Substituted pyrazolopyrimidine compound and pharmaceutical use thereof

Abstract

To provide: a substituted pyrazolopyrimidine compound having an inhibitory activity on NLRP3 inflammasomes or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing the same; a pharmaceutical use thereof, etc.SOLUTION: The present invention provides a compound of formula [I] or a pharmaceutically acceptable salt thereof (in the formula, each symbol is as defined in the specification).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a substituted pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and medical uses thereof, etc. [Background technology]

[0002] NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is a pattern recognition receptor belonging to the NLR (NOD-like receptors) family and is expressed not only in phagocytes such as macrophages and microglia but also in non-immune cells such as glomerular epithelial cells and renal tubular epithelial cells.

[0003] NLRP3 recognizes DAMPs (Danger Associated Molecular Patterns), which are molecular patterns specific to cytotoxic factors (ATP, HMGB1, S100, uric acid crystals, silica, etc.), and PAMPs (Pathogen Associated Molecular Patterns), which are molecular patterns specific to pathogenic microorganisms (viruses, bacteria, fungi, etc.), and is activated by binding to these molecules.

[0004] Activated NLRP3 associates with the adaptor protein ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine ​​protease caspase 1 through protein-protein interactions to form the intracellular protein complex NLRP3 inflammasome. Upon formation of the NLRP3 inflammasome, caspase 1 in the complex is converted to an active form, which converts proIL-1β, the precursor of the proinflammatory cytokine IL-1β, into active IL-1β, and proIL-18, the precursor of IL-18, into active IL-18. Activated IL-1β secreted outside the cell induces inflammatory responses through the induction of inflammatory cytokines and chemokines by surrounding cells and the activation of immune cells such as T cells.

[0005] In the brain and cerebrospinal fluid of multiple sclerosis patients, an increase in the amount of DAMPs (Non-Patent Document 1), the expression level of caspase 1 in the lesions, and the amount of IL-1β in the cerebrospinal fluid were observed (Non-Patent Document 2). In addition, activated microglia are present in the lesions of the chronic progression stage of this disease (Non-Patent Document 3), and activated microglia stimulated by DAMPs produce inflammatory cytokines such as IL-1β to induce neuroinflammation and neurological disorders (Non-Patent Document 4). Therefore, it is thought that the NLRP3 inflammasome is involved in the pathological expression of multiple sclerosis.

[0006] Myelin Oligodendrocyte Glycoprotein (MOG) 35-55 EAE model mice develop motor dysfunction similar to that of multiple sclerosis. However, NLRP3 knockout mice show no evidence of MOG 35-55In EAE models, the onset of motor dysfunction is suppressed (Non-Patent Document 5). In addition, in cuprizone model mice created by administering the copper chelating compound cuprizone to mice, central nervous system demyelination similar to multiple sclerosis occurs, but the progression of demyelination is delayed in NLRP3 knockout mice in the cuprizone model (Non-Patent Document 6). JC-171, an NLPR3 inflammasome inhibitor, inhibits MOG 35-55 In an EAE model, administration after onset of the disease suppressed motor dysfunction (Non-Patent Document 7). Therefore, NLRP3 inflammasome inhibitors are considered to be a therapeutic agent for multiple sclerosis.

[0007] Increased expression of NLRP3 inflammasome-related genes has been reported in the kidneys of patients with chronic kidney disease (Non-Patent Documents 8 and 9). Furthermore, in a 5 / 6 nephrectomy model, a non-clinical chronic kidney disease model, the inhibitory effect of NLRP3 knockout on proteinuria and tubulointerstitial fibrosis has been reported (Non-Patent Document 10). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for chronic kidney disease.

[0008] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the intestines of patients with inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease) (Non-Patent Document 11). It has been reported that IL-1β produced by activation of NLRP3 is increased in the intestinal mucosa of IBD patients, and that increased IL-1β secretion from the colonic region is positively correlated with worsening of the pathology (Non-Patent Document 11). It has also been reported that insufficiency of CARD8, which negatively controls inflammasome activity, increases susceptibility to Crohn's disease, and that activation of NLRP3 inflammasome enhances IL-1β production from monocytes (Non-Patent Document 12). It has been reported that NLRP3 deficiency suppresses intestinal pathology in the TNBS-induced colitis model, which is a colitis model (Non-Patent Document 13). From the above results, it is believed that NLRP3 inflammasome inhibitors will be therapeutic agents for inflammatory bowel disease.

[0009] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the atherosclerotic sites of the coronary arteries of patients with myocardial infarction (Non-Patent Document 14). In addition, it has been reported that NLRP3 knockout suppresses the formation of lesions in high-fat diet-fed low-density lipoprotein receptor (LDL) receptor-deficient mice, which are an atherosclerosis model (Non-Patent Document 15). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as therapeutic agents for atherosclerosis.

[0010] Cryopyrin-associated periodic syndrome (CAPS) is a general term for autoinflammatory diseases caused by activating mutations in the NLRP3 gene, and is classified into three disease types: mild familial cold autoinflammatory syndrome (FCAS), moderate Muckle-Wells syndrome (MWS), and severe chronic infantile neurologic cutaneous, and articular syndrome (CINCA) or neonatal onset multisystem inflammatory disease (NOMID) (Non-Patent Document 16). More than 200 mutations in the NLRP3 gene have been reported in CAPS (Non-Patent Document 17). These NLRP3 gene mutations cause the formation and activation of the NLRP3 inflammasome even in the absence of activating signals. Mice expressing CAPS-associated NLRP3 mutations exhibit systemic lethal inflammation dependent on the NLRP3 inflammasome and downstream signaling molecules IL-1β and IL-18 (Non-Patent Document 18). In mice expressing CAPS-associated NLRP3 mutations, the NLRP3 inflammasome inhibitor CY-09 suppressed systemic lethal inflammation and improved survival rates (Non-Patent Document 19). Based on these results, NLRP3 inflammasome inhibitors are considered to be a therapeutic agent for CAPS.

[0011] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the liver tissue of patients with nonalcoholic steatohepatitis (NASH) (Non-Patent Document 20). In addition, it has been reported that NLRP3 knockout has an inhibitory effect on liver fibrosis in a choline-deficient amino acid replacement diet loading model, which is a NASH model (Non-Patent Document 20). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for NASH.

[0012] In gout and gouty arthritis, uric acid crystals deposited in joints and periarticular tissues induce inflammation (Non-Patent Document 21). Uric acid crystals activate NLRP3 in macrophages to produce IL-1β and IL-18 (Non-Patent Document 22). In an arthritis model involving intra-articular uric acid injection, the NLRP3 inflammasome inhibitor OLT1177 suppressed arthritis (Non-Patent Document 23). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for gout and gouty arthritis.

[0013] Increased expression of NLRP3 inflammasome-related genes has been reported in the synovium and peripheral blood mononuclear cells of patients with rheumatoid arthritis (Non-Patent Document 24). In addition, increased expression of NLRP3 inflammasome-related genes in synovium has been reported in collagen-induced arthritis, a model of rheumatoid arthritis (Non-Patent Document 25). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as therapeutic agents for rheumatoid arthritis.

[0014] It has been reported that trinitrochlorobenzene, which induces contact dermatitis, increases IL-1β production from human skin keratinocytes via NLRP3 activation, and that NLRP3 knockout suppresses the onset of dermatitis in a trinitrochlorobenzene-induced contact dermatitis model (Non-Patent Document 26). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as therapeutic agents for contact dermatitis.

[0015] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the tears and ocular surface of dry eye patients (Non-Patent Documents 27, 28). In addition, when cultured human corneal epithelial cells are subjected to hyperosmotic stress to induce a dry eye condition, it has been reported that the expression of NLRP3 inflammasome-related genes and IL-1β production are increased, and that IL-1β production is suppressed by knocking down the NLRP3 gene (Non-Patent Document 28). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as a treatment for dry eye.

[0016] It has been reported that the expression of the ASC domain of the NLRP3 inflammasome is increased in macrophages and neutrophils infiltrating into the myocardial tissue of patients with acute myocardial infarction (Non-Patent Document 29). In addition, it has been reported that in an ischemia-reperfusion model, which is a myocardial infarction model, the expression of NLRP3 inflammasome-related genes is increased in the infarcted area, and knockdown of the NLRP3 gene reduces the infarct area and suppresses the decrease in myocardial contractility (Non-Patent Document 30). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as therapeutic agents for ischemic heart diseases such as acute myocardial infarction.

[0017] It has been reported that the expression of IL-1β or IL-18 is increased in the serum and glomeruli of patients with systemic lupus erythematosus (SLE) (Non-Patent Documents 31 and 32), and that the expression of the NLRP3 gene and the production of IL-1β are increased in macrophages (Non-Patent Document 33). In addition, in Nlrp3-R258W mice with an activating mutation in the NLRP3 gene, the lupus nephritis-like symptoms expressed by administration of pristane are exacerbated (Non-Patent Document 34). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as therapeutic agents for SLE.

[0018] In addition to the above diseases, diseases for which NLRP3 inflammasome inhibitors are expected to be effective include systemic juvenile idiopathic arthritis (Non-Patent Document 35), recurrent pericarditis (Non-Patent Document 36), adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome) (Non-Patent Document 37), Schnitzler syndrome (Non-Patent Document 38), IL-1 receptor antagonist molecule deficiency (Non-Patent Document 39), familial Mediterranean fever (Non-Patent Document 40), mevalonate kinase deficiency (Non-Patent Document 40), hyper IgD syndrome (Non-Patent Document 40), TNF receptor-associated periodic syndrome (Non-Patent Document 40), Behcet's disease (Non-Patent Document 41), and lung cancer (Non-Patent Document 42). The therapeutic effects of anti-IL-1β antibodies such as canakinumab and IL-1 inhibitors such as rilonacept have been reported for these diseases. Since the NLRP3 inflammasome is involved in the production of inflammatory cytokines such as IL-1β, NLRP3 inflammasome inhibitors are thought to be a potential treatment for these diseases.

[0019] It has been reported that the NLRP3 rs10733113 genotype is significantly increased in psoriasis patients, and that they are more susceptible to psoriasis (Non-Patent Document 43). It has also been reported that NLRP3 deficiency suppresses psoriasis symptoms in an IL-23-induced psoriasis model (Non-Patent Document 44). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for psoriasis.

[0020] Gout, atherosclerosis (arteriosclerosis), and chronic kidney disease, which are associated with NLRP3 inflammasome activation, are accompanied by hypertension. It has been reported that NLRP3 deficiency suppresses hypertension in a mouse left renal artery stenosis model (Non-Patent Document 45). In addition, it has been reported that MCC950, an NLRP3 inflammasome inhibitor, suppresses hypertension in a deoxycorticosterone acetate salt mouse model (Non-Patent Document 46). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for hypertension.

[0021] It has been reported that NLRP3 expression is enhanced in the proliferative membrane of patients with diabetic retinopathy (Non-Patent Document 47). In addition, NLRP3 expression is enhanced in the STZ-induced retinopathy model, which is a diabetic retinopathy model (Non-Patent Document 48). In this model, it has been reported that reduction in NLRP3 expression by NLRP3 shRNA reduces IL-1β and VEGF secretion, increases ganglion cell mass, and recovers from retinal damage (Non-Patent Document 49). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for diabetic retinopathy.

[0022] In Alzheimer's disease patients, MCI (mild cognitive impairment) patients, and APP / PS1 mice, which are Alzheimer's disease model mice, NLRP3 inflammasome activation occurs in the brain, and NLRP3 deficiency in APP / PS1 mice suppresses the expression of spatial memory impairment (Non-Patent Document 50). MCC950, an NLRP3 inhibitor, suppresses NLRP3 activation in microglia in APP / PS1 mice and improves cognitive dysfunction (Non-Patent Document 51). Therefore, NLRP3 inflammasome inhibitors are thought to be a therapeutic drug for Alzheimer's disease and MCI.

[0023] In the substantia nigra of Parkinson's disease patients and mice injected with α-synuclein PFF (pre-formed fibril), a model of Parkinson's disease, increased expression of NLRP3 inflammasome-related molecules in microglia and activation of NLRP3 inflammasome occur (Non-Patent Document 52). The NLRP3 inhibitor MCC950 suppresses NLRP3 activation in the substantia nigra and inhibits neuronal death of dopamine neurons in the substantia nigra in mice injected with α-synuclein PFF (Non-Patent Document 52). Therefore, it is thought that NLRP3 inflammasome inhibitors will be a therapeutic drug for Parkinson's disease.

[0024] In patients with Huntington's disease, the cerebrospinal fluid concentration of IL-1β, an NLRP3 inflammasome-related cytokine, increases (Non-Patent Document 53). In R6 / 2 mice, a pathological model of Huntington's disease, the expression level of NLRP3 inflammasome in the striatum increases (Non-Patent Document 54). The NLRP3 inhibitor MCC950 suppresses NLRP3 inflammasome activation in the striatum of R6 / 2 mice, inhibits neuronal cell death in the striatum, and inhibits symptom progression (Non-Patent Document 55). Therefore, it is thought that NLRP3 inflammasome inhibitors will be a therapeutic drug for Huntington's disease.

[0025] In the spinal cord of amyotrophic lateral sclerosis (ALS) patients, the expression of NLRP3 inflammasome, IL-18, and active caspase 1 is increased (Non-Patent Document 56). In the spinal cord of ALS model mice, SOD1G93A mice and TDP-43Q331K mice, the mRNA expression of IL-1β, Nlrp3, Pycard, and Casp1 is increased (Non-Patent Document 57). The NLRP3 inhibitor MCC950 suppresses NLRP3 activation in microglia induced by SOD1G93A and TDP-43 proteins, and reduces IL-1β production (Non-Patent Document 57). In SOD1G93A mice, the deficiency of IL-1β or caspase1 extends the survival time, and the administration of an IL-1β receptor antibody inhibits the progression of the disease and extends the survival time (Non-Patent Document 58). Therefore, NLRP3 inflammasome inhibitors are considered to be a potential treatment for ALS.

[0026] In the brain tissue and cerebrospinal fluid of patients with traumatic brain injury (TBI), the expression level of NLRP3 inflammasome increases (Non-Patent Documents 59, 60). In the brain tissue of TBI model rats, the expression level of NLRP3 inflammasome increases, and the expression levels of IL-1β and IL-18 also increase (Non-Patent Document 61). The NLRP3 inhibitor MCC950 suppresses IL-1β production in TBI model mice and suppresses the expression of neurological symptoms after brain trauma (Non-Patent Document 62). Therefore, it is thought that NLRP3 inflammasome inhibitors will be a therapeutic drug for TBI.

[0027] In the brain tissue of cerebral infarction patients, MCAO (middle cerebral artery occlusion) mice, and intracerebral hemorrhage model rats, the expression of NLRP3 inflammasome, IL-1β, and IL-18 is increased (Non-Patent Documents 63, 64). In addition, the NLRP3 inhibitor MCC950 showed neuroprotective effects in MCAO and intracerebral hemorrhage model rats. Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for cerebral infarction and cerebral hemorrhage.

[0028] In brain tissues of patients with temporal lobe epilepsy and in pilocarpine-induced epilepsy model mice, expression of NLRP inflammasomes increases (Non-Patent Documents 65, 66). In addition, in pilocarpine-induced epilepsy model mice, NLRP3 inflammasome deficiency and administration of the NLRP3 inhibitor MCC950 suppress apoptosis of hippocampal neurons, which causes epilepsy (Non-Patent Document 66). Therefore, NLRP3 inflammasome inhibitors are considered to be a therapeutic drug for epilepsy.

[0029] In the peripheral blood of patients with depression, the expression level of NLRP3 inflammasome, IL-1β concentration, and IL-18 concentration are increased, and the IL-1β concentration and depression symptom score are correlated (Non-Patent Document 67). In the pathological models of depression, such as the LPS-induced model, the chronic stress-induced model, or the social defeat model, the expression levels of NLRP3 inflammasome, IL-1β, or IL-18 in brain tissue are increased, and NLRP3 inflammasome activation occurs (Non-Patent Documents 68, 69, 70). In addition, in pathological models, administration of the NLRP3 inhibitor MCC950 or NLRP3 deficiency shows an improvement effect on depressive symptoms (Non-Patent Documents 69, 70). Therefore, it is thought that NLRP3 inflammasome inhibitors can be used as therapeutic drugs for depression.

[0030] In the peripheral blood of patients with autism spectrum disorder (ASD), the expression level of NLRP3 inflammasome, IL-1β, and IL-18 are increased (Non-Patent Document 71). In the maternal immune activation (MIA) model, administration of PolyIC to pregnant animals causes ASD symptoms in offspring, but in this model, IL-1β expression is increased in the fetal brain, and administration of the NLRP3 inhibitor MCC950 to the mother suppresses the expression of ASD symptoms in offspring (Non-Patent Document 72). Therefore, NLRP3 inflammasome inhibitors are thought to be a therapeutic drug for ASD.

[0031] In the spinal cord of mice with spinal cord injury, NLRP3 inflammasome or IL-1β expression is increased, and NLRP3 activation is observed (Non-Patent Documents 73, 74). In addition, when the NLRP3 inhibitor MCC950 is administered to mice after spinal cord injury, it suppresses NLRP3 activation and IL-1β expression in the spinal cord, and promotes recovery of motor function (Non-Patent Document 73). Therefore, it is thought that NLRP3 inflammasome inhibitors can be used as therapeutic agents for spinal cord injury.

[0032] In an intestinal perforation model, which is a sepsis model animal, increased expression and activation of NLRP3 inflammasome or IL-1β occurs in the brain, causing damage to hippocampal neurons and memory impairment, which is a symptom of septic encephalopathy (Non-Patent Documents 75, 76). When the NLRP3 inhibitor MCC950 is administered to an intestinal perforation model, NLRP3 inflammasome activation is suppressed and memory impairment is improved (Non-Patent Document 76). Therefore, it is thought that NLRP3 inflammasome inhibitors can be used as therapeutic agents for septic encephalopathy.

[0033] In the chronic constriction injury (CCI) model, which is a neuropathic pain model animal, the expression levels of IL-1β and NLRP3 inflammasome-related molecules are increased in glial cells and neurons in the spinal cord (Non-Patent Document 77). In addition, in the paclitaxel-induced pain model, which is a neuropathic pain model in anticancer drug-induced neuropathy, the expression levels of NLRP3 inflammasome-related molecules are increased in the dorsal root ganglion and sciatic nerve (Non-Patent Document 78). In addition, in trigeminal neuralgia model animals, the expression level of NLRP3 inflammasome in the spinal dorsal horn is increased, and by deleting NLRP3 in the spinal cord, the activation of NLRP3 inflammasome in the spinal cord and allodynia to mechanical stimulation are suppressed (Non-Patent Document 79). Therefore, it is thought that NLRP3 inflammasome inhibitors will be a therapeutic drug for neuropathic pain.

[0034] In mice infected with SARS-CoV-2, increased expression of IL-1β and NLRP3 inflammasome-related molecules was observed in lung tissue. On the other hand, in NLRP3 knockout mice, no increase in their expression was observed, and severe respiratory inflammation caused by SARS-CoV-2 was suppressed. In addition, administration of the NLRP3 inhibitor MCC950 to mice infected with SARS-CoV-2 suppressed activation of the NLRP3 inflammasome and excessive immune responses in the lungs (Non-Patent Document 80). Therefore, NLRP3 inflammasome inhibitors are thought to be a treatment for COVID-19 caused by SARS-CoV-2.

[0035] In the cerebral cortex of patients with frontotemporal dementia with tau protein mutations, an increase in the ASC domain of the NLRP3 inflammasome and mature IL-1β protein has been reported (Non-Patent Document 81). In addition, an increase in the ASC domain of the NLRP3 inflammasome and post-cleavage caspase1 has been reported in the cerebral cortex of Tau22 mice (human mutant tau protein expressing mice), a model of frontotemporal dementia, and an inhibitory effect on tau lesion formation and cognitive decline by NLRP3 knockout has also been reported (Non-Patent Document 81). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for frontotemporal dementia.

[0036] In patients with NLRP3-associated autoinflammatory disease (NLRP3-AID) caused by activating mutations in the NLRP3 gene, the formation of drusen, which is thought to be the causative agent of age-related macular degeneration (AMD), was observed (Non-Patent Document 82). In addition, in an Alu RNA-induced retinal pigment epithelial cell degeneration model, which is one of the age-related macular degeneration models, NLRP3 inhibitors suppressed the degeneration of retinal pigment epithelial cells (Non-Patent Document 83). In a laser-induced choroidal neovascularization model, which is another model of age-related macular degeneration, NLRP3 inhibitors suppressed angiogenesis (Non-Patent Document 83). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for age-related macular degeneration.

[0037] In patients with diabetic macular edema, diabetes increases retinal vascular permeability, causing blood components to leak into the retina (Non-Patent Document 84). The NLRP3 inhibitor MCC950 improved the increased retinal vascular permeability in STZ-induced diabetic mice (Non-Patent Document 85). Therefore, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic agent for diabetic macular edema.

[0038] Hereditary transient corneal endotheliitis is one of the cryopyrin-associated periodic fever syndromes caused by activating mutations in the NLRP3 gene (Non-Patent Document 86). Therefore, it is thought that NLRP3 inflammasome inhibitors will be a therapeutic agent for hereditary transient corneal endotheliitis. [Prior art documents] [Non-patent literature]

[0039] [Non-patent document 1] Andersson, A et al., Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol., 2008, Vol 84 (5), p.1248-55 [Non-Patent Document 2] Voet, S et al., A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation. Nat Commun., 2018, Vol 9(1), p2036. [Non-Patent Document 3] Politis, M et al., Increased PK11195 PET binding in the cortex of patients with MS correlates with disability. Neurology, 2012, Vol 79(6), p523-30. [Non-patent document 4] Hernandez-Pedro, N et al., PAMP-DAMPs interactions mediates development and progression of multiple sclerosis. Front Biosci (Schol Ed), 2016, Vol 8, p13-28. [Non-patent document 5] Denis, G et al., NLRP3 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis by Mediating Th1 and Th17 Responses. J Immunol., 2010, Vol 185 (2) p974-981 [Non-Patent Document 6] Jha, S et al., The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci., 2010 Vol 30(47), p15811-20 [Non-Patent Document 7] Guo, C et al., Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis. ACS Chem Neurosci., 2017, Vol 8(10), p2194-2201 [Non-Patent Document 8] Akosua Vilaysane et al., The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD. J Am Soc Nephrol. 2010 Oct; 21(10): 1732-1744. [Non-Patent Document 9] Shahzad K et al., Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015 Jan;87(1):74-84. [ Abstract ]Gong W et al., NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5 / 6 nephrectomy. Am J Physiol Renal Physiol. 2016 May 15;310(10):F1081-8 [ PubMed ] Ranson N et al., NLRP3-dependent and -independent processing of Interleukin-1β in active Ulcerative colitis. Int J Mol Sci 2018:20p:E57. [ Abstract ] Mao L et al., Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn's disease. J Clin Invest 2018: vol 128:1793–1806. [Vol.13]Bauer c. et al., Protective and aggravating effects of NLRP3 inlammasome activation in IBD models: influence of genetic and environmental factors. Dig.Dec 2012 Vol 30 Suppl 1 82-90. [ PubMed ] Paramel VG et al., NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. J Am Heart Assoc. 2016 May 20;5(5):e003031. [Non-Patent Document 15] Duewell P et al., NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010 Apr 29;464(7293):1357-61. [Non-Patent Document 16] Broderick L et al., The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol. 2015;10:395-424. [Non-Patent Document 17] Sarrauste MC et al., INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 2003 Jan 1;31(1):282-5. [Non-Patent Document 18] Brydges SD et al., Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest. 2013 Nov;123(11):4695-705. [Non-Patent Document 19] Jiang H et al., Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017 Nov 6;214(11):3219-3238. [Non-Patent Document 20] Wree A et al., NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl). 2014 Oct;92(10):1069-82. [Non-Patent Document 21] So AK et al., Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol. 2017 Nov;13(11):639-647. [Non-Patent Document 22] Martinon F et al., Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006 Mar 9;440(7081):237-41. [Non-Patent Document 23] Marchetti C et al., NLRP3 inflammasome inhibitor OLT1177 suppresses joint inflammation in murine models of acute arthritis. Arthritis Res Ther. 2018 Aug 3;20(1):169. [Non-Patent Document 24] Mathews RJ et al., Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis. 2014 Jun;73(6):1202-10. [Non-Patent Document 25] Zhang Y et al., NLRP3 Inflammasome Plays an Important Role in the Pathogenesis of Collagen-Induced Arthritis. Mediators Inflamm. 2016;2016:9656270. [Non-Patent Document 26] Watanabe H et al., Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity. J Invest Dermatol. 2007 Aug;127(8):1956-63. [Non-Patent Document 27] Niu L et al., Upregulation of NLRP3 Inflammasome in the Tears and Ocular Surface of Dry Eye Patients. PLoS One. 2015 May 11;10(5):e0126277. [Non-Patent Document 28] Zheng Q et al., Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients. Exp Eye Res. 2015 May;134:133-40. [Non-Patent Document 29] Kawaguchi M et al., Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia / reperfusion injury. Circulation. 2011 Feb 15;123(6):594-604. [Non-Patent Document 30] Sandanger O et al., The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013 Jul 1;99(1):164-74. [Non-Patent Document 31] Dellalibera-Joviliano R et al., Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus. J Rheumatol. 2003 Mar;30(3):485-92. [Non-Patent Document 32] Tucci M et al., Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008 Jan;58(1):251-62. [Non-Patent Document 33] Yang CA et al., Sex-dependent differential activation of NLRP3 and AIM2 inflammasomes in SLE macrophages. Rheumatology (Oxford). 2015 Feb;54(2):324-31. [Non-Patent Document 34] Lu A et al., Hyperactivation of the NLRP3 Inflammasome in Myeloid Cells Leads to Severe Organ Damage in Experimental Lupus. J Immunol. 2017 Feb 1;198(3):1119-1129. [Non-Patent Document 35] Ruperto N et al., Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2396-406. [Non-Patent Document 36] Klein AL et al., Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis. N Engl J Med. 2021 Jan 7; 384(1):31-41. [Non-Patent Document 37]Junge G et al., Adult onset Still's disease-The evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review). Seminars in Arthritis Rheumatism 2017 Oct; 47(2):295-302. [Non-Patent Document 38] Krause K et al., Efficacy and safety of canakinumab in Schnitzler syndrome: A multicenter randomized placebo-controlled study. J Allergy Clin Immunol. 2017 Apr;139(4):1311-1320. [Non-Patent Document 39] Garg M et al., Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017 Aug 17;2(16). [Non-Patent Document 40] De Benedetti F et al., Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018 May 17;378(20):1908-1919. [Non-Patent Document 41] Emmi G et al., Efficacy and safety profile of anti-interleukin-1 treatment in Behcet's disease: a multicenter retrospective study. Clin. Rheumatol., 35 (2016), pp. 1281-1286. [Non-Patent Document 42] Ridker PM et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Lancet (2017) 390 1833-42. [Non-Patent Document 43] M Carlstrom et al., Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility. Exp Dermatol. (2012) 21:932-7. [Non-Patent Document 44] J. A Diaz-Perez et al., Extracellular ATP and IL-23 Form a Local Inflammatory Circuit Leading to the Development of a Neutrophil-Dependent Psoriasiform Dermatitis. J Invest Dermatol. (2018) 138:2595-605. [Non-Patent Document 45] Wang Q et al., Renin-Dependent Hypertension in Mice Requires the NLRP3-Inflammasome. J. Hypertens (2014) 3:187. [Non-Patent Document 46]Krishnan SM et al., Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc. Res. (2019) 115 4: 776-787. [Non-patent document 47] Zhang Y et al., Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction. Cell Death Dis. 2017 Jul 20; 8(7):e2941. [Non-patent document 48] Sheng Li et al., Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation. Exp Anim. 2019 May 8;68(2):221-231. [Non-Patent Document 49] Guangrui Chai et al., NLRP3 Blockade Suppresses Pro-Inflammatory and Pro-Angiogenic Cytokine Secretion in Diabetic Retinopathy. Diabetes Metab Syndr Obes. 2020 Aug 25;13:3047-3058. [Non-Patent Document 50] Heneka MT et al., NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP / PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. [Non-Patent Document 51] Dempsey C et al., . Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP / PS1 mice. Brain Behav Immun. 2017 Mar; 61:306-316. [Non-Patent Document 52] Gordon R et al., Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018 Oct 31;10(465):eaah4066. [Non-Patent Document 53] Rodrigues FB et al., Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease. PLoS One. 2016 Sep 22;11(9):e0163479. [Non-Patent Document 54] Paldino E et al., Pyroptotic cell death in the R6 / 2 mouse model of Huntington's disease: new insight on the inflammasome. Cell Death Discov. 2020 Jul 31;6:69. [Non-Patent Document 55] Chen KP et al., A selective inhibitor of the NLRP3 inflammasome as a potential therapeutic approach for neuroprotection in a transgenic mouse model of Huntington's disease. J Neuroinflammation. 2022 Feb 26;19(1):56. [Non-Patent Document 56] Johann S et al., NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015 Dec;63(12):2260-73. [Non-Patent Document 57] Deora V et al., The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020 Feb;68(2):407-421. [Non-Patent Document 58] Meissner F et al., A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci US A. 2010 Jul 20;107(29):13046-50. [Non-Patent Document 59] Lin C et al., Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Exp Neurol. 2017 Apr;290:115-122. [Non-Patent Document 60] Wallisch JS et al., Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children. Neurocrit Care. 2017 Aug;27(1):44-50. [Non-Patent Document 61] Liu HD et al., Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 2013 Oct;38(10):2072-83. [Non-Patent Document 62] Ismael S et al., MCC950, the Selective Inhibitor of Nucleotide Oligomerization Domain-Like Receptor Protein-3 Inflammasome, Protects Mice against Traumatic Brain Injury. J Neurotrauma. 2018 Jun 1;35(11):1294-1303. [Non-Patent Document 63] Fann DY et al., Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013 Sep 5;4(9):e790. [Non-Patent Document 64] Feng L et al., P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation. 2015 Oct 17;12:190. [Non-Patent Document 65] Yue J et al., NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: molecular insights into their interdependence. Neuropathol Appl Neurobiol. 2020 Dec;46(7):770-785. [Non-Patent Document 66] Wu C et al., The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury. Front Neurol. 2020 Feb 7;10:1418. [Non-Patent Document 67] Alcocer-Gomez E et al., NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav Immun. 2014 Feb;36:111-7. [Non-Patent Document 68] Zhang Y et al., Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci Ther. 2014 Feb;20(2):119-24. [Non-Patent Document 69] Iwata M et al., Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor. Biol Psychiatry. 2016 Jul 1;80(1):12-22. [Non-Patent Document 70] Li W et al., Inhibition of the NLRP3 inflammasome with MCC950 prevents chronic social isolation-induced depression-like behavior in male mice. Neurosci Lett. 2021 Nov 20;765:136290. [Non-Patent Document 71] Saresella M et al., Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun. 2016 Oct;57:125-133. [Non-Patent Document 72] Szabo D et al., Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1β pathway. Brain Behav Immun. 2022 Mar;101:318-332. [Non-Patent Document 73] Amo-Aparicio J et al., Inhibition of the NLRP3 inflammasome by OLT1177 induces functional protection and myelin preservation after spinal cord injury. Exp Neurol. 2022 Jan;347:113889. [Non-Patent Document 74] Jiao J et al., MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury. Front Mol Biosci. 2020 Mar 3;7:37. [Non-Patent Document 75] Ding H et al., Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis-associated encephalopathy. CNS Neurosci Ther. 2022 Feb;28(2):247-258. [Non-Patent Document 76] Fu Q et al., NLRP3 / Caspase-1 Pathway-Induced Pyroptosis Mediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy. Inflammation. 2019 Feb;42(1):306-318. [Non-Patent Document 77] Xu L et al., MiR-34c Ameliorates Neuropathic Pain by Targeting NLRP3 in a Mouse Model of Chronic Constriction Injury. Neuroscience. 2019 Feb 10;399:125-134. [Non-Patent Document 78] Jia M et al., Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain. Mol Pain. 2017 Jan-Dec;13:1744806917719804. [Non-Patent Document 79] Sun X et al., The NLRP3-related inflammasome modulates pain behavior in a rat model of trigeminal neuropathic pain. Life Sci. 2021 Jul 15;277:119489. [Non-Patent Document 80] Zeng J et al., Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice. EBioMedicine. 2022 Jan;75:103803. [Non-Patent Document 81] Ising C, et al., NLRP3 inflammasome activation drives tau pathology. Nature. 2019 Nov; 575(7784): 669-673. [Non-Patent Document 82] Bing Li, et al., Early onset drusen and RPE dysfunction in a patient with NLRP3-AID, Ocul Immunol Inflamm. 2022 Nov 17;1-4. [Non-Patent Document 83] Benjamin J Fowler, et al., Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity, Science. 2014 Nov 21;346(6212):1000-3. [Non-Patent Document 84] Funatsu, H., Advances in the Treatment of Macular Edema, Diabetes 48(10): 721-723, 2005. [Non-Patent Document 85] Keke Ge, et al., Down-expression of the NLRP3 inflammasome delays the progression of diabetic retinopathy, Microvasc Res. 2022 Jan;139:104265. [Non-Patent Document 86] Joni A Turunen, et al., Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene, Am J Ophthalmol. 2018 Apr;188:41-50. Summary of the Invention

[0040] The present invention provides a substituted pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and a medicinal use thereof, etc. That is, the present invention includes the following exemplary embodiments.

[0041] [Section 1] A compound of formula [I] or a pharma- ceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [I] or a pharma- ceutically acceptable salt thereof" is also referred to as "compound [I]"). [ka] {In the formula, Substructure: [ka] teeth, (1) Formula: [ka] [During the ceremony, R 5 is hydrogen or C 1-4 alkyl {wherein the alkyl is (a) carboxy, (b)-CO-C 1-4 Alkoxy, or (c)-CO-NR6 R 7 (where R 6 and R 7 are each independently hydrogen or C 1-4 alkyl), optionally substituted with or (2) Formula: [ka] (In the formula, R 8 is C 1-4 (It is alkyl) The structure is represented by The ring group Cy is (1) Formula: [ka] (In the formula, R 9 and R 10 are each independently (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl, R 11 and R 12 are each independently (a) hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl, R 13 teeth, (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 Alkoxy, (d) halogens, (e)C1-6 Haloalkyl, (f)-OC 1-4 haloalkyl, or (g) C 3-6 cycloalkyl, where the cycloalkyl is optionally substituted with one or two halogens; or R 13 is R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) may form a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms. or (2) Formula: [ka] (In the formula, R 14 and R 15 are each independently 1-4 Alkyl or C 1-4 is haloalkyl, R 16 is C 1-6 Alkyl or C 3-6 cycloalkyl) is a group represented by R 1 teeth, (1) Hydrogen, (2) Cyano, (3) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (4) C 1-4 haloalkyl, or (5)-CO-C 1-4 alkyl, R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, (3) C 1-6alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (7)-OC 1-4 Haloalkyl, (8)-OR 17 (where R 17 is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C 3-6 Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or Equation (11): [ka] or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a) cyano, (b)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (c) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with 1 or 2 halogens; (e) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (g) C 5-6 Cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (i) Formula: [ka] {where, R 20 teeth, (1) C 1-4 Alkyl, or (2)-NR 21 R 22 (where R 21 and R 22 are each independently (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. may form a group represented by the formula: [Section 2] Substructure: [ka] but, (1) Formula: [ka] (In the formula, R 5 is equivalent to term 1) Item 2. The compound according to item 1, which has a structure represented by the following formula: or a pharma- ceutically acceptable salt thereof. [Section 3] R 1 Item 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 4] R 5 The compound according to any one of items 1 to 3, wherein is hydrogen, or a pharma- ceutically acceptable salt thereof. [Section 5] The ring group Cy is (1) Formula: [ka] (In the formula, R 9 , R 10 , R 11 , R 12 and R 13 is equivalent to term 1) Item 5. The compound according to any one of items 1 to 4, wherein the compound is a group represented by the following formula: [Section 6] Item 6. The compound according to any one of items 1 to 5, which is represented by formula [II] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 and R 13 is equivalent to term 1) [Section 7] R 11 and R 12 7. The compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 8] Item 8. The compound according to any one of items 1 to 7, which is represented by formula [III] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 2 , R 3 , R 4 , R 9 , R 10 and R 13 is equivalent to term 1) [Section 9] R 9 and R 10 At least one of (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4Alkoxy, (3) halogens, (4) C 1-4 haloalkyl, or (5)-OC 1-4 Item 9. The compound according to any one of items 1 to 8, which is haloalkyl, or a pharma- ceutically acceptable salt thereof. [Section 10] R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (f) Formula: [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. Item 10. The compound according to any one of items 1 to 9, or a pharma- ceutically acceptable salt thereof, which may form a group represented by the following formula: [Section 11] R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 substituted with alkoxy; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; or Formula (c): [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. Item 11. The compound according to any one of items 1 to 10, or a pharma- ceutically acceptable salt thereof, which may form a group represented by the following formula: [Section 12] The structural formula: [ka] Item 2. The compound according to item 1, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of TIFF2024120882000017.tif186150. [Section 13] The structural formula: [ka] Item 2. The compound according to item 1, selected from the group consisting of: [Section 14] Item 14. A pharmaceutical composition comprising the compound according to any one of items 1 to 13 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. [Section 15] Item 14. An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 13 or a pharma- ceutically acceptable salt thereof. [Section 16] Item 14. The compound according to any one of Items 1 to 13 or a pharma- ceutical acceptable salt thereof, which is used for the treatment of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 17] Item 17. The therapeutic or preventive agent according to Item 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 18] Item 17. The therapeutic or preventive agent according to Item 16, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 19] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 13 or a pharma- ceutically acceptable salt thereof to a mammal. [Section 20] Item 15. A method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, A method for treating or preventing a disease selected from the group consisting of adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 21] Item 21. The method according to item 20, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 22] Item 21. The method according to Item 20, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 23] Use of the compound or a pharma- ceutical acceptable salt thereof according to any one of items 1 to 13 for the manufacture of an NLRP3 inflammasome inhibitor. [Section 24] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease Item 14. Use of the compound or a pharmacologic agent thereof according to any one of items 1 to 13 for the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of chronic myocardial infarction, idiopathic pulmonary syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 25] Item 25. The use according to item 24, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 26] Item 25. The use according to Item 24, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multiorgan inflammatory disease. [Section 27] Item 14. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 13 for use in inhibiting NLRP3 inflammasome. [Section 28] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic fatty liver disease, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease, Item 14. The compound or a pharmacologic acceptable salt thereof according to any one of items 1 to 13 for use in the treatment or prevention of a disease selected from the group consisting of myeloma, myeloma-associated leukemia, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 29] Item 29. The compound or a pharma- ceutically acceptable salt thereof according to item 28, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 30] Item 29. The compound or a pharma- ceutically acceptable salt thereof according to item 28, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multiorgan inflammatory disease. [Section 31] Item 14. A pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel ... and a commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF) syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 32] Item 14. A pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient suffering from multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage leukemia), and / or chronic myocardial infarction. and a commercial kit comprising a description of the pharmaceutical composition, the description of which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction (CI)-associated pulmonary disease (COPD), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 16A] Item 15. A compound according to any one of items 1 to 13 or a pharma- ceutical agent comprising the compound or a pharma- ceutical agent thereof for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and myelopathy), and / or other conditions. A therapeutic or preventive agent for a disease selected from the group consisting of inflammatory bowel disease, chronic obstructive pulmonary disease, chronic myocardial infarction, chronic obstructive pulmonary disease, chronic myocardial infarction, chronic obstructive pulmonary disease (COPD), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 17A] The therapeutic or preventive agent according to Item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 18A] Item 16A. The treatment or prevention agent according to Item 16A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 19A] Item 15. A method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic phosphoinositide-induced inflammatory disease), and / or chronic inflammatory diseases, comprising administering to a mammal a therapeutically effective amount of the compound according to any one of items 1 to 13 or a pharmacologic salt thereof. A method for treating or preventing a disease selected from the group consisting of inflammatory bowel disease, myelofibrosis, myelofibrosis, pulmonary ... [Section 20A] The method according to paragraph 19A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 21A] The method according to item 19A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 22A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic fatty liver disease, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Item 14. Use of the compound or a pharmacologic agent for the treatment or prevention of a disease selected from the group consisting of inflammatory bowel disease, inflammatory bowel disease, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 23A] The use according to paragraph 22A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 24A] The use according to Item 22A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 25A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency Item 14. The compound or a pharmacologic agent according to any one of items 1 to 13, for use in the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 26A] The compound or a pharma- ceutically acceptable salt thereof according to Item 25A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 27A] The compound or a pharma- ceutically acceptable salt thereof according to Item 25A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 28A] Item 14. A pharmaceutical composition according to Item 14, and a method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, I and a commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of L-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 29A] Item 15. The pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient suffering from multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, A commercial kit comprising a description of the pharmaceutical composition, the description of which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The definitions of terms used in this specification are as follows.

[0043] In the chemical formula: [ka] The wavy line indicates the bonding site of the structure or group shown in the chemical formula.

[0044] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4"Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferred are methyl and ethyl. More preferred is methyl.

[0045] "C 1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Preferred are methyl, ethyl, isopropyl, and isopentyl. More preferred is methyl.

[0046] "C 1-4 Alkoxy means the above "C 1-4 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferred are methoxy and ethoxy.

[0047] "C 1-6 Alkoxy means the above "C 1-6 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-6Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, and 2-ethylbutoxy. Preferred are methoxy, ethoxy, and isopentyloxy.

[0048] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine. More preferred is fluorine.

[0049] "C 1-4 "Haloalkyl" refers to the above "C" substituted with 1 to 7 halogens independently selected from the above "halogen" group. 1-4 "C" means "alkyl". 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. Preferred are monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. More preferred is difluoromethyl.

[0050] "C 1-6 "Haloalkyl" refers to the above "C" substituted with 1 to 9 halogens independently selected from the above "halogen" group. 1-6 "C" means "alkyl". 1-6"Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl. Preferred are trifluoromethyl, 1,1-difluoroethyl, and 1-fluoro-1-methylethyl. More preferred is 1,1-difluoroethyl.

[0051] "C 3-6 "Cycloalkyl" means a monocyclic saturated hydrocarbon ring group having 3 to 6 carbon atoms. 3-6 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0052] "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring-constituting atoms. "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, and dioxanyl. Preferred are oxetanyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, and dioxanyl.

[0053] "4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms" means a 4- to 7-membered monocyclic saturated heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. "4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms" includes, for example, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydrothiophenyl ... These include tetrahydropyranyl, 1,2-diazacyclohexanyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, thiomorpholinyl, dioxanyl, azepanyl, oxepanyl, diazepanyl (e.g. 1,4-diazepanyl), oxazepanyl (e.g. 1,4-oxazepanyl and 1,2-oxazepanyl), dioxepanyl (e.g. 1,4-dioxepanyl), and thiazepanyl. Preferred are oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dioxanyl, and dioxepanyl.

[0054] "C 5-6 "Cycloalkenyl" means a monocyclic partially unsaturated hydrocarbon ring group having 5 to 6 carbon atoms and containing at least one double bond. 5-6 "Cycloalkenyl" includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Preferred is cyclopentenyl.

[0055] "C 5-6"Cycloalkene" means a monocyclic partially unsaturated hydrocarbon ring having 5 to 6 carbon atoms and containing at least one double bond. 5-6 "Cycloalkene" includes, for example, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene.

[0056] "5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- or 6-membered monocyclic partially unsaturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring-constituting atoms and containing at least one double bond. "5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, pyrrolinyl, pyrazolinyl, imidazolinyl, dihydrofuranyl, dioxolyl, oxazolinyl, isoxazolinyl, tetrahydropyridinyl, tetrahydropyrimidyl, tetrahydropyridazinyl, tetrahydropyrazinyl, dihydropyridinyl, dihydropyranyl, dihydrodioxynyl, pyranyl, and dihydrooxazinyl. Dihydrofuranyl and dihydropyranyl are preferred.

[0057] "5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms" means a 5- to 7-membered monocyclic partially unsaturated heterocycle containing 1 or 2 oxygen atoms and at least one double bond in addition to carbon atoms as ring-constituting atoms. "5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms" includes, for example, dihydrofuran, dioxole, dihydropyran, dihydrodioxine, pyran, tetrahydrooxepin, dihydrodioxepin, dihydrooxepin, and dioxepin. Dihydropyran is preferable.

[0058] The term "7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" refers to a 7- to 9-membered saturated fused heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. Examples of the "7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" include the following groups: [ka] Includes:

[0059] "5- to 8-membered bridged cycloalkyl" means a 5- to 8-membered bridged cyclic saturated hydrocarbon group. "5- to 8-membered bridged cycloalkyl" includes, for example, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Bicyclo[1.1.1]pentyl is preferred.

[0060] "5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- to 8-membered bridged saturated heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. "5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, the following groups: [ka] Includes:

[0061] In some embodiments of the present invention, the moiety of formula [I]: [ka] is R 13 R 11 or R 12and, when taken together with the carbon atom to which they are attached to form a ring structure, as a whole, a 9- to 11-membered partially unsaturated fused ring group which may contain one or two oxygen atoms, R 9 and R 10 and R 11 or R 12 The fused ring group is substituted with, for example, the following group: [ka] Examples include:

[0062] The phrase "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is replaced with β. For example, "C optionally substituted with hydroxy" means that 1-6 "Alkyl" means C 1-6 The alkyl is unsubstituted or 1-6 This means that any hydrogen in the alkyl is replaced with hydroxy.

[0063] Specific embodiments of each substituent of the compound of formula [I] are exemplified below, but each substituent of the compound of formula [I] is not limited to the specific embodiments, and the compound of formula [I] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0064] Substructure: [ka] is preferably of the formula: [ka] (In the formula, R 5 are as defined above) The structure is shown below.

[0065] R 5 is preferably hydrogen.

[0066] The ring group Cy preferably has the formula: [ka] (wherein each symbol has the same meaning as defined above) It is a group represented by the following formula:

[0067] R 9 and R 10 are preferably each independently (a)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-4 haloalkyl, or (e)-OC 1-4 Haloalkyl.

[0068] R 9 and R 10 More preferably, each independently represents C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy).

[0069] R 11 and R 12 are preferably each independently hydrogen or C 1-4 It is an alkyl.

[0070] R 11 and R 12 is more preferably hydrogen.

[0071] R 13 is preferably (a)C 1-4 Alkyl, (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-6 Haloalkyl, (e)-OC 1-4 haloalkyl, or (f)C3-6 cycloalkyl, where the cycloalkyl is optionally substituted with one or two halogens; or R 13 is R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.

[0072] R 13 More preferably, C 1-6 Haloalkyl or -OC 1-4 It is haloalkyl.

[0073] Substructure: [ka] In the above, preferably, R 9 and R 10 are each independently (a)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-4 haloalkyl, or (e)-OC 1-4 haloalkyl; R 11 and R 12 are each independently hydrogen or C 1-4 is alkyl; R 13 teeth, (a)C 1-4 Alkyl, (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-6 Haloalkyl, (e)-OC1-4 haloalkyl, or (f)C 3-6 cycloalkyl, where the cycloalkyl is optionally substituted with one or two halogens; or R 13 is R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.

[0074] More preferred substructures: [ka] teeth, R 9 and R 10 are each independently 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 11 and R 12 is hydrogen; R 13 is C 1-6 Haloalkyl or -OC 1-4 It is haloalkyl.

[0075] More preferred substructures: [ka] teeth, R 9 and R 10 are each independently 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 11 and R 12 is hydrogen; R 13 is C 1-6 It is haloalkyl.

[0076] Another more preferred substructure: [ka] teeth, R 9 and R 10 are each independently 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 11 and R 12 is hydrogen; R 13 -OC 1-4 It is haloalkyl.

[0077] R 1 is preferably hydrogen.

[0078] R 2 , R 3 and R 4 are preferably each independently (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (f) Formula: [ka] (In the formula, R 20 are as defined above) This forms a group represented by the formula:

[0079] More preferred R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 substituted with alkoxy; or R 2 , R 3 and R 4together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; or Formula (c): [ka] (In the formula, R 20 are as defined above) This forms a group represented by the formula:

[0080] More preferred R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, aryl, arylsulfonyl, arylalkyl, arylsulfonyl ... R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); or Formula (b): [ka] (In the formula, R 21 and R 22 are as defined above) This forms a group represented by the formula:

[0081] Another more preferred R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) Hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, and optionally substituted with 1 or 2 substituents independently selected from the group consisting of

[0082] Another more preferred R 2 , R 3 and R 4 is R 2 , R 3 and R 4 Together with the carbon atom to which it is attached, -CR 2 R 3 R 4 The group is C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), which may be substituted with 1 to 3 substituents independently selected from the group consisting of:

[0083] R 20 is preferably -NR 21 R 22 (where R 21 and R 22 is as defined above).

[0084] One preferred embodiment of the compound of formula [I] is Substructure: [ka] But the formula: [ka] The structure is represented by: R 5 is hydrogen; The ring group Cy has the formula: [ka] is a group represented by the formula: R 9 and R 10 However, each independently, (a)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-4 haloalkyl, or (e)-OC 1-4 haloalkyl; R 11 and R 12 each independently represents hydrogen or C 1-4 is alkyl; R 13 but, (a)C 1-4 Alkyl, (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-6 Haloalkyl, (e)-OC 1-4 haloalkyl, or (f)C 3-6 cycloalkyl, where the cycloalkyl is optionally substituted with one or two halogens; or R 13 is R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; R 1 is hydrogen; R 2 , R 3 and R 4 However, each independently, (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (f) Formula: [ka] (In the formula, R 20 are as defined above) The compound of formula [I] forms a group represented by the formula:

[0085] Another preferred embodiment of the compound of formula [I] is Substructure: [ka] but, (1) Formula: [ka] [During the ceremony, R 5 is hydrogen or C 1-4 alkyl {wherein the alkyl is (a) carboxy, (b)-CO-C 1-4 Alkoxy, or (c)-CO-NR 6 R 7 (where R 6 and R 7 are each independently hydrogen or C 1-4 alkyl), optionally substituted with or (2) Formula: [ka] (In the formula, R 8 is C 1-4 (It is alkyl) The structure is represented by: The ring group Cy is (1) Formula: [ka] (In the formula, R 9 and R 10 are each independently (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl, R 11 and R 12 are each independently (a) hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl, R 13 teeth, (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 Alkoxy, (d) C 1-6 haloalkyl, or (e)-OC 1-4 haloalkyl, or R 13 is R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) may form a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms. or (2) Formula: [ka] (In the formula, R 14 and R 15 are each independently 1-4 Alkyl or C 1-4 is haloalkyl, R 16 is C 1-6 Alkyl or C 3-6 cycloalkyl) is a group represented by the formula: R 1 but, (1) Hydrogen, (2) Cyano, (3) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (4) C 1-4 haloalkyl, or (5)-CO-C 1-4 alkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (7)-OC 1-4 Haloalkyl, (8)-OR 17 (where R 17 is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C 3-6 Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or Equation (11): [ka] or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a) cyano, (b)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (c) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with 1 or 2 halogens; (e) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (g) C 5-6 Cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (i) Formula: [ka] {where, R 20 teeth, (1) C 1-4 Alkyl, or (2)-NR 21 R 22 (where R 21 and R 22 are each independently (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. The compound of formula [I] forms a group represented by the formula:

[0086] Another preferred embodiment of the compound of formula [I] is a compound of formula [II]: [ka] A compound represented by the formula: R 9 and R 10 Each of them is independent. (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl; R 11 and R 12 Each of them is independent. (a) hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl; R 13 but, (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 Alkoxy, (d) C 1-6 haloalkyl, or (e)-OC 1-4 haloalkyl, or R 13 R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (7)-OC 1-4 Haloalkyl, (8)-OR 17 (where R 17 is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C 3-6 Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or Equation (11): [ka] or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R3 R 4 The base is (a) cyano, (b)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (c) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with 1 or 2 halogens; (e) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4alkyl, optionally substituted with (g) C 5-6 Cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (i) Formula: [ka] {where, R 20 teeth, (1) C 1-4 Alkyl, or (2)-NR 21 R 22 (where R 21 and R 22 are each independently (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. This forms a group represented by the formula:

[0087] A preferred embodiment of the compound of formula [II] is a compound of formula [III]: [ka] A compound represented by the formula: R 9 and R 10 Each of them is independent. (a) hydrogen, (b)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl; R 13 but, (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 Alkoxy, (d) C 1-6 haloalkyl, or (e)-OC 1-4 haloalkyl, or R 13 R 11 or R 12 together with the carbon atoms to which they are attached (a)C 5-6 Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (7)-OC 1-4 Haloalkyl, (8)-OR 17 (where R 17 is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C 3-6 Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or Equation (11): [ka] or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a) cyano, (b)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (c) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with 1 or 2 halogens; (e) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (g) C 5-6 Cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (i) Formula: [ka] {where, R 20 teeth, (1) C 1-4 Alkyl, or (2)-NR 21 R 22 (where R 21 and R 22 are each independently (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. This forms a group represented by the formula:

[0088] A preferred embodiment of the compound of formula [III] is R 9 and R 10 Each of them is independent. (a)C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (b)C 1-4 Alkoxy, (c) halogens, (d) C 1-4 haloalkyl, or (e)-OC 1-4 haloalkyl; R 13 But, C 1-6 Haloalkyl or -OC 1-4 haloalkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C 1-4Haloalkyl, where the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (f) Formula: [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. This forms a group represented by the formula:

[0089] A more preferred embodiment of the compound of formula [III] is R 9 and R 10 are each independently, C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 13 But, C 1-6 Haloalkyl or -OC 1-4 haloalkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4Alkoxy, and (c)-SO2-C 1-4 alkyl, (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (5) C 1-4 Haloalkyl, where the haloalkyl is hydroxy or C 1-4 substituted with alkoxy; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The base is (a)C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; or Formula (c): [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. This forms a group represented by the formula:

[0090] A further preferred embodiment of the compound of formula [III] is R 9 and R 10 are each independently, C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 13 But, C 1-6 Haloalkyl or -OC 1-4 haloalkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4alkyl, aryl, arylsulfonyl, arylalkyl, arylsulfonyl ... R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The group is C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), which may be substituted with 1 to 3 substituents independently selected from the group consisting of:

[0091] An even more preferred embodiment of the compound of formula [III] is R 9 and R 10 are each independently, C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 13 But, C 1-6 is haloalkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, aryl, arylsulfonyl, arylalkyl, arylsulfonyl ... R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The group is C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), which may be substituted with 1 to 3 substituents independently selected from the group consisting of:

[0092] Another more preferred embodiment of the compound of formula [III] is R 9 and R 10 are each independently, C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); R 13 But, -OC 1-4 haloalkyl; R 2 , R 3 and R 4 Each of them is independent. (1) Hydrogen, (2) Hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, aryl, arylsulfonyl, arylalkyl, arylsulfonyl ... R 2 , R 3 and R 4 together with the carbon atom to which they are attached, form -CR 2 R 3 R 4 The group is C 3-6 Cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 Alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), which may be substituted with 1 to 3 substituents independently selected from the group consisting of:

[0093] Another preferred embodiment of the compound of formula [I] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X], or [XI]: [ka] (In the formula, R 9 , R 10 , R 12 , R 14 , R 15 , and R 16 are as defined above) It is a compound represented by the formula:

[0094] As used herein, the term "pharmaceutical acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutical acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, the compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base, or an organic base to obtain a pharma- ceutically acceptable salt thereof.

[0095] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid, and preferably salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferred examples of the salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.

[0096] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium, and preferably salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferred are salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0097] Compound [I] may exist as a solvate. A solvate is, for example, a compound [I] coordinated with a solvent molecule. The solvate may be any pharma- ceutically acceptable solvate, and may include hydrate, acetate solvate, acetone solvate, ethanol solvate, and dimethylsulfoxide solvate of compound [I]. Specifically, the solvate may include hemihydrate, monohydrate, dihydrate, monoacetate solvate, monoacetone solvate, or monoethanol solvate of the sodium salt of the compound of formula [I], or monohydrate, monoacetone solvate, or 2 / 3 ethanol solvate of the dihydrochloride salt of the compound of formula [I]. These solvates may be obtained according to known methods.

[0098] Compound [I] may exist as a tautomer. In that case, compound [I] may exist as an individual tautomer or a mixture of tautomers. For example, the compound [I] may have the following formula: [ka] The structures shown in are as follows, unless otherwise noted: (1) [ka] (2) [ka] (3) [ka] (4) [ka] or (5) It means that these mixtures can exist and / or be expressed as such.

[0099] Compound [I] may have a carbon-carbon double bond, and in that case, compound [I] may exist as an E form, a Z form, or a mixture of E and Z forms. Compound [I] may have stereoisomers that should be recognized as cis / trans isomers. In that case, compound [I] may exist as a cis form, a trans form, or a mixture of cis and trans forms. Compound [I] may have one or more asymmetric carbons, in which case compound [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers. Compound [I] may exist as atropisomers, in which case compound [I] may exist as an individual atropisomer or a mixture of atropisomers. Compound [I] may simultaneously contain multiple structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0100] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned isomers that may exist, unless otherwise noted.

[0101] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization, or the individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or by stereoselective reactions.

[0102] Separation of the individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, well known in the art. Alternatively, one of the enantiomers can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries and asymmetric catalysts.

[0103] Absolute configuration may be determined by the X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0104] Compound [I] is an isotope ( 2 H(D), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 18 O. 18 F, 35 S, 123I, etc. For example, when the compound of formula [I] has a methyl group, the methyl group can be replaced with a -CD3 group, and the compound obtained in this way is also included in the present invention. The isotopically labeled compound [I] can be useful in medicine, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostics (positron emission tomography (PET), single photon emission computed tomography (SPECT), etc.). The isotopically labeled compound [I] can be prepared by known methods or the methods described herein, using an isotopically labeled compound instead of a non-isotopically labeled compound.

[0105] Compound [I] is preferably a substantially purified compound [I], more preferably a compound [I] purified to a purity of 80% or more.

[0106] The pharmaceutical composition of the present invention may be prepared by appropriately mixing an appropriate amount of compound [I] with at least one or more pharma- ceutically acceptable carriers, etc., according to a method known in the technical field of pharmaceutical preparations. The content of compound [I] in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the entire composition.

[0107] Dosage forms of compound [I] include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0108] Examples of "pharmaceutical acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used as necessary.

[0109] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like. The "fluidizing agent" includes light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. "Soothing agents" include benzyl alcohol and the like. Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more of these. Examples of the "preservatives" include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. Examples of "coloring agents" include food dyes (food red No. 2 or 3, food yellow No. 4 or 5, etc.), β-carotene, and the like. "Sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0110] The pharmaceutical composition of the present invention can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to mammals other than humans (mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.) and humans. The dosage (also referred to as "therapeutically effective amount" in this specification) varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when orally administered to an adult patient is usually in the range of about 0.01 mg to 1 g per day as the compound of formula [I] or a pharma- ceutically acceptable salt thereof, which is the active ingredient. These amounts can be administered once or in several divided doses.

[0111] Compound [I] has an NLRP3 inflammasome inhibitory effect, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity. Examples of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphoid tissue inflammation), and the like. and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0112] "Inhibiting NLRP3 inflammasome" means inhibiting the function of NLRP3 inflammasome to eliminate or weaken its activity, for example, means inhibiting the function of NLRP3 inflammasome based on the conditions of Test Example 1 described below. By inhibiting the function of NLRP3 inflammasome, the production amount of IL-1β and / or IL-18 is suppressed, preferably the production amount of IL-1β and IL-18 is suppressed. "Inhibiting NLRP3 inflammasome" preferably means "inhibiting human NLRP3 inflammasome".

[0113] Since compound [I] has NLRP3 inflammasome inhibitory activity, compound [I] or a pharma- ceutically acceptable salt thereof can be used as an NLRP3 inflammasome inhibitor either as is or after being appropriately formulated.

[0114] As used herein, "treatment" includes amelioration of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence. As used herein, "prevention" includes suppressing and delaying the onset of symptoms.

[0115] As long as there is no contradiction between an embodiment disclosed in one place in this specification and an embodiment disclosed in another place, any combination of two or more of these is also intended to be encompassed by the present invention.

[0116] [General manufacturing method] General methods for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof are illustrated below. However, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof is not limited to these methods. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they can be used to proceed to the next step without isolation and / or purification. In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature between 1°C and 40°C. The abbreviations are as follows. HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0117] Production method A1: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can be prepared, for example, by the following Preparation Method A1. [ka] {where, R 2 , R 3 , R 4 and the ring group Cy are as defined above, R A11 are each independently 1-4 is alkyl, R A12 is a boronic acid, a boronic ester (e.g., a boronic acid pinacol ester), a trifluoroborate, or tributyltin; L A11 , L A12 , and L A13 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy). (Process A1-1) The compound [A1-3] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof with the compound [A1-2] in a solvent in the presence of an acid. Examples of acids include sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid, and p-toluenesulfonic acid. Preferred acids are sulfuric acid or p-toluenesulfonic acid. Examples of the solvent include toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. A preferred solvent is toluene. The reaction temperature is, for example, from 0°C to 150°C, preferably from 5°C to 40°C. The compound [A1-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A1-2] is a commercially available product, or may be prepared from a commercially available product by a known method.

[0118] (Process A1-2) The compound [A1-5] or a salt thereof can be produced by reacting the compound [A1-3] or a salt thereof with the compound [A1-4] or a salt thereof in a solvent in the presence of a base. Examples of bases include triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene, and N,N-diisopropylethylamine. A preferred base is triethylamine or N,N-diisopropylethylamine. Examples of the solvent include toluene, methanol, ethanol, tetrahydrofuran, and mixtures thereof. The preferred solvent is toluene or methanol. The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 40°C. The compound [A1-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0119] (Process A1-3) The compound [A1-6] or a salt thereof can be produced by reacting the compound [A1-5] or a salt thereof in a solvent in the presence of an acid. Examples of acids include trifluoroacetic acid, sulfuric acid, hydrochloric acid, and triethylsilyl trifluoromethanesulfonate. A preferred acid is trifluoroacetic acid. Examples of the solvent include toluene, tetrahydrofuran, ethyl acetate, cyclopentyl methyl ether, dichloromethane, and mixtures thereof. A preferred solvent is toluene. The reaction temperature is, for example, from -78°C to 60°C, preferably from 0°C to 40°C.

[0120] (Process A1-4) The compound [A1-7] or a salt thereof can be produced by reacting the compound [A1-6] or a salt thereof in a solvent in the presence of a base. Bases include, for example, sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide. Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, chloroform, and mixtures thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from 0°C to 150°C, preferably from 50°C to 100°C.

[0121] (Process A1-5) The compound [IA] or a salt thereof can be prepared by reacting a compound [A1-7] or a salt thereof with a compound [A1-8] or a salt thereof in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). A preferred catalyst is [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct. Examples of bases include tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. A preferred base is tripotassium phosphate. R A12 When the boronic acid is, for example, a boronic acid ester (such as a pinacol boronic acid ester), or a trifluoroborate, the solvent may be, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, or a mixture thereof. A preferred solvent is a mixture of toluene and water. R A12 When the solvent is, for example, tributyltin, examples of the solvent include toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylsulfoxide. The preferred solvent is N,N-dimethylacetamide. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [A1-8] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. Instead of compound [A1-8] or a salt thereof, this production method may be carried out using a compound or a salt thereof having a functional group or a protected functional group that can be converted into compound [A1-8] or a salt thereof by a known reaction to obtain a compound or a salt thereof corresponding to compound [IA], and then the functional group may be converted to produce compound [IA] or a salt thereof.

[0122] In this production method, instead of compound [A1-4] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the benzene ring by a known reaction, or a salt thereof, is used to carry out this production method, and a compound corresponding to compound [IA] or a salt thereof is obtained, and then the functional group or the protected substituent is converted to the various substituents to produce compound [IA] or a salt thereof. For example, instead of compound [A1-4] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the benzene ring by a known reaction, or a salt thereof, may be used to produce compound [IA] or a salt thereof. A41 or a salt thereof, to obtain a compound corresponding to compound [IA], i.e., compound [IB] or a salt thereof, and then subjecting L to Production Method A4. A41 Cy A41 The compound [IC] or a salt thereof may be prepared by converting the compound [IC] into

[0123] Production method A2: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can also be prepared, for example, by the following Preparation Method A2. [ka] {where, R 2 , R 3 , R 4 , L A11 , L A12 , R A12 and the ring group Cy are as defined above, R A21 is a protecting group for hydroxy (e.g., benzyl, 4-methoxybenzyl, and 2-methoxybenzyl), and R A21 is preferably benzyl. (Process A2-1) The compound [A2-1] or a salt thereof can be produced by reacting the compound [A1-6] or a salt thereof in a solvent in the presence of an alcohol and a base. Alcohols include, for example, benzyl alcohol, 4-methoxybenzyl alcohol and 2-methoxybenzyl alcohol. A preferred alcohol is benzyl alcohol. Examples of the base include sodium hydride, potassium tert-butoxide, and sodium tert-butoxide. A preferred base is sodium hydride. Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and a mixture thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -20°C to 100°C, preferably from 0°C to 50°C.

[0124] (Process A2-2) The compound [A2-2] or a salt thereof can be produced by reacting the compound [A2-1] or a salt thereof with the compound [A1-8] or a salt thereof in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). A preferred catalyst is [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct. Examples of bases include tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. A preferred base is tripotassium phosphate. R A12When the boronic acid is, for example, a boronic acid ester (such as a pinacol boronic acid ester), or a trifluoroborate, the solvent may be, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, or a mixture thereof. A preferred solvent is a mixture of toluene and water. R A12 When the solvent is, for example, tributyltin, examples of the solvent include toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylsulfoxide. The preferred solvent is N,N-dimethylacetamide. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C.

[0125] (Process A2-3) Compound [IA] or a salt thereof is R A21 The deprotection reaction can be carried out by removing R A21 The process may be carried out under suitable conditions depending on the type of material. For example, R A21 When is benzyl, the compound [IA] or a salt thereof can be prepared by reacting the compound [A2-2] or a salt thereof in the presence of an acid. If necessary, a solvent may be added. Acids include, for example, formic acid, trifluoroacetic acid, and hydrochloric acid. A preferred acid is formic acid. The reaction temperature is, for example, 0°C to 120°C, preferably 10°C to 100°C. Solvents include, for example, toluene, tetrahydrofuran, and 1,4-dioxane. Instead of compound [A1-8] or a salt thereof, this production method may be carried out using a compound or a salt thereof having a functional group or a protected functional group that can be converted into compound [A1-8] or a salt thereof by a known reaction to obtain a compound or a salt thereof corresponding to compound [IA], and then the functional group may be converted to produce compound [IA] or a salt thereof.

[0126] Production method A3: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can also be prepared, for example, by the following Preparation Method A3. [ka] {where, R 2 , R 3 , R 4 and the ring group Cy are as defined above, R A31 is C 1-4 is alkyl, R A32 is hydrogen or an amino protecting group (e.g., tert-butoxycarbonyl), R A33 is hydrogen or C 1-4 alkyl} (Process A3-1) Compound [A3-3] or a salt thereof can be produced by reacting compound [A3-1] or a salt thereof with compound [A3-2] or a salt thereof in a solvent in the presence of an oxidizing agent, an acid and an additive. Oxidizing agents include, for example, sodium nitrite, butyl nitrite, and isoamyl nitrite. A preferred oxidizing agent is sodium nitrite. Examples of acids include concentrated hydrochloric acid, concentrated sulfuric acid, and nitric acid. A preferred acid is concentrated hydrochloric acid. Additives include, for example, sodium acetate and potassium acetate. A preferred additive is sodium acetate. Examples of the solvent include ethanol, methanol, butanol, water, and mixtures thereof. A preferred solvent is a mixture of ethanol and water. The reaction temperature is, for example, from -40°C to 50°C, preferably from -10°C to 40°C. The compound [A3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A3-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0127] (Process A3-2) The compound [A3-5] or a salt thereof can be produced by reacting the compound [A3-3] or a salt thereof with the compound [A3-4] in a solvent in the presence of a base. Examples of bases include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene. A preferred base is triethylamine. Examples of the solvent include chloroform, 1,2-dichloroethane, dichloromethane, and mixtures thereof. The preferred solvent is chloroform. The reaction temperature is, for example, from 20°C to 120°C, preferably from 50°C to 100°C. The compound [A3-4] is a commercially available product.

[0128] (Process A3-3) The compound [A3-6] or a salt thereof can be produced by reacting the compound [A3-5] or a salt thereof in a solvent in the presence of a base. Examples of bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide. A preferred base is sodium hydroxide. Examples of the solvent include ethanol, methanol, butanol, tetrahydrofuran, water, and mixtures thereof. A preferred solvent is a mixture of ethanol and water. The reaction temperature is, for example, 0°C to 100°C, preferably 5°C to 50°C.

[0129] (Process A3-4) The compound [A3-7] or a salt thereof can be produced by reacting the compound [A3-6] or a salt thereof in a solvent in the presence of a reactant and a base. Reactants include, for example, sodium azide and diphenylphosphoryl azide. A preferred reactant is diphenylphosphoryl azide. Examples of bases include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene. A preferred base is triethylamine. Examples of the solvent include tert-butanol, benzyl alcohol, tetrahydrofuran, and mixtures thereof. The preferred solvent is tert-butanol. The reaction temperature is, for example, from 0°C to 150°C, preferably from 50°C to 120°C.

[0130] (Process A3-5) The compound [A3-8] or a salt thereof can be produced by reacting the compound [A3-7] or a salt thereof in a solvent in the presence of an oxidizing agent and a base. Examples of the oxidizing agent include hydrogen peroxide, iron oxide, and manganese dioxide. The preferred oxidizing agent is hydrogen peroxide. Examples of bases include sodium hydroxide, potassium hydroxide, and barium hydroxide. A preferred base is sodium hydroxide. Examples of the solvent include ethanol, dimethyl sulfoxide, water, and a mixture thereof. A preferred solvent is a mixture of ethanol, dimethyl sulfoxide, and water. The reaction temperature is, for example, from -20°C to 50°C, preferably from 10°C to 40°C.

[0131] (Process A3-6) The compound [A3-9] or a salt thereof is R A32 The deprotection reaction can be carried out by removing R A32 The process may be carried out under suitable conditions depending on the type of material. For example, R A32 When is tert-butoxycarbonyl, the compound [A3-9] or a salt thereof can be produced by reacting a compound [A3-8] or a salt thereof in a solvent in the presence of an acid. Acids include, for example, hydrogen chloride, trifluoroacetic acid and sulfuric acid. A preferred acid is hydrogen chloride. Examples of the solvent include ethyl acetate, cyclopentyl methyl ether, and mixtures thereof. The preferred solvent is ethyl acetate. The reaction temperature is, for example, 0°C to 80°C, preferably 10°C to 50°C. The compound [A3-9] or a salt thereof may be prepared by reversing the procedures of steps A3-5 and A3-6.

[0132] (Process A3-7) The compound [A3-11] or a salt thereof can be produced by reacting the compound [A3-9] or a salt thereof with the compound [A3-10] or a salt thereof in a solvent in the presence of a condensing agent and a base. Condensing agents include, for example, HATU, WSC, and propylphosphonic anhydride. A preferred condensing agent is HATU. Examples of bases include sodium methoxide, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene. A preferred base is N,N-diisopropylethylamine. Examples of the solvent include methanol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. The preferred solvent is N-methylpyrrolidone. The reaction temperature is, for example, from 0°C to 120°C, preferably from 50°C to 100°C. The compound [A3-10] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0133] (Process A3-8) The compound [IA] or a salt thereof can be prepared by reacting a compound [A3-11] or a salt thereof in a solvent in the presence of a base. Examples of bases include sodium methoxide, sodium tert-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene. A preferred base is 1,8-diazabicyclo[5,4,0]-7-undecene. Examples of the solvent include ethanol, methanol, butanol, water, and mixtures thereof. A preferred solvent is a mixture of ethanol and water. The reaction temperature is, for example, from 0°C to 180°C, preferably from 50°C to 150°C. Instead of compound [A3-10] or a salt thereof, this manufacturing method may be carried out using a compound or its salt having a functional group or a protected functional group that can be converted into compound [A3-10] or a salt thereof by a known reaction to obtain a compound or its salt corresponding to compound [IA], and then the functional group may be converted to produce compound [IA] or its salt.

[0134] In this production method, instead of compound [A3-1] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the benzene ring by known reactions, or a salt thereof, may be used to carry out this production method to obtain a compound corresponding to compound [IA] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [IA] or a salt thereof. For example, instead of compound [A3-1] or a salt thereof, a compound having an amino group and the below-described L A41 or a salt thereof, to obtain a compound corresponding to compound [IA], i.e., compound [IB] or a salt thereof, and then, by Production Method A4, A41 Cy A41 The compound [IC] or a salt thereof may be prepared by converting the compound [IC] into

[0135] In this manufacturing method, instead of compound [A3-1] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the benzene ring by a known reaction, or a salt thereof, may be used to carry out this manufacturing method, to obtain a compound corresponding to compound [A3-8] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [A3-8] or a salt thereof. For example, instead of compound [A3-1] or a salt thereof, a compound having an amino group and the below-described L A41 or a salt thereof, to obtain a compound corresponding to compound [A3-8], i.e., compound [A3-8-A] or a salt thereof, and then subjecting the compound to production method A5. A41 Cy A41 To prepare the compound [A3-8-B] or a salt thereof,

[0136] Production method A4: Production method of compound [IC] or a salt thereof The compound [IC] or a salt thereof can be produced, for example, by the following Production Method A4. [ka] [In the formula, R 2 , R 3 , and R 4 is as defined above, Cy A41 is C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two halogens; L A41 is a leaving group (e.g., halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy), provided that the leaving group is attached at the ortho or para position of the benzene ring. (Process A4-1) Compound [IC] or a salt thereof can be prepared by reacting compound [IB] or a salt thereof with compound [A4-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. A preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. Examples of bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate. Examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixtures thereof. A preferred solvent is a mixture of toluene and water. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. Compound [IB] or a salt thereof may be prepared from a commercially available product by a known method. Compound [IB] or a salt thereof may be prepared, for example, by the above-mentioned preparation method. The compound [A4-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.

[0137] Production method A5: Production method for compound [A3-8-B] or a salt thereof The compound [A3-8-B] or a salt thereof can be produced, for example, by the following Production Method A5. [ka] (wherein each symbol is as defined above) (Process A5-1) Compound [A3-8-B] or a salt thereof can be produced by reacting compound [A3-8-A] or a salt thereof with compound [A4-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. A preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. Examples of bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate. Examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixtures thereof. A preferred solvent is a mixture of toluene and water. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [A3-8-A] or a salt thereof may be produced from a commercially available product by a known method. The compound [A3-8-A] or a salt thereof may be produced, for example, by the above-mentioned production method.

[0138] Production method A6: Production method of compound [ID] or a salt thereof, or compound [IE] or a salt thereof The compound [ID] or a salt thereof, or the compound [IE] or a salt thereof can also be produced, for example, by the following Production Method A6. [ka] {where, R 2 , R 3 , R 4 , R 8 and the ring group Cy are as defined above, R A61 is C 1-4 is alkyl, L A61 is a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy) (Process A6-1) Compound [ID] or a salt thereof, or compound [IE] or a salt thereof can be produced by reacting compound [IA] or a salt thereof with compound [A6-1] in a solvent in the presence of a base. Examples of bases include cesium carbonate, sodium methoxide, sodium hydride and potassium carbonate. A preferred base is sodium hydride. Solvents include, for example, methanol, N,N-dimethylformamide and tetrahydrofuran. A preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 100°C, preferably 10°C to 50°C. The compound [A6-1] is a commercially available product, or may be prepared from a commercially available product by a known method. EXAMPLES

[0139] Next, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof will be specifically described with reference to Preparation Examples. However, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof is not limited to these Preparation Examples. Unless otherwise specified, % indicates % by weight. Ratios shown in mixed solvents indicate volume ratios unless otherwise specified. NMR was measured at 400 MHz.

[0140] [Production Example 1]: Synthesis of 2-(2,4-dimethylphenyl)-5,6-dimethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 13) [ka] Step 1-1: 4-chloro-2-(2,4-dimethylphenyl)-6-methyl-2H-pyrazolo[3,4-d]pyrimidine [ka] 4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (2.0 g) was added to a mixture of (2,4-dimethylphenyl)hydrazine hydrochloride (2.0 g), triethylamine (3.2 mL), and ethanol (40 mL) at 0° C. under an argon atmosphere, and the mixture was stirred at 100° C. for 3 hours, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 10 vol% to 70 vol% ethyl acetate / hexane) to obtain the title compound (1.6 g). 1 H-NMR (CDCl3) δ: 8.19 (1H, s), 7.29 (1H, d, J = 8.1 Hz), 7.19 (1H, t, J = 0.6 Hz), 7.15-7.13 (1H, m), 2.81 (3H, s), 2.41 (3H, s), 2.25 (3H, s).

[0141] Step 1-2: 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 4-chloro-2-(2,4-dimethylphenyl)-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (1.6 g) and 1,2-dimethoxyethane (13 mL) was added with 4M aqueous sodium hydroxide solution (6.3 mL), stirred at 110° C. for 6 hours, and then neutralized with 2M hydrochloric acid. The residue was purified by column chromatography (developing solvent: 10 vol% to 100 vol% ethyl acetate / hexane) to obtain the title compound (1.2 g). 1 H-NMR (DMSO-D6) δ: 11.71 (1H, br s), 8.68 (1H, s), 7.31 (1H, d, J = 8.1 Hz), 7.23 (1H, s), 7.17 (1H, d, J = 8.1 Hz), 2.34 (3H, s), 2.31 (3H, s), 2.15 (3H, s). LC-MS (MH+): 255.

[0142] Step 1-3: 2-(2,4-dimethylphenyl)-5,6-dimethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (50 mg) and N,N-dimethylformamide (0.5 mL), cesium carbonate (130 mg) and iodomethane (0.024 mL) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the title compound (32 mg). 1H-NMR (DMSO-d6) δ: 8.74 (1H, s), 7.33 (1H, d, J = 7.9 Hz), 7.25-7.25 (1H, m), 7.19-7.17 (1H, m), 3.48 (3H, s), 2.56 (3H, s), 2.36 (3H, s), 2.16 (3H, s). LC-MS(MH+): 269.

[0143] [Production Example 2]: Synthesis of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 83) and 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 88) [ka] Step 2-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (500 mL) and sulfuric acid (1.1 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (170 g) and toluene (1.0 L), and the mixture was stirred at room temperature for 2.5 hours. Basic silica gel (Fujisilica, 330 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hours, after which the added silica gel was removed by filtration. The silica gel was washed with ethyl acetate, and the solvent was removed under reduced pressure to obtain the title compound (175 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s).

[0144] Step 2-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (82 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (80 g) and methanol (560 mL), and then cooled in an ice bath. Triethylamine (133 mL) was slowly added to the reaction mixture, and the mixture was stirred at the same temperature for 1.5 hours. The resulting solid was collected by filtration and washed successively with methanol (150 mL) and hexane (100 mL) to obtain the title compound (120 g). 1 H-NMR (CDCl3) δ: 8.28 (1H, d, J = 4.4 Hz), 7.10 (2H, s), 6.14 (1H, d, J = 4.9 Hz), 5.56 (1H, s), 3.45 (6H, s), 2.43 (6H, s). LC-MS (MH+): 436.

[0145] Step 2-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] Trifluoroacetic acid (43 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (121 g) and toluene (970 mL) at 0° C. under a nitrogen atmosphere over 10 minutes. The reaction mixture was slowly added dropwise to an ice-cooled mixture of tripotassium phosphate (120 g), water (400 mL), and tetrahydrofuran (640 mL). After separation of the organic layer, the aqueous layer was extracted with ethyl acetate. All the organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a crude product (109 g). LC-MS (MH+): 372.

[0146] Step 2-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine crude product (109 g) and tetrahydrofuran (830 mL), 4 M aqueous sodium hydroxide solution (210 mL) was added at room temperature and stirred at 65° C. for 5 hours. After cooling the reaction mixture in an ice bath, 2 M hydrochloric acid (280 mL) was slowly added dropwise. After the reaction mixture was extracted with ethyl acetate, the aqueous layer was extracted again with a mixture of ethyl acetate / tetrahydrofuran (v / v = 1 / 4). All the organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether (550 mL) and ethyl acetate (150 mL) were added to the obtained crude product, and the mixture was stirred for 1 hour. The solid was then filtered to obtain the title compound (79 g). 1H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 8.81 (1H, s), 7.53 (2H, s), 1.95 (6H, s). LC-MS (MH+): 354.

[0147] Step 2-5: 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.0 g), cyclopropylboronic acid (1.2 g), toluene (15 mL) and 2 M aqueous potassium phosphate solution (7.1 mL) were added with 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.37 g) and stirred at 100°C for 5 hours. The reaction mixture was allowed to cool to room temperature, water was added and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 30vol% to 80vol% ethyl acetate / hexane) to obtain the title compound (740 mg). 1H-NMR (DMSO-D6) δ: 11.98 (1H, s), 8.57 (1H, s), 6.94 (2H, s), 1.99-1.89 (8H, m), 1.08 (2H, t, J = 3.7 Hz), 1.02-0.95 (4H, m), 0.72 (2H, dt, J = 8.6, 3.2 Hz). LC-MS(MH+): 321.

[0148] Step 2-6: 6-Cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde [ka] Under an argon atmosphere at 0°C, lithium bis(trimethylsilyl)amide (1.1 M tetrahydrofuran solution, 1.1 mL) was added to a mixture of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (100 mg) and tetrahydrofuran (1.0 mL), and the mixture was stirred at the same temperature for 10 minutes. N,N-dimethylformamide (0.12 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (110 mg). LC-MS (MH+): 349.

[0149] Step 2-7: 6-Cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 83) [ka] Sodium borohydride (35 mg) was added to a mixture of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde crude product (110 mg), methanol (1.1 mL) and tetrahydrofuran (1.1 mL) in a water bath, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 20 vol% to 80 vol% ethyl acetate / hexane) to obtain the title compound (60 mg). 1H-NMR (DMSO-D6) δ: 12.04 (1H, s), 6.92 (2H, s), 4.46 (2H, d, J = 4.9 Hz), 1.98-1.90 (2H, m), 1.84 (6H, s), 1.09-1.05 (2H, m), 1.01-0.97 (4H, m), 0.75-0.72 (2H, m). (1 peak lost (OH)) LC-MS (MH+): 351.

[0150] Step 2-8: 3-(bromomethyl)-6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere at 0°C, phosphorus tribromide (8.1 μL) was added to a mixture of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (30 mg) and deuterated chloroform (1.5 mL), and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (36 mg). LC-MS (MH+): 413.

[0151] Step 2-9: 6-Cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 88) [ka] At 0°C, a 5 M solution of sodium methoxide in methanol (0.086 mL) was added to a mixture of the crude product of 3-(bromomethyl)-6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (36 mg) and tetrahydrofuran (1.1 mL), and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 20 vol% to 60 vol% ethyl acetate / hexane) and then reverse phase column chromatography (developing solvent: 10 vol% to 100 vol% acetonitrile / water) to obtain the title compound (5.7 mg). 1 H-NMR (DMSO-D6) δ: 12.04 (1H, s), 6.94 (2H, s), 4.39 (2H, s), 3.15 (3H, s), 1.99-1.90 (2H, m), 1.82 (6H, s), 1.09-1.07 (2H, m), 1.02-0.96 (4H, m), 0.76-0.72 (2H, m). LC-MS (MH+): 365.

[0152] [Production Example 3]: Synthesis of 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 147) and 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146) [ka] Step 3-1: methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate [ka] To a mixture of 4-bromo-2,6-dimethylaniline (45 g) and ethanol (72 mL), water (54 mL) and concentrated hydrochloric acid (47.3 mL) were added at room temperature. The reaction mixture was cooled to below -10°C, and then an aqueous solution (54 mL) of sodium nitrite (17.1 g) was slowly added dropwise while keeping the temperature below 0°C. After stirring at the same temperature for 30 minutes, an aqueous solution (315 mL) of methyl 2-chloro-3-oxobutanoate (27.1 mL) and sodium acetate (55.4 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound.

[0153] Step 3-2: Methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate [ka] To a mixture of the crude product of methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate and chloroform (575 mL), fumaronitrile (20.2 g) and triethylamine (36.1 mL) were added, and the mixture was stirred at 80°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer obtained was washed with saturated saline, and then anhydrous magnesium sulfate and silica gel (200 g) were added. The mixture was stirred at room temperature for 1 hour, and filtered through a column covered with basic silica gel (Fujisilicia, 200 g) (elution solvent: ethyl acetate), and the solvent was distilled off under reduced pressure. The obtained solid was stirred with a mixture of ethyl acetate (50 mL) and hexane (50 mL), and the solid was collected by filtration. The obtained solid was washed with a mixture of ethyl acetate (50 mL) and hexane (50 mL) to obtain the title compound (38.9 g). 1 H-NMR (DMSO-D6) δ: 9.00 (1H, s), 7.57 (2H, s), 3.90 (3H, s), 1.96 (6H, s).

[0154] Step 3-3: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid [ka] To a mixture of methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate (36 g) and methanol (360 mL), 2M aqueous sodium hydroxide solution (108 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid and stirred at room temperature for 30 minutes. Water (200 mL) was added to the reaction mixture and stirred for another 2 hours. The resulting solid was collected by filtration and washed with water and hexane in that order to obtain the title compound (33.8 g). 1 H-NMR (DMSO-D6) δ: 13.85 (1H, br s), 8.95 (1H, s), 7.56 (2H, s), 1.97 (6H, s).

[0155] Step 3-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile [ka] Under a nitrogen atmosphere, diphenylphosphoryl azide (34.0 mL) was added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (33.8 g), triethylamine (29.4 mL) and tert-butanol (507 mL), and the mixture was stirred at 90°C for 8 hours, and the solvent was distilled off under reduced pressure. Trifluoroacetic acid (24.4 mL) was added to a mixture of the residue and chloroform (200 mL), and the mixture was stirred at room temperature overnight. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: 1vol% to 40vol% ethyl acetate / hexane) to obtain the title compound (30.7 g). 1 H-NMR (DMSO-D6) δ: 8.31 (1H, s), 7.46 (2H, s), 5.76 (2H, s), 2.01 (6H, s). LC-MS (MH+): 291.

[0156] Step 3-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide [ka] Sodium hydroxide (12.7 g) and 30% hydrogen peroxide (43.1 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (30.7 g), ethanol (184 mL) and dimethyl sulfoxide (46 mL) under ice bath. The reaction mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium sulfite solution was added. The mixture was acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 30vol% to 100vol% ethyl acetate / hexane) to obtain the title compound (8.11 g). 1 H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.45 (2H, s), 7.30 (1H, br s), 6.91 (1H, br s), 5.53 (2H, br s), 2.02 (6H, s).

[0157] Step 3-6: 2-(4-bromo-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (922 mg) and N,N-diisopropylethylamine (627 mg) were added to a mixture of trans-2-fluorocyclopropane-1-carboxylic acid (252 mg) and N,N-dimethylformamide (3.0 mL), and the mixture was stirred at room temperature for 5 minutes. 3-Amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (300 mg) was added to the reaction mixture, and the mixture was stirred at 50°C for 3 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (4.8 mL), water (4.8 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.17 mL) were added to the residue and stirred at 90°C for 24 hours, after which 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) was added and stirred at 100°C for 14 hours. The reaction mixture was allowed to cool, and then ethyl acetate was added and washed with water and saturated saline in that order. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 33vol% to 50vol% ethyl acetate / hexane) to obtain the title compound (237 mg). 1 H-NMR (CDCl3) δ: 9.91 (1H, br s), 8.07 (1H, s), 7.34 (2H, s), 5.19-4.98 (1H, m), 2.31-2.16 (1H, m), 2.02 (6H, s), 1.83-1.64 (2H, m).

[0158] Step 3-7: 2-[4-(1-ethoxyvinyl)-2,6-dimethylphenyl]-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (237 mg), tributyl(1-ethoxyvinyl)stannane (340 mg), bis(triphenylphosphine)palladium(II) dichloride (44.1 mg) and toluene (4.7 mL) was stirred at 120° C. for 1 hour. The reaction mixture was allowed to cool, and then purified by column chromatography (developing solvent: 20 vol% to 50 vol% ethyl acetate / hexane) to obtain the title compound (149 mg). 1 H-NMR (CDCl3) δ: 10.46 (1H, br s), 8.08 (1H, s), 7.43 (2H, s), 5.20-5.00 (1H, m), 4.68 (1H, d, J = 2.8 Hz), 4.27 (1H, d, J = 2.8 Hz), 3.94 (2H, q, J = 7.0 Hz), 2.36-2.24 (1H, m), 2.05 (6H, s), 1.83-1.63 (2H, m), 1.45 (3H, t, J = 7.0 Hz).

[0159] Step 3-8: 2-(4-acetyl-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a mixture of 2-[4-(1-ethoxyvinyl)-2,6-dimethylphenyl]-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (149 mg), 2M hydrochloric acid (1.0 mL) and tetrahydrofuran (2.0 mL) was stirred at 50° C. for 1 hour. The reaction mixture was allowed to cool, ethyl acetate was added, and the mixture was washed with saturated saline. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (138 mg). 1 H-NMR (CDCl3) δ: 10.22 (1H, br s), 8.11 (1H, s), 7.76 (2H, s), 5.20-4.99 (1H, m), 2.64 (3H, s), 2.34-2.23 (1H, m), 2.12 (6H, s), 1.84-1.64 (2H, m).

[0160] Step 3-9: 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1RS,2SR)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 142) [ka] Under an argon atmosphere, a mixture of 2-(4-acetyl-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (110 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (1.1 mL) was stirred at 70° C. for 4 hours. The reaction mixture was slowly added dropwise to a stirred saturated aqueous sodium bicarbonate solution under ice cooling, and then extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 20 vol% to 50 vol% ethyl acetate / hexane) to obtain the title compound (89 mg). 1 H-NMR (CDCl3) δ: 10.14 (br s, 1H), 8.10 (s, 1H), 7.32 (s, 2H), 5.20-5.16 (m, 0.5H), 5.04-5.00 (m, 0.5H), 2.33-2.22 (m, 1H), 2.08 (s, 6H), 1.95 (t, 3H, J = 18.3 Hz), 1.84-1.63 (m, 2H). LC-MS (MH+): 363.

[0161] Step 3-10: 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 147), and 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146) [ka] 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1RS,2SR)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (89 mg) was optically resolved by column chromatography using a chiral column {Apparatus name: Japan Analytical Industry Co., Ltd. Automatic Recycle Preparative HPLC LaboACE LC-7080; Column: Daicel CHIRALPAK IH, 20 mm (ID) x 250 mm (L), 5 μm; Guard column: Daicel CHIRALPAK IH, 10 mm (ID) x 20 mm (L), 5 μm; Column temperature: 30°C; Mobile phase flow rate: 20 mL / min; Mobile phase mixing ratio: isocratic, hexane / ethanol = 80 / 20} to obtain the first peak fraction (24.2 ~ 32.0 As the first peak fraction (34.3 to 44.0 min), 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 147 compound, 38 mg) was obtained, and as the second peak fraction (34.3 to 44.0 min), 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146 compound, 38 mg) was obtained. The absolute stereoconfiguration of the compound of Example 147 was determined by X-ray crystal structure analysis. [2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 147] 1 H-NMR (CDCl3) δ: 10.47 (br s, 1H), 8.10 (s, 1H), 7.32 (s, 2H), 5.21-5.00 (m, 1H), 2.37-2.24 (m, 1H), 2.09 (s, 6H), 1.95 (t, 3H, J = 18.1 Hz), 1.83-1.65 (m, 2H). LC-MS (MH+): 363. [2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 146] 1 H-NMR (CDCl3) δ: 10.21 (br s, 1H), 8.10 (s, 1H), 7.32 (s, 2H), 5.20-5.00 (m, 1H), 2.34-2.23 (m, 1H), 2.08 (s, 6H), 1.95 (t, 3H, J = 18.1 Hz), 1.83-1.65 (m, 2H). LC-MS (MH+): 363.

[0162] [Production Example 4]: Synthesis of (R)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 154) and (S)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 155) [ka] Step 4-1: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-ol [ka] Under an argon atmosphere, a 1.56 M n-butyllithium hexane solution (13.8 mL) was added dropwise to a mixture of 2,5-dibromo-1,3-dimethylbenzene (6.0 g) and tetrahydrofuran (120 mL) at -78°C over 5 minutes. The mixture was stirred at the same temperature for 15 minutes, acetaldehyde (3.0 g) was added, and the mixture was stirred in an ice bath for 15 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with a mixture of ethyl acetate and hexane. The resulting organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of the title compound (7.4 g).

[0163] Step 4-2: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one [ka] Dess-Martin reagent (5.8 g) was slowly added to a mixture of crude 1-(4-bromo-3,5-dimethylphenyl)ethan-1-ol (3.7 g) and dichloromethane (30 mL) in a water bath, and the mixture was stirred at room temperature for 30 minutes. Isopropanol (1.0 mL) was added to the reaction mixture, and the mixture was purified by column chromatography (developing solvent: 10 vol% ethyl acetate / hexane) to obtain the title compound (2.1 g). 1H-NMR (CDCl3) δ: 7.64 (2H, s), 2.57 (3H, s), 2.47 (6H, s).

[0164] Step 4-3: 2-Bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene [ka] Under an argon atmosphere, a mixture of 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one (3.2 g) synthesized in the same manner as in step 4-2 and bis(2-methoxyethyl)aminosulfur trifluoride (12.5 g) was stirred at 85° C. for 2 hours. The reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution stirred under ice cooling, and then extracted with a hexane / ethyl acetate mixture. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: 0 vol% to 10 vol% ethyl acetate / hexane) to obtain the title compound (1.6 g). 1H-NMR (CDCl3) δ: 7.20 (2H, s), 2.45 (6H, s), 1.89 (3H, t, J = 18.1 Hz).

[0165] Step 4-4: Di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate [ka] Under an argon atmosphere at -78 °C, a 1.56 M n-butyllithium hexane solution (2.3 mL) was dropped into a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (750 mg) and tetrahydrofuran (15 mL), and after stirring at the same temperature for 10 minutes, di-tert-butyl azodicarboxylate (1.0 g) was added. After stirring at the same temperature for 15 minutes, acetic acid (0.3 mL) was added, and then the mixture was diluted with ethyl acetate. The reaction mixture was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 5 vol% to 20 vol% ethyl acetate / hexane) to obtain the title compound (854 mg). 1H-NMR (CDCl3) δ: 7.19 (2H, d, J = 4.6 Hz), 6.59 (1H, br s), 2.38 (6H, s), 1.95-1.82 (3H, m), 1.49-1.37 (18H, br m).

[0166] Step 4-5: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride [ka] A mixture of di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate (854 mg) and 4M hydrogen chloride in ethyl acetate (17.1 mL) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the mixture was dried at room temperature under reduced pressure for 1 hour to obtain the title compound (497 mg). 1H-NMR (DMSO-D6) δ: 9.60 (3H, s), 7.30 (2H, s), 6.85 (1H, br s), 2.41 (6H, s), 1.93 (3H, t, J = 18.8 Hz).

[0167] Step 4-6: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (500 mL) and sulfuric acid (1.0 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (165 g) in toluene (990 mL), and the mixture was stirred at room temperature for 1.5 hours. Basic silica gel (Fujisilica, 330 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hours. The silica gel was then filtered off. The silica gel was washed with ethyl acetate (1.3 L), and the solvent was removed under reduced pressure to give the title compound (177 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s).

[0168] Step 4-7: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine [ka] To a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (541 mg), triethylamine (0.88 mL) and methanol (9.9 mL), {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (497 mg) was added at 0°C and stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture and stirred. The resulting solid was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (885 mg). 1H-NMR (CDCl3) δ: 8.35 (1H, d, J = 4.6 Hz), 7.12 (2H, s), 6.28 (1H, d, J = 4.9 Hz), 5.58 (1H, s), 3.48 (6H, s), 2.50 (6H, s), 1.88 (3H, t, J = 18.1 Hz).

[0169] Step 4-8: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Trifluoroacetic acid (0.40 mL) was added to a mixture of the crude product of 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine (885 mg) and toluene (8.9 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled on ice, and 2M potassium phosphate aqueous solution (4.0 mL) was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 5vol% to 33vol% ethyl acetate / hexane) to obtain the title compound (441 mg). 1H-NMR (CDCl3) δ: 8.21 (1H, s), 7.37 (2H, s), 2.07 (6H, s), 1.95 (3H, t, J = 18.1 Hz).

[0170] Step 4-9: 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, benzyl alcohol (0.15 mL) was added to a mixture of sodium hydride (60% in oil, 52 mg) and tetrahydrofuran (8.8 mL), and the mixture was stirred at 50°C for 30 minutes. After cooling the reaction mixture on ice, 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (440 mg) was added, and the mixture was stirred at the same temperature for 30 minutes. 2M hydrochloric acid (0.75 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was stirred and collected with a mixture of hexane / ethyl acetate (v / v = 4 / 1) to give the title compound (470 mg). 1H-NMR (CDCl3) δ: 8.04 (1H, s), 7.54 (2H, d, J = 6.5 Hz), 7.46-7.39 (3H, m), 7.32 (2H, s), 5.66 (2H, s), 2.04 (6H, s), 1.93 (3H, t, J = 18.1 Hz).

[0171] Step 4-10: 1-[4-(benzyloxy)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidin-6-yl]ethan-1-one [ka] Under an argon atmosphere, a mixture of 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (200 mg), tributyl(1-ethoxyvinyl)tin (253 mg), bis(triphenylphosphine)palladium(II) dichloride (33 mg) and toluene (4.0 mL) was stirred at 100°C for 2 hours. The reaction mixture was allowed to cool to room temperature, 2M hydrochloric acid (4.0 mL) was added, and the mixture was stirred at 50°C for 1.5 hours. The reaction mixture was allowed to cool to room temperature, and then extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 10vol% to 50vol% ethyl acetate / hexane) to obtain the title compound as a crude product (85 mg). 1H-NMR (DMSO-D6) δ: 9.06 (1H, d, J = 10.9 Hz), 7.62 (2H, t, J = 4.3 Hz), 7.53 (2H, s), 7.45-7.36 (3H, m), 5.73 (2H, s), 2.74 (3H, s), 2.07-1.98 (9H, m).

[0172] Step 4-11: 6-Acetyl-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 1-[4-(benzyloxy)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidin-6-yl]ethan-1-one crude product (85 mg) and formic acid (0.85 mL) was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate, water, and a saturated aqueous solution of sodium bicarbonate were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (68 mg). 1H-NMR (DMSO-D6) δ: 11.80 (1H, s), 8.91 (1H, s), 7.52 (2H, s), 2.63 (3H, s), 2.05-1.99 (9H, m).

[0173] Step 4-12: (RS)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 144) [ka] Under ice cooling, sodium borohydride (47 mg) was added to a mixture of 6-acetyl-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (142 mg) synthesized in the same manner as in step 4-11 and methanol (2.8 mL), and the mixture was stirred at the same temperature for 30 minutes, after which the solvent was distilled off under reduced pressure. Ethyl acetate, water, and a saturated aqueous solution of ammonium chloride were added to the residue, and the layers were separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by reversed-phase column chromatography (developing solvent: 10 vol% to 100 vol% acetonitrile / water) to obtain the title compound (87 mg). 1H-NMR (DMSO-D6) δ: 11.32 (1H, s), 8.75 (1H, s), 7.49 (2H, s), 5.65 (1H, s), 4.58 (1H, dd, J = 13.6, 6.2 Hz), 2.01 (9H, dd, J = 21.4, 16.5 Hz), 1.43 (3H, d, J = 6.5 Hz). LC-MS (MH+): 349.

[0174] Step 4-13: (R)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 154), and (S)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 155) [ka] (RS)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (85 mg) was optically resolved using supercritical fluid chromatography {instrument name: Waters SFC Prep15 System; column: Daicel CHIRALPAK IH / SFC, 10 mm (ID) x 250 mm (L), 5 μm; column temperature: 40°C; mobile phase flow rate: 15 mL / min; mobile phase mixing ratio: isocratic, carbon dioxide / methanol = 92 / 8} to obtain the first peak fraction (8.0-9.5 As the first peak fraction (11.2 to 13.3 min), (R)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound of Example 154, 33.4 mg) was obtained, and as the second peak fraction (11.2 to 13.3 min), (S)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (35.6 mg) was obtained. The absolute stereoconfiguration of the compound of Example 154 was determined by X-ray crystal structure analysis. [(R)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 154] 1H-NMR (DMSO-D6) δ: 11.35 (1H, s), 8.76 (1H, s), 7.49 (2H, s), 5.64 (1H, d, J = 5.1 Hz), 4.61-4.55 (1H, m), 2.04-1.98 (9H, m), 1.44 (3H, d, J = 6.5 Hz). LC-MS (MH+): 349. [(S)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 155] 1H-NMR (DMSO-D6) δ: 11.37 (1H, s), 8.74 (1H, s), 7.49 (2H, s), 5.67 (1H, s), 4.58 (1H, q, J = 6.6 Hz), 2.04-1.98 (9H, m), 1.43 (3H, d, J = 6.5 Hz). LC-MS (MH+): 349.

[0175] [Production Example 5]: Synthesis of (R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 165) and (S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 166) [ka] Step 5-1: 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene [ka] At -18°C, 8 M aqueous potassium hydroxide solution (59.8 mL) and diethyl (bromodifluoromethyl)phosphonate (38.3 mL) were added to a mixture of 3,5-dimethyl-4-nitrophenol (20 g) and acetonitrile (120 mL). After stirring at the same temperature for 30 minutes, the temperature was raised to room temperature and stirred for another 30 minutes. At 0°C, concentrated hydrochloric acid (20 mL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 0 vol% to 11 vol% ethyl acetate / hexane) to obtain the title compound (23.1 g). 1H-NMR (CDCl3) δ: 6.88 (2H, s), 6.52 (1H, t, J = 73.1 Hz), 2.33 (6H, s).

[0176] Step 5-2: 4-(difluoromethoxy)-2,6-dimethylaniline hydrochloride [ka] To a mixture of 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene (23.1 g) and ethanol (130 mL), 10% palladium on carbon (566 mg) was added and stirred overnight at room temperature under a hydrogen atmosphere (normal pressure). The palladium catalyst was removed by filtration using Celite, and the solvent was distilled off under reduced pressure. Under ice cooling, a 4M solution of hydrogen chloride in ethyl acetate (35 mL) and a mixture of hexane / ethyl acetate (v / v = 3 / 1, 100 mL) were added to the residue. The resulting solid was collected by filtration and washed with a mixture of hexane / ethyl acetate (v / v = 3 / 1) to obtain the title compound (19.9 g). 1H-NMR (DMSO-D6) δ: 7.14 (1H, t, J = 74.3 Hz), 6.93 (2H, s), 2.32 (6H, s). LC-MS (MH+): 188.

[0177] Step 5-3: {4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazine hydrochloride [ka] To a mixture of 4-(difluoromethoxy)-2,6-dimethylaniline hydrochloride (19.5 g) and 6 M hydrochloric acid (98 mL), concentrated hydrochloric acid (59 mL) was added, and then cooled to -10°C. At the same temperature, sodium nitrite (6.3 g) aqueous solution (19.5 mL) was slowly added dropwise over 10 minutes, and the mixture was stirred for another 2 hours. At the same temperature, a mixture of tin(II) chloride dihydrate (29.5 g) and concentrated hydrochloric acid (33 mL) was added to the reaction mixture, and the mixture was stirred for 1.5 hours while naturally warming to room temperature. The resulting solid was collected by filtration and washed with 2 M hydrochloric acid and diisopropyl ether in that order to obtain the title compound (10 g). 1H-NMR (DMSO-D6) δ: 9.61 (3H, s), 7.20 (1H, t, J = 74.4 Hz), 6.93 (2H, s), 6.77 (1H, br s), 2.39 (6H, s).

[0178] Step 5-4: 2,4-dichloro-6-[2-{4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine [ka] At 0°C, triethylamine (16.2 mL) was added to a mixture of {4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazine hydrochloride (7.9 g), 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (10 g) synthesized in the same manner as in step 4-6 of Production Example 4, and methanol (100 mL). The reaction mixture was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the resulting salt was removed by filtration. The solvent was then distilled off under reduced pressure to obtain a crude product of the title compound.

[0179] Step 5-5: 4,6-dichloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Trifluoroacetic acid (12.7 mL) was added to a mixture of the crude product of 2,4-dichloro-6-[2-{4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine and toluene (278 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was left to stand overnight, and the solvent was distilled off under reduced pressure. The residue was neutralized by adding a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound.

[0180] Step 5-6: 6-chloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of the crude product of 4,6-dichloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine and tetrahydrofuran (118 mL) was added with 2 M aqueous sodium hydroxide solution (32.9 mL) and stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 25 vol% to 55 vol% ethyl acetate / hexane). The obtained solid was stirred and collected by filtration using a diisopropyl ether / ethyl acetate mixture (v / v = 2 / 1) to obtain the title compound (4.83 g). 1H-NMR (DMSO-D6) δ: 12.88 (1H, s), 8.81 (1H, s), 7.32 (1H, t, J = 73.9 Hz), 7.12 (2H, s), 1.98 (6H, s).

[0181] Step 5-7: 2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a mixture of 6-chloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (300 mg), tributyl(1-ethoxyvinyl)tin (477 mg), bis(triphenylphosphine)palladium(II) dichloride (62 mg) and toluene (6.0 mL) was stirred at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the layers were separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (331 mg). LC-MS (MH+): 377.

[0182] Step 5-8: 6-Acetyl-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of the crude product of 2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (332 mg) and tetrahydrofuran (5.0 mL), 2M hydrochloric acid (5.0 mL) was added and stirred at room temperature for 30 minutes, then stirred at 50°C for 1.5 hours. After cooling the reaction mixture to room temperature, ethyl acetate, water and a saturated aqueous solution of sodium bicarbonate were added and the mixture was separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 30vol% to 80vol% ethyl acetate / hexane) to obtain the title compound (271 mg). 1H-NMR (DMSO-D6) δ: 11.79 (1H, s), 8.88 (1H, s), 7.33 (1H, t, J = 73.8 Hz), 7.15 (2H, s), 2.63 (3H, s), 1.99 (6H, s).

[0183] Step 5-9: (RS)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 141) [ka] Sodium borohydride (59 mg) was added to a mixture of 6-acetyl-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (271 mg), methanol (5.4 mL) and tetrahydrofuran (2.7 mL) at 0°C, and the mixture was stirred at the same temperature for 45 minutes. After the solvent was distilled off under reduced pressure, ethyl acetate, water and a saturated aqueous solution of ammonium chloride were added and separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 60vol% to 100vol% ethyl acetate / hexane, followed by 0vol% to 10vol% methanol / ethyl acetate) to obtain the title compound (98 mg). 1H-NMR (DMSO-D6) δ: 11.33 (1H, s), 8.72 (1H, d, J = 0.5 Hz), 7.32 (1H, t, J = 73.9 Hz), 7.12 (2H, s), 5.64 (1H, s), 4.58 (1H, d, J = 5.5 Hz), 1.98 (6H, s), 1.43 (3H, d, J = 6.5 Hz). LC-MS (MH+): 351.

[0184] Step 5-10: (R)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 165), and (S)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 166) [ka] (RS)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (98 mg) was optically resolved by column chromatography using a chiral column {Apparatus name: Japan Analytical Industry Co., Ltd. Automatic Recycle Preparative HPLC LaboACE LC-7080; Column: Daicel CHIRALPAK IJ, 20 mm (ID) x 250 mm (L), 5 μm; Column temperature: Room temperature; Mobile phase flow rate: 15 mL / min; Mobile phase mixing ratio: isocratic, water / acetonitrile = 70 / 30} to obtain the first peak fraction (23.2-28.5 As the first peak fraction (28.9-34.5 min), (R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound of Example 165, 42.9 mg) was obtained, and as the second peak fraction (28.9-34.5 min), (S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound of Example 166, 42.6 mg) was obtained. The absolute stereoconfiguration of the compound of Example 165 was determined by X-ray crystal structure analysis. [(R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 165] 1H-NMR (DMSO-D6) δ: 11.30 (1H, s), 8.71 (1H, s), 7.32 (1H, t, J = 73.9 Hz), 7.12 (2H, s), 5.61 (1H, s), 4.57 (1H, q, J = 6.6 Hz), 1.98 (6H, s), 1.43 (3H, d, J = 6.7 Hz). LC-MS (MH+): 351. [(S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 166] 1H-NMR (DMSO-D6) δ: 11.31 (1H, br s), 8.71 (1H, s), 7.32 (1H, t, J = 73.9 Hz), 7.12 (2H, s), 5.65 (1H, br s), 4.57 (1H, q, J = 6.5 Hz), 1.98 (6H, s), 1.43 (3H, d, J = 6.7 Hz). LC-MS (MH+): 351.

[0185] [Production Example 6]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 163, racemic form) and each optically active substance (Examples 178 and 179) [ka] Step 6-1: Methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate [ka] Concentrated hydrochloric acid (47 mL) was added to a mixture of 4-bromo-2,6-dimethylaniline (45 g), ethanol (72 mL), and water (25 mL), and then cooled to -10°C. At the same temperature, an aqueous solution (54 mL) of sodium nitrite (17.1 g) was slowly added dropwise to the reaction mixture over 30 minutes, and the mixture was stirred for another 30 minutes. At the same temperature, an aqueous solution (315 mL) of methyl 2-chloro-3-oxobutanoate (27 mL) and sodium acetate (55.4 g) was added dropwise to the reaction mixture. The reaction mixture was stirred for another 2 hours, and the aqueous layer was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound.

[0186] Step 6-2: Methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate [ka] Under an argon atmosphere, triethylamine (36 mL) and fumaronitrile (20 g) were added to a mixture of the crude product of methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate and chloroform (580 mL). The reaction mixture was heated to 80° C. and stirred for 40 minutes. After cooling the reaction mixture to room temperature, silica gel (250 g) was added and stirred for 30 minutes. The added silica gel was removed by filtration using Celite, and the silica gel was washed with ethyl acetate. After distilling off the solvent under reduced pressure, the obtained solid was washed with ethyl acetate to obtain the title compound (36.7 g). 1H-NMR (DMSO-D6) δ: 9.01 (1H, s), 7.57 (2H, s), 3.90 (3H, s), 1.96 (6H, s).

[0187] Step 6-3: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid [ka] To a mixture of methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate (36 g) and methanol (360 mL), 2 M aqueous sodium hydroxide solution (110 mL) was added and stirred at room temperature for 2.5 hours. The reaction mixture was neutralized with 6 M hydrochloric acid, and the resulting solid was filtered. 1 M hydrochloric acid, saturated saline, and ethyl acetate were added to the resulting solid, and the layers were separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain target product 1. In addition, the mother liquor obtained when the solid was filtered was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain target product 2. Target products 1 and 2 were combined and stirred in a mixture of ethyl acetate / diisopropyl ether / hexane, and the solid was filtered to obtain the title compound (30 g). 1H-NMR (DMSO-D6) δ: 13.86 (1H, s), 8.95 (1H, s), 7.56 (2H, s), 1.97 (6H, s).

[0188] Step 6-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile [ka] Under an argon atmosphere, triethylamine (26 mL) and diphenylphosphoryl azide (30 mL) were added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (30 g) and tert-butanol (450 mL), and the mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with chloroform (180 mL), and trifluoroacetic acid (22 mL) was added, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to 0° C., neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 1 vol% to 40 vol% ethyl acetate / hexane). The obtained solid was washed with ethyl acetate / diisopropyl ether to obtain the title compound (11 g). 1H-NMR (DMSO-D6) δ: 8.31 (1H, s), 7.46 (2H, s), 5.76 (2H, s), 2.01 (6H, s).

[0189] Step 6-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide [ka] Under an argon atmosphere, sodium hydroxide (4.5 g) and 30% hydrogen peroxide (15 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (11 g), ethanol (66 mL) and dimethyl sulfoxide (17 mL) at 0°C. After stirring at room temperature for 40 minutes, a saturated aqueous solution of sodium sulfite and concentrated hydrochloric acid were added. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate / diisopropyl ether to give the title compound (10 g). 1H-NMR (DMSO-D6) δ: 7.97 (1H, s), 7.45 (2H, s), 7.31 (1H, br s), 6.91 (1H, br s), 5.53 (2H, s), 2.02 (6H, s).

[0190] Step 6-6: 2,2'-[1,2-ethanediylbis(oxy)]diacetate dimethyl [ka] Under an argon atmosphere, sulfuric acid (0.15 mL) was added to a mixture of 2,2'-[1,2-ethanediylbis(oxy)]diacetic acid (10 g) and methanol (50 mL) at room temperature. The reaction mixture was stirred at 80°C for 24 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium bicarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 29 vol% to 50 vol% hexane / ethyl acetate) to obtain the title compound (9.5 g). 1H-NMR (DMSO-D6) δ: 4.14 (4H, s), 3.65 (6H, s), 3.61 (4H, s).

[0191] Step 6-7: Methyl 6-oxo-1,4-dioxepane-5-carboxylate [ka] A mixture of 2,2'-[1,2-ethanediylbis(oxy)]diacetate dimethyl (9.5 g) and tetrahydrofuran (150 mL) was added dropwise to a mixture of sodium tert-butoxide (9.8 g) and tetrahydrofuran (150 mL) over 1 hour at 100°C under an argon atmosphere. After stirring at the same temperature for 3 hours, the mixture was cooled to room temperature and stirred overnight. Acetic acid (6.6 mL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 5vol% to 60vol% hexane / ethyl acetate) to obtain the title compound (3.2 g). 1H-NMR (DMSO-D6) δ: 5.10 (1H, s), 4.35 (1H, d, J = 17.6 Hz), 4.25 (1H, d, J = 17.8 Hz), 4.10-4.00 (2H, m), 3.92-3.85 (1H, m), 3.72-3.65 (4H, m).

[0192] Step 6-8: Methyl 6-[{(trifluoromethyl)sulfonyl}oxy]-2,3-dihydro-5H-1,4-dioxepine 7-carboxylate [ka] Under an argon atmosphere at 0°C, N,N-diisopropylethylamine (7.1 mL) and trifluoromethanesulfonic anhydride (3.4 mL) were added to a mixture of methyl 6-oxo-1,4-dioxepane-5-carboxylate (3.0 g) and deuterated chloroform (35 mL), and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate, water, and ethyl acetate were added to the reaction mixture, and the mixture was separated into layers. The aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 0 vol% to 30 vol% hexane / ethyl acetate) to obtain the title compound (4.8 g). 1H-NMR (DMSO-D6) δ: 4.49 (2H, s), 4.21-4.18 (2H, m), 3.89-3.87 (2H, m), 3.77 (3H, s).

[0193] Step 6-9: Methyl 1,4-dioxepane-5-carboxylate [ka] Nickel(II) chloride (0.6 g) was added to a mixture of methyl 6-[{(trifluoromethyl)sulfonyl}oxy]-2,3-dihydro-5H-1,4-dioxepine-7-carboxylate (4.8 g) and methanol (71 mL) at 0°C. Sodium borohydride (2.1 g) was added to the reaction mixture in four portions at the same temperature, and the mixture was then warmed to room temperature and stirred for another hour. A saturated aqueous solution of ammonium chloride, water, and ethyl acetate were added to the reaction mixture to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography (developing solvent: 5 vol% to 60 vol% hexane / ethyl acetate) to obtain the title compound (1.7 g). 1H-NMR (DMSO-D6) δ: 4.36 (1H, dd, J = 9.7, 5.4 Hz), 3.87-3.84 (1H, m), 3.71-3.64 (8H, m), 2.27-2.19 (1H, m), 2.07-1.97 (1H, m).

[0194] Step 6-10: 2-(4-bromo-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (600 mg), methyl 1,4-dioxepane-5-carboxylate (370 mg), sodium methoxide (5M methanol solution, 1.6 mL) and methanol (3.6 mL) was stirred at 120°C for 2 hours under microwave irradiation. After cooling the reaction mixture to room temperature, 1M hydrochloric acid, water and ethyl acetate were added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 20vol% to 100vol% hexane / ethyl acetate) to obtain the title compound (380 mg). 1H-NMR (DMSO-D6) δ: 11.65 (1H, s), 8.75 (1H, s), 7.54 (2H, s), 4.69 (1H, dd, J = 9.5, 4.9 Hz), 4.02-3.96 (1H, m), 3.78-3.68 (5H, m), 2.43-2.39 (1H, m), 2.33-2.29 (1H, m), 1.96 (6H, s).

[0195] Step 6-11: (RS)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 163) [ka] Under an argon atmosphere, 2-(4-bromo-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (155 mg), cyclopropylboronic acid (95 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (24 mg), and toluene (3.0 mL) were mixed with 2M potassium phosphate aqueous solution (0.55 mL) and stirred at 100°C for 2 hours. After cooling the reaction mixture to room temperature, water was added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. All the organic layers were mixed and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography (developing solvent: 20vol% to 80vol% hexane / ethyl acetate). Then, the residue was purified by reverse-phase column chromatography (developing solvent: 20 vol% to 100 vol% acetonitrile / water) to obtain the title compound (96 mg). 1H-NMR (DMSO-D6) δ: 11.61 (1H, s), 8.67 (1H, s), 6.96 (2H, s), 4.69 (1H, dd, J = 9.4, 5.0 Hz), 4.01-3.98 (1H, m), 3.87-3.69 (5H, m), 2.45-2.40 (1H, m), 2.32-2.29 (1H, m), 1.97-1.91 (7H, m), 1.01-0.96 (2H, m), 0.74 (2H, dt, J = 8.3, 3.2 Hz). LC-MS (MH+): 381.

[0196] Step 6-12: Optically active substances of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Examples 178 and 179) [ka] (RS)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (97 mg) was optically resolved using supercritical fluid chromatography {Apparatus name: Waters SFC Prep15 System; Column: Daicel CHIRALPAK IG / SFC, 10 mm (ID) x 250 mm (L), 5 μm; Column temperature: 40° C.; Mobile phase flow rate: 15 mL / min; Mobile phase mixing ratio: isocratic, carbon dioxide / methanol = 60 / 40} to obtain the compound of Example 178 (37 mg) as the first peak fraction (6.4-7.7 min), and the compound of Example 179 (40 mg) as the second peak fraction (9.2-11.5 min). Example 178 1H-NMR (DMSO-D6) δ: 11.61 (1H, s), 8.66 (1H, s), 6.96 (2H, s), 4.68 (1H, dd, J = 9.2, 4.8 Hz), 4.01-3.98 (1H, m), 3.83-3.73 (5H, m), 2.38-2.32 (2H, m), 1.95-1.92 (7H, m), 0.98 (2H, td, J = 7.1, 4.7 Hz), 0.76-0.72 (2H, m). LC-MS (MH+): 381. Example 179 1 H-NMR (DMSO-D6) δ: 11.62 (1H, s), 8.66 (1H, s), 6.96 (2H, s), 4.68 (1H, dd, J = 9.4, 4.6 Hz), 4.00 (1H, t, J = 8.1 Hz), 3.84-3.69 (5H, m), 2.43-2.29 (2H, m), 1.94-1.91 (7H, m), 0.98 (2H, dd, J = 13.2, 5.1 Hz), 0.73 (2H, q, J = 4.8 Hz). LC-MS (MH+): 381.

[0197] [Production Example 7]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-4-methoxy-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (Example 210) [ka] Step 7-1: 2-(4-bromo-2,6-dimethylphenyl)-4-chloro-6-methyl-2H-pyrazolo[3,4-d]pyrimidine [ka] 4,6-Dichloro-2-methylpyrimidine-5-carbaldehyde (150 mg) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (200 mg), triethylamine (0.44 mL), tetrahydrofuran (1.5 mL) and water (0.75 mL) at 0°C under an argon atmosphere, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 10 vol% to 70 vol% ethyl acetate / hexane) to obtain the title compound (100 mg). 1 H-NMR (CDCl3) δ: 8.11 (1H, s), 7.39 (2H, s), 2.84 (3H, s), 2.01 (6H, s). LC-MS (MH+): 353.

[0198] Step 7-2: 2-(4-bromo-2,6-dimethylphenyl)-4-methoxy-6-methyl-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, a 5 M solution of sodium methoxide in methanol (0.28 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-4-chloro-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (100 mg) and methanol (1.5 mL), and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 10 vol% to 80 vol% ethyl acetate / hexane) to obtain the title compound (15 mg). 1 H-NMR (DMSO-D6) δ: 8.82 (1H, s), 7.56 (2H, s), 4.09 (3H, s), 2.58 (3H, s), 1.93 (6H, s). LC-MS (MH+): 347.

[0199] The compounds of the other examples were obtained by the same methods as those of the above-mentioned production methods and production examples, or by using known methods as necessary. The structural formula and physical property data of each example compound are shown in the following table.

[0200] [Table 1] TIFF2024120882000132.tif245163 TIFF2024120882000133.tif222163 TIFF2024120882000134.tif242163 TIFF2024120882000135.tif230163 TIFF2024120882000136.tif222163 TIFF2024120882000137.tif229163 TIFF2024120882000138.tif224163 TIFF2024120882000139.tif233163 TIFF2024120882000140.tif249164 TIFF2024120882000141.tif253164 TIFF2024120882000142.tif222162 TIFF2024120882000143.tif225163 TIFF2024120882000144.tif235163 TIFF2024120882000145.tif239163 TIFF2024120882000146.tif239163 TIFF2024120882000147.tif235164 TIFF2024120882000148.tif248161 TIFF2024120882000149.tif235163 TIFF2024120882000150.tif218163 TIFF2024120882000151.tif241163 TIFF2024120882000152.tif230163 TIFF2024120882000153.tif235163 TIFF2024120882000154.tif251164 TIFF2024120882000155.tif231163 TIFF2024120882000156.tif241163 TIFF2024120882000157.tif230162 TIFF2024120882000158.tif30162

[0201] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory effect The NLRP3 inflammasome inhibitory effect of the test substance was evaluated based on the suppressive effect on IL-1β production in THP1-Null cells (product number thp-null, InvivoGen). The cells were maintained and cultured in RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 25 mmol / L HEPES, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL normocin, and 200 μg / mL hygromycin B (37°C, 5% CO2 / 95% air). Cells suspended in assay medium (RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin) containing 0.5 μmol / L PMA were seeded (25,000 cells / 25 μL / well) on Corning® 384-well Flat Clear Bottom Black Polystyrene TC-treated Microplates and cultured overnight (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and assay medium containing 1 μg / mL Lipopolysaccharides (product number L2654, Sigma-Aldrich®) was added (25 μL / well) and cultured for 3 hours (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and a medium solution prepared with Opti-MEM™ medium (product number 31985-070, Invitrogen) was added (20 μL / well) to the blank set wells and the control set wells, and cultured for 15 minutes (37°C, 5% CO2 / 95% air). In addition, the test substance solution was added (20 μL / well) to the test substance set wells. Furthermore, Opti-MEM™ medium containing Nigericin (product number N7143, Sigma-Aldrich™) was added (5 μL / well) to the control set wells and the test substance set wells, and cultured for 1.5 hours (37°C, 5% CO2 / 95% air). The final concentration of Nigericin was 7.5 μmol / L. Opti-MEM™ medium was added (5 μL / well) to the blank set wells. The culture supernatant was stored frozen (-20°C) until IL-1β was measured. The IL-1β in the culture supernatant was quantified using AlphaLISA (registered trademark) Human IL-1β Detection Kit (product number AL220C, Perkin Elmer). Fluorescence intensity was measured using a microplate reader EnSpier (model number 2300-00J, Perkin Elmer) or EnSight (model number HH34000000, Perkin Elmer) according to the attached instruction manual. The inhibition rate of the test substance well was calculated by setting the blank well as 100% and the control well as 0%. The IC of the test substance 50 The values ​​(50% inhibitory concentration) were calculated by logistic regression analysis. The results for each example compound are shown in the table below.

[0202] [Table 2] TIFF2024120882000160.tif23295 TIFF2024120882000161.tif23395 TIFF2024120882000162.tif23395 TIFF2024120882000163.tif12394

[0203] Examples of the formulation of the present invention include the following formulations, however, the present invention is not limited to these formulation examples. Formulation Example 1 (Capsule Production) (1) Compound of Example 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg (1), (2), (3) and (4) are mixed and filled into a gelatin capsule.

[0204] Formulation Example 2 (Tablet Production) (1) Compound of Example 1 10 g (2) Lactose 50g (3) 15g corn starch (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of (1), (2) and (3) and 30 g of (4) are mixed with water, vacuum dried, and then granulated. 14 g of (4) and 1 g of (5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained. [Industrial Applicability]

[0205] The compound of formula [I] or a pharma- ceutical acceptable salt thereof has an inhibitory effect on the NLRP3 inflammasome, and is therefore useful in treating a variety of conditions, including multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage inflammatory disease), and in treating chronic inflammatory diseases such as bronchitis, bronchitis, and bronchitis. The compound is expected to be useful as a therapeutic or preventive agent for a disease selected from the group consisting of phage activation syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

Claims

1. A compound of the formula [I] or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 {During the ceremony, Substructure: 【Chemistry 2】 teeth, (1) Formula: 【Chemistry 3】 [During the ceremony, R ５ is hydrogen or C １－４ alkyl {wherein the alkyl is (a) carboxy, (b) -CO-C １－４ Alkoxy, or (c) -CO-NR ６ R ７ (Here, R ６ and R ７ are each independently hydrogen or C １－４ alkyl), optionally substituted with or (2) Formula: 【Chemistry 4】 (In the formula, R ８ is C １－４ is alkyl) The structure is represented by The ring group Cy is (1) Formula: 【Chemistry 5】 (In the formula, R ９ and R １０ are each independently (a) hydrogen, (b) C １－４ Alkyl, wherein the alkyl is １－４ optionally substituted with alkoxy; (c) C １－４ Alkoxy, (d) halogen, (e) C １－４ haloalkyl, or (f) -O-C １－４ haloalkyl, R １１ and R １２ are each independently (a) hydrogen, (b) C １－４ Alkyl, or (c) C １－４ haloalkyl, R １３ teeth, (a) hydrogen, (b) C １－４ Alkyl, (c) C １－４ Alkoxy, (d) halogen, (e) C １－６ Haloalkyl, (f) -O-C １－４ haloalkyl, or (g) C ３－６ cycloalkyl, where the cycloalkyl is optionally substituted with one or two halogens; or R １３ is R １１ Or R １２ together with the carbon atoms to which they are attached (a) C ５－６ Cycloalkene, or (b) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; or (2) Formula: 【Chemistry 6】 (In the formula, R １４ and R １５ are each independently １－４ Alkyl or C １－４ is haloalkyl, R １６ is C １－６ Alkyl or C ３－６ cycloalkyl) is a group represented by R １ teeth, (1) hydrogen, (2) cyano, (3) C １－４ Alkyl (wherein the alkyl is hydroxy or C １－４ optionally substituted with alkoxy; (4) C １－４ haloalkyl, or (5) -CO-C １－４ alkyl, R ２ , R ３ and R ４ are each independently (1) hydrogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, and (c) -SO ２ -C １－４ alkyl, (4) C １－６ Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C １－４ Haloalkyl (wherein the haloalkyl is hydroxy or C １－４ optionally substituted with alkoxy; (7) -O-C １－４ Haloalkyl, (8) -OR １７ (Here, R １７ is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C ３－６ Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or (11) Formula: 【Chemistry 7】 or R ２ , R ３ and R ４ together with the carbon atom to which they are attached, -CR ２ R ３ R ４ The base is (a) cyano, (b) C ３－６ cycloalkyl {wherein said cycloalkyl is (1) Cyano, (2) C １－４ Alkyl (wherein the alkyl is hydroxy or C １－４ optionally substituted with alkoxy; (3) C １－４ Alkoxy, (4) halogens, and (5) -CO-NR １８ R １９ (Here, R １８ and R １９ are each independently hydrogen or C １－４ alkyl); (c) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) hydroxy, (2) C １－４ Alkyl, (3) C １－４ Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with 1 or 2 halogen atoms; (e) a 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is a C １－４ alkyl, optionally substituted with (g) C ５－６ Cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (i) Formula: 【Chemistry 8】 {In the formula, R ２０ teeth, (1) C １－４ Alkyl, or (2) -NR ２１ R ２２ (Here, R ２１ and R ２２ are each independently (a) hydrogen, (b) C １－４ Alkyl, (c) C １－４ haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. may form a group represented by the formula

2. Substructure: 【Chemistry 9】 but, (1) Formula: 【Chemistry 10】 (In the formula, R ５ has the same meaning as in claim 1) 2. The compound of claim 1, which has the structure: or a pharma- ceutically acceptable salt thereof.

3. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

4. R ５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

5. The ring group Cy is (1) Formula: 【Chemistry 11】 (In the formula, R ９ , R １０ , R １１ , R １２ and R １３ has the same meaning as in claim 1) 2. The compound according to claim 1, which is a group represented by: or a pharma- ceutically acceptable salt thereof.

6. The compound according to claim 1, represented by the formula [II] or a pharma- ceutically acceptable salt thereof. 【Chemistry 12】 (In the formula, R ２ , R ３ , R ４ , R ９ , R １０ , R １１ , R １２ and R １３ has the same meaning as in claim 1)

7. R １１ and R １２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

8. The compound according to claim 1, represented by the formula [III] or a pharma- ceutically acceptable salt thereof. 【Chemistry 13】 (In the formula, R ２ , R ３ , R ４ , R ９ , R １０ and R １３ has the same meaning as in claim 1)

9. R ９ and R １０ At least one of (1) C １－４ Alkyl, wherein the alkyl is １－４ optionally substituted with alkoxy; (2) C １－４ Alkoxy, (3) halogens, (4) C １－４ haloalkyl, or (5) -O-C １－４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

10. R ２ , R ３ and R ４ are each independently (1) hydrogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, and (c) -SO ２ -C １－４ alkyl, (4) C １－６ Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C １－４ Haloalkyl (wherein the haloalkyl is hydroxy or C １－４ optionally substituted with alkoxy; (6) -O-C １－４ haloalkyl, or (7) C ３－６ cycloalkyl; or R ２ , R ３ and R ４ together with the carbon atom to which they are attached, -CR ２ R ３ R ４ The base is (a) C ３－６ cycloalkyl {wherein said cycloalkyl is (1) Cyano, (2) C １－４ Alkyl (wherein the alkyl is hydroxy or C １－４ optionally substituted with alkoxy; (3) C １－４ Alkoxy, (4) halogens, and (5) -CO-NR １８ R １９ (Here, R １８ and R １９ are each independently hydrogen or C １－４ alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) hydroxy, (2) C １－４ Alkyl, (3) C １－４ Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) a 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is a C １－４ alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, or (f) Formula: 【Chemistry 14】 {In the formula, R ２１ and R ２２ are each independently (1) hydrogen, (2) C １－４ Alkyl, (3) C １－４ haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which may form a group represented by the following formula:

11. R ２ , R ３ and R ４ are each independently (1) hydrogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, and (c) -SO ２ -C １－４ alkyl, (4) C １－６ Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (5) C １－４ Haloalkyl (wherein the haloalkyl is hydroxy or C １－４ substituted with alkoxy; or R ２ , R ３ and R ４ together with the carbon atom to which they are attached, -CR ２ R ３ R ４ The base is (a) C ３－６ cycloalkyl {wherein said cycloalkyl is (1) Cyano, (2) C １－４ Alkyl (wherein the alkyl is hydroxy or C １－４ optionally substituted with alkoxy; (3) C １－４ Alkoxy, (4) halogens, and (5) -CO-NR １８ R １９ (Here, R １８ and R １９ are each independently hydrogen or C １－４ alkyl); (b) a 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) hydroxy, (2) C １－４ Alkyl, (3) C １－４ Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; or (c) Formula: 【Chemistry 15】 {In the formula, R ２１ and R ２２ are each independently (1) hydrogen, (2) C １－４ Alkyl, (3) C １－４ haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which may form a group represented by the following formula:

12. The structural formula: 【Chemistry 16】 【change】 2. The compound of claim 1, selected from the group consisting of:

13. The structural formula: 【Chemistry 17】 2. The compound of claim 1, selected from the group consisting of:

14. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 18】

15. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 19】

16. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 20】

17. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 21】

18. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemical 22】

19. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 23】

20. A compound represented by the following structural formula or a pharma- ceutically acceptable salt thereof. 【Chemistry 24】

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

22. 21. An NLRP3 inflammasome inhibitor comprising a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof.

23. 21. A therapeutic or preventive agent for a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryopyrin-associated periodic fever syndrome, non-alcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury, comprising the compound according to any one of claims 1 to 20 or a pharma-ceutical acceptable salt thereof.

24. The therapeutic or prophylactic agent according to claim 23, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

25. The therapeutic or prophylactic agent according to claim 23, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease.

26. A method for inhibiting the NLRP3 inflammasome, comprising administering to a mammal a therapeutically effective amount of a compound described in any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof.

27. A method for treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryopyrin-associated periodic fever syndrome, non-alcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharma- ceutical acceptable salt thereof.

28. 28. The method of claim 27, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

29. 28. The method of claim 27, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous articular syndrome, or neonatal onset multisystem inflammatory disease.

30. Use of a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof for the manufacture of an NLRP3 inflammasome inhibitor.

31. Use of the compound according to any one of claims 1 to 20 or a pharma- ceutical acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryopyrin-associated periodic fever syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

32. 32. The use according to claim 31 , wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

33. 32. The use according to claim 31, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome or neonatal onset multisystem inflammatory disease.

34. 21. A compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, for use in inhibiting the NLRP3 inflammasome.

35. 21. The compound according to any one of claims 1 to 20, or a pharma- ceutical acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryopyrin-associated periodic fever syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

36. 36. The compound of claim 35, or a pharma- ceutically acceptable salt thereof, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

37. 36. The compound according to claim 35, or a pharma- ceutically acceptable salt thereof, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multisystem inflammatory disease.

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