group, (g) 5- or 6-membered non-aromatic heterocyclic group, (h) Carboxy group, (i) 4- to 6-membered non-aromatic heterocyclyloxy groups, and (j) cyano group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2)(a) C 1-6 alkyl group, (b) C 1-6 Alkoxy group, (c) Halogen atom, (d) cyano group, and (e) Formula: -(CH 2 ) a -O-(CH 2 ) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups, (3)(a) Halogen atoms, and (b) C 1-6 Alkoxy group C may be substituted with one to three substituents selected from the following. 6-14 Aryl group, (4)(a) Halogen atom, (b)(i) Halogen atoms and (ii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups. 1-6 alkyl group, (c) C 1-6 Alkoxy groups, and (d) Together with the 5- or 6-membered aromatic heterocyclic group to which they are bonded, they form an 8- to 10-membered condensed heterocyclic group, formula: -(CH 2 ) a -O-(CH 2 ) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) A 5- or 6-membered aromatic heterocyclic group which may be substituted with one to three substituents selected from, or (5)(a) Oxo group, (b) C 1-6 alkyl group, (c) Halogen atoms, and (d) C 1-6 Alkoxy group A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following: and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 3 but, (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2)(i) Halogen atom, (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy group C may be substituted with one to four substituents selected from the following. 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atom, (5) Hydroxyl group, (6) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group, (7) A 5- or 6-membered aromatic heterocyclic group, (8) Cyano group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) Halogen atoms, or (4) C 3-8 Cycloalkyl groups and R 6 but, (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) C 2-6 Alkenyl group, (5) Halogen atom, (6) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group, (7) A 5- or 6-membered aromatic heterocyclic group, (8) an amino group, or (9) Nitro group The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. L is either O or a bond; X, CR 4 and; Y, CR 5 and; R 1 However, C may be halogenated. 1-6 C may be substituted with an alkoxy group. 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, they each act independently (1) C which may be substituted with one to three halogen atoms 1-6 Alkyl alkyl group, or (2) Halogen atom and; R 5 and R 7 However, both are hydrogen atoms; and R 6 but, (1) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (2) Halogen atoms, or (3) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. L is O; X is N or CR 4 and; Y is N or CR 5 and; R 1 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered heterocyclic group; R 2 However, a hydrogen atom, or a substituted C 1-6 It is an alkyl group; R 3 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or a halogen atom; R 4 and R 8 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 An alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, or a cyano group; R 5 and R 7 each independently is a hydrogen atom, an optionally substituted C 1-6 alkyl group, or a halogen atom; and R 6 However, hydrogen atoms may be substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 An alkoxy group, or a substituted 5- or 6-membered heterocyclic group, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. L is O; X is N or CR 4 and; Y is N or CR 5 and; R 1 but, (1)(a) Halogen atom, (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy group, (d) G-C 1-6 Alkylamino group, and (e) C 7-16 Aralkyloxy group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2)(a) C 1-6 Alkoxy group, (b) cyano group, and (c) Formula: -(CH 2 ) a -O-(CH 2 ) b - A base represented by the formula (where a and b are integers from 0 to 3, and the sum of a and b is from 2 to 4) C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups, (3) C 6-14 Aryl group, or (4) 4- to 6-membered non-aromatic heterocyclic groups and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 3 but, (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2)(i) Halogen atom, (ii) Hydroxyl group, and (iii) C 1-6 Alkoxy group C may be substituted with one to four substituents selected from the following. 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atom, (5) Hydroxyl group, (6) C 1-6 Alkoxy group, (7) A 5- or 6-membered aromatic heterocyclic group, (8) Cyano group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C 1-6 Alkyl alkyl group, or (3) Halogen atoms and R 6 but, (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) C 2-6 Alkenyl group, (5) Halogen atom, (6) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group, or (7) 5- or 6-membered aromatic heterocyclic groups That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. L is O; X, CR 4 and; Y, CR 5 and; R 1 However, 1 to 3 C 1-6 C may be substituted with an alkoxy group. 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, they each act independently (1) C which may be substituted with one to three halogen atoms 1-6 Alkyl alkyl group, or (2) Halogen atom and; R 5 and R 7 However, both are hydrogen atoms; and R 6 but, (1) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (2) Halogen atoms, or (3) C which may be substituted with one to three halogen atoms 1-6 Alkoxy group That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. L is O; X, CR 4 and; Y, CR 5 and; R 1 However, C 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both are C 1-6 It is an alkyl group; R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 It is a cycloalkyl group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. L is a combination; X is N or CR 4 and; Y is N or CR 5 and; R 1 However, C may be substituted. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 6-14 An aryl group, or a substituted 4- to 6-membered non-aromatic heterocyclic group; R 2 However, a hydrogen atom, or a substituted C 1-6 It is an alkyl group; R 3 However, hydrogen atoms may be substituted C 1-6 It is an alkyl group or halogen atom; R 4 and R 8 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, halogen atoms, hydroxyl groups, and optionally substituted C 1-6 An alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, or a cyano group; R 5 and R 7 However, each of them can be independently a hydrogen atom or a substituted C atom. 1-6 Alkyl alkyl groups, halogen atoms, or optionally substituted C 3-8 It is a cycloalkyl group; and R 6 However, hydrogen atoms may be substituted C 1-6 Alkyl alkyl groups, or substituted C 3-8 Cycloalkyl groups, may be substituted C 2-6 Alkenyl group, halogen atom, possibly substituted C 1-6 The group is an alkoxy group, a substituted or otherwise substituted 5- or 6-membered heterocyclic group, an amino group, or a nitro group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. L is a combination; X, CR 4 and; Y, CR 5 and; R 1 but, (1)(a) Halogen atom, (b) Hydroxyl group, (c) C may be halogenated 1-6 Alkoxy group, (d) C 7-16 Aralkyloxy group, (e) A 5- or 6-membered aromatic heterocyclic group, (f) A 5- or 6-membered non-aromatic heterocyclic group, (g) Carboxy group, (h) 4- to 6-membered non-aromatic heterocyclyloxy groups, and (i) cyano group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2)(a) C 1-6 alkyl group, (b) C 1-6 Alkoxy group, (c) Halogen atoms, and (d) cyano group C may be substituted with one to three substituents selected from the following. 3-8 Cycloalkyl groups, (3)(a) Halogen atoms, and (b) C 1-6 Alkoxy group C may be substituted with one to three substituents selected from the following. 6-14 Aryl group, or (4)(a) Oxo group, (b) C 1-6 alkyl group, (c) Halogen atoms, and (d) C 1-6 Alkoxy group A 4- to 6-membered non-aromatic heterocyclic group which may be substituted with one to three substituents selected from the following: and; R 2 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 3 but, (1) A hydrogen atom, or (2) C 1-6 alkyl group and; R 4 and R 8 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with 1 to 4 halogen atoms 1-6 alkyl group, (3) Halogen atoms, (4) Hydroxyl group, or (5) C 1-6 Alkoxy group and; R 5 and R 7 However, they each act independently (1) Hydrogen atom, (2) C which may be substituted with one to three halogen atoms 1-6 alkyl group, (3) Halogen atoms, or (4) C 3-8 Cycloalkyl groups and R 6 but, (1) Hydrogen atom, (2) C 1-6 alkyl group (3) C which may be substituted with one to three halogen atoms 3-8 Cycloalkyl groups, (4) Halogen atom, (5) an amino group, or (6) Nitro group That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. L is a combination; X, CR 4 and; Y, CR 5 and; R 1 However, C may be halogenated. 1-6 C may be substituted with an alkoxy group. 1-6 It is an alkyl group; R 2 However, it is a hydrogen atom; R 3 However, it is a hydrogen atom; R 4 and R 8 However, both C atoms may be substituted with one to three halogen atoms. 1-6 It is an alkyl group; R 5 and R 7 However, both are hydrogen atoms; and R 6 However, C 3-8 It is a cycloalkyl group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The compound: 2-(4-bromo-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2-fluoro-6-methylphenyl)-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[2-bromo-4-(difluoromethoxy)-6-methylphenyl]-6-ethoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[4-cyclopropyl-2-(difluoromethyl)-6-fluorophenyl]-6-(2-methoxyethoxy)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-[(difluoromethoxy)methyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; 2-[4-(1-fluorocyclopropyl)-2,6-dimethylphenyl]-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one; and 2-[4-Cyclopropyl-2-(difluoromethyl)-6-methylphenyl]-6-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

12. A method for treating a disease, disorder, or condition in a subject, comprising administering an effective amount of the compound or pharmaceutically acceptable salt defined in claim 1 to the subject, wherein the disease, disorder, or condition is related to NLRP3.

13. A method for treating a disease, disorder, or condition in a subject, comprising administering an effective amount of the compound or pharmaceutically acceptable salt defined in claim 1 to the subject, wherein the disease, disorder, or condition is associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

14. A method for treating cryopyrin-associated periodic syndromes (CAPS) in a subject, comprising administering an effective amount of the compound or pharmaceutically acceptable salt defined in claim 1 to the subject.

15. The method according to claim 14, wherein the cryopyrin-associated periodic syndrome is selected from the group consisting of neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

16. A method for treating a neurodegenerative disease, disorder, or condition in a subject, comprising administering an effective amount of the compound or pharmaceutically acceptable salt defined in claim 1 to the subject.

17. A method for treating Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or prion disease in a subject, comprising administering an effective amount of the compound or pharmaceutically acceptable salt defined in claim 1 to the subject.

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

19. The pharmaceutical agent according to claim 18, which is a treatment agent for diseases, disorders, or conditions associated with NLRP3.

20. The pharmaceutical agent according to claim 18, which is a treatment agent for diseases, disorders, or conditions associated with heterozygous gain-of-function mutations in the NLRP3 gene.

21. The pharmaceutical agent according to claim 18, which is a therapeutic agent for cryopyrin-associated periodic syndromes (CAPS).

22. The pharmaceutical product according to claim 21, wherein the cryopyrin-associated periodic syndrome is selected from neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

23. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NLRP3.

24. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for the treatment of a disease, disorder or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

25. Use of the compound defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cryopyrin-associated periodic syndromes (CAPS).

26. The use according to claim 25, wherein the cryopyrin-associated periodic syndrome is selected from neonatal multisystem inflammatory disease (NOMID / CINCA), Macklewells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS).

27. A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases, disorders, or conditions associated with NLRP3.

28. A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition associated with a heterozygous gain-of-function mutation in the NLRP3 gene.

29. A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of cryopyrin-associated periodic syndromes (CAPS).

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

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