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  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to a 6-alkoxypyrazolopyrimidine 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.
• 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.
• Niu L et al. Upregulation of NLRP3 Inflammasome in the Tears and Ocular Surface of Dry Eye Patients.
• 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.
• 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. Ridker P.M. et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Lancet (2017) 390 1833-42. M Carlstrom et al., Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility. Exp Dermatol. (2012) 21:932-7. J.
• NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Dempsey C et al., . Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid- ⁇ and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017 Mar; 61:306-316. Gordon R et al., Inflammasome inhibition prevents ⁇ -synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018 Oct 31;10(465):eaah4066.
• Rodrigues FB et al. Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease. PLoS One. 2016 Sep 22;11(9):e0163479.
• 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.
• 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.
• NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015 Dec;63(12):2260-73. Deora V et al., The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020 Feb;68(2):407-421. 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.
• the present invention provides a 6-alkoxypyrazolopyrimidine compound or a pharma- ceutical acceptable salt thereof having NLRP3 inflammasome inhibitory activity, a pharmaceutical composition containing the same, and a pharmaceutical use thereof. That is, the present invention includes the following exemplary aspects.
• 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]").
• the ring group Cy is (1) Formula: (Wherein, R4 and R5 are each independently (a) hydrogen, (b) cyano, (c) C 1-6 alkyl ⁇ wherein the alkyl is (1) hydroxy, (2) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (3) C 3-6 cycloalkyl; (d) C 1-4 alkoxy, (e) halogen, (f) C1-4 haloalkyl, (g) —O—C 1-4 haloalkyl, (h) —O—CD 3 , or (i) C 3-6 cycloalkyl; R 6 and R 7 are each independently (a) hydrogen, (b) C 1-4 alkyl, (c) C 1-4 alkoxy, or (d) halogen; R8 is (a) hydrogen, (b) C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy or C 1-4 alkoxy; (c) C 1-6 alky
• R 9 and R 10 are each independently C 1-4 alkyl or C 1-4 haloalkyl;
• R 11 is C 1-6 alkyl.
• R1 is (1) hydrogen, (2) cyano, (3) C 1-4 alkyl, (4) halogen, or (5) C 3-6 cycloalkyl;
• R2 is hydrogen or C1-4 alkyl;
• R3 is (1) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) cyano, (c) C 1-4 alkoxy, (d) -NR 12 R 13 , where R 12 and R 13 are each independently C 1-4 alkyl; (e) —SO 2 —C 1-6 alkyl, (f) C 3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted by cyano, or C 1-4 alkyl which may be substituted by C 1-4 alkoxy); (g) a 4- to 6-membered heterocycloalkyl
• R 4 and R 5 are defined as in item 1.
• At least one of R 4 and R 5 is (1) cyano, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl; (3) C 1-4 alkoxy, (4) halogens, (5) C1-4 haloalkyl, (6) —O—C 1-4 haloalkyl,
• R 3 is (1) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) cyano, (c) C 1-4 alkoxy, (d) -NR 12 R 13 , where R 12 and R 13 are each independently C 1-4 alkyl; (e) —SO 2 —C 1-6 alkyl, (f) C 3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted by cyano, or C 1-4 alkyl which may be substituted by C 1-4 alkoxy); (g) a 4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom, wherein the heterocycloalkyl is optionally substituted with one or two oxo groups; and (h) phenyl; or (2) a 4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom, wherein the heterocycloalkyl is optionally substituted with one or two oxo groups; or a pharmacorice
• Item 9 The structural formula: Item 2.
• Item 10 A pharmaceutical composition comprising the compound according to any one of items 1 to 9 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.
• Item 11 Item 10.
• An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 9 or a pharma- ceutically acceptable salt thereof.
• Item 12 Item 10.
• Item 13 Item 13. The therapeutic or prophylactic agent according to Item 12, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• Item 14 Item 13. The therapeutic or prophylactic agent according to Item 12, 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 a compound according to any one of items 1 to 9 or a pharma- ceutically acceptable salt thereof to a mammal.
• Item 16 Item 10.
• Item 17 Item 17. The method of item 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• 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.
• 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'
• Item 10 hemophagocytic lymphohistiocytosis and macrophage activation syndrome
• a disease selected from the group consisting of chronic myocardial infarction, chronic obstructive pulmonary disease, ...
• Item 21 The use according to item 20, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• Item 22 Item 21.
• 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 23 Item 10. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 9, for use in inhibiting NLRP3 inflammasome.
• Item 24 Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g.
• familial cold autoinflammatory syndrome Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease
• 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), Schnitz's disease Item 10.
• the compound or a pharmacologic agent thereof for use in the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction, chronic obstructive pulmonary disease, chronic pulmonary disease, chronic 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, chronic obstructive pulmonary disease, chronic pulmonary disease, chronic pulmonary syndrome, IL
• Item 25 The compound or a pharma- ceutically acceptable salt thereof according to Item 24, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• Item 26 Item 25. The compound or a pharma- ceutically acceptable salt thereof 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 10.
• a pharmaceutical composition according to Item 10 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 steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), and a method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease
• 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 10 A pharmaceutical composition according to Item 10, 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/or chronic inflammatory diseases.
• inflammatory bowel disease
• IPA idiopathic pulmonary artery disease
• PAD pulmonary artery disease
• 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.
• Item 10 A compound according to any one of items 1 to 9 or a pharma- ceutical agent 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 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-Wells syndrome),
• Item 12A The therapeutic or prophylactic agent according to Item 12A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• Item 14A Item 12B.
• the therapeutic or prophylactic agent according to Item 12A, 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 15A Item 10.
• ischemic heart 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.
• 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
• hemophagocytic lymphohistiocytosis and macrophage activation syndrome Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency
• a disease selected from the group consisting of 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, or a pharmac
• 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.
• 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 steatohepatitis gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye
• ischemic heart disease e.g. acute myocardial infarction
• systemic lupus erythematosus systemic juvenile idiopathic arthritis
• relapsing pericarditis adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency Item 10.
• the compound or a pharmacologic acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction, 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 chronic myocardial infarction, familial Mediterranean fever, mevalonate kinase
• [Item 22A] The compound or a pharma- ceutically acceptable salt thereof according to Item 21A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
• [Item 23A] The compound or a pharma- ceutically acceptable salt thereof according to Item 21A, 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 24A Item 10.
• a pharmaceutical composition according to Item 10 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
• Item 10 A pharmaceutical composition according to Item 10, 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 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, A commercial kit comprising a description of
• 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. Preferred are methyl and ethyl.
• 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, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and isopentyl.
• 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.
• Halogen includes, for example, fluorine, chlorine, bromine, and iodine.
• 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. Difluoromethyl and trifluoromethyl are preferred.
• 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, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluor
• C 3-6 cycloalkyl means a monocyclic saturated hydrocarbon ring group having 3 to 6 carbon atoms.
• C 3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred are cyclopropyl, cyclobutyl, and cyclohexyl.
• “4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom” means a 4- to 6-membered monocyclic saturated heterocyclic group containing one oxygen or sulfur atom as a ring-constituting atom other than carbon atoms.
• "4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom” includes, for example, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, and tetrahydrothiopyranyl. Preferred are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiopyranyl.
• "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. Dihydrofuran and dihydropyran are preferred.
• the moiety of formula [I] When R8 forms a ring structure together with R6 or R7 and the carbon atom to which they are bonded, it is a 9- to 11-membered partially unsaturated fused ring group which may contain 1 or 2 oxygen atoms as a whole, and forms a fused ring group substituted with R6 or R7 together with R4 and R5 .
• Examples of 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.
• 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:
• R4 and R5 are preferably each independently (a) hydrogen, (b) C 1-6 alkyl ⁇ wherein the alkyl is (1) hydroxy, (2) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (3) C 3-6 cycloalkyl; (c) C 1-4 alkoxy, (d) halogen, (e) C1-4 haloalkyl, (f) —O—C 1-4 haloalkyl, or (g) C 3-6 cycloalkyl.
• R 6 and R 7 are preferably each independently hydrogen, or C 1-4 alkyl.
• R8 is preferably (a) C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy or C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O-Ci -4 haloalkyl, or (f) C3-6 cycloalkyl, where the cycloalkyl may be substituted with 1 or 2 hydroxy or halogen; or R8 together with R6 or R7 and the carbon atom to which they are attached form a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.
• Partial structure is preferably R4 and R5 are each independently (a) hydrogen, (b) C 1-6 alkyl ⁇ wherein the alkyl is (1) hydroxy, (2) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (3) C 3-6 cycloalkyl; (c) C 1-4 alkoxy, (d) halogen, (e) C1-4 haloalkyl, (f) —O—C 1-4 haloalkyl, or (g) C 3-6 cycloalkyl; R 6 and R 7 are each independently hydrogen or C 1-4 alkyl; R8 is (a) C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy or C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O-Ci -4 haloalkyl, or (f) C3-6 cycloalkyl,
• R 1 is preferably hydrogen.
• R2 is preferably hydrogen.
• R3 is preferably (1) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) cyano, (c) C 1-4 alkoxy, (d) -NR 12 R 13 , where R 12 and R 13 are each independently C 1-4 alkyl; (e) —SO 2 —C 1-6 alkyl, (f) C 3-6 cycloalkyl (wherein the cycloalkyl is optionally substituted by cyano, or C 1-4 alkyl which may be substituted by C 1-4 alkoxy); (g) a 4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom, wherein the heterocycloalkyl is optionally substituted with one or two oxo groups; and (h) phenyl, (2) C 1-6 haloalkyl, where the haloalkyl is optionally substituted with hydroxy; or (3) 4- to 6-membered heterocycloalkyl containing one oxygen or sulfur atom, where the heterocyclo
• the ring group Cy is represented by the formula: is a group represented by the formula:
• R4 and R5 are each independently (a) hydrogen, (b) C 1-6 alkyl ⁇ wherein the alkyl is (1) hydroxy, (2) optionally substituted with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkoxy, and (3) C 3-6 cycloalkyl; (c) C 1-4 alkoxy, (d) halogen, (e) C1-4 haloalkyl, (f) —O—C 1-4 haloalkyl, or (g) C 3-6 cycloalkyl;
• R 6 and R 7 are each independently hydrogen or C 1-4 alkyl;
• R8 is (a) C 1-6 alkyl, wherein the alkyl is optionally substituted with hydroxy or C 1-4 alkoxy; (b) C 1-4 alkoxy, (c) a halogen, (d) C1-6 haloalkyl, (e) -O
• 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- ceutical 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.
• 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.
• Cy and R3 are as defined above;
• Each R A11 is independently C 1-4 alkyl;
• L A11 , L A12 , and L A13 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).
• Step A1-1) The compound [A1-3] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof with the compound [A1-2] in a solvent in the presence of an acid.
• Examples of 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.
• Examples of the solvent include toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixtures thereof.
• a preferred solvent is toluene.
• the reaction temperature is, for example, from 0°C to 150°C, preferably from 5°C to 40°C.
• the compound [A1-1] or a salt thereof is a commercially available product, or may be 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.
• bases 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 prepared by reacting a compound [A1-7] or a salt thereof with a compound [A1-8] or a salt thereof in a solvent in the presence of a base.
• bases include sodium methoxide, sodium ethoxide, and sodium hydride.
• Preferred bases are sodium methoxide or sodium hydride.
• the solvent include N-methyl-2-pyrrolidone, N,N-dimethylformamide, methanol, ethanol, isopropanol, and mixtures thereof.
• the preferred solvent is methanol or N,N-dimethylformamide.
• the reaction temperature is, for example, from 0°C to 120°C, preferably from 60°C to 120°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 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 A2 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 A2 may be converted to ring Cy A2 by production method A2 to produce compound [I-C] or a salt thereof.
• Production Method A2 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 A2.
• R 3 is as defined above, Cy A2 is C 3-6 cycloalkyl ⁇ wherein the cycloalkyl may be substituted with 1 or 2 hydroxy or halogen ⁇ ;
• L A2 is a leaving group (e.g., halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy), provided that the leaving group is attached to the ortho or para position of the benzene ring.
• Step A2-1 Compound [IC] or a salt thereof can be produced by reacting compound [IB] or a salt thereof with compound [A2-1] 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 [A2-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.
• Production Method A3 Production Method of the Compound [ID] or a Salt thereof
• the compound [ID] or a salt thereof can also be produced, for example, by the following Production Method A3.
• Cy and R3 are as defined above; R A3 is C 1-4 alkyl; L A3 is a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).
• Step A3-1) The compound [ID] or a salt thereof can be prepared by reacting a compound [IA] or a salt thereof with a compound [A3-1] 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 [A3-1] is a commercially available product, or may be produced from a commercially available product by a known method.
• Production Method A4 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 A4.
• Cy and R3 are as defined above;
• L A41 and L A42 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).
• Step A4-1) The compound [A4-3] or a salt thereof can be produced by reacting a compound [A4-1] or a salt thereof with a compound [A4-2] or a salt thereof in a solvent in the presence of a base.
• bases include triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]-7-undecene.
• a preferred base is triethylamine.
• the solvent include methanol, ethanol, tetrahydrofuran, toluene, cyclopentyl methyl ether, acetonitrile, water, and mixtures thereof.
• a preferred solvent is a mixture of tetrahydrofuran and water.
• the reaction temperature is, for example, from ⁇ 20° C. to 80° C., preferably from 0° C. to room temperature.
• the compound [A4-1] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
• the compound [A4-2] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
• the compound [IA] or a salt thereof can be produced by reacting a compound [A4-3] or a salt thereof in a solvent in the presence of an acid.
• Acids include, for example, formic acid, trifluoroacetic acid, and hydrochloric acid. A preferred acid is trifluoroacetic acid.
• the solvent include toluene, water, acetonitrile, tetrahydrofuran, and mixtures thereof. A preferred solvent is toluene.
• the reaction temperature is, for example, from 0° C. to 100° C., preferably from 0° C. to room temperature.
• 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 A2 , or a salt thereof may be used to carry out this production method, to obtain a compound corresponding to compound [I-A], i.e., compound [I-B] or a salt thereof, and then L A2 may be converted to ring Cy A2 by production method A2 to produce compound [I-C] or a salt thereof.
• 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 (19 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (19 g) and methanol (130 mL), and the reaction mixture was cooled in an ice bath. Triethylamine (31 mL) was slowly added to the reaction mixture, and the mixture was stirred at the same temperature for 2 hours.
• Step 2-3 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine Under an argon atmosphere, trifluoroacetic acid (10 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (29 g) and toluene (230 mL). The reaction mixture was stirred for another hour and then slowly added dropwise to an ice-cooled aqueous solution (93 mL) of tripotassium phosphate (28 g).
• Step 2-4 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
• a mixture of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine crude product (24 g) and tetrahydrofuran (200 mL) was added with 4 M aqueous sodium hydroxide solution (49 mL) and stirred at 65°C for 5 hours.
• the reaction mixture was cooled in an ice bath, and 2 M hydrochloric acid (66 mL) was slowly added dropwise.
• Step 2-5 6-Methoxy-2-(4-methoxy-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Under an argon atmosphere, 5 M sodium methoxide in methanol (3.4 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.0 g) and N,N-dimethylformamide (10 mL), and the mixture was heated to reflux at 120°C for 1 hour.
• Step 3-1 4-chloro-6-(2-(4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazinyl)-2-methoxypyrimidine-5-carbaldehyde
• 4-chloro-6-(2-(4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazinyl)-2-methoxypyrimidine-5-carbaldehyde To a mixture of (4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazine hydrochloride (50 mg), N,N-diisopropylethylamine (0.15 mL), tetrahydrofuran (0.75 ml), and water (0.25 ml), 4,6-dichloro-2-methoxypyrimidine-5-carbaldehyde (48 mg) was added and stirred at room temperature for 1 hour.
• Step 3-2 2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-methoxy-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one Under an argon atmosphere, trifluoroacetic acid (33 ⁇ l) was added to a mixture of the crude product of 4-chloro-6-(2-(4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazinyl)-2-methoxypyrimidine-5-carbaldehyde (80 mg) and toluene (0.80 mL), and the mixture was stirred at room temperature for 3 hours.
• 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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