Substituted pyrazolopyrimidine compounds and their medical uses

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to a substituted pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof having NLRP3 inflammasome inhibitory activity, a pharmaceutical composition containing the same, and medical uses thereof. [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 phagocytic cells 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 NLRP3 inflammasome formation, caspase-1 within the complex is converted to its active form, which converts proIL-1β, the precursor of the proinflammatory cytokine IL-1β, to active IL-1β, and proIL-18, the precursor of IL-18, to active IL-18. The extracellularly secreted active IL-1β induces inflammatory responses by inducing the production of inflammatory cytokines and chemokines by surrounding cells and activating immune cells such as T cells.

[0005] Increased levels of DAMPs were observed in the brains and cerebrospinal fluid of multiple sclerosis patients (Non-Patent Document 1), as well as increased caspase 1 expression in lesions and increased IL-1β levels in cerebrospinal fluid (Non-Patent Document 2). Furthermore, activated microglia are present in lesions during the chronic progression stage of this disease (Non-Patent Document 3), and activated microglia stimulated by DAMPs produce inflammatory cytokines such as IL-1β, inducing neuroinflammation and neurological disorders (Non-Patent Document 4). Therefore, the NLRP3 inflammasome is thought to be involved in the pathogenesis of multiple sclerosis.

[0006] Myelin Oligodendrocyte Glycoprotein (MOG) produced by sensitizing mice to MOG 35-55 EAE model mice exhibit motor dysfunction similar to that seen in multiple sclerosis. However, NLRP3 knockout mice exhibited no significant motor deficits. 35-55In EAE models, the onset of motor dysfunction is suppressed (Non-Patent Document 5). Furthermore, in cuprizone model mice created by administering the copper chelating compound cuprizone to mice, central nervous system demyelination similar to multiple sclerosis develops, but the progression of demyelination is delayed in NLRP3 knockout mice (Non-Patent Document 6). JC-171, an NLPR3 inflammasome inhibitor, inhibits MOG 35-55 In an EAE model, administration after the onset of symptoms suppressed motor dysfunction (Non-Patent Document 7). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for multiple sclerosis.

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

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

[0009] Increased expression of NLRP3 inflammasome-related genes has been reported in atherosclerotic areas of the coronary arteries of patients with myocardial infarction (Non-Patent Document 14). Furthermore, it has been reported that NLRP3 knockout suppresses lesion formation in high-fat diet-fed low-density lipoprotein receptor (LDL) receptor-deficient mice, a model of atherosclerosis (Non-Patent Document 15). Based on these results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for atherosclerosis.

[0010] Cryopyrin-associated periodic syndrome (CAPS) is a collective term for autoinflammatory diseases caused by activating mutations in the NLRP3 gene. It is classified into three disease types: mild familial cold autoinflammatory syndrome (FCAS), moderate Muckle-Wells syndrome (MWS), and severe chronic infantile neurologic cutaneous and articular syndrome (CINCA) or neonatal onset multisystem inflammatory disease (NOMID) (Non-Patent Document 16). More than 200 mutations in the NLRP3 gene have been reported in CAPS (Non-Patent Document 17). These NLRP3 gene mutations result in the formation and activation of the NLRP3 inflammasome even in the absence of activating signals. 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 (Non-Patent Document 19). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents 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). Furthermore, it has been reported that NLRP3 knockout suppresses liver fibrosis in a choline-deficient, amino acid-substituted diet model of NASH (Non-Patent Document 20). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents 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, leading to the production of IL-1β and IL-18 (Non-Patent Document 22). In an arthritis model induced by intra-articular uric acid injection, the NLRP3 inflammasome inhibitor OLT1177 suppressed arthritis (Non-Patent Document 23). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for gout and gouty arthritis.

[0013] Increased expression of NLRP3 inflammasome-related genes has been reported in the synovial membranes and peripheral blood mononuclear cells of patients with rheumatoid arthritis (Non-Patent Document 24). Increased expression of NLRP3 inflammasome-related genes has also been reported in the synovial membranes of collagen-induced arthritis, a model of rheumatoid arthritis (Non-Patent Document 25). Based on these results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for rheumatoid arthritis.

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

[0015] Increased expression of NLRP3 inflammasome-related genes has been reported in the tears and ocular surface of dry eye patients (Non-Patent Documents 27, 28). Furthermore, when cultured human corneal epithelial cells are subjected to hyperosmotic stress to induce dry eye, increased expression of NLRP3 inflammasome-related genes and increased IL-1β production have been observed, and knockdown of the NLRP3 gene has been reported to suppress IL-1β production (Non-Patent Document 28). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for dry eye.

[0016] It has been reported that the expression of the ASC domain of the NLRP3 inflammasome is elevated in macrophages and neutrophils infiltrating the myocardial tissue of patients with acute myocardial infarction (Non-Patent Document 29). Furthermore, in an ischemia-reperfusion model of myocardial infarction, it has been reported that the expression of NLRP3 inflammasome-related genes is elevated in the infarcted area, and that knockdown of the NLRP3 gene reduces the infarct size and myocardial contractility (Non-Patent Document 30). Based on these results, it is believed that NLRP3 inflammasome inhibitors could be used as therapeutic agents for ischemic heart disease, 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 NLRP3 gene expression and IL-1β production are increased in macrophages (Non-Patent Document 33). Furthermore, in Nlrp3-R258W mice, which have an activating mutation in the NLRP3 gene, administration of pristane exacerbates lupus nephritis-like symptoms (Non-Patent Document 34). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for SLE.

[0018] In addition to the above diseases, diseases for which NLRP3 inflammasome inhibitors are expected to be effective include systemic juvenile idiopathic arthritis (Non-Patent Document 35), recurrent pericarditis (Non-Patent Document 36), adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome) (Non-Patent Document 37), Schnitzler syndrome (Non-Patent Document 38), IL-1 receptor antagonist molecule deficiency (Non-Patent Document 39), familial Mediterranean fever (Non-Patent Document 40), mevalonate kinase deficiency (Non-Patent Document 40), hyper-IgD syndrome (Non-Patent Document 40), TNF receptor-associated periodic syndrome (Non-Patent Document 40), Behçet'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 elevated in psoriasis patients, increasing their susceptibility 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, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for psoriasis.

[0020] Gout, atherosclerosis, and chronic kidney disease, which are associated with NLRP3 inflammasome activation, are accompanied by hypertension. NLRP3 deficiency has been reported to suppress hypertension in a mouse left renal artery stenosis model (Non-Patent Document 45). Furthermore, the NLRP3 inflammasome inhibitor MCC950 has been reported to suppress hypertension in a deoxycorticosterone acetate-treated mouse model (Non-Patent Document 46). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for hypertension.

[0021] It has been reported that NLRP3 expression is elevated in the proliferative membranes of patients with diabetic retinopathy (Non-Patent Document 47). Furthermore, NLRP3 expression is elevated in the STZ-induced diabetic retinopathy model (Non-Patent Document 48). In this model, it has been reported that reduction of NLRP3 expression by NLRP3 shRNA results in decreased IL-1β and VEGF secretion, increased ganglion cell mass, and recovery from retinal damage (Non-Patent Document 49). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for diabetic retinopathy.

[0022] NLRP3 inflammasome activation occurs in the brains of patients with Alzheimer's disease, mild cognitive impairment (MCI), and APP / PS1 mice, a mouse model of Alzheimer's disease. NLRP3 deficiency in APP / PS1 mice suppresses the development of spatial memory impairment (Non-Patent Document 50). The NLRP3 inhibitor MCC950 suppresses NLRP3 activation in microglia and improves cognitive dysfunction in APP / PS1 mice (Non-Patent Document 51). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for Alzheimer's disease and MCI.

[0023] In the substantia nigra of Parkinson's disease patients and mice injected with α-synuclein preformed fibrils (PFFs), a pathological model of Parkinson's disease, increased expression of NLRP3 inflammasome-related molecules in microglia and activation of the NLRP3 inflammasome occur (Non-Patent Document 52). The NLRP3 inhibitor MCC950 suppresses NLRP3 activation in the substantia nigra and inhibits the neuronal death of dopamine neurons in the substantia nigra in mice injected with α-synuclein PFFs (Non-Patent Document 52). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for Parkinson's disease.

[0024] In patients with Huntington's disease, the cerebrospinal fluid concentration of IL-1β, an NLRP3 inflammasome-associated cytokine, is increased (Non-Patent Document 53). In R6 / 2 mice, a pathological model of Huntington's disease, NLRP3 inflammasome expression levels in the striatum are increased (Non-Patent Document 54). The NLRP3 inhibitor MCC950 suppresses NLRP3 inflammasome activation in the striatum of R6 / 2 mice, suppressing neuronal cell death in the striatum and symptom progression (Non-Patent Document 55). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for Huntington's disease.

[0025] In the spinal cords of patients with amyotrophic lateral sclerosis (ALS), expression of the NLRP3 inflammasome, IL-18, and activated caspase 1 is increased (Non-Patent Document 56). In the spinal cords of ALS model mice, SOD1G93A mice and TDP-43Q331K mice, 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, reducing IL-1β production (Non-Patent Document 57). In SOD1G93A mice, deficiency of IL-1β or caspase 1 extends survival, and administration of an IL-1β receptor antibody suppresses disease progression and extends survival (Non-Patent Document 58). Therefore, NLRP3 inflammasome inhibitors are considered to be potential treatments for ALS.

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

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

[0028] Expression of the NLRP3 inflammasome is increased in the brain tissue of patients with temporal lobe epilepsy and in pilocarpine-induced epilepsy model mice (Non-Patent Documents 65, 66). Furthermore, in pilocarpine-induced epilepsy model mice, NLRP3 inflammasome deficiency and administration of the NLRP3 inhibitor MCC950 suppressed hippocampal neuronal apoptosis, which is the cause of epilepsy (Non-Patent Document 66). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for epilepsy.

[0029] In the peripheral blood of patients with depression, NLRP3 inflammasome expression levels, IL-1β levels, and IL-18 levels are increased, and IL-1β levels correlate with depression symptom scores (Non-Patent Document 67). In pathological models of depression, such as LPS-induced models, chronic stress-induced models, and social defeat models, increased expression of NLRP3 inflammasome, IL-1β, or IL-18 in brain tissue and NLRP3 inflammasome activation occur (Non-Patent Documents 68, 69, 70). Furthermore, in pathological models, administration of the NLRP3 inhibitor MCC950 or NLRP3 deficiency has been shown to improve depressive symptoms (Non-Patent Documents 69, 70). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for depression.

[0030] In the peripheral blood of patients with autism spectrum disorder (ASD), NLRP3 inflammasome expression levels and IL-1β and IL-18 concentrations are increased (Non-Patent Document 71). In the maternal immune activation (MIA) model, administration of PolyIC to pregnant animals causes ASD symptoms in offspring. In this model, IL-1β expression is increased in the fetal brain, and administration of the NLRP3 inhibitor MCC950 to the mother suppresses the onset of ASD symptoms in offspring (Non-Patent Document 72). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents 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). Furthermore, administration of the NLRP3 inhibitor MCC950 to mice after spinal cord injury suppresses NLRP3 activation and IL-1β expression in the spinal cord and promotes recovery of motor function (Non-Patent Document 73). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for spinal cord injury.

[0032] In an intestinal perforation model, an animal model of sepsis, increased expression and activation of the NLRP3 inflammasome or IL-1β occurs in the brain, resulting in hippocampal neuronal damage and memory impairment, a symptom of septic encephalopathy (Non-Patent Documents 75, 76). Administration of the NLRP3 inhibitor MCC950 to an intestinal perforation model suppresses NLRP3 inflammasome activation and improves memory impairment (Non-Patent Document 76). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for septic encephalopathy.

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

[0034] Mice infected with SARS-CoV-2 exhibit increased expression of IL-1β and NLRP3 inflammasome-related molecules in lung tissue. In contrast, NLRP3 knockout mice exhibit no increase in these expression levels, and severe respiratory inflammation caused by SARS-CoV-2 is suppressed. Furthermore, administration of the NLRP3 inhibitor MCC950 to SARS-CoV-2-infected mice suppresses NLRP3 inflammasome activation and excessive immune responses in the lungs (Non-Patent Document 80). Therefore, NLRP3 inflammasome inhibitors are considered to be a potential treatment for COVID-19 caused by SARS-CoV-2.

[0035] Increased levels of the ASC domain of the NLRP3 inflammasome and mature IL-1β protein have been reported in the cerebral cortex of patients with frontotemporal dementia with tau protein mutations (Non-Patent Document 81). Increased levels of the ASC domain of the NLRP3 inflammasome and post-cleavage caspase 1 have also been reported in the cerebral cortex of Tau22 mice (mice expressing human mutant tau protein), a model of frontotemporal dementia. NLRP3 knockout has also been reported to suppress tau pathology formation and cognitive decline (Non-Patent Document 81). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for frontotemporal dementia.

[0036] Patients with NLRP3-associated autoinflammatory disease (NLRP3-AID), caused by activating mutations in the NLRP3 gene, exhibited drusen formation, which is thought to be the causative agent of age-related macular degeneration (AMD) (Non-Patent Document 82). Furthermore, in an Alu RNA-induced retinal pigment epithelial cell degeneration model, a model of age-related macular degeneration, NLRP3 inhibitors suppressed retinal pigment epithelial cell degeneration (Non-Patent Document 83). In a laser-induced choroidal neovascularization model, another model of age-related macular degeneration, NLRP3 inhibitors suppressed angiogenesis (Non-Patent Document 83). Based on these results, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for age-related macular degeneration.

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

[0038] Hereditary transient keratoephtheria is a cryopyrin-associated periodic fever syndrome caused by activating mutations in the NLRP3 gene (Non-patent Document 86). Therefore, NLRP3 inflammasome inhibitors are thought to be a potential therapeutic agent for hereditary transient keratoephtheria. [Prior art documents] [Non-patent literature]

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[Non-Patent Document 86] Joni A Turunen, et al., Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene, Am J Ophthalmol. 2018 Apr;188:41-50. Summary of the Invention

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

[0041] [Section 1] A compound of formula [I] or a pharmaceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [I] or a pharmaceutically acceptable salt thereof" may also be referred to as "compound [I]"). [ka] {In the formula, Substructure: [ka] teeth, (1) Formula: [ka] [During the ceremony, R 5 is hydrogen or C 1-4 alkyl {wherein the alkyl is (a) carboxy, (b)-CO-C 1-4 alkoxy, or (c)-CO-NR6 R 7 (where R 6 and R 7 are each independently hydrogen or C 1-4 alkyl), optionally substituted with or (2) Formula: [ka] (In the formula, R 8 is C 1-4 alkyl) The structure is represented by The ring group Cy is (1) Formula: [ka] (In the formula, R 9 and R 10 are each independently (a) hydrogen, (b)C 1-4 Alkyl (wherein the alkyl is C 1-4 optionally substituted with alkoxy; (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl, R 11 and R 12 are each independently (a) hydrogen, (b)C 1-4 alkyl, or (c)C 1-4 haloalkyl, R 13 teeth, (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 Alkoxy, (d) halogens, (e)C1-6 haloalkyl, (f)-OC 1-4 haloalkyl, or (g)C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two halogens; or R 13 is R 11 or R 12 , together with the carbon atoms to which they are attached, (a)C 5-6 a cycloalkene, or (b) may form a 5- to 7-membered heterocycloalkene containing one or two oxygen atoms. or a group represented by (2) Formula: [ka] (In the formula, R 14 and R 15 are each independently, C 1-4 Alkyl or C 1-4 is haloalkyl, R 16 is C 1-6 Alkyl or C 3-6 cycloalkyl) is a group represented by R 1 teeth, (1) Hydrogen, (2) Cyano, (3) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (4) C 1-4 haloalkyl, or (5)-CO-C 1-4 alkyl, R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) hydroxy, (3) C 1-6alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) halogens, (6) C 1-4 haloalkyl (wherein the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (7)-OC 1-4 haloalkyl, (8)-OR 17 (where R 17 is a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; (9) C 3-6 cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl is optionally substituted with oxo; or Equation (11): [ka] or R 2 , R 3 and R 4 together with the carbon atoms to which they are attached form -CR 2 R 3 R 4 The base is (a) cyano, (b)C 3-6 cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), which may be substituted with 1 to 3 substituents independently selected from the group consisting of: (c) 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (d) a 7- to 9-membered saturated fused heterocyclic group containing one or two heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocyclic group is optionally substituted with one or two halogen atoms; (e) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (f) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (g)C 5-6 cycloalkenyl, (h) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (i) Formula: [ka] {where, R 20 teeth, (1)C 1-4 alkyl, or (2)-NR 21 R 22 (where R 21 and R 22 are each independently (a) hydrogen, (b)C 1-4 Alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. may form a group represented by the formula: [Section 2] Substructure: [ka] but, (1) Formula: [ka] (In the formula, R 5 is equivalent to term 1) Item 2. The compound according to Item 1, which has the structure represented by the following formula: or a pharmaceutically acceptable salt thereof. [Section 3] R 1 Item 3. The compound or pharmaceutically acceptable salt thereof according to Item 1 or 2, wherein is hydrogen. [Section 4] R 5 Item 4. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein is hydrogen. [Section 5] The ring group Cy is (1) Formula: [ka] (In the formula, R 9 , R 10 , R 11 , R 12 and R 13 is equivalent to term 1) Item 5. The compound according to any one of Items 1 to 4, wherein the compound is a group represented by the formula: or a pharmaceutically acceptable salt thereof. [Section 6] Item 6. The compound according to any one of items 1 to 5, which is represented by formula [II] or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 and R 13 is equivalent to term 1) [Section 7] R 11 and R 12 Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is hydrogen. [Section 8] Item 8. The compound according to any one of items 1 to 7, which is represented by formula [III] or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 2 , R 3 , R 4 , R 9 , R 10 and R 13 is equivalent to term 1) [Section 9] R 9 and R 10 At least one of (1)C 1-4 Alkyl (wherein the alkyl is C 1-4 optionally substituted with alkoxy; (2) C 1-4Alkoxy, (3) halogens, (4) C 1-4 haloalkyl, or (5)-OC 1-4 Item 9. The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof, which is haloalkyl. [Section 10] R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C 1-4 haloalkyl (wherein the haloalkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl, or R 2 , R 3 and R 4 together with the carbon atoms to which they are attached form -CR 2 R 3 R 4 The base is (a)C 3-6 cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), optionally substituted with 1 to 3 substituents independently selected from the group consisting of (b) a 4- to 7-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is optionally substituted with hydroxy. 1-4 alkyl, optionally substituted with (e) a 5- or 6-membered heterocycloalkenyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (f) Formula: [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. Item 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, which may form a group represented by the following formula: [Section 11] R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of (4) C 1-6 Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, optionally substituted with (5) C 1-4 haloalkyl (wherein the haloalkyl is hydroxy or C 1-4 substituted with alkoxy), or R 2 , R 3 and R 4 together with the carbon atoms to which they are attached form -CR 2 R 3 R 4 The base is (a)C 3-6 cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), optionally substituted with 1 to 3 substituents independently selected from the group consisting of (b) a 4- to 7-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) Hydroxy, (2) C 1-4 Alkyl, (3) C 1-4 Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; or Formula (c): [ka] {where, R 21 and R 22 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, (3) C 1-4 haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, which may form a group represented by the following formula: [Section 12] The following structural formula: [ka] Item 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of TIFF0007737490000017.tif186150. [Section 13] The following structural formula: [ka] Item 1. The compound according to item 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [Section 14] Item 14. A pharmaceutical composition comprising the compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [Section 15] Item 14. An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof. [Section 16] Item 14. A compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 17] Item 17. The therapeutic or preventive agent according to Item 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 18] Item 17. The therapeutic or preventive agent according to Item 16, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multiorgan inflammatory disease. [Section 19] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal. [Section 20] Item 14. A method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, A method for treating or preventing a disease selected from the group consisting of adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist 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 21] Item 21. The method according to Item 20, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 22] Item 21. The method according to Item 20, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 23] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 13 for the manufacture of an NLRP3 inflammasome inhibitor. [Section 24] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease Item 14. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13 for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of inflammatory bowel disease, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 25] Item 25. The use according to Item 24, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 26] Item 25. The use according to Item 24, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 27] Item 14. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 13, for use in inhibiting NLRP3 inflammasome. [Section 28] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease Item 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13 for use in the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF) 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 29] Item 29. The compound or a pharmaceutically acceptable salt thereof according to Item 28, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 30] Item 29. The compound or a pharmaceutically acceptable salt thereof according to Item 28, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 31] Item 14. A pharmaceutical composition according to Item 14, and administration of the pharmaceutical composition to a patient suffering from multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), and and a commercial package containing a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF) syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 32] Item 14. A pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient suffering from multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage leukemia), and and 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 inflammatory bowel disease (IL-1 receptor antagonist deficiency syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 16A] Item 14. A compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof, for use in treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous 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 myeloma), and a therapeutic or preventive agent for a disease selected from the group consisting of inflammatory bowel disease (IGD), leukemia, leukemia-associated leukemia (IL-1 receptor antagonist deficiency), leukemia-associated leukemia-associated leukemia (LEU), leukemia-associated ... [Section 17A] The therapeutic or prophylactic agent according to Item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 18A] Item 16A. The therapeutic or preventive agent according to Item 16A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 19A] Item 14. A method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic phosphoinositide ... systemic lupus erythematosus, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematosus, recurrent pericarditis, systemic lupus erythematos A method for treating or preventing a disease selected from the group consisting of inflammatory bowel disease (inflammatory disease, leukemia, 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, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, 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 multisystem inflammatory disease. [Section 22A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Item 14. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13 for the manufacture of a therapeutic or preventive agent for a disease selected from the group consisting of aromatic Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 23A] The use according to paragraph 22A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 24A] The use according to Item 22A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 25A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency Item 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13 for use in the treatment or prevention of a disease selected from the group consisting of idiopathic rheumatoid arthritis, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 26A] The compound or a pharmaceutically acceptable salt thereof according to Item 25A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 27A] The compound or a pharmaceutically acceptable salt thereof according to Item 25A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, or neonatal-onset multisystem inflammatory disease. [Section 28A] Item 14. A pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient suffering from or having a disease, such as, multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's syndrome, I and a commercial package comprising a description of the pharmaceutical composition, which describes that the composition can be used for the treatment or prevention of a disease selected from the group consisting of L-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 29A] Item 15. The pharmaceutical composition according to Item 14, and a method for administering the pharmaceutical composition to a patient suffering from a disease such as multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's syndrome, and 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 IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. DETAILED DESCRIPTION OF THE INVENTION

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

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

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

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

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

[0047] "C 1-6 "Alkoxy" refers to 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. Preferred are methoxy, ethoxy, and isopentyloxy.

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

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

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

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

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

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

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

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

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

[0057] "5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms" means a 5- to 7-membered monocyclic partially unsaturated heterocycle containing 1 or 2 oxygen atoms as ring-constituting atoms other than carbon atoms and containing at least one double bond. Examples of "5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms" include dihydrofuran, dioxole, dihydropyran, dihydrodioxine, pyran, tetrahydrooxepin, dihydrodioxepin, dihydrooxepin, and dioxepin. Dihydropyran is preferred.

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

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

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

[0061] In some embodiments of the present invention, the moiety of formula [I]: [ka] is R 13 R 11 or R 12and when these together with the carbon atoms to which they are attached form a ring structure, the whole is a 9- to 11-membered partially unsaturated fused ring group which may contain 1 or 2 oxygen atoms, and R 9 and R 10 and R 11 or R 12 The fused ring group includes, for example, the following groups: [ka] Examples include:

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

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

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

[0065] R 5 is preferably hydrogen.

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

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

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

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

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

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

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

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

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

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

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

[0077] R 1 is preferably hydrogen.

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

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

[0080] Even more preferable R 2 , R 3 and R 4 are each independently (1) Hydrogen, (2) hydroxy, or (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of R 2 , R 3 and R 4 together with the carbon atoms to which they are attached form -CR 2 R 3 R 4 The base is (a)C 3-6 cycloalkyl {wherein the cycloalkyl is (1) Cyano, (2) C 1-4 alkyl (wherein the alkyl is hydroxy or C 1-4 optionally substituted with alkoxy; (3) C 1-4 Alkoxy, (4) halogens, and (5)-CO-NR 18 R 19 (where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl), optionally substituted with 1 to 3 substituents independently selected from the group consisting of; Formula (b): [ka] (In the formula, R 21 and R 22 are the same as defined above) This forms a group represented by the formula:

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

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

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

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

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

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

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

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

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

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

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

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

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

[0094] As used herein, the term "pharmaceutically 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 pharmaceutically 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, pp. 1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, the compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base to obtain a pharmaceutically acceptable salt thereof.

[0095] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred examples include 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 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, or 2-hydroxy-1-ethanesulfonic acid.

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

[0097] Compound [I] may exist as a solvate. A solvate is, for example, a compound [I] coordinated with solvent molecules. The solvate may be any pharmaceutically acceptable solvate, including a hydrate, acetate solvate, acetone solvate, ethanol solvate, and dimethyl sulfoxide solvate of compound [I]. Specific examples include the hemihydrate, monohydrate, dihydrate, monoacetate solvate, monoacetone solvate, and monoethanol solvate of the compound of formula [I], as well as the monohydrate, monoacetone solvate, and 2 / 3 ethanol solvate of the sodium salt of the compound of formula [I]. These solvates can be obtained according to known methods.

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

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

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

[0101] Diastereomeric mixtures can be separated into 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 stereoselective reactions.

[0102] Separation of 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 enantiomer can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries and asymmetric catalysts.

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

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

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

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

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

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

[0109] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like. Examples of the "fluidizing agent" include 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, methylcellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of "buffers" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like. "Soothing agents" include benzyl alcohol and the like. Examples of "bases" 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, tragacanth gum, 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 thereof. Examples of the "preservative" include ethyl parahydroxybenzoate, 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 (such as food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), β-carotene, and the like. Examples of "sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, etc.

[0110] The pharmaceutical composition of the present invention can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. The dosage (also referred to herein as a "therapeutically effective amount") varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day of the compound of formula [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient. These amounts can be administered in one or several divided doses.

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

[0112] "Inhibiting NLRP3 inflammasome" means inhibiting the function of NLRP3 inflammasome to eliminate or attenuate its activity, for example, inhibiting the function of NLRP3 inflammasome under the conditions of Test Example 1 described below. Inhibiting the function of NLRP3 inflammasome suppresses the production of IL-1β and / or IL-18, preferably suppressing the production of IL-1β and IL-18. "Inhibiting NLRP3 inflammasome" preferably means "inhibiting human NLRP3 inflammasome."

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

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

[0115] Unless one embodiment disclosed in one place in this specification contradicts an embodiment disclosed in another place, any combination of two or more of these is also intended to be encompassed by the present invention.

[0116] [General manufacturing method] General methods for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof are exemplified below: However, the method for producing the compound of formula [I] or a pharmaceutically acceptable salt thereof is not limited to these methods. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases 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 in one embodiment, it is 1°C to 40°C. The abbreviations are as follows: HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0199] The compounds of the other examples were obtained by the same methods as those 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 table below.

[0200] [Table 1] TIFF0007737490000132.tif245163 TIFF0007737490000133.tif222163 TIFF0007737490000134.tif242163 TIFF0007737490000135.tif230163 TIFF0007737490000136.tif222163 TIFF0007737490000137.tif229163 TIFF0007737490000138.tif224163 TIFF0007737490000139.tif233163 TIFF0007737490000140.tif249164 TIFF0007737490000141.tif253164 TIFF0007737490000142.tif222162 TIFF0007737490000143.tif225163 TIFF0007737490000144.tif235163 TIFF0007737490000145.tif239163 TIFF0007737490000146.tif239163 TIFF0007737490000147.tif235164 TIFF0007737490000148.tif248161 TIFF0007737490000149.tif235163 TIFF0007737490000150.tif218163 TIFF0007737490000151.tif241163 TIFF0007737490000152.tif230163 TIFF0007737490000153.tif235163 TIFF0007737490000154.tif251164 TIFF0007737490000155.tif231163 TIFF0007737490000156.tif241163 TIFF0007737490000157.tif230162 TIFF0007737490000158.tif30162

[0201] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory effect The inhibitory effect of test substances on NLRP3 inflammasome activity was evaluated by their suppression of IL-1β production in THP1-Null cells (product number thp-null, InvivoGen). 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 at 37°C in a 5% CO2 / 95% air atmosphere. 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 onto Corning® 384-well Flat Clear Bottom Black Polystyrene TC-treated Microplates (25,000 cells / 25 μL / well) and cultured overnight at 37°C in 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). The culture was then cultured for 3 hours at 37°C in 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 blank and control wells and incubated for 15 minutes (37°C, 5% CO2 / 95% air). Test substance solution was added (20 μL / well) to test substance wells. Furthermore, Opti-MEM™ medium containing Nigericin (product number N7143, Sigma-Aldrich®) was added (5 μL / well) to control and test substance wells and incubated 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 blank wells. The culture supernatant was stored frozen (-20°C) until IL-1β measurement. 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 (product number 2300-00J, Perkin Elmer) or EnSight (product number HH34000000, Perkin Elmer) according to the attached operating instructions. The inhibition rate of the test substance well was calculated by setting the blank well as 100% and the control well as 0%. The IC of the test substance 50 The values ​​(50% inhibitory concentration) were calculated by logistic regression analysis. The results for each example compound are shown in the table below.

[0202] [Table 2] TIFF0007737490000160.tif23295 TIFF0007737490000161.tif23395 TIFF0007737490000162.tif23395 TIFF0007737490000163.tif12394

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

[0204] Formulation Example 2 (Tablet Production) (1) Compound of Example 1 10 g (2) Lactose 50g (3) 15g corn starch (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of (1), (2), and (3) and 30 g of (4) are kneaded with water, vacuum dried, and then sized. 14 g of (4) and 1 g of (5) are mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets, each containing 10 mg of the compound of Example 1, are thus obtained. [Industrial Applicability]

[0205] The compound of formula [I] or a pharmaceutically acceptable salt thereof has an inhibitory effect on the NLRP3 inflammasome, and is thereby effective in treating a variety of diseases, including multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), 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 other conditions. The compound is expected to be useful as a therapeutic or preventive agent for a disease selected from the group consisting of phage activation syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

Claims

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

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

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

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

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

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

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

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

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

10. R ２ , R ３ and R ４ are each independently (1) hydrogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, and (c) -SO ２ -C １－４ alkyl, optionally substituted with 1 or 2 substituents independently selected from the group consisting of (4) C １－６ Alkoxy {wherein the alkoxy is (a) hydroxy, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, (5) C １－４ haloalkyl (wherein the haloalkyl is hydroxy or C １－４ optionally substituted with alkoxy); (6) -O-C １－４ haloalkyl, or (7) C ３－６ cycloalkyl, or R ２ , R ３ and R ４ together with the carbon atom to which they are attached form -CR ２ R ３ R ４ The base is (a) C ３－６ cycloalkyl {wherein the cycloalkyl is (1) cyano, (2) C １－４ alkyl (wherein the alkyl is hydroxy or C １－４ optionally substituted with alkoxy); (3) C １－４ Alkoxy, (4) halogens, and (5) -CO-NR １８ R １９ (where R １８ and R １９ are each independently hydrogen or C １－４ alkyl); (b) a 4- to 7-membered heterocycloalkyl containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl is (1) hydroxy, (2) C １－４ Alkyl, (3) C １－４ Alkoxy, and (4) halogen, or one of the ring atoms of the heterocycloalkyl may be substituted by one or two oxo; (c) a 5- to 8-membered bridged cycloalkyl, wherein the bridged cycloalkyl is optionally substituted with halogen; (d) a 5- to 8-membered bridged heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl is a C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 1 １－４ alkyl, optionally substituted with (e) Formula: 【Chemistry 14】 {In the formula, R ２１ and R ２２ are each independently (1) hydrogen, (2) C １－４ Alkyl, (3) C １－４ haloalkyl, or (4) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may form a group represented by the following formula:

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

12. The following structural formula: 【Chemistry 16】 【change】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

13. The following structural formula: 【Chemistry 17】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

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

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

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

17. A compound represented by the following structural formula or a pharmaceutically acceptable salt thereof. ​

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

19. A compound represented by the following structural formula or a pharmaceutically acceptable salt thereof. 【Chemical 23】

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

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

22. 21. An NLRP3 inflammasome inhibitor comprising the compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

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

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

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

26. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of an NLRP3 inflammasome inhibitor.

27. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cryopyrin-associated periodic fever syndrome, non-alcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

28. 28. The use according to claim 27, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

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

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

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

32. 32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

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

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