Pyrazolopyrimidine compound and pharmaceutical use thereof

Abstract

To provide a pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and pharmaceutical uses therefor.SOLUTION: The present invention provides a compound of formula [IA] or a pharmaceutically acceptable salt thereof. (In the formula, each symbol is as defined in the specifications).SELECTED DRAWING: None

Description

[Technical field]

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

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

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

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

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

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

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

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

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

[0010] Cryopyrin-associated periodic syndrome (CAPS) is a general term for autoinflammatory diseases caused by activating mutations in the NLRP3 gene, and is classified into three disease types: mild familial cold autoinflammatory syndrome (FCAS), moderate Muckle-Wells syndrome (MWS), and severe chronic infantile neurologic cutaneous, and articular syndrome (CINCA) or neonatal onset multisystem inflammatory disease (NOMID) (Non-Patent Document 16). More than 200 mutations in the NLRP3 gene have been reported in CAPS (Non-Patent Document 17). These NLRP3 gene mutations cause the formation and activation of the NLRP3 inflammasome even in the absence of 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 rates (Non-Patent Document 19). Based on these results, NLRP3 inflammasome inhibitors are considered to be a therapeutic agent for CAPS.

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

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

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

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

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

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

[0017] It has been reported that the expression of IL-1β or IL-18 is increased in the serum and glomeruli of patients with systemic lupus erythematosus (SLE) (Non-Patent Documents 31 and 32), and that the expression of the NLRP3 gene and the production of IL-1β are increased in macrophages (Non-Patent Document 33). In addition, in Nlrp3-R258W mice with an activating mutation in the NLRP3 gene, the lupus nephritis-like symptoms expressed by administration of pristane are exacerbated (Non-Patent Document 34). Based on these results, it is believed that NLRP3 inflammasome inhibitors can be used as 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), Behcet's disease (Non-Patent Document 41), and lung cancer (Non-Patent Document 42). The therapeutic effects of anti-IL-1β antibodies such as canakinumab and IL-1 inhibitors such as rilonacept have been reported for these diseases. Since the NLRP3 inflammasome is involved in the production of inflammatory cytokines such as IL-1β, NLRP3 inflammasome inhibitors are thought to be a potential treatment for these diseases.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0035] In the cerebral cortex of patients with frontotemporal dementia with tau protein mutations, an increase in the ASC domain of the NLRP3 inflammasome and mature IL-1β protein has been reported (Non-Patent Document 81). In addition, an increase in the ASC domain of the NLRP3 inflammasome and post-cleavage caspase1 has been reported in the cerebral cortex of Tau22 mice (human mutant tau protein expressing mice), a model of frontotemporal dementia, and an inhibitory effect on tau lesion formation and cognitive decline by NLRP3 knockout has also been reported (Non-Patent Document 81). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for frontotemporal dementia.

[0036] In patients with NLRP3-associated autoinflammatory disease (NLRP3-AID) caused by activating mutations in the NLRP3 gene, the formation of drusen, which is thought to be the causative agent of age-related macular degeneration (AMD), was observed (Non-Patent Document 82). In addition, in an Alu RNA-induced retinal pigment epithelial cell degeneration model, which is one of the age-related macular degeneration models, NLRP3 inhibitors suppressed the degeneration of retinal pigment epithelial cells (Non-Patent Document 83). In a laser-induced choroidal neovascularization model, which is another model of age-related macular degeneration, NLRP3 inhibitors suppressed angiogenesis (Non-Patent Document 83). From these results, it is believed that NLRP3 inflammasome inhibitors will be a therapeutic drug for age-related macular degeneration.

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

[0038] Hereditary transient corneal endotheliitis is one of the cryopyrin-associated periodic fever syndromes caused by activating mutations in the NLRP3 gene (Non-Patent Document 86). Therefore, it is thought that NLRP inflammasome inhibitors will be a therapeutic agent for hereditary transient corneal endotheliitis. [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 pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharma- ceutical acceptable salt thereof, a pharmaceutical composition containing the same, and a medicinal use thereof, etc. That is, the present invention includes the following exemplary embodiments.

[0041] [Section 1] A compound of formula [I] or a pharma- ceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [I] or a pharma- ceutically acceptable salt thereof" is also referred to as "compound [I]"). [ka] [During the ceremony, [ka] is a single bond or a double bond, R 1 and R 2 are each independently (1) Hydrogen, (2) Hydroxy, (3) Cyano, (4) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6cycloalkyl; (5) C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (6) halogens, (7) C 1-4 Haloalkyl, (8)-CHO, (9)-OC 1-4 Haloalkyl, (10)-OC 3-6 Cycloalkyl, (11)-CO-C 1-4 Alkyl, (12)-CO-C 3-6 Cycloalkyl, (13)-NR 7 R 8 (where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, -NR 7 R 8 the groups may form a 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (14) C 3-6 cycloalkyl, R 3 and R 4 are each independently (1) Hydrogen, (2) C 1-4 Alkyl, or (3) C 1-4 haloalkyl, R 5 teeth, (1) Hydrogen, (2) Cyano, (3) C 1-6 Alkyl, (4) C 2-6 Alkenyl, (5) C 2-5Alkynyl, (6) C 1-4 Alkoxy, (7) halogens, (8) C 1-6 Haloalkyl, (9) C 2-6 Haloalkenyl, (10)-OC 1-4 Haloalkyl, (11) C 3-6 Cycloalkyl, where the cycloalkyl is selected from 1 to 3 halogens or C 1-4 may be substituted with haloalkyl, (12) C 5-6 cycloalkenyl, or (13) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; R 6 teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) halogens, (4) C 1-4 haloalkyl, or (5) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; m is 0, 1, or 2; n is 0 or 1, When n is 0, X 1 , X 2 , X 3 and X 4 are each independently a carbon, nitrogen, oxygen or sulfur atom, 1 , X 2 , X 3 Or X 4 The total number of nitrogen, oxygen and sulfur atoms as X is 1, 2 or 3, and the total number of oxygen and sulfur atoms as X is 0 or 1; 1 , X 2 , X 3and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl, When n is 1, X 1 , X 2 , X 3 , X 4 and X 5 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , X 4 Or X 5 The total number of nitrogen atoms as X is 1 or 2; 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 and together with adjacent carbon atoms form a heteroaryl. [Section 2] R 3 and R 4 Item 2. The compound according to item 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 3] Item 3. The compound according to item 1 or 2, which is represented by formula [II] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, each symbol has the same meaning as in Item 1.) [Section 4] Item 3. The compound according to item 1 or 2, which is represented by formula [III] or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, each symbol has the same meaning as in Item 1.) [Section 5] A pharmaceutical composition comprising the compound according to any one of items 1 to 4 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. [Section 6] Item 5. An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 4 or a pharma- ceutically acceptable salt thereof. [Section 7] Item 5: A compound according to any one of items 1 to 4 or a pharma- ceutical agent for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, articular syndrome, and neonatal-onset multi-organ inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., pulmonary arthritis, pulmonary edema ... For example, a therapeutic or preventive agent for a disease selected from the group consisting of 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 8] Item 8. The therapeutic or preventive agent according to Item 7, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 9] Item 8. The therapeutic or preventive agent according to Item 7, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 10] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 4 or a pharma- ceutically acceptable salt thereof to a mammal. [Section 11] Item 5. 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, 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 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 12] Item 12. The method according to item 11, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 13] Item 12. The method according to item 11, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 14] Use of the compound or a pharma- ceutical acceptable salt thereof according to any one of items 1 to 4 for the manufacture of an NLRP3 inflammasome inhibitor. [Section 15] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's disease, Item 5. Use of the compound or a pharmacokinetic / metabolic syndrome (MSS), 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, or a pharmacokinetic / metabolic syndrome (MES). [Section 16] Item 16. The use according to Item 15, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 17] Item 16. The use according to Item 15, 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 18] Item 5. The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 4 for use in inhibiting NLRP3 inflammasome. [Section 19] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitz's disease Item 5. The compound or a pharmacologic agent thereof according to any one of Items 1 to 4 for use in the treatment or prevention of a disease selected from the group consisting of chronic myocardial infarction, chronic obstructive pulmonary disease, chronic pulmonary disease, chronic pulmonary syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 20] Item 20. The compound or a pharma- ceutically acceptable salt thereof according to item 19, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 21] Item 20. The compound or a pharma- ceutically acceptable salt thereof according to item 19, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 22] Item 5. A pharmaceutical composition according to Item 5, and a method for administering the pharmaceutical composition to a patient having an illness, 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), and a method for administering the pharmaceutical composition to a patient having an illness, such as ... and a commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of idiopathic pulmonary fibrosis (IPF) syndrome, Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome. [Section 23] Item 5. A pharmaceutical composition according to Item 5, and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel ...). and a commercial kit comprising a description of the pharmaceutical composition, the description of which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of 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 1A] A compound of formula [IA] or a pharma- ceutically acceptable salt thereof (hereinafter, in this specification, "a compound of formula [IA] or a pharma- ceutically acceptable salt thereof" is also referred to as "compound [IA]"). [ka] [In the formula, the bond: [ka] is a single bond or a double bond, R 1 and R 2 are each independently (1) Hydrogen, (2) Hydroxy, (3) Cyano, (4) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C1-4 Alkoxy, and (c)C 3-6 cycloalkyl; (5) C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (6) halogens, (7) C 1-4 Haloalkyl, (8)-CHO, (9)-OC 1-4 Haloalkyl, (10)-OC 3-6 Cycloalkyl, (11)-CO-C 1-4 Alkyl, (12)-CO-C 3-6 Cycloalkyl, (13)-NR 7 R 8 (where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl; or R 7 and R 8 together with the nitrogen atom to which they are attached, -NR 7 R 8 the groups may form a 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or (14) C 3-6 cycloalkyl, R 3A and R 4A are each independently (1) Hydrogen, (2) C 1-4 Alkyl, or (3) C 1-4 haloalkyl, R 5A teeth, (1) Hydrogen, (2) Cyano, (3) C 1-6 Alkyl, (4) C2-6 Alkenyl, (5) C 2-5 Alkynyl, (6) C 1-4 Alkoxy, (7) halogens, (8) C 1-6 Haloalkyl, (9) C 2-6 Haloalkenyl, (10)-OC 1-4 Haloalkyl, (11) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; (12) C 5-6 cycloalkenyl, or (13) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; or R 5A is R 3A or R 4A together with the carbon atoms to which they are attached (1) C 5-6 Cycloalkene, or (2) may form a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; R 6A is independently (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) halogens, (4) C 1-4 haloalkyl, or (5) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; m is 0, 1, or 2; When m is 2, Two adjacent R 6A is the X where these are bonded 1 , X 2 , X 3 , X 4 and X 5 may be taken together with adjacent two of: n is 0 or 1, When n is 0, X 1 , X 2 , X 3 and X 4 are each independently a carbon, nitrogen, oxygen or sulfur atom, 1 , X 2 , X 3 Or X 4 The total number of nitrogen, oxygen and sulfur atoms as X is 1, 2 or 3, and the total number of oxygen and sulfur atoms as X is 0 or 1; 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl, When n is 1, X 1 , X 2 , X 3 , X 4 and X 5 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , X 4 Or X 5 The total number of nitrogen atoms as X is 1 or 2; 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 and together with adjacent carbon atoms form a heteroaryl. [Section 2A] R 3A and R 4A The compound according to Item 1A, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. [Section 3A] The compound according to item 1A or 2A, which is represented by formula [IIA], or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 and m has the same meaning as in Item 1A). [Section 4A] X 1 , X 2 , X 3 and X 4 But X 1 and X 4 and R 2 , taken together with adjacent carbon atoms, form a pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, or triazolyl group, or a pharma- ceutically acceptable salt thereof according to any one of items 1A to 3A. [Section 5A] X 1 , X 2 , X 3 and X 4 But X 1 and X 4 and R 2 are taken together with adjacent carbon atoms to form a pyrazolyl, imidazolyl, or thiazolyl group, or a pharma- ceutically acceptable salt thereof according to any one of items 1A to 4A. [Section 6A] X 1 , X 2 , X 3 and X 4 But X 1 and X 4 and together with the adjacent carbon atoms, Formula (1): [ka] , Equation (2): [ka] or formula (3): [ka] The compound according to any one of items 1A to 5A, or a pharma- ceutically acceptable salt thereof, which forms: [Section 7A] The compound according to item 1A or 2A, which is represented by formula [IIIA], or a pharma- ceutically acceptable salt thereof. [ka] (In the formula, R 1 , R 2 , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 and m has the same meaning as in Item 1A). [Section 8A] X 1 , X 2 , X 3 , X 4 and X 5 But X 1 and X 5 and taken together with adjacent carbon atoms to form pyridyl, pyridazinyl, pyrimidyl, or pyrazinyl, or a pharma- ceutically acceptable salt thereof according to any one of items 1A, 2A, and 7A. [Section 9A] X 1 , X 2 , X 3 , X 4 and X 5 But X 1 and X 5 and , taken together with adjacent carbon atoms, form pyridazinyl or pyrimidyl, or a pharma- ceutically acceptable salt thereof, according to any one of items 1A, 2A, 7A, and 8A. [Section 10A] X1 , X 2 , X 3 , X 4 and X 5 But X 1 and X 5 and together with the adjacent carbon atoms, Formula (1'): [ka] or formula (2'): [ka] The compound according to any one of items 1A, 2A, 7A, 8A and 9A, or a pharma- ceutically acceptable salt thereof, which forms: [Section 11A] The compound or a pharma- ceutically acceptable salt thereof according to any one of Items 1A to 10A, wherein m is 0 or 1. [Section 12A] R 1 and R 2 At least one of C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6 cycloalkyl; The compound according to any one of items 1A to 11A, or a pharma- ceutically acceptable salt thereof, wherein R is halogen. [Section 13A] The structural formula: [ka] or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: [Section 14A] A pharmaceutical composition comprising the compound according to any one of items 1A to 13A or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. [Section 15A] An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1A to 13A or a pharma- ceutically acceptable salt thereof. [Section 16A] The present invention relates to a compound according to any one of items 1A to 13A or a pharma- ceutical agent for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multi-organ inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and A therapeutic or preventive agent for a disease selected from the group consisting of 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. [Section 17A] The therapeutic or preventive agent according to Item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 18A] Item 16A. The treatment or prevention 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 multi-organ inflammatory disease. [Section 19A] The treatment or prevention agent according to Item 16A, wherein the disease is selected from the group consisting of multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, and hereditary transient corneal endotheliitis. [Section 20A] A method for inhibiting NLRP3 inflammasome, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of paragraphs 1A to 13A or a pharma- ceutically acceptable salt thereof. [Section 21A] 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 rheumatoid arthritis), and the like, comprising administering to a mammal a therapeutically effective amount of the compound according to any one of items 1A to 13A or a pharmacologic salt thereof. A method for treating or preventing a disease selected from the group consisting of inflammatory bowel disease, myelopathy, rheumatoid arthritis, 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 22A] The method according to paragraph 21A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 23A] The method according to item 21A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 24A] The method according to Item 21A, wherein the disease is selected from the group consisting of multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, and hereditary transient corneal endotheliitis. [Section 25A] Use of the compound or a pharma- ceutical acceptable salt thereof according to any one of items 1A to 13A for the manufacture of an NLRP3 inflammasome inhibitor. [Section 26A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndromes (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, family Item 13. Use of the compound or a pharmacologic agent thereof according to any one of Items 1A to 13A for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of chronic 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 27A] The use according to paragraph 26A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 28A] The use according to Item 26A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 29A] The use according to Item 26A, wherein the disease is selected from the group consisting of multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, and hereditary transient corneal endotheliitis. [Section 30A] The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1A to 13A for use in inhibiting NLRP3 inflammasome. [Section 31A] Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g. acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g. hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, The compound or a pharmacologic acceptable salt thereof according to any one of items 1A to 13A for use in the treatment or prevention of a disease selected from the group consisting of familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. [Section 32A] The compound or a pharma- ceutically acceptable salt thereof according to Item 31A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [Section 33A] The compound or a pharma- ceutically acceptable salt thereof according to Item 31A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, or neonatal-onset multi-organ inflammatory disease. [Section 34A] The compound or a pharma- ceutical acceptable salt thereof according to Item 31A, wherein the disease is selected from the group consisting of multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, and hereditary transient corneal endotheliitis. [Section 35A] A pharmaceutical composition according to Item 14A, and a method for treating multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological, cutaneous, and articular syndrome, and neonatal-onset multiorgan inflammatory disease), nonalcoholic 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, I and a commercial package comprising a description of the pharmaceutical composition, the description of which states that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of 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 36A] The pharmaceutical composition according to Item 14A, and a method for administering the pharmaceutical composition to a patient having an inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset multi-organ inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler's syndrome, A commercial kit comprising a description of the pharmaceutical composition, the description of which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic 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 PREFERRED EMBODIMENTS

[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. Preferred are methyl and ethyl. More preferred is methyl.

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

[0046] "C 2-6 "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one double bond. 2-6 "Alkenyl" includes, for example, vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,1-dimethyl-2-propenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, and 1-methyl-2-butenyl.

[0047] "C 2-5 "Alkynyl" means a straight or branched unsaturated hydrocarbon group containing from 2 to 5 carbon atoms and containing at least one triple bond. 2-5 "Alkynyl" includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 2-pentynyl.

[0048] "C 1-4 Alkoxy means the above "C 1-4"C" means a group in which "alkyl" is bonded to an oxygen atom. 1-4 "Alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferably, it is methoxy.

[0049] "C 1-6 Alkoxy means the above "C 1-6 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-6 "Alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, and 2-ethylbutoxy.

[0050] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine.

[0051] "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. Difluoromethyl and trifluoromethyl are preferred.

[0052] "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 and 1,1-difluoroethyl.

[0053] "C 2-6 "Haloalkenyl" refers to the above "C" substituted with 1 to 9 halogens independently selected from the above "halogen" group. 2-6 "C" means "alkenyl". 2-6 "Haloalkenyl" includes, for example, 2-fluoroethenyl, 3-chloropropenyl, 2-fluoropropenyl, 1-trifluoromethylethenyl, and 4,4,4-trifluoro-2-butenyl.

[0054] "C 3-6 "Cycloalkyl" means a monocyclic saturated hydrocarbon ring group having 3 to 6 carbon atoms. 3-6 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred is cyclopropyl.

[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. Cyclopentene is preferred.

[0056] "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.

[0057] "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms in addition to carbon atoms as ring-constituting atoms. "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, and dioxanyl. Oxetanyl is preferred.

[0058] "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, in addition to carbon atoms as ring-constituting atoms. "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, and dioxanyl.

[0059] The term "5- to 7-membered heterocycloalkane containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- to 7-membered monocyclic saturated heterocycle 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 7-membered heterocycloalkane containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, pyrrolidine, tetrahydrofuran, imidazolidine, pyrazolidine, dioxolane, oxazolidine, isoxazolidine, piperidine, tetrahydropyran, 1,2-diazacyclohexane, 1,3-diazacyclohexane, piperazine, dioxane, morpholine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, azepane, oxepane, diazepane (e.g., 1,4-diazepane), dioxepane (e.g., 1,4-dioxepane), and oxazepane (e.g., 1,4-oxazepane and 1,2-oxazepane). Pyrrolidine, morpholine, and tetrahydro-1,3-oxazine are preferred.

[0060] "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 and at least one double bond in addition to carbon atoms as ring-constituting atoms. "5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms" includes, for example, dihydrofuran, dioxole, dihydropyran, dihydrodioxine, pyran, tetrahydrooxepin, dihydrodioxepin, dihydrooxepin, and dioxepin. Dihydropyran is preferable.

[0061] The term "5- to 7-membered heterocycloalkene containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" means a 5- to 7-membered monocyclic partially unsaturated heterocycle which contains, in addition to carbon atoms as ring-constituting atoms, 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms and contains at least one double bond. "5- to 7-membered heterocycloalkene containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms" includes, for example, pyrroline, pyrazoline, imidazoline, dihydrofuran, dioxole, oxazoline, isoxazoline, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, tetrahydropyrazine, dihydropyridine, dihydropyran, dihydrodioxine, pyran, dihydrooxazine, tetrahydroazepine, tetrahydrodiazepine, dihydroazepine, dihydrodiazepine, tetrahydrooxepine, dihydrodioxepine, dihydrooxepine, dioxepine, tetrahydrooxazepine, and dihydrooxazepine. Pyrroline and dihydrooxazine are preferred.

[0062] In one embodiment of the present invention, n in formula [I] and formula [IA] is 0, and X 1 , X 2 , X 3 and X 4 are each independently a carbon, nitrogen, oxygen or sulfur atom; X 1 , X 2 , X 3 and X 4 X1 and X 4 and adjacent carbon atoms together to form a heteroaryl, where X 1 , X 2 , X 3 Or X 4 The total number of nitrogen, oxygen and sulfur atoms as the heteroaryl group is 1, 2 or 3, and the total number of oxygen and sulfur atoms is 0 or 1. That is, the heteroaryl group means a 5-membered monocyclic aromatic heterocyclic group which contains, other than carbon atoms as ring-constituting atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms, and the total number of oxygen and sulfur atoms is 0 or 1. Such heteroaryls include, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl), and triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl).Preferably, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl. More preferred are pyrazolyl, imidazolyl and thiazolyl. Further preferred are the following groups: [ka] It is.

[0063] In another embodiment of the present invention, n in formula [I] and formula [IA] is 1, and X 1 , X 2 , X 3 , X 4 and X 5 are each independently a carbon or nitrogen atom; X 1 , X 2 , X 3 , X 4 and X 5X 1 and X 5 and adjacent carbon atoms together to form a heteroaryl, where X 1 , X 2 , X 3 , X 4 Or X 5 The total number of nitrogen atoms as the heteroaryl is 1 or 2. That is, the heteroaryl means a 6-membered monocyclic aromatic heterocyclic group containing 1 or 2 nitrogen atoms as ring-constituting atoms other than carbon atoms. Such heteroaryl includes, for example, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl. Pyrimidyl and pyridazinyl are preferred. More preferred are the following groups: [ka] It is.

[0064] In some embodiments of the present invention, the moiety of formula [IA]: [ka] is two adjacent R 6A However, these are combined with X 1 , X 2 , X 3 , X 4 and X 5 When two of the above are taken together to form a ring structure, the ring structure as a whole forms an 8- to 11-membered partially unsaturated fused ring group containing 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Examples of the fused ring group include the following groups: [ka] Examples include:

[0065] In some embodiments of the present invention, the moiety of formula [IA]: [ka] is R 5A R 3A or R 4Aand, when taken together with the carbon atom to which they are attached to form a ring structure, as a whole, a 9- to 11-membered partially unsaturated fused ring group which may contain one or two oxygen atoms, R 1 and R 2 and R 3A or R 4A The fused ring group is substituted with, for example, the following group: [ka] Examples include:

[0066] The phrase "α may be substituted" with β means that α is unsubstituted or any substitutable hydrogen of α is replaced with β. For example, "C optionally substituted with hydroxy" means that 1-6 "Alkyl" means C 1-6 The alkyl is unsubstituted or 1-6 This means that any hydrogen in the alkyl is replaced with hydroxy.

[0067] Specific embodiments of each substituent of the compounds of formula [I] and formula [IA] are exemplified below, but each substituent of the compounds of formula [I] and formula [IA] is not limited to the specific embodiments, and the compounds of formula [I] and formula [IA] also include embodiments in which any two or more of the specific embodiments of each substituent are combined.

[0068] R 1 and R 2 are preferably each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6 cycloalkyl; (3) C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (4) halogens, (5) C 1-4 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 Cycloalkyl.

[0069] R 1 and R 2 are preferably each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6 cycloalkyl; (3) Halogen.

[0070] R 1 and R 2 More preferably, each independently represents C 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 substituted with alkoxy).

[0071] R 3 and R 4 is preferably hydrogen.

[0072] R 5 is preferably (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6Cycloalkyl, where the cycloalkyl is selected from 1 to 3 halogens or C 1-4 may be substituted with haloalkyl.

[0073] Substructure: [ka] is preferably R 1 and R 2 are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6 cycloalkyl; (3) C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (4) halogens, (5) C 1-4 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; R 3 and R 4 is preferably hydrogen; R 5 teeth, (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6Cycloalkyl, where the cycloalkyl is selected from 1 to 3 halogens or C 1-4 may be substituted with haloalkyl.

[0074] R 3A and R 4A are preferably each independently hydrogen or C 1-4 It is an alkyl.

[0075] R 3A and R 4A is more preferably hydrogen.

[0076] R 5A is preferably (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; R 5A is R 3A or R 4A together with the carbon atoms to which they are attached (1) C 5-6 Cycloalkene, or (2) Forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.

[0077] R 5A is more preferably (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0078] R 5A More preferably, (1) Halogen, or (2) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0079] R 5A is even more preferably C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0080] Substructure: [ka] is preferably R 1 and R 2 are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6cycloalkyl; (3) a halogen; R 3A and R 4A are each independently hydrogen or C 1-4 is alkyl; R 5A teeth, (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; R 5A is R 3A or R 4A together with the carbon atoms to which they are attached (1) C 5-6 Cycloalkene, or (2) Forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms.

[0081] Substructure: [ka] is more preferably R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 3A and R4A is hydrogen; R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0082] Substructure: [ka] More preferably, R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 3A and R 4A is hydrogen; R 5A teeth, (1) Halogen, or (2) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0083] Substructure: [ka] is even more preferably R 1 and R 2 are each independently 1-6Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 3A and R 4A is hydrogen; R 5A is C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0084] R 6 is preferably (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) Halogen, or (4) C 1-4 Haloalkyl.

[0085] R 6A is preferably independently (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) Halogen, or (4) C 1-4 Haloalkyl.

[0086] R 6A More preferably, each independently represents C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy).

[0087] m is preferably 0 or 1.

[0088] X 1 is preferably a carbon, nitrogen, or oxygen atom. X 1 is more preferably a carbon or nitrogen atom.

[0089] X 2 is preferably a carbon or nitrogen atom.

[0090] X 3 is preferably a carbon, nitrogen, or sulfur atom.

[0091] X 4 is preferably a carbon, nitrogen, or sulfur atom. X 4 is more preferably a carbon atom.

[0092] X 5 is preferably a carbon atom.

[0093] n is preferably 0.

[0094] Substructure: [ka] When n is 0, preferably m is 0 or 1; R 6A teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4 the total number of nitrogen, oxygen and sulfur atoms as is 1, 2, or 3, and the total number of oxygen and sulfur atoms as is 0 or 1); X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0095] Substructure: [ka] is more preferably, when n is 0, m is 0 or 1; R 6A teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4 the total number of nitrogen, oxygen and sulfur atoms as the ring structure is 2 or 3, and the total number of oxygen and sulfur atoms as the ring structure is 0 or 1; X 1 , X 2 , X3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0096] Substructure: [ka] is more preferably, when n is 0, m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); X 1 is a nitrogen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, or sulfur atom; X 4 is a carbon atom (where X 1 , X 2 , or X 3 The total number of nitrogen and sulfur atoms in the X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0097] Substructure: [ka] is even more preferably, when n is 0, formula: [ka] ,formula: [ka] or the formula: [ka] , and m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy).

[0098] Substructure: [ka] is preferably, when n is 1, m is 0 or 1; R 6A teeth, (1) C 1-4 Alkoxy, (2) Halogen, or (3) C 1-4 haloalkyl; X 1 , X 2 , X 3 , and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , or X 4 the total number of nitrogen atoms as is 1 or 2); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with adjacent carbon atoms to form a heteroaryl.

[0099] Substructure: [ka] is more preferably, when n is 1, m is 0; X1 , and X 2 are each independently a carbon or nitrogen atom; X 3 is a nitrogen atom (where X 1 , X 2 , or X 3 The total number of nitrogen atoms as is 2); X 4 , and X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with adjacent carbon atoms to form a heteroaryl.

[0100] Substructure: [ka] is more preferably, when n is 1, formula: [ka] or formula: [ka] , is.

[0101] Substructure: [ka] is preferably m is 0 or 1; R 6A teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4 the total number of nitrogen, oxygen and sulfur atoms as the ring structure is 2 or 3, and the total number of oxygen and sulfur atoms as the ring structure is 0 or 1; X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0102] Substructure: [ka] is more preferably m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4the total number of nitrogen, oxygen and sulfur atoms as the ring structure is 2 or 3, and the total number of oxygen and sulfur atoms as the ring structure is 0 or 1; X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0103] Substructure: [ka] More preferably, m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); X 1 is a nitrogen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, or sulfur atom; X 4 is a carbon atom (where X 1 , X 2 , or X 3 The total number of nitrogen and sulfur atoms in the X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0104] Substructure: [ka] is even more preferably formula: [ka] ,formula: [ka] or the formula: [ka] , and m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy).

[0105] Substructure: [ka] is preferably m is 0 or 1; R 6A teeth, (1) C 1-4 Alkoxy, (2) Halogen, or (3) C 1-4 haloalkyl; X 1 , X 2 , X 3 , and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , or X 4 the total number of nitrogen atoms as is 1 or 2); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with adjacent carbon atoms to form a heteroaryl.

[0106] Substructure: [ka] is more preferably m is 0; X 1 , and X 2 are each independently a carbon or nitrogen atom; X 3 is a nitrogen atom (where X 1 , X 2 , or X 3 The total number of nitrogen atoms as is 2); X 4 , and X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with adjacent carbon atoms to form a heteroaryl.

[0107] Substructure: [ka] More preferably, formula: [ka] or formula: [ka] , is.

[0108] One preferred embodiment of the compound of formula [I] is R 1 and R 2 are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C3-6 cycloalkyl; (3) C 1-6 Alkoxy, wherein the alkoxy is 3-6 optionally substituted with cycloalkyl; (4) halogens, (5) C 1-4 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; R 3 and R 4 is preferably hydrogen; R 5 teeth, (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 haloalkyl, or (7) C 3-6 Cycloalkyl, where the cycloalkyl is selected from 1 to 3 halogens or C 1-4 (optionally substituted with haloalkyl); R 6 teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) Halogen, or (4) C 1-4 haloalkyl; m is 0, 1, or 2; n is 0 or 1; When n is 0, X 1 , X 2 , X 3 and X 4are each independently a carbon, nitrogen, oxygen or sulfur atom, 1 , X 2 , X 3 Or X 4 The total number of nitrogen, oxygen and sulfur atoms as X is 1, 2 or 3, and the total number of oxygen and sulfur atoms as X is 0 or 1; 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl; When n is 1, X 1 , X 2 , X 3 , X 4 and X 5 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , X 4 Or X 5 The total number of nitrogen atoms as X is 1 or 2; 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 and taken together with adjacent carbon atoms to form a heteroaryl,

[0109] A preferred embodiment of the compound of formula [IA] is R 1 and R 2 are each independently (1) Hydrogen, (2) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, and (c)C 3-6 cycloalkyl; (3) a halogen; R3A and R 4A are each independently (1) Hydrogen, or (2) C 1-4 alkyl; R 5A teeth, (1) Hydrogen, (2) C 1-6 Alkyl, (3) C 1-4 Alkoxy, (4) halogens, (5) C 1-6 Haloalkyl, (6)-OC 1-4 Haloalkyl, (7) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; R 5A is R 3A or R 4A together with the carbon atoms to which they are attached (1) C 5-6 Cycloalkene, or (2) forming a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms; m is 0 or 1; R 6A teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 Alkoxy, (3) Halogen, or (4) C 1-4 haloalkyl; n is 0 or 1; When n is 0, X 1 is a carbon, nitrogen or oxygen atom; X2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4 the total number of nitrogen, oxygen and sulfur atoms as the ring structure is 2 or 3, and the total number of oxygen and sulfur atoms as the ring structure is 0 or 1; X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl; When n is 1, X 1 , X 2 , X 3 , and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , or X 4 the total number of nitrogen atoms as is 1 or 2); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 and together with adjacent carbon atoms form a heteroaryl,

[0110] Another preferred embodiment of the compound of formula [IA] is R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 3A and R 4Ais hydrogen; R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 alkoxy); n is 0 or 1; When n is 0, X 1 is a nitrogen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, or sulfur atom; X 4 is a carbon atom (where X 1 , X 2 , or X 3 The total number of nitrogen and sulfur atoms in the X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl; When n is 1, X 1 , and X 2 are each independently a carbon or nitrogen atom; X 3 is a nitrogen atom (where X 1 , X 2 , or X 3 The total number of nitrogen atoms as is 2); X 4 , and X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 and together with adjacent carbon atoms form a heteroaryl,

[0111] Yet another preferred embodiment of the compound of formula [IA] is the compound of formula [IIA]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A teeth, (1) C 1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (wherein X 1 , X 2 , X 3 Or X 4 the total number of nitrogen, oxygen and sulfur atoms as the ring structure is 2 or 3, and the total number of oxygen and sulfur atoms as the ring structure is 0 or 1; X 1 , X 2 , X 3 and X 4 X 1 and X 4 together with adjacent carbon atoms to form a heteroaryl.

[0112] Yet another preferred embodiment of the compound of formula [IA] is the compound of formula [IIIA]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R6A teeth, (1) C 1-4 Alkoxy, (2) Halogen, or (3) C 1-4 haloalkyl; X 1 , X 2 , X 3 , and X 4 are each independently a carbon or nitrogen atom (wherein X 1 , X 2 , X 3 , or X 4 the total number of nitrogen atoms as is 1 or 2); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with adjacent carbon atoms to form a heteroaryl.

[0113] A preferred embodiment of the compound of formula [IIA] is R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A teeth, (1) C1-4 Alkyl, wherein the alkyl is 1-4 optionally substituted with alkoxy; (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 , X 2 , X 3 and X 4 But X 1 and X 4 together with the adjacent carbon atoms to form a pyrazolyl, imidazolyl, or thiazolyl.

[0114] Another preferred embodiment of the compound of formula [IIA] is the compound of formula [IIA-I]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy.

[0115] Yet another preferred embodiment of the compound of formula [IIA] is the compound of formula [IIA-II]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy.

[0116] Yet another preferred embodiment of the compound of formula [IIA] is the compound of formula [IIA-III]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0 or 1; R 6A is C 1-4 Alkyl, wherein the alkyl is 1-4 substituted with alkoxy.

[0117] A preferred embodiment of the compound of formula [IIIA] is R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; m is 0; X 1 , X 2 , X 3 , X 4 and X 5 X 1 and X 5 together with the adjacent carbon atoms to form a pyridazinyl or pyrimidyl.

[0118] Another preferred embodiment of the compound of formula [IIIA] is the compound of formula [IIIA-I]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0119] Yet another preferred embodiment of the compound of formula [IIIA] is the compound of formula [IIIA-II]: [ka] A compound represented by the formula: R 1 and R 2 are each independently 1-6 Alkyl (wherein the alkyl is hydroxy or C 1-4 alkoxy); R 5A teeth, (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl}.

[0120] Another preferred embodiment of the compound of formula [IA] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X], or [XI]: [ka] [In the formula, R 1 , R 2 , R 3A , and R 4A has the same meaning as in Section 1A. It is a compound represented by the formula:

[0121] As used herein, the term "pharmaceutical acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutical acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, p1-19 (1977); (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, a pharma- ceutically acceptable salt thereof can be obtained by reacting a compound of formula [I] or formula [IA] with an inorganic acid, an organic acid, an inorganic base, or an organic base.

[0122] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid, and preferably salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid. Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferred examples of the salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and 2-hydroxy-1-ethanesulfonic acid.

[0123] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium, and preferably salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferred are salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0124] Compound [I] or compound [IA] may exist as a solvate. A solvate is, for example, a compound [I] or compound [IA] coordinated with a solvent molecule. The solvate may be any pharma- ceutically acceptable solvate, and may include hydrate, acetate solvate, acetone solvate, ethanol solvate, and dimethylsulfoxide solvate of compound [I] or compound [IA]. Specifically, the solvate may include hemihydrate, monohydrate, dihydrate, monoacetate solvate, monoacetone solvate, or monoethanol solvate of the sodium salt of the compound of formula [I] or formula [IA], or monohydrate, monoacetone solvate, or 2 / 3 ethanol solvate of the dihydrochloride salt of the compound of formula [I] or formula [IA]. These solvates may be obtained according to known methods.

[0125] Compound [I] or compound [IA] may exist as a tautomer. In that case, compound [I] or compound [IA] may exist as an individual tautomer or a mixture of tautomers. For example, the compound [I] or compound [IA] may exist as a tautomer of the following formula: [ka] The structure shown in is, unless otherwise noted, (1) [ka] (2) [ka] (3) [ka] (4) [ka] or (5) It means that these mixtures can exist and / or be expressed as such. Compound [I] or compound [IA] may have a carbon-carbon double bond. In that case, compound [I] or compound [IA] may exist as an E form, a Z form, or a mixture of E and Z forms. Compound [I] or compound [IA] may have stereoisomers that should be recognized as cis / trans isomers. In that case, compound [I] or compound [IA] may exist as a cis form, a trans form, or a mixture of cis and trans forms. Compound [I] or compound [IA] may have one or more asymmetric carbon atoms. In that case, compound [I] or compound [IA] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers. Compound [I] or compound [IA] may exist as atropisomers, in which case compound [I] or compound [IA] may exist as an individual atropisomer or a mixture of atropisomers. Compound [I] or compound [IA] may simultaneously contain multiple structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0126] In this specification, formulae, chemical structures or compound names expressed without specifying stereochemistry include all of the above-mentioned isomers that may exist, unless otherwise noted.

[0127] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization, or the individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or by stereoselective reactions.

[0128] Separation of the individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a diastereomeric mixture formed by reacting a mixture of enantiomers with a substantially pure enantiomer, known as a chiral auxiliary, by standard methods such as fractional crystallization or chromatography. The separated diastereomer can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, well known in the art. Alternatively, one of the enantiomers can be obtained by using substantially pure optically active starting materials or by stereoselective synthesis (asymmetric induction) of prochiral intermediates using chiral auxiliaries and asymmetric catalysts.

[0129] Absolute configuration may be determined by the X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0130] Compound [I] or compound [IA] 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, 123I, etc. For example, when the compound of formula [I] or formula [IA] has a methyl group, the methyl group can be replaced with a -CD3 group, and the compound obtained in this way is also included in the present invention. The isotopically labeled compound [I] or compound [IA] can be useful in medicine, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostics (positron emission tomography (PET), single photon emission computed tomography (SPECT), etc.). The isotopically labeled compound [I] or compound [IA] can be prepared by using an isotopically labeled compound instead of a non-isotopically labeled compound according to known methods or the methods described herein.

[0131] Compound [I] or compound [IA] is preferably a substantially purified compound [I] or compound [IA], more preferably a compound [I] or compound [IA] purified to a purity of 80% or more.

[0132] The pharmaceutical composition of the present invention may be prepared by mixing compound [I] or compound [IA] with at least one or more pharma- ceutically acceptable carriers in an appropriate amount, as appropriate, according to a method known in the technical field of pharmaceutical preparations. The content of compound [I] or compound [IA] in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the entire composition.

[0133] Dosage forms of compound [I] or compound [IA] include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0134] Examples of "pharmaceutical acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid preparations, solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used as necessary.

[0135] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like. Examples of "binders" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like. The "fluidizing agent" includes light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like. "Soothing agents" include benzyl alcohol and the like. Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more of these. Examples of the "preservatives" include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. Examples of "coloring agents" include food dyes (food red No. 2 or 3, food yellow No. 4 or 5, etc.), β-carotene, and the like. "Sweetening agents" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0136] The pharmaceutical composition of the present invention can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to mammals other than humans (mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.) and humans. The dosage (also referred to as "therapeutically effective amount" in this specification) varies depending on the subject of administration, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when orally administered to an adult patient is usually in the range of about 0.01 mg to 1 g per day as the compound of formula [I] or formula [IA] or a pharma- ceutical acceptable salt thereof, which is the active ingredient. These amounts can be administered once or in several divided doses.

[0137] Compound [I] or compound [IA] has an NLRP3 inflammasome inhibitory effect, and is therefore useful for the treatment and / or prevention of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity. Examples of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome, and neonatal-onset 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 lymphoid tissue inflammation), and the like. 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.

[0138] "Inhibiting NLRP3 inflammasome" means inhibiting the function of NLRP3 inflammasome to eliminate or weaken its activity, for example, means inhibiting the function of NLRP3 inflammasome based on the conditions of Test Example 1 described below. By inhibiting the function of NLRP3 inflammasome, the production amount of IL-1β and / or IL-18 is suppressed, preferably the production amount of IL-1β and IL-18 is suppressed. "Inhibiting NLRP3 inflammasome" preferably means "inhibiting human NLRP3 inflammasome".

[0139] Since compound [I] or compound [IA] has NLRP3 inflammasome inhibitory activity, compound [I] or compound [IA] or a pharma- ceutically acceptable salt thereof can be used as an NLRP3 inflammasome inhibitor either as is or after being appropriately formulated.

[0140] As used herein, "treatment" includes amelioration of symptoms, prevention of aggravation, maintenance of remission, prevention of recurrence, and even prevention of recurrence. As used herein, "prevention" includes suppressing and delaying the onset of symptoms.

[0141] As long as there is no contradiction between an embodiment disclosed in one place in this specification and an embodiment disclosed in another place, any combination of two or more of these is also intended to be encompassed by the present invention.

[0142] [General manufacturing method] General methods for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof are exemplified below. However, the methods for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof are not limited to these methods. The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they can be used to proceed to the next step without isolation and / or purification. In this specification, room temperature refers to a temperature in an uncontrolled state, and one embodiment is a temperature between 1°C and 40°C. 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

[0143] Production method A1: Production method of compound [I] or a salt thereof Compound [I] or a salt thereof can be produced, for example, by the following Production Method A1. [ka] {where, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; R A11 are each independently 1-4 is alkyl, R A12 is a boronic acid, a boronic 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 acids include sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid, and p-toluenesulfonic acid. Preferred acids are sulfuric acid or p-toluenesulfonic acid. Examples of the solvent include toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. A preferred solvent is toluene. The reaction temperature is, for example, from 0°C to 150°C, preferably from 5°C to 40°C. The compound [A1-1] or a salt thereof is a commercially available product, or may be 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.

[0144] (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 bases include triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene, and N,N-diisopropylethylamine. A preferred base is triethylamine or N,N-diisopropylethylamine. Examples of the solvent include toluene, methanol, ethanol, tetrahydrofuran, and mixtures thereof. The preferred solvent is toluene or methanol. The reaction temperature is, for example, from -78°C to 100°C, preferably from 0°C to 40°C. The compound [A1-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0145] (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.

[0146] (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. Bases include, for example, 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, from 0°C to 150°C, preferably from 50°C to 100°C.

[0147] (Process A1-5) Compound [I] or a salt thereof can be produced by reacting compound [A1-7] or a salt thereof with 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(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]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 bases include tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. A preferred base is tripotassium phosphate. R A12 When the boronic acid is, for example, a boronic acid ester (such as a pinacol boronic acid ester), or a trifluoroborate, the solvent may be, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, or a mixture thereof. A preferred solvent is a mixture 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 dimethylsulfoxide. The preferred solvent is N,N-dimethylacetamide. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [A1-8] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0148] In this manufacturing 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 a known reaction, or a salt thereof, is used to carry out this manufacturing method, and a compound corresponding to compound [I] or a salt thereof is obtained, and then the functional group or the protected substituent is converted to the various substituents to produce compound [I] or a salt thereof. For example, 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 a known reaction, or a salt thereof, is used to produce compound [I] or a salt thereof. A41 The present production method is carried out using a hydrazine compound or a salt thereof having a phenyl group substituted therewith, to obtain a compound corresponding to compound [I], i.e., compound [IA] or a salt thereof, and then the compound is reacted with L A41 Cy A41 The compound [IB] or a salt thereof may be prepared by converting the compound [IB] into

[0149] Production method A1A: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can be produced in the same manner as in production method A1 by using compound [A1A-4] or a salt thereof instead of compound [A1-4] or a salt thereof, and compound [A1A-8] or a salt thereof instead of compound [A1-8] or a salt thereof. [ka] (wherein each symbol is as defined above) The compound [A1A-4] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A1A-8] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0150] In this production method, instead of compound [A1A-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 a known reaction, 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 the functional group or the protected substituent may be converted to the various substituents to produce compound [IA] or a salt thereof. For example, instead of compound [A1A-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 a known reaction, or a salt thereof, may be used to produce compound [IA] or a salt thereof. A41 or a salt thereof, to obtain a compound corresponding to compound [IA], i.e., compound [IA-A] or a salt thereof, and then subjecting L to Production Method A4A. A41 Cy A41A Compound [IA-B] or a salt thereof may be prepared by converting the compound [IA-B] into the following compound:

[0151] Production method A2: Production method of compound [I] or a salt thereof Compound [I] or a salt thereof can also be produced, for example, by the following Production Method A2. [ka] {where, R 1 , R 2 , R 3 , R 4 , R 5 , R 6, X 1 , X 2 , X 3 , X 4 , X 5 , m, n, L A11 , L A12 , and R A12 is as defined above, R A21 is a protecting group for a hydroxy group (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. Alcohols include, for example, benzyl alcohol, 4-methoxybenzyl alcohol and 2-methoxybenzyl alcohol. A preferred alcohol is benzyl alcohol. Examples of the base include sodium hydride, potassium tert-butoxide, and sodium tert-butoxide. A preferred base is sodium hydride. Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and 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.

[0152] (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(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II). Preferred catalysts are [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II). Examples of bases include tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. Preferred bases are tripotassium phosphate or lithium chloride. R A12 When the boronic acid is, for example, a boronic acid ester (such as a pinacol boronic acid ester), or a trifluoroborate, the solvent may be, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide, or a mixture thereof. A preferred solvent is a mixture 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 dimethylsulfoxide. The preferred solvent is N,N-dimethylacetamide. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C.

[0153] (Process A2-3) The compound [I] or a salt thereof can be produced by reacting the compound [A2-2] or a salt thereof in the presence of an acid. 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.

[0154] Production method A2A: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can also be prepared, for example, by the following Preparation Method A2A. [ka] (wherein each symbol is as defined above) (Process A2A-1) Compound [A2A-1] or a salt thereof can be produced in the same manner as in step A2-1, by using compound [A1A-6] or a salt thereof instead of compound [A1-6] or a salt thereof.

[0155] (Process A2A-2) Compound [A2A-2] or a salt thereof can be produced in the same manner as in step A2-2 by using compound [A1A-8] or a salt thereof instead of compound [A1-8] or a salt thereof.

[0156] (Process A2A-3) 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 [A2A-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. Solvents include, for example, toluene, tetrahydrofuran, and 1,4-dioxane. The reaction temperature is, for example, 0°C to 120°C, preferably 10°C to 100°C.

[0157] Production method A3: Production method of compound [I] or a salt thereof Compound [I] or a salt thereof can also be produced, for example, by the following Production Method A3. [ka] {where, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; R A31 is C 1-4 is alkyl, R A32 is a protecting group for an amino 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. Oxidizing agents include, for example, sodium nitrite, butyl nitrite, and isoamyl nitrite. A 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. A preferred additive is sodium acetate. 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 a commercially available product, or may be prepared from a commercially available product by a known method. The compound [A3-2] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0158] (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 bases 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, from 20°C to 120°C, preferably from 50°C to 100°C. The compound [A3-4] is a commercially available product.

[0159] (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.

[0160] (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. Reactants include, for example, sodium azide and diphenylphosphoryl azide. A preferred reactant is diphenylphosphoryl azide. Examples of bases 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, from 0°C to 150°C, preferably from 50°C to 120°C.

[0161] (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.

[0162] (Process A3-6) The 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 a compound [A3-8] or a salt thereof in a solvent in the presence of an acid. Acids include, for example, hydrogen chloride, trifluoroacetic acid and sulfuric acid. A preferred acid is hydrogen chloride. Examples of the solvent include ethyl acetate, cyclopentyl methyl ether, and mixtures thereof. The 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.

[0163] (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 bases 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-dimethylacetamide, and mixtures thereof. The preferred solvent is N-methylpyrrolidone. The reaction temperature is, for example, from 0°C to 120°C, preferably from 50°C to 100°C. The compound [A3-10] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0164] (Process A3-8) The compound [I] or a salt thereof can be produced by reacting a compound [A3-11] or a salt thereof in a solvent in the presence of a base. Examples of bases 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, from 0°C to 180°C, preferably from 50°C to 150°C.

[0165] 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 [I] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [I] or a salt thereof. For example, instead of compound [A3-1] or a salt thereof, a compound having an amino group and the below-described L A41 or a salt thereof, to obtain a compound corresponding to compound [I], i.e., compound [IA] or a salt thereof, and then, by Production Method A4, A41 Cy A41 The compound [IB] or a salt thereof may be prepared by converting the compound [IB] into

[0166] In this manufacturing 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 manufacturing method, to obtain a compound corresponding to compound [A3-9] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [A3-9] 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. A41or a salt thereof, to obtain a compound corresponding to compound [A3-9], i.e., compound [A3-9-A] or a salt thereof, and then subjecting the compound to production method A5. A41 Cy A41 The compound [A3-9-B] or a salt thereof may be prepared by converting the compound [A3-9-B] into the following compound:

[0167] Production method A3A: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can also be prepared, for example, by the following Preparation Method A3A. [ka] {where, R 1 , R 2 , R 3A , R 4A , R 5A , R 6A , R A31 , R A33 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; R A32A is hydrogen or a protecting group for an amino group (e.g., tert-butoxycarbonyl). (Process A3A-1) Compound [A3A-3] or a salt thereof can be produced in the same manner as in step A3-1 by using compound [A3A-1] or a salt thereof instead of compound [A3-1] or a salt thereof. The compound [A3A-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0168] (Process A3A-2) Compound [A3A-5] or a salt thereof can be produced in the same manner as in step A3-2 by using compound [A3A-3] or a salt thereof instead of compound [A3-3] or a salt thereof.

[0169] (Process A3A-3) Compound [A3A-6] or a salt thereof can be produced in the same manner as in step A3-3 by using compound [A3A-5] or a salt thereof instead of compound [A3-5] or a salt thereof.

[0170] (Process A3A-4) Compound [A3A-7] or a salt thereof can be produced in the same manner as in step A3-4 by using compound [A3A-6] or a salt thereof instead of compound [A3-6] or a salt thereof.

[0171] (Process A3A-5) Compound [A3A-8] or a salt thereof can be produced in the same manner as in step A3-5 by using compound [A3A-7] or a salt thereof instead of compound [A3-7] or a salt thereof.

[0172] (Process A3A-6) The compound [A3A-9] or a salt thereof is R A32A The deprotection reaction can be carried out by removing R A32A The process may be carried out under suitable conditions depending on the type of material. For example, R A32A When is tert-butoxycarbonyl, the compound [A3A-9] or a salt thereof can be produced by reacting the compound [A3A-8] or a salt thereof in a solvent in the presence of an acid. 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. The preferred solvent is ethyl acetate. The reaction temperature is, for example, 0°C to 80°C, preferably 10°C to 50°C. The compound [A3A-9] or a salt thereof may be prepared by subjecting the compound [A3A-7] or a salt thereof to the reaction of step A3A-6 and then the reaction of step A3A-5.

[0173] (Process A3A-7) Compound [A3A-11] or a salt thereof can be produced in the same manner as in step A3-7 by using compound [A3A-9] or a salt thereof instead of compound [A3-9] or a salt thereof, and compound [A3A-10] or a salt thereof instead of compound [A3-10] or a salt thereof. The compound [A3A-10] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0174] (Process A3A-8) Compound [IA] or a salt thereof can be produced in the same manner as in Step A3-8, by using compound [A3A-11] or a salt thereof instead of compound [A3-11] or a salt thereof.

[0175] In this production method, instead of compound [A3A-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 the functional group or the protected substituent may be converted to the various substituents to produce compound [IA] or a salt thereof. For example, instead of compound [A3A-1] or a salt thereof, a compound having an amino group and the below-described L A41 or a salt thereof, to obtain a compound corresponding to compound [IA], i.e., compound [IA-A] or a salt thereof, and then, by production method A4A, L A41 Cy A41A Compound [IA-B] or a salt thereof may be prepared by converting the compound [IA-B] into the following compound:

[0176] In this production method, instead of compound [A3A-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 [A3A-8] or a salt thereof, and then the functional group or the protected substituent may be converted to the various substituents to produce compound [A3A-8] or a salt thereof. For example, instead of compound [A3A-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 [A3A-8], i.e., compound [A3A-8-A] or a salt thereof, and then subjecting the compound to production process A5A to L A41 Cy A41A To prepare the compound [A3A-8-B] or a salt thereof,

[0177] Production method A4: Production method of compound [IB] or a salt thereof Compound [IB] or a salt thereof can be produced, for example, by the following Production Method A4. [ka] {where, R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; Cy A41 is C 3-6 Cycloalkyl, where the cycloalkyl is selected from 1 to 3 halogens or C 1-4 substituted with haloalkyl; 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 [IB] or a salt thereof can be prepared by reacting compound [IA] 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, from 10°C to 200°C, preferably from 50°C to 150°C. Compound [IA] or a salt thereof may be prepared from a commercially available product by a known method. Compound [IA] or a salt thereof may be prepared, for example, by the above-mentioned preparation method. The compound [A4-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.

[0178] Production method A4A: Production method of compound [IA-B] or a salt thereof Compound [IA-B] or a salt thereof can be produced in the same manner as in production method A4 by using compound [IA-A] or a salt thereof instead of compound [IA] or a salt thereof, and compound [A4A-1] or a salt thereof instead of compound [A4-1] or a salt thereof. [ka] [In the formula, R 6A , L A41 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; Cy A41A is C 3-6Cycloalkyl {wherein the cycloalkyl is (a) hydroxy, (b) halogens, and (c)C 1-4 haloalkyl; and Compound [IA-A] or a salt thereof may be prepared from a commercially available product by a known method. Compound [IA-A] or a salt thereof may be prepared, for example, by the above-mentioned preparation method. The compound [A4A-1] or a derivative thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0179] Production method A5: Production method for compound [A3-9-B] or a salt thereof The compound [A3-9-B] or a salt thereof can be produced, for example, by the following Production Method A5. [ka] (wherein each symbol is as defined above) (Process A5-1) Compound [A3-9-B] or a salt thereof can be produced by reacting compound [A3-9-A] or a salt thereof with compound [A4-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. A preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. Examples of bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate. Examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixtures thereof. A preferred solvent is a mixture of toluene and water. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [A3-9-A] or a salt thereof may be produced from a commercially available product by a known method. The compound [A3-9-A] or a salt thereof may be produced, for example, by the above-mentioned production method.

[0180] Production method A5A: Production method for compound [A3A-8-B] or a salt thereof The compound [A3A-8-B] or a salt thereof can be produced, for example, by the following Production Method A5A. [ka] (wherein each symbol is as defined above) (Process A5A-1) The compound [A3A-8-B] or a salt thereof can be produced by reacting the compound [A3A-8-A] or a salt thereof with the compound [A4A-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. A preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride. Examples of bases include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate. Examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixtures thereof. A preferred solvent is a mixture of toluene and water. The reaction temperature is, for example, from 10°C to 200°C, preferably from 50°C to 150°C. The compound [A3A-8-A] or a salt thereof may be produced from a commercially available product by a known method. The compound [A3A-8-A] or a salt thereof may be produced, for example, by the above-mentioned production method.

[0181] Production method A6: Production method of compound [IA] or a salt thereof Compound [IA] or a salt thereof can be prepared, for example, by the following Preparation Method A6. [ka] {where, R 1 , R 2 , R 3A , R 4A , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above; R A61 is hydrogen or a protecting group for an amino group (e.g., trimethylsilyl), R A62 , and R A63 are each independently 1-4 is alkyl, L A61 , and L A62 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy). (Process A6-1) The compound [A6-2] or a salt thereof can be produced by reacting the compound [A6-1] or a salt thereof in a solvent in the presence of a reactant. An acid may be added as necessary. The reactants include lithium bis(trimethylsilyl)amide, ammonia, and ammonium chloride. The preferred reactant is lithium bis(trimethylsilyl)amide. The acid includes, for example, hydrogen chloride and sulfuric acid. Examples of the solvent include methanol, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, from -78°C to 40°C, preferably from -10°C to 10°C. The compound [A6-1] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0182] (Process A6-2) The compound [A6-4] or a salt thereof can be produced by reacting the compound [A6-2] or a salt thereof with the compound [A6-3] or a salt thereof in a solvent. Examples of the solvent include methanol, ethanol, isopropanol, tetrahydrofuran, and mixtures thereof. A preferred solvent is a mixture of tetrahydrofuran and methanol. The reaction temperature is, for example, from room temperature to 120°C, preferably from 60°C to 100°C. The compound [A6-3] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0183] (Process A6-3) Compound [A6-5] or a salt thereof can be produced by reacting compound [A6-4] or a salt thereof in a solvent in the presence of a Vilsmeier reagent, followed by adding phosphorus oxychloride and heating (reaction temperature: for example, 80°C). Examples of the solvent include N,N-dimethylformamide, toluene, benzene, and a mixture thereof. A preferred solvent is a mixture of N,N-dimethylformamide and toluene. The reaction temperature is, for example, from -20°C to 100°C, preferably from -10°C to 90°C. The Vilsmeier reagent is prepared, for example, from phosphorus oxychloride and N,N-dimethylformamide.

[0184] (Process A6-4) The compound [A6-7] or a salt thereof can be produced by reacting the compound [A6-5] or a salt thereof with the compound [A6-6] or a salt thereof in a solvent in the presence of a base. Examples of bases include triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]-7-undecene. A preferred base is triethylamine. Examples of the solvent include methanol, ethanol, tetrahydrofuran, toluene, cyclopentyl methyl ether, acetonitrile, water, and mixtures thereof. A preferred solvent is a mixture of tetrahydrofuran and water. The reaction temperature is, for example, from −20° C. to 80° C., preferably from 0° C. to room temperature. The compound [A6-6] or a salt thereof is a commercially available product, or may be prepared from a commercially available product by a known method.

[0185] (Process A6-5) The compound [IA] or a salt thereof can be prepared by reacting a compound [A6-7] or a salt thereof in a solvent in the presence of an acid. Acids include, for example, formic acid, trifluoroacetic acid, and hydrochloric acid. A preferred acid is trifluoroacetic acid. Examples of the solvent include water, acetonitrile, tetrahydrofuran, and a mixture thereof. A preferred solvent is a mixture of acetonitrile and water. The reaction temperature is, for example, 0°C to 100°C, preferably 50°C to 70°C.

[0186] In this production method, instead of compound [A6-6] or a salt thereof, a compound having a functional group or a protected substituent that can be converted to various substituents on the benzene ring by a known reaction, or a salt thereof, is used to carry out this production method, and a compound corresponding to compound [IA] or a salt thereof is obtained, and then the functional group or the protected substituent is converted to the various substituents to produce compound [IA] or a salt thereof. For example, instead of compound [A6-6] or a salt thereof, L A41or a salt thereof, to obtain a compound corresponding to compound [IA], i.e., compound [IA-A] or a salt thereof, and then subjecting L to Production Method A4A. A41 Cy A41A Compound [IA-B] or a salt thereof may be prepared by converting the compound [IA-B] into the following compound: EXAMPLES

[0187] Next, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof will be specifically described with reference to Preparation Examples. However, the method for producing the compound of formula [I] or a pharma- ceutically acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutically acceptable salt thereof is not limited to these Preparation Examples. Unless otherwise specified, % indicates % by weight. Ratios shown in mixed solvents indicate volume ratios unless otherwise specified. NMR was measured at 400 MHz.

[0188] [Production Example 1]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 4) [ka] Step 1-1: Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under a nitrogen atmosphere at 0°C, N,N-diisopropylethylamine (224 mL) and benzyl chloroformate (83 mL) were added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (147 g) and tetrahydrofuran (1000 mL), and the mixture was stirred at room temperature for 40 minutes. Toluene (441 mL) and water (441 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. After separation, the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to about 1 L. Hexane (294 mL) was added to the residue, and the mixture was stirred for 1 hour, and then hexane (294 mL) was added and stirred for 15 minutes. The obtained solid was collected by filtration and washed with a hexane / toluene mixture (v / v = 2 / 1) to obtain the title compound (179 g). 1 H-NMR (CDCl3) δ: 7.32 (5H, br s), 7.09 (2H, s), 6.52 (1H, br s), 5.67 (1H, br s), 5.06 (2H, s), 2.33 (6H, br s).

[0189] Step 1-2: Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under an argon atmosphere, tripotassium phosphate (190 g) was dissolved in water (357 mL), and then toluene (715 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate (89.3 g), cyclopropylboronic acid (61.7 g) and [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (4.18 g) were added and stirred at 105°C for 4 hours. The reaction mixture was allowed to cool to room temperature, and then 6 M hydrochloric acid (298 mL) was added and the mixture was separated. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane (450 mL) was added to the residue and stirred, and the obtained solid was collected by filtration to obtain the title compound (64.2 g). 1H-NMR (CDCl3) δ: 7.31 (5H, br s), 6.68 (2H, s), 6.48 (1H, br s), 5.65 (1H, br s), 5.06 (2H, s), 2.32 (6H, br s), 1.80-1.73 (1H, m), 0.87-0.84 (2H, m), 0.61-0.59 (2H, m).

[0190] Step 1-3: (4-Cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride [ka] Under a nitrogen atmosphere, 4 M aqueous sodium hydroxide solution (536 mL) was added to a mixture of benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate (133 g) synthesized in the same manner as in step 1-2 and ethanol (798 mL), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled on ice, and acetic acid (73.6 mL) was added, followed by extraction with toluene (1 L). The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated to approximately 1 / 4 of the liquid volume. Toluene (500 mL) was added to the resulting mixture, and a 4 M solution of hydrogen chloride in dioxane (102 mL) was slowly added under ice-cooling and stirring. Hexane (50 mL) was added, and the mixture was stirred at room temperature for 10 minutes, after which the resulting solid was filtered and washed with hexane to obtain the title compound (83 g). 1 H-NMR (DMSO-d6) δ: 9.50 (3H, br s), 6.79 (2H, s), 6.66 (1H, br s), 2.33 (6H, s), 1.83-1.81 (1H, m), 0.97-0.84 (2H, m), 0.65-0.62 (2H, m).

[0191] Step 1-4: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine [ka] Under a nitrogen atmosphere, trimethyl orthoformate (750 mL) and sulfuric acid (1.6 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (250 g) and toluene (1.5 L), and the mixture was stirred at room temperature for 1.5 hours. Basic silica gel (Fujisilica, 500 g) was added to the reaction mixture, and after stirring for 2 hours, the added silica gel was removed by filtration. The silica gel was washed with ethyl acetate (1.0 L), and the solvent was removed under reduced pressure to obtain the title compound (268 g). 1 H-NMR (CDCl3) δ: 5.70 (1H, s), 3.50 (6H, s).

[0192] Step 1-5: 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Under ice cooling in a nitrogen atmosphere, (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride (83 g) and triethylamine (102 mL) were added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (94 g) and toluene (1160 mL), and the mixture was stirred at the same temperature for 40 minutes. Trifluoroacetic acid (98 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. In an ice bath, the reaction mixture was slowly added dropwise to an aqueous solution (776 mL) of tripotassium phosphate (310 g), and the mixture was stirred at room temperature for 10 minutes. After separation, the aqueous layer was extracted with toluene. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product (162 g) of the title compound. 1 H-NMR (CDCl3) δ: 8.17 (1H, s), 6.89 (2H, s), 1.98 (6H, s), 1.94-1.87 (1H, m), 1.07-1.01 (2H, m), 0.77-0.72 (2H, m).

[0193] Step 1-6: 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under a nitrogen atmosphere, 2M aqueous sodium hydroxide solution (913 mL) was added to a mixture of crude 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (162 g) and tetrahydrofuran (970 mL), and the mixture was stirred at 75° C. for 3 hours. After ice-cooling the reaction mixture, 6 M hydrochloric acid (243 mL) was added. Ethyl acetate was added to the reaction mixture to separate the layers, and the aqueous layer was extracted with ethyl acetate. All the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained solid, and the mixture was stirred at room temperature for 10 minutes, after which the solid was filtered and washed with ethyl acetate. The obtained solid was dried under reduced pressure to obtain the title compound (74 g). 1 H-NMR (DMSO-D6) δ: 12.89 (1H, br s), 8.80 (1H, s), 7.00 (2H, s), 2.03-1.95 (7H, m), 1.03-1.01 (2H, m), 0.78-0.76 (2H, m).

[0194] Step 1-7: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, tripotassium phosphate (148 g) was dissolved in water (510 mL), followed by addition of toluene (880 mL), 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (73 g), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (57.9 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (4.73 g). The reaction mixture was stirred at 110°C for 3 hours and then allowed to cool to 60°C. Tetrahydrofuran (290 mL) was added, and the mixture was cooled to 15°C in an ice bath, followed by slow dropwise addition of 6 M hydrochloric acid (193 mL) with stirring, followed by stirring for 20 minutes. Tetrahydrofuran (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Toluene (500 mL) and ethyl acetate (500 mL) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The obtained solid was filtered and washed with toluene. The obtained solid was dissolved in tetrahydrofuran (800 mL), and ISOLUTE Si-TMT (metal scavenging silica gel, Biotage, 0.47 mmol TMT / g, 49 g) was added, and the mixture was stirred at room temperature for 2 hours. The added ISOLUTE Si-TMT was filtered and washed with ethyl acetate (700 mL). Silica gel (70 g) and basic silica gel (Fujisilicia, 70 g) were added to the obtained solution, and the mixture was stirred at room temperature for 3 hours. The added silica gel was filtered off and washed successively with a mixture of ethyl acetate / tetrahydrofuran (v / v = 1 / 1, 300 mL) and ethyl acetate (700 mL), and then the solvent was distilled off under reduced pressure. Acetone (180 mL) was added to the resulting solid, and the mixture was stirred for 30 minutes under ice-cooling. The resulting solid was collected by filtration, washed with cold acetone (180 mL), and then dried under reduced pressure to give the title compound as a crystal (α crystal, 49.7 g). 1H-NMR (DMSO-D6) δ: 11.21 (1H, s), 8.70 (1H, s), 7.90 (1H, d, J = 2.3 Hz), 6.97 (2H, s), 6.96 (1H, d, J = 2.3 Hz), 3.98 (3H, s), 1.96-1.94 (7H, m), 1.01-0.97 (2H, m), 0.75-0.73 (2H, m). LC-MS(MH+):361.

[0195] Step 1-8: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one monohydrate [ka] Crystals of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (α crystals, 16.0 g) were dissolved in methanol (100 mL) under heating at 80°C. Water (100 mL) was added at the same temperature and stirred for 1 hour, and then water (200 mL) was added. The mixture was allowed to cool to room temperature and stirred for another 2 hours. The obtained solid was filtered and dried under reduced pressure to obtain crystals of the title compound (β crystals, 16.2 g). 1 H-NMR (DMSO-d6) δ: 11.19 (1H, s), 8.69 (1H, s), 7.90 (1H, d, J = 2.3 Hz), 6.97 (2H, s), 6.95 (1H, d, J = 2.3 Hz), 3.97 (3H, s), 1.98-1.91 (7H, m), 1.00-0.98 (2H, m), 0.76-0.72 (2H, m). LC-MS(MH+): 361

[0196] [Production Example 2]: Synthesis of 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 8) [ka] Step 2-1: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one [ka] Under an argon atmosphere at -78 °C, a solution of n-butyllithium in n-hexane (1.59 M, 25.2 mL) was slowly added dropwise to a mixture of 2,5-dibromo-1,3-dimethylbenzene (11.6 g) and tetrahydrofuran (170 mL), and the mixture was stirred at the same temperature for 20 minutes. N-Methoxy-N-methylacetamide (5.61 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (5.79 g). 1 H-NMR (CDCl3) δ: 7.64 (2H, s), 2.57 (3H, s), 2.47 (6H, s).

[0197] Step 2-2: 2-Bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene [ka] Under an argon atmosphere at 0°C, 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one (5.0 g) was added with a 50% bis(2-methoxyethyl)aminosulfur trifluoride tetrahydrofuran solution (48.7 mL) and methanol (0.089 mL), and the mixture was stirred at 80°C for 7 hours. The reaction mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (3.58 g). 1 H-NMR (CDCl3) δ: 7.20 (2H, s), 2.44 (6H, s), 1.88 (3H, t, J = 18.1 Hz).

[0198] Step 2-3: Di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate [ka] Under an argon atmosphere at -78 °C, a solution of n-butyllithium in n-hexane (1.56 M, 11 mL) was added to a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (3.58 g) and tetrahydrofuran (72 mL), and the mixture was stirred at the same temperature for 30 minutes. Di-tert-butyl azodicarboxylate (4.96 g) was added to the reaction mixture, and the mixture was stirred for another 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (3.38 g). 1 H-NMR (CDCl3) δ: 7.19-7.18 (2H, m), 6.60 (1H, br s), 2.38 (6H, s), 1.94-1.82 (3H, m), 1.55-1.37 (18H, m).

[0199] Step 2-4: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride [ka] To di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate (3.38 g), 4 M hydrogen chloride in ethyl acetate (34 mL) was added and stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure to give the title compound (2.0 g). 1 H-NMR (DMSO-D6) δ: 9.61 (3H, br s), 7.29 (2H, s), 6.85 (1H, br s), 2.42 (6H, s), 1.93 (3H, t, J = 18.8 Hz).

[0200] Step 2-5: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine [ka] 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (2.18 g) synthesized in the same manner as in step 1-4 of Production Example 1 was added to a mixture of {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (2.0 g), triethylamine (3.53 mL), and methanol (40 mL) under an argon atmosphere at 0° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Ethyl acetate was added, the resulting solid was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the crude product (3.56 g) of the title compound. LC-MS (MH+): 421.

[0201] Step 2-6: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, trifluoroacetic acid (1.62 mL) was slowly added dropwise to a mixture of crude 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine (3.56 g) and toluene (36 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly added dropwise to a 2M aqueous solution of tripotassium phosphate, and then extracted with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (1.89 g). LC-MS (MH+): 357.

[0202] Step 2-7: 6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] A mixture of 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (1.89 g) and tetrahydrofuran (19 mL) was added with 2M aqueous sodium hydroxide solution (5.29 mL) and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid and then extracted with ethyl acetate. The organic layer obtained was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate), and the obtained solid was stirred in a mixture of ethyl acetate / diisopropyl ether. The solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.03 g). 1 H-NMR (DMSO-D6) δ: 12.90 (1H, br s), 8.85 (1H, s), 7.49 (2H, s), 2.03-1.98 (9H, m).

[0203] Step 2-8: 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.03 g) and toluene / water (v / v = 5 / 1,12.9 mL) were added to a mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.949 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.198 g), and tripotassium phosphate (1.94 g), and the mixture was stirred at 105° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and 2M hydrochloric acid was slowly added dropwise, after which the reaction mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran and ethyl acetate, and then ISOLUTE Si-TMT (metal scavenging silica gel, Biotage, 0.47 mmol TMT / g, 3 g) was added and stirred at room temperature for 1 hour. The added ISOLUTE Si-TMT was filtered off and washed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate). The obtained solid was stirred in a mixture of ethyl acetate / diisopropyl ether, and the solid was filtered to obtain the title compound (1.02 g). 1 H-NMR (DMSO-D6) δ: 11.28 (1H, s), 8.80 (1H, s), 7.90 (1H, d, J = 2.2 Hz), 7.50 (2H, s), 6.96 (1H, d, J = 2.2 Hz), 3.98 (3H, s), 2.05-1.98 (9H, m). LC-MS(MH+):385.

[0204] [Production Example 3]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 39) [ka] Step 3-1: Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under a nitrogen atmosphere at 0°C, N,N-diisopropylethylamine (220 mL) and benzyl chloroformate (82 mL) were added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (150 g) and tetrahydrofuran (1.0 L), and the mixture was stirred at room temperature for 1 hour. Toluene (500 mL) and water (500 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. After layer separation, the obtained organic layer was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Toluene (200 mL) and hexane (600 mL) were added to the residue, and the mixture was stirred. The obtained solid was collected by filtration to obtain the title compound (180 g). 1 H-NMR (CDCl3) δ: 7.32 (5H, br s), 7.09 (2H, s), 6.52 (1H, br s), 5.67 (1H, br s), 5.06 (2H, s), 2.33 (6H, br s).

[0205] Step 3-2: Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate [ka] Under a nitrogen atmosphere, tripotassium phosphate (380 g) was dissolved in water (710 mL), followed by the addition of toluene (1400 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate (180 g), cyclopropylboronic acid (110 g) and [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (8.3 g) and stirring at 110 °C for 5 hours. The reaction mixture was allowed to cool to room temperature, and then 6 M hydrochloric acid (600 mL) was added and stirred for 10 minutes. The aqueous layer was removed by a separation operation, and the resulting organic layer was dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. Toluene / hexane mixed solution (v / v = 1 / 1, 360 mL) was added to the residue and stirred for 2 hours, followed by the addition of hexane (360 mL) and further stirring for 1 hour. The resulting solid was collected by filtration and washed successively with a toluene / hexane mixed solution (v / v = 1 / 10, 550 mL) and hexane (300 mL) to obtain the title compound (100 g). 1 H-NMR (CDCl3) δ: 7.31 (5H, br s), 6.68 (2H, s), 6.48 (1H, br s), 5.65 (1H, br s), 5.06 (2H, s), 2.32 (6H, br s), 1.80-1.73 (1H, m), 0.87-0.84 (2H, m), 0.61-0.59 (2H, m).

[0206] Step 3-3: (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride [ka] Under a nitrogen atmosphere, 4 M aqueous sodium hydroxide solution (400 mL) was added to a mixture of benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate (100 g) and ethanol (600 mL), and the mixture was stirred at 80° C. for 3 hours. After cooling the reaction mixture, acetic acid (55 mL) was added, and the mixture was extracted with toluene. The organic layer obtained was dried over anhydrous magnesium sulfate, and then concentrated to about 1 / 4 of the liquid volume. Toluene (400 mL) was added to the mixture obtained, and 4 M hydrogen chloride solution in 1,4-dioxane (77 mL) was slowly added under ice-cooling and stirring. After stirring at room temperature for 30 minutes, hexane (40 mL) was added, and the mixture was stirred for another 5 minutes. The resulting solid was collected by filtration, washed with a toluene / hexane mixture (v / v = 1 / 1) and hexane in that order, to obtain the title compound (54 g). 1 H-NMR (DMSO-d6) δ: 9.50 (3H, br s), 6.79 (2H, s), 6.66 (1H, br s), 2.33 (6H, s), 1.83-1.81 (1H, m), 0.97-0.84 (2H, m), 0.65-0.62 (2H, m).

[0207] Step 3-4: 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Under ice cooling in a nitrogen atmosphere, (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride (54 g) and triethylamine (68 mL) were added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (63 g) synthesized in the same manner as in step 1-4 of Production Example 1 and toluene (780 mL), and the mixture was stirred at the same temperature for 40 minutes. Trifluoroacetic acid (66 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. In an ice bath, the reaction mixture was slowly added dropwise to a solution of tripotassium phosphate (210 g) in water (470 mL), and the mixture was stirred at room temperature for 10 minutes. After separating the organic layer, the aqueous layer was extracted with toluene. All the organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (102 g). A part of the obtained crude product was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (1.6 g). LC-MS (MH+): 333.

[0208] Step 3-5: 4-(benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, benzyl alcohol (630 mg) was added to a mixture of sodium hydride (60% in oil, 200 mg) and tetrahydrofuran (24 mL), and the mixture was stirred at 50 °C for 30 minutes. The reaction mixture was cooled in an ice bath, and 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (1.6 g) was added, and the mixture was stirred at the same temperature for 30 minutes. 2 M hydrochloric acid (0.73 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was added to a mixture of hexane / ethyl acetate (v / v = 4 / 1) and stirred, and the solid was collected by filtration to obtain the title compound (1.8 g). 1H-NMR (CDCl3) δ: 8.00 (1H, s), 7.55-7.52 (2H, m), 7.43-7.41 (3H, m), 6.85 (2H, s), 5.64 (2H, s), 1.95 (6H, s), 1.91-1.86 (1H, m), 1.02-0.99 (2H, m), 0.73-0.71 (2H, m). LC-MS (MH+): 405.

[0209] Step 3-6: Mixture of 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (12 mg), lithium chloride (7.3 mg), and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.11 mL) were added to a mixture of 4-(benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (70 mg) and N,N-dimethylacetamide (1.0 mL), and the mixture was stirred at 120 °C for 3 hours. The reaction mixture was purified by column chromatography (developing solvent: methanol / ethyl acetate) to give a mixture of 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (110 mg). 4-(Benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine LC-MS (MH+): 451. 2-(4-Cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one LC-MS (MH+): 361.

[0210] Step 3-7: 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one mixture (110 mg) was added with formic acid (1.0 mL), stirred at 90 ° C for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by reverse phase column chromatography (developing solvent: acetonitrile / water), and solidified with hexane / ethyl acetate to obtain the title compound (23 mg). 1 H-NMR (DMSO-D6) δ: 10.77 (1H, br s), 8.70 (1H, s), 8.06 (1H, d, J = 1.3 Hz), 7.87 (1H, d, J = 1.3 Hz), 7.00 (2H, s), 3.80 (3H, s), 2.02-1.94 (7H, m), 1.04-1.01 (2H, m), 0.79-0.76 (2H, m). LC-MS (MH+): 361.

[0211] [Production Example 4]: Synthesis of 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 41) [ka] Step 4-1: tert-Butyl (4-iodo-2,6-dimethylphenyl)carbamate [ka] To a mixture of 4-iodo-2,6-dimethylaniline (24 g) and ethanol (73 mL), di-tert-butyl dicarbonate (40 mL) was added and stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting solid was collected by filtration and washed with water and hexane. The resulting solid was dissolved in ethyl acetate (150 mL), silica gel (24 g) was added, and the mixture was stirred for 15 minutes, after which the added silica gel was removed by filtration. The silica gel was washed with a mixture of hexane / ethyl acetate (v / v = 1 / 1), and the solvent was distilled off under reduced pressure. The resulting solid was stirred and washed with hexane, and then collected by filtration to obtain the title compound (29 g). 1 H-NMR (DMSO-D6) δ: 8.43 (1H, br s), 7.43 (2H, s), 2.11 (6H, s), 1.44 (9H, s).

[0212] Step 4-2: Ethyl 2-[4-{(tert-butoxycarbonyl)amino)}-3,5-dimethylphenyl]-2,2-difluoroacetate [ka] Under a nitrogen atmosphere, 2-bromo-2,2-difluoroethyl acetate (21 mL) and copper (16 g) were added to a mixture of tert-butyl (4-iodo-2,6-dimethylphenyl)carbamate (29 g) and dimethyl sulfoxide (230 mL), and the mixture was stirred at 70 °C for 4 hours. After removing the solid by filtration, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with a saturated aqueous ammonium chloride solution, water, and saturated saline, and anhydrous sodium sulfate and silica gel were added and stirred. After removing the solid by filtration and washing with ethyl acetate, the solvent was distilled off under reduced pressure to obtain the title compound (18 g). 1 H-NMR (DMSO-D6) δ: 8.63 (1H, br s), 7.27 (2H, s), 4.31 (2H, q, J = 7.0 Hz), 2.21 (6H, s), 1.45 (9H, s), 1.23 (3H, t, J = 7.0 Hz).

[0213] Step 4-3: tert-Butyl {4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl}carbamate [ka] Under nitrogen atmosphere, sodium borohydride (2.7 g) was slowly added over 16 minutes to a mixture of ethyl 2-[4-{(tert-butoxycarbonyl)amino)}-3,5-dimethylphenyl]-2,2-difluoroacetate (30 g) synthesized in the same manner as in step 4-2 and ethanol (240 mL). The reaction mixture was stirred at room temperature for 30 minutes and then cooled in an ice bath. 1M hydrochloric acid was slowly added at the same temperature, and then diluted with ethyl acetate, hexane, and water. The resulting mixture was separated, and the aqueous layer was extracted with an ethyl acetate / hexane mixture (v / v = 1 / 1). All the organic layers were combined, washed with water, saturated aqueous sodium bicarbonate, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was stirred in a hexane / ethyl acetate mixture (180 mL / 9 mL). The obtained solid was collected by filtration and washed with hexane to obtain the title compound (25 g). 1 H-NMR (DMSO-D6) δ: 8.53 (1H, br s), 7.19 (2H, s), 5.58 (1H, t, J = 6.2 Hz), 3.81 (2H, td, J = 14.1, 6.2 Hz), 2.19 (6H, s), 1.45 (9H, s).

[0214] Step 4-4: 2-[4-{(tert-butoxycarbonyl)amino}-3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate [ka] Under ice-cooling in a nitrogen atmosphere, trifluoromethanesulfonic anhydride (9.4 mL) was slowly added dropwise to a mixture of tert-butyl {4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl}carbamate (16 g), pyridine (5.6 mL) and toluene (130 mL), and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of sodium bicarbonate in that order, and then anhydrous sodium sulfate and silica gel were added, and the mixture was stirred at room temperature for 15 minutes. The solid was removed by filtration, washed with a mixture of ethyl acetate / toluene (v / v = 1 / 2), and the solvent was distilled off under reduced pressure. A mixture of hexane / ethyl acetate (v / v = 30 / 1, 50 mL) was added to the residue, and the mixture was stirred at room temperature for 1.5 hours, and then stirred under ice-cooling for 15 minutes. The resulting solid was collected by filtration and washed with hexane to obtain the title compound (21 g). 1 H-NMR (DMSO-D6) δ: 8.63 (1H, br s), 7.33 (2H, s), 5.33 (2H, t, J = 13.9 Hz), 2.22 (6H, s), 1.45 (9H, s).

[0215] Step 4-5: tert-Butyl {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}carbamate [ka] Under a nitrogen atmosphere, sodium borohydride (2.7 g) was slowly added to a mixture of 2-[4-{(tert-butoxycarbonyl)amino}-3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate (21 g) and dimethylsulfoxide (150 mL). The reaction mixture was stirred overnight at room temperature, and then 1 M hydrochloric acid (60 mL) and water (140 mL) were added in a water bath. The resulting mixture was extracted with ethyl acetate / hexane (v / v = 6 / 5), washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of the title compound (14 g).

[0216] Step 4-6: 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride [ka] A mixture of the crude product of tert-butyl {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}carbamate (14 g) and ethyl acetate (68 mL) was added with 4 M hydrogen chloride in ethyl acetate (140 mL) and stirred at room temperature for 2 hours. The obtained solid was collected by filtration and washed with ethyl acetate to obtain the title compound (11 g). 1 H-NMR (DMSO-D6) δ: 7.15 (2H, s), 7.10 (3H, br s), 2.24 (6H, s), 1.90 (3H, t, J = 19.1 Hz).

[0217] Step 4-7: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride [ka] To 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride (2.0 g), concentrated hydrochloric acid (9.0 mL) and 6 M hydrochloric acid (15 mL) were added, and the mixture was cooled to -20 ° C. A solution of sodium nitrite (690 mg) in water (3.0 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 ° C for 40 minutes. A solution of tin(II) chloride dihydrate (6.1 g) in concentrated sulfuric acid (9.0 mL) was slowly added dropwise over 5 minutes at -20 ° C., and the mixture was stirred at 0 ° C. for 5 hours. The obtained solid was collected by filtration, and then washed with ice-cooled 2 M hydrochloric acid and a mixture of hexane / ethyl acetate (v / v = 4 / 1) in that order to obtain the title compound (1.8 g). 1 H-NMR (DMSO-D6) δ: 9.68 (3H, br s), 7.29 (2H, s), 6.84 (1H, s), 2.42 (6H, s), 1.93 (3H, t, J = 18.9 Hz).

[0218] Step 4-8: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine [ka] Under an argon atmosphere at 0°C, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (540 mg) synthesized in the same manner as in step 1-4 of Production Example 1 was added to a mixture of {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (500 mg), triethylamine (0.88 mL) and methanol (10 mL), and the mixture was stirred at room temperature for 1.5 hours. After the solvent was distilled off under reduced pressure, ethyl acetate was added and the solid was removed by filtration. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product (890 mg). LC-MS (MH+): 421.

[0219] Step 4-9: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, trifluoroacetic acid (0.40 mL) was added to a mixture of 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazinyl]-5-(dimethoxymethyl)pyrimidine crude product (890 mg) and toluene (8.9 mL), and the mixture was stirred at room temperature for 1 hour, then added dropwise to a 2M aqueous solution of tripotassium phosphate. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: hexane / ethyl acetate) to obtain the title compound (520 mg). 1 H-NMR (DMSO-D6) δ: 9.36 (1H, s), 7.55 (2H, s), 2.05-2.00 (9H, m). LC-MS (MH+): 357.

[0220] Step 4-10: 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine [ka] Under an argon atmosphere, sodium hydride (60% in oil, 61 mg) was added to a mixture of benzyl alcohol (0.18 mL) and tetrahydrofuran (10 mL), and the mixture was stirred at 50 °C for 30 minutes. After cooling the reaction mixture to 0 °C, 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (520 mg) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and then 2 M hydrochloric acid (1.0 mL) was added, followed by extraction with ethyl acetate. The obtained organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was stirred with a mixture of hexane / diisopropyl ether (v / v = 1 / 1), and the solid was collected by filtration to obtain the title compound (430 mg). 1 H-NMR (DMSO-D6) δ: 9.05 (1H, s), 7.59-7.57 (2H, m), 7.51 (2H, s), 7.45-7.41 (3H, m), 5.65 (2H, s), 2.04-1.98 (9H, m).

[0221] Step 4-11: 2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (13 mg), lithium chloride (7.9 mg), and 1-methyl-4-(tributylstannyl)-1H-imidazole (0.12 mL) were added to a mixture of 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (80 mg) and N,N-dimethylacetamide (1.0 mL), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was purified by column chromatography (developing solvent: methanol / ethyl acetate) and reversed-phase column chromatography (developing solvent: acetonitrile / water) to obtain the title compound (8.2 mg). 1 H-NMR (DMSO-D6) δ: 10.78 (1H, s), 8.77 (1H, s), 8.04 (1H, d, J = 1.3 Hz), 7.84 (1H, d, J = 1.3 Hz), 7.49 (2H, s), 3.77 (3H, s), 2.05-1.98 (9H, m). LC-MS (MH+): 385.

[0222] [Production Example 5]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-6-(pyrimidin-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 12) [ka] Step 5-1: Methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate [ka] A mixture of 4-bromo-2,6-dimethylaniline (45 g), ethanol (72 mL), water (25 mL), and concentrated hydrochloric acid (47 mL) was cooled to -10°C, and then an aqueous solution (54 mL) of sodium nitrite (17 g) was slowly added dropwise over 30 minutes. After stirring at the same temperature for 30 minutes, methyl 2-chloro-3-oxobutanoate (27 mL) and sodium acetate (55 g) were added in sequence, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (81 g). 1 H-NMR (CDCl3) δ: 7.28 (2H, t, J = 0.6 Hz), 7.19 (1H, br s), 3.90 (3H, s), 2.34 (6H, s).

[0223] Step 5-2: 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 crude methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate (81 g) and chloroform (580 mL), and the mixture was stirred at 80° C. for 40 minutes. The reaction mixture was allowed to cool to room temperature, and silica gel (250 g) was added and the mixture was stirred at room temperature for 30 minutes. The silica gel was removed by filtration using Celite, and then washed with ethyl acetate. The solvent was removed from all the obtained organic layers under reduced pressure, and the obtained solid was washed with ethyl acetate to obtain the title compound (37 g). 1 H-NMR (DMSO-d6) δ: 9.01 (1H, s), 7.57 (2H, s), 3.90 (3H, s), 1.98 (6H, s).

[0224] Step 5-3: 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 solution (110 mL) was added and stirred at room temperature for 2.5 hours. 6 M hydrochloric acid was added to the reaction mixture to adjust the liquid to pH = 1, and then extraction was performed using ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained solid, a mixture of ethyl acetate / diisopropyl ether (v / v = 1 / 1, 200 mL) was added and stirred for 5 minutes, and hexane was added until no solid precipitated. The obtained solid was collected by filtration to obtain the title compound (30 g). 1 H-NMR (DMSO-d6) δ: 13.86 (1H, br s), 8.96 (1H, s), 7.56 (2H, s), 1.97 (6H, s).

[0225] Step 5-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile [ka] 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 t-butanol (450 mL) at room temperature under an argon atmosphere, and the mixture was stirred at 90° C. for 3 hours. The solvent was removed under reduced pressure, and chloroform (180 mL) and trifluoroacetic acid (22 mL) were added to the residue, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to 0° C. and neutralized with a saturated aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (developing solvent: 15 vol% to 60 vol% ethyl acetate / hexane), and the resulting solid was washed with a mixture of diisopropyl ether / ethyl acetate (v / v = 1 / 1) to obtain the title compound (11 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.

[0226] Step 5-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide [ka] Under an argon atmosphere at 0°C, sodium hydroxide (4.5 g) and 30% hydrogen peroxide (15 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (11 g), dimethyl sulfoxide (17 mL), and ethanol (66 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was cooled to 0°C, and then a saturated aqueous solution of sodium sulfite was added. 12 M hydrochloric acid was added to the reaction mixture to adjust the liquid to pH = 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with a mixture of diisopropyl ether / ethyl acetate (v / v = 1 / 1) to obtain the title compound (10 g). 1 H-NMR (DMSO-d6) δ: 7.97 (1H, s), 7.45 (2H, s), 7.31 (1H, br s), 6.91 (1H, br s), 5.53 (2H, s), 2.02 (6H, s). LC-MS (MH+): 309.

[0227] Step 5-6: N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide [ka] To a mixture of pyrimidine-4-carboxylic acid (60 mg) and N,N-dimethylformamide (1.5 mL), HATU (180 mg) and N,N-diisopropylethylamine (160 mg) were added and stirred at room temperature for 5 minutes. Then, 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (75 mg) was added and stirred at 50°C for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated saline in that order. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude product of the title compound (100 mg). LC-MS (MH+): 415.

[0228] Step 5-7: 2-(4-bromo-2,6-dimethylphenyl)-6-(pyrimidin-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mL) was added to a mixture of the crude product of N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide (100 mg), ethanol (1.0 mL), and water (1.0 mL), and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated saline in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 50 vol% to 100 vol% ethyl acetate / hexane) to obtain the title compound (47 mg). 1 H-NMR (CDCl3) δ: 10.62 (1H, br s), 9.36 (1H, d, J = 1.4 Hz), 9.03 (1H, d, J = 5.3 Hz), 8.54 (1H, dd, J = 5.2, 1.5 Hz), 8.18 (1H, s), 7.38 (2H, s), 2.06 (6H, s). LC-MS (MH+): 397.

[0229] [Production Example 6]: Synthesis of 2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 59) [ka] Step 6-1: (6-chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride [ka] To a mixture of 6-chloro-2,3-dihydro-1H-inden-5-amine (1.0 g) and 6 M hydrochloric acid (5.0 mL), concentrated hydrochloric acid (3.0 mL) was added, and the mixture was cooled to 0°C. To the reaction mixture, an aqueous solution (1.0 mL) of sodium nitrite (0.43 g) was slowly added dropwise over 3 minutes, and the mixture was stirred at the same temperature for 70 minutes. To the reaction mixture, a mixture of tin(II) chloride dihydrate (2.8 g) and concentrated hydrochloric acid (2.3 mL) was slowly added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 1 hour, and then at room temperature for 2 hours. The resulting solid was collected by filtration and washed successively with 2 M hydrochloric acid and diisopropyl ether to obtain the title compound (1.2 g). 1 H-NMR (DMSO-D6) δ: 10.12 (3H, br s), 7.86 (1H, br s), 7.28 (1H, s), 7.00 (1H, s), 2.83-2.81 (4H, m), 2.06-1.99 (2H, m).

[0230] Step 6-2: Lithium 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-olate [ka] Under an argon atmosphere at 0°C, a 1.2 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (500 mL) was added to a mixture of 1-methyl-1H-pyrazole-3-carbonitrile (53 g) and tetrahydrofuran (11 mL), and the mixture was stirred at room temperature for 2 hours. After cooling the reaction mixture to 5°C, dimethyl malonate (110 mL) and methanol (320 mL) were added, and the mixture was stirred at 80°C for 24 hours. After cooling the reaction mixture to room temperature, tetrahydrofuran (320 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with a methanol / tetrahydrofuran mixture (v / v = 1 / 2, 150 mL) and tetrahydrofuran (200 mL) in that order to obtain the title compound (100 g). 1H-NMR (CD3OD) δ: 7.64 (1H, d, J = 2.2 Hz), 6.91 (1H, d, J = 2.2 Hz), 5.11 (1H, s), 3.97 (3H, s).

[0231] Step 6-3: 4,6-dichloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-5-carbaldehyde [ka] Phosphorus oxychloride (64 mL) was added to N,N-dimethylformamide (270 mL) at 0°C under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0°C, and then slowly added dropwise to a mixture of lithium 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-olate (90 g) and toluene (270 mL) cooled to 0°C. The reaction mixture was stirred overnight at room temperature, and then cooled again to 0°C. Phosphorus oxychloride (380 mL) was slowly added dropwise to the reaction mixture, and then stirred at 80°C for 6 hours. The reaction mixture was allowed to cool to room temperature, and then slowly added dropwise to a mixture of disodium hydrogen phosphate (770 g) and water (3.0 L) cooled to below 10°C. The mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with water to obtain the title compound (79 g). 1 H-NMR (DMSO-D6) δ: 10.28 (1H, s), 7.92 (1H, d, J = 2.5 Hz), 7.03 (1H, d, J = 2.5 Hz), 4.00 (3H, s).

[0232] Step 6-4: 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine [ka] To a mixture of (6-chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride (100 mg), N,N-diisopropylethylamine (0.40 mL), tetrahydrofuran (1.5 mL) and water (0.50 mL), 4,6-dichloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-5-carbaldehyde (120 mg) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and then it was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 1vol% to 100vol% ethyl acetate / hexane) to obtain the title compound (55 mg). 1 H-NMR (DMSO-D6) δ: 9.25 (1H, s), 7.85 (1H, d, J = 2.2 Hz), 7.66-7.64 (2H, m), 6.99 (1H, d, J = 2.2 Hz), 3.98 (3H, s), 3.02-2.93 (4H, m), 2.15-2.10 (2H, m).

[0233] Step 6-5: 2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one [ka] Under an argon atmosphere, trifluoroacetic acid (0.033 mL) was added to a mixture of 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine (55 mg), acetonitrile (0.55 mL) and water (0.28 mL), and the mixture was stirred at 60° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (developing solvent: 1 vol% to 100 vol% ethyl acetate / hexane), and the residue was solidified using an ethyl acetate / hexane mixture (v / v = 1 / 5, 12 mL) to obtain the title compound (44 mg). 1 H-NMR (DMSO-D6) δ: 11.28 (1H, br s), 8.85 (1H, s), 7.90 (1H, d, J = 2.5 Hz), 7.57 (2H, d, J = 11.5 Hz), 6.96 (1H, d, J = 2.5 Hz), 3.98 (3H, s), 2.98-2.91 (4H, m), 2.14-2.07 (2H, m). LC-MS (MH+): 367.

[0234] The compounds of the other examples were obtained by the same methods as those of the above-mentioned production methods and production examples, or by using known methods as necessary. The structural formula and physical property data of each example compound are shown in the following table. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] TIFF2025013515000134.tif155161

[0235] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory effect The NLRP3 inflammasome inhibitory effect of the test substance was evaluated based on the suppressive effect on IL-1β production in THP1-Null cells (product number thp-null, InvivoGen). The cells were maintained and cultured in RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 25 mmol / L HEPES, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL normocin, and 200 μg / mL hygromycin B (37°C, 5% CO2 / 95% air). Cells suspended in assay medium (RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin) containing 0.5 μmol / L PMA were seeded (25,000 cells / 25 μL / well) on Corning® 384-well Flat Clear Bottom Black Polystyrene TC-treated Microplates and cultured overnight (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and assay medium containing 1 μg / mL Lipopolysaccharides (product number L2654, Sigma-Aldrich®) was added (25 μL / well) and cultured for 3 hours (37°C setting, 5% CO2 / 95% air). The culture supernatant was removed, and a medium solution prepared with Opti-MEM™ medium (product number 31985-070, Invitrogen) was added (20 μL / well) to the blank set wells and the control set wells, and cultured for 15 minutes (37°C, 5% CO2 / 95% air). In addition, the test substance solution was added (20 μL / well) to the test substance set wells. Furthermore, Opti-MEM™ medium containing Nigericin (product number N7143, Sigma-Aldrich™) was added (5 μL / well) to the control set wells and the test substance set wells, and cultured for 1.5 hours (37°C, 5% CO2 / 95% air). The final concentration of Nigericin was 7.5 μmol / L. Opti-MEM™ medium was added (5 μL / well) to the blank set wells. The culture supernatant was stored frozen (-20°C) until IL-1β was measured. The IL-1β in the culture supernatant was quantified using AlphaLISA (registered trademark) Human IL-1β Detection Kit (product number AL220C, Perkin Elmer). Fluorescence intensity was measured using a microplate reader EnSpier (model number 2300-00J, Perkin Elmer) or EnSight (model number HH34000000, Perkin Elmer) according to the attached instruction manual. The inhibition rate of the test substance well was calculated by setting the blank well as 100% and the control well as 0%. The IC of the test substance 50 The values ​​(50% inhibitory concentration) were calculated by logistic regression analysis. The results for each example compound are shown in the table below.

[0236] [Table 8] [Table 9]

[0237] Examples of the formulation of the present invention include the following formulations, however, the present invention is not limited to these formulation examples. Formulation Example 1 (Capsule Production) (1) Compound of Example 1 30 mg (2) Microcrystalline cellulose 10 mg (3) Lactose 19mg (4) Magnesium stearate 1 mg (1), (2), (3) and (4) are mixed and filled into a gelatin capsule.

[0238] Formulation Example 2 (Tablet Production) (1) Compound of Example 1 10 g (2) Lactose 50g (3) 15g corn starch (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of (1), (2) and (3) and 30 g of (4) are mixed with water, vacuum dried, and then granulated. 14 g of (4) and 1 g of (5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained. [Industrial Applicability]

[0239] The compound of formula [I] or a pharma- ceutical acceptable salt thereof, or the compound of formula [IA] or a pharma- ceutical acceptable salt thereof, has an inhibitory effect on 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), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytosis), and the like. The compound is expected to be useful as a therapeutic or preventive agent for a disease selected from the group consisting of phagocytic 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, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

Claims

[Claim 1] The invention described in the specification.