Pyrazolopyrimidine compound and medical application thereof

Abstract

Provided are a pyrazolopyrimidine compound having an NLRP3 inflammasome inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and pharmaceutical uses thereof, and the like. Compounds of Formula [IA]: # imgabs0 # or a pharmaceutically acceptable salt thereof wherein each symbol is defined in the specification.

Description

Technical Field

[0001] The present invention relates to a pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof having NLRP3 inflammasome inhibitory activity, a pharmaceutical composition containing the same, and medical uses thereof. Background Art

[0002] NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a pattern recognition receptor that belongs to the NLR (NOD-like receptor) family and is also expressed in non-immune cells such as glomerular epithelial cells and tubular epithelial cells, as well as phagocytic cells such as macrophages and microglia.

[0003] NLRP3 recognizes DAMPs (danger-associated molecular patterns) that are specific molecular patterns of cell-damaging factors (such as ATP, HMGB1, S100, urate crystals, and silica) and PAMPs (pathogen-associated molecular patterns) that are specific molecular patterns of pathogenic microorganisms (such as viruses, bacteria, and fungi), and binds to these molecules to become activated.

[0004] Activated NLRP3 associates with the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine ​​protease caspase 1 through protein-protein interactions to form the NLRP3 inflammasome, which is a cellular protein complex. The formation of the NLRP3 inflammasome converts caspase 1 in the complex into its activated form, and activated caspase 1 converts proIL-1β, which is a precursor of the proinflammatory cytokine IL-1β, into the activated form of IL-1β, while it also converts proIL-18, which is a precursor of IL-18, into the activated form of IL-18. The activated IL-1β secreted extracellularly induces the production of proinflammatory cytokines-chemokines by surrounding cells and activates immune cells (such as T cells), which causes an inflammatory response.

[0005] In patients with multiple sclerosis, an increase in the amount of DAMPs was observed in the brain and cerebrospinal fluid (non-patent document 1), and an increase in the expression level of caspase 1 in the involved parts, as well as an increase in the amount of IL-1β in the cerebrospinal fluid (non-patent document 2) were also observed. It has been reported that during the chronic progressive phase of the disease, activated microglia are present in the involved parts (non-patent document 3), and activated microglia stimulated by DAMPs produce proinflammatory cytokines such as IL-1β, which induce neuroinflammation and neurological disorders (non-patent document 4). Therefore, NLRP3 inflammasomes are believed to be involved in the expression of the disease state of multiple sclerosis.

[0006] MOG prepared by sensitization of myelin oligodendrocyte glycoprotein (MOG) 35-55 EAE model mice showed motor impairment similar to that seen in multiple sclerosis. 35-55 In the EAE model, the onset of motor impairment in NLRP3 knockout mice was suppressed (Non-Patent Document 5). The cyclohexanone oxalyl dihydrazone model mice prepared by administering the copper chelate compound cyclohexanone oxalyl dihydrazone to mice showed central nervous system demyelination as seen in multiple sclerosis, and in the cyclohexanone oxalyl dihydrazone model, the progression of demyelination was delayed in NLRP3 knockout mice (Non-Patent Document 6). In MOG 35-55 In the EAE model, administration of the NLPR3 inflammasome inhibitor JC-171 after onset of the disease suppressed the impairment of motor function (Non-Patent Document 7). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of multiple sclerosis.

[0007] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the kidneys of patients with chronic kidney disease (Non-patent Documents 8, 9). In addition, the inhibitory activity of proteinuria and tubulointerstitial fibrosis obtained by NLRP3 knockout in a non-clinical chronic kidney disease model (i.e., 5 / 6 nephrectomy model) has been reported (Non-patent Document 10). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of chronic kidney disease.

[0008] It has been reported that the expression of NLRP3 inflammasome-related genes increases in the intestines of patients with inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease) (non-patent literature 11). It has been reported that the IL-1β produced by NLRP3 activation in the intestinal mucosa of IBD patients increases, and the increased secretion of IL-1β from the colon region is positively correlated with the deterioration of the disease state (non-patent literature 11). It has also been reported that the dysfunction of CARD8, which negatively regulates the activity of inflammasomes, increases the susceptibility of Crohn's disease, while the activation of NLRP3 inflammasomes increases the production of IL-1β from monocytes (non-patent literature 12). The inhibition of intestinal lesions by NLRP3 deficiency in the TNBS-induced colitis model (a colitis model) has been reported (non-patent literature 13). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of inflammatory bowel disease.

[0009] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in the atherosclerotic region of the coronary arteries of patients with myocardial infarction (Non-Patent Document 14). In addition, it has been reported that lesion formation is inhibited by NLRP3 knockout in low-density lipoprotein receptor (LDL) receptor-deficient mice (an atherosclerosis model) fed a high-fat diet (Non-Patent Document 15). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of atherosclerosis.

[0010] Cryopyrin-associated periodic syndrome (CAPS) is a common name for autoinflammatory diseases caused by activating mutations in the NLRP3 gene, which are divided into the following three disease types: mild disease type of familial cold autoinflammatory syndrome (FCAS), moderate disease type of Muckler-Wells syndrome (MWS), severe disease type of chronic infantile neurocutaneous articular syndrome (CINCA) or neonatal multisystem inflammatory disease (NOMID) (Non-patent literature 16). More than 200 mutations of the NLRP3 gene in CAPS have been reported (Non-patent literature 17). These NLRP3 gene mutations can cause the formation and activation of NLRP3 inflammasomes even in the absence of activation signals. Mice expressing CAPS-associated NLRP3 mutations show systemic lethal inflammation that depends on IL-1β and IL-18, which are NLRP3 inflammasomes and downstream signal transduction molecules (Non-patent literature 18). In a mouse strain expressing CAPS-associated NLRP3 mutations, CY-09, an NLRP3 inflammasome inhibitor, suppressed systemic lethal inflammation and improved survival (Non-Patent Document 19). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of CAPS.

[0011] It has been reported that the expression of NLRP3 inflammasome-related genes is increased in liver tissue of patients with nonalcoholic steatohepatitis (NASH) (Non-Patent Document 20). In addition, it has been reported that liver fibrosis is suppressed by NLRP3 knockout in a choline-deficient amino acid-restricted diet feeding model (a NASH model) (Non-Patent Document 20). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of NASH.

[0012] In gout and gouty arthritis, urate crystals deposited in joints and periarticular tissues induce inflammation (non-patent literature 21). Urate crystals activate macrophage NLRP3 to produce IL-1β and IL-18 (non-patent literature 22). OLT1177 (a NLRP3 inflammasome inhibitor) inhibits arthritis in an arthritis model of intra-articular urate injection (non-patent literature 23). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of gout and gouty arthritis.

[0013] It has been reported that the expression of NLRP3 inflammasome-related genes in the joint synovium and peripheral blood mononuclear cells of patients with rheumatoid arthritis increases (non-patent literature 24). In addition, it has been reported that in collagen-induced arthritis (a model of rheumatoid arthritis), the expression of NLRP3 inflammasome-related genes in the synovium increases (non-patent literature 25). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of rheumatoid arthritis.

[0014] It has been reported that trinitrochlorobenzene, which induces contact dermatitis, increases IL-1β production from human skin keratinocytes via NLRP3 activation, and in a trinitrochlorobenzene-induced dermatitis model (a model of contact dermatitis), NLRP3 knockout inhibits the development of dermatitis (Non-patent Document 26). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of contact dermatitis.

[0015] It has been reported that the expression of NLRP3 inflammasome-related genes in the tears and ocular surface of patients with dry eye is increased (Non-Patent Documents 27 and 28). In addition, it has been reported that when cultured human corneal epithelial cells are subjected to hyperosmotic stress to induce dry eye disease, increased expression of NLRP3 inflammasome-related genes and increased IL-1β production are observed, and IL-1β production is inhibited by knockdown of the NLRP3 gene (Non-Patent Document 28). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of dry eye.

[0016] It has been reported that the expression of the ASC domain of the NLRP3 inflammasome in macrophages and neutrophils infiltrating the myocardial tissue of patients with acute myocardial infarction increases (non-patent literature 29). In addition, it has been reported that the expression of NLRP3 inflammasome-related genes at the infarct site was increased in the ischemia-reperfusion model (a myocardial infarction model), and the knockout of the NLRP3 gene reduced the infarct area and inhibited the decrease in myocardial contractility (non-patent literature 30). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of ischemic heart diseases such as acute myocardial infarction.

[0017] It has been reported that the expression of IL-1β or IL-18 in the serum and glomeruli of patients with systemic lupus erythematosus (SLE) increases (non-patent literature 31, 32), and the expression of NLRP3 gene in macrophages and the production of IL-1β increase (non-patent literature 33). In Nlrp3-R258W mice with an activating mutation of the NLRP3 gene, lupus nephritis-like symptoms caused by the administration of pristane are aggravated (non-patent literature 34). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of SLE.

[0018] In addition to the above diseases, diseases for which NLRP3 inflammasome inhibitors are expected to be effective include systemic juvenile idiopathic arthritis (non-patent document 35), recurrent pericarditis (non-patent document 36), adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome) (non-patent document 37), Schnitzler syndrome (non-patent document 38), IL-1 receptor antagonist deficiency (non-patent document 39), familial Mediterranean fever (non-patent document 40), mevalonate kinase deficiency (non-patent document 40), high IgD syndrome (non-patent document 40), TNF receptor-associated periodic syndrome (non-patent document 40), Behcet's disease (non-patent document 41), lung cancer (non-patent document 42), etc. It has been reported that anti-IL-1β antibodies (e.g., canakinumab) and IL-1 inhibitors (e.g., rilonacept) are effective in treating these diseases. Since the NLRP3 inflammasome is involved in the production of proinflammatory cytokines such as IL-1β, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of these diseases.

[0019] It has been reported that the NLRP3 rs10733113 genotype is significantly increased in psoriasis patients and increases psoriasis susceptibility (Non-patent Document 43). In addition, it has been reported that NLRP3 deletion suppresses psoriasis symptoms in an IL-23-induced psoriasis model (a psoriasis model) (Non-patent Document 44). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for treating psoriasis.

[0020] Gout, atherosclerosis (arteriosclerosis) and chronic kidney disease associated with NLRP3 inflammasome activation are related to hypertension. It has been reported that NLRP3 deletion inhibits hypertension in a mouse model of left renal artery stenosis (non-patent literature 45). In addition, MCC950 (a NLRP3 inflammasome inhibitor) has been reported to inhibit hypertension in a mouse model of deoxycorticosterone acetate (non-patent literature 46). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of hypertension.

[0021] It has been reported that NLRP3 expression is enhanced in the fibrovascular membrane of patients with diabetic retinopathy (non-patent literature 47). In addition, NLRP3 expression is increased in the STZ-induced retinopathy model (a model of diabetic retinopathy) (non-patent literature 48). In this model, it has been reported that NLRP3 expression reduced by NLRP3 shRNA showed reduced IL-1β and VEGF secretion, increased ganglion cell mass and recovery of retinal damage (non-patent literature 49). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of diabetic retinopathy.

[0022] NLRP3 inflammasome activation occurs in the brains of patients with Alzheimer's disease, MCI (mild cognitive impairment) patients, and APP / PS1 mice (an Alzheimer's disease model mouse). NLRP3 deletion in APP / PS1 mice inhibits the development of spatial memory impairment (non-patent literature 50). MCC950 (a NLRP3 inhibitor) inhibits NLRP3 activation in microglia and improves cognitive impairment in APP / PS1 mice (non-patent literature 51). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of Alzheimer's disease and MCI.

[0023] In the substantia nigra of Parkinson's disease patients and mice injected with α-synuclein PFFs (preformed fibrils) (a pathological model of Parkinson's disease), increased expression of NLRP3 inflammasome-related molecules and NLRP3 inflammasome activation occurred in microglia (non-patent literature 52). In mice injected with α-synuclein PFFs, MCC950 (a NLRP3 inhibitor) inhibited NLRP3 activation in the substantia nigra and inhibited neuronal death of dopamine neurons in the substantia nigra (non-patent literature 52). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of Parkinson's disease.

[0024] In patients with Huntington's disease, cerebrospinal fluid levels of IL-1β (a NLRP3 inflammasome-related cytokine) are elevated (Non-Patent Document 53). The expression level of NLRP3 inflammasomes in the striatum of R6 / 2 mice (Huntington's disease model) is elevated (Non-Patent Document 54). MCC950 (a NLRP3 inhibitor) inhibits NLRP3 inflammasome activation in the striatum of R6 / 2 mice, inhibits neuronal death in the striatum, and inhibits symptom progression (Non-Patent Document 55). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of Huntington's disease.

[0025] In the spinal cord of patients with amyotrophic lateral sclerosis (ALS), the expression of NLRP3 inflammasomes, IL-18, and active caspase 1 increases (non-patent literature 56). In the spinal cords of SOD1G93A mice and TDP-43Q331K mice as ALS model mice, the mRNA expression of IL-1β, Nlrp3, Pycard, and Casp1 increases (non-patent literature 57). MCC950 (a NLRP3 inhibitor) inhibits NLRP3 activation induced by SOD1G93A and TDP-43 proteins in microglia and reduces IL-1β production (non-patent literature 57). In SOD1G93A mice, the absence of IL-1β or caspase 1 prolongs survival time, and the administration of IL-1β receptor antibodies inhibits disease progression and prolongs survival time (non-patent literature 58). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of ALS.

[0026] The expression level of NLRP3 inflammasomes is increased in brain tissue and cerebrospinal fluid of patients with traumatic brain injury (TBI) (Non-Patent Documents 59 and 60). In the brain tissue of TBI model rats, the expression level of NLRP3 inflammasomes is increased, and the expression levels of IL-1β and IL-18 are also increased (Non-Patent Document 61). MCC950 (an NLRP3 inhibitor) inhibits IL-1β production in TBI model mice and inhibits the development of neurological symptoms after brain injury (Non-Patent Document 62). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of TBI.

[0027] In patients with cerebral infarction, middle cerebral artery occlusion (MCAO) mice (a cerebral infarction model) and rats with intracranial hemorrhage model, the expression of NLRP3 inflammasomes, IL-1β and IL-18 increased in brain tissue (non-patent literature 63, 64). In addition, MCC950 (an NLRP 3 inhibitor) showed neuroprotective effects in MCAO models and intracranial hemorrhage model rats. Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of cerebral infarction and intracranial hemorrhage.

[0028] The expression of NLRP inflammasomes is increased in brain tissues of patients with temporal lobe epilepsy and in pilocarpine-induced epilepsy model mice (Non-patent Documents 65 and 66). In addition, in pilocarpine-induced epilepsy model mice, NLRP3 inflammasome deficiency and administration of MCC950 (an NLRP3 inhibitor) inhibited hippocampal neuron apoptosis that leads to the development of epilepsy (Non-patent Document 66). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of epilepsy.

[0029] In the peripheral blood of patients with depression, the expression level of NLRP3 inflammasome, IL-1β level and IL-18 level are increased, and the IL-1β level is correlated with the depressive symptom score (non-patent literature 67). In the LPS-induced model (a chronic stress-induced model) or the social frustration model, which is a pathological model of depression, the expression level of NLRP3 inflammasome, IL-1β or IL-18 in brain tissue is increased, and the NLRP3 inflammasome is activated (non-patent literature 68, 69 and 70). In the pathological model, the administration of MCC950 (a NLRP3 inhibitor) or the loss of NLRP3 improves depressive symptoms (non-patent literature 69 and 70). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of depression.

[0030] The expression of NLRP3 inflammasomes and the levels of IL-1β and IL-18 in the peripheral blood of patients with autism spectrum disorder (ASD) are increased (non-patent literature 71). In the maternal immune activation (MIA) model, the administration of PolyIC to pregnant animals causes ASD symptoms in offspring. The expression of IL-1β in the fetal brain of this model is increased, and the administration of MCC950 (an NLRP3 inhibitor) to the mother suppresses the ASD symptoms in the offspring (non-patent literature 72). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of ASD.

[0031] In the spinal cord of mice with spinal cord injury, NLRP3 inflammasome or IL-1β expression increased, and NLRP3 activation was observed (Non-patent Documents 73 and 74). Administration of MCC950 (an NLRP3 inhibitor) to mice after spinal cord injury inhibited NLRP3 activation and IL-1β expression in the spinal cord and promoted the recovery of motor function (Non-patent Document 73). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of spinal cord injury.

[0032] In the intestinal perforation model (a sepsis animal model), the expression and activation of NLRP3 inflammasomes or IL-1β in the brain increased, leading to damage to hippocampal neurons and memory loss, which are symptoms of septic encephalopathy (Non-patent Documents 75 and 76). When MCC950 (an NLRP3 inhibitor) was applied to the intestinal perforation model, NLRP3 inflammasome activation was inhibited and memory impairment was improved (Non-patent Document 76). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of septic encephalopathy.

[0033] In the chronic constriction injury (CCI) model (an animal model of neuropathic pain), the expression levels of IL-1β and NLRP3 inflammasome-related molecules in glial cells and neurons in the spinal cord increased (non-patent literature 77). In the paclitaxel-induced pain model (a neuropathic pain model of anticancer drug-induced neuropathy), the expression levels of NLRP3 inflammasome-related molecules in dorsal root ganglia and sciatic nerve increased (non-patent literature 78). In trigeminal neuralgia model animals, the expression level of NLRP3 inflammasomes in the dorsal horn of the spinal cord increased, and the silent NLRP3 in the spinal cord inhibited the activation of NLRP3 inflammasomes and mechanical hyperalgesia in the spinal cord (non-patent literature 79). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of neuropathic pain.

[0034] Mice infected with SARS-CoV-2 showed increased expression levels of IL-1β and NLRP3 inflammasome-related molecules in lung tissue. On the other hand, NLRP3 knockout mice did not show an increase in their expression levels, and the severe respiratory inflammation caused by SARS-CoV-2 was reduced. In addition, administration of the NLRP3 inhibitor MCC950 to mice infected with SARS-CoV-2 inhibited the activation of NLRP3 inflammasomes in the lungs and suppressed dysregulated immune responses (non-patent literature 80). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of COVID-19 caused by SARS-CoV-2.

[0035] It has been reported that the ASC domain of the NLRP3 inflammasome and mature IL-1β protein are increased in the cerebral cortex of patients with frontotemporal dementia (mutations in tau protein) (Non-patent document 81). It has also been reported that the ASC domain of the NLRP3 inflammasome and the increase of truncated caspase 1 in the cerebral cortex of Tau22 mice (mice expressing human mutant tau protein), a model of frontotemporal dementia, are increased, indicating that knockout of NLRP3 inhibits the formation of tau pathologies and cognitive decline (Non-patent document 81). These results suggest that NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of frontotemporal dementia.

[0036] Drusen, a possible pathogenic substance believed to cause age-related macular degeneration (AMD), has been shown to form in patients with NLRP3-related autoinflammatory disease (NLRP3-AID) caused by activating mutations in the NLRP3 gene (non-patent literature 82). NLRP3 inhibitors also inhibited the degeneration of retinal pigment epithelial cells in one of the age-related macular degeneration models (a model of Alu RNA-induced degeneration in retinal pigment epithelial cells) (non-patent literature 83). NLRP3 inhibitors inhibited angiogenesis in another age-related macular degeneration model with laser-induced choroidal neovascularization (non-patent literature 83). These results indicate that NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of age-related macular degeneration.

[0037] Diabetes increases retinal vascular permeability in patients with diabetic macular edema, causing blood components to leak into the retina (Non-Patent Document 84). MCC950 (an NLRP3 inhibitor) alleviates the increased vascular permeability in STZ-induced diabetic mice (Non-Patent Document 85). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of diabetic macular edema.

[0038] Hereditary transient corneal endotheliitis is one of the cryptopyrin-related periodic syndromes caused by activating mutations in the NLRP3 gene (Non-Patent Document 86). Therefore, NLRP3 inflammation inhibitors are considered to be drugs for treating hereditary transient corneal endotheliitis.

[0039] Citation List

[0040] Non-patent literature

[0041] [Non-patent document 1] Andersson, A et al., Pivotal advance: HMGB1 expression inactive lesions of human and experimental multiple sclerosis. J Leukoc Biol., 2008, Vol. 84(5), pp. 1248-55

[0042] [Non-patent document 2] Voet, S et al., A20 critically controls microglia activity and inhibits inflamma some-dependent neuroinflammation. Nat Commun., 2018, Vol. 9(1), p. 2036

[0043] [Non-patent document 3] Politis, M et al., Increased PK11195 PET binding in the cortex of patients with MS correlations with disability. Neurology, 2012, V 79(6), 523-30

[0044] [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, pp. 13-28

[0045] [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), pp. 974-981

[0046] [Non-patent document 6] Jha, S et al., The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci., 2010, Vol. 30(47), pp. 15811-20

[0047] [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), pp. 2194-2201

[0048] [Non-patent document 8] Akosua Vilaysane et al., The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD. J Am Soc Nephrol. 2010 Oct;21(10):1732-1744.

[0049] [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.

[0050] [Non-patent document 10] Gong W et al., NLRP3 deletion protects against renalfibrosis and attenuates mitochondrial abnormality in mouse with 5 / 6 nephrectomy. Am J Physiol Renal Physiol. 2016 May 15;310(10):F1081-8

[0051] [Non-patent document 11] Ranson N et al., NLRP3-dependent and -independent processing of Interleiukin-1β in active ulcerative colitis. Int J mol Sci 2018:20pii:E57.

[0052] [Non-patent document 12] Mao L et al., Loss-of-function CARD8 mutation causes NLRP3inflammasome activation and Crohn's disease. J Clin Invest 2018: Vol. 128: 1793-1806.

[0053] [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. Dig. Dis 2012, Vol. 30 Suppl 182-90.

[0054] [Non-patent document 14] Paramel VG et al., NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. J Am Heart Assoc. 2016 May 20;5(5):e003031.

[0055] [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.

[0056] [Non-patent document 16] Broderick L et al., The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol. 2015; 10: 395-424.

[0057] [Non-patent document 17] Sarrauste MC et al., INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 2003 Jan 1; 31(1): 282-5.

[0058] [Non-patent document 18] Brydges SD et al., Divergence of IL-1, IL-18, and cell deathin NLRP3 inflammasomopathies. J Clin Invest. 2013 Nov; 123(11): 4695-705.

[0059] [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.

[0060] [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.

[0061] [Non-patent document 21] So AK et al., Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol. 2017 Nov; 13(11): 639-647.

[0062] [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.

[0063] [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.

[0064] [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.

[0065] [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.

[0066] [Non-patent document 26] Watanabe H et al., Activation of the IL-1beta-processing inflammation is involved in contact hypersensitivity. J Invest Dermatol. 2007 Aug; 127(8): 1956-63.

[0067] [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.

[0068] [Non-patent document 28] Zheng Q et al., Reactive oxygen species activated NLRP3inflammasomes initiate inflammation in hyperosmolarity stressed human cornealepithelial cells and environment-induced dry eye patients. Exp Eye Res. 2015 May; 134:133-40.

[0069] [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.

[0070] [Non-patent document 30] Sandanger O et al., The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013 Jul 1; 99(1): 164-74.

[0071] [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.

[0072] [Non-patent document 32] Tucci M et al., Glomerular accumulation of plasmacytoiddendritic cells in active lupus nephritis: role of interleukin-18. Arthritis Rheum. 2008 Jan; 58(1): 251-62.

[0073] [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.

[0074] [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.

[0075] [Non-patent document 35] Ruperto N et al., Two randomized trials of canakinumab insystemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2396-406.

[0076] [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.

[0077] [Non-patent document 37] Junge G et al., Adult onset Still's disease-The evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review). Seminars in Arthritis Rheumatism 2017 Oct;47(2):295-302.

[0078] [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.

[0079] [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).

[0080] [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.

[0081] [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.

[0082] [Non-patent document 42] Ridker PM et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Lancet (2017) 3901833-42.

[0083] [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.

[0084] [Non-patent document 44] JA Diaz-Perez et al., Extracellular ATP and IL-23Form aLocal Inflammatory Circuit Leading to the Development of a Neutrophil-Dependent Psoriasiform Dermatitis. J Invest Dermatol. (2018) 138: 2595-605.

[0085] [Non-patent document 45] Wang Q et al., Renin-Dependent Hypertensionin Mice Requires the NLRP3-Inflammasome. J. Hypertens (2014) 3: 187.

[0086] [Non-patent document 46] Krishnan SM et al., Pharmacological inhibition of the NLRP3inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc. Res. (2019) 1154: 776-787.

[0087] [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.

[0088] [Non-patent document 48] Sheng Li et al. Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3inflammasome formation. Exp Anim. 2019 May 8;68(2):221-231.

[0089] [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.

[0090] [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.

[0091] [Non-patent document 51] Dempsey C et al., Inhibiting the NLRP3inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP / PS1 mice. Brain Behav Immun. 2017 Mar;61:306-316.

[0092] [Non-patent document 52] Gordon R et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018 Oct 31;10(465):eaah4066.

[0093] [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.

[0094] [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.

[0095] [Non-patent document 55] Chen KP et al., A selective inhibitor of the NLRP3inflammasome as a potential therapeutic approach for neuroprotection in a transgenic mouse model of Huntington's disease. J Neuroinflammation. 2022 Feb 26;19(1):56.

[0096] [Non-patent document 56] Johann S et al., NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015 Dec; 63(12): 2260-73.

[0097] [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.

[0098] [Non-patent document 58] Meissner F et al., A. Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci USA. 2010 Jul 20; 107(29): 13046-50.

[0099] [Non-patent document 59] Lin C et al., Omega-3 fatty acids regulate NLRP3 inflammation and prevent behavioral deficits after traumatic brain injury. Exp Neurol. 2017 Apr;290:115-122.

[0100] [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.

[0101] [Non-patent document 61] Liu HD et al., Expression of the NLRP3inflammasome incerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 2013 Oct;38(10):2072-83.

[0102] [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.

[0103] [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.

[0104] [Non-patent document 64] Feng L et al., P2X7R blockade prevents NLRP3inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite. J Neuroinflammation. 2015 Oct 17;12:190.

[0105] [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.

[0106] [Non-patent document 66] Wu C et al., The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury. Front Neurol. 2020 Feb 7;10:1418.

[0107] [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.

[0108] [Non-patent document 68] Zhang Y et al., Involvement of inflammasome activation inlipopolysaccharide-induced mice depressive-like behaviors. CNS Neurosci Ther. 2014 Feb;20(2):119-24.

[0109] [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.

[0110] [Non-patent document 70] Li W et al., Inhibition of the NLRP3 inflammasome with MCC950 prevents chronic social isolation-induced depression-like behavior inmale mice. Neurosci Lett. 2021 Nov 20;765:136290.

[0111] [Non-patent document 71] Saresella M et al., Multiple inflammasome complexes are activated in autistic spectrum disorders. Brain Behav Immun. 2016 Oct;57:125-133.

[0112] [Non-patent document 72] Szabo D et al., Maternal P2X7 receptor inhibition prevents sautism-like phenotype in male mouse offspring through the NLRP3-IL-1β pathway. Brain Behav Immun. 2022 Mar;101:318-332.

[0113] [Non-patent document 73] Amo-Aparicio J et al., Inhibition of the NLRP3inflammasome by OLT1177 induces functional protection and myelin preservation after spinalcord injury. Exp Neurol. 2022 Jan;347:113889.

[0114] [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.

[0115] [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.

[0116] [Non-patent document 76] Fu Q et al., NLRP3 / Caspase-1Pathway-Induced PyroptosisMediated Cognitive Deficits in a Mouse Model of Sepsis-Associated Encephalopathy. Inflammation. 2019 Feb;42(1):306-318.

[0117] [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.

[0118] [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.

[0119] [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.

[0120] [Non-patent document 80] Zeng J et al., Specific inhibition of the NLRP3inflammasome suppresses immune overactivation and alleviates COVID-19like pathology in mice. EBioMedicine. 2022 Jan;75:103803.

[0121] [Non-patent document 81] Ising C, et al., NLRP3 inflammasome activation drives taupathology. Nature. 2019 Nov; 575(7784): 669-673.

[0122] [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.

[0123] [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.

[0124] [Non-patent document 84] Hideharu Funatsu, Development of treatment for macular edema, Diabetes 48(10):721-723, 2005.

[0125] [Non-patent document 85] Keke Ge, et al., Down-expression of the NLRP3inflammasome delays the progression of diabetic retinopathy, Microvasc Res. 2022 Jan;139:104265.

[0126] [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, PyrinDomain-Containing 3 (NLRP3) Gene, Am J Ophthalmol. 2018 Apr;188:41-50. Summary of the invention

[0127] The present invention provides a pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and medical uses thereof, etc. Specifically, the present invention includes the embodiments shown below.

[0128] Project 1

[0129] Compound of formula [I]:

[0130]

[0131] or a pharmaceutically acceptable salt thereof (hereinafter referred to as "compound [I] or a pharmaceutically acceptable salt thereof"),

[0132] Among them, the keys represented by:

[0133]

[0134] is a single bond or a double bond;

[0135] R 1 and R 2 Each independently

[0136] (1) Hydrogen,

[0137] (2) hydroxyl group,

[0138] (3) cyano group,

[0139] (4)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0140] (a) hydroxyl group,

[0141] (b)C 1-4 Alkoxy, and

[0142] (c)C 3-6 Cycloalkyl,

[0143] (5)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution,

[0144] (6) Halogen,

[0145] (7)C 1-4 Haloalkyl,

[0146] (8) -CHO,

[0147] (9)-OC 1-4 Haloalkyl,

[0148] (10)-OC 3-6 Cycloalkyl,

[0149] (11)-CO-C 1-4 alkyl,

[0150] (12)-CO-C 3-6 Cycloalkyl,

[0151] (13)-NR 7 R 8 , where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl, or alternatively, R 7 and R 8 can bond with the nitrogen atom to which they are attached, and the -NR 7 R 8 The group may form a 5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or

[0152] (14)C 3-6 Cycloalkyl,

[0153] R 3 and R 4 Each independently

[0154] (1) Hydrogen,

[0155] (2)C 1-4 Alkyl, or

[0156] (3)C 1-4 Haloalkyl,

[0157] R 5 for

[0158] (1) Hydrogen,

[0159] (2) cyano group,

[0160] (3)C 1-6 alkyl,

[0161] (4)C 2-6 Alkenyl,

[0162] (5)C 2-5 Alkynyl,

[0163] (6)C 1-4 Alkoxy,

[0164] (7) Halogen,

[0165] (8)C 1-6 Haloalkyl,

[0166] (9)C 2-6 Halogenated alkenyl,

[0167] (10)-OC 1-4 Haloalkyl,

[0168] (11)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 to 3 halogen or C 1-4 Haloalkyl substitution,

[0169] (12)C 5-6 Cycloalkenyl, or

[0170] (13) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms,

[0171] R 6 for

[0172] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0173] (2)C 1-4 Alkoxy,

[0174] (3) Halogen,

[0175] (4)C 1-4 haloalkyl, or

[0176] (5) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms,

[0177] m is 0, 1, or 2,

[0178] n is 0 or 1,

[0179] The condition is that when n is 0, then X 1 , X2 , X 3 and X 4 Each independently represents a carbon, nitrogen, oxygen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1, and X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group, and

[0180] The condition is that when n is 1, then X 1 , X 2 , X 3 , X 4 and X 5 Each independently represents a carbon or nitrogen atom, wherein X 1 , X 2 , X 3 , X 4 or X 5 The total number of nitrogen atoms is 1 or 2, and X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0181] Project 2

[0182] The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 For hydrogen.

[0183] Project 3

[0184] The compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [II]:

[0185]

[0186] The symbols are as defined in item 1.

[0187] Project 4

[0188] The compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [III]:

[0189]

[0190] The symbols are as defined in item 1.

[0191] Project 5

[0192] A pharmaceutical composition comprising the compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0193] Item 6

[0194] A NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof.

[0195] Item 7

[0196] An agent for treating or preventing a disease selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis), The invention relates to a compound of any one of items 1 to 4, wherein the compound is a pharmaceutically acceptable salt thereof. The compound is a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof.

[0197] Item 8

[0198] The agent according to item 7, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0199] Item 9

[0200] The agent according to item 7, wherein the cryptopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0201] Item 10

[0202] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof to a mammal.

[0203] Project 11

[0204] A method for treating or preventing a disease selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and Macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, high 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, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19 and TNF receptor-associated periodic syndrome, which comprises administering to a mammal a therapeutically effective amount of a compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof.

[0205] Project 12

[0206] The method according to item 11, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0207] Project 13

[0208] The method according to item 11, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0209] Project 14

[0210] Use of the compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inflammasome inhibitor.

[0211] Project 15

[0212] Use of a compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic syncope, arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0213] Project 16

[0214] The use according to item 15, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0215] Project 17

[0216] The use according to item 15, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0217] Project 18

[0218] The compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 inflammasome.

[0219] Project 19

[0220] The compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis, and neonatal multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis inflammation, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0221] Project 20

[0222] The compound for use according to Item 19 or a pharmaceutically acceptable salt thereof, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0223] Project 21

[0224] The compound for use according to item 19 or a pharmaceutically acceptable salt thereof, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0225] Project 22

[0226] A package for commercial use, comprising the pharmaceutical composition according to item 5 and a written document related to the pharmaceutical composition, wherein the document describes that the composition can be used to treat or prevent a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (such as familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (such as 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 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, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0227] Project 23

[0228] A kit for commercial use, comprising the pharmaceutical composition according to item 5 and a written document related to the pharmaceutical composition, wherein the document describes that the composition can be used to treat or prevent a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (such as familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome and neonatal onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (such as 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 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, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0229] Project 1A

[0230] Compound of formula [IA]:

[0231]

[0232] or a pharmaceutically acceptable salt thereof (hereinafter "a compound of formula [IA] or a pharmaceutically acceptable salt thereof" is also referred to as "compound [IA]"),

[0233] Among them, the keys represented by:

[0234]

[0235] is a single bond or a double bond;

[0236] R 1 and R 2 Each independently

[0237] (1) Hydrogen,

[0238] (2) hydroxyl group,

[0239] (3) cyano group,

[0240] (4)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0241] (a) hydroxyl group,

[0242] (b)C 1-4 Alkoxy, and

[0243] (c)C 3-6 Cycloalkyl,

[0244] (5)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution,

[0245] (6) Halogen,

[0246] (7)C 1-4 Haloalkyl,

[0247] (8) -CHO,

[0248] (9)-OC 1-4 Haloalkyl,

[0249] (10)-OC 3-6 Cycloalkyl,

[0250] (11)-CO-C 1-4 alkyl,

[0251] (12)-CO-C 3-6 Cycloalkyl,

[0252] (13)-NR 7 R 8 , where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl, or alternatively, R 7 and R 8 can bond with the nitrogen atom to which they are attached, and the -NR 7 R 8 The group may form a 5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or

[0253] (14)C 3-6 Cycloalkyl,

[0254] R 3A and R 4A Each independently

[0255] (1) Hydrogen,

[0256] (2)C 1-4 Alkyl, or

[0257] (3)C 1-4 Haloalkyl,

[0258] R 5A for

[0259] (1) Hydrogen,

[0260] (2) cyano group,

[0261] (3)C 1-6 alkyl,

[0262] (4)C 2-6 Alkenyl,

[0263] (5)C 2-5 Alkynyl,

[0264] (6)C 1-4 Alkoxy,

[0265] (7) Halogen,

[0266] (8)C 1-6 Haloalkyl,

[0267] (9)C 2-6 Halogenated alkenyl,

[0268] (10)-OC 1-4 Haloalkyl,

[0269] (11)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0270] (a) hydroxyl group,

[0271] (b) halogens, and

[0272] (c)C 1-4 Haloalkyl,

[0273] (12)C 5-6 Cycloalkenyl, or

[0274] (13) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or alternatively R 5A Can be used with R 3A or R 4A and the carbon atoms they are attached to combine to form:

[0275] (1)C 5-6 Cyclic olefins, or

[0276] (2) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms,

[0277] R 6A Independently

[0278] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0279] (2)C 1-4 Alkoxy,

[0280] (3) Halogen,

[0281] (4)C 1-4 haloalkyl, or

[0282] (5) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms,

[0283] m is 0, 1, or 2,

[0284] The condition is that when m is 2, then two adjacent R 6A Can be connected to the X 1 , X 2 , X 3 Two adjacent atoms in X4 and X5 are combined together to form a 5- to 7-membered heterocycloalkane or heterocycloalkene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms,

[0285] n is 0 or 1,

[0286] The condition is that when n is 0, then X 1 , X 2 , X 3 and X 4 Each independently represents a carbon, nitrogen, oxygen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1, and X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group, and

[0287] The condition is that when n is 1, then X 1 , X 2 , X 3 , X 4 and X 5 Each independently represents a carbon or nitrogen atom, wherein X 1 , X 2 , X 3 , X 4 or X5 The total number of nitrogen atoms is 1 or 2, and X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0288] Project 2A

[0289] The compound according to item 1A or a pharmaceutically acceptable salt thereof, wherein R 3A and R 4A For hydrogen.

[0290] Project 3A

[0291] The compound according to item 1A or 2A or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [IIA]:

[0292]

[0293] Where R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 and m are defined as those defined in item 1A.

[0294] Project 4A

[0295] A compound according to any one of items 1A to 3A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are joined together to form a pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl or triazolyl group.

[0296] Project 5A

[0297] A compound according to any one of items 1A to 4A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a pyrazolyl, imidazolyl or thiazolyl group.

[0298] Project 6A

[0299] A compound according to any one of items 1A to 5A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a group of formula (1):

[0300]

[0301] The group of formula (2):

[0302] or

[0303] The group of formula (3):

[0304]

[0305] Project 7A

[0306] The compound according to item 1A or 2A or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [IIIA]:

[0307]

[0308] Where R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 and m are defined as those defined in Item 1A.

[0309] Project 8A

[0310] A compound according to any one of items 1A, 2A or 7A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are joined together to form a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group.

[0311] Project 9A

[0312] A compound according to any one of items 1A, 2A, 7A or 8A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a pyridazinyl or pyrimidinyl group.

[0313] Project 10A

[0314] A compound according to any one of items 1A, 2A, 7A, 8A or 9A, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a group of formula (1'):

[0315] or

[0316] The group of formula (2'):

[0317]

[0318] Project 11A

[0319] The compound according to any one of items 1A to 10A, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

[0320] Project 12A

[0321] A compound according to any one of items 1A to 11A, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 At least one of:

[0322] C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0323] (a) hydroxyl group,

[0324] (b)C 1-4 Alkoxy, and

[0325] (c)C 3-6 Cycloalkyl, or

[0326] halogen.

[0327] Project 13A

[0328] A compound selected from the following structural formulas:

[0329]

[0330]

[0331] or a pharmaceutically acceptable salt thereof.

[0332] Project 14A

[0333] A pharmaceutical composition comprising the compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0334] Project 15A

[0335] A NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1A to 13A, or a pharmaceutically acceptable salt thereof.

[0336] Project 16A

[0337] An agent for treating or preventing a disease selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schneider's disease Tschiller 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, intracranial 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, comprising a compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof.

[0338] Project 17A

[0339] The agent according to item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0340] Project 18A

[0341] The agent according to item 16A, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0342] Project 19A

[0343] The agent according to item 16A, wherein the disease is selected from multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema and hereditary transient corneal endotheliitis.

[0344] Project 20A

[0345] A method for inhibiting NLRP3 inflammasome, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof.

[0346] Project 21A

[0347] A method for treating or preventing a disease selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, I L-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, intracranial 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, which comprises administering to a mammal a therapeutically effective amount of a compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof.

[0348] Project 22A

[0349] The method according to item 21A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0350] Project 23A

[0351] The method according to item 21A, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0352] Project 24A

[0353] The method according to item 21A, wherein the disease is selected from multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema and hereditary transient corneal endotheliitis.

[0354] Project 25A

[0355] Use of the compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inflammasome inhibitor.

[0356] Project 26A

[0357] Use of a compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, 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, intracranial 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.

[0358] Project 27A

[0359] The use according to item 26A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0360] Project 28A

[0361] The use according to item 26A, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0362] Project 29A

[0363] The use according to item 26A, wherein the disease is selected from multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema and hereditary transient corneal endotheliitis.

[0364] Project 30A

[0365] A compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 inflammasome.

[0366] Project 31A

[0367] A compound according to any one of items 1A to 13A or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, and adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial 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.

[0368] Project 32A

[0369] The compound for use according to Item 31A or a pharmaceutically acceptable salt thereof, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0370] Project 33A

[0371] The compound for use according to Item 31A or a pharmaceutically acceptable salt thereof, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal-onset multisystem inflammatory disease.

[0372] Project 34A

[0373] The compound for use according to Item 31A or a pharmaceutically acceptable salt thereof, wherein the disease is selected from multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema and hereditary transient corneal endotheliitis.

[0374] Item 35A

[0375] A kit for commercial use, comprising a pharmaceutical composition according to item 14A and a written document related to the pharmaceutical composition, wherein the document describes that the composition can be used to treat or prevent a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (such as familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis and neonatal onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye syndrome, ischemic heart disease (such as acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, Recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist 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, intracranial 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.

[0376] Item 36A

[0377] A kit for commercial use, comprising a pharmaceutical composition according to item 14A and a written document related to the pharmaceutical composition, wherein the document describes that the composition can be used to treat or prevent a disease selected from the following: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (such as familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis and neonatal onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye syndrome, ischemic heart disease (such as acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, Recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist 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, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. DETAILED DESCRIPTION

[0378] The following are definitions of terms that may be used herein.

[0379] The following wavy lines:

[0380]

[0381] In the chemical formulae herein, it refers to the binding site of the moiety or group represented by the chemical formula.

[0382] The term "C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 The "alkyl group" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Preferably, it includes methyl and ethyl. More preferably, it includes methyl.

[0383] The term "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6The "alkyl group" 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. Preferably, methyl and ethyl are included. More preferably, methyl is included.

[0384] The term "C 2-6 "Alkenyl" refers to a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing at least one double bond. 2-6 The term "alkenyl" includes, for example, vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,1-dimethyl-2-propenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl and 1-methyl-2-butenyl.

[0385] The term "C 2-5 "Alkynyl" refers to a straight or branched unsaturated hydrocarbon group having 2 to 5 carbon atoms and containing at least one triple bond. 2-5 The term "alkynyl" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 2-pentynyl.

[0386] The term "C 1-4 "Alkoxy" refers to a "C 1-4 Alkyl" is a group bonded to an oxygen atom. 1-4 The "alkoxy group" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy. Preferably, it includes methoxy.

[0387] The term "C 1-6 "Alkoxy" refers to a "C 1-6 Alkyl" is a group bonded to an oxygen atom. 1-6 The “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.

[0388] The term "halogen" includes, for example, fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

[0389] The term "C 1-4"Haloalkyl" refers to the "C" defined above substituted by 1 to 7 halogen atoms independently selected from the "halogen" defined above. 1-4 Alkyl". "C 1-4 The "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. Preferably, difluoromethyl and trifluoromethyl are included.

[0390] The term "C 1-6 "Haloalkyl" refers to the above-defined "C" substituted by 1 to 9 halogen atoms independently selected from the above-defined "halogen" 1-6 Alkyl". "C 1-6 The "haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl. Preferably, trifluoromethyl and 1,1-difluoroethyl are included.

[0391] The term "C 2-6 The "haloalkenyl" refers to the "C" defined above substituted by 1 to 9 halogen atoms independently selected from the "halogen" defined above. 2-6 "C 2-6 The "haloalkenyl group" includes, for example, 2-fluorovinyl, 3-chloropropenyl, 2-fluoropropenyl, 1-trifluoromethylvinyl and 4,4,4-trifluoro-2-butenyl.

[0392] The term "C 3-6 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. 3-6 The "cycloalkyl group" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferably, it includes cyclopropyl.

[0393] The term "C 5-6 "Cycloolefin" refers to a monocyclic partially unsaturated hydrocarbon ring having 5 to 6 carbon atoms and containing at least one double bond. 5-6 The "cycloolefin" includes, for example, cyclopentene, cyclopentadiene, cyclohexene and cyclohexadiene. Preferably, cyclopentene is included.

[0394] The term "C5-6 "Cycloalkenyl" refers to a monocyclic partially unsaturated hydrocarbon group having 5 to 6 carbon atoms and containing at least one double bond. 5-6 The term "cycloalkenyl" includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl.

[0395] The term "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 4- to 6-membered monocyclic saturated heterocyclic group containing one or two heteroatoms independently selected from nitrogen and oxygen atoms as ring-constituting atoms in addition to carbon atoms."4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" includes, for example, azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexane, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl and dioxetanyl. Preferably, oxetanyl is included.

[0396] The term "5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 5- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms as ring-constituting atoms in addition to carbon atoms. "5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" includes, for example, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl and dioxanyl.

[0397] The term "5- to 7-membered heterocycloalkane containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 5- to 7-membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms as ring-constituting atoms in addition to carbon atoms. "5- to 7-membered heterocycloalkanes containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" include, for example, pyrrolidine, tetrahydrofuran, imidazolidine, pyrazolidine, dioxolane, oxazolidine, isoxazolidine, piperidine, tetrahydropyran, 1,2-diazacyclohexane, 1,3-diazacyclohexane, piperazine, dioxane, morpholine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, azepane, oxepane, diazepane (e.g., 1,4-diazacycloheptan), dioxepane (e.g., 1,4-dioxepane) and oxazepane (e.g., 1,4-oxazepane and 1,2-oxazepane). Preferably, pyrrolidine, morpholine and tetrahydro-1,3-oxazine are included.

[0398] The term "5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms" refers to a 5- to 7-membered monocyclic partially unsaturated heterocyclic ring containing 1 or 2 oxygen atoms as ring-constituting atoms in addition to carbon atoms and containing at least one double bond. "5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms" includes, for example, dihydrofuran, dioxole, dihydropyran, dihydrodioxin, pyran, tetrahydrooxepin, dihydrodioxepin, dihydrooxepin and dioxepin. Preferably, dihydropyran is included.

[0399] The term "5- to 7-membered heterocyclic olefin containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 5- to 7-membered monocyclic partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms as ring-constituting atoms in addition to carbon atoms and containing at least one double bond. The “5- to 7-membered heterocyclic olefin containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms” includes, for example, pyrroline, pyrazoline, imidazoline, dihydrofuran, dioxole, oxazoline, isoxazoline, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, tetrahydropyrazine, dihydropyridine, dihydropyran, dihydrodioxin, pyran, dihydrooxazine, tetrahydroazepine, tetrahydrodiazepine, dihydroazepine, dihydrodiazepine, tetrahydrooxazepine, dihydrodioxazepine, dihydrooxazepine, dioxazepine, tetrahydrooxazepine and dihydrooxazepine. Pyrroline and dihydrooxazine are preferably included.

[0400] In one embodiment of the present invention, n in formula [I] and formula [IA] is 0; X 1 , X 2 , X 3 and X 4 are each independently a carbon, nitrogen, oxygen or sulfur atom; X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group in which X 1 , X 2 , X 3 or X 4The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1. The heteroaryl group refers to a 5-membered monocyclic aromatic heterocyclic group containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms as ring-constituting atoms in addition to carbon atoms, wherein the total number of oxygen and sulfur atoms is 0 or 1. Heteroaryl groups include, for example, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, and 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl) and triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl). Preferably, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl are included. More preferably, pyrazolyl, imidazolyl and thiazolyl are included. Even more preferably, the following groups are included:

[0401]

[0402] In another embodiment of the present invention, n in formula [I] and formula [IA] is 1; X 1 , X 2 , X 3 , X 4 and X 5 Each independently represents a carbon or nitrogen atom; X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group in which X 1 , X 2 , X 3 , X 4 or X 5 The total number of nitrogen atoms is 1 or 2. Heteroaryl refers to a 6-membered monocyclic aromatic heterocyclic group containing 1 or 2 nitrogen atoms as ring-constituting atoms in addition to carbon atoms. The heteroaryl group includes, for example, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. Preferably, it includes pyrimidyl and pyridazinyl. More preferably, it includes the following groups:

[0403]

[0404] In certain embodiments of the present invention, the partial structure in formula [IA] is:

[0405]

[0406] The two adjacent R 6A The X to which they are connected 1 , X 2 , X 3 , X 4 and X 5 The adjacent two of them are combined together to form a ring structure, forming an 8- to 11-membered partially unsaturated fused ring group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms as a whole. The fused ring group includes, for example, the following groups:

[0407]

[0408] In certain embodiments of the present invention, the partial structure in formula [IA] is:

[0409]

[0410] Where R 5A With R 3A or R 4A and the carbon atoms to which they are attached are combined together to form a ring structure, forming as a whole a 9- to 11-membered partially unsaturated fused ring group, the fused ring group optionally containing 1 or 2 oxygen atoms, the fused ring group being R 1 and R 2 and R 3A or R 4A The fused ring group includes, for example, the following groups:

[0411]

[0412] The phrase wherein α may be "optionally substituted with β" means that α is unsubstituted, or any substitutable hydrogen atom of α is substituted with β, for example, "C 1-6 "Alkyl is optionally substituted with hydroxyl" means C 1-6 The alkyl group is unsubstituted, or C 1-6 Any hydrogen atom of the alkyl group is substituted by a hydroxy group.

[0413] The embodiments of each substituent in the compound of formula [I] or [IA] are described below. However, each substituent of the compound of formula [I] or [IA] is not limited to these embodiments, and the compound of formula [I] or [IA] also includes any combination of two or more of these embodiments in each substituent.

[0414] R 1 and R 2 Preferably, each independently is

[0415] (1) Hydrogen,

[0416] (2)C 1-6Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0417] (a) hydroxyl group,

[0418] (b)C 1-4 Alkoxy, and

[0419] (c)C 3-6 Cycloalkyl,

[0420] (3)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution,

[0421] (4) Halogen,

[0422] (5)C 1-4 Haloalkyl,

[0423] (6)-OC 1-4 A haloalkyl group, or

[0424] (7)C 3-6 Cycloalkyl.

[0425] R 1 and R 2 Preferably, each independently is

[0426] (1) Hydrogen,

[0427] (2)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0428] (a) hydroxyl group,

[0429] (b)C 1-4 Alkoxy, and

[0430] (c)C 3-6 Cycloalkyl, or

[0431] (3) Halogen.

[0432] R 1 and R 2 More preferably, each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution.

[0433] R 3 and R 4 Preferred is hydrogen.

[0434] R 5 Preferably

[0435] (1) Hydrogen,

[0436] (2)C 1-6 alkyl,

[0437] (3)C 1-4 Alkoxy,

[0438] (4) Halogen,

[0439] (5)C 1-6 Haloalkyl,

[0440] (6)-OC 1-4 haloalkyl, or

[0441] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 to 3 halogen or C 1-4 Haloalkyl substitution.

[0442] In the following partial structure:

[0443]

[0444] Preferably, R 1 and R 2 Each independently

[0445] (1) Hydrogen,

[0446] (2)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0447] (a) hydroxyl group,

[0448] (b)C 1-4 Alkoxy, and

[0449] (c)C 3-6 Cycloalkyl,

[0450] (3)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution,

[0451] (4) Halogen,

[0452] (5)C 1-4 Haloalkyl,

[0453] (6)-OC 1-4 haloalkyl, or

[0454] (7)C 3-6 Cycloalkyl;

[0455] R 3 and R 4Preferably, it is hydrogen; and

[0456] R 5 for

[0457] (1) Hydrogen,

[0458] (2)C 1-6 alkyl,

[0459] (3)C 1-4 Alkoxy,

[0460] (4) Halogen,

[0461] (5)C 1-6 Haloalkyl,

[0462] (6)-OC 1-4 haloalkyl, or

[0463] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 to 3 halogen or C 1-4 Haloalkyl substitution.

[0464] R 3A and R 4A Preferably each independently is hydrogen or C 1-4 alkyl.

[0465] R 3A and R 4A More preferred is hydrogen.

[0466] R 5A Preferably

[0467] (1) Hydrogen,

[0468] (2)C 1-6 alkyl,

[0469] (3)C 1-4 Alkoxy,

[0470] (4) Halogen,

[0471] (5)C 1-6 Haloalkyl,

[0472] (6)-OC 1-4 haloalkyl, or

[0473] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0474] (a) hydroxyl group,

[0475] (b) halogen, and

[0476] (c)C 1-4 haloalkyl, or

[0477] R 5A With R 3A or R 4A and the carbon atoms to which they are attached combine to form

[0478] (1)C 5-6 Cyclic olefins, or

[0479] (2) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms.

[0480] R 5A More preferably

[0481] (1) Halogen,

[0482] (2)C 1-6 haloalkyl, or

[0483] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0484] (a) hydroxyl group,

[0485] (b) halogens, and

[0486] (c)C 1-4 Halogenated alkyl.

[0487] R 5A Still more preferably

[0488] (1) Halogen, or

[0489] (2)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0490] (a) hydroxyl group,

[0491] (b) halogens, and

[0492] (c)C 1-4 Halogenated alkyl.

[0493] R 5A Still more preferably C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0494] (a) hydroxyl group,

[0495] (b) halogens, and

[0496] (c)C1-4 Halogenated alkyl.

[0497] In the following partial structure:

[0498]

[0499] Preferably, R 1 and R 2 Each independently

[0500] (1) Hydrogen,

[0501] (2)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0502] (a) hydroxyl group,

[0503] (b)C 1-4 Alkoxy, and

[0504] (c)C 3-6 Cycloalkyl, or

[0505] (3) Halogen;

[0506] R 3A and R 4A are independently hydrogen or C 1-4 alkyl;

[0507] R 5A for

[0508] (1) Hydrogen,

[0509] (2)C 1-6 alkyl,

[0510] (3)C 1-4 Alkoxy,

[0511] (4) Halogen,

[0512] (5)C 1-6 Haloalkyl,

[0513] (6)-OC 1-4 haloalkyl, or

[0514] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0515] (a) hydroxyl group,

[0516] (b) halogens, and

[0517] (c)C 1-4 haloalkyl, or

[0518] R 5A With R 3A or R 4A and the carbon atoms to which they are attached combine to form

[0519] (1)C 5-6 Cyclic olefins, or

[0520] (2) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms.

[0521] In the following partial structure:

[0522]

[0523] More preferably, R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0524] R 3A and R 4A is hydrogen;

[0525] R 5A for

[0526] (1) Halogen,

[0527] (2)C 1-6 haloalkyl, or

[0528] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0529] (a) hydroxyl group,

[0530] (b) halogens, and

[0531] (c)C 1-4 Halogenated alkyl.

[0532] In the following partial structure:

[0533]

[0534] Still more preferably, R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0535] R 3A and R 4Ais hydrogen;

[0536] R 5A for

[0537] (1) Halogen, or

[0538] (2)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0539] (a) hydroxyl group,

[0540] (b) halogens, and

[0541] (c)C 1-4 Halogenated alkyl.

[0542] In the following partial structure:

[0543]

[0544] Still more preferably, R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0545] R 3A and R 4A is hydrogen;

[0546] R 5A C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0547] (a) hydroxyl group,

[0548] (b) halogens, and

[0549] (c)C 1-4 Halogenated alkyl.

[0550] R 6 Preferably

[0551] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0552] (2)C 1-4 Alkoxy,

[0553] (3) Halogen, or

[0554] (4)C 1-4 Halogenated alkyl.

[0555] R6A Preferably independently

[0556] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0557] (2)C 1-4 Alkoxy,

[0558] (3) Halogen, or

[0559] (4)C 1-4 Halogenated alkyl.

[0560] R 6A More preferably, C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0561] m is preferably 0 or 1.

[0562] X 1 Preferred are carbon, nitrogen or oxygen atoms.

[0563] X 1 More preferred is a carbon or nitrogen atom.

[0564] X 2 Preferred are carbon or nitrogen atoms.

[0565] X 3 Preferred are carbon, nitrogen or sulfur atoms.

[0566] X 4 Preferred are carbon, nitrogen or sulfur atoms.

[0567] X 4 More preferably, it is a carbon atom.

[0568] X 5 Preferred are carbon atoms.

[0569] n is preferably zero.

[0570] In the following partial structure:

[0571]

[0572] When n is 0, then preferably,

[0573] m is 0 or 1;

[0574] R 6A for

[0575] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4Alkoxy substitution,

[0576] (2)C 1-4 haloalkyl, or

[0577] (3) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms;

[0578] X 1 is a carbon, nitrogen or oxygen atom;

[0579] X 2 is a carbon or nitrogen atom;

[0580] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0581] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1; and

[0582] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0583] In the following partial structure:

[0584]

[0585] When n is 0, then more preferably,

[0586] m is 0 or 1;

[0587] R 6A for

[0588] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0589] (2)C 1-4 haloalkyl, or

[0590] (3) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms;

[0591] X 1 is a carbon, nitrogen or oxygen atom;

[0592] X2 is a carbon or nitrogen atom;

[0593] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0594] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1; and

[0595] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0596] In the following partial structure:

[0597]

[0598] When n is 0, then still more preferably,

[0599] m is 0 or 1;

[0600] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0601] X 1 is a nitrogen atom;

[0602] X 2 is a carbon or nitrogen atom;

[0603] X 3 is a carbon, nitrogen or sulfur atom;

[0604] X 4 is a carbon atom, where X 1 , X 2 or X 3 The total number of nitrogen and sulfur atoms is 2; and

[0605] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0606] The following is part of the structure:

[0607]

[0608] When n is 0, it is more preferably any one of the following groups:

[0609] or

[0610] Where m is 0 or 1; and

[0611] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0612] In the following partial structure:

[0613]

[0614] When n is 1, then preferably,

[0615] m is 0 or 1;

[0616] R 6A for

[0617] (1)C 1-4 Alkoxy,

[0618] (2) Halogen, or

[0619] (3)C 1-4 Haloalkyl;

[0620] X 1 , X 2 , X 3 and X 4 Each independently represents a carbon or nitrogen atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen atoms is 1 or 2;

[0621] X 5 is a carbon atom; and

[0622] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0623] In the following partial structure:

[0624]

[0625] When n is 1, then more preferably,

[0626] m is 0;

[0627] X 1 and X 2 are each independently a carbon or nitrogen atom;

[0628] X 3 is a nitrogen atom, where X 1 , X 2 or X 3 The total number of nitrogen atoms is 2;

[0629] X 4 and X 5 is a carbon atom; and

[0630] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0631] The following is part of the structure:

[0632]

[0633] When n is 1, it is more preferably one of the following groups:

[0634]

[0635] In the following partial structure:

[0636]

[0637] Preferably,

[0638] m is 0 or 1;

[0639] R 6A for

[0640] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0641] (2)C 1-4 haloalkyl, or

[0642] (3) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms;

[0643] X 1 is a carbon, nitrogen or oxygen atom;

[0644] X 2 is a carbon or nitrogen atom;

[0645] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0646] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1; and

[0647] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0648] In the following partial structure:

[0649]

[0650] More preferably,

[0651] m is 0 or 1;

[0652] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0653] X 1 is a carbon, nitrogen or oxygen atom;

[0654] X 2 is a carbon or nitrogen atom;

[0655] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0656] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1; and

[0657] X 1 , X 2 , X3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0658] In the following partial structure:

[0659]

[0660] More preferably,

[0661] m is 0 or 1;

[0662] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0663] X 1 is a nitrogen atom;

[0664] X 2 is a carbon or nitrogen atom;

[0665] X 3 is a carbon, nitrogen or sulfur atom;

[0666] X 4 is a carbon atom, where X 1 , X 2 or X 3 The total number of nitrogen and sulfur atoms is 2; and

[0667] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0668] The following is part of the structure:

[0669]

[0670] Still more preferably any one of the following groups:

[0671] or

[0672] Where m is 0 or 1; and

[0673] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0674] In the following partial structure:

[0675]

[0676] Preferably,

[0677] m is 0 or 1;

[0678] R 6A for

[0679] (1)C 1-4 Alkoxy,

[0680] (2) Halogen, or

[0681] (3)C 1-4 Haloalkyl;

[0682] X 1 , X 2 , X 3 and X 4 Each independently represents a carbon atom or a nitrogen atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen atoms is 1 or 2;

[0683] X 5 is a carbon atom; and

[0684] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0685] In the following partial structure:

[0686]

[0687] More preferably,

[0688] m is 0;

[0689] X 1 and X 2 are each independently a carbon atom or a nitrogen atom;

[0690] X 3 is a nitrogen atom, where X 1 , X 2 or X 3 The total number of nitrogen atoms is 2;

[0691] X4 and X 5 is a carbon atom; and

[0692] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0693] The following is part of the structure:

[0694]

[0695] Still more preferably one of the following groups:

[0696]

[0697] A preferred embodiment of the compound of formula [I] is a compound of formula [I] wherein

[0698] R 1 and R 2 Each independently

[0699] (1) Hydrogen,

[0700] (2)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0701] (a) hydroxyl group,

[0702] (b)C 1-4 Alkoxy, and

[0703] (c)C 3-6 Cycloalkyl,

[0704] (3)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution,

[0705] (4) Halogen,

[0706] (5)C 1-4 Haloalkyl,

[0707] (6)-OC 1-4 haloalkyl, or

[0708] (7)C 3-6 Cycloalkyl;

[0709] R 3 and R 4 Preferably hydrogen;

[0710] R 5 for

[0711] (1) Hydrogen,

[0712] (2)C 1-6 alkyl,

[0713] (3)C 1-4 Alkoxy,

[0714] (4) Halogen,

[0715] (5)C 1-6 Haloalkyl,

[0716] (6)-OC 1-4 haloalkyl, or

[0717] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 to 3 halogen or C 1-4 Haloalkyl substitution;

[0718] R 6 for

[0719] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0720] (2)C 1-4 Alkoxy,

[0721] (3) Halogen, or

[0722] (4)C 1-4 Haloalkyl;

[0723] m is 0, 1 or 2;

[0724] n is 0 or 1;

[0725] The condition is that when n is 0, then X 1 , X 2 , X 3 and X 4 Each independently represents a carbon, nitrogen, oxygen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1, and X 1 , X 2 , X 3 and X 4 With X 1 and X 4Adjacent carbon atoms are bonded together to form a heteroaryl group; and

[0726] The condition is that when n is 1, then X 1 , X 2 , X 3 , X 4 and X 5 Each independently represents a carbon or nitrogen atom, wherein X 1 , X 2 , X 3 , X 4 or X 5 The total number of nitrogen atoms is 1 or 2, and X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0727] A preferred embodiment of the compound of formula [IA] is a compound of formula [IA] wherein

[0728] R 1 and R 2 Each independently

[0729] (1) Hydrogen,

[0730] (2)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following:

[0731] (a) hydroxyl group,

[0732] (b)C 1-4 Alkoxy, and

[0733] (c)C 3-6 Cycloalkyl,

[0734] (3) Halogen;

[0735] R 3A and R 4A Each independently

[0736] (1) Hydrogen, or

[0737] (2)C 1-4 alkyl;

[0738] R 5A for

[0739] (1) Hydrogen,

[0740] (2)C 1-6 alkyl,

[0741] (3)C 1-4 Alkoxy,

[0742] (4) Halogen,

[0743] (5)C 1-6 Haloalkyl,

[0744] (6)-OC 1-4 Haloalkyl,

[0745] (7)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0746] (a) hydroxyl group,

[0747] (b) halogens, and

[0748] (c)C 1-4 haloalkyl, or

[0749] R 5A With R 3A or R 4A and the carbon atoms to which they are attached combine to form:

[0750] (1)C 5-6 Cyclic olefins, or

[0751] (2) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms;

[0752] m is 0 or 1;

[0753] R 6A for

[0754] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0755] (2)C 1-4 Alkoxy,

[0756] (3) Halogen, or

[0757] (4)C 1-4 Haloalkyl;

[0758] n is 0 or 1;

[0759] The condition is that when n is 0, then

[0760] X 1 is a carbon, nitrogen or oxygen atom;

[0761] X 2 is a carbon or nitrogen atom;

[0762] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0763] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 2 or 3 and the total number of oxygen and sulfur atoms is 0 or 1; and

[0764] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are joined together to form a heteroaryl group; and provided that when n is 1, then

[0765] X 1 , X 2 , X 3 and X 4 Each independently represents a carbon atom or a nitrogen atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen atoms is 1 or 2;

[0766] X 5 is a carbon atom; and

[0767] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0768] Another preferred embodiment of the compound of formula [IA] is a compound of formula [IA] wherein

[0769] R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0770] R 3A and R 4A is hydrogen;

[0771] R 5A for

[0772] (1) Halogen,

[0773] (2)C 1-6 haloalkyl, or

[0774] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0775] (a) hydroxyl group,

[0776] (b) halogens, and

[0777] (c)C 1-4 Haloalkyl;

[0778] m is 0 or 1;

[0779] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0780] n is 0 or 1;

[0781] The condition is that when n is 0, then

[0782] X 1 is a nitrogen atom;

[0783] X 2 is a carbon or nitrogen atom;

[0784] X 3 is a carbon, nitrogen or sulfur atom;

[0785] X 4 is a carbon atom, where X 1 , X 2 or X 3 The total number of nitrogen atoms and sulfur atoms is 2; and

[0786] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are joined together to form a heteroaryl group; and provided that when n is 1, then

[0787] X 1 and X 2 are each independently a carbon atom or a nitrogen atom;

[0788] X 3 is a nitrogen atom, where X 1 , X 2 or X 3The total number of nitrogen atoms is 2;

[0789] X 4 and X 5 is a carbon atom; and

[0790] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0791] Another preferred embodiment of the compound of formula [IA] is the compound of formula [IIA]:

[0792]

[0793] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0794] R 5A for

[0795] (1) Halogen,

[0796] (2)C 1-6 haloalkyl, or

[0797] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0798] (a) hydroxyl group,

[0799] (b) halogens, and

[0800] (c)C 1-4 Haloalkyl;

[0801] m is 0 or 1;

[0802] R 6A for

[0803] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0804] (2)C 1-4 haloalkyl, or

[0805] (3) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms;

[0806] X 1 is a carbon, nitrogen or oxygen atom;

[0807] X 2 is a carbon or nitrogen atom;

[0808] X 3 is a carbon, nitrogen, oxygen or sulfur atom;

[0809] X 4 is a carbon, nitrogen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1; and

[0810] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0811] Another preferred embodiment of the compound of formula [IA] is a compound of formula [IIIA]:

[0812]

[0813] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0814] R 5A for

[0815] (1) Halogen,

[0816] (2)C 1-6 haloalkyl, or

[0817] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0818] (a) hydroxyl group,

[0819] (b) halogens, and

[0820] (c)C 1-4 Haloalkyl;

[0821] m is 0 or 1;

[0822] R 6A for

[0823] (1)C 1-4 Alkoxy,

[0824] (2) Halogen, or

[0825] (3)C 1-4 Haloalkyl;

[0826] X 1 , X 2 , X 3 and X 4 Each independently represents a carbon atom or a nitrogen atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen atoms is 1 or 2;

[0827] X 5 is a carbon atom; and

[0828] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

[0829] In a preferred embodiment of the compound of formula [IIA], R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0830] R 5A for

[0831] (1) Halogen,

[0832] (2)C 1-6 haloalkyl, or

[0833] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0834] (a) hydroxyl group,

[0835] (b) halogens, and

[0836] (c)C 1-4Haloalkyl;

[0837] m is 0 or 1;

[0838] R 6A for

[0839] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0840] (2)C 1-4 haloalkyl, or

[0841] (3) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms; and

[0842] X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a pyrazolyl, imidazolyl or thiazolyl group.

[0843] Another preferred embodiment of the compound of formula [IIA] is a compound of formula [IIA-I]:

[0844]

[0845] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0846] R 5A for

[0847] (1) Halogen,

[0848] (2)C 1-6 haloalkyl, or

[0849] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0850] (a) hydroxyl group,

[0851] (b) halogens, and

[0852] (c)C 1-4 Haloalkyl;

[0853] m is 0 or 1;

[0854] R6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0855] Another preferred embodiment of the compound of formula [IIA] is a compound of formula [IIA-II]:

[0856]

[0857] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0858] R 5A for

[0859] (1) Halogen,

[0860] (2)C 1-6 haloalkyl, or

[0861] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0862] (a) hydroxyl group,

[0863] (b) halogens, and

[0864] (c)C 1-4 Haloalkyl;

[0865] m is 0 or 1;

[0866] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0867] Another preferred embodiment of the compound of formula [IIA] is a compound of formula [IIA-III]:

[0868]

[0869] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0870] R 5A for

[0871] (1) Halogen,

[0872] (2)C 1-6 haloalkyl, or

[0873] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0874] (a) hydroxyl group,

[0875] (b) halogens, and

[0876] (c)C 1-4 Haloalkyl;

[0877] m is 0 or 1;

[0878] R 6A C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0879] In a preferred embodiment of the compound of formula [IIIA], R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0880] R 5A for

[0881] (1) Halogen,

[0882] (2)C 1-6 haloalkyl, or

[0883] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0884] (a) hydroxyl group,

[0885] (b) halogens, and

[0886] (c)C 1-4 Haloalkyl;

[0887] m is 0; and

[0888] X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a pyridazinyl or pyrimidinyl group.

[0889] Another preferred embodiment of the compound of formula [IIIA] is a compound of formula [IIIA-I]:

[0890]

[0891] Where R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0892] R 5A for

[0893] (1) Halogen,

[0894] (2)C 1-6 haloalkyl, or

[0895] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0896] (a) hydroxyl group,

[0897] (b) halogens, and

[0898] (c)C 1-4 Halogenated alkyl.

[0899] Another preferred embodiment of the compound of formula [IIIA] is a compound of formula [IIIA-II]:

[0900]

[0901] Among them, R 1 and R 2 Each independently is C 1-6 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution;

[0902] R 5A for

[0903] (1) Halogen,

[0904] (2)C 1-6 haloalkyl, or

[0905] (3)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[0906] (a) hydroxyl group,

[0907] (b) halogens, and

[0908] (c)C 1-4 Halogenated alkyl.

[0909] Another preferred embodiment of the compound of formula [IA] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X] or [XI]:

[0910]

[0911] Where R 1 , R 2 , R 3A and R 4A Defined as those defined in item 1A.

[0912] The term "pharmaceutically acceptable salt" as used herein may be any salt known in the art that is not associated with excessive toxicity. Such pharmaceutically acceptable salts specifically include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references:

[0913] (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977),

[0914] (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

[0915] (c) Paulekuhn et al., J. Med. Chem., 50, pp. 6665-6672 (2007).

[0916] The compound of formula [I] or formula [IA] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se to give a corresponding pharmaceutically acceptable salt thereof.

[0917] Such salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid. Such salts preferably include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

[0918] Such salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, dehydrated methylene citric acid, benzoic acid, benzenesulfonic acid, calcium ethylenediaminetetraacetic acid, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycollylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, The salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid are preferably included.

[0919] Such salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth and ammonium. Such salts preferably include salts with sodium, potassium, calcium, magnesium and zinc.

[0920] Such salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine and lysine. Such salts preferably include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, lysine.

[0921] Compound [I] or Compound [IA] may exist in the form of a solvate thereof. The term "solvate" refers to a compound in which a solvent molecule is coordinated with, for example, Compound [I] or Compound [IA]. The solvate may be any pharmaceutically acceptable solvate; and includes, for example, hydrates, acetic acid solvates, acetone solvates, ethanolates and dimethyl sulfoxide solvates of Compound [I] or Compound [IA]. Such solvates specifically include hemihydrates, monohydrates, dihydrates, monoacetic acid solvates, monoacetone solvates and monoethanolates of compounds of Formula [I] or Formula [IA]; monohydrates and monoacetone solvates of the sodium salt of compounds of Formula [I] or Formula [IA]; and 2 / 3 ethanolates of the dihydrochloride salt of compounds of Formula [I] or Formula [IA]. These solvates may be obtained according to any known method.

[0922] Compound [I] or Compound [IA] may exist as tautomers. In that case, Compound [I] or Compound [IA] may exist as a single tautomer or a mixture of tautomers. For example, a structure represented by the following formula:

[0923]

[0924] Unless otherwise indicated, the compounds represented by the structure may exist as and / or be represented by the following formula: (1)

[0926] (2)

[0928] (3)

[0930] (4)

[0932] or

[0933] (5) A mixture of these structures.

[0934] Compound [I] or compound [IA] may have a carbon-carbon double bond. In that case, compound [I] or compound [IA] may exist as an E-isomer, a Z-isomer, or a mixture of an E-isomer and a Z-isomer.

[0935] Compound [I] or Compound [IA] may exist as stereoisomers, which should be regarded as cis / trans isomers. In that case, Compound [I] or Compound [IA] may exist as cis isomers, trans isomers, or a mixture of cis and trans isomers.

[0936] Compound [I] or Compound [IA] may have one or more asymmetric carbon atoms. In that case, Compound [I] or Compound [IA] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.

[0937] Compound [I] or Compound [IA] may exist as an atropisomer. In that case, Compound [I] or Compound [IA] may exist as a single atropisomer or a mixture of atropisomers.

[0938] Compound [I] or compound [IA] may simultaneously have a plurality of structural features that can provide the above isomers. Compound [I] or compound [IA] may also contain the above isomers in any ratio.

[0939] Unless otherwise stated, formulas, chemical structures or chemical names herein that do not specify stereochemistry include all such isomers that may exist.

[0940] Diastereomeric mixtures can be separated into individual diastereomers by conventional methods, for example chromatography, crystallization. Individual diastereomers can also be prepared by using stereochemically single isomers of starting materials or by synthetic methods using stereoselective reactions.

[0941] A mixture of enantiomers can be separated into each single enantiomer by methods well known in the art. For example, a mixture of enantiomers can be reacted with a substantially pure enantiomer known as a chiral auxiliary to form a mixture of diastereomers, which can then be separated into diastereomers or substantially pure single diastereomers with an increased isomer ratio by conventional methods such as fractional crystallization or chromatography. The isolated diastereomer can be converted into a desired enantiomer by removing the added chiral auxiliary under a cleavage reaction. A mixture of enantiomers can also be directly separated using a chiral stationary phase by chromatography well known in the art. Alternatively, any enantiomer can also be obtained by stereoselective synthesis (i.e., asymmetric induction) of a prochiral intermediate using substantially pure and optically active raw materials or chiral auxiliary or asymmetric catalyst.

[0942] The absolute configuration may be determined by X-ray crystallographic analysis of crystalline products or intermediates. In that case, if necessary, the crystallized product or intermediate may be induced by a reagent having an asymmetric center of known configuration.

[0943] Compound [I] or compound [IA] may be modified with isotopic atoms such as 2 H(D), 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 18 O. 18 F. 35 S and 123I labeling. For example, in the case where the compound of formula [I] or formula [IA] has a methyl group, the methyl group can be replaced by a -CD3 group. The compounds thus obtained are also included in the present invention. The compounds of formula [I] or formula [IA] labeled with isotopic atoms can be used for drugs, pharmacokinetic studies, in vitro and / or in vivo assays and / or diagnosis, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). The compounds of formula [I] or formula [IA] labeled with isotopic atoms can be prepared according to known methods or methods described herein, using isotope-labeled compounds instead of corresponding unlabeled compounds.

[0944] Compound [I] or Compound [IA] is preferably a substantially purified Compound [I] or Compound [IA]. A more preferred one is Compound [I] or Compound [IA] purified to a purity of 80% or more.

[0945] The pharmaceutical composition of the present invention can be prepared by optionally mixing compound [I] or compound [IA] with at least one or more pharmaceutically acceptable carriers in a certain amount according to methods known in the field of pharmaceutical preparations. The content of compound [I] or compound [IA] in the pharmaceutical composition varies depending on the dosage form and dosage, and is, for example, 0.1 to 100% by weight of the composition.

[0946] The dosage form of compound [I] or compound [IA] includes oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions; and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[0947] The term "pharmaceutically acceptable carrier" as used herein includes various organic or inorganic carrier substances conventionally used for formulation ingredients. Such substances include, for example, excipients, disintegrants, binders, fluidizers and lubricants for solid preparations; solvents, solubilizers, suspending agents, tonicity agents, buffers and soothing agents for liquid preparations; and bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, extenders, solubilizers, dissolving agents and suspending agents for semi-solid preparations. If necessary, additives such as preservatives, antioxidants, colorants and sweeteners may be further used.

[0948] Such excipients include, for example, lactose, soft sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and gum arabic.

[0949] Such disintegrants include, for example, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, cross-linked carboxymethylcellulose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose and crystalline cellulose.

[0950] Such binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, crystalline cellulose, soft sugar, dextrin, starch, gelatin, sodium carboxymethyl cellulose and gum arabic.

[0951] Such fluidizing agents include, for example, light anhydrous silicic acid and magnesium stearate.

[0952] Such lubricants include, for example, magnesium stearate, calcium stearate and talc.

[0953] Such solvents include, for example, purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.

[0954] Such dissolving agents include, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate and sodium citrate.

[0955] Such suspending agents include, for example, benzalkonium chloride, carboxymethylcellulose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose and glyceryl monostearate.

[0956] Such tonicity agents include, for example, glucose, D-sorbitol, sodium chloride, and D-mannitol.

[0957] Such buffers include, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[0958] Such soothing agents include, for example, benzyl alcohol.

[0959] Such bases include, for example, water, oils from animals or plants (e.g., olive oil, corn oil, peanut oil, sesame oil, and castor oil), lower alcohols (e.g., ethanol, propanol, propylene glycol, 1,3-butylene glycol, and phenol), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (e.g., white petrolatum, liquid paraffin, and paraffin), hydrophilic petrolatum, purified lanolin, absorption ointments, aqueous lanolin, hydrophilic ointments, starch, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose), synthetic polymers (e.g., carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol, and polyvinyl pyrrolidone), propylene glycol, polyethylene glycol (e.g., polyethylene glycol 200 to 600), and combinations of two or more thereof.

[0960] Such preservatives include, for example, ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate and sorbic acid.

[0961] Such antioxidants include, for example, sodium sulfite and ascorbic acid.

[0962] Such coloring agents include, for example, food coloring (eg, food red No. 2 or No. 3, food yellow No. 4 or No. 5) and beta-carotene.

[0963] Such sweeteners include, for example, sodium saccharin, dipotassium glycyrrhizinate and aspartame.

[0964] The pharmaceutical composition of the present invention is administered orally or parenterally (e.g., topically, rectally, intravenously, intramuscularly, and subcutaneously) to humans and mammals other than humans, such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys. Although the dosage (which may be referred to herein as a "therapeutically effective amount") may vary depending on the subject, disease, symptom, dosage form, route of administration, etc., for example, when administered orally to an adult patient, the dosage of the compound of formula [I] or a pharmaceutically acceptable salt thereof or the compound of formula [IA] or a pharmaceutically acceptable salt thereof as the active ingredient is generally about 0.01 mg to 1 g per day. The dosage may be administered once to several times in divided amounts.

[0965] Compound [I] or Compound [IA] has inhibitory activity of NLRP3 inflammasome and is used for treating and / or preventing various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity. Various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include, for example, diseases selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., Such as hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial 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.

[0966] The expression "inhibiting NLRP3 inflammasome" means inhibiting the function of NLRP3 inflammasome so that its activity disappears or decreases; and for example, inhibiting the function of NLRP3 inflammasome based on the conditions of Test Example 1 as described below. Inhibiting the function of NLRP3 inflammasome inhibits the production of IL-1β and / or IL-18, and preferably the production of IL-1β and IL-18. Preferably, "inhibiting NLRP3 inflammasome" means "inhibiting human NLRP3 inflammasome".

[0967] Compound [I] or Compound [IA] has NLRP3 inflammasome inhibitory activity, and Compound [I] or Compound [IA] or a pharmaceutically acceptable salt thereof can be used as it is or can be formulated (if necessary) for use as a NLRP3 inflammasome inhibitor.

[0968] The term "treating" as used herein includes ameliorating symptoms, preventing exacerbations, maintaining remission, preventing exacerbations and preventing relapses.

[0969] As used herein, the term "prevention" includes both inhibition and delaying the onset of symptoms.

[0970] As long as the embodiments disclosed herein are compatible with other embodiments disclosed in other parts of the specification, any combination of two or more of these embodiments is also intended to be included in the present invention.

[0971] General preparation method

[0972] A general method for preparing a compound of formula [I] or a pharmaceutically acceptable salt thereof or a compound of formula [IA] or a pharmaceutically acceptable salt thereof is shown below. However, the method for preparing a compound of formula [I] or a pharmaceutically acceptable salt thereof or a compound of formula [IA] or a pharmaceutically acceptable salt thereof is not limited thereto.

[0973] Each compound obtained in each step may be isolated and / or purified according to any known method (eg, distillation, recrystallization and column chromatography) if necessary, or may optionally be subjected to the subsequent step without isolation and / or purification.

[0974] As used herein, the term "room temperature" refers to a temperature that is not controlled and includes 1°C to 40°C as one embodiment.

[0975] The abbreviations used in this article are as follows.

[0976] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0977] WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0978] Preparation method A1: Preparation method of compound [I] or its salt

[0979] Compound [I] or a salt thereof can be produced, for example, according to the following Production Method A1.

[0980]

[0981] In this scheme, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above,

[0982] R A11 Each independently is C 1-4 alkyl,

[0983] R A12 is boric acid, a boric acid ester (e.g., pinacol borate), a trifluoroborate, or tributyltin, and

[0984] L A11 , L A12 and L A13 Each is independently a leaving group (eg, halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).

[0985] (Step A1-1)

[0986] 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.

[0987] The acid includes, for example, sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid and p-toluenesulfonic acid. The acid is preferably sulfuric acid or p-toluenesulfonic acid.

[0988] The solvent includes, for example, toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane and mixed solvents thereof. The solvent is preferably toluene.

[0989] The reaction temperature ranges from 0°C to 150°C, for example, and preferably from 5°C to 40°C.

[0990] The compound [A1-1] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[0991] Compound [A1-2] is commercially available or can be prepared from a commercially available product according to a known method.

[0992] (Step A1-2)

[0993] The compound [A1-5] or a salt thereof can be produced by reacting the compound [A1-3] or a salt thereof with the compound [A1-4] or a salt thereof in a solvent in the presence of a base.

[0994] The base includes, for example, triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene and N,N-diisopropylethylamine. The base is preferably triethylamine or N,N-diisopropylethylamine.

[0995] The solvent includes, for example, toluene, methanol, ethanol, tetrahydrofuran and mixed solvents thereof. The solvent is preferably toluene or methanol.

[0996] The reaction temperature ranges from, for example, -78°C to 100°C, preferably from 0°C to 40°C.

[0997] Compound [A1-4] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[0998] (Step A1-3)

[0999] The compound [A1-6] or a salt thereof can be produced by reacting the compound [A1-5] or a salt thereof in a solvent in the presence of an acid.

[1000] The acid includes, for example, trifluoroacetic acid, sulfuric acid, hydrochloric acid and triethylsilyl trifluoromethanesulfonate. The acid is preferably trifluoroacetic acid.

[1001] The solvent includes, for example, toluene, tetrahydrofuran, ethyl acetate, cyclopentyl methyl ether, dichloromethane and mixed solvents thereof. The solvent is preferably toluene.

[1002] The reaction temperature ranges from, for example, -78°C to 60°C, preferably from 0°C to 40°C.

[1003] (Step A1-4)

[1004] The compound [A1-7] or a salt thereof can be produced by reacting the compound [A1-6] or a salt thereof in a solvent in the presence of a base.

[1005] The base includes, for example, sodium hydroxide and potassium hydroxide. The base is preferably sodium hydroxide.

[1006] The solvent includes, for example, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, chloroform and a mixed solvent thereof. The solvent is preferably tetrahydrofuran.

[1007] The reaction temperature ranges from 0°C to 150°C, for example, and preferably from 50°C to 100°C.

[1008] (Step A1-5)

[1009] The compound [I] or a salt thereof can be produced by reacting the compound [A1-7] 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.

[1010] The catalyst includes, for example, [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct.

[1011] The base includes, for example, tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. The base is preferably tripotassium phosphate.

[1012] When R A12 When the solvent is, for example, boric acid, boric acid ester (such as boric acid pinacol ester) or trifluoroborate, the solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide and a mixed solvent thereof. The solvent is preferably a mixed solvent of toluene and water.

[1013] When R A12 When it is tributyltin, for example, the solvent includes toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide. The solvent is preferably N,N-dimethylacetamide.

[1014] The reaction temperature ranges from 10°C to 200°C, for example, and preferably from 50°C to 150°C.

[1015] Compound [A1-8] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1016] The preparation method can be carried out by replacing compound [A1-4] or its salt with a compound or its salt having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions to obtain a compound corresponding to compound [I] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [I] or its salt. For example, the preparation method can be carried out by replacing compound [A1-4] or its salt with a compound having L as mentioned below. A41The phenyl-substituted hydrazine compound or its salt is substituted for compound [A1-4] or its salt to obtain a compound corresponding to compound [I], that is, compound [IA] or its salt, and then L is treated according to preparation method A4. A41 Converted to cycloCy A41 To obtain compound [IB] or a salt thereof.

[1017] Preparation method A1A: Preparation method of compound [IA] or a salt thereof

[1018] Compound [IA] or a salt thereof can be produced according to Production Method A1 using compound [A1A-4] or a salt thereof instead of compound [A1-4] or a salt thereof, and using compound [A1A-8] or a salt thereof instead of compound [A1-8] or a salt thereof.

[1019]

[1020] In this scheme, the symbols are as defined above.

[1021] Compound [A1A-4] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1022] Compound [A1A-8] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1023] The preparation method can be carried out by replacing compound [A1A-4] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [IA] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [IA] or its salt. For example, the preparation method can be carried out by replacing compound [A1A-4] or its salt with a compound having L as mentioned below A41 The phenyl-substituted hydrazine compound or its salt is substituted for compound [A1A-4] or its salt to obtain a compound corresponding to compound [IA], that is, compound [IA-A] or its salt, and then L is treated according to the preparation method A4A. A41 Converted to cycloCy A41A To obtain compound [IA-B] or a salt thereof.

[1024] Preparation method A2: Preparation method of compound [I] or its salt

[1025] Compound [I] or a salt thereof can also be produced by, for example, the following production method A2.

[1026]

[1027] In this scheme, R 1 , R 2 , R 3, R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m, n, L A11 , L A12 and R A12 As defined above,

[1028] R A21 is a protecting group for a hydroxyl group (e.g., benzyl, 4-methoxybenzyl, and 2-methoxybenzyl), and R A21 Preferred is benzyl.

[1029] (Step A2-1)

[1030] The compound [A2-1] or a salt thereof can be produced by reacting the compound [A1-6] or a salt thereof in a solvent in the presence of an alcohol and a base.

[1031] The alcohol includes, for example, benzyl alcohol, 4-methoxybenzyl alcohol and 2-methoxybenzyl alcohol. The alcohol is preferably benzyl alcohol.

[1032] The base includes, for example, sodium hydride, potassium tert-butoxide and sodium tert-butoxide. The base is preferably sodium hydride.

[1033] The solvent includes, for example, tetrahydrofuran, N,N-dimethylformamide and a mixed solvent thereof. The solvent is preferably tetrahydrofuran.

[1034] The reaction temperature ranges from, for example, -20°C to 100°C, preferably from 0°C to 50°C.

[1035] (Step A2-2)

[1036] 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.

[1037] The catalyst includes, for example, [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[1038] The base includes, for example, tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. The base is preferably tripotassium phosphate or lithium chloride.

[1039] When R A12 When the solvent is, for example, boric acid, boric acid ester (such as boric acid pinacol ester) or trifluoroborate, the solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide and a mixed solvent thereof. The solvent is preferably a mixed solvent of toluene and water.

[1040] When R A12 In the case of tributyltin, for example, the solvent includes, for example, toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide. The solvent is preferably N,N-dimethylacetamide.

[1041] The reaction temperature ranges from 10°C to 200°C, for example, and preferably from 50°C to 150°C.

[1042] (Step A2-3)

[1043] The compound [I] or a salt thereof can be produced by reacting the compound [A2-2] or a salt thereof in the presence of an acid.

[1044] The acid includes, for example, formic acid, trifluoroacetic acid and hydrochloric acid. The acid is preferably formic acid.

[1045] The reaction temperature ranges from 0°C to 120°C, for example, and preferably from 10°C to 100°C.

[1046] Preparation method A2A: Preparation method of compound [IA] or its salt

[1047] Compound [IA] or a salt thereof can also be produced by, for example, the following production method A2A.

[1048]

[1049] In this scheme, the symbols are as defined above.

[1050] (Step A2A-1)

[1051] Compound [A2A-1] or a salt thereof can be produced according to Step A2-1 using compound [A1A-6] or a salt thereof instead of compound [A1-6] or a salt thereof.

[1052] (Step A2A-2)

[1053] Compound [A2A-2] or a salt thereof can be produced according to Step A2-2 using compound [A1A-8] or a salt thereof instead of compound [A1-8] or a salt thereof.

[1054] (Step A2A-3)

[1055] Compound [IA] or a salt thereof can be prepared by reacting R A21 It can be prepared by removing from compound [A2A-2] or a salt thereof. The deprotection reaction can be carried out according to R A21 Under appropriate conditions.

[1056] For example, when R A21 In the case of a benzyl group, compound [IA] or a salt thereof can be prepared by reacting compound [A2A-2] or a salt thereof in the presence of an acid. A solvent may be optionally added during the reaction.

[1057] The acid includes, for example, formic acid, trifluoroacetic acid and hydrochloric acid. The acid is preferably formic acid.

[1058] The solvent includes, for example, toluene, tetrahydrofuran, and 1,4-dioxane.

[1059] The reaction temperature ranges from 0°C to 120°C, for example, and preferably from 10°C to 100°C.

[1060] Preparation method A3: Preparation method of compound [I] or its salt

[1061] Compound [I] or a salt thereof can also be produced by, for example, the following production method A3.

[1062]

[1063] In this scheme, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above,

[1064] R A31 C 1-4 alkyl,

[1065] R A32 is a protecting group for an amino group (e.g., tert-butyloxycarbonyl), and

[1066] R A33 is hydrogen or C 1-4 alkyl.

[1067] (Step A3-1)

[1068] The compound [A3-3] or a salt thereof can be produced by reacting the compound [A3-1] or a salt thereof with the compound [A3-2] or a salt thereof in a solvent in the presence of an oxidizing agent, an acid and an additive.

[1069] The oxidizing agent includes, for example, sodium nitrite, butyl nitrite and isoamyl nitrite. The oxidizing agent is preferably sodium nitrite.

[1070] The acid includes, for example, concentrated hydrochloric acid, concentrated sulfuric acid and nitric acid. The acid is preferably concentrated hydrochloric acid.

[1071] The additive includes, for example, sodium acetate and potassium acetate. The additive is preferably sodium acetate.

[1072] The solvent includes, for example, ethanol, methanol, butanol, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1073] The reaction temperature ranges from, for example, -40°C to 50°C, preferably from -10°C to 40°C.

[1074] Compound [A3-1] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1075] Compound [A3-2] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1076] (Step A3-2)

[1077] 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.

[1078] The base includes, for example, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably triethylamine.

[1079] The solvent includes, for example, chloroform, 1,2-dichloroethane, dichloromethane and mixed solvents thereof. The solvent is preferably chloroform.

[1080] The reaction temperature ranges from 20°C to 120°C, for example, and preferably from 50°C to 100°C.

[1081] Compound [A3-4] is commercially available.

[1082] (Step A3-3)

[1083] 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.

[1084] The base includes, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide. The base is preferably sodium hydroxide.

[1085] The solvent includes, for example, ethanol, methanol, butanol, tetrahydrofuran, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1086] The reaction temperature ranges from, for example, 0°C to 100°C, preferably from 5°C to 50°C.

[1087] (Step A3-4)

[1088] The compound [A3-7] or a salt thereof can be produced by reacting the compound [A3-6] or a salt thereof in a solvent in the presence of a reactant and a base.

[1089] The reactant includes, for example, sodium azide and diphenylphosphoryl azide. The reactant is preferably diphenylphosphoryl azide.

[1090] The base includes, for example, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably triethylamine.

[1091] The solvent includes, for example, tert-butyl alcohol, benzyl alcohol, tetrahydrofuran and mixed solvents thereof. The solvent is preferably tert-butyl alcohol.

[1092] The reaction temperature ranges from, for example, 0°C to 150°C, preferably from 50°C to 120°C.

[1093] (Step A3-5)

[1094] The compound [A3-8] or a salt thereof can be produced by reacting the compound [A3-7] or a salt thereof in a solvent in the presence of an oxidizing agent and a base.

[1095] The oxidant includes, for example, hydrogen peroxide solution, ferrosoferric oxide and manganese dioxide. The oxidant is preferably hydrogen peroxide solution.

[1096] The base includes, for example, sodium hydroxide, potassium hydroxide and barium hydroxide. The base is preferably sodium hydroxide.

[1097] The solvent includes, for example, ethanol, dimethyl sulfoxide, water and a mixed solvent thereof. The solvent is preferably a mixed solvent of ethanol, dimethyl sulfoxide and water.

[1098] The reaction temperature ranges from, for example, -20°C to 50°C, preferably from 10°C to 40°C.

[1099] (Step A3-6)

[1100] Compound [A3-9] or a salt thereof can be prepared by reacting RA32 It can be prepared by removing from compound [A3-8] or a salt thereof. The deprotection reaction can be carried out according to R A32 Under appropriate conditions.

[1101] For example, when R A32 In the case of a tert-butoxycarbonyl group, the compound [A3-9] or a salt thereof can be produced by reacting the compound [A3-8] or a salt thereof in a solvent in the presence of an acid.

[1102] The acid includes, for example, hydrochloric acid, trifluoroacetic acid and sulfuric acid. The acid is preferably hydrochloric acid.

[1103] The solvent includes, for example, ethyl acetate, cyclopentyl methyl ether and mixed solvents thereof. The solvent is preferably ethyl acetate.

[1104] The reaction temperature ranges from, for example, 0°C to 80°C, preferably from 10°C to 50°C.

[1105] The compound [A3-9] or a salt thereof can also be prepared by reversing the order of steps A3-5 and A3-6.

[1106] (Step A3-7)

[1107] 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.

[1108] The condensing agent includes, for example, HATU, WSC and propylphosphonic anhydride. The condensing agent is preferably HATU.

[1109] The base includes, for example, sodium methoxide, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably N,N-diisopropylethylamine.

[1110] The solvent includes, for example, methanol, N-methylpyrrolidone, N,N-dimethylacetamide and mixed solvents thereof. The solvent is preferably N-methylpyrrolidone.

[1111] The reaction temperature ranges from, for example, 0°C to 120°C, preferably 50°C to 100°C.

[1112] Compound [A3-10] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1113] (Step A3-8)

[1114] The compound [I] or a salt thereof can be produced by reacting the compound [A3-11] or a salt thereof in a solvent in the presence of a base.

[1115] The base includes, for example, sodium methoxide, sodium tert-butoxide and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably 1,8-diazabicyclo[5,4,0]-7-undecene.

[1116] The solvent includes, for example, ethanol, methanol, butanol, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1117] The reaction temperature ranges from, for example, 0°C to 180°C, preferably from 50°C to 150°C.

[1118] The preparation method can be carried out by replacing compound [A3-1] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [I] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [I] or its salt. For example, the preparation method can be carried out by replacing compound [A3-1] or its salt with a compound having an amino group and L on the benzene ring as mentioned below A41 The compound or its salt replaces the compound [A3-1] or its salt to obtain the compound corresponding to the compound [I], that is, the compound [IA] or its salt, and then L is treated according to the preparation method A4. A41 Converted to cycloCy A41 To obtain compound [IB] or a salt thereof.

[1119] The preparation method can be carried out by replacing compound [A3-1] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [A3-9] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [A3-9] or its salt. For example, the preparation method can be carried out by replacing compound [A3-1] or its salt with a compound having an amino group and L on the benzene ring as mentioned below. A41 The compound or its salt replaces the compound [A3-1] or its salt to obtain the compound corresponding to the compound [A3-9], that is, the compound [A3-9-A] or its salt, and then L is replaced according to the preparation method A5. A41 Converted to cycloCy A41 To obtain compound [A3-9-B] or a salt thereof.

[1120] Preparation method A3A: Preparation method of compound [IA] or its salt

[1121] Compound [IA] or a salt thereof can also be produced by, for example, the following production method A3A.

[1122]

[1123] In this scheme, R1 , R 2 , R 3A , R 4A , R 5A , R 6A , R A31 , R A33 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above, and

[1124] R A32A is a protecting group for hydrogen or an amino group (eg tert-butyloxycarbonyl).

[1125] (Step A3A-1)

[1126] Compound [A3A-3] or a salt thereof can be produced according to Step A3-1 using compound [A3A-1] or a salt thereof instead of compound [A3-1] or a salt thereof.

[1127] The compound [A3A-1] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1128] (Step A3A-2)

[1129] Compound [A3A-5] or a salt thereof can be produced according to Step A3-2 using compound [A3A-3] or a salt thereof instead of compound [A3-3] or a salt thereof.

[1130] (Step A3A-3)

[1131] Compound [A3A-6] or a salt thereof can be produced according to Step A3-3 using compound [A3A-5] or a salt thereof instead of compound [A3-5] or a salt thereof.

[1132] (Step A3A-4)

[1133] Compound [A3A-7] or a salt thereof can be produced according to Step A3-4 using compound [A3A-6] or a salt thereof instead of compound [A3-6] or a salt thereof.

[1134] (Step A3A-5)

[1135] Compound [A3A-8] or a salt thereof can be produced according to Step A3-5 using compound [A3A-7] or a salt thereof instead of compound [A3-7] or a salt thereof.

[1136] (Step A3A-6)

[1137] Compound [A3A-9] or a salt thereof can be prepared by reacting RA32A It is prepared by removing from compound [A3A-8] or a salt thereof. The deprotection reaction can be carried out according to R A32A Under appropriate conditions.

[1138] For example, when R A32A In the case of a tert-butyloxycarbonyl group, the compound [A3A-9] or a salt thereof can be produced by reacting the compound [A3A-8] or a salt thereof in a solvent in the presence of an acid.

[1139] The acid includes, for example, hydrochloric acid, trifluoroacetic acid and sulfuric acid. The acid is preferably hydrochloric acid.

[1140] The solvent includes, for example, ethyl acetate, cyclopentyl methyl ether and mixed solvents thereof. The solvent is preferably ethyl acetate.

[1141] The reaction temperature ranges from, for example, 0°C to 80°C, preferably from 10°C to 50°C.

[1142] The compound [A3A-9] or a salt thereof can also be produced by subjecting the compound [A3A-7] or a salt thereof to step A3A-6, and then subjecting the compound [A3A-5].

[1143] (Step A3A-7)

[1144] Compound [A3A-11] or a salt thereof can be produced according to Step A3-7 using compound [A3A-9] or a salt thereof instead of compound [A3-9] or a salt thereof and using compound [A3A-10] or a salt thereof instead of compound [A3-10] or a salt thereof.

[1145] Compound [A3A-10] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1146] (Step A3A-8)

[1147] Compound [IA] or a salt thereof can be prepared according to Step A3-8 using compound [A3A-11] or a salt thereof instead of compound [A3-11] or a salt thereof.

[1148] The preparation method can be carried out by replacing compound [A3A-1] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [IA] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [IA] or its salt. For example, the preparation method can be carried out by replacing compound [A3A-1] or its salt with a compound having an amino group and L on the benzene ring as mentioned below. A41The compound or its salt is substituted for compound [A3A-1] or its salt to obtain a compound corresponding to compound [IA], that is, compound [IA-A] or its salt, and then L is replaced according to preparation method A4A. A41 Converted to cycloCy A41A To obtain compound [IA-B] or a salt thereof.

[1149] The preparation method can be carried out by replacing compound [A3A-1] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [A3A-8] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [A3A-8] or its salt. For example, the preparation method can be carried out by replacing compound [A3A-1] or its salt with a compound having an amino group and L on the benzene ring as mentioned below. A41 The compound or its salt is substituted for compound [A3A-1] or its salt to obtain a compound corresponding to compound [A3A-8], that is, compound [A3A-8-A] or its salt, and then L is replaced according to preparation method A5A. A41 Converted to cycloCy A41A To obtain compound [A3A-8-B] or a salt thereof.

[1150] Preparation method A4: Preparation method of compound [IB] or its salt

[1151] Compound [IB] or a salt thereof can be produced by, for example, the following Production Method A4.

[1152]

[1153] In this scheme, R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above,

[1154] Cy A41 C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 to 3 halogen or C 1-4 haloalkyl substitution, and

[1155] L A41 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.

[1156] (Step A4-1)

[1157] Compound [IB] or a salt thereof can be prepared by reacting compound [IA] or a salt thereof with compound [A4-1] or a derivative thereof (eg, cyclopropylboronic acid pinacol ester and cyclopropyltrifluoroborate potassium) in a solvent in the presence of a catalyst and a base.

[1158] The catalyst includes, for example, [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).

[1159] The base includes, for example, tripotassium phosphate, cesium carbonate and potassium carbonate. The base is preferably tripotassium phosphate.

[1160] The solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane and a mixed solvent thereof. The solvent is preferably a mixed solvent of toluene and water.

[1161] The reaction temperature ranges from, for example, 10°C to 200°C, preferably from 50°C to 150°C.

[1162] Compound [IA] or a salt thereof can be prepared from a commercially available product according to a known method. Compound [IA] or a salt thereof can be prepared, for example, by the above-mentioned preparation method.

[1163] Compound [A4-1] or a derivative thereof is commercially available, or can be produced from a commercially available product according to a known method.

[1164] Preparation method A4A: Preparation method of compound [IA-B] or its salt

[1165] Compound [IA-B] or a salt thereof can be produced according to Production Method A4 using compound [IA-A] or a salt thereof instead of compound [IA] or a salt thereof and using compound [A4A-1] or a salt thereof instead of compound [A4-1] or a salt thereof.

[1166]

[1167] In this scheme, R 6A , L A41 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above, and

[1168] Cy A41A C 3-6Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from:

[1169] (a) hydroxyl group,

[1170] (b) halogens, and

[1171] (c)C 1-4 Halogenated alkyl.

[1172] Compound [IA-A] or a salt thereof can be produced from a commercially available product according to a known method. Compound [IA-A] or a salt thereof can be produced by, for example, the above-mentioned production method.

[1173] The compound [A4A-1] or a derivative thereof is commercially available, or can be produced from a commercially available product according to a known method.

[1174] Preparation method A5: Preparation method of compound [A3-9-B] or its salt

[1175] The compound [A3-9-B] or a salt thereof can be produced by, for example, the following production method A5.

[1176]

[1177] In this scheme, the symbols are as defined above.

[1178] (Step A5-1)

[1179] Compound [A3-9-B] or a salt thereof can be prepared by reacting compound [A3-9-A] or a salt thereof with compound [A4-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and cyclopropyltrifluoroborate potassium) in a solvent in the presence of a catalyst and a base.

[1180] The catalyst includes, for example, [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).

[1181] The base includes, for example, tripotassium phosphate, cesium carbonate and potassium carbonate. The base is preferably tripotassium phosphate.

[1182] The solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane and a mixed solvent thereof. The solvent is preferably a mixed solvent of toluene and water.

[1183] The reaction temperature ranges from, for example, 10°C to 200°C, preferably from 50°C to 150°C.

[1184] Compound [A3-9-A] or a salt thereof can be prepared from a commercially available product according to a known method. Compound [A3-9-A] or a salt thereof can be prepared by, for example, the above-mentioned preparation method.

[1185] Preparation method A5A: Preparation method of compound [A3A-8-B] or its salt

[1186] The compound [A3A-8-B] or a salt thereof can be produced by, for example, the following production method A5A.

[1187]

[1188] In this scheme, the symbols are as defined above.

[1189] (Step A5A-1)

[1190] Compound [A3A-8-B] or a salt thereof can be prepared by reacting compound [A3A-8-A] or a salt thereof with compound [A4A-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and cyclopropyltrifluoroborate potassium) in a solvent in the presence of a catalyst and a base.

[1191] The catalyst includes, for example, [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).

[1192] The base includes, for example, tripotassium phosphate, cesium carbonate and potassium carbonate. The base is preferably tripotassium phosphate.

[1193] The solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane and a mixed solvent thereof. The solvent is preferably a mixed solvent of toluene and water.

[1194] The reaction temperature ranges from, for example, 10°C to 200°C, preferably from 50°C to 150°C.

[1195] Compound [A3A-8-A] or a salt thereof can be produced from a commercially available product according to a known method. Compound [A3A-8-A] or a salt thereof can be produced by, for example, the above-mentioned production method.

[1196] Preparation method A6: Preparation method of compound [IA] or its salt

[1197] Compound [IA] or a salt thereof can be produced by, for example, the following production method A6.

[1198]

[1199] In this scheme, R1 , R 2 , R 3A , R 4A , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above,

[1200] R A61 is hydrogen, or a protecting group for an amino group (e.g., trimethylsilyl),

[1201] R A62 and R A63 Each independently is C 1-4 Alkyl, and

[1202] L A61 and L A62 Each is independently a leaving group (eg, halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).

[1203] (Step A6-1)

[1204] The compound [A6-2] or a salt thereof can be prepared by reacting the compound [A6-1] or a salt thereof in a solvent in the presence of a reactant. An acid may be optionally added during the reaction.

[1205] The reactants include lithium bis(trimethylsilyl)amide, ammonia water and ammonium chloride. The reactant is preferably lithium bis(trimethylsilyl)amide.

[1206] The acid includes, for example, hydrochloric acid, sulfuric acid.

[1207] The solvent includes, for example, methanol, tetrahydrofuran, 1,4-dioxane and mixed solvents thereof. The solvent is preferably tetrahydrofuran.

[1208] The reaction temperature ranges from, for example, -78°C to 40°C, preferably from -10°C to 10°C.

[1209] The compound [A6-1] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1210] (Step A6-2)

[1211] The compound [A6-4] or a salt thereof can be produced by reacting the compound [A6-2] or a salt thereof with the compound [A6-3] or a salt thereof in a solvent.

[1212] The solvent includes, for example, methanol, ethanol, isopropanol, tetrahydrofuran and a mixed solvent thereof. The solvent is preferably a mixed solvent of tetrahydrofuran and methanol.

[1213] The reaction temperature ranges from room temperature to 120°C, for example, and preferably from 60°C to 100°C.

[1214] The compound [A6-3] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1215] (Step A6-3)

[1216] Compound [A6-5] or a salt thereof can be prepared by reacting compound [A6-4] or a salt thereof in a solvent in the presence of a Vilsmeier reagent, followed by adding phosphorus oxychloride and heating; the reaction temperature is, for example, 80°C.

[1217] The solvent includes, for example, N,N-dimethylformamide, toluene, benzene and a mixed solvent thereof. The solvent is preferably a mixed solvent of N,N-dimethylformamide and toluene.

[1218] The reaction temperature ranges from, for example, -20°C to 100°C, preferably from -10°C to 90°C.

[1219] The Vilsmeier reagent is prepared from, for example, phosphorus oxychloride and N,N-dimethylformamide.

[1220] (Step A6-4)

[1221] The compound [A6-7] or a salt thereof can be produced by reacting the compound [A6-5] or a salt thereof with the compound [A6-6] or a salt thereof in a solvent in the presence of a base.

[1222] The base includes, for example, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably triethylamine.

[1223] The solvent includes, for example, methanol, ethanol, tetrahydrofuran, toluene, cyclopentyl methyl ether, acetonitrile, water and mixed solvents thereof. The solvent is preferably a mixed solvent of tetrahydrofuran and water.

[1224] The reaction temperature ranges from, for example, -20°C to 80°C, preferably from 0°C to room temperature.

[1225] Compound [A6-6] or a salt thereof is commercially available, or can be prepared from a commercially available product according to a known method.

[1226] (Step A6-5)

[1227] Compound [IA] or a salt thereof can be produced by reacting compound [A6-7] or a salt thereof in a solvent in the presence of an acid.

[1228] The acid includes, for example, formic acid, trifluoroacetic acid and hydrochloric acid. The acid is preferably trifluoroacetic acid.

[1229] The solvent includes, for example, water, acetonitrile, tetrahydrofuran and a mixed solvent thereof. The solvent is preferably a mixed solvent of acetonitrile and water.

[1230] The reaction temperature ranges from 0°C to 100°C, for example, and preferably from 50°C to 70°C.

[1231] The preparation method can be carried out by replacing compound [A6-6] or its salt with a compound having a functional group or a protected substituent on the benzene ring which can be converted into various substituents by known reactions or a salt thereof to obtain a compound corresponding to compound [IA] or its salt, and then converting the functional group or the protected substituent into various substituents to obtain compound [IA] or its salt. For example, the preparation method can be carried out by replacing compound [A6-6] or its salt with a compound having L A41 The phenyl-substituted hydrazine compound or its salt is substituted for compound [A6-6] or its salt to obtain a compound corresponding to compound [IA], that is, compound [IA-A] or its salt, and then L is treated according to preparation method A4A. A41 Converted to cycloCy A41A To obtain compound [IA-B] or a salt thereof.

[1232] Example

[1233] The preparation method of the compound of formula [I] or its pharmaceutically acceptable salt, or the compound of formula [IA] or its pharmaceutically acceptable salt is specifically described in the following preparation examples. However, the preparation method of the compound of formula [I] or its pharmaceutically acceptable salt, or the compound of formula [IA] or its pharmaceutically acceptable salt is not intended to be limited thereto.

[1234] Unless otherwise specified, % refers to weight %. Unless otherwise specified, the ratios listed in the mixed solvent refer to volume ratios.

[1235] NMR was measured at 400 MHz.

[1236] [Preparation Example 1]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 4)

[1237]

[1238] Step 1-1: Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate

[1239]

[1240] Under a nitrogen atmosphere at 0 ° C, N, N-diisopropylethylamine (224 mL) and benzyl chloroformate (83 mL) were added to a mixture of (4-bromo-2,6-dimethylphenyl) hydrazine hydrochloride (147 g) and tetrahydrofuran (1000 mL), and the mixture was stirred at room temperature for 40 minutes. Toluene (441 mL) and water (441 mL) were added to the reaction mixture, which was then stirred at room temperature for 20 minutes. After separation, the resulting organic layer was dried over anhydrous sodium sulfate, and about 1 L of solvent was removed under reduced pressure. Hexane (294 mL) was added to the residue, and the mixture was stirred for 1 hour. Then, hexane (294 mL) was added thereto, and the mixture was stirred for 15 minutes. The resulting solid was collected by filtration and then washed with a mixed solution of hexane / toluene (v / v=2 / 1) to obtain the title compound (179 g)

[1241] 1 H-NMR (CDCl3) δ: 7.32 (5H, br s), 7.09 (2H, s), 6.52 (1H, br s), 5.67 (1H, br s), 5.06 (2H, s), 2.33 (6H, br s).

[1242] Step 1-2: Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate

[1243]

[1244] Under an argon atmosphere, tripotassium phosphate (190 g) was dissolved in water (357 mL), to which was then added toluene (715 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate (89.3 g), cyclopropylboronic acid (61.7 g) and [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (4.18 g), and the mixture was stirred at 105° C. for 4 hours. The reaction mixture was cooled to room temperature and then separated after adding 6M hydrochloric acid (298 mL). The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed under reduced pressure. Hexane (450 mL) was added to the residue, and the mixture was stirred. The obtained solid was then collected by filtration to obtain the title compound (64.2 g).

[1245] 1H-NMR(CDCl3)δ:7.31(5H,br s),6.68(2H,s),6.48(1H,br s),5.65(1H,br s),5.06(2H,s),2.32(6H,br s),1.80-1.73(1H,m),0.87-0.84(2H,m),0.61-0.59(2H,m).

[1246] Step 1-3: (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride

[1247]

[1248] Under nitrogen atmosphere, 4M sodium hydroxide aqueous solution (536mL) was added to a mixture of 2-(4-cyclopropyl-2,6-dimethylphenyl) hydrazine-1-formic acid benzyl ester (133g) and ethanol (798mL) synthesized according to step 1-2, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was ice-cooled and added thereto. Then, the mixture was extracted with toluene (1L) after adding acetic acid (73.6mL). The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated until the volume of the solution became about 1 / 4. Toluene (500mL) was added to the obtained mixture, and a 4M solution of hydrochloric acid in dioxane (102mL) was slowly added to the mixture under stirring under ice cooling. Hexane (50mL) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Then, the obtained solid was collected by filtration and washed with hexane to obtain the title compound (83g).

[1249] 1 H-NMR(DMSO-d6)δ:9.50(3H,br s),6.79(2H,s),6.66(1H,br s),2.33(6H,s),1.83-1.81(1H,m),0.97-0.84(2H,m),0.65-0.62(2H,m).

[1250] Step 1-4: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine

[1251]

[1252] Under nitrogen atmosphere, trimethyl orthoformate (750mL) and sulfuric acid (1.6mL) were added to the mixture of 2,4,6-trichloropyrimidine-5-carboxaldehyde (250g) and toluene (1.5L), and the mixture was stirred at room temperature for 1.5 hours. Alkaline silica gel (Fuji Silysia, 500g) was added to the reaction mixture, and the mixture was stirred for 2 hours. Then, the silica gel added was removed by filtration. The silica gel was washed with ethyl acetate (1.0L), and then the solvent was removed under reduced pressure to obtain the title compound (268g).

[1253] 1 H-NMR (CDCl3) δ: 5.70 (1H, s), 3.50 (6H, s).

[1254] Step 1-5: 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine

[1255]

[1256] Under nitrogen atmosphere, (4-cyclopropyl-2,6-dimethylphenyl) hydrazine hydrochloride (83g) and triethylamine (102mL) were added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl) pyrimidine (94g) and toluene (1160mL) under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. Trifluoroacetic acid (98mL) was added dropwise and slowly to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Under an ice bath, the reaction mixture was added dropwise and slowly to an aqueous solution (776mL) of tripotassium phosphate (310g), and the mixture was then stirred at room temperature for 10 minutes. After separation, the obtained aqueous layer was extracted with toluene. All organic layers were collected and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (162g) of the title compound.

[1257] 1 H-NMR(CDCl3)δ:8.17(1H,s),6.89(2H,s),1.98(6H,s),1.94-1.87(1H,m),1.07-1.01(2H,m),0.77-0.72(2H,m).

[1258] Step 1-6: 6-Chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1259]

[1260] Under a nitrogen atmosphere, 2M aqueous sodium hydroxide solution (913mL) was added to a mixture of a crude product (162g) of 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine and tetrahydrofuran (970mL), and the mixture was stirred at 75°C for 3 hours. The reaction mixture was ice-cooled, and 6M hydrochloric acid (243mL) was then added thereto. Ethyl acetate was added to the reaction mixture, and after separation, the aqueous layer was extracted with ethyl acetate. All organic layers were collected and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained solid, and the mixture was stirred at room temperature for 10 minutes. Then, the obtained solid was collected by filtration and washed with ethyl acetate. The obtained solid was dried under reduced pressure to obtain the title compound (74g).

[1261] 1 H-NMR(DMSO-D6)δ:12.89(1H,br s),8.80(1H,s),7.00(2H,s),2.03-1.95(7H,m),1.03-1.01(2H,m),0.78-0.76(2H,m).

[1262] Step 1-7: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1263]

[1264] Under an argon atmosphere, tripotassium phosphate (148 g) was dissolved in water (510 mL), and then toluene (880 mL), 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (73 g), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (57.9 g), and [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (4.73 g) were added thereto. The reaction mixture was stirred at 110° C. for 3 hours and then cooled to 60° C. Tetrahydrofuran (290 mL) was added thereto, and the mixture was cooled to 15° C. with an ice bath. Then, 6M hydrochloric acid (193mL) was added dropwise thereto slowly, and the mixture was stirred for 20 minutes. Tetrahydrofuran (150mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The gained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Toluene (500mL) and ethyl acetate (500mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. Then, the gained solid was collected by filtration and washed with toluene. The gained solid was dissolved in tetrahydrofuran (800mL), and then ISOLUTE Si-TMT (metal removal silica gel, manufactured by Biotage, 0.47mmol TMT / g, 49g) was added thereto. The mixture was stirred at room temperature for 2 hours. ISOLUTE Si-TMT added was removed by filtration, and washed with ethyl acetate (700mL). Silica gel (70g) and alkaline silica gel (Fuji Silysia, 70g) were added to the gained solution, and the mixture was stirred at room temperature for 3 hours. The added silica gel was removed by filtration and washed sequentially with a mixed solution of ethyl acetate / tetrahydrofuran (v / v=1 / 1, 300 mL) and ethyl acetate (700 mL), and then the solvent was removed under reduced pressure.

[1265] To the obtained solid was added acetone (180 mL), and the mixture was stirred under ice-cooling for 30 minutes. The obtained solid was collected by filtration, washed with cooled acetone (180 mL), and then dried under reduced pressure to obtain crystals of the title compound (α form, 49.7 g).

[1266] 1H-NMR(DMSO-D6)δ:11.21(1H,s),8.70(1H,s),7.90(1H,d,J=2.3Hz),6.97(2H,s),6.96 (1H,d,J=2.3Hz),3.98(3H,s),1.96-1.94(7H,m),1.01-0.97(2H,m),0.75-0.73(2H,m).

[1267] LC-MS (MH+):361.

[1268] Step 1-8: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one monohydrate

[1269]

[1270] Crystals of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (α-type, 16.0 g) were dissolved in methanol (100 mL) under heating at 80°C. Water (100 mL) was added thereto at the same temperature, and the mixture was stirred for 1 hour. Then, water (200 mL) was added thereto. The mixture was cooled to room temperature and stirred for another 2 hours. The resulting solid was collected by filtration and then dried under reduced pressure to obtain crystals of the title compound (β-type, 16.2 g).

[1271] 1 H-NMR(DMSO-d6)δ:11.19(1H,s),8.69(1H,s),7.90(1H,d,J=2.3Hz),6.97(2H,s),6.95 (1H,d,J=2.3Hz),3.97(3H,s),1.98-1.91(7H,m),1.00-0.98(2H,m),0.76-0.72(2H,m).

[1272] LC-MS (MH+): 361

[1273] [Preparation Example 2]: Synthesis of 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 8)

[1274]

[1275] Step 2-1: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one

[1276]

[1277] Under an argon atmosphere, a solution of n-butyl lithium in n-hexane (1.59M, 25.2mL) was added dropwise and slowly to a mixture of 2,5-dibromo-1,3-dimethylbenzene (11.6g) and tetrahydrofuran (170mL) at -78°C, and the mixture was stirred for 20 minutes at the same temperature. N-methoxy-N-methylacetamide (5.61mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. 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 washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (5.79g).

[1278] 1 H-NMR(CDCl3)δ:7.64(2H,s),2.57(3H,s),2.47(6H,s).

[1279] Step 2-2: 2-Bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene

[1280]

[1281] Under argon atmosphere, 1-(4-bromo-3,5-dimethylphenyl)ethane-1-one (5.0 g) was added to a 50% solution of bis(2-methoxyethyl)aminosulfur trifluoride in tetrahydrofuran (48.7 mL) and methanol (0.089 mL) at 0°C, and the mixture was stirred at 80°C for 7 hours. The reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (3.58 g).

[1282] 1 H-NMR(CDCl3)δ:7.20(2H,s),2.44(6H,s),1.88(3H,t,J=18.1Hz).

[1283] Step 2-3: Di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate

[1284]

[1285] Under an argon atmosphere, a solution of n-butyllithium in n-hexane (1.56M, 11mL) was added to a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (3.58g) and tetrahydrofuran (72mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Di-tert-butyl azodicarboxylate (4.96g) was added to the reaction mixture, and the mixture was stirred for another 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (3.38g).

[1286] 1 H-NMR(CDCl3)δ:7.19-7.18(2H,m),6.60(1H,br s),2.38(6H,s),1.94-1.82(3H,m),1.55-1.37(18H,m).

[1287] Step 2-4: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride

[1288]

[1289] To di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate (3.38 g) was added 4M solution of hydrochloric acid in ethyl acetate (34 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to give the title compound (2.0 g).

[1290] 1 H-NMR (DMSO-D6) δ: 9.61 (3H, br s), 7.29 (2H, s), 6.85 (1H, br s), 2.42 (6H, s), 1.93 (3H, t, J = 18.8 Hz).

[1291] Step 2-5: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazino]-5-(dimethoxymethyl)pyrimidine

[1292]

[1293] Under an argon atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (2.18 g) was added to a mixture of {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (2.0 g), triethylamine (3.53 mL) and methanol (40 mL) at 0°C, which was synthesized according to steps 1-4 of Preparation Example 1. The mixture was stirred at room temperature for 1 hour, and then the solvent was removed under reduced pressure. Ethyl acetate was added thereto. The resulting solid was removed by filtration, and then the solvent was removed under reduced pressure to obtain a crude product (3.56 g) of the title compound.

[1294] LC-MS (MH+): 421.

[1295] Step 2-6: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1296]

[1297] Under argon atmosphere, trifluoroacetic acid (1.62 mL) was added dropwise and slowly to a mixture of a crude product (3.56 g) of 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine]-5-(dimethoxymethyl)pyrimidine and toluene (36 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise and slowly to a 2M aqueous solution of tripotassium phosphate, and then extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (1.89 g).

[1298] LC-MS (MH+): 357.

[1299] Step 2-7: 6-Chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1300]

[1301] 2M aqueous sodium hydroxide solution (5.29mL) was added to a mixture of 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (1.89g) and tetrahydrofuran (19mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate), and the resulting solid was then stirred in a mixed solution of ethyl acetate / diisopropyl ether. The resulting solid was collected by filtration and then dried under reduced pressure to obtain the title compound (1.03g).

[1302] 1 H-NMR(DMSO-D6)δ:12.90(1H,br s),8.85(1H,s),7.49(2H,s),2.03-1.98(9H,m).

[1303] Step 2-8: 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1304]

[1305] Under argon atmosphere, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (0.949 g), [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.198 gram) and tripotassium phosphate (1.94 g) were added to a mixture of 6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.03 g) and toluene / water (v / v=5 / 1, 12.9 mL), and the mixture was stirred at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, and 2M hydrochloric acid was added dropwise and slowly thereto. Then, the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure.

[1306] The residue was dissolved in a mixed solution of tetrahydrofuran / ethyl acetate, to which was then added ISOLUTE Si-TMT (metal scavenging silica gel, manufactured by Biotage, 0.47mmol TMT / g, 3g). The mixture was then stirred at room temperature for 1 hour. The added ISOLUTE Si-TMT was removed by filtration, and washed with ethyl acetate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing agent: hexane / ethyl acetate). The resulting solid was stirred in a mixed solution of ethyl acetate / diisopropyl ether, and the resulting solid was then collected by filtration to obtain the title compound (1.02g).

[1307] 1 H-NMR (DMSO-D6) δ: 11.28 (1H, s), 8.80 (1H, s), 7.90 (1H, d, J = 2.2 Hz), 7.50 (2H, s), 6.96 (1H, d, J = 2.2 Hz), 3.98 (3H, s), 2.05-1.98 (9H, m).

[1308] LC-MS (MH+): 385.

[1309] [Preparation Example 3]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 39)

[1310]

[1311] Step 3-1: Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate

[1312]

[1313] Under a nitrogen atmosphere, N,N-diisopropylethylamine (220mL) and benzyl chloroformate (82mL) were added to a mixture of (4-bromo-2,6-dimethylphenyl) hydrazine hydrochloride (150g) and tetrahydrofuran (1.0L) at 0°C, and the mixture was stirred at room temperature for 1 hour. Toluene (500mL) and water (500mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. After separation, the organic layer was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Toluene (200mL) and hexane (600mL) were added to the residue, and the mixture was stirred. Then, the solid was collected by filtration to obtain the title compound (180g).

[1314] 1H-NMR (CDCl3) δ: 7.32 (5H, br s), 7.09 (2H, s), 6.52 (1H, br s), 5.67 (1H, br s), 5.06 (2H, s), 2.33 (6H, br s).

[1315] Step 3-2: Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate

[1316]

[1317] Under a nitrogen atmosphere, tripotassium phosphate (380 g) was dissolved in water (710 mL), and toluene (1400 mL), 2-(4-bromo-2,6-dimethylphenyl) hydrazine-1-carboxylic acid benzyl ester (180 g), cyclopropylboronic acid (110 g) and [1,1'-bis(di-phenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (8.3 g) were then added thereto. The mixture was stirred at 110° C. for 5 hours. The reaction mixture was cooled to room temperature, and 6M hydrochloric acid (600 mL) was then added thereto. The mixture was then stirred for 10 minutes. The aqueous layer was removed by separation, and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure. A mixed solution of toluene / hexane (v / v=1 / 1, 360 mL) was added to the residue, and the mixture was stirred for 2 hours. Hexane (360 mL) was then added thereto, and the mixture was stirred for another 1 hour. The obtained solid was collected by filtration, and washed sequentially with a toluene / hexane mixed solution (v / v=1 / 10, 550 mL) and hexane (300 mL) to give the title compound (100 g).

[1318] 1 H-NMR(CDCl3)δ:7.31(5H,br s),6.68(2H,s),6.48(1H,br s),5.65(1H,br s),5.06(2H,s),2.32(6H,br s),1.80-1.73(1H,m),0.87-0.84(2H,m),0.61-0.59(2H,m).

[1319] Step 3-3: (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride

[1320]

[1321] Under a nitrogen atmosphere, 4M aqueous sodium hydroxide solution (400mL) was added to a mixture of 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylic acid benzyl ester (100g) and ethanol (600mL), and the mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled, and acetic acid (55mL) was then added thereto. Then, the mixture was extracted with toluene. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated until the volume of the solution became about 1 / 4. Toluene (400mL) was added to the resulting mixture, and a 4M solution of hydrochloric acid in 1,4-dioxane (77mL) was slowly added to the mixture under stirring under ice cooling. The mixture was stirred at room temperature for 30 minutes, and then hexane (40mL) was added thereto. The mixture was stirred for another 5 minutes. The resulting solid was collected by filtration, and then washed sequentially with a mixed solution of toluene / hexane (v / v=1 / 1) and hexane to obtain the title compound (54g).

[1322] 1 H-NMR(DMSO-d6)δ:9.50(3H,br s),6.79(2H,s),6.66(1H,br s),2.33(6H,s),1.83-1.81(1H,m),0.97-0.84(2H,m),0.65-0.62(2H,m).

[1323] Step 3-4: 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine

[1324]

[1325] Under nitrogen atmosphere, (4-cyclopropyl-2,6-dimethylphenyl) hydrazine hydrochloride (54g) and triethylamine (68mL) were added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl) pyrimidine (63g) and toluene (780mL) synthesized in step 1-4 of Preparation Example 1 under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. Trifluoroacetic acid (66mL) was added dropwise and slowly to the reaction mixture, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was added dropwise and slowly to a solution of tripotassium phosphate (210g) in water (470mL) under ice cooling, and then the mixture was stirred at room temperature for 10 minutes. The organic layer was separated, and the aqueous layer was then extracted with toluene. All organic layers were collected and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (102g) of the title compound. A portion of the obtained crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (1.6 g).

[1326] LC-MS (MH+): 333.

[1327] Step 3-5: 4-(Benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine

[1328]

[1329] Under an argon atmosphere, benzyl alcohol (630 mg) was added to a mixture of sodium hydride (60% in oil, 200 mg) and tetrahydrofuran (24 mL), and the mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was cooled under ice cooling, and then 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (1.6 g) was added thereto. The mixture was stirred at the same temperature for 30 minutes. 2M hydrochloric acid (0.73 mL) was added to the reaction mixture, and the mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was added to a mixed solution of hexane / ethyl acetate (v / v=4 / 1), and the mixture was stirred. Then, the resulting solid was collected by filtration to obtain the title compound (1.8 g).

[1330] 1 H-NMR(CDCl3)δ:8.00(1H,s),7.55-7.52(2H,m),7.43-7.41(3H,m),6.85(2H,s),5 .64(2H,s),1.95(6H,s),1.91-1.86(1H,m),1.02-0.99(2H,m),0.73-0.71(2H,m).

[1331] LC-MS (MH+): 405.

[1332] Step 3-6: A mixture of 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one.

[1333]

[1334] Under an argon atmosphere, to a mixture of 4-(benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (70 mg) and N,N-dimethylacetamide (1.0 mL) were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (12 mg), lithium chloride (7.3 mg) and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.11 mL), and the mixture was stirred at 120° C. for 3 hrs. The reaction mixture was purified by column chromatography (developing solvent: methanol / ethyl acetate) to give a mixture of 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (110 mg).

[1335] 4-(Benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine

[1336] LC-MS (MH+): 451.

[1337] 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1338] LC-MS (MH+):361.

[1339] Step 3-7: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1340]

[1341] Under an argon atmosphere, formic acid (1.0 mL) was added to a mixture of 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (110 mg), and the mixture was stirred at 90° C. for 1 hour. The solvent was then removed under reduced pressure. The residue was purified by reverse phase column chromatography (developing solvent: acetonitrile / water) and then treated with hexane / ethyl acetate to give a solid, the title compound (23 mg).

[1342] 1 H-NMR(DMSO-D6)δ:10.77(1H,br s),8.70(1H,s),8.06(1H,d,J=1.3Hz),7.87(1H,d,J=1.3Hz),7.00(2H,s ),3.80(3H,s),2.02-1.94(7H,m),1.04-1.01(2H,m),0.79-0.76(2H,m).

[1343] LC-MS (MH+):361.

[1344] [Preparation Example 4]: Synthesis of 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 41)

[1345]

[1346] Step 4-1: tert-Butyl (4-iodo-2,6-dimethylphenyl)carbamate

[1347]

[1348] To a mixture of 4-iodo-2,6-dimethylaniline (24g) and ethanol (73mL), di-tert-butyl dicarbonate (40mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the obtained solid was then collected by filtration, and washed with water and hexane. The obtained solid was dissolved in ethyl acetate (150mL), and silica gel (24g) was then added thereto. The mixture was stirred for 15 minutes, and the added silica gel was then removed by filtration. The silica gel was washed with a mixed solution of hexane / ethyl acetate (v / v=1 / 1), and then the solvent was removed under reduced pressure. The obtained solid was stirred and washed with hexane, and then collected by filtration to obtain the title compound (29g).

[1349] 1 H-NMR(DMSO-D6)δ:8.43(1H,br s),7.43(2H,s),2.11(6H,s),1.44(9H,s).

[1350] Step 4-2: Ethyl 2-[4-{(tert-butyloxycarbonyl)amino)}-3,5-dimethylphenyl]-2,2-difluoroacetate

[1351]

[1352] Under a nitrogen atmosphere, 2-bromo-2,2-difluoroethyl acetate (21 mL) and copper (16 g) were added to a mixture of (4-iodo-2,6-dimethylphenyl)carbamic acid tert-butyl ester (29 g) and dimethyl sulfoxide (230 mL), and the mixture was stirred at 70 ° C for 4 hours. The solid was removed by filtration, and a saturated aqueous solution of ammonium chloride was added to the resultant. The mixture was then extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in sequence, and anhydrous sodium sulfate and silica gel were then added thereto. The mixture was stirred. The resulting solid was removed by filtration and washed with ethyl acetate, and then the solvent was removed under reduced pressure to obtain the title compound (18 g).

[1353] 1 H-NMR (DMSO-D6) δ: 8.63 (1H, br s), 7.27 (2H, s), 4.31 (2H, q, J = 7.0Hz), 2.21 (6H, s), 1.45 (9H, s), 1.23 (3H, t, J = 7.0Hz).

[1354] Step 4-3: tert-Butyl {4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl}carbamate

[1355]

[1356] Under nitrogen atmosphere, sodium borohydride (2.7 g) was slowly added to a mixture of ethyl 2-[4-{(tert-butyloxycarbonyl)amino)}-3,5-dimethylphenyl]-2,2-difluoroacetate (30 g) and ethanol (240 mL) synthesized according to step 4-2 over 16 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled with an ice bath. 1M hydrochloric acid was slowly added thereto at the same temperature, and then the mixture was diluted with ethyl acetate, hexane and water. The resulting mixture was separated, and the aqueous layer was then extracted with a mixed solution of ethyl acetate / hexane (v / v=1 / 1). All organic layers were collected, and then washed with water, saturated sodium bicarbonate aqueous solution and brine in sequence and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure. The residue was stirred in a mixed solution of hexane / ethyl acetate (180 mL / 9 mL). The resulting solid was collected by filtration and then washed with hexane to obtain the title compound (25 g).

[1357] 1 H-NMR(DMSO-D6)δ:8.53(1H,br s),7.19(2H,s),5.58(1H,t,J=6.2Hz),3.81(2H,td,J=14.1,6.2Hz),2.19(6H,s),1.45(9H,s)

[1358] Step 4-4: 2-[4-{(tert-Butyloxycarbonyl)amino}-3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate

[1359]

[1360] Under a nitrogen atmosphere, trifluoromethanesulfonic anhydride (9.4 mL) was added dropwise and slowly to a mixture of {4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl}carbamic acid tert-butyl ester (16 g), pyridine (5.6 mL) and toluene (130 mL) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 1M hydrochloric acid, water and saturated sodium bicarbonate aqueous solution in sequence, and anhydrous sodium sulfate and silica gel were added thereto. Then, the mixture was stirred at room temperature for 15 minutes. The resulting solid was removed by filtration, and the resultant was then washed with a mixed solution of ethyl acetate / toluene (v / v=1 / 2). Then, the solvent was removed under reduced pressure. A mixed solution of hexane / ethyl acetate (v / v=30 / 1, 50 mL) was added to the residue, and the mixture was stirred at room temperature for 1.5 hours. Then, the mixture was stirred for 15 minutes under ice cooling. The resulting solid was collected by filtration and then washed with hexane to give the title compound (21 g).

[1361] 1 H-NMR (DMSO-D6) δ: 8.63 (1H, br s), 7.33 (2H, s), 5.33 (2H, t, J = 13.9 Hz), 2.22 (6H, s), 1.45 (9H, s).

[1362] Step 4-5: tert-Butyl {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}carbamate

[1363]

[1364] Under nitrogen atmosphere, sodium borohydride (2.7 g) was slowly added to a mixture of 2-[4-{(tert-butyloxycarbonyl)amino}-3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate (21 g) and dimethyl sulfoxide (150 mL). The reaction mixture was stirred at room temperature overnight, and then 1M hydrochloric acid (60 mL) and water (140 mL) were added thereto under a water bath. The resulting mixture was extracted with ethyl acetate / hexane (v / v=6 / 5), then washed with water and saturated sodium bicarbonate aqueous solution in turn, and dried over anhydrous sodium sulfate. Then, the solvent was removed under reduced pressure to obtain a crude product (14 g) of the title compound.

[1365] Step 4-6: 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride

[1366]

[1367] To a mixture of a crude product of tert-butyl {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}carbamate (14 g) and ethyl acetate (68 mL) was added a 4M solution of hydrogen chloride in ethyl acetate (140 mL), and the mixture was stirred at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with ethyl acetate to give the title compound (11 g).

[1368] 1 H-NMR (DMSO-D6) δ: 7.15 (2H, s), 7.10 (3H, br s), 2.24 (6H, s), 1.90 (3H, t, J = 19.1Hz).

[1369] Step 4-7: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride

[1370]

[1371] Concentrated hydrochloric acid (9.0 mL) and 6M hydrochloric acid (15 mL) were added to 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride (2.0 g), and the mixture was cooled to -20°C. A solution of sodium nitrite (690 mg) in water (3.0 mL) was added dropwise and slowly to the reaction mixture, and the mixture was stirred at 0°C for 40 minutes. A solution of tin (II) chloride dihydrate (6.1 g) in concentrated sulfuric acid (9.0 mL) was added dropwise and slowly at -20°C over 5 minutes, and the mixture was stirred at 0°C for 5 hours. The resulting solid was collected by filtration, and then washed sequentially with an ice-cold 2M hydrochloric acid and a mixed solution of hexane / ethyl acetate (v / v=4 / 1) to obtain the title compound (1.8 g).

[1372] 1 H-NMR (DMSO-D6) δ: 9.68 (3H, br s), 7.29 (2H, s), 6.84 (1H, s), 2.42 (6H, s), 1.93 (3H, t, J = 18.9Hz).

[1373] Step 4-8: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazino]-5-(dimethoxymethyl)pyrimidine

[1374]

[1375] Under an argon atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (540 mg) synthesized according to steps 1-4 of Preparation Example 1 was added to a mixture of {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (500 mg), triethylamine (0.88 mL) and methanol (10 mL) at 0° C., and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and ethyl acetate was then added thereto. The resulting solid was removed by filtration, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (890 mg).

[1376] LC-MS (MH+): 421.

[1377] Step 4-9: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1378]

[1379] Under argon atmosphere, trifluoroacetic acid (0.40 mL) was added to a mixture of 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine]-5-(dimethoxymethyl)pyrimidine crude product (890 mg) and toluene (8.9 mL), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was added dropwise to an aqueous solution of 2M tripotassium phosphate. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (520 mg).

[1380] 1 H-NMR(DMSO-D6)δ:9.36(1H,s),7.55(2H,s),2.05-2.00(9H,m).

[1381] LC-MS (MH+): 357.

[1382] Step 4-10: 4-(Benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1383]

[1384] Under an argon atmosphere, sodium hydride (60% in oil, 61 mg) was added to a mixture of benzyl alcohol (0.18 mL) and tetrahydrofuran (10 mL), and the mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was cooled to 0 ° C, and 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (520 mg) was then added thereto. Then, the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and 2M hydrochloric acid (1.0 mL) was then added thereto. The mixture was then extracted with ethyl acetate. The resulting organic layer was washed with water and brine in sequence, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was stirred with a mixed solution of hexane / diisopropyl ether (v / v=1 / 1), and the resulting solid was collected by filtration to obtain the title compound (430 mg).

[1385] 1 H-NMR(DMSO-D6)δ:9.05(1H,s),7.59-7.57(2H,m),7.51(2H,s),7.45-7.41(3H,m),5.65(2H,s),2.04-1.98(9H,m).

[1386] Step 4-11: 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1387]

[1388] Under an argon atmosphere, to a mixture of 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (80 mg) and N,N-dimethylacetamide (1.0 mL) were added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (13 mg), lithium chloride (7.9 mg) and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.12 mL), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was purified by column chromatography (developing solvent: methanol / ethyl acetate) and reverse phase column chromatography (developing solvent: acetonitrile / water) to obtain the title compound (8.2 mg).

[1389] 1 H-NMR (DMSO-D6) δ: 10.78 (1H, s), 8.77 (1H, s), 8.04 (1H, d, J = 1.3 Hz), 7.84 (1H, d, J = 1.3 Hz), 7.49 (2H, s), 3.77 (3H, s), 2.05-1.98 (9H, m).

[1390] LC-MS (MH+): 385.

[1391] [Preparation Example 5]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-6-(pyrimidin-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 12)

[1392]

[1393] Step 5-1: 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetic acid methyl ester

[1394]

[1395] A mixture of 4-bromo-2,6-dimethylaniline (45 g), ethanol (72 mL), water (25 mL) and concentrated hydrochloric acid (47 mL) was cooled to -10 ° C, and then an aqueous solution (54 mL) of sodium nitrite (17 g) was added dropwise and slowly over 30 minutes. The mixture was stirred at the same temperature for 30 minutes, and then methyl 2-chloro-3-oxobutanoate (27 mL) and sodium acetate (55 g) were added thereto in sequence. Then, the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (81 grams) of the title compound.

[1396] 1 H-NMR (CDCl3) δ: 7.28 (2H, t, J = 0.6 Hz), 7.19 (1H, br s), 3.90 (3H, s), 2.34 (6H, s).

[1397] Step 5-2: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid methyl ester

[1398]

[1399] Under argon atmosphere, triethylamine (36mL) and fumaric acid nitrile (Fumaronitrile) (20g) were added to the crude product (81g) of 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazono}-2-chloroacetic acid methyl ester and chloroform (580mL) mixture, and then the mixture was stirred at 80 ° C for 40 minutes. The reaction mixture was cooled to room temperature, and silica gel (250g) was then added thereto. Then, the mixture was stirred at room temperature for 30 minutes. Silica gel was removed by filtration with diatomaceous earth, and then washed with ethyl acetate. The solvent was removed under reduced pressure from all the resulting organic layers, and the resulting solid was washed with ethyl acetate to obtain the title compound (37g).

[1400] 1 H-NMR(DMSO-d6)δ:9.01(1H,s),7.57(2H,s),3.90(3H,s),1.98(6H,s).

[1401] Step 5-3: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid

[1402]

[1403] 2M aqueous sodium hydroxide solution (110mL) was added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-formic acid methyl ester (36g) and methanol (360mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH=1 by adding 6M hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. A mixed solution of ethyl acetate / diisopropyl ether (v / v=1 / 1,200mL) was added to the obtained solid, and the mixture was stirred for 5 minutes. Then, hexane was added thereto until the solid stopped precipitation. The obtained solid was collected by filtration to obtain the title compound (30g).

[1404] 1 H-NMR(DMSO-d6)δ:13.86(1H,br s),8.96(1H,s),7.56(2H,s),1.97(6H,s).

[1405] Step 5-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

[1406]

[1407] Under an argon atmosphere, triethylamine (26 mL) and diphenylphosphoryl azide (30 mL) were added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (30 g) and tert-butyl alcohol (450 mL) at room temperature, and the mixture was stirred at 90 ° C for 3 hours. The solvent was removed under reduced pressure, and chloroform (180 mL) and trifluoroacetic acid (22 mL) were added to the residue. The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and then neutralized with a saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: 15% to 60% by volume of ethyl acetate / hexane), and the resulting solid was washed with a mixed solution of diisopropyl ether / ethyl acetate (v / v=1 / 1) to obtain the title compound (11 g).

[1408] 1 H-NMR(DMSO-d6)δ:8.31(1H,s),7.46(2H,s),5.76(2H,s),2.01(6H,s).

[1409] LC-MS (MH+): 291.

[1410] Step 5-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide

[1411]

[1412] Under argon atmosphere, sodium hydroxide (4.5 g) and 30% hydrogen peroxide solution (15 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (11 g), dimethyl sulfoxide (17 mL) and ethanol (66 mL) at 0 ° C, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was cooled to 0 ° C, and then a saturated aqueous sodium sulfite solution was added thereto. The reaction mixture was adjusted to pH = 2 by adding 12M hydrochloric acid, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained solid was washed with a mixed solution of diisopropyl ether / ethyl acetate (v / v = 1 / 1) to obtain the title compound (10 g).

[1413] 1 H-NMR(DMSO-d6)δ:7.97(1H,s),7.45(2H,s),7.31(1H,br s),6.91(1H,br s),5.53(2H,s),2.02(6H,s).

[1414] LC-MS(MH+):309.

[1415] Step 5-6: N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide

[1416]

[1417] To a mixture of pyrimidine-4-carboxylic acid (60 mg) and N,N-dimethylformamide (1.5 mL) were added HATU (180 mg) and N,N-diisopropylethylamine (160 mg), and the mixture was stirred at room temperature for 5 minutes. Then, 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (75 mg) was added thereto, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and then washed with water and brine in sequence. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product of the title compound (100 mg).

[1418] LC-MS (MH+):415.

[1419] Step 5-7: 2-(4-bromo-2,6-dimethylphenyl)-6-(pyrimidin-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1420]

[1421] Under an argon atmosphere, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mL) was added to a mixture of a crude product (100 mg) of N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide, ethanol (1.0 mL) and water (1.0 mL), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and water was added thereto. Then, the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine in sequence, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: 50% to 100% by volume of ethyl acetate / hexane) to obtain the title compound (47 mg).

[1422] 1 H-NMR (CDCl3) δ: 10.62 (1H, br s), 9.36 (1H, d, J = 1.4Hz), 9.03 (1H, d, J = 5.3Hz), 8.54 (1H, dd, J = 5.2, 1.5Hz), 8.18 (1H, s), 7.38 (2H, s), 2.06 (6H, s).

[1423] LC-MS (MH+):397.

[1424] [Preparation Example 6]: Synthesis of 2-(6-chloro-2,3-dihydro-1H-indene-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 59)

[1425]

[1426] Step 6-1: (6-Chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride

[1427]

[1428] Concentrated hydrochloric acid (3.0 mL) was added to a mixture of 6-chloro-2,3-dihydro-1H-indene-5-amine (1.0 g) and 6M hydrochloric acid (5.0 mL), and the mixture was then cooled to 0 ° C. An aqueous solution (1.0 mL) of sodium nitrite (0.43 g) was added dropwise and slowly to the reaction mixture over 3 minutes. Then, the mixture was stirred at the same temperature for 70 minutes. A mixture of tin chloride (II) (2.8 g) and concentrated hydrochloric acid (2.3 mL) was added dropwise and slowly to the reaction mixture over 5 minutes. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with 2M hydrochloric acid and diisopropyl ether in sequence to obtain the title compound (1.2 g).

[1429] 1 H-NMR(DMSO-D6)δ:10.12(3H,br s),7.86(1H,br s),7.28(1H,s),7.00(1H,s),2.83-2.81(4H,m),2.06-1.99(2H,m).

[1430] Step 6-2: Lithium 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4-olate

[1431]

[1432] Under argon atmosphere, 1.2M solution (500mL) of lithium bis(trimethylsilyl)amide in tetrahydrofuran was added to a mixture of 1-methyl-1H-pyrazole-3-carbonitrile (53g) and tetrahydrofuran (11mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 5°C, and then dimethyl malonate (110mL) and methanol (320mL) were added thereto. The mixture was stirred at 80°C for 24 hours. The reaction mixture was cooled to room temperature, and then tetrahydrofuran (320mL) was added thereto. The mixture was stirred at room temperature for 1 hour. The obtained solid was collected by filtration, and then washed with a mixed solution of methanol / tetrahydrofuran (v / v=1 / 2, 150mL) and tetrahydrofuran (200mL) in sequence to obtain the title compound (100g).

[1433] 1 H-NMR(CD3OD)δ:7.64(1H,d,J=2.2Hz), 6.91(1H,d,J=2.2Hz), 5.11(1H,s), 3.97(3H,s).

[1434] Step 6-3: 4,6-dichloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-5-carbaldehyde

[1435]

[1436] Under a nitrogen atmosphere, phosphorus oxychloride (64 mL) was added to N, N-dimethylformamide (270 mL) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C, and then added dropwise and slowly to a mixture of 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4-alcohol lithium (90 g) and toluene (270 mL) cooled to 0 ° C. The reaction mixture was stirred at room temperature overnight and then cooled to 0 ° C again. Phosphorus oxychloride (380 mL) was added dropwise and slowly to the reaction mixture, and then the mixture was stirred at 80 ° C for 6 hours. The reaction mixture was cooled to room temperature, and then added dropwise and slowly to a mixture of sodium hydrogen phosphate (770 g) and water (3.0 L) cooled to less than 10 ° C. The mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for 1 hour. The resulting solid was collected by filtration and then washed with water to obtain the title compound (79 g).

[1437] 1 H-NMR (DMSO-D6) δ: 10.28 (1H, s), 7.92 (1H, d, J = 2.5 Hz), 7.03 (1H, d, J = 2.5 Hz), 4.00 (3H, s).

[1438] Step 6-4: 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine

[1439]

[1440] 4,6-dichloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-5-carbaldehyde (120 mg) was added to a mixture of (6-chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride (100 mg), N,N-diisopropylethylamine (0.40 mL), tetrahydrofuran (1.5 mL) and water (0.50 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: 1% to 100% by volume of ethyl acetate / hexane) to obtain the title compound (55 mg).

[1441] 1H-NMR(DMSO-D6)δ:9.25(1H,s),7.85(1H,d,J=2.2Hz),7.66-7.64(2H,m), 6.99(1H,d,J=2.2Hz), 3.98(3H,s), 3.02-2.93(4H,m), 2.15-2.10(2H,m).

[1442] Step 6-5: 2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1443]

[1444] Under argon protection, trifluoroacetic acid (0.033 mL) was added to a mixture of 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine (55 mg), acetonitrile (0.55 mL) and water (0.28 mL), and the mixture was stirred at 60 ° C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: 1% to 100% by volume of ethyl acetate / hexane) and then treated with a mixed solution of ethyl acetate / hexane (v / v=1 / 5, 12 mL) to obtain a solid, the title compound (44 mg).

[1445] 1 H-NMR(DMSO-D6)δ:11.28(1H,br s),8.85(1H,s),7.90(1H,d,J=2.5Hz),7.57(2H,d,J=11.5Hz),6.96(1H,d,J=2.5Hz),3.98(3H,s),2.98-2.91(4H,m),2.14-2.07(2H,m).

[1446] LC-MS (MH+): 367.

[1447] Example compounds other than those described above can be obtained in a manner similar to the above preparation methods and preparation examples, or by known methods if necessary. The structure and physical property data of each example compound are shown in the following table.

[1448]

[1449]

[1450]

[1451]

[1452]

[1453]

[1454]

[1455]

[1456]

[1457]

[1458]

[1459]

[1460]

[1461]

[1462]

[1463] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory activity

[1464] The NLRP3 inflammasome inhibitory activity of the test compound was evaluated based on the inhibitory activity of IL-1β production in THP1-Null cells (Product No.: thp-null, InvivoGen). Cells were maintained in RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 25mmol / L HEPES, 100U / mL penicillin, 100μg / mL streptomycin, 100μg / mL normocin, and 200μg / mL hygromycin B (set at 37°C, 5% CO2 / 95% air).

[1465] The cells were suspended in a medium for determination (RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 100U / mL penicillin and 100μg / mL streptomycin) containing 0.5μmol / L PMA, and the suspended cells were inoculated in a Corning (registered trademark) 384-well transparent flat-bottom black polystyrene TC-treated microplate (25,000 cells / 25μL / well), followed by incubation (set at 37°C, 5% CO2 / 95% air) overnight. The supernatant of the culture was removed, and a medium for determination (25μL / well) containing 1μg / mL lipopolysaccharide (Product No.: L2654, Sigma-Aldrich (registered trademark)) was added thereto. Then, the culture was further incubated for 3 hours (set at 37°C, 5% CO2 / 95% air). The supernatant of the culture was removed. Then, the vehicle solution prepared by Opti-MEM (trademark) culture medium (product number: 31985-070, Invitrogen) is added to the blank setting well and the control setting well (20 μL / well), and then incubated for 15 minutes (set at 37°C, 5% CO2 / 95% air). The solution containing the test compound (20 μL / well) is added to the test compound setting well. In addition, the Opti-MEM (trademark) culture medium containing nigericin (Nigericin) (product number: N7143, Sigma-Aldrich (registered trademark)) is added to the control setting well and the test compound setting well (5 μL / well), followed by incubation for 1.5 hours (set at 37°C, 5% CO2 / 95% air). The final concentration of nigericin is adjusted to 7.5 μmol / L. Opti-MEM (trademark) culture medium of 5 μL / well is added to the blank setting well. The supernatant of the culture is stored frozen (set at -20°C) until IL-1β is measured.

[1466] The amount of IL-1β in the culture supernatant was quantified using the AlphaLISA (registered trademark) human IL-1β detection kit (product number: AL220C, PerkinElmer). The fluorescence intensity was measured using a microplate reader EnSpier (model: 2300-00J, Perkin Elmer) or EnSight (model: HH34000000, Perkin Elmer) according to the attached program manual. The inhibition rate of the test compound setting wells was calculated based on the blank setting wells being 100% and the control setting wells being 0%. The IC50 value (i.e., 50% inhibition concentration) of the test compound was calculated by logistic regression analysis. The results of the compounds of each example are shown in the table below.

[1467]

[1468]

[1469]

[1470]

[1471] Formulation examples of the present invention include the following formulations, but are not intended to be limited thereto.

[1472] Formulation Example 1: Preparation of Capsules

[1473] Ingredients (1), (2), (3) and (4) are mixed to fill into gelatin capsules.

[1474] Formulation Example 2: Preparation of Tablets

[1475]

[1476] The entire amount of ingredients (1), (2) and (3) and 30 g of ingredient (4) were combined with water, vacuum dried, and then granulated. The resulting granules were mixed with 14 g of ingredient (4) and 1 g of ingredient (5), and compressed using a tablet press. In this way, 1000 tablets were obtained, each of which contained 10 mg of the compound of Example 1.

[1477] Industrial Applicability

[1478] The compound of formula [I] or a pharmaceutically acceptable salt thereof, or the compound of formula [IA] or a pharmaceutically acceptable salt thereof has NLRP3 inflammasome inhibitory activity and is therefore expected to be useful for treating or preventing a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryptopyrin-associated periodic syndrome (e.g., familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous arthritis, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent myocardial infarction, and schizophrenia. Idiopathic pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

Claims

1. A compound of formula [IA]: or a pharmaceutically acceptable salt thereof, in, The key represented by: is a single bond or a double bond; R 1 and R 2 Each independently (1) Hydrogen, (2) Hydroxyl groups, (3) cyano group, (4)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following: (a) hydroxyl group, (b)C 1-4 Alkoxy, and (c)C 3-6 Cycloalkyl, (5)C 1-6 Alkoxy, wherein the alkoxy may be optionally replaced by C 3-6 Cycloalkyl substitution, (6) Halogen, (7)C 1-4 Haloalkyl, (8) -CHO, (9)-OC 1-4 Haloalkyl, (10)-OC 3-6 Cycloalkyl, (11)-CO-C 1-4 alkyl, (12)-CO-C 3-6 Cycloalkyl, (13)-NR 7 R 8 , where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl, or alternatively, R 7 and R 8 can be bonded together with the nitrogen atom to which they are attached, and the -NR 7 R 8 The group may form a 5- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or (14)C 3-6 Cycloalkyl, R 3A and R 4A Each independently (1) Hydrogen, (2)C 1-4 Alkyl, or (3)C 1-4 Haloalkyl, R 5A for (1) Hydrogen, (2) cyano group, (3)C 1-6 alkyl, (4)C 2-6 Alkenyl, (5)C 2-5 Alkynyl, (6)C 1-4 Alkoxy, (7) Halogen, (8)C 1-6 Haloalkyl, (9)C 2-6 Halogenated alkenyl, (10)-OC 1-4 Haloalkyl, (11)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from: (a) hydroxyl group, (b) halogens, and (c)C 1-4 Haloalkyl, (12)C 5-6 Cycloalkenyl, or (13) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or alternatively R 5A Can be used with R 3A or R 4A and the carbon atoms to which they are attached combine to form: (1)C 5-6 Cyclic olefins, or (2) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms, R 6A Independently (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution, (2)C 1-4 Alkoxy, (3) Halogen, (4)C 1-4 haloalkyl, or (5) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom, m is 0, 1, or 2, The condition is that when m is 2, then two adjacent R 6A Can be connected to the X 1 , X 2 , X 3 , X 4 and X 5 Two adjacent atoms in are combined together to form a 5- to 7-membered heterocycloalkane or heterocycloalkene containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, n is 0 or 1, The condition is that when n is 0, then X 1 , X 2 , X 3 and X 4 Each independently represents a carbon, nitrogen, oxygen or sulfur atom, wherein X 1 , X 2 , X 3 or X 4 The total number of nitrogen, oxygen and sulfur atoms is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1, and X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a heteroaryl group, and The condition is that when n is 1, then X 1 , X 2 , X 3 , X 4 and X 5 Each independently represents a carbon atom or a nitrogen atom, wherein X 1 , X 2 , X 3 , X 4 or X 5 The total number of nitrogen atoms is 1 or 2, and X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a heteroaryl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3A and R 4A For hydrogen.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [IIA]: Where R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 and m are defined as those defined in claim 1.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are joined together to form a pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl or triazolyl group.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a pyrazolyl, imidazolyl or thiazolyl group.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 With X 1 and X 4 Adjacent carbon atoms are bonded together to form a group of formula (1): The group of formula (2): or The group of formula (3):

7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [IIIA]: Where R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 and m are defined as those defined in claim 1.

8. A compound according to any one of claims 1, 2 or 7 or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are joined together to form a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group.

9. A compound according to any one of claims 1, 2, 7 or 8, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a pyridazinyl or pyrimidinyl group.

10. A compound according to any one of claims 1, 2, 7, 8 or 9, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 With X 1 and X 5 Adjacent carbon atoms are bonded together to form a group of formula (1'): or The group of formula (2'): 11 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 At least one of: C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following: (a) hydroxyl group, (b)C 1-4 Alkoxy, and (c)C 3-6 Cycloalkyl, or halogen.

13. A compound selected from the following structural formula: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15 . An NLRP3 inflammasome inhibitor comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

16. An agent for treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryptopyrin-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury, comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

17. The agent according to claim 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

18. The agent according to claim 16, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, or neonatal-onset multisystem inflammatory disease.

19. The agent according to claim 16, wherein the disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury.

20. A method for inhibiting NLRP3 inflammasome, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

21. A method for treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryptopyrin-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

23. The method of claim 21, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome, or neonatal-onset multisystem inflammatory disease.

24. The method of claim 21, wherein the disease is selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

25. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inflammasome inhibitor.

26. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryptopyrin-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury.

27. The use according to claim 26, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

28. The use according to claim 26, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal onset multisystem inflammatory disease.

29. The use according to claim 26, wherein the disease is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury.

30. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 inflammasome.

31. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryptopyrin-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury.

32. The compound for use according to claim 31 or a pharmaceutically acceptable salt thereof, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

33. The compound for use according to claim 31 or a pharmaceutically acceptable salt thereof, wherein the cryopyrin-associated periodic syndrome is familial cold autoinflammatory syndrome, Muckler-Wells syndrome, chronic infantile neurocutaneous articular syndrome or neonatal onset multisystem inflammatory disease.

34. The compound for use according to claim 31 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury.

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