6-aminopyrazolopyrimidine compound and pharmaceutical use thereof

Abstract

To provide a compound having an inhibitory activity on NLRP3 inflammasomes.SOLUTION: The present invention provides compounds of formula [IA] or pharmaceutically acceptable salts thereof. Specifically, the compounds of the formula below are illustrated.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a 6-aminopyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and medical uses thereof, etc. [Background technology]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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[0036] The present invention provides a 6-aminopyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and a medicinal use thereof, etc. That is, the present invention includes the following exemplary embodiments.

[0037] [Section 1] A compound of formula [I] or a pharma- ceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [I] or a pharma- ceutically acceptable salt thereof" is also referred to as "compound [I]"). [ka] {In the formula, Substructure: [ka] teeth, (1) Formula: [ka] {In the formula, R 4 is hydrogen or C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or cyano; or (2) Formula: [ka] [During the ceremony, R 5 is C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b) cyano, (c)C 1-4 Alkoxy, or (d) C 3-6 cycloalkyl, optionally substituted with 1-4 haloalkyl] The structure is represented by The ring group Cy is (1) Formula: [ka] (In the formula, R 6 and R 7 are each independently (a) hydrogen, (b) hydroxy, (c) Cyano, (d) C1-6 alkyl {wherein the alkyl is (1) Hydroxy, (2) C 1-4 Alkoxy, and (3) C 3-6 cycloalkyl; (e)C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (f) halogens, (g) C 1-4 Haloalkyl, (h)-CHO, (i)-OC 1-4 Haloalkyl, (j)-OC 3-6 Cycloalkyl, (k)-CO-C 1-4 Alkyl, (m)-CO-C 3-6 Cycloalkyl, (n)-NR 11 R 12 (where R 11 and R 12 are each independently hydrogen or 2,4-dimethoxybenzyl; or R 11 and R 12 together with the nitrogen atom to which they are attached, -NR 11 R 12 the groups may form a 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (o)C 3-6 cycloalkyl, R 8 and R 9 are each independently (a) hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl, R 10 teeth, (a) hydrogen, (b) cyano, (c)C 1-6 Alkyl, (d) C 2-6 Alkenyl, (e)C 2-5 Alkynyl, (f)C 1-4 Alkoxy, (g) halogens, (h)C 1-6 Haloalkyl, (I C 2-6 Haloalkenyl, (j)-OC 1-4 Haloalkyl, (k)C 3-6 Cycloalkyl, where the cycloalkyl is C 1-4 may be substituted with haloalkyl, (m)C 5-6 cycloalkenyl, or (n) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. A group represented by the formula: (2) Formula: [ka] {In the formula, R 13 and R 14 are each independently hydrogen or C 1-4 is alkyl, R 15 is C 1-4 Haloalkyl or C 3-6 cycloalkyl} A group represented by the formula: (3) Formula: [ka] (In the formula, R 16 is C 1-6 is alkyl or halogen; R 17 is halogen or C 1-4 haloalkyl) or (4) Formula: [ka] is a group represented by R 1 is hydrogen or C 1-4 is alkyl, R 2 and R 3 are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a)C 1-4 Alkoxy, (b)C 3-6 cycloalkyl, or (c) phenyl, wherein the phenyl is C 1-4 substituted with alkoxy); (3) C 1-4 Alkoxy, (4) C 1-4 Haloalkyl, (5)-CD3, (6)-CO-C 1-4 Alkyl, (7) C 3-6 Cycloalkyl, (8) 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is 1-4 may be substituted with alkyl, (9) phenyl, or Equation (10): [ka] or Or, R 2 and R 3 together with the nitrogen atom to which they are attached, -NR 2 R 3 The base (a) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, or (c) phenyl, optionally substituted with (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 Haloalkyl, (7)-OC 1-4 Haloalkyl, (8)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (9)-CO-C 1-6 Alkoxy, (10)-CO-C 3-6 Cycloalkyl, (11)-CONH-C 1-4 Alkyl, (12)-NHCO-C 1-4 Alkyl, (13)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (14)-SO2-C 1-4 Alkyl, (15)-SO2-C 3-6 Cycloalkyl, (16)C 3-6 Cycloalkyl, (17) phenyl, Equation (18): [ka] and (19) oxo, (b) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (c) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (1) Halogen, (2)-CO-C 1-4 Alkyl, and (3)-CO-C 1-6 alkoxy; (d) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (1) Halogen, (2)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (3)-SO2-C 1-4 alkyl, and [Section 2] Substructure: [ka] but, (1) Formula: [ka] (In the formula, R 4 is equivalent to term 1) Item 2. The compound according to item 1, which has a structure represented by the following formula: or a pharma- ceutically acceptable salt thereof. [Section 3] R 1Item 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 4] R 4 The compound according to any one of items 1 to 3, wherein is hydrogen, or a pharma- ceutically acceptable salt thereof. [Section 5] The ring group Cy is (1) Formula: [ka] (In the formula, each symbol has the same meaning as in Item 1.) Item 5. The compound according to any one of items 1 to 4, wherein the compound is a group represented by the following formula: [Section 6] 6. The compound according to any one of items 1 to 5, which is represented by formula [II] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, each symbol has the same meaning as in Item 1.) [Section 7] R 8 and R 9 Item 7. The compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 8] Item 8. The compound according to any one of items 1 to 7, which is represented by formula [IIa] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 6 , R 7 , and R 10 is equivalent to term 1, Ring group Cy 1 teeth, (1) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (a) hydroxy, (b) cyano, (c)C 1-6 alkyl {wherein the alkyl is (1) Hydroxy, (2) C 1-4 Alkoxy, or (3) phenyl, optionally substituted with (d) C 1-4 Alkoxy, (e) halogens, (f)C 1-4 Haloalkyl, (g)-OC 1-4 Haloalkyl, (h)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (i)-CO-C 1-6 Alkoxy, (j)-CO-C 3-6 Cycloalkyl, (k)-CONH-C 1-4 Alkyl, (m)-NHCO-C 1-4 Alkyl, (n)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (o)-SO2-C 1-4 Alkyl, (p)-SO2-C 3-6 Cycloalkyl, (q)C 3-6 Cycloalkyl, (r) phenyl, (s) expression: [ka] and (t) oxo, (2) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (3) A 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (a) halogens, (b)-CO-C 1-4 Alkyl, and (c)-CO-C 1-6 alkoxy; (4) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (a) halogens, (b)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (c)-SO2-C 1-4 alkyl, and [Section 9] A pharmaceutical composition comprising the compound according to any one of items 1 to 8 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. [Section 10] Item 9. An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 8 or a pharma- ceutically acceptable salt thereof. [Section 11] Item 9. A therapeutic or preventive agent for 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, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / neonatal onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, and TNF receptor-associated periodic syndrome. [Section 12] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 8 or a pharma- ceutically acceptable salt thereof to a mammal. [Section 13] Item 10. The method of claim 1, further comprising administering to a mammal a therapeutically effective amount of the compound according to any one of items 1 to 8 or a pharma- ceutical acceptable salt thereof, to treat multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, and the like. A method for treating or preventing a disease selected from the group consisting of gout, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, and TNF receptor-associated periodic syndrome. [Section 14] Use of the compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 8 for the manufacture of an NLRP3 inflammasome inhibitor. [Section 15] Item 10. Use of the compound according to any one of items 1 to 8 or a pharma- ceutical acceptable salt thereof for the manufacture of an agent for the treatment or prophylaxis of 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, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / neonatal-onset multi-organ inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, and TNF receptor-associated periodic syndrome. [Section 16] The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 8 for use in inhibiting NLRP3 inflammasome. [Section 17] Item 9. The compound according to any one of items 1 to 8, or a pharma- ceutical acceptable salt thereof, for use in the treatment or prophylaxis of 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, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / 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, hyper-IgD syndrome, and TNF receptor-associated periodic syndrome. [Section 18] Item 9. A pharmaceutical composition according to Item 9, and a method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / neonatal onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), total liver disease, osteoporosis ... A commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of 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 molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, and TNF receptor-associated periodic syndrome. [Section 19] Item 9. The pharmaceutical composition according to Item 9, and a method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome / neonatal onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), A commercial kit comprising a description of the pharmaceutical composition, which is described as being usable for the treatment or prevention of a disease selected from the group consisting of 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 molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome and TNF receptor-associated periodic syndrome.

[0038] [Section 1A] A compound of formula [IA] or a pharma- ceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [IA] or a pharma- ceutically acceptable salt thereof" is also referred to as "compound [IA]"). [ka] {In the formula, Substructure: [ka] teeth, (1) Formula: [ka] {In the formula, R 4 is hydrogen or C 1-4 alkyl, wherein the alkyl may be substituted with hydroxy or cyano; or (2) Formula: [ka] [During the ceremony, R 5 is C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b) cyano, (c)C 1-4 Alkoxy, or (d) C 3-6 cycloalkyl, optionally substituted with 1-4 haloalkyl] The structure is represented by Ring group Cy A teeth, (1) Formula: [ka] (In the formula, R 6 and R 7 are each independently (a) hydrogen, (b) hydroxy, (c) Cyano, (d) C 1-6 alkyl {wherein the alkyl is (1) Hydroxy, (2) C1-4 Alkoxy, and (3) C 3-6 cycloalkyl; (e)C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (f) halogens, (g) C 1-4 Haloalkyl, (h)-CHO, (i)-OC 1-4 Haloalkyl, (j)-OC 3-6 Cycloalkyl, (k)-CO-C 1-4 Alkyl, (m)-CO-C 3-6 Cycloalkyl, (n)-NR 11 R 12 (where R 11 and R 12 are each independently hydrogen or 2,4-dimethoxybenzyl; or R 11 and R 12 together with the nitrogen atom to which they are attached, -NR 11 R 12 the groups may form a 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (o)C 3-6 cycloalkyl, R 8 and R 9 are each independently (a) hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl, R 10 teeth, (a) hydrogen, (b) cyano, (c)C 1-6 Alkyl, (d) C2-6 Alkenyl, (e)C 2-5 Alkynyl, (f)C 1-4 Alkoxy, (g) halogens, (h)C 1-6 Haloalkyl, (I C 2-6 Haloalkenyl, (j)-OC 1-4 Haloalkyl, (k)C 3-6 Cycloalkyl, where the cycloalkyl is C 1-4 may be substituted with haloalkyl, (m)C 5-6 cycloalkenyl, or (n) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. A group represented by the formula: (2) Formula: [ka] {In the formula, R 13 and R 14 are each independently hydrogen or C 1-4 is alkyl, R 15 is C 1-4 Haloalkyl or C 3-6 cycloalkyl} A group represented by the formula: (3) Formula: [ka] (In the formula, R 16 is C 1-6 is alkyl or halogen; R 17 is halogen or C 1-4 haloalkyl) A group represented by the formula: (4) Formula: [ka] or Equation (5): [ka] (In the formula, R 20 and R 21 are each independently 1-4 Alkyl or C 1-4 is haloalkyl, R 22 is C 1-6 Alkyl or C 3-6 cycloalkyl) is a group represented by R 1 is hydrogen or C 1-4 is alkyl, R 2A and R 3A are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 alkoxy, wherein the alkoxy is optionally substituted with hydroxy; (c)C 3-6 cycloalkyl, or (d) phenyl, wherein the phenyl is C 1-4 substituted with alkoxy); (3) C 1-4 Alkoxy, (4) C 1-4 Haloalkyl, (5)-CD3, (6)-CO-C 1-4 Alkyl, (7) C 3-6 Cycloalkyl, (8) 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is 1-4 may be substituted with alkyl, (9) phenyl, or Equation (10): [ka] or Or, R 2A and R 3A together with the nitrogen atom to which they are attached, -NR 2A R 3A The base is (a) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, or (c) phenyl, optionally substituted with (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 Haloalkyl, (7)-OC 1-4 Haloalkyl, (8)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (9)-CO-C 1-6 Alkoxy, (10)-CO-C 3-6 Cycloalkyl, (11)-CONH-C 1-4 Alkyl, (12)-NHCO-C 1-4 Alkyl, (13)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (14)-SO2-C 1-4Alkyl, (15)-SO2-C 3-6 Cycloalkyl, (16)C 3-6 Cycloalkyl, (17) phenyl, Equation (18): [ka] and (19) oxo, (b) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (c) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (1) Halogen, (2)-CO-C 1-4 Alkyl, and (3)-CO-C 1-6 alkoxy; (d) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (1) Halogen, (2)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (3)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of (e) Formula: [ka] may form a group represented by the formula: [Section 2A] Substructure: [ka] but, (1) Formula: [ka] (In the formula, R 4 is equivalent to item 1A) or a pharma- ceutically acceptable salt thereof according to item 1A. [Section 3A] R 1 The compound according to item 1A or 2A, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 4A] R 4 The compound according to any one of items 1A to 3A, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 5A] Ring group Cy A but, (1) Formula: [ka] (In the formula, each symbol has the same meaning as in Item 1A.) or a pharma- ceutically acceptable salt thereof according to any one of Items 1A to 4A, wherein R is a group represented by the following formula: [Section 6A] The compound according to any one of items 1A to 5A, which is represented by formula [IIA] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, each symbol has the same meaning as in Item 1A.) [Section 7A] R 8 and R 9 The compound according to any one of items 1A to 6A, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 8A] The compound according to any one of items 1A to 7A, which is represented by formula [IIIA], or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 6 , R 7 , and R 10 is synonymous with Item 1A, Ring group Cy B teeth, (1) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (a) hydroxy, (b) cyano, (c)C 1-6 alkyl {wherein the alkyl is (1) Hydroxy, (2) C 1-4 Alkoxy, or (3) phenyl, optionally substituted with (d) C 1-4 Alkoxy, (e) halogens, (f)C 1-4 Haloalkyl, (g)-OC 1-4 Haloalkyl, (h)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (i)-CO-C 1-6 Alkoxy, (j)-CO-C 3-6 Cycloalkyl, (k)-CONH-C 1-4 Alkyl, (m)-NHCO-C 1-4 Alkyl, (n)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (o)-SO2-C 1-4 Alkyl, (p)-SO2-C 3-6 Cycloalkyl, (q)C3-6 Cycloalkyl, (r) phenyl, (s) expression: [ka] and (t) oxo, (2) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (3) A 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (a) halogens, (b)-CO-C 1-4 Alkyl, and (c)-CO-C 1-6 alkoxy; (4) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (a) halogens, (b)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of Equation (5): [ka] is a group represented by the formula: [Section 9A] Ring group Cy B but, (1) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (a) hydroxy, (b) cyano, (c)C 1-6 alkyl {wherein the alkyl is (1) Hydroxy, (2) C 1-4 Alkoxy, or (3) phenyl, optionally substituted with (d) C 1-4 Alkoxy, (e) halogens, (f)C 1-4 Haloalkyl, (g)-OC 1-4 Haloalkyl, (h)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (i)-CO-C 1-6 Alkoxy, (j)-CO-C 3-6 Cycloalkyl, (k)-CONH-C 1-4 Alkyl, (m)-NHCO-C 1-4 Alkyl, (n)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (o)-SO2-C 1-4 Alkyl, (p)-SO2-C 3-6 Cycloalkyl, (q)C 3-6 Cycloalkyl, (r) phenyl, (s) expression: [ka] and (t) oxo; or (2) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (a) halogens, (b)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of The compound according to Item 8A, or a pharma- ceutically acceptable salt thereof, wherein: [Section 10A] Ring group Cy B is a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, wherein said heterocycloalkyl is (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, or (c) phenyl, optionally substituted with (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 Haloalkyl, (7)-OC 1-4 Haloalkyl, (8)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (9)-CO-C 1-6 Alkoxy, (10)-CO-C 3-6 Cycloalkyl, (11)-CONH-C 1-4Alkyl, (12)-NHCO-C 1-4 Alkyl, (13)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (14)-SO2-C 1-4 Alkyl, (15)-SO2-C 3-6 Cycloalkyl, (16)C 3-6 Cycloalkyl, (17) phenyl, Equation (18): [ka] and (19) oxo, and optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo, or a pharma- ceutically acceptable salt thereof. [Section 11A] Ring group Cy B is a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, wherein said heterocycloalkyl is (1) Cyano, (2) C 1-6 Alkyl {wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, (5)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (6)-CO-C 1-6 Alkoxy, (7)-CO-C 3-6 Cycloalkyl, (8)-SO2-C 1-4 Alkyl, (9)-SO2-C3-6 Cycloalkyl, Equation (10): [ka] and (11) oxo, and optionally substituted with 1 to 4 substituents independently selected from the group consisting of oxo. [Section 12A] The structural formula: TIFF2024112817000042.tif21678, or a pharma- ceutically acceptable salt thereof according to Item 1A. [Section 13A] A pharmaceutical composition comprising the compound according to any one of items 1A to 12A or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. [Section 14A] An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1A to 12A or a pharma- ceutically acceptable salt thereof. [Section 15A] The compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A or a pharma- ceutical agent containing a compound according to any one of Items 1A to 12A A therapeutic or preventive agent for a disease selected from the group consisting of chronic kidney disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 16A] The therapeutic or prophylactic agent according to Item 15A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 17A] Item 15A. The treatment or prevention agent according to Item 15A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 18A] A method for inhibiting NLRP3 inflammasome, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs 1A to 12A or a pharma- ceutically acceptable salt thereof. [Section 19A] A method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, or the like, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of items 1A to 12A or a pharma- ceutical acceptable salt thereof. inflammatory bowel syndrome, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic fatty liver disease, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease A method for treating or preventing a disease selected from the group consisting of chronic myocardial infarction, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 20A] The method according to paragraph 19A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 21A] The method according to item 19A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 22A] Use of the compound or a pharma- ceutical acceptable salt thereof according to any one of items 1A to 12A for the manufacture of an NLRP3 inflammasome inhibitor. [Section 23A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic 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 Item 13. Use of the compound or a pharmacokinetic / metabolic activator deficiency syndrome (MERS), IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 24A] The use according to paragraph 23A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 25A] The use according to Item 23A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 26A] The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1A to 12A for use in inhibiting NLRP3 inflammasome. [Section 27A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease, 13. The compound or a pharmacologic acceptable salt thereof according to any one of items 1A to 12A for use in the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction, idiopathic pulmonary syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 28A] The compound or a pharma- ceutically acceptable salt thereof according to Item 27A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 29A] The compound or a pharma- ceutically acceptable salt thereof according to Item 27A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 30A] A pharmaceutical composition according to Item 13A, and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel ... and a commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF) syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 31A] A pharmaceutical composition according to Item 13A, and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage leukemia), and / or chronic inflammatory diseases (e.g., hemophagocytic lymphohistiocytosis and macrophage leukemia). and a commercial kit comprising a description of the pharmaceutical composition, the description of which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction (CI)-associated pulmonary disease (COPD), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] The definitions of terms used in this specification are as follows.

[0040] In the chemical formula: [ka] The wavy line indicates the bonding site of the structure or group shown in the chemical formula.

[0041] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

[0042] "C1-6 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. Methyl is preferred.

[0043] "C 2-6 "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one double bond. 2-6 "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.

[0044] "C 2-5 "Alkynyl" means a straight or branched unsaturated hydrocarbon group containing from 2 to 5 carbon atoms and containing at least one triple bond. 2-5 "Alkynyl" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 2-pentynyl.

[0045] "C 1-4 Alkoxy means the above "C 1-4 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy.

[0046] "C 1-6Alkoxy means the above "C 1-6 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-6 "Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, and 2-ethylbutoxy.

[0047] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine.

[0048] "C 1-4 "Haloalkyl" refers to the above "C" substituted with 1 to 7 halogens independently selected from the above "halogen" group. 1-4 "C" means "alkyl". 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 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.

[0049] "C 1-6 "Haloalkyl" refers to the above "C" substituted with 1 to 9 halogens independently selected from the above "halogen" group. 1-6 "C" means "alkyl". 1-6"Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0050] "C 2-6 "Haloalkenyl" refers to the above "C" substituted with 1 to 9 halogens independently selected from the above "halogen" group. 2-6 "C" means "alkenyl". 2-6 "Haloalkenyl" includes, for example, 2-fluoroethenyl, 3-chloropropenyl, 2-fluoropropenyl, 1-trifluoromethylethenyl, and 4,4,4-trifluoro-2-butenyl.

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

[0052] "C 5-6 "Cycloalkenyl" means a monocyclic partially unsaturated hydrocarbon ring group having 5 to 6 carbon atoms and containing at least one double bond. 5-6 "Cycloalkenyl" includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.

[0053] "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring-constituting atoms. "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, and dioxanyl.

[0054] "4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms" means a 4- to 7-membered monocyclic saturated heterocyclic group containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, in addition to carbon atoms as ring-constituting atoms. "4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms" includes, for example, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl. , piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, thiomorpholinyl, dioxanyl, hexahydrotriazinyl, azepanyl, oxepanyl, diazepanyl (e.g. 1,4-diazepanyl), oxazepanyl (e.g. 1,4-oxazepanyl and 1,2-oxazepanyl), dioxazepanyl (e.g. 1,5,2-dioxazepanyl), and thiazepanyl. Preferred is morpholinyl.

[0055] "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms as ring-constituting atoms. "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of 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.

[0056] "7- to 9-membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 7- to 9-membered spiro-type saturated heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. "7- to 9-membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, the following groups: [ka] Includes:

[0057] The term "6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" refers to a 6- to 9-membered fused heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, and a fused ring group containing at least one saturated ring in the ring constituting the fused ring. Examples of the "6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" include the following groups: [ka] Includes:

[0058] "6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 6- to 8-membered bridged saturated heterocyclic group containing, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. "6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, the following groups: [ka] Preferably, the following groups are included: The file is TIFF2024112817000047.tif4436.

[0059] The phrase "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is replaced with β. For example, "C optionally substituted with hydroxy" means that 1-6 "Alkyl" means C 1-6 The alkyl is unsubstituted or 1-6 This means that any hydrogen in the alkyl is replaced with hydroxy.

[0060] Specific embodiments of each substituent of the compound of formula [I] are exemplified below, but each substituent of the compound of formula [I] is not limited to the specific embodiments, and the compound of formula [I] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0061] Substructure: [ka] is preferably of the formula: [ka] (In the formula, R 4 are as defined above) The structure is shown below.

[0062] The ring group Cy is preferably (1) Formula: [ka] (wherein each symbol has the same meaning as defined above) A group represented by the formula: (2) Formula: [ka] (wherein each symbol has the same meaning as defined above) or (3) Formula: [ka] (wherein each symbol has the same meaning as defined above) It is a group represented by the following formula:

[0063] R 1 is preferably hydrogen.

[0064] R 2 and R 3 are preferably each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a)C 1-4 Alkoxy, (b)C 3-6 cycloalkyl, or (c) phenyl, wherein the phenyl is C 1-4 substituted with alkoxy); (3) C 1-4 Alkoxy, (4) C 1-4 Haloalkyl, (5)-CD3, (6)-CO-C1-4 Alkyl, (7) C 3-6 Cycloalkyl, (8) 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is 1-4 may be substituted with alkyl, or (9) Phenyl, or Or, R 2 and R 3 together with the nitrogen atom to which they are attached, -NR 2 R 3 The base is (a) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, or (c) phenyl, optionally substituted with (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 Haloalkyl, (7)-OC 1-4 Haloalkyl, (8)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (9)-CO-C 1-6 Alkoxy, (10)-CO-C 3-6 Cycloalkyl, (11)-CONH-C 1-4 Alkyl, (12)-NHCO-C 1-4 Alkyl, (13)-NR 18 R19 (where R 18 and R 19 are each independently 1-4 alkyl), (14)-SO2-C 1-4 Alkyl, (15)-SO2-C 3-6 Cycloalkyl, (16)C 3-6 Cycloalkyl, (17) phenyl, Equation (18): [ka] and (19) oxo, (b) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (c) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (1) Halogen, (2)-CO-C 1-4 Alkyl, and (3)-CO-C 1-6 alkoxy; (d) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (1) Halogen, (2)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (3)-SO2-C 1-4 alkyl, and the like.

[0065] Specific embodiments of each substituent of the compound of formula [IA] are exemplified below, but each substituent of the compound of formula [IA] is not limited to those specific embodiments, and the compound of formula [IA] also includes embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0066] Substructure: [ka] is preferably of the formula: [ka] (In the formula, R 4 are as defined above) The structure is shown below.

[0067] R 4 is preferably hydrogen.

[0068] Ring group Cy A is preferably formula: [ka] (wherein each symbol has the same meaning as defined above) It is a group represented by the following formula:

[0069] R 6 and R 7 Preferred embodiments of the formula (I) are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-4 Haloalkyl, -OC 1-4 Haloalkyl or C 3-6 It is cycloalkyl. R 6 and R 7 More preferred embodiments of the formula (I) are each independently hydrogen, C 1-6 It is alkyl or halogen. R 6 and R 7Preferred specific examples of each are independently methyl, fluorine or chlorine.

[0070] R 8 and R 9 is preferably hydrogen.

[0071] R 10 A preferred embodiment of the present invention is 1-6 Alkyl, C 1-4 Alkoxy, halogen, C 1-6 Haloalkyl, -OC 1-4 Haloalkyl or C 3-6 It is cycloalkyl. R 10 A further preferred embodiment of the formula is halogen or C 3-6 It is cycloalkyl. R 10 Preferred examples of are bromine or cyclopropyl.

[0072] Ring group Cy A is preferably formula: [ka] is a group represented by the formula: R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-4 Haloalkyl, -OC 1-4 Haloalkyl or C 3-6 is cycloalkyl; R 8 and R 9 is hydrogen; R 10 is C 1-6 Alkyl, C 1-4 Alkoxy, halogen, C 1-6 Haloalkyl, -OC 1-4 Haloalkyl or C 3-6 It is cycloalkyl.

[0073] Ring group Cy AMore preferably, formula: [ka] is a group represented by the formula: R 6 and R 7 are each independently hydrogen, C 1-6 is alkyl or halogen; R 8 and R 9 is hydrogen; R 10 is halogen or C 3-6 It is cycloalkyl.

[0074] R 1 is preferably hydrogen.

[0075] R 2A and R 3A is preferably R 2A and R 3A together with the nitrogen atom to which they are attached, -NR 2A R 3A The base is (1) a 6-membered heterocycloalkyl containing two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms; or (2) forming a 7-membered bridged heterocycloalkyl containing two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;

[0076] One preferred embodiment of the compound of formula [I] is Substructure: [ka] But the formula: [ka] (In the formula, R 4 are as defined above) The structure is represented by: The ring group Cy is (1) Formula: [ka] (wherein each symbol has the same meaning as defined above) A group represented by the formula: (2) Formula: [ka] (wherein each symbol has the same meaning as defined above) or (3) Formula: [ka] (wherein each symbol has the same meaning as defined above) is a group represented by the formula: R 1 is hydrogen; R 2 and R 3 However, each independently, (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a)C 1-4 Alkoxy, (b)C 3-6 cycloalkyl, or (c) phenyl, wherein the phenyl is C 1-4 substituted with alkoxy); (3) C 1-4 Alkoxy, (4) C 1-4 Haloalkyl, (5)-CD3, (6)-CO-C 1-4 Alkyl, (7) C 3-6 Cycloalkyl, (8) 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is 1-4 may be substituted with alkyl, or (9) Phenyl, or Or, R2 and R 3 together with the nitrogen atom to which they are attached, -NR 2 R 3 The base is (a) a 4- to 7-membered heterocycloalkyl containing from 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) Cyano, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, or (c) phenyl, optionally substituted with (4) C 1-4 Alkoxy, (5) halogens, (6) C 1-4 Haloalkyl, (7)-OC 1-4 Haloalkyl, (8)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (9)-CO-C 1-6 Alkoxy, (10)-CO-C 3-6 Cycloalkyl, (11)-CONH-C 1-4 Alkyl, (12)-NHCO-C 1-4 Alkyl, (13)-NR 18 R 19 (where R 18 and R 19 are each independently 1-4 alkyl), (14)-SO2-C 1-4 Alkyl, (15)-SO2-C 3-6 Cycloalkyl, (16)C 3-6 Cycloalkyl, (17) phenyl, Equation (18): [ka] and (19) oxo, (b) 7-9 membered spiroheterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiroheterocycloalkyl is optionally substituted with hydroxy; (c) a 6- to 9-membered saturated or partially unsaturated fused ring group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms {wherein the fused ring group is (1) Halogen, (2)-CO-C 1-4 Alkyl, and (3)-CO-C 1-6 alkoxy; (d) a 6- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (1) Halogen, (2)-CO-C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy, and (3)-SO2-C 1-4 and alkyl, which may be substituted with 1 or 2 substituents independently selected from the group consisting of:

[0077] A preferred embodiment of the compound of formula [IA] is Substructure: [ka] But the formula: [ka] The structure is represented by: R 4 is hydrogen; Ring group Cy A but, formula: [ka] is a group represented by the formula: R 6 and R 7 are each independently hydrogen, C 1-6 is alkyl or halogen; R 8 and R 9 is hydrogen; R 10 But halogen or C 3-6 is cycloalkyl; R 1 is hydrogen; R 2A and R 3A together with the nitrogen atom to which they are attached, -NR 2A R 3A The compounds of formula [IA] are those in which the group forms a 6-membered heterocycloalkyl containing two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms.

[0078] Another preferred embodiment of the compound of formula [IA] is Substructure: [ka] But the formula: [ka] The structure is represented by: R 4 is hydrogen; Ring group Cy A but, formula: [ka] is a group represented by the formula: R 6 and R7 are each independently hydrogen, C 1-6 is alkyl or halogen; R 8 and R 9 is hydrogen; R 10 But halogen or C 3-6 is cycloalkyl; R 1 is hydrogen; R 2A and R 3A together with the nitrogen atom to which they are attached, -NR 2A R 3A The compounds of formula [IA] are those in which the groups form a 7-membered bridged heterocycloalkyl containing two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms.

[0079] As used herein, the term "pharmaceutical acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutical acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, a pharma- ceutically acceptable salt thereof can be obtained by reacting a compound of formula [I] or formula [IA] with an inorganic acid, an organic acid, an inorganic base, or an organic base.

[0080] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid, and preferably salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferred examples of the salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.

[0081] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium, and preferably salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferred are salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0082] Compound [I] or compound [IA] may exist as a solvate. A solvate is, for example, a compound [I] or compound [IA] coordinated with a solvent molecule. The solvate may be any pharma- ceutically acceptable solvate, and may include hydrate, acetate solvate, acetone solvate, ethanol solvate, and dimethylsulfoxide solvate of compound [I] or compound [IA]. Specifically, the solvate may include hemihydrate, monohydrate, dihydrate, monoacetate solvate, monoacetone solvate, or monoethanol solvate of the sodium salt of the compound of formula [I] or formula [IA], or monohydrate, monoacetone solvate, or 2 / 3 ethanol solvate of the dihydrochloride salt of the compound of formula [I] or formula [IA]. These solvates may be obtained according to known methods.

[0083] Compound [I] or compound [IA] may exist as a tautomer. In that case, compound [I] or compound [IA] may exist as an individual tautomer or a mixture of tautomers. For example, the compound [I] or compound [IA] may exist as a tautomer of the following formula: [ka] The structure shown in is, unless otherwise noted, (1) [ka] (2) [ka] (3) [ka] (4) [ka] or (5) It means that these mixtures can exist and / or be expressed as such. Compound [I] or compound [IA] may have a carbon double bond. In that case, compound [I] or compound [IA] may exist as an E form, a Z form, or a mixture of E and Z forms. Compound [I] or compound [IA] may have stereoisomers that should be recognized as cis / trans isomers. In that case, compound [I] or compound [IA] may exist as a cis form, a trans form, or a mixture of cis and trans forms. 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. Compound [I] or compound [IA] may exist as atropisomers, in which case compound [I] or compound [IA] may exist as an individual atropisomer or a mixture of atropisomers. Compound [I] or compound [IA] may simultaneously contain multiple structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0084] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned isomers that may exist, unless otherwise noted.

[0085] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization, or the individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or by stereoselective reactions.

[0086] Separation of the individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, well known in the art. Alternatively, one of the enantiomers can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries and asymmetric catalysts.

[0087] Absolute configuration may be determined by the X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0088] Compound [I] or compound [IA] is an isotope ( 2 H(D), 3 H, 14 C. 35 For example, when the compound of formula [I] or formula [IA] has a methyl group, the methyl group may be replaced with a -CD3 group, and the compound thus obtained is also included in the present invention.

[0089] Compound [I] or compound [IA] is preferably a substantially purified compound [I] or compound [IA], more preferably a compound [I] or compound [IA] purified to a purity of 80% or more.

[0090] The pharmaceutical composition of the present invention may be prepared by mixing compound [I] or compound [IA] with at least one or more pharma- ceutically acceptable carriers in an appropriate amount, as appropriate, according to a method known in the technical field of pharmaceutical preparations. The content of compound [I] or compound [IA] in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the entire composition.

[0091] Dosage forms of compound [I] or compound [IA] include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0092] Examples of "pharmaceutical acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used as necessary.

[0093] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like. The "fluidizing agent" includes light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. "Soothing agents" include benzyl alcohol and the like. Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more of these. Examples of the "preservatives" include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. Examples of "coloring agents" include food dyes (food red No. 2 or 3, food yellow No. 4 or 5, etc.), β-carotene, and the like. "Sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0094] The pharmaceutical composition of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, etc.) to mammals other than humans (mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.) and humans. The dosage (also referred to as "therapeutically effective amount" in this specification) varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when orally administered to an adult patient is usually in the range of about 0.01 mg to 1 g per day as the active ingredient, the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof. These amounts can be administered once or in several divided doses.

[0095] Compound [I] or compound [IA] has an NLRP3 inflammasome inhibitory effect, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity. Examples of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic fatty liver disease, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult The present invention includes diseases selected from the group consisting of onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0096] "Inhibiting NLRP3 inflammasome" means inhibiting the function of NLRP3 inflammasome to eliminate or weaken its activity, for example, means inhibiting the function of NLRP3 inflammasome based on the conditions of Test Example 1 described below. By inhibiting the function of NLRP3 inflammasome, the production amount of IL-1β and / or IL-18 is suppressed, preferably the production amount of IL-1β and IL-18 is suppressed. "Inhibiting NLRP3 inflammasome" preferably means "inhibiting human NLRP3 inflammasome".

[0097] As used herein, "treatment" includes amelioration of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence. As used herein, "prevention" includes suppressing and delaying the onset of symptoms.

[0098] As long as there is no contradiction between an embodiment disclosed in one place in this specification and an embodiment disclosed in another place, any combination of two or more of these is also intended to be encompassed by the present invention.

[0099] [General manufacturing method] General methods for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof are exemplified below. However, the methods for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof are not limited to these methods. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they can be used to proceed to the next step without isolation and / or purification. In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature between 1°C and 40°C.

[0100] Production method A1: A method for producing compound [IA] or a salt thereof, or compound [IB] or a salt thereof Compound [IA] or a salt thereof, or compound [IB] or a salt thereof can be produced, for example, by the following Production Method A1. [ka] {where, Cy, R 2 , R 3 , and R 5 is as defined above, R 5A is C 1-4 alkyl, optionally substituted with hydroxy or cyano; L A11 is a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy) (Process A1-1) Compound [IA] or a salt thereof, or compound [IB] or a salt thereof can be produced by reacting compound [IC] or a salt thereof with compound [A1-1] or a salt thereof in a solvent in the presence of a base. Examples of bases include sodium hydride and potassium carbonate. A preferred base is sodium hydride. Examples of the solvent include N,N-dimethylformamide and tetrahydrofuran. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 100°C, preferably 10°C to 50°C. The compound [A1-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0101] Production method A1A: A method for producing compound [IA-A] or a salt thereof, or compound [IA-B] or a salt thereof By using compound [IA-C] or a salt thereof instead of compound [IC] or a salt thereof, compound [IA-A] or a salt thereof, or compound [IA-B] or a salt thereof can be produced in the same manner as in production method A1. [ka] (wherein each symbol is as defined above)

[0102] Production method A2: Production method of compound [IC] or a salt thereof The compound [IC] or a salt thereof can be produced, for example, by the following Production Method A2. [ka] {where, Cy, R 2 , and R 3 is as defined above, R A21 are each independently 1-4 is alkyl, L A21 , L A22 , and L A23 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy). (Process A2-1) The compound [A2-3] or a salt thereof can be produced by reacting the compound [A2-1] or a salt thereof with the compound [A2-2] in a solvent in the presence of an acid catalyst. Examples of the acid catalyst include sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid, and p-toluenesulfonic acid. The preferred acid catalyst is sulfuric acid or p-toluenesulfonic acid. Examples of the solvent include toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. A preferred solvent is toluene. The reaction temperature is, for example, from 0°C to 150°C, preferably from 5°C to 40°C. The compound [A2-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A2-2] is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A2-2) The compound [A2-5] or a salt thereof can be produced by reacting the compound [A2-3] or a salt thereof with the compound [A2-4] or a salt thereof in a solvent in the presence of a base. Examples of bases include triethylamine, diazabicycloundecene, and diisopropylethylamine. Preferred bases are triethylamine or diisopropylethylamine. Examples of the solvent include methanol, ethanol, tetrahydrofuran, and mixtures thereof. The preferred solvent is methanol. The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 20°C. The compound [A2-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A2-3) The compound [A2-6] or a salt thereof can be produced by reacting the compound [A2-5] or a salt thereof in a solvent in the presence of an acid catalyst. Examples of acid catalysts include trifluoroacetic acid, sulfuric acid, and triethylsilyl trifluoromethanesulfonate. A preferred acid catalyst is trifluoroacetic acid. Examples of the solvent include toluene, tetrahydrofuran, dichloromethane, and mixtures thereof. The preferred solvent is toluene. The reaction temperature is, for example, from -78°C to 50°C, preferably from 0°C to 20°C. (Process A2-4) The compound [A2-7] or a salt thereof can be produced by reacting the compound [A2-6] or a salt thereof in a solvent in the presence of a base. Bases include, for example, sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, chloroform, and mixtures thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from 0°C to 150°C, preferably from 50°C to 100°C. (Process A2-5) Compound [IC] or a salt thereof can be prepared by reacting compound [A2-7] or a salt thereof with compound [A2-8] or a salt thereof in a solvent. A base may be added, if necessary. Examples of the solvent include N-methylpyrrolidinone, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof. The preferred solvent is N-methylpyrrolidone. Examples of bases include triethylamine, diisopropylethylamine, and diazabicycloundecene. A preferred base is diisopropylethylamine. The reaction temperature is, for example, from 0°C to 200°C, preferably from 80°C to 180°C. The compound [A2-8] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. In this production method, instead of compound [A2-4] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the ring Cy by a known reaction, or a salt thereof, is used to carry out this production method, and a compound corresponding to compound [IC] or a salt thereof is obtained, and then the functional group or the protected substituent is converted to the various substituents to produce compound [IC] or a salt thereof. For example, instead of compound [A2-4] or a salt thereof, A51 The present production method is carried out using a hydrazine compound or a salt thereof having a phenyl group substituted therewith, to obtain a compound corresponding to compound [IC], i.e., compound [IE] or a salt thereof, and then the compound is subjected to production method A5 to obtain L A51 Cy A51 The compound [IF] or a salt thereof may be prepared by converting the compound [IF] into

[0103] Production method A2A: Production method of compound [IA-C] or a salt thereof Compound [IA-C] or a salt thereof can be produced in the same manner as in production method A2 by using compound [A2A-4] or a salt thereof instead of compound [A2-4] or a salt thereof, and compound [A2A-8] or a salt thereof instead of compound [A2-8] or a salt thereof. [ka] (wherein each symbol is as defined above) The compound [A2A-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A2A-8] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. In this production method, instead of the compound [A2A-4] or a salt thereof, a ring Cy is A The present production method may be carried out using a compound or a salt thereof having a functional group or a protected substituent that can be converted into the above-mentioned various substituents, to obtain a compound or a salt thereof corresponding to compound [IA-C], and then the functional group or the protected substituent may be converted into the various substituents to produce compound [IA-C] or a salt thereof. For example, compound [A2A-4] or a salt thereof may be replaced with L A51 or a salt thereof, to obtain a compound corresponding to compound [IA-C], i.e., compound [IA-E] or a salt thereof, and then subjecting the compound to production process A5A. A51 Cy A51 Compound [IA-F] or a salt thereof may be prepared by converting the compound [IA-F] into the following compound:

[0104] Production method A3: Production method of compound [IC] or a salt thereof The compound [IC] or a salt thereof can be produced, for example, by the following Production Method A3. [ka] {where, Cy, R 2 , and R 3 is as defined above, R A31 and R A32 are each independently 1-4 is alkyl, L A31 is a leaving group (e.g., halogen, and trifluoromethanesulfonyloxy) (Process A3-1) 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 a catalyst and a base. Examples of catalysts include copper(I) iodide and copper(I) bromide. A preferred catalyst is copper(I) iodide. Examples of bases include cesium carbonate and potassium carbonate. A preferred base is cesium carbonate. Examples of the solvent include dimethyl sulfoxide, 1,4-dioxane, and mixtures thereof. The preferred solvent is dimethyl sulfoxide. The reaction temperature is, for example, from 10°C to 200°C, preferably from 120°C to 180°C. The compound [A3-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A3-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A3-2) The compound [A3-5] or a salt thereof can be produced by reacting the compound [A3-3] or a salt thereof with the compound [A3-4] or a salt thereof in a solvent. Examples of the solvent include acetonitrile, dichloromethane, chloroform, and mixtures thereof. A preferred solvent is acetonitrile. The reaction temperature is, for example, 0°C to 80°C, preferably 0°C to 40°C. The compound [A3-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A3-3) The compound [A3-7] or a salt thereof can be produced by reacting the compound [A3-5] or a salt thereof with the compound [A3-6] or a salt thereof in a solvent in the presence of a condensing agent and a base. Examples of bases include triethylamine, diazabicycloundecene, and diisopropylethylamine. A preferred base is triethylamine. Condensation agents include, for example, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N,N'-dicyclohexylcarbodiimide. A preferred condensation agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. Examples of the solvent include chloroform, dichloromethane, tetrahydrofuran, and mixtures thereof. The preferred solvent is chloroform. The reaction temperature is, for example, 0°C to 100°C, preferably 10°C to 50°C. The compound [A3-6] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A3-4) The compound [IC] or a salt thereof can be produced by reacting a compound [A3-7] or a salt thereof in a solvent in the presence of an acid catalyst. Acid catalysts include, for example, trifluoroacetic acid, hydrochloric acid, and sulfuric acid. A preferred acid catalyst is trifluoroacetic acid. Examples of the solvent include water, tetrahydrofuran, and mixtures thereof. The preferred solvent is water. The reaction temperature is, for example, from 0°C to 150°C, preferably from 80°C to 120°C. In this production method, instead of compound [A3-2] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the ring Cy by a known reaction, or a salt thereof, may be used to carry out this production method, to obtain a compound corresponding to compound [IC] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [IC] or a salt thereof. For example, instead of compound [A3-2] or a salt thereof, a compound having L on the benzene ring may be used. A31 and L, which will be described later. A51 or a salt thereof, to obtain a compound corresponding to compound [IC], i.e., compound [IE] or a salt thereof, and then, by Production Method A5, A51 Cy A51 The compound [IF] or a salt thereof may be prepared by converting the compound [IF] into

[0105] Production method A3A: Production method of compound [IA-C] or a salt thereof Compound [IA-C] or a salt thereof can be produced in the same manner as in production method A3 by using compound [A3A-2] or a salt thereof instead of compound [A3-2] or a salt thereof, and compound [A3A-6] or a salt thereof instead of compound [A3-6] or a salt thereof. [ka] (wherein each symbol is as defined above) The compound [A3A-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A3A-6] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. In this production method, instead of the compound [A3A-2] or a salt thereof, a ring Cy is A The present production method may be carried out using a compound or a salt thereof having a functional group or a protected substituent that can be converted to the above-mentioned various substituents, to obtain a compound or a salt thereof corresponding to compound [IA-C], and then the functional group or the protected substituent may be converted to the various substituents to produce compound [IA-C] or a salt thereof. For example, compound [A3A-2] or a salt thereof may be replaced by compound [A3A-3] having L on the benzene ring. A31 and L, which will be described later. A51 or a salt thereof, to obtain a compound corresponding to compound [IA-C], i.e., compound [IA-E] or a salt thereof, and then, by Production Method A5A, A51 Cy A51 Compound [IA-F] or a salt thereof may be prepared by converting the compound [IA-F] into the following compound:

[0106] Production method A4: Production method of compound [ID] or its salt Compound [ID] or a salt thereof can be produced, for example, by the following Production Method A4. [ka] {where, Cy, R 1 , R 2 , and R3 is as defined above, L A41 and L A42 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy). (Process A4-1) The compound [A4-3] or a salt thereof can be produced by reacting the compound [A4-1] or a salt thereof with the compound [A4-2] or a salt thereof in a solvent in the presence of a base. Examples of bases include triethylamine, diisopropylethylamine, and diazabicycloundecene. A preferred base is triethylamine. Examples of the solvent include methanol, ethanol, tetrahydrofuran, toluene, and mixtures thereof. A preferred solvent is ethanol. The reaction temperature is, for example, from -78°C to 150°C, preferably from 0°C to 120°C. The compound [A4-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A4-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. (Process A4-2) The compound [ID] or a salt thereof can be produced by reacting the compound [A4-3] or a salt thereof in a solvent in the presence of a base. Bases include, for example, sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide. Examples of the solvent include water, dioxane, 1,2-dimethoxyethane, and mixtures thereof. A preferred solvent is a mixture of dioxane and water. The reaction temperature is, for example, from 0°C to 150°C, preferably from 80°C to 120°C. In this production method, instead of compound [A4-2] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the ring Cy by a known reaction, or a salt thereof, is used to carry out this production method, and a compound corresponding to compound [ID] or a salt thereof is obtained, and then the functional group or the protected substituent is converted to the various substituents to produce compound [ID] or a salt thereof. For example, instead of compound [A4-2] or a salt thereof, A51 The present production method is carried out using a hydrazine compound or a salt thereof having a phenyl group substituted therewith, to obtain a compound corresponding to compound [ID], i.e., compound [IE] or a salt thereof, and then the compound is subjected to production method A5 to obtain L A51 Cy A51 The compound [IF] or a salt thereof may be prepared by converting the compound [IF] into

[0107] Production method A4A: Production method of compound [IA-D] or a salt thereof Compound [IA-D] or a salt thereof can be produced in the same manner as in production method A4 by using compound [A4A-1] or a salt thereof instead of compound [A4-1] or a salt thereof, and compound [A4A-2] or a salt thereof instead of compound [A4-2] or a salt thereof. [ka] (wherein each symbol is as defined above) The compound [A4A-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A4A-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. In this production method, instead of the compound [A4A-2] or a salt thereof, a ring Cy is A The present production method may be carried out using a compound or a salt thereof having a functional group or a protected substituent that can be converted into the above-mentioned various substituents, to obtain a compound or a salt thereof corresponding to compound [IA-D], and then the functional group or the protected substituent may be converted into the various substituents to produce compound [IA-D] or a salt thereof. For example, compound [A4A-2] or a salt thereof may be replaced with LA51 or a salt thereof, to obtain a compound corresponding to compound [IA-D], i.e., compound [IA-E] or a salt thereof, and then subjecting the compound to production process A5A. A51 Cy A51 Compound [IA-F] or a salt thereof may be prepared by converting the compound [IA-F] into the following compound:

[0108] Production method A5: Production method of compound [IF] or a salt thereof The compound [IF] or a salt thereof can be produced, for example, by the following Production Method A5. [ka] {where, R 2 and R 3 is as defined above, Cy A51 is C 3-6 Cycloalkyl, where the cycloalkyl is C 1-4 substituted with haloalkyl; L A51 is a leaving group (e.g., halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy), provided that the leaving group is attached at the ortho or para position of the benzene ring. (Process A5-1) Compound [IF] or a salt thereof can be produced by reacting compound [IE] or a salt thereof with compound [A5-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. A preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. Examples of bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate. Examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixtures thereof. A preferred solvent is a mixture of toluene and water. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [IE] or a salt thereof may be produced from a commercially available product by a known method. The compound [IE] or a salt thereof may be produced, for example, by the above-mentioned production method. The compound [A5-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.

[0109] Production method A5A: Production method of compound [IA-F] or a salt thereof Compound [IA-F] or a salt thereof can be produced in the same manner as in Production Method A5 by using compound [IA-E] or a salt thereof instead of compound [IE] or a salt thereof. [ka] (wherein each symbol is as defined above) The compound [IA-E] or a salt thereof may be prepared from a commercially available product by a known method. The compound [IA-E] or a salt thereof may be prepared, for example, by the above-mentioned preparation method. EXAMPLES

[0110] Next, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof will be specifically described with reference to Preparation Examples. However, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof is not limited to these Preparation Examples. NMR was measured at 400 MHz.

[0111] [Production Example 1]: Synthesis of 6-(pyrrolidin-1-yl)-2-(o-tolyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 3) [ka] Step 1-1: 4-chloro-6-(pyrrolidin-1-yl)-2-(o-tolyl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, 4,6-dichloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbaldehyde (200 mg) was added to a mixture of o-tolylhydrazine (120 mg), triethylamine (0.23 mL), and ethanol (4.0 mL) at -78°C, and the mixture was stirred overnight while naturally warming to room temperature. Water was added to the reaction mixture, and then it was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (97 mg). 1 H-NMR (CDCl3) δ: 7.96 (1H, s), 7.41-7.28 (4H, m), 3.70-3.69 (4H, m), 2.32 (3H, s), 2.01-1.97 (4H, m). Step 1-2: 6-(pyrrolidin-1-yl)-2-(o-tolyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of 4-chloro-6-(pyrrolidin-1-yl)-2-(o-tolyl)-2H-pyrazolo[3,4-d]pyrimidine (97 mg) and 1,2-dimethoxyethane (1.5 mL), 2 M aqueous sodium hydroxide solution (1.5 mL) was added and stirred at 110°C for 6 hours. The reaction mixture was allowed to cool to room temperature and neutralized with 2 M hydrochloric acid. The resulting mixture was extracted with a mixture of ethyl acetate / tetrahydrofuran, washed with saturated saline, and the solvent was distilled off under reduced pressure. The residual ethyl acetate / hexane mixture was stirred at room temperature for 10 minutes, and the resulting solid was collected by filtration to give the title compound (55 mg). 1 H-NMR (DMSO-D6) δ: 10.53 (1H, br s), 8.50 (1H, s), 7.41-7.32 (4H, m), 3.47-3.46 (4H, m), 2.23 (3H, s), 1.90-1.87 (4H, m). LC-MS (MH+): 296.

[0112] [Production Example 2]: Synthesis of 2-(2,6-dichlorophenyl)-6-(pyrrolidin-1-yl)-2,5-dihydro-4H-pyrazole[3,4-d]pyrimidin-4-one (Example 30) [ka] Step 2-1: 2-(2,6-dichlorophenyl)-6-(pyrrolidin-1-yl)-2,5-dihydro-4H-pyrazole[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 4,6-dichloro-2-(pyrrolidin-1-yl)pyrimidine-5-carbaldehyde (80 mg) was added to a mixture of (2,6-dichlorophenyl)hydrazine hydrochloride (76 mg), triethylamine (0.14 mL), and ethanol (1.6 mL) at 0°C, and the mixture was stirred under heating and reflux for 3 hours, after which the solvent was distilled off under reduced pressure. The residue was mixed with acetic acid (2.0 mL) and stirred under heating and reflux for 3 hours, after which the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) and then solidified with a mixture of ethyl acetate / hexane to obtain the title compound (26 mg). 1 H-NMR (DMSO-D6) δ: 10.60 (1H, br s), 8.57 (1H, s), 7.71 (2H, dd, J = 8.2, 0.8 Hz), 7.60 (1H, dd, J = 8.9, 7.3 Hz), 3.48-3.46 (4H, m), 1.90-1.87 (4H, m). LC-MS (MH+): 350.

[0113] [Production Example 3]: Synthesis of 2-(4-bromo-2-methylphenyl)-5-methyl-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 88) [ka] Step 3-1: 4-(2-(4-bromo-2-methylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] 2,4,6-Trichloro-5-(dimethoxymethyl)pyrimidine (1.5 g) synthesized in the same manner as in step 5-1 of Production Example 5 was added to a mixture of (4-bromo-2-methylphenyl)hydrazine hydrochloride (1.4 g), triethylamine (2.4 mL), and methanol (30 mL) under an argon atmosphere at 0° C., and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (2.4 g). 1 H-NMR (CDCl3) δ: 8.31 (1H, d, J = 4.6 Hz), 7.24-7.23 (1H, m), 7.19 (1H, d, J = 8.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.15 (1H, d, J = 4.6 Hz), 5.64 (1H, d, J = 0.7 Hz), 3.52 (6H, s), 2.29 (3H, s). Step 3-2: 2-(4-bromo-2-methylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] To a mixture of 4-(2-(4-bromo-2-methylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (2.4 g) and tetrahydrofuran (50 mL), trifluoroacetic acid (10 mL) was added and stirred at room temperature for 10 minutes. After removing the solvent under reduced pressure, the obtained solid was washed with a mixture of hexane / ethyl acetate (v / v = 1 / 1) to obtain the title compound (1.4 g). 1 H-NMR (DMSO-D6) δ: 9.39 (1H, s), 7.78 (1H, d, J = 2.1 Hz), 7.66 (1H, dd, J = 8.6, 2.3 Hz), 7.54 (1H, d, J = 8.6 Hz), 2.22 (3H, s). Step 3-3: 2-(4-bromo-2-methylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyridin-4-one [ka] A mixture of 2-(4-bromo-2-methylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine (1.0 g) and tetrahydrofuran (20 mL) was added with 2M aqueous sodium hydroxide solution (5.6 mL) and stirred at 80°C for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid, water was added, and the resulting solid was filtered. The obtained solid was purified by slurrying with ethanol to obtain the title compound (920 mg). 1 H-NMR (DMSO-D6) δ: 12.86 (1H, br s), 8.91 (1H, s), 7.71 (1H, d, J = 2.1 Hz), 7.59 (1H, dd, J = 8.4, 2.2 Hz), 7.43 (1H, d, J = 8.3 Hz), 2.20 (3H, s). LC-MS (MH+): 341. Step 3-4: 2-(4-bromo-2-methylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Morpholine (64 mg) was added to a mixture of 2-(4-bromo-2-methylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyridin-4-one (50 mg) and tetrahydrofuran (1.0 mL), and the mixture was stirred at 80°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The solid obtained was washed with hexane / ethyl acetate (v / v = 1 / 1) to give the title compound (56 mg). 1H-NMR (CDCl3) δ: 10.17 (1H, br s), 8.07 (1H, s), 7.49 (1H, d, J = 1.8 Hz), 7.44-7.42 (1H, m), 7.27 (1H, s), 3.81-3.80 (4H, m), 3.69-3.68 (4H, m), 2.29 (3H, s). LC-MS (MH+): 390. Step 3-5: 2-(4-bromo-2-methylphenyl)-5-methyl-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, sodium hydride (60% in oil, 4.3 mg) was added to a mixture of 2-(4-bromo-2-methylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (28 mg) and N,N-dimethylformamide (0.56 mL), and the mixture was stirred at room temperature for 2 hours. After that, methyl iodide (0.013 mL) was added and the mixture was stirred for 2 hours. Acetic acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (hexane / ethyl acetate) to obtain the title compound (6 mg). 1 H-NMR (CDCl3) δ: 8.15 (1H, s), 7.51 (1H, d, J = 2.1 Hz), 7.45 (1H, dd, J = 8.8, 2.1 Hz), 7.27 (1H, d, J = 8.8 Hz), 3.90-3.85 (4H, m), 3.57 (3H, s), 3.32-3.26 (4H, m), 2.30 (3H, s). LC-MS (MH+): 404.

[0114] [Production Example 4]: Synthesis of 4-(2-(4-bromo-2-methylphenyl)-4-methoxy-2H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine (Example 89) [ka] Step 4-1: 4-(2-(4-bromo-2-methylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] 2,4,6-Trichloro-5-(dimethoxymethyl)pyrimidine (1.5 g) synthesized in the same manner as in Step 5-1 of Production Example 5 was added to a mixture of (4-bromo-2-methylphenyl)hydrazine hydrochloride (1.4 g) and triethylamine (2.4 mL) in methanol (30 mL) at 0°C under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (2.4 g). 1 H-NMR (CDCl3) δ: 8.31 (1H, d, J = 4.6 Hz), 7.24-7.23 (1H, m), 7.19 (1H, d, J = 8.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 6.15 (1H, d, J = 4.6 Hz), 5.64 (1H, d, J = 0.7 Hz), 3.52 (6H, s), 2.29 (3H, s). Step 4-2: 2-(4-bromo-2-methylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] To a mixture of 4-(2-(4-bromo-2-methylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (2.4 g) and tetrahydrofuran (50 mL), trifluoroacetic acid (10 mL) was added and stirred at room temperature for 10 minutes. After removing the solvent under reduced pressure, the obtained solid was washed with a mixture of hexane / ethyl acetate (v / v = 1 / 1) to obtain the title compound (1.4 g). 1H-NMR (DMSO-D6) δ: 9.39 (1H, s), 7.78 (1H, d, J = 2.1 Hz), 7.66 (1H, dd, J = 8.6, 2.3 Hz), 7.54 (1H, d, J = 8.6 Hz), 2.22 (3H, s). Step 4-3: 2-(4-bromo-2-methylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyridin-4-one [ka] A mixture of 2-(4-bromo-2-methylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine (1.0 g) and tetrahydrofuran (20 mL) was added with 2M aqueous sodium hydroxide solution (5.6 mL) and stirred at 80°C for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid, water was added, and the resulting solid was filtered. The obtained solid was purified by slurrying with ethanol to obtain the title compound (920 mg). 1 H-NMR (DMSO-D6) δ: 12.86 (1H, br s), 8.91 (1H, s), 7.71 (1H, d, J = 2.1 Hz), 7.59 (1H, dd, J = 8.4, 2.2 Hz), 7.43 (1H, d, J = 8.3 Hz), 2.20 (3H, s). LC-MS (MH+): 341. Step 4-4: 2-(4-bromo-2-methylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Morpholine (64 mg) was added to a mixture of 2-(4-bromo-2-methylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyridin-4-one (50 mg) and tetrahydrofuran (1.0 mL), and the mixture was stirred at 80°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The solid obtained was washed with hexane / ethyl acetate (v / v = 1 / 1) to give the title compound (56 mg). 1 H-NMR (CDCl3) δ: 10.17 (1H, br s), 8.07 (1H, s), 7.49 (1H, d, J = 1.8 Hz), 7.44-7.42 (1H, m), 7.27 (1H, s), 3.81-3.80 (4H, m), 3.69-3.68 (4H, m), 2.29 (3H, s). LC-MS (MH+): 390. Step 4-5: 4-(2-(4-bromo-2-methylphenyl)-4-methoxy-2H-pyrazolo[3,4-d]pyrimidin-6-yl)morpholine [ka] Under an argon atmosphere, sodium hydride (60% in oil, 4.3 mg) was added to a mixture of 2-(4-bromo-2-methylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (28 mg) and N,N-dimethylformamide (0.56 mL), and the mixture was stirred at room temperature for 2 hours. After that, methyl iodide (0.013 mL) was added and the mixture was stirred for 2 hours. Acetic acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (hexane / ethyl acetate) to give the title compound (13 mg). 1H-NMR (CDCl3) δ: 7.89 (1H, s), 7.50 (1H, d, J = 2.0 Hz), 7.43 (1H, dd, J = 8.3, 2.0 Hz), 7.28 (1H, d, J = 8.3 Hz), 4.08 (3H, s), 3.96-3.91 (4H, m), 3.81-3.76 (4H, m), 2.30 (3H, s). LC-MS (MH+): 404.

[0115] [Production Example 5]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 94) [ka] Step 5-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (300 mL) and sulfuric acid (0.63 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (100 g) and toluene (600 mL), and the mixture was stirred at room temperature for 1.5 hours. Basic silica gel (Fujisilica, 200 g) was added to the reaction mixture, and after stirring for 1 hour, the added silica gel was removed by filtration. After washing the silica gel with ethyl acetate (1.5 L), the solvent was removed under reduced pressure to obtain the title compound (108 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s). Step 5-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (61 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (60 g) and methanol (420 mL), and the reaction mixture was cooled to 2°C or less in an ice bath. Triethylamine (100 mL) was added to the reaction mixture over 25 minutes while maintaining the temperature at 9°C or less, and the mixture was stirred at the same temperature for 3 hours. The resulting solid was collected by filtration and washed successively with methanol (150 mL) and hexane (100 mL) to obtain the title compound (93.3 g). 1 H-NMR (CDCl3) δ: 8.28 (1H, d, J = 4.4 Hz), 7.10 (2H, s), 6.14 (1H, d, J = 4.9 Hz), 5.56 (1H, s), 3.45 (6H, s), 2.43 (6H, s). LC-MS (MH+): 436. Step 5-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] Under a nitrogen atmosphere, trifluoroacetic acid (33 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (93.3 g) and toluene (750 mL) over 40 minutes while maintaining the temperature at 24°C or lower. The reaction mixture was stirred for another hour, and then slowly added dropwise to an ice-cooled mixture of tripotassium phosphate (91 g) in water / tetrahydrofuran (300 mL / 500 mL) over 20 minutes while maintaining the temperature at 10°C or lower. After separating the organic layer, saturated saline was added to the aqueous layer, and the mixture was extracted with ethyl acetate. All the organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (80.9 g). LC-MS (MH+): 372. Step 5-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine crude product (80.9 g) and tetrahydrofuran (640 mL) was added with 4 M aqueous sodium hydroxide solution (160 mL) at room temperature and stirred at 66°C for 5 hours. The reaction mixture was cooled to below 2°C in an ice bath, and 2 M hydrochloric acid (220 mL) was slowly added dropwise while keeping the temperature below 12°C. The reaction mixture was extracted with ethyl acetate and washed with saturated saline. All the aqueous layers obtained were washed with ethyl acetate and then with saturated saline. All the aqueous layers were combined and extracted again with a mixture of ethyl acetate / tetrahydrofuran (v / v = 3 / 1), and then washed with saturated saline. All the organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained crude product, diisopropyl ether (650 mL) was added and stirred for 30 minutes, and then the solid was collected by filtration to obtain the title compound (68.6 g). 1 H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 8.81 (1H, s), 7.53 (2H, s), 1.95 (6H, s). LC-MS (MH+): 354. Step 5-5: 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one acetone solvate [ka] Under a nitrogen atmosphere, morpholine (49 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (66.6 g) and 1-methylpyrrolidin-2-one (270 mL), and the mixture was stirred at 105°C for 1 hour, then cooled to 55°C in a water bath. Water (1000 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration and washed successively with water and hexane to obtain the crude product of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (65.5 g). 1-Methylpyrrolidin-2-one (160 mL) was added to the crude product of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (65.5 g), and the mixture was stirred at 85°C for 40 minutes, after which the resulting solution was filtered to remove dust while hot. While stirring the resulting solution at 65°C, acetone (1000 mL) was added over 40 minutes, and then water (390 mL) was slowly added dropwise over 20 minutes. The resulting mixture was stirred overnight while being allowed to cool. The resulting solid was collected by filtration and washed with an acetone / water mixture (v / v = 1 / 2, 100 mL). The resulting solid was stirred in a mixture of ethanol / acetone (v / v = 1 / 2, 840 mL) at 63°C for 2 hours, then stirred overnight while cooling. The solid was collected by filtration and washed with a mixture of ethanol / acetone (v / v = 1 / 1, 50 mL) to give a mixture of the title compound and 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (56.5 g). 1 H-NMR (DMSO-D6) δ: 10.95 (1H, br s), 8.49 (1H, s), 7.49 (2H, s), 3.65-3.64 (4H, m), 3.53-3.52 (4H, m), 2.07 (6H, s), 1.96 (6H, s). Step 5-6: 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one acetone solvate and 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (56.5 g) was ball milled (wet with acetone) and then dehydrated by desolvation and vacuum drying under heating (90°C) to obtain crystals of the title compound (49.1 g). 1 H-NMR (DMSO-D6) δ: 10.95 (1H, br s), 8.50 (1H, s), 7.49 (2H, s), 3.65-3.64 (4H, m), 3.53-3.52 (4H, m), 1.96 (6H, s). LC-MS (MH+):404.

[0116] [Production Example 6]: Synthesis of 2-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 98) [ka] Step 6-1: methyl 3-amino-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate [ka] To a mixture of methyl 3-amino-1H-pyrazole-4-carboxylate (300 mg) and dimethyl sulfoxide (2.0 mL), 5-bromo-4-methyl-2-(trifluoromethyl)pyridine (510 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.13 mL), copper (I) iodide (81 mg), and cesium carbonate (690 mg) were added and stirred at 140°C overnight. The reaction mixture was allowed to cool to room temperature, and then methyl iodide (0.27 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography (eluent: hexane / ethyl acetate) to obtain the title compound (89 mg). 1 H-NMR (CDCl3) δ: 8.65 (1H, s), 7.88 (1H, s), 7.62 (1H, s), 4.85 (2H, br s), 3.85 (3H, s), 2.49 (3H, s). Step 6-2: Methyl 3-(3-(ethoxycarbonyl)thioureido)-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate [ka] Under an argon atmosphere, ethoxycarbonyl isothiocyanate (0.042 mL) was added to a mixture of methyl 3-amino-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate (89 mg) and acetonitrile (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure to give the crude product of the title compound (128 mg). LC-MS (MH+): 432. Step 6-3: methyl 3-((((ethoxycarbonyl)amino)(morpholino)methylene)amino)-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate [ka] To a mixture of the crude product of methyl 3-(3-(ethoxycarbonyl)thioureido)-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate (64 mg) and chloroform (2.0 mL), morpholine (0.021 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg), and triethylamine (0.052 mL) were added, and the mixture was stirred at room temperature for 3 hours, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (60 mg). LC-MS (MH+): 485. Step 6-4: 2-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Water (0.5 mL) and trifluoroacetic acid (2.0 mL) were added to methyl 3-((((ethoxycarbonyl)amino)(morpholino)methylene)amino)-1-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-carboxylate (60 mg), and the mixture was stirred at 120°C overnight. After the solvent was removed under reduced pressure, tetrahydrofuran (2.0 mL) and a saturated aqueous solution of sodium bicarbonate (6.0 mL) were added, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate), and the obtained solid was washed with a mixed solution of ethyl acetate / diisopropyl ether to give the title compound (27 mg). 1 H-NMR (DMSO-D6) δ: 11.02 (1H, br s), 8.84 (1H, s), 8.83 (1H, s), 8.08 (1H, s), 3.66-3.65 (4H, m), 3.56-3.55 (4H, m), 2.46 (3H, s). LC-MS (MH+): 381.

[0117] [Production Example 7]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 124) [ka] Step 7-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (230 mL) and sulfuric acid (0.48 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (76 g) and toluene (450 mL), and the mixture was stirred at room temperature for 1.5 hours. Basic silica gel (Fuji Silysia Chemical Co., Ltd., 150 g) was added to the reaction mixture, and after stirring for 1 hour, the added silica gel was removed by filtration. After washing the silica gel with ethyl acetate (1.2 L), the solvent was distilled off under reduced pressure to obtain the title compound (82 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s). Step 7-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (46 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (45 g) and methanol (320 mL), and the reaction mixture was cooled to below 2°C in an ice bath. Triethylamine (75 mL) was slowly added to the reaction mixture while keeping the temperature below 9°C, and the mixture was stirred at the same temperature for 2 hours. The resulting solid was collected by filtration and washed successively with methanol (120 mL) and hexane (100 mL) to obtain the title compound (69.8 g). 1H-NMR (CDCl3) δ: 8.28 (1H, d, J = 4.4 Hz), 7.10 (2H, s), 6.14 (1H, d, J = 4.9 Hz), 5.56 (1H, s), 3.45 (6H, s), 2.43 (6H, s). LC-MS (MH+): 436. Step 7-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] Under a nitrogen atmosphere, trifluoroacetic acid (25 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (69.8 g) and toluene (560 mL) over 40 minutes while maintaining the temperature below 24°C. The reaction mixture was stirred for another hour, and then slowly added dropwise to an ice-cooled solution of tripotassium phosphate (68 g) in water (230 mL) over 10 minutes while maintaining the temperature below 10°C. The reaction mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of the title compound (61.8 g). LC-MS (MH+): 372. Step 7-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine crude product (59.5 g) and tetrahydrofuran (480 mL) was added with 4 M aqueous sodium hydroxide solution (120 mL) at room temperature and stirred at 65°C for 4 hours. The reaction mixture was cooled to below 2°C in an ice bath, and 2 M hydrochloric acid (220 mL) was slowly added dropwise while keeping the temperature below 10°C. The reaction mixture was extracted with ethyl acetate, and then washed with a mixture of saturated aqueous sodium bicarbonate and saturated saline (v / v = 1 / 1) and saturated saline in that order. All the aqueous layers used for washing were extracted with a mixture of ethyl acetate and tetrahydrofuran (v / v = 2 / 1). All the obtained organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether (600 mL) was added to the obtained crude product and stirred for 1 hour, and then the solid was collected by filtration and washed with diisopropyl ether (200 mL) to obtain the title compound (51.7 g). 1 H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 8.81 (1H, s), 7.53 (2H, s), 1.95 (6H, s). LC-MS (MH+): 354. Step 7-5: 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under a nitrogen atmosphere, morpholine (38 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (51.7 g) and 1-methylpyrrolidin-2-one (210 mL), and the mixture was stirred at 105°C for 1.5 hours, then cooled to 55°C in a water bath. Water (800 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After stirring in a water bath for an additional hour, the resulting solid was filtered and washed with water and hexane in turn. The mixture of the obtained solid and methanol (130 mL) was stirred at 65°C for 3 hours, gradually cooled to room temperature over 2 hours, and then stirred at room temperature for an additional hour. The solid was filtered and washed with methanol to obtain the title compound (47.1 g). 1 H-NMR (DMSO-D6) δ: 10.95 (1H, br s), 8.50 (1H, s), 7.49 (2H, s), 3.65-3.64 (4H, m), 3.53-3.52 (4H, m), 1.96 (6H, s). LC-MS (MH+): 404. Step 7-6: 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a solution of tripotassium phosphate (32 g) in water (40 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (20 g), cyclopropylboronic acid (12 g), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (970 mg), and toluene (200 mL), and the mixture was stirred at 90°C for 2 hours, after which tetrahydrofuran (250 mL) was added at 60°C and the mixture was allowed to cool to room temperature. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. After washing all the organic layers with saturated saline, tetrahydrofuran (50 mL) was added and the mixture was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate. After filtering off the anhydrous sodium sulfate and anhydrous magnesium sulfate, N1-(2-aminoethyl)ethane-1,2-diamine (2.0 mL) was added and stirred for 30 minutes, and silica gel (Kanto Chemical Co., Ltd., silica gel 60N, 40 g) was added and stirred at room temperature for 1.5 hours. The silica gel was filtered off and washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (23.2 g). The crude title compounds (5.5 g and 23.9 g, respectively) were obtained by the same procedure using 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5 g and 20 g). A mixture of the obtained crude product of the title compound (40.6 g) and methanol (200 mL) was stirred at 65°C for 4 hours, and then stirred at room temperature for 3 hours. The solid collected by filtration was washed with methanol (50 mL). A mixture of the obtained solid and methanol (200 mL) was stirred at 65°C for 4 hours, and then stirred at room temperature for 2.5 hours. The solid collected by filtration was washed with methanol (40 mL). A mixture of the obtained solid and methanol (260 mL) was stirred at 70°C for 8 hours, and then stirred at room temperature for 1 hour. The solid collected by filtration was washed with methanol (20 mL). A mixture of the obtained solid and ethyl acetate (460 mL) was stirred at 70°C for 4 hours, and then at room temperature for 2 hours. The collected solid was washed with ethyl acetate (50 mL) to obtain the title compound (26.2 g). 1 H-NMR (CDCl3) δ: 9.87 (1H, br s), 7.92 (1H, s), 6.84 (2H, s), 3.86-3.79 (4H, m), 3.75-3.68 (4H, m), 2.03 (6H, s), 1.93-1.84 (1H, m), 1.04-0.96 (2H, m), 0.76-0.70 (2H, m). LC-MS (MH+): 366.

[0118] [Production Example 8]: Synthesis of 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 209) [ka] Step 8-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (75 mL) and sulfuric acid (0.16 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (25 g) and toluene (150 mL), and the mixture was stirred at room temperature for 1 hour. Basic silica gel (Fuji Silysia Chemical Co., Ltd., 50 g) was added to the reaction mixture, and after stirring for 30 minutes, the added silica gel was removed by filtration. After washing the silica gel with ethyl acetate (150 mL), the solvent was distilled off under reduced pressure to obtain the title compound (29 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s). Step 8-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (16 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (16 g) and methanol (160 mL), and then triethylamine (27 mL) was added over 5 minutes while keeping the temperature below 40°C, and the mixture was stirred at the same temperature for 1 hour. The resulting solid was collected by filtration and washed with methanol (150 mL) to obtain the title compound (21 g). 1H-NMR (CDCl3) δ: 8.28 (1H, d, J = 4.4 Hz), 7.10 (2H, s), 6.14 (1H, d, J = 4.9 Hz), 5.56 (1H, s), 3.45 (6H, s), 2.43 (6H, s). LC-MS (MH+): 436. Step 8-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] Under a nitrogen atmosphere, trifluoroacetic acid (21 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (21 g) and toluene (170 mL) over 5 minutes while maintaining the temperature below 30° C. The reaction mixture was stirred for an additional 30 minutes, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (24.5 g). LC-MS (MH+): 372. Step 8-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] To a mixture of crude 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine (24.5 g) and tetrahydrofuran (180 mL), 2 M aqueous sodium hydroxide solution (100 mL) was added at room temperature and stirred at 65°C for 1.5 hours. 2 M hydrochloric acid (100 mL) was slowly added dropwise to the reaction mixture while keeping the temperature below 30°C. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether (130 mL) was added to the obtained crude product and stirred for 20 minutes, and the solid was filtered to obtain the title compound (12 g). 1H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 8.81 (1H, s), 7.53 (2H, s), 1.95 (6H, s). LC-MS (MH+): 354. Step 8-5: 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(4-bromo-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (60 mg) and 1-methylpyrrolidin-2-one (1.2 mL) was added with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (35 mg) and triethylamine (0.071 mL), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was purified by reversed-phase C18 column chromatography (developing solvent: acetonitrile / water) to obtain the title compound (80 mg). 1 H-NMR (DMSO-D6) δ: 10.82 (1H, s), 8.47 (1H, s), 7.50 (2H, s), 4.97 (1H, s), 4.65 (1H, s), 3.81-3.72 (2H, m), 3.52 (1H, dd, J = 10.2, 1.0 Hz), 3.41-3.38 (1H, m), 1.98 (6H, s), 1.93-1.83 (2H, m). LC-MS (MH+): 416. Step 8-6: 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(4-bromo-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (71 mg), cyclopropylboronic acid (44 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (28 mg), and 1,2-dimethoxyethane (2.1 mL) were added with 2M potassium phosphate aqueous solution (0.26 mL) and stirred at 100°C for 2 hours, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: methanol / ethyl acetate) and reversed-phase C18 column chromatography (developing solvent: acetonitrile / water) to obtain the title compound (29 mg). 1 H-NMR (DMSO-D6) δ: 10.79 (1H, s), 8.38 (1H, d, J = 1.2 Hz), 6.92 (2H, s), 4.96 (1H, s), 4.65 (1H, s), 3.76 (2H, dd, J = 11.9, 7.5 Hz), 3.51 (1H, d, J = 10.6 Hz), 3.39 (1H, d, J = 10.9 Hz), 1.93-1.83 (9H, m), 0.97 (2H, dd, J = 13.4, 4.9 Hz), 0.72 (2H, q, J = 5.0 Hz). LC-MS (MH+): 378.

[0119] [Production Example 9]: Synthesis of 2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 298) [ka] Step 9-1: 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene [ka] Under an argon atmosphere, cesium carbonate (2.9 g) and sodium chlorodifluoroacetate (2.3 g) were added to a mixture of 3,5-dimethyl-4-nitrophenol (1.0 g) and N,N-dimethylformamide (10 mL), and the mixture was stirred at 100°C for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The resulting organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (750 mg). 1 H-NMR (CDCl3) δ: 6.87 (2H, s), 6.51 (1H, t, J = 73.1 Hz), 2.32 (6H, s). Step 9-2: 4-(difluoromethoxy)-2,6-dimethylaniline [ka] To a mixture of 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene (750 mg) and ethanol (10 mL), 10% palladium carbon (75 mg) was added and stirred overnight at room temperature under a hydrogen atmosphere (normal pressure). The palladium catalyst was removed by filtration through Celite, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (720 mg). 1 H-NMR (CDCl3) δ: 6.74 (2H, s), 6.35 (1H, t, J = 75.1 Hz), 3.50 (2H, br s), 2.16 (6H, s). Step 9-3: (4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazine hydrochloride [ka] To a mixture of 4-(difluoromethoxy)-2,6-dimethylaniline (720 mg) and 6 M hydrochloric acid (3.6 mL), concentrated hydrochloric acid (2.1 mL) was added, and the mixture was cooled to -16°C. To the reaction mixture at the same temperature, sodium nitrite (280 mg) aqueous solution (7.2 mL) was slowly added dropwise over 3 minutes, and the mixture was stirred for an additional 70 minutes. To the reaction mixture at the same temperature, a solution of tin(II) chloride dihydrate (1.8 g) in concentrated hydrochloric acid (1.6 mL) was added dropwise over 5 minutes, and the mixture was stirred for 1 hour, after which the refrigerant was removed and the mixture was stirred for an additional 2 hours. The resulting solid was filtered and washed with a small amount of 2 M hydrochloric acid and diisopropyl ether to obtain the title compound (560 mg). 1 H-NMR (DMSO-D6) δ: 9.49 (3H, br s), 7.19 (1H, t, J = 74.1 Hz), 6.93 (2H, s), 6.77 (1H, br s), 2.37 (6H, s). Step 9-4: 2,4-dichloro-6-(2-(4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazinyl)-5-(dimethoxymethyl)pyrimidine [ka] Under an argon atmosphere, triethylamine (0.98 mL) was added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (600 mg) synthesized in the same manner as in Step 5-1 of Production Example 5, (4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazine hydrochloride (560 mg), and methanol (5.6 mL), and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, ethyl acetate was added, and the resulting salt was removed using Celite to obtain the crude product of the title compound. LC-MS (MH+): 423. Step 9-5: 4,6-dichloro-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, trifluoroacetic acid (1.0 mL) was added dropwise to a mixture of the crude product of 2,4-dichloro-6-(2-(4-(difluoromethoxy)-2,6-dimethylphenyl)hydrazinyl)-5-(dimethoxymethyl)pyrimidine and toluene (7.9 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 4 M aqueous sodium hydroxide solution and then extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound. LC-MS (MH+): 359. Step 9-6: 6-chloro-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of the crude product of 4,6-dichloro-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine and tetrahydrofuran (8.4 mL) was added with 2 M aqueous sodium hydroxide solution (4.7 mL) and stirred at 85°C for 1.5 hours. The reaction mixture was neutralized with 2 M hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate), and the obtained solid was washed with diisopropyl ether to obtain the title compound (150 mg). 1 H-NMR (DMSO-D6) δ: 12.87 (1H, br s), 8.80 (1H, s), 7.31 (1H, t, J = 73.8 Hz), 7.11 (2H, s), 1.96 (6H, s). Step 9-7: 2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, morpholine (0.023 mL) was added to a mixture of 6-chloro-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (30 mg) and 1-methylpyrrolidin-2-one (1.0 mL), and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was purified by column chromatography (developing solvent: hexane / ethyl acetate), and the resulting solid was washed with water to obtain the title compound (14 mg). 1 H-NMR (DMSO-D6) δ: 10.94 (1H, br s), 8.48 (1H, s), 7.29 (1H, t, J = 73.8 Hz), 7.07 (2H, s), 3.66-3.64 (4H, m), 3.54-3.52 (4H, m), 1.97 (6H, s). LC-MS (MH+): 392.

[0120] [Production Example 10]: Synthesis of (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride [ka] Step 10-1: Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under an argon atmosphere, N,N-diisopropylethylamine (38.2 mL) and benzyl chloroformate (14.2 mL) were slowly added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (25 g) in tetrahydrofuran (250 mL) at 0°C over 2 minutes, and the mixture was stirred at room temperature for 1 hour. Hexane (100 mL) was added to the reaction mixture, which was then washed with water (100 mL) and saturated saline solution in that order. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the mixture was stirred for 20 minutes. The resulting solid was collected by filtration to give the title compound (30.3 g). 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). Step 10-2: Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under an argon atmosphere, tripotassium phosphate (21.3 g) was dissolved in water (40 mL), and toluene (100 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate (10 g), cyclopropylboronic acid (6.91 g), and bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (700 mg) were added and stirred at 105°C for 4 hours. The reaction mixture was allowed to cool to room temperature, neutralized with 6 M hydrochloric acid (40 mL), and extracted twice with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. ISOLUTE Si-TMT (metal scavenging silica gel, Biotage, 0.49 mmol TMT / g, 5.25 g) was added to the organic layer, and the mixture was stirred at room temperature for 1.5 hours. The silica gel was then filtered off, and the solvent was removed under reduced pressure. Hexane (50 mL) was added to the residue, and the mixture was stirred. The resulting solid was filtered off to obtain the title compound (6.3 g). 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). Step 10-3: (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride [ka] Under an argon atmosphere, 4 M aqueous sodium hydroxide solution (48 mL) was added to a mixture of benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate (6.0 g) in ethanol (48 mL) and stirred at 80°C for 4 hours. After cooling the reaction mixture, acetic acid (5.5 mL) was added and the mixture was extracted twice with toluene. The organic layer was dried over anhydrous magnesium sulfate and concentrated to approximately 1 / 3 of the original volume. A 4 M solution of hydrogen chloride in dioxane (4.6 mL) was added to the mixture and stirred at room temperature for 10 minutes. The resulting solid was filtered and washed with hexane to obtain the title compound (3.7 g). 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).

[0121] [Production Example 11]: Synthesis of 2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-6-(pyrrolidin-1-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 343) [ka] Step 11-1: 4-iodo-1-isopropyl-3,5-dimethyl-1H-pyrazole [ka] To a mixture of 4-iodo-3,5-dimethyl-1H-pyrazole (2.0 g) and N,N-dimethylformamide (20 mL), cesium carbonate (7.0 g) and 2-iodopropane (1.1 mL) were added and stirred at room temperature overnight. The reaction mixture was stirred at 50 °C for an additional 2 hours, water was added, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the title compound (2.1 g). 1H-NMR (DMSO-D6) δ: 4.53-4.44 (1H, m), 2.23 (3H, s), 2.09 (3H, s), 1.31 (6H, d, J = 6.5 Hz). Step 11-2: Di-tert-butyl 1-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate [ka] A 1.56 M n-butyllithium hexane solution (3.2 mL) was added to a mixture of 4-iodo-1-isopropyl-3,5-dimethyl-1H-pyrazole (1.0 g) and tetrahydrofuran (20 mL) at -78 °C under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. Di-tert-butyl (E)-diazene-1,2-dicarboxylate (1.3 g) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (1.0 g). LC-MS (MH+): 369. Step 11-3: 4-hydrazinyl-1-isopropyl-3,5-dimethyl-1H-pyrazole hydrochloride [ka] To di-tert-butyl 1-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (1.0 g), 4 M hydrogen chloride in cyclopropyl methyl ether (10 mL) was added and stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound (570 mg). 1H-NMR (DMSO-D6) δ: 9.36 (3H, br s), 4.44-4.37 (1H, m), 4.09 (1H, br s), 2.23 (3H, s), 2.17 (3H, s), 1.31 (6H, d, J = 6.5 Hz). Step 11-4: 2,4-dichloro-5-(dimethoxymethyl)-6-(2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)hydrazinyl)pyrimidine [ka] Triethylamine (3.1 mL) was added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (710 mg) synthesized in the same manner as in step 5-1 of Production Example 5 and methanol (11 mL), and the mixture was stirred at room temperature for 15 minutes. 4-Hydrazinyl-1-isopropyl-3,5-dimethyl-1H-pyrazole hydrochloride (570 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. The solvent was then distilled off under reduced pressure to obtain the crude product of the title compound. LC-MS (MH+): 389. Step 11-5: 4,6-dichloro-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Trifluoroacetic acid (0.85 mL) was added to a mixture of the crude product of 2,4-dichloro-5-(dimethoxymethyl)-6-(2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)hydrazinyl)pyrimidine and toluene (11 mL), and the mixture was stirred at room temperature for 1 hour, and then neutralized with 2 M aqueous sodium hydroxide solution (8.3 mL). The resulting mixture was diluted with water and ethyl acetate, and then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound. LC-MS (MH+): 325. Step 11-6: 6-chloro-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of the crude product of 4,6-dichloro-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and tetrahydrofuran (9.0 mL) was added with 4 M aqueous sodium hydroxide solution (2.8 mL), stirred at 75 °C for 1.5 hours, and then cooled to room temperature. The reaction mixture was neutralized with 2 M hydrochloric acid, diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by reversed-phase column chromatography (developing solvent: acetonitrile / water) to obtain the title compound (130 mg). LC-MS (MH+): 307. Step 11-7: 2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-6-(pyrrolidin-1-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Pyrrolidine (0.17 mL) was added to a mixture of 6-chloro-2-(1-isopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (130 mg) and tetrahydrofuran (1.3 mL), and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was purified by reversed-phase column chromatography (eluent: acetonitrile / water) and column chromatography (eluent: hexane / ethyl acetate) to give the title compound (19 mg). 1H-NMR (DMSO-D6) δ: 10.50 (1H, s), 8.37 (1H, s), 4.53-4.47 (1H, m), 3.47 (4H, t, J = 6.7 Hz), 2.20 (3H, s), 2.10 (3H, s), 1.90 (4H, t, J = 6.6 Hz), 1.38 (6H, d, J = 6.7 Hz). LC-MS (MH+):342.

[0122] [Production Example 12]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,5,2-dioxazepan-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 349) [ka] Step 12-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (500 mL) and sulfuric acid (1.1 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (170 g) and toluene (1.0 L), and the mixture was stirred at room temperature for 1.5 hours. Basic silica gel (Fujisilica, 330 g) was added to the reaction mixture, and after stirring for 1.5 hours, the added silica gel was removed by filtration. After washing the silica gel with ethyl acetate, the solvent was distilled off under reduced pressure to obtain the title compound (180 g). 1 H-NMR (CDCl3) δ: 5.68 (1H, s), 3.49 (6H, s). Step 12-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (82 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (80 g) and methanol (560 mL), and the reaction mixture was cooled in an ice bath. Triethylamine (130 mL) was slowly added to the reaction mixture, and the mixture was stirred at the same temperature for 2 hours. The resulting solid was collected by filtration and washed with methanol (150 mL) and hexane (100 mL) successively to obtain the title compound (69.8 g). 1 H-NMR (CDCl3)δ: 8.28 (1H, d, J = 4.4 Hz), 7.10 (2H, s), 6.14 (1H, d, J = 4.9 Hz), 5.56 (1H, s), 3.45 (6H, s), 2.43 (6H, s). LC-MS (MH+): 436. Step 12-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine [ka] Under a nitrogen atmosphere, trifluoroacetic acid (43 mL) was slowly added dropwise to a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazinyl)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (120 g) and toluene (970 mL) over 10 minutes while keeping the temperature below 26 °C. The reaction mixture was stirred for another 30 minutes and then slowly added dropwise to an ice-cooled solution of tripotassium phosphate (120 g) in water (400 mL). Ethyl acetate (100 mL) and tetrahydrofuran (640 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. All the organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (109 g). LC-MS (MH+): 372. Step 12-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine crude product (109 g) and tetrahydrofuran (830 mL) was added with 4 M aqueous sodium hydroxide solution (210 mL) at room temperature and stirred at 80 °C for 5 hours. 2 M hydrochloric acid (280 mL) was slowly added dropwise to the reaction mixture in an ice bath, and the reaction mixture was extracted with ethyl acetate. The aqueous layer was further extracted with a mixture of tetrahydrofuran / ethyl acetate (v / v = 4 / 1). All the organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether (550 mL) and ethyl acetate (150 mL) were added to the obtained crude product, and the mixture was stirred for 1 hour. The solid was collected by filtration to obtain the title compound (79 g). 1 H-NMR (DMSO-D6) δ: 12.88 (1H, br s), 8.81 (1H, s), 7.53 (2H, s), 1.95 (6H, s). LC-MS (MH+): 354. Step 12-5: 2-(4-bromo-2,6-dimethylphenyl)-6-(1,5,2-dioxazepan-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under a nitrogen atmosphere, 1,5,2-dioxazepane hydrochloride (1.8 g) and N,N-diisopropylethylamine (3.0 mL) were added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (3.0 g) and 1-methylpyrrolidin-2-one (10 mL), and the mixture was stirred at 140 °C for 2.5 hours and then cooled to room temperature. Water (20 mL) was slowly added dropwise to the reaction mixture, and the resulting solid was collected by filtration and washed with water and hexane in that order. A mixture of the obtained solid and diisopropyl ether (10 mL) was stirred at room temperature for 1 hour. The solid was collected by filtration and washed with diisopropyl ether to obtain the title compound (3.5 g). 1 H-NMR (DMSO-D6) δ: 11.26 (1H, s), 8.56 (1H, s), 7.50 (2H, s), 4.13-4.11 (2H, m), 3.88 (4H, s), 3.80-3.78 (2H, m), 1.96 (6H, s). LC-MS (MH+):420. Step 12-6: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,5,2-dioxazepan-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, a solution of potassium phosphate tripotassium (5.2 g) in water (7 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-(1,5,2-dioxazepan-2-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (3.5 g), cyclopropylboronic acid (1.6 g), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (540 mg) and toluene (35 mL). The mixture was stirred at 105 °C for 3 hours and then allowed to cool to room temperature. ISOLUTE Si-TMT (metal scavenging silica gel, Biotage, 0.47 mmol TMT / g, 5.0 g) was added and stirred at room temperature for 2 hours, then silica gel (25 mL) was added and stirred for an additional hour. The added silica gel was filtered off and washed with ethyl acetate, and the solvent was distilled off under reduced pressure. A mixture of the residue and ethyl acetate (15 mL) was stirred at 80 °C for 1 hour and then allowed to cool to room temperature. Diisopropyl ether (15 mL) was added and stirred at room temperature for an additional 30 minutes, after which the solid was filtered off and washed with diisopropyl ether to obtain the title compound (2.6 g). 1 H-NMR (DMSO-D6) δ: 11.21 (1H, br s), 8.48 (1H, s), 6.92 (2H, s), 4.13-4.11 (2H, m), 3.88 (4H, s), 3.80-3.78 (2H, m), 1.94-1.89 (7H, m), 0.97-0.95 (2H, m), 0.72-0.70 (2H, m). LC-MS (MH+):382.

[0123] The compounds of the other examples were obtained by the same methods as those in the above-mentioned production methods and production examples, or by using known methods as necessary. The structural formula and physical property data of each example compound are shown in the following table.

[0124] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory effect The NLRP3 inflammasome inhibitory effect of the test substance was evaluated based on the suppressive effect on IL-1β production in THP1-Null cells (product number thp-null, InvivoGen). The cells were maintained and cultured in RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 25 mmol / L HEPES, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL normocin, and 200 μg / mL hygromycin B (37°C, 5% CO2 / 95% air). Cells suspended in assay medium (RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin) containing 0.5 μmol / L PMA were seeded (25,000 cells / 25 μL / well) on Corning® 384-well Flat Clear Bottom Black Polystyrene TC-treated Microplates and cultured overnight (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and assay medium containing 1 μg / mL Lipopolysaccharides (product number L2654, Sigma-Aldrich®) was added (25 μL / well) and cultured for 3 hours (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and a medium solution prepared with Opti-MEM™ medium (product number 31985-070, Invitrogen) was added (20 μL / well) to the blank set wells and the control set wells, and cultured for 15 minutes (37°C, 5% CO2 / 95% air). In addition, the test substance solution was added (20 μL / well) to the test substance set wells. Furthermore, Opti-MEM™ medium containing Nigericin (product number N7143, Sigma-Aldrich™) was added (5 μL / well) to the control set wells and the test substance set wells, and cultured for 1.5 hours (37°C, 5% CO2 / 95% air). The final concentration of Nigericin was 7.5 μmol / L. Opti-MEM™ medium was added (5 μL / well) to the blank set wells. The culture supernatant was stored frozen (-20°C) until IL-1β was measured. The IL-1β in the culture supernatant was quantified using AlphaLISA (registered trademark) Human IL-1β Detection Kit (product number AL220C, Perkin Elmer). Fluorescence intensity was measured using a microplate reader EnSpier (model number 2300-00J, Perkin Elmer) or EnSight (model number HH34000000, Perkin Elmer) according to the attached instruction manual. The inhibition rate of the test substance well was calculated by setting the blank well as 100% and the control well as 0%. The IC of the test substance 50 The values ​​(50% inhibitory concentration) were calculated by logistic regression analysis. The results for each example compound are shown in the table below.

[0125] [Table 1] TIFF2024112817000157.tif249147 TIFF2024112817000158.tif253147 TIFF2024112817000159.tif248147 TIFF2024112817000160.tif247147 TIFF2024112817000161.tif249142 TIFF2024112817000162.tif249146 TIFF2024112817000163.tif254140 TIFF2024112817000164.tif252146 TIFF2024112817000165.tif247147 TIFF2024112817000166.tif246146 TIFF2024112817000167.tif243147 TIFF2024112817000168.tif250140 TIFF2024112817000169.tif235142 TIFF2024112817000170.tif250138 TIFF2024112817000171.tif248145 TIFF2024112817000172.tif251145 TIFF2024112817000173.tif249141 TIFF2024112817000174.tif251147 TIFF2024112817000175.tif249143 TIFF2024112817000176.tif253149 TIFF2024112817000177.tif251148 TIFF2024112817000178.tif250147 TIFF2024112817000179.tif249139 TIFF2024112817000180.tif246147 TIFF2024112817000181.tif245141 TIFF2024112817000182.tif247147 TIFF2024112817000183.tif223149 TIFF2024112817000184.tif249139 TIFF2024112817000185.tif252147 TIFF2024112817000186.tif248137 TIFF2024112817000187.tif254147 TIFF2024112817000188.tif249147 TIFF2024112817000189.tif245145 TIFF2024112817000190.tif239147 TIFF2024112817000191.tif216147 TIFF2024112817000192.tif232148 TIFF2024112817000193.tif249142 TIFF2024112817000194.tif176149

[0126]

Table 2

[0127]

Table 3

[0128] Examples of the formulation of the present invention include the following formulations, however, the present invention is not limited to these formulation examples. Formulation Example 1 (Capsule Production) (1) Compound of Example 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg (1), (2), (3) and (4) are mixed and filled into a gelatin capsule.

[0129] Formulation Example 2 (Tablet Production) (1) Compound of Example 1 10 g (2) Lactose 50g (3) 15g corn starch (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of (1), (2) and (3) and 30 g of (4) are mixed with water, vacuum dried, and then granulated. 14 g of (4) and 1 g of (5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained. [Industrial Applicability]

[0130] The compound of formula [I] or a pharma- ceutical acceptable salt thereof, or the compound of formula [IA] or a pharma-ceutical acceptable salt thereof, has an inhibitory effect on NLRP3 inflammasome, and is therefore useful in treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multi-organ inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., It is expected to be useful for the treatment or prevention of a disease selected from the group consisting of hemophagocytic lymphohistiocytosis and macrophage activation syndrome, Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

Claims

[Claim 1] The invention described in the specification.