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Definitions

• the present invention relates to a substituted pyrazolopyrimidine compound or a pharma- ceutical acceptable salt thereof having NLRP3 inflammasome inhibitory activity, a pharmaceutical composition containing the same, and pharmaceutical uses thereof.
• 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.
• 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 becomes activated by binding to these molecules.
• DAMPs Dannger Associated Molecular Patterns
• cytotoxic factors ATP, HMGB1, S100, uric acid crystals, silica, etc.
• PAMPs Pathogen Associated Molecular Patterns
• 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.
• ASC Apoptosis-associated speck-like protein containing a caspase recruitment domain
• caspase 1 in the complex is converted to an active form, which converts proIL-1 ⁇ , the precursor of the proinflammatory cytokine IL-1 ⁇ , into active IL-1 ⁇ , and proIL-18, the precursor of IL-18, into active IL-18.
• Activated IL-1 ⁇ secreted outside the cell induces inflammatory responses through the induction of inflammatory cytokine and chemokine production by surrounding cells and the activation of immune cells such as T cells.
• Non-Patent Document 1 In the brains and cerebrospinal fluid of multiple sclerosis patients, increased amounts of DAMPs (Non-Patent Document 1), increased expression of caspase 1 in lesions, and increased amounts of IL-1 ⁇ in cerebrospinal fluid (Non-Patent Document 2) were observed.
• activated microglia are present in lesions in the chronic progression stage of this disease (Non-Patent Document 3), and activated microglia stimulated by DAMPs produce inflammatory cytokines such as IL-1 ⁇ , inducing neuroinflammation and neurological disorders (Non-Patent Document 4). Therefore, it is believed that the NLRP3 inflammasome is involved in the pathological manifestation of multiple sclerosis.
• Non-Patent Document 5 In the MOG 35-55 EAE model mouse, which was created by sensitizing mice to myelin oligodendrocyte glycoprotein (MOG), motor dysfunction similar to that of multiple sclerosis is observed. However, in the NLRP3 knockout mouse, the onset of motor dysfunction is suppressed in the MOG 35-55 EAE model (Non-Patent Document 5). In the cuprizone model mouse, which was created by administering the copper chelating compound cuprizone to mice, central nervous demyelination similar to that of multiple sclerosis is observed, but the progression of demyelination is delayed in the NLRP3 knockout mouse cuprizone model (Non-Patent Document 6).
• NLPR3 inflammasome inhibitor JC-171 suppressed motor dysfunction in the MOG 35-55 EAE model when administered after onset (Non-Patent Document 7). Therefore, it is thought that NLRP3 inflammasome inhibitors can be used as a therapeutic agent for multiple sclerosis.
• Non-Patent Documents 8 and 9 It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the kidneys of patients with chronic kidney disease. Furthermore, it has been reported that NLRP3 knockout suppresses proteinuria and tubulointerstitial fibrosis in a 5/6 nephrectomy model, a non-clinical chronic kidney disease model (Non-Patent Document 10). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for chronic kidney disease.
• Non-Patent Document 11 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-1 ⁇ produced by activation of NLRP3 is increased in the intestinal mucosa of IBD patients, and that increased IL-1 ⁇ secretion from the colon is positively correlated with worsening of the pathology (Non-Patent Document 11).
• 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. Based on the above results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for inflammatory bowel disease.
• Non-Patent Document 14 It has been reported that increased expression of NLRP3 inflammasome-related genes is observed in atherosclerotic areas of the coronary arteries of patients with myocardial infarction.
• Non-Patent Document 15 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, an atherosclerosis model. Based on these results, it is believed that NLRP3 inflammasome inhibitors could be used as a treatment for atherosclerosis.
• LDL low-density lipoprotein receptor
• Cryopyrin-associated periodic syndrome 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 result in the formation and activation of the NLRP3 inflammasome even in the absence of activating signals.
• FCAS mild familial cold autoinflammatory syndrome
• MFS moderate Muckle-Wells syndrome
• NOMID neonatal onset multisystem inflammatory disease
• Non-Patent Document 18 Mice expressing CAPS-associated NLRP3 mutations exhibit systemic, lethal inflammation dependent on the NLRP3 inflammasome and downstream signaling molecules IL-1 ⁇ 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.
• Non-Patent Document 20 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 model, which is a NASH model (Non-Patent Document 20). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a treatment for NASH.
• NASH nonalcoholic steatohepatitis
• Non-Patent Document 21 In gout and gouty arthritis, uric acid crystals deposited in the joints and peri-articular tissues induce inflammation (Non-Patent Document 21). Uric acid crystals activate NLRP3 in macrophages, leading to the production of IL-1 ⁇ 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). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a treatment for gout and gouty arthritis.
• NLRP3 inflammasome-related genes Elevated 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). Elevated expression of NLRP3 inflammasome-related genes has also been reported in the synovium of collagen-induced arthritis, a model of rheumatoid arthritis (Non-Patent Document 25). Based on these results, it is believed that NLRP3 inflammasome inhibitors could be used as a treatment for rheumatoid arthritis.
• Trinitrochlorobenzene which induces contact dermatitis, increases IL-1 ⁇ production from human skin keratinocytes via NLRP3 activation, and it has been reported that NLRP3 knockout also 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 could be used as a treatment for contact dermatitis.
• Non-Patent Documents 27, 28 It has been reported that increased expression of NLRP3 inflammasome-related genes is observed in the tears and ocular surface of dry eye patients.
• Non-Patent Documents 27, 28 when cultured human corneal epithelial cells are subjected to hyperosmotic stress to induce a dry eye condition, increased expression of NLRP3 inflammasome-related genes and increased IL-1 ⁇ production are observed, and it has been reported that knockdown of the NLRP3 gene suppresses IL-1 ⁇ production (Non-Patent Document 28). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a treatment for dry eye.
• Non-Patent Document 29 It has been reported that increased expression of the ASC domain of the NLRP3 inflammasome is observed in macrophages and neutrophils that infiltrate the myocardial tissue of patients with acute myocardial infarction.
• increased expression of NLRP3 inflammasome-related genes is observed in the infarcted area in an ischemia-reperfusion model, which is a model of myocardial infarction, and that 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 will be a therapeutic drug for ischemic heart disease such as acute myocardial infarction.
• Non-Patent Documents 31 and 32 It has been reported that the expression of IL-1 ⁇ 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-1 ⁇ are increased in macrophages (Non-Patent Document 33). Furthermore, in Nlrp3-R258W mice, which have an activating mutation in the NLRP3 gene, lupus nephritis-like symptoms that appear when pristane is administered are exacerbated (Non-Patent Document 34). Based on these results, it is believed that NLRP3 inflammasome inhibitors could be used as a treatment for SLE.
• Non-Patent Document 35 systemic juvenile idiopathic arthritis
• Non-Patent Document 36 recurrent pericarditis
• 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 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
• Behçet's disease Non-Patent Document 41
• lung cancer Non-Patent Document 42.
• anti-IL-1 ⁇ 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-1 ⁇ , NLRP3 inflammasome inhibitors are thought to be a therapeutic agent for these diseases.
• Non-Patent Document 43 It has been reported that the NLRP3 rs10733113 genotype is significantly increased in psoriasis patients, and that this increases their susceptibility to psoriasis. It has also been reported that NLRP3 deficiency suppresses psoriasis symptoms in the IL-23-induced psoriasis model (Non-Patent Document 44). Based on these results, it is believed that NLRP3 inflammasome inhibitors could be used as a treatment for psoriasis.
• NLRP3 inflammasome inhibitors could be used as a treatment for hypertension.
• Non-Patent Document 47 It has been reported that NLRP3 expression is elevated in the proliferative membrane of patients with diabetic retinopathy (Non-Patent Document 47). Furthermore, NLRP3 expression is elevated 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 of NLRP3 expression by NLRP3 shRNA results in decreased IL-1 ⁇ and VEGF secretion, increased ganglion cell mass, and recovery from retinal damage (Non-Patent Document 49). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a treatment for diabetic retinopathy.
• NLRP3 inflammasome activation occurs in the brains of Alzheimer's disease patients, MCI (mild cognitive impairment) patients, and APP/PS1 mice, a mouse model of Alzheimer's disease, and NLRP3 deficiency in APP/PS1 mice suppresses the development of spatial memory impairment (Non-Patent Document 50).
• the NLRP3 inhibitor MCC950 suppresses NLRP3 activation in microglia and improves cognitive dysfunction in APP/PS1 mice (Non-Patent Document 51). Therefore, NLRP3 inflammasome inhibitors are thought to be a potential treatment for Alzheimer's disease and MCI.
• Non-Patent Document 52 In the substantia nigra of Parkinson's disease patients and mice injected with ⁇ -synuclein PFF (preformed fibril), a model of Parkinson's disease, increased expression of NLRP3 inflammasome-related molecules in microglia and activation of the 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 ⁇ -synuclein PFF (Non-Patent Document 52). Therefore, it is believed that NLRP3 inflammasome inhibitors could be a treatment for Parkinson's disease.
• Non-Patent Document 53 In patients with Huntington's disease, the cerebrospinal fluid concentration of IL-1 ⁇ , an NLRP3 inflammasome-associated cytokine, is increased (Non-Patent Document 53). In R6/2 mice, a pathological model of Huntington's disease, the expression level of NLRP3 inflammasome in the striatum is increased (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 suppresses the progression of symptoms (Non-Patent Document 55). Therefore, it is thought that NLRP3 inflammasome inhibitors could be a treatment for Huntington's disease.
• Non-Patent Document 56 In the spinal cord of patients with amyotrophic lateral sclerosis (ALS), expression of the NLRP3 inflammasome, IL-18, and active caspase 1 is increased (Non-Patent Document 56). In the spinal cord of ALS model mice SOD1G93A and TDP-43Q331K, mRNA expression of IL-1 ⁇ , 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-1 ⁇ production (Non-Patent Document 57).
• Non-Patent Document 58 NLRP3 inflammasome inhibitors are considered to be a potential treatment for ALS.
• NLRP3 inflammasome The expression level of NLRP3 inflammasome is increased in the brain tissue and cerebrospinal fluid of patients with traumatic brain injury (TBI) (Non-Patent Documents 59, 60). In the brain tissue of TBI model rats, the expression level of NLRP3 inflammasome is increased, as are the levels of IL-1 ⁇ and IL-18 (Non-Patent Document 61).
• the NLRP3 inhibitor MCC950 suppresses the production of IL-1 ⁇ in TBI model mice and suppresses the onset of neurological symptoms after brain trauma (Non-Patent Document 62). Therefore, it is thought that NLRP3 inflammasome inhibitors could be used as a treatment for TBI.
• mice with middle cerebral artery occlusion (MCAO) as a cerebral infarction model, and rats with intracerebral hemorrhage model the expression of NLRP3 inflammasome, IL-1 ⁇ , and IL-18 is increased (Non-Patent Documents 63, 64).
• the NLRP3 inhibitor MCC950 showed neuroprotective effects in MCAO and intracerebral hemorrhage rat models. Therefore, NLRP3 inflammasome inhibitors are thought to be potential treatments for cerebral infarction and cerebral hemorrhage.
• NLRP inflammasome expression is increased in brain tissue from patients with temporal lobe epilepsy and in pilocarpine-induced epilepsy model mice (Non-Patent Documents 65, 66). Furthermore, 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 potential treatment for epilepsy.
• Non-Patent Document 67 In the peripheral blood of patients with depression, the expression levels of NLRP3 inflammasome, IL-1 ⁇ concentration, and IL-18 concentration are increased, and the IL-1 ⁇ concentration correlates with the depression symptom score (Non-Patent Document 67).
• the expression levels of NLRP3 inflammasome, IL-1 ⁇ , and IL-18 in brain tissue are increased, and NLRP3 inflammasome activation occurs (Non-Patent Documents 68, 69, 70).
• NLRP3 inflammasome inhibitors are considered to be a treatment for depression.
• Non-Patent Document 71 In the peripheral blood of patients with autism spectrum disorder (ASD), the expression levels of NLRP3 inflammasome and the concentrations of IL-1 ⁇ and IL-18 are increased (Non-Patent Document 71).
• MIA maternal immune activation
• IL-1 ⁇ expression is increased in the fetal brain, and administration of the NLRP3 inhibitor MCC950 to the mother suppresses the expression of ASD symptoms in the offspring (Non-Patent Document 72). Therefore, NLRP3 inflammasome inhibitors are thought to be a potential treatment for ASD.
• Non-Patent Documents 73, 74 NLRP3 inflammasome or IL-1 ⁇ expression is increased, and NLRP3 activation is observed. Furthermore, when the NLRP3 inhibitor MCC950 is administered to mice after spinal cord injury, it suppresses NLRP3 activation and IL-1 ⁇ expression in the spinal cord, promoting the recovery of motor function (Non-Patent Document 73). Therefore, NLRP3 inflammasome inhibitors are thought to be a therapeutic drug for spinal cord injury.
• Non-Patent Documents 75 and 76 In an intestinal perforation model, which is an animal model of sepsis, increased expression and activation of NLRP3 inflammasome or IL-1 ⁇ occurs in the brain, causing damage to hippocampal neurons and memory impairment, a symptom of septic encephalopathy (Non-Patent Documents 75 and 76).
• NLRP3 inhibitor MCC950 When the NLRP3 inhibitor MCC950 is administered to the 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 a treatment for septic encephalopathy.
• Non-Patent Document 77 In the chronic constriction injury (CCI) model, an animal model of neuropathic pain, the expression levels of IL-1 ⁇ 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, 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).
• CCI chronic constriction injury
• Non-Patent Document 79 NLRP3 inflammasome inhibitors can be used as therapeutic agents for neuropathic pain.
• NLRP3 inflammasome inhibitors are thought to be a treatment for COVID-19 caused by SARS-CoV-2.
• Non-Patent Document 81 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-1 ⁇ protein has been reported (Non-Patent Document 81). In addition, an increase in the ASC domain of the NLRP3 inflammasome and post-cleavage caspase 1 has been reported in the cerebral cortex of Tau22 mice (mice expressing human mutant tau protein), a model of frontotemporal dementia, and it has also been reported that NLRP3 knockout has an inhibitory effect on tau lesion formation and cognitive decline (Non-Patent Document 81). Based on these results, it is believed that NLRP3 inflammasome inhibitors could be a treatment for frontotemporal dementia.
• Non-Patent Document 82 In patients with NLRP3-associated autoinflammatory disease (NLRP3-AID), which is 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). Furthermore, in an Alu RNA-induced retinal pigment epithelial cell degeneration model, which is a model of age-related macular degeneration, an NLRP3 inhibitor suppressed the degeneration of retinal pigment epithelial cells (Non-Patent Document 83).
• Non-Patent Document 83 In a laser-induced choroidal neovascularization model, which is another model of age-related macular degeneration, an NLRP3 inhibitor suppressed angiogenesis (Non-Patent Document 83). Based on these results, it is believed that NLRP3 inflammasome inhibitors will be a treatment for age-related macular degeneration.
• Non-Patent Document 84 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 increased retinal vascular permeability in STZ-induced diabetic mice (Non-Patent Document 85). Therefore, NLRP3 inflammasome inhibitors are thought to be a potential treatment for diabetic macular edema.
• 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, NLRP3 inflammasome inhibitors are thought to be a potential treatment for hereditary transient corneal endotheliitis.
• 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.
• 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.
• 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.
• Non-patent Document 10 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.
• Non-patent Document 11 Ranson N et al., NLRP3-dependent and -independent processing Interleiukin-1 ⁇ in active Ulcerative colitis. Int J mol Sci 2018: 20pii:E57.
• Non-Patent Document 12 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.
• Non-Patent Document 13 Bauer C. et al., Protective and aggravating effects of NLRP3 inlammasome activation in IBD models : influence of genetic and environmental factors.
• Non-patent Document 14 Paramel V G 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 M C 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.
• Sandanger O et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury.
• 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.
• 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).
• 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.
• 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 S M et al., Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc. Res.
• 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., .
• Non-Patent Document 52 Gordon R et al., Inflammasome inhibition prevents ⁇ -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.
• 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 U S 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-1 ⁇ 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.
• Non-patent Document 72 Szabo D et al., Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1 ⁇ 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.
• Zeng J et al. Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice. EBioMedicine.
• 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.
• 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]”).
• R 9 and R 10 each independently represent (a) hydrogen, (b) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 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 each independently represent (a) hydrogen, (b) C 1-4 alkyl, or (c) C 1-4 haloalkyl;
• R13 is (a) hydrogen, (b) C 1-4 alkyl, (c) C 1-4 alkoxy, (d) halogen, (e) C1-6 haloalkyl, (f) -O- Ci_4 haloalkyl; or (g) C3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 halogens; or R13 taken together with R11 or R
• R 14 and R 15 are each independently C 1-4 alkyl or C 1-4 haloalkyl;
• R 16 is C 1-6 alkyl or C 3-6 cycloalkyl.
• R1 is (1) hydrogen, (2) cyano, (3) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy;
• R 2 , R 3 and R 4 each independently represent (1) hydrogen, (2) hydroxy, (3) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (c) —SO 2 —C 1-4 alkyl;
• C 1-6 alkoxy wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4-
• R 9 and R 10 are the same as defined in item 1.
• At least one of R 9 and R 10 is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy); (2) C 1-4 alkoxy, (3) halogens,
• R 2 , R 3 and R 4 each independently represent (1) hydrogen, (2) hydroxy, (3) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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 may be substituted with hydroxy or C 1-4 alkoxy; (6) -O-Ci -4 haloalkyl, or (7) C3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR
• R 21 and R 22 each independently represent (1) hydrogen, (2) C 1-4 alkyl, (3) a 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.
• R 2 , R 3 and R 4 each independently represent (1) hydrogen, (2) hydroxy, (3) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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) a C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy or C 1-4 alkoxy; R 2 , R 3 and R 4 together with
• 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: [Item 12] The structural formula: Item 2. The compound according to item 1, selected from the group consisting of: [Item 13] The structural formula: Item 2. The compound according to item 1, selected from the group consisting of: [Item 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. [Item 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.
• Item 14 A compound according to any one of items 1 to 13 or a pharma- ceutical acceptable salt thereof for use in 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, 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, and adult-onset Still's disease.
• inflammatory bowel disease e.g., ulcerative colitis and Crohn's disease
• hemophagocytic lymphohistiocytosis and macrophage activation syndrome e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome
• Schnitzler syndrome IL-1 receptor antagonist molecule deficiency
• familial Mediterranean fever e.g., 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.
• Item 17 Item 17. The therapeutic or prophylactic agent according to Item 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• Item 18 Item 17. The therapeutic or prophylactic 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.
• a method for inhibiting NLRP3 inflammasome comprising administering a therapeutically effective amount of the compound according to any one of items 1 to 13 or a pharma- ceutically acceptable salt thereof to a mammal.
• Item 20 Item 15.
• 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.
• Multiple sclerosis, chronic kidney disease, inflammatory bowel disease e.g.
• 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 fatty liver disease e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease
• non-alcoholic fatty liver disease e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease
• non-alcoholic fatty liver disease e.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'
• a therapeutic or prophylactic 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.
• 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
• Item 25 Item 25.
• Item 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.
• Item 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.
• Multiple sclerosis, chronic kidney disease, inflammatory bowel disease e.g.
• 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 fatty liver disease e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease
• non-alcoholic fatty liver disease e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease
• non-alcoholic fatty liver disease e.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'
• 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.
• 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.
• Item 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.
• Item 31 Item 15.
• 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.
• IPF idiopathic pulmonary fibrosis
• Schnitzler syndrome IL-1 receptor antagonist molecule deficiency
• familial Mediterranean fever familial Mediterranean fever
• mevalonate kinase deficiency hyper IgD syndrome
• Item 15 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), 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 and a commercial kit comprising a description of the
• [Item 16A] Item 14. A compound according to any one of items 1 to 13 or a pharma- ceutical agent comprising the compound ...
• a therapeutic or preventive agent for a disease selected from the group consisting of amyloid plaque, leukemia, leukemia, and pediatric rheumatoid arthritis (LEA), amyloid plaque, leukemia, and rheumatoid arthritis (HPA), amyloid plaque, leukemia, and rheumatoid arthritis (HPA).
• LOA pediatric rheumatoid arthritis
• HPA amyloid plaque, leukemia, and rheumatoid arthritis
• HPA amyloid plaque, leukemia, and rheumatoid arthritis
• HPA amyloid plaque, leukemia, and rheumatoid arthritis
• HPA amyloid plaque, leukemia, and rheumatoid arthritis
• [Item 17A] Item 16A.
• 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.
• 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.
• inflammatory bowel disease e.g.
• 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.
• 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.
• 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.
• 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,
• 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.
• familial cold autoinflammatory syndrome Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome and neonatal-onset multisystem inflammatory disease
• non-alcoholic 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 Item 14.
• the compound or a pharmacologic agent thereof 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.
• a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF), familial
• [Item 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.
• [Item 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.
• Item 28A Item 15.
• 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 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, 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
• Item 15 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 multi-organ inflammatory disease), non-alcoholic fatty liver disease, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g.
• 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
• C 1-4 alkyl means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms.
• C 1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Methyl and ethyl are preferred. Methyl is more preferred.
• C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
• C 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.
• C 1-4 alkoxy means a group in which the above “C 1-4 alkyl” is bonded to an oxygen atom.
• C 1-4 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferred are methoxy and ethoxy.
• C 1-6 alkoxy refers to a group in which the above “C 1-6 alkyl” is bonded to an oxygen atom.
• C 1-6 alkoxy 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.
• Halogen includes, for example, fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine. More preferred is fluorine.
• C 1-4 haloalkyl means the above “C 1-4 alkyl” substituted with 1 to 7 halogens independently selected from the above “halogen” group.
• C 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, triflu
• C 1-6 haloalkyl means the above “C 1-6 alkyl” substituted with 1 to 9 halogens independently selected from the above “halogen” group.
• C 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-
• C 3-6 cycloalkyl means a monocyclic saturated hydrocarbon ring group having from 3 to 6 carbon atoms.
• C 3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• 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, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen 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.
• 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 ...
• 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.
• 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.
• C 5-6 cycloalkenyl includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Cyclopentenyl is preferable.
• C 5-6 cycloalkene means a monocyclic partially unsaturated hydrocarbon ring having 5 to 6 carbon atoms and containing at least one double bond.
• C 5-6 cycloalkene includes, for example, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene.
• 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 other than 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, dihydrodioxinyl, pyranyl, and dihydrooxazinyl. Dihydrofuranyl and dihydropyranyl are preferred.
• "5- to 7-membered heterocycloalkene containing one or two oxygen atoms” means a 5- to 7-membered monocyclic partially unsaturated heterocycle containing one or two oxygen atoms as ring-constituting atoms other than carbon atoms and containing at least one double bond.
• "5- to 7-membered heterocycloalkene containing one or two oxygen atoms” includes, for example, dihydrofuran, dioxole, dihydropyran, dihydrodioxine, pyran, tetrahydrooxepine, dihydrodioxepine, dihydrooxepine, and dioxepine. Dihydropyran is preferable.
• 7- to 9-membered saturated fused heterocyclic group containing one or two 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, one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms.
• Examples of the "7- to 9-membered saturated fused heterocyclic group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms” include the following groups: Includes:
• “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.
• "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: Includes:
• the ring structure as a whole is a 9- to 11-membered partially unsaturated fused ring group which may contain 1 or 2 oxygen atoms, and which forms a fused ring group substituted with R 9 and R 10 and R 11 or R 12.
• the fused ring group include the following groups: Examples include:
• C 1-6 alkyl optionally substituted with hydroxy means that C 1-6 alkyl is unsubstituted, or any hydrogen in C 1-6 alkyl is substituted with hydroxy.
• Partial structure is preferably of the formula: (In the formula, R5 is as defined above.) The structure is shown below.
• R5 is preferably hydrogen.
• the ring group Cy preferably has the formula: (In the formula, each symbol has the same meaning as defined above.) It is a group represented by the following formula:
• R 9 and R 10 are preferably each independently (a) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C 1-4 haloalkyl, or (e) —O—C 1-4 haloalkyl.
• R 9 and R 10 are more preferably each independently C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy).
• R 11 and R 12 are preferably each independently hydrogen or C 1-4 alkyl.
• R 11 and R 12 are more preferably hydrogen.
• R 13 is preferably (a) C 1-4 alkyl, (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O- Ci_4 haloalkyl; or (f) C3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 halogens; or R13 taken together with R11 or R12 and the carbon atom to which they are attached is (a) a C 5-6 cycloalkene, or (b) a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.
• R 13 is more preferably C 1-6 haloalkyl, or —O—C 1-4 haloalkyl.
• R 9 and R 10 are each independently (a) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C 1-4 haloalkyl, or (e) —O—C 1-4 haloalkyl;
• R 11 and R 12 are each independently hydrogen or C 1-4 alkyl;
• R13 is (a) C 1-4 alkyl, (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O- Ci_4 haloalkyl; or (f) C3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 halogens; or R13 taken together with R11 or R12 and the carbon atom to which they are attached is (a) a C 5-6 cycloalkene, or (b) a
• teeth, R 9 and R 10 are each independently C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; R 11 and R 12 are hydrogen; R 13 is C 1-6 haloalkyl, or —O—C 1-4 haloalkyl.
• teeth, R 9 and R 10 are each independently C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; R 11 and R 12 are hydrogen; R 13 is C 1-6 haloalkyl.
• teeth, R 9 and R 10 are each independently C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; R 11 and R 12 are hydrogen; R 13 is —O—C 1-4 haloalkyl.
• R 1 is preferably hydrogen.
• 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) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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 may be substituted with hydroxy or C 1-4 alkoxy); (6) -O-Ci -4 haloalkyl, or (7) C3-6 cycloalkyl; or R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R
• 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) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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) a C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy or C 1-4 alkoxy; R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R 3 R 4 group: (a) C 3-6 cycloalkyl ⁇ wherein the cyclo
• 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) —SO 2 —C 1-4 alkyl; R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R 3 R 4 group: (a) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy; (3) C 1-4 alkoxy, (4) halogen, and (5) —CO—NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl; or (b) a compound of the formula: (In the formula, R 21 and R 22 are defined as above.) This forms a group represented by the formula:
• 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) —SO 2 —C 1-4 alkyl.
• R 2 , R 3 and R 4 taken together with the carbon atom to which they are attached, are a -CR 2 R 3 R 4 group, C 3-6 cycloalkyl, where the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy; (3) C 1-4 alkoxy, (4) halogen, and (5) -CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.
• R 20 is preferably --NR 21 R 22 (wherein R 21 and R 22 are as defined above).
• R5 is hydrogen
• the ring group Cy is represented by the formula: is a group represented by the formula:
• R 9 and R 10 are each independently (a) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C 1-4 haloalkyl, or (e) —O—C 1-4 haloalkyl;
• R 11 and R 12 are each independently hydrogen or C 1-4 alkyl;
• R13 is (a) C 1-4 alkyl, (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O- Ci_4 haloalkyl; or (f) C3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 halogens; or
• Another preferred embodiment of the compound of formula [I] is Partial structure: but, (1) Formula: [Wherein, 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. or (2) a structure represented by formula: (Wherein, R 8 is C 1-4 alkyl.
• the structure is represented by the formula:
• the ring group Cy is (1) Formula: (Wherein, R 9 and R 10 each independently represent (a) hydrogen, (b) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 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 each independently represent (a) hydrogen, (b) C 1-4 alkyl, or (c) C 1-4 haloalkyl; R13 is (a) hydrogen, (b) C 1-4 alkyl, (c) C 1-4 alkoxy, (d) C 1-6 haloalkyl, or (e) —O—C 1-4 haloalkyl; or R 13 together with R 11 or R 12 and the carbon atom to which they are attached is (a) a C 5-6 cycloalkene, or (b) a 5- to 7
• R 14 and R 15 are each independently C 1-4 alkyl or C 1-4 haloalkyl;
• R 16 is C 1-6 alkyl or C 3-6 cycloalkyl.
• R1 is (1) hydrogen, (2) cyano, (3) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy;
• 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) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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)
• R 9 and R 10 are each independently (a) hydrogen, (b) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 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;
• R13 is (a) hydrogen, (b) C 1-4 alkyl, (c) C 1-4 alkoxy, (d) C 1-6 haloalkyl; or (e) —O—C 1-4 haloalkyl; or R 13 together with R 11 or R 12 and the carbon atom to which they are attached is (a) a C 5-6 cycloalkene, or (b)
• a preferred embodiment of the compound of formula [II] is a compound of formula [III]:
• R 9 and R 10 are each independently (a) hydrogen, (b) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; (c) C 1-4 alkoxy, (d) halogen, (e) C 1-4 haloalkyl, or (f) —O—C 1-4 haloalkyl;
• R13 is (a) hydrogen, (b) C 1-4 alkyl, (c) C 1-4 alkoxy, (d) C 1-6 haloalkyl; or (e) —O—C 1-4 haloalkyl; or R 13 taken together with R 11 or R 12 and the carbon atom to which they are attached is (a) a C 5-6 cycloalkene, or (b) a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; R 2 , R 3 and R 4 are each independently (
• R 9 and R 10 are each independently (a) C 1-4 alkyl, wherein the alkyl is optionally substituted with C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C 1-4 haloalkyl, or (e) —O—C 1-4 haloalkyl; R 13 is C 1-6 haloalkyl, or —O—C 1-4 haloalkyl; 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) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 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-member
• R 21 and R 22 each independently represent (1) hydrogen, (2) C 1-4 alkyl, (3) a 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.
• R 9 and R 10 are each independently C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy);
• R 13 is C 1-6 haloalkyl, or —O—C 1-4 haloalkyl;
• 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) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (c) —SO 2 —C 1-4 alkyl;
• 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) a C 1-4 haloalkyl, wherein the haloalkyl, wherein the haloal
• R 9 and R 10 are each independently C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy);
• R 13 is C 1-6 haloalkyl, or —O—C 1-4 haloalkyl;
• 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) —SO 2 —C 1-4 alkyl;
• R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R 3 R 4 group, which is a C 3-6 cycloalkyl, (1) Cyano, (2) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy; (3) C 1-4 alkoxy, (4) halogen, and (5) -CO-NR 18 R 19 , where R 18 and R
• R 9 and R 10 are each independently C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy);
• R 13 is C 1-6 haloalkyl;
• 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) —SO 2 —C 1-4 alkyl;
• R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R 3 R 4 group, which is a C 3-6 cycloalkyl, (1) Cyano, (2) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy; (3) C 1-4 alkoxy, (4) halogen, and (5) -CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.
• R 9 and R 10 are each independently C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy);
• R 13 is -O-C 1-4 haloalkyl;
• 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) —SO 2 —C 1-4 alkyl;
• R 2 , R 3 and R 4 together with the carbon atom to which they are attached form the -CR 2 R 3 R 4 group, which is a C 3-6 cycloalkyl, (1) Cyano, (2) C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy; (3) C 1-4 alkoxy, (4) halogen, and (5) -CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl
• Another preferred embodiment of the compound of formula [I] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X], or [XI]: (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:
• 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 in, for example, the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (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.
• the compound of the 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.
• 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, methylni
• 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.
• 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.
• 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 examples thereof include the hydrate, acetate solvate, acetone solvate, ethanol solvate, and dimethyl sulfoxide solvate of compound [I]. Specific examples include the hemihydrate, monohydrate, dihydrate, monoacetate solvate, monoacetone solvate, and monoethanol solvate of the compound of formula [I], or the monohydrate, monoacetone solvate, and 2/3 ethanol solvate of the sodium salt of the compound of formula [I]. These solvates can be obtained according to known methods.
• Compound [I] may exist as a tautomer.
• compound [I] may exist as an individual tautomer or a mixture of tautomers.
• the compound [I] may exist as a tautomer of the following formula: The structures shown in are as follows, unless otherwise noted: (1) (2) (3) (4) or (5) a mixture thereof.
• Compound [I] may have a carbon-carbon double bond. In that case, compound [I] may exist as an E-form, a Z-form, or a mixture of E-form and Z-form. 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 that 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.
• compound [I] may exist as an individual atropisomer or a mixture of atropisomers.
• Compound [I] may simultaneously contain a plurality of structural features that give rise to the above isomers, and may contain the above isomers in any ratio.
• Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization.
• the individual diastereomers can be prepared by synthetic methods using stereochemically homogeneous starting materials or by stereoselective reactions.
• 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 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, the 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.
• the absolute configuration can be determined by X-ray crystallography of a crystalline product or intermediate. If necessary, a crystalline product or intermediate that has been derivatized with a reagent containing an asymmetric center of known configuration may be used.
• Compound [I] may be labeled with an isotope (such as 2H (D), 3H , 11C , 13C , 14C , 13N , 15N , 15O , 18O , 18F , 35S , 123I , etc.).
• an isotope such as 2H (D), 3H , 11C , 13C , 14C , 13N , 15N , 15O , 18O , 18F , 35S , 123I , etc.
• Compound [I] labeled with an isotope may be useful in medicine, pharmacokinetic studies, in vitro and/or in vivo assays, and/or diagnostic agents (such as positron emission tomography (PET), single photon emission computed tomography (SPECT)).
• Compound [I] labeled with an isotope may be prepared according to known methods or the methods described herein, using an isotope-labeled compound instead of a non
• Compound [I] is preferably a substantially purified compound [I]. More preferably, compound [I] is purified to a purity of 80% or more.
• the pharmaceutical composition of the present invention may be prepared by mixing compound [I] with at least one or more pharma- ceutically acceptable carriers in an appropriate amount, as appropriate, 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.
• 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.
• “Pharmaceutically 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.
• excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic and the like.
• disintegrant examples include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
• binder examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
• fluidizing agent includes light anhydrous silicic acid, magnesium stearate, and the like.
• Lubricants include magnesium stearate, calcium stearate, talc, and the like.
• 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.
• Smoothing agents include benzyl alcohol and the like.
• base examples 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 esters thereof, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, water-absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (ma)
• preservatives examples include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.
• Antioxidants include sodium sulfite, ascorbic acid, and the like.
• coloring agents include food dyes (Food Red No. 2 or No. 3, Food Yellow No. 4 or No. 5, etc.), ⁇ -carotene, and the like.
• “Sweetening agents” include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.
• 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 the "therapeutically effective amount" in this specification
• the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day of the compound of formula [I] or a pharma- ceutical acceptable salt thereof, which is the active ingredient.
• 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.
• 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 of 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 idi
• 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.
• “Inhibiting the NLRP3 inflammasome” means inhibiting the function of the NLRP3 inflammasome to eliminate or weaken its activity, for example, inhibiting the function of the NLRP3 inflammasome based on the conditions of Test Example 1 described below. By inhibiting the function of the NLRP3 inflammasome, the amount of IL-1 ⁇ and/or IL-18 produced is suppressed, preferably the amount of IL-1 ⁇ and IL-18 produced is suppressed. "Inhibiting the NLRP3 inflammasome” preferably means “inhibiting human NLRP3 inflammasome.”
• 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.
• treatment includes amelioration of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence.
• prevention includes suppressing and delaying the onset of symptoms.
• HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
• WSC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
• Production Method A1 Production Method of the Compound [IA] or a Salt thereof
• the compound [IA] or a salt thereof can be produced, for example, by the following Production Method A1.
• R 2 , R 3 , R 4 and the ring group Cy are as defined above;
• Each R A11 is independently C 1-4 alkyl;
• R A12 is a boronic acid, a boronic acid 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).
• 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.
• the acid include sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid, and p-toluenesulfonic acid.
• the preferred acid is sulfuric acid or p-toluenesulfonic acid.
• 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 produced from a commercially available product by a known method.
• the compound [A1-2] is a commercially available product, or may be produced from a commercially available product by a known method.
• the compound [A1-5] or a salt thereof can be produced by reacting a compound [A1-3] or a salt thereof with a compound [A1-4] or a salt thereof in a solvent in the presence of a base.
• a base include triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene, and N,N-diisopropylethylamine.
• a preferred base is triethylamine or N,N-diisopropylethylamine.
• 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 produced from a commercially available product by a known method.
• the compound [A1-6] or a salt thereof can be produced by reacting a compound [A1-5] or a salt thereof in a solvent in the presence of an acid.
• acids include trifluoroacetic acid, sulfuric acid, hydrochloric acid, and triethylsilyl trifluoromethanesulfonate.
• a preferred acid is trifluoroacetic acid.
• the solvent include toluene, tetrahydrofuran, ethyl acetate, cyclopentyl methyl ether, dichloromethane, and mixtures thereof.
• the preferred solvent is toluene.
• the reaction temperature is, for example, from -78°C to 60°C, preferably from 0°C to 40°C.
• the compound [A1-7] or a salt thereof can be produced by reacting a 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.
• 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.
• the compound [IA] or a salt thereof can be produced 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.
• the catalyst examples 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.
• bases include tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride.
• a preferred base is tripotassium phosphate.
• R A12 is, for example, a boronic acid, a boronic acid ester (such as a pinacol boronic acid ester), or a trifluoroborate
• examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, and a mixed solvent thereof.
• a preferred solvent is a mixed solvent of toluene and water.
• the solvent includes, for example, toluene, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethylsulfoxide.
• a 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 produced from a commercially available product by a known method.
• a compound 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, or a salt thereof may be used to carry out this production method to obtain a compound corresponding to compound [I-A] or a salt thereof, and then the functional group may be converted to produce compound [I-A] 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 production method, to obtain a compound corresponding to compound [I-A] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [I-A] or a salt thereof.
• a hydrazine compound substituted with a phenyl group having L A41 described below, or a salt thereof may be used to carry out this production method, to obtain a compound corresponding to compound [I-A], that is, compound [I-B] or a salt thereof, and then L A41 may be converted to ring Cy A41 by production method A4 to produce compound [I-C] or a salt thereof.
• Production Method A2 Production Method of the Compound [IA] or a Salt thereof
• the compound [IA] or a salt thereof can also be produced, for example, by the following Production Method A2.
• 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 hydroxy-protecting group (e.g., benzyl, 4-methoxybenzyl, and 2-methoxybenzyl), and R A21 is preferably benzyl.
• the compound [A2-1] or a salt thereof can be produced by reacting a compound [A1-6] or a salt thereof in a solvent in the presence of an alcohol and a base.
• the 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 mixtures 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.
• 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.
• a 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 solvent is a mixed solvent of toluene and water.
• the solvent includes, for example, toluene, N,N-dimethylacetamide, N,N-dimethylformamide, and dimethylsulfoxide.
• a 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 [IA] or a salt thereof can be produced by removing R A21 of the compound [A2-2] or a salt thereof by a deprotection reaction.
• the deprotection reaction may be carried out under suitable conditions depending on the type of R A21 .
• R A21 is benzyl
• the compound [IA] or a salt thereof can be produced by reacting the compound [A2-2] or a salt thereof in the presence of an acid.
• a solvent may be added, if necessary.
• Acids include, for example, formic acid, trifluoroacetic acid, and hydrochloric acid. A preferred acid is formic acid.
• the reaction temperature is, for example, from 0°C to 120°C, preferably from 10°C to 100°C.
• Solvents include, for example, toluene, tetrahydrofuran, and 1,4-dioxane.
• a compound 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, or a salt thereof may be used to carry out this production method to obtain a compound corresponding to compound [I-A] or a salt thereof, and then the functional group may be converted to produce compound [I-A] or a salt thereof.
• Production Method A3 Production Method of the Compound [IA] or a Salt thereof
• the compound [IA] or a salt thereof can also be produced, for example, by the following Production Method A3.
• R 2 , R 3 , R 4 and the ring group Cy are as defined above;
• R A31 is C 1-4 alkyl;
• R A32 is hydrogen or an amino-protecting group (e.g., tert-butoxycarbonyl);
• R A33 is hydrogen or C 1-4 alkyl.
• Step A3-1 The compound [A3-3] or a salt thereof can be produced by reacting a compound [A3-1] or a salt thereof with a 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.
• 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.
• 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 produced 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 produced from a commercially available product by a known method.
• 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.
• a base include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene.
• a preferred base is triethylamine.
• 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.
• 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.
• bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.
• a preferred base is sodium hydroxide.
• 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, from 0°C to 100°C, preferably from 5°C to 50°C.
• the compound [A3-7] or a salt thereof can be produced by reacting a compound [A3-6] or a salt thereof in a solvent in the presence of a reacting agent and a base.
• Reactants include, for example, sodium azide and diphenylphosphoryl azide.
• a preferred reactant is diphenylphosphoryl azide.
• the base include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene.
• a preferred base is triethylamine.
• 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.
• the compound [A3-8] or a salt thereof can be produced by reacting a compound [A3-7] or a salt thereof in a solvent in the presence of an oxidizing agent and a base.
• the oxidizing agent include hydrogen peroxide, iron oxide, and manganese dioxide.
• the preferred oxidizing agent is hydrogen peroxide.
• bases include sodium hydroxide, potassium hydroxide, and barium hydroxide.
• a preferred base is sodium hydroxide.
• 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.
• the compound [A3-9] or a salt thereof can be produced by removing R A32 from the compound [A3-8] or a salt thereof by a deprotection reaction.
• the deprotection reaction may be carried out under suitable conditions depending on the type of R A32 .
• R A32 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.
• the solvent examples include ethyl acetate, cyclopentyl methyl ether, and mixtures thereof.
• the preferred solvent is ethyl acetate.
• the reaction temperature is, for example, from 0°C to 80°C, preferably from 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.
• Step 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.
• the base 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.
• 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 produced from a commercially available product by a known method.
• the compound [IA] or a salt thereof can be produced by reacting a compound [A3-11] or a salt thereof in a solvent in the presence of a base.
• a base 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.
• 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.
• a compound 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, or a salt thereof may be used to carry out this production method to obtain a compound corresponding to compound [I-A] or a salt thereof, and then the functional group may be converted to produce compound [I-A] 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 production method, to obtain a compound corresponding to compound [I-A] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [I-A] or a salt thereof.
• a compound having an amino group and L A41 described below on the benzene ring, or a salt thereof may be used to carry out this production method, to obtain a compound corresponding to compound [I-A], that is, compound [I-B] or a salt thereof, and then L A41 may be converted to ring Cy A41 by production method A4 to produce compound [I-C] 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 production 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.
• a compound having an amino group and L A41 described below on the benzene ring, or a salt thereof may be used to carry out this production method, to obtain a compound corresponding to compound [A3-8], that is, compound [A3-8-A] or a salt thereof, and then L A41 may be converted to ring Cy A41 by production method A5 to produce compound [A3-8-B] or a salt thereof.
• Production Method A4 Production Method of the Compound [IC] or a Salt thereof
• the compound [IC] or a salt thereof can be produced, for example, by the following Production Method A4.
• Cy A41 is C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 halogens;
• L A41 is a leaving group (e.g., halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy), provided that the leaving group is bonded to the ortho or para position of the benzene ring.
• Step A4-1 Compound [IC] or a salt thereof can be produced 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.
• compound [IB] or a salt thereof e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate
• 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.
• bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate.
• the solvent examples include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and a mixture 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 [IB] or a salt thereof may be produced from a commercially available product by a known method.
• the compound [IB] or a salt thereof may be produced, for example, by the above-mentioned production 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.
• Production Method A5 Production Method of the 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. (wherein each symbol has the same meaning as defined above)
• Step A5-1 The compound [A3-8-B] or a salt thereof can be produced by reacting the compound [A3-8-A] or a salt thereof with the 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.
• a derivative thereof e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate
• 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.
• bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate.
• the solvent examples include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and a mixture 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.
• Production method A6 Production method for compound [ID] or a salt thereof, or compound [IE] or a salt thereof
• the compound [ID] or a salt thereof, or compound [IE] or a salt thereof can also be produced, for example, by the production method A6 shown below.
• R 2 , R 3 , R 4 , R 8 and the ring group Cy are as defined above;
• R A61 is C 1-4 alkyl;
• L A61 is a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).
• Step 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.
• bases include cesium carbonate, sodium methoxide, sodium hydride and potassium carbonate.
• a preferred base is sodium hydride.
• the solvent include methanol, N,N-dimethylformamide, and tetrahydrofuran.
• the 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 produced from a commercially available product by a known method.
• Step 1-1 4-chloro-2-(2,4-dimethylphenyl)-6-methyl-2H-pyrazolo[3,4-d]pyrimidine 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.
• Step 1-2 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 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 neutralized with 2M hydrochloric acid.
• Step 1-3 2-(2,4-dimethylphenyl)-5,6-dimethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 50 mg
• N,N-dimethylformamide 0.5 mL
• cesium carbonate 130 mg
• iodomethane 0.024 mL
• Step 2-2 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine 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.
• Step 2-3 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine 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.
• Step 2-4 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine 109 g
• tetrahydrofuran 830 mL
• 4 M aqueous sodium hydroxide solution 210 mL
• the reaction mixture was cooled in an ice bath, and 2 M hydrochloric acid (280 mL) was slowly added dropwise.
• Step 2-5 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 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.
• reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with ethyl acetate.
• the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed 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).
• Step 2-6 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde
• Lithium bis(trimethylsilyl)amide 1.1 M tetrahydrofuran solution, 1.1 mL
• 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 100 mg
• tetrahydrofuran 1.0 mL
• 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).
• 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)
• Sodium borohydride 35 mg was added to a mixture of crude 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde (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.
• Step 2-8 3-(bromomethyl)-6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Under an argon atmosphere at 0°C, phosphorus tribromide (8.1 ⁇ L) 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.
• 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)
• 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.
• 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.
• Step 3-2 Methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate
• fumaronitrile (20.2 g) and triethylamine (36.1 mL) were added and stirred at 80°C for 4 hours.
• the obtained organic layer was washed with saturated saline, and then anhydrous magnesium sulfate and silica gel (200 g) were added.
• Step 3-3 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid
• 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.
• Step 3-4 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile
• 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, after which the solvent was distilled off under reduced pressure.
• Step 3-5 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide
• 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.
• 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 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.
• 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 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.
• 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 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.
• 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) 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.
• reaction mixture was slowly added dropwise to a stirred saturated aqueous solution of sodium bicarbonate under ice cooling, and then extracted 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: 20vol% to 50vol% ethyl acetate/hexane) to obtain the title compound (89 mg).
• 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) 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 subject
• Step 4-2 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one 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 (eluent: 10 vol% ethyl acetate/hexane) to obtain the title compound (2.1 g). 1H-NMR (CDCl3) ⁇ : 7.64 (2H, s), 2.57 (3H, s), 2.47 (6H, s).
• Step 4-3 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene 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 stirred saturated aqueous sodium bicarbonate solution under ice cooling, and then extracted with a mixture of hexane/ethyl acetate.
• Step 4-4 Di-tert-butyl 1- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine-1,2-dicarboxylate Under an argon atmosphere at -78 °C, a 1.56 M n-butyllithium hexane solution (2.3 mL) was added dropwise to a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (750 mg) and tetrahydrofuran (15 mL), and the mixture was stirred at the same temperature for 10 minutes, after which di-tert-butyl azodicarboxylate (1.0 g) was added.
• Step 4-5 ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride
• Step 4-6 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine 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 (Fujisilicia, 330 g) was added to the reaction mixture, and after stirring for 1.5 hours, the added silica gel was removed by filtration. The silica gel was washed with ethyl acetate (1.3 L), and the solvent was removed under reduced pressure to obtain the title compound (177 g).
• Step 4-7 2,4-dichloro-6-[2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine
• 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine 541 mg
• triethylamine (0.88 mL)
• methanol 9.9 mL
• ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride (497 mg) at 0°C, and the mixture was stirred at room temperature for 1 hour.
• Step 4-8 4,6-dichloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine Trifluoroacetic acid (0.40 mL) was added to a mixture of crude 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.
• Step 4-9 4-(benzyloxy)-6-chloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine 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.
• 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 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.
• Step 4-11 6-acetyl-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure.
• 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) 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.
• 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)
• Step 5-3 ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride
• 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 the mixture was cooled to -10°C.
• an aqueous solution (19.5 mL) of sodium nitrite (6.3 g) was slowly added dropwise over 10 minutes, and the mixture was stirred for another 2 hours.
• Step 5-4 2,4-dichloro-6-[2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine
• 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 the crude product of the title compound.
• Step 5-5 4,6-dichloro-2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine 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.
• Step 5-6 6-chloro-2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ -2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 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.
• Step 5-7 2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ -6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 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.
• Step 5-8 6-Acetyl-2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ -2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• 2- ⁇ 4-(difluoromethoxy)-2,6-dimethylphenyl ⁇ -6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 332 mg
• 2M hydrochloric acid 5.0 mL
• 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) 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.
• 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) (RS)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (98 mg) was subjected to optical separation by column chromatography using a chiral column ⁇ instrument name: Japan Analytical Industry Co., Ltd.
• Example 165 The absolute configuration of the compound of Example 165 was determined by X-ray crystal structure analysis.
• Step 6-2 Methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate 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 to room temperature, silica gel (250 g) was added and stirred for 30 minutes.
• Step 6-3 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid
• 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.
• 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) ⁇ : 13.86 (1H, s), 8.95 (1H, s), 7.56 (2H, s), 1.97 (6H, s).
• Step 6-4 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile
• triethylamine 26 mL
• diphenylphosphoryl azide 30 mL
• 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid 30 g
• tert-butanol 450 mL
• Step 6-5 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide 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.
• Step 6-6 2,2'-[1,2-ethanediylbis(oxy)]diacetate dimethyl 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.
• Step 6-7 Methyl 6-oxo-1,4-dioxepane-5-carboxylate A mixture of dimethyl 2,2'-[1,2-ethanediylbis(oxy)]diacetate (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.
• Step 6-8 Methyl 6-[ ⁇ (trifluoromethyl)sulfonyl ⁇ oxy]-2,3-dihydro-5H-1,4-dioxepine 7-carboxylate 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.
• N,N-diisopropylethylamine 7.1 mL
• trifluoromethanesulfonic anhydride 3.4 mL
• Step 6-9 Methyl 1,4-dioxepane-5-carboxylate 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 in four portions to the reaction mixture at the same temperature, and the mixture was then warmed to room temperature and stirred for another hour.
• 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
• 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) Under an argon atmosphere, a mixture of 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) was added with 2M aqueous potassium phosphate (0.55 mL) and stirred at 100°C for 2 hours.
• 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)
• (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 ⁇ m; column temperature: 40° C.; mobile phase flow rate: 15 mL/min; mobile phase mixing ratio: isocratic, carbon dioxide/methanol
• Step 7-1 2-(4-bromo-2,6-dimethylphenyl)-4-chloro-6-methyl-2H-pyrazolo[3,4-d]pyrimidine 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.
• Step 7-2 2-(4-bromo-2,6-dimethylphenyl)-4-methoxy-6-methyl-2H-pyrazolo[3,4-d]pyrimidine 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.
• Test Example 1 Evaluation of NLRP3 inflammasome inhibitory effect The NLRP3 inflammasome inhibitory effect of the test substance was evaluated based on the inhibitory effect on IL-1 ⁇ 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 ⁇ g/mL streptomycin, 100 ⁇ g/mL normocin, and 200 ⁇ g/mL hygromycin B (37°C setting, 5% CO 2 /95% air).
• the culture supernatant was removed, and assay medium containing 1 ⁇ g/mL Lipopolysaccharides (product number L2654, Sigma-Aldrich®) was added (25 ⁇ L/well) and cultured for 3 hours (37°C, 5% CO 2 /95% air).
• the culture supernatant was removed, and a medium solution prepared with Opti-MEMTM medium (product number 31985-070, Invitrogen) was added (20 ⁇ L/well) to the blank and control wells and incubated for 15 minutes (at 37° C., 5% CO 2 /95% air).
• the test substance solution was added (20 ⁇ L/well) to the test substance wells.
• Opti-MEMTM medium containing Nigericin (product number N7143, Sigma-Aldrich®) was added (5 ⁇ L/well) to the control and test substance wells and incubated for 1.5 hours (at 37° C., 5% CO 2 /95% air). The final concentration of Nigericin was 7.5 ⁇ mol/L.
• Opti-MEMTM medium was added (5 ⁇ L/well) to the blank wells. The culture supernatant was frozen and stored (at -20° C.) until IL-1 ⁇ was measured. The IL-1 ⁇ in the culture supernatant was quantified using AlphaLISA® Human IL-1 ⁇ Detection Kit (product number AL220C, Perkin Elmer).
• the 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 IC50 value (50% inhibitory concentration) of the test substance was calculated by logistic regression analysis. The results of each example compound are shown in the table below.
• Formulation Example 1 (Production of Capsules) (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.
• Formulation Example 2 (Production of Tablets) (1) Compound of Example 1 10 g (2) Lactose 50g (3) Corn starch, 15g (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 sized. 14 g of (4) and 1 g of (5) are mixed with the sized powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets, each containing 10 mg of the compound of Example 1, are obtained.
• 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 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 Mackle

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