Substituted pyrazolopyrimidine compound and medical application thereof

Abstract

The present invention provides a substituted pyrazolopyrimidine compound having an NLRP3 inflammasome inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, a pharmaceutical use thereof, and the like. A compound of formula [I] or a pharmaceutically acceptable salt thereof, wherein each symbol is as defined in the specification.

Description

Technical Field

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

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

[0003] NLRP3 recognizes DAMPs (Danger-Associated Molecular Patterns), which are molecular patterns specific to cell-damaging factors (such as ATP, HMGB1, S100, urate crystals, and silica), and PAMPs (Pathogen-Associated Molecular Patterns), which are molecular patterns specific to pathogenic microorganisms (such as viruses, bacteria, and fungi), and binds to these molecules to become activated.

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

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

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

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

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

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

[0010] Cold-associated periodic syndrome (CAPS) (a common name for autoinflammatory diseases caused by activating mutations in the NLRP3 gene) is classified into three disease types: mild familial cold autoinflammatory syndrome (FCAS), moderate Mueller syndrome (MWS), severe chronic infantile neurocutaneous arthritis (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 that is dependent on IL-1β and IL-18, which are NLRP3 inflammasomes and downstream signaling molecules (Non-patent Document 18). In a mouse strain expressing a CAPS-associated NLRP3 mutation, CY-09, an NLRP3 inflammasome inhibitor, suppressed lethal systemic inflammation and improved survival (Non-Patent Document 19). Therefore, NLRP3 inflammasome inhibitors are considered promising drugs for the treatment of CAPS.

[0011] Increased expression of NLRP3 inflammasome-related genes has been reported in liver tissue of patients with nonalcoholic steatohepatitis (NASH) (Non-Patent Document 20). Furthermore, it has been reported that NLRP3 knockout inhibits liver fibrosis in a choline-deficient amino acid-restricted diet model (a NASH model) (Non-Patent Document 20). Therefore, NLRP3 inflammasome inhibitors are considered as drugs for the treatment of NASH.

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

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

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

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

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

[0017] It has been reported that the expression of IL-1β or IL-18 is increased in the serum and glomeruli of patients with systemic lupus erythematosus (SLE) (Non-Patent Documents 31, 32), and that the expression of the NLRP3 gene and the production of IL-1β in macrophages are increased (Non-Patent Document 33). In Nlrp3-R258W mice with an activating mutation in the NLRP3 gene, administration of pristane exacerbated lupus nephritis-like symptoms (Non-Patent Document 34). Therefore, NLRP3 inflammasome inhibitors are considered as drugs for the treatment of SLE.

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

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

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

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

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

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

[0024] In patients with Huntington's disease (Huntington's disease), cerebrospinal fluid levels of IL-1β (a NLRP3 inflammasome-related cytokine) increase (non-patent literature 53). In the striatum of R6 / 2 mice (a Huntington's disease model), the expression level of NLRP3 inflammasome increases (non-patent literature 54). MCC950 (a NLRP3 inhibitor) inhibits NLRP3 inflammasome activation in the striatum of R6 / 2 mice, inhibits neuronal cell death in the striatum, and inhibits symptom progression (non-patent literature 55). Thus, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of Huntington's disease.

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

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

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

[0028] The expression of NLRP inflammasomes is increased in brain tissue from patients with temporal lobe epilepsy and in pilocarpine-induced epilepsy models (Non-Patent Documents 65 and 66). Furthermore, in pilocarpine-induced epilepsy models, NLRP3 inflammasome deficiency and administration of MCC950 (an NLRP3 inhibitor) inhibited hippocampal neuronal apoptosis, which leads to the development of epilepsy (Non-Patent Document 66). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of epilepsy.

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

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

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

[0032] In the intestinal perforation model (an animal model of sepsis), increased expression and activation of the NLRP3 inflammasome or IL-1β occur in the brain, leading to hippocampal neuronal damage and memory impairment, a symptom of septic encephalopathy (Non-Patent Documents 75 and 76). When MCC950 (an NLRP3 inhibitor) is administered to the intestinal perforation model, NLRP3 inflammasome activation is suppressed and memory impairment is improved (Non-Patent Document 76). Therefore, NLRP3 inflammasome inhibitors are considered to be drugs for the treatment of septic encephalopathy.

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

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

[0035] Increased expression of the ASC domain of the NLRP3 inflammasome and mature IL-1β protein has been reported in the cerebral cortex of patients with frontotemporal dementia who harbor tau protein mutations (Non-Patent Document 81). Increased expression of the ASC domain of the NLRP3 inflammasome and truncated caspase 1 has also been reported in the cerebral cortex of Tau22 mice, a model of frontotemporal dementia that expresses human mutant tau protein, suggesting that knockout of NLRP3 suppresses tau pathology and cognitive decline (Non-Patent Document 81). These results suggest that NLRP3 inflammasome inhibitors may be considered as therapeutic agents for frontotemporal dementia.

[0036] It has been confirmed that drusen, a possible pathogenic substance that is considered to cause age-related macular degeneration (AMD), are formed in patients with NLRP3-related autoinflammatory diseases (NLRP3-AID) caused by activating mutations in the NLRP3 gene (non-patent literature 82). NLRP3 inhibitors also inhibited the degeneration of retinal pigment epithelial cells in one of the age-related macular degeneration models, which has Alu RNA-induced degeneration of retinal pigment epithelial cells (non-patent literature 83). NLRP3 inhibitors inhibited neovascularization in another age-related macular degeneration model, which has laser-induced choroidal neovascularization (non-patent literature 83). These results suggest that NLRP3 inflammasome inhibitors are considered to be a drug for treating age-related macular degeneration.

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

[0038] Hereditary transient corneal endotheliitis is one of the pyrogen-associated periodic syndromes, which is caused by activating mutations in the NLRP3 gene (Non-Patent Document 86). Therefore, NLRP3 inflammasome inhibitors are considered as a drug for the treatment of hereditary transient corneal endotheliitis.

[0039] Citation List

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

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[0113] [Non-Patent Document 73] Amo-Aparicio J et al. Inhibition of the NLRP3 inflammasome by OLT1177 induces functional protection and myelin preservation after spinal cord injury. Exp Neurol. 2022 Jan;347:113889.

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[0122] [Non-Patent Document 82] Bing Li et al., Early onset drusen and RPE dysfunction in a patient with NLRP3-AID. Ocul Immunol Inflamm. 2022, Nov 17;1-4.

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[0126] [Non-Patent Document 86] Joni A Turunen et al., Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene. Am J Ophthalmol. 2018 Apr;188:41-50. Summary of the Invention

[0127] The present invention provides substituted pyrazolopyrimidine compounds or pharmaceutically acceptable salts thereof having NLRP3 inflammasome inhibitory activity, pharmaceutical compositions comprising the same, and medical uses thereof. Specifically, the present invention includes the following embodiments:

[0128] Item 1. Compound of formula [I]:

[0129]

[0130] or a pharmaceutically acceptable salt thereof (“a compound of formula [I] or a pharmaceutically acceptable salt thereof” is also referred to herein as “compound [I]”),

[0131] Some of the structures:

[0132]

[0133] yes

[0134] (1) The structure shown in the following formula:

[0135]

[0136] where R 5 is hydrogen or C 1-4 Alkyl, wherein the alkyl group may be optionally substituted with the following substituents:

[0137] (a) carboxyl,

[0138] (b)-CO-C 1-4 Alkoxy, or

[0139] (c)-CO-NR 6 R 7 , where R 6 and R 7 are each independently hydrogen or C 1-4 Alkyl, or

[0140] (2) The structure of the following formula:

[0141]

[0142] where R 8 It is C 1-4 alkyl;

[0143] The cyclic group Cy is

[0144] (1) A group represented by the following formula:

[0145]

[0146] where R 9 and R 10 Each independently is

[0147] (a) Hydrogen,

[0148] (b)C 1-4 Alkyl, wherein the alkyl group may be optionally C 1-4 Alkoxy substitution,

[0149] (c)C 1-4 Alkoxy,

[0150] (d) halogens,

[0151] (e)C 1-4 haloalkyl, or

[0152] (f)-OC 1-4 haloalkyl,

[0153] R 11 and R 12 Each independently is

[0154] (a) Hydrogen,

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

[0156] (c)C 1-4 alkyl halide;

[0157] R 13 yes

[0158] (a) Hydrogen,

[0159] (b)C 1-4 alkyl,

[0160] (c)C 1-4 Alkoxy,

[0161] (d) halogens,

[0162] (e)C1-6 Halogenated alkyl,

[0163] (f)-OC 1-4 haloalkyl, or

[0164] (g)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by one or two halogen atoms, or

[0165] R 13 Can be used with R 11 or R 12 Together with the carbon atom to which it is attached, it forms:

[0166] (a)C 5-6 Cyclic olefins, or

[0167] (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms, or

[0168] (2) A group represented by the following formula:

[0169]

[0170] Among them, R 14 and R 15 Each independently is C 1-4 Alkyl or C 1-4 haloalkyl,

[0171] R 16 C 1-6 Alkyl or C 3-6 Cycloalkyl,

[0172] R 1 for:

[0173] (1) Hydrogen,

[0174] (2) cyano,

[0175] (3)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0176] (4)C 1-4 haloalkyl, or

[0177] (5)-CO-C 1-4 alkyl,

[0178] R 2 、R 3 and R 4 Each independently

[0179] (1) Hydrogen,

[0180] (2) hydroxyl groups,

[0181] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0182] (a) hydroxyl groups,

[0183] (b)C 1-4 Alkoxy, and

[0184] (c)-SO2-C 1-4 alkyl,

[0185] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0186] (a) hydroxyl groups,

[0187] (b) phenyl, or

[0188] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0189] (5) halogens,

[0190] (6)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0191] (7)-OC 1-4 haloalkyl,

[0192] (8)-OR 17 , where R 17 is a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0193] (9)C 3-6 Cycloalkyl,

[0194] (10) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocycloalkyl group may be optionally substituted with oxo, or

[0195] (11) A group represented by the following formula:

[0196] or

[0197] R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R3 R 4 Groups can be formed as:

[0198] (a) cyano group,

[0199] (b)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0200] (1) cyano,

[0201] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0202] (3)C 1-4 Alkoxy,

[0203] (4) Halogen, and

[0204] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0205] (c) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0206] (1) hydroxyl groups,

[0207] (2)C 1-4 alkyl,

[0208] (3)C 1-4 Alkoxy, and

[0209] (4) Halogen, or

[0210] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0211] (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the fused heterocyclic group may be optionally substituted by 1 or 2 halogen atoms,

[0212] (e) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0213] (f) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally substituted by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0214] (g)C 5-6 Cycloalkenyl,

[0215] (h) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0216] (i) a group represented by the following formula:

[0217]

[0218] Among them, R 20 for:

[0219] (1)C 1-4 Alkyl, or

[0220] (2)-NR 21 R 22 , where R 21 and R 22 Each independently

[0221] (a) Hydrogen,

[0222] (b)C 1-4 alkyl,

[0223] (c)C 1-4 haloalkyl, or

[0224] (d) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom.

[0225] Project 2

[0226] The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the partial structure

[0227]

[0228] for

[0229] (1) The structure shown in the following formula:

[0230]

[0231] Among them, R 5 Same definition as in item 1.

[0232] Project 3

[0233] The compound according to item 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

[0234] Project 4

[0235] The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 5 For hydrogen.

[0236] Project 5

[0237] The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the cyclic group Cy is:

[0238] (1) A group represented by the following formula:

[0239]

[0240] Among them, R 9 、R 10 、R 11 、R 12 and R 13 Same definition as in item 1.

[0241] Project 6

[0242] The compound according to any one of items 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [II],

[0243]

[0244] Among them, R 2 、R 3 、R 4 、R 9 、R 10 、R 11 、R 12 and R 13 Same definition as in item 1.

[0245] Project 7

[0246] The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 For hydrogen.

[0247] Project 8

[0248] The compound according to any one of items 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula [III],

[0249]

[0250] Among them, R 2 、R 3 、R 4 、R 9 、R 10 and R 13 Same definition as in item 1.

[0251] Project 9

[0252] The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 At least one of:

[0253] (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0254] (2)C 1-4 Alkoxy,

[0255] (3) Halogen,

[0256] (4)C 1-4 haloalkyl, or

[0257] (5)-OC 1-4 Halogenated alkyl.

[0258] Project 10

[0259] The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 3 and R 4 Each independently

[0260] (1) Hydrogen,

[0261] (2) hydroxyl groups,

[0262] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0263] (a) hydroxyl groups,

[0264] (b)C 1-4 Alkoxy, and

[0265] (c)-SO2-C 1-4 alkyl,

[0266] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with,

[0267] (a) hydroxyl groups,

[0268] (b) phenyl, or

[0269] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0270] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0271] (6)-OC 1-4 a haloalkyl group, or

[0272] (7)C 3-6 Cycloalkyl, or

[0273] R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R 3 R 4 Groups can be formed as:

[0274] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0275] (1) cyano,

[0276] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0277] (3)C 1-4 Alkoxy,

[0278] (4) Halogen, and

[0279] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0280] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0281] (1) hydroxyl groups,

[0282] (2)C 1-4 alkyl,

[0283] (3)C 1-4 Alkoxy, and

[0284] (4) Halogen, or

[0285] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0286] (c) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0287] (d) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally replaced by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0288] (e) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0289] (f) a group represented by the following formula:

[0290]

[0291] Among them, R 21 and R 22 Each independently

[0292] (1) Hydrogen,

[0293] (2)C 1-4 alkyl,

[0294] (3)C 1-4 haloalkyl, or

[0295] (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

[0296] Project 11

[0297] The compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 3 and R 4 Each independently

[0298] (1) Hydrogen,

[0299] (2) hydroxyl groups,

[0300] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0301] (a) hydroxyl groups,

[0302] (b)C 1-4 Alkoxy, and

[0303] (c)-SO2-C 1-4 alkyl,

[0304] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0305] (a) hydroxyl groups,

[0306] (b) phenyl, or

[0307] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or

[0308] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substituted, or

[0309] R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R 3 R 4 Groups can be formed as:

[0310] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0311] (1) cyano,

[0312] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0313] (3)C 1-4 Alkoxy,

[0314] (4) Halogen, and

[0315] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0316] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0317] (1) hydroxyl groups,

[0318] (2)C 1-4 alkyl,

[0319] (3)C 1-4 Alkoxy, and

[0320] (4) Halogen, or

[0321] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups, or

[0322] (c) a group represented by the following formula:

[0323]

[0324] Among them, R 21 and R 22 Each independently

[0325] (1) Hydrogen,

[0326] (2)C 1-4 alkyl,

[0327] (3)C 1-4 haloalkyl, or

[0328] (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

[0329] Project 12

[0330] According to the compound of item 1 or a pharmaceutically acceptable salt thereof, the compound is selected from the following formula:

[0331]

[0332]

[0333]

[0334] Project 13

[0335] The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following formula:

[0336]

[0337] Project 14

[0338] A pharmaceutical composition comprising the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0339] Project 15

[0340] An NLRP3 inflammasome inhibitor comprising the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof.

[0341] Project 16

[0342] A drug comprising a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, for treating or preventing a disease selected from the following diseases: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, and chronic infantile neurocutaneous articular syndrome / neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic Arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0343] Project 17

[0344] The medicament according to item 16, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0345] Project 18

[0346] The drug according to Project 16, wherein the cold-promoting periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weiss syndrome, chronic infantile neurocutaneous arthritis syndrome or neonatal-onset multisystem inflammatory disease.

[0347] Project 19

[0348] A method for inhibiting NLRP3 inflammasome, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal.

[0349] Project 20

[0350] A method for treating or preventing a disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic Juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0351] Project 21

[0352] The method according to item 20, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0353] Project 22

[0354] According to the method of item 20, the cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous arthritis syndrome or neonatal onset multisystem inflammatory disease.

[0355] Project 23

[0356] Use of the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inflammasome inhibitor.

[0357] Project 24

[0358] Use of a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease, wherein the disease is selected from: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (such as familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome and neonatal multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (such as acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic encephalitis, These include: rheumatoid arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0359] Project 25

[0360] The use according to item 24, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0361] Project 26

[0362] According to the use of Project 24, the cold-inflammatory-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous and articular syndrome, or neonatal multisystem inflammatory disease.

[0363] Project 27

[0364] The compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 inflammasome.

[0365] Project 28

[0366] The compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof is used for treating or preventing a disease selected from the following diseases: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndrome (such as familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (such as acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic joint disease, Arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0367] Project 29

[0368] The compound or pharmaceutically acceptable salt thereof according to Item 28, wherein for use, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0369] Project 30

[0370] According to the compound or pharmaceutically acceptable salt thereof of Item 28, wherein the cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome, or neonatal multisystem inflammatory disease.

[0371] Project 31

[0372] A commercial package comprising a pharmaceutical composition according to claim 14 and written materials associated therewith, wherein the written materials indicate that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus , systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0373] Project 32

[0374] A commercial kit comprising a pharmaceutical composition according to claim 14 and written materials related thereto, wherein the written materials indicate that the pharmaceutical composition can be used to treat or prevent a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous articular syndrome, and neonatal-onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus , systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, and TNF receptor-associated periodic syndrome.

[0375] Project 16A

[0376] A drug comprising a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, for treating or preventing a disease selected from the following diseases: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Mueller-Weiss syndrome, chronic infantile neurocutaneous arthritis, and neonatal multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset schizoaffective syndrome, Teal 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, Behçet disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0377] Project 17A

[0378] A medicine according to Item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0379] Project 18A

[0380] The drug according to Item 16A, wherein the cryoinflammatory-associated periodic syndrome is familial cold autoinflammatory syndrome, Mueller-Weiss syndrome, chronic infantile neurocutaneous arthritis syndrome or neonatal-onset multisystem inflammatory disease.

[0381] Project 19A

[0382] A method for treating or preventing a disease, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal, wherein the disease is selected from the following diseases: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous arthritis, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing heart disease Pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0383] Project 20A

[0384] The method according to item 19A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0385] Project 21A

[0386] The method according to item 19A, wherein the cryoprotectin-associated periodic syndrome is familial cold autoinflammatory syndrome, Mueller-Weiss syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal-onset multisystem inflammatory disease.

[0387] Project 22A

[0388] Use of a compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease, wherein the disease is selected from: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous arthritis, and neonatal multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0389] Project 23A

[0390] The use according to item 22A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0391] Project 24A

[0392] According to the use of item 22A, the periodic syndrome associated with pyrogen is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal onset multisystem inflammatory disease.

[0393] Project 25A

[0394] The compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from the following diseases: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous and articular syndrome, and neonatal-onset multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0395] Project 26A

[0396] The compound or pharmaceutically acceptable salt thereof according to Item 25A, wherein, for use, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0397] Project 27A

[0398] According to the compound or pharmaceutically acceptable salt thereof of Item 25A, wherein, with respect to use, the cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal-onset multisystem inflammatory disease.

[0399] Project 28A

[0400] A package for commercial use, comprising a pharmaceutical composition according to item 14 and a written document related to the pharmaceutical composition, which describes that the composition can be used to treat or prevent a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous arthritis, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing heart disease, Pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[0401] Project 29A

[0402] A kit for commercial use, comprising a pharmaceutical composition according to item 14 and a written document related to the pharmaceutical composition, wherein the document describes that the composition can be used to treat or prevent a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Muir-Wei syndrome, chronic infantile neurocutaneous arthritis, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing Pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome. DETAILED DESCRIPTION

[0403] The following are definitions of terms that may be used in this article.

[0404] The following wavy lines in chemical formulas:

[0405]

[0406] It refers herein to the binding site of the moiety or group represented by the chemical formula.

[0407] The term "C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 The "alkyl group" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Preferably, it includes methyl and ethyl. More preferably, it includes methyl.

[0408] The term "C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6The “alkyl group” includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Preferably, it includes methyl, ethyl, isopropyl and isopentyl. More preferably, it includes methyl.

[0409] The term "C 1-4 "Alkoxy" refers to a group wherein the above-defined "C 1-4 Alkyl" is a group bonded to an oxygen atom. 1-4 The "alkoxy" includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy. Preferably, it includes methoxy and ethoxy.

[0410] The term "C 1-6 "Alkoxy" refers to a group wherein the above-defined "C 1-6 Alkyl" is a group bonded to an oxygen atom. 1-6 The “alkoxy” includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy and 2-ethylbutoxy. Preferably, methoxy, ethoxy and isopentoxy are included.

[0411] The term "halogen" includes, for example, fluorine, chlorine, bromine and iodine. Preferably, it includes fluorine, chlorine and bromine. More preferably, it includes fluorine.

[0412] The term "C 1-4 "Haloalkyl" refers to the above-defined "C" substituted by 1 to 7 halogen atoms independently selected from the above-defined "halogen" 1-4 Alkyl". "C 1-4 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl. Preferably, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl are included. More preferably, difluoromethyl is included.

[0413] The term "C 1-6"Haloalkyl" refers to the above-defined "C" substituted by 1 to 9 halogen atoms independently selected from the above-defined "halogen" 1-6 Alkyl". "C 1-6 "Haloalkyl" includes, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1-fluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl. Preferably, trifluoromethyl, 1,1-difluoroethyl and 1-fluoro-1-methylethyl are included. More preferably, 1,1-difluoroethyl is included.

[0414] The term "C 3-6 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms. 3-6 "Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0415] The term "4- to 6-membered heterocycloalkyl radicals comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 4- to 6-membered monocyclic saturated heterocyclic radical comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms as ring atoms in addition to carbon atoms. "4- to 6-membered heterocycloalkyl radicals comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" include, for example, azetidinyl, oxetane, diazetidinyl, dioxetane, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolane, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexane, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl and dioxane. Preferably, oxetane, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl and dioxane are included.

[0416] The term "a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom" refers to a 4- to 7-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom and a carbon atom as ring atoms. "A 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom" includes, for example, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, 1, 2-diazacyclohexane, 1,3-diazacyclohexane, piperazinyl, morpholinyl, tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, thiomorpholinyl, dioxane, azepanyl, oxepanyl, diazepanyl (e.g., 1,4-diazacycloheptanyl), oxazepanyl (e.g., 1,4-oxazepanyl and 1,2-oxazepanyl), dioxepanyl (e.g., 1,4-dioxepanyl) and thiazinyl. Preferably, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, dioxane and dioxepanyl are included.

[0417] The term "C 5-6 "Cycloalkenyl" refers to a monocyclic partially unsaturated hydrocarbon group having 5 to 6 carbon atoms and containing at least one double bond. 5-6 The "cycloalkenyl group" includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl. Preferably, it includes cyclopentenyl.

[0418] The term "C 5-6 "Cycloolefin" refers to a monocyclic partially unsaturated hydrocarbon ring containing 5 to 6 carbon atoms and at least one double bond. 5-6 "Cycloolefins" include, for example, cyclopentene, cyclopentadiene, cyclohexene and cyclohexadiene.

[0419] The term "5-yuan or 6-yuan heterocycloalkenyl groups comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a monocyclic partially unsaturated heterocyclic group comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms and a carbon atom, and at least one double bond as ring atoms. "5-yuan or 6-yuan heterocycloalkenyl groups comprising 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" include, for example, pyrrolinyl, pyrazolinyl, imidazolinyl, dihydrofuranyl, dioxolyl, oxazolinyl, isoxazolinyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, tetrahydropyrazinyl, dihydropyridyl, dihydropyranyl, dihydrodioxinyl, pyranyl and dihydro 4,4-dimethyloxazolinyl. Preferably, dihydrofuranyl and dihydropyranyl are included.

[0420] The term "5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms" refers to a 5- to 7-membered monocyclic partially unsaturated heterocycle containing 1 or 2 oxygen atoms and carbon atoms as ring atoms, and at least one double bond. "5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms" includes, for example, dihydrofuran, dioxole, dihydropyran, dihydrodioxin, pyran, tetrahydrooxepin, dihydrodioxepine, dihydrooxepine, and dioxepine. Preferably, dihydropyran is included.

[0421] The term "a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms and a carbon atom as ring atoms. "A 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" includes, for example, the following groups:

[0422]

[0423] The term "5- to 8-membered bridged cycloalkyl" refers to a 5- to 8-membered bridged cyclic saturated hydrocarbon group. "5- to 8-membered bridged cycloalkyl" includes, for example, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Preferably, it includes bicyclo[1.1.1]pentyl.

[0424] The term "5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" refers to a 5- to 8-membered bridged saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms and a carbon atom as ring atoms. "5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms" includes, for example, the following groups:

[0425]

[0426] In certain embodiments of the present invention, R 13 With R 11 or R 12 Together with the carbon atoms to which they are connected, they form a ring structure, and the partial structure in formula [I] is:

[0427]

[0428] The whole forms a 9- to 11-membered partially unsaturated fused ring group optionally containing 1 or 2 oxygen atoms, wherein the ring group is R 9 and R 10 and R 11 or R 12 The fused ring group includes, for example, the following groups:

[0429]

[0430] The phrase wherein α is "optionally substituted with β" means that α is unsubstituted or any substitutable hydrogen atom of α is substituted with β. For example, "C 1-6 "Alkyl" refers to C 1-6 The alkyl group is unsubstituted, or C 1-6 Any hydrogen atom of the alkyl group is replaced by a hydroxy group.

[0431] The embodiments of each substituent of the compound of formula [I] are shown below. However, each substituent of the compound of formula [I] is not limited to these embodiments, and the compound of formula [I] also includes any combination of two or more of these embodiments of each substituent.

[0432] Partial structure:

[0433]

[0434] Preferably, the structure is:

[0435]

[0436] Among them, R 5 Same as the above definition.

[0437] R 5 Preferred is hydrogen.

[0438] The cyclic group Cy is preferably a group represented by the following formula:

[0439]

[0440] The symbols are the same as defined above.

[0441] Preferably, R 9 and R 10 Each independently

[0442] (a)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0443] (b)C 1-4 Alkoxy,

[0444] (c) halogens,

[0445] (d)C 1-4 a haloalkyl group, or

[0446] (e)-OC 1-4 Halogenated alkyl.

[0447] More preferably, R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution.

[0448] Preferably, R 11 and R 12 are each independently hydrogen or C 1-4 alkyl.

[0449] More preferably, R 11 and R 12 For hydrogen.

[0450] Preferably, R 13 for

[0451] (a)C 1-4 alkyl,

[0452] (b)C 1-4 Alkoxy,

[0453] (c) halogens,

[0454] (d)C 1-6 Halogenated alkyl,

[0455] (e)-OC 1-4 a haloalkyl group, or

[0456] (f)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 or 2 halogen atoms, or

[0457] R 13 With R 11 or R 12Together with the carbon atoms to which they are attached, they form:

[0458] (a)C 5-6 Cyclic olefins, or

[0459] (b) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms.

[0460] More preferably, R 13 C 1-6 Haloalkyl or -OC 1-4 Halogenated alkyl.

[0461] In the partial structure:

[0462] middle,

[0463] Preferably,

[0464] R 9 and R 10 Each independently

[0465] (a)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0466] (b)C 1-4 Alkoxy,

[0467] (c) halogens,

[0468] (d)C 1-4 a haloalkyl group, or

[0469] (e)-OC 1-4 alkyl halide;

[0470] R 11 and R 12 are each independently hydrogen or C 1-4 alkyl;

[0471] R 13 for

[0472] (a)C 1-4 alkyl,

[0473] (b)C 1-4 Alkoxy,

[0474] (c) halogens,

[0475] (d)C 1-6 Halogenated alkyl,

[0476] (e)-OC 1-4 a haloalkyl group, or

[0477] (f)C3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 or 2 halogen atoms, or

[0478] R 13 With R 11 or R 12 Together with the carbon atoms to which they are attached, they form:

[0479] (a)C 5-6 Cyclic olefins, or

[0480] (b) 5- to 7-membered heterocyclic olefins containing 1 or 2 oxygen atoms.

[0481] In the partial structure:

[0482] middle,

[0483] More preferably,

[0484] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0485] R 11 and R 12 is hydrogen; and

[0486] R 13 C 1-6 Haloalkyl or -OC 1-4 Halogenated alkyl.

[0487] In the partial structure:

[0488] middle,

[0489] More preferably,

[0490] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0491] R 11 and R 12 is hydrogen; and

[0492] R 13 C 1-6 Halogenated alkyl.

[0493] In the partial structure:

[0494] middle,

[0495] More preferably,

[0496] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0497] R 11 and R 12 is hydrogen; and

[0498] R 13 For-OC 1-4 Halogenated alkyl.

[0499] R 1 Preferred is hydrogen.

[0500] Preferably, R 2 、R 3 and R 4 Each independently

[0501] (1) Hydrogen,

[0502] (2) hydroxyl groups,

[0503] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0504] (a) hydroxyl groups,

[0505] (b)C 1-4 Alkoxy, and

[0506] (c)-SO2-C 1-4 alkyl,

[0507] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0508] (a) hydroxyl groups,

[0509] (b) phenyl, or

[0510] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0511] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0512] (6)-OC 1-4 a haloalkyl group, or

[0513] (7)C 3-6 Cycloalkyl, or

[0514] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0515] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0516] (1) cyano,

[0517] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0518] (3)C 1-4 Alkoxy,

[0519] (4) halogen, and

[0520] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0521] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0522] (1) hydroxyl groups,

[0523] (2)C 1-4 alkyl,

[0524] (3)C 1-4 Alkoxy, and

[0525] (4) Halogen, or

[0526] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0527] (c) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0528] (d) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally replaced by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0529] (e) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0530] (f) a group represented by the following formula:

[0531]

[0532] Among them, R 20 Same as the above definition.

[0533] More preferably, R 2 、R 3 and R 4 Each independently

[0534] (1) Hydrogen,

[0535] (2) hydroxyl groups,

[0536] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0537] (a) hydroxyl groups,

[0538] (b)C 1-4 Alkoxy, and

[0539] (c)-SO2-C 1-4 alkyl,

[0540] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0541] (a) hydroxyl groups,

[0542] (b) phenyl, or

[0543] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or

[0544] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substituted, or

[0545] R 2 、R 3 and R 4together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0546] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0547] (1) cyano,

[0548] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0549] (3)C 1-4 Alkoxy,

[0550] (4) halogen, and

[0551] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0552] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0553] (1) hydroxyl groups,

[0554] (2)C 1-4 alkyl,

[0555] (3)C 1-4 Alkoxy, and

[0556] (4) Halogen, or

[0557] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups, or

[0558] (c) a group represented by the following formula:

[0559]

[0560] Among them, R 20 Same as the above definition.

[0561] More preferably, R 2 、R 3 and R 4 Each independently

[0562] (1) Hydrogen,

[0563] (2) hydroxyl groups, or

[0564] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0565] (a) hydroxyl groups,

[0566] (b)C 1-4 Alkoxy, and

[0567] (c)-SO2-C 1-4 Alkyl, or

[0568] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0569] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0570] (1) cyano,

[0571] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0572] (3)C 1-4 Alkoxy,

[0573] (4) Halogen, and

[0574] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 Alkyl, or

[0575] (b) a group represented by the following formula:

[0576]

[0577] Among them, R 21 and R 22 Same as the above definition.

[0578] More preferably, R 2 、R 3 and R4 Each independently

[0579] (1) Hydrogen,

[0580] (2) hydroxyl groups, or

[0581] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0582] (a) hydroxyl groups,

[0583] (b)C 1-4 Alkoxy, and

[0584] (c)-SO2-C 1-4 alkyl.

[0585] More preferably, R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed into C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0586] (1) cyano,

[0587] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0588] (3)C 1-4 Alkoxy,

[0589] (4) Halogen, and

[0590] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.

[0591] Preferably, R 20 -NR 21 R 22 , where R 21 and R 22 Same as the above definition.

[0592] In a preferred embodiment of the compound of formula [I],

[0593] Partial structure:

[0594]

[0595] For the structure of the following formula:

[0596]

[0597] R 5 is hydrogen;

[0598] The cyclic group Cy is a group of the formula:

[0599]

[0600] R 9 and R 10 Each independently

[0601] (a)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0602] (b)C 1-4 Alkoxy,

[0603] (c) halogens,

[0604] (d)C 1-4 a haloalkyl group, or

[0605] (e)-OC 1-4 alkyl halide;

[0606] R 11 and R 12 are each independently hydrogen or C 1-4 alkyl;

[0607] R 13 for:

[0608] (a)C 1-4 alkyl,

[0609] (b)C 1-4 Alkoxy,

[0610] (c) halogens,

[0611] (d)C 1-6 Halogenated alkyl,

[0612] (e)-OC 1-4 a haloalkyl group, or

[0613] (f)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 or 2 halogen atoms, or

[0614] R 13 With R11 or R 12 Together with the carbon atoms to which they are attached, they form:

[0615] (a)C 5-6 Cyclic olefins, or

[0616] (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms;

[0617] R 1 is hydrogen; and

[0618] R 2 、R 3 and R 4 Each independently

[0619] (1) Hydrogen,

[0620] (2) hydroxyl groups,

[0621] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0622] (a) hydroxyl groups,

[0623] (b)C 1-4 Alkoxy, and

[0624] (c)-SO2-C 1-4 alkyl,

[0625] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0626] (a) hydroxyl groups,

[0627] (b) phenyl, or

[0628] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0629] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0630] (6)-OC 1-4 a haloalkyl group, or

[0631] (7)C 3-6 Cycloalkyl, or

[0632] R 2 、R 3 and R 4together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0633] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0634] (1) cyano group,

[0635] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0636] (3)C 1-4 Alkoxy,

[0637] (4) Halogen, and

[0638] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0639] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0640] (1) hydroxyl groups,

[0641] (2)C 1-4 alkyl,

[0642] (3)C 1-4 Alkoxy, and

[0643] (4) Halogen, or

[0644] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0645] (c) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0646] (d) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally replaced by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0647] (e) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0648] (f) a group represented by the following formula:

[0649]

[0650] Among them, R 20 Same as the above definition.

[0651] Another preferred embodiment of the compound of formula [I] is a compound of formula [I], wherein the partial structure

[0652]

[0653] for

[0654] (1) The structure of the following formula:

[0655]

[0656] Among them, R 5 is hydrogen or C 1-4 Alkyl, wherein the alkyl may be optionally substituted with:

[0657] (a) carboxyl,

[0658] (b)-CO-C 1-4 Alkoxy, or

[0659] (c)-CO-NR 6 R 7 , where R 6 and R 7 are each independently hydrogen or C 1-4 Alkyl, or

[0660] (2) The structure of the following formula:

[0661]

[0662] Among them, R 8 C 1-4 alkyl;

[0663] The ring group Cy is

[0664] (1) A group represented by the following formula:

[0665]

[0666] Among them, R 9 and R 10 Each independently

[0667] (a) Hydrogen,

[0668] (b)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0669] (c)C 1-4 Alkoxy,

[0670] (d) halogens,

[0671] (e)C 1-4 haloalkyl, or

[0672] (f)-OC 1-4 haloalkyl,

[0673] R 11 and R 12 Each independently

[0674] (a) Hydrogen,

[0675] (b)C 1-4 Alkyl, or

[0676] (c)C 1-4 haloalkyl,

[0677] R 13 for

[0678] (a) Hydrogen,

[0679] (b)C 1-4 alkyl,

[0680] (c)C 1-4 Alkoxy,

[0681] (d)C 1-6 haloalkyl, or

[0682] (e)-OC 1-4 a haloalkyl group, or

[0683] R 13 Can be used with R 11 or R 12 and the carbon atoms to which they are attached to form: (a) C 5-6 Cyclic olefins, or

[0684] (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms, or

[0685] (2) A group represented by the following formula:

[0686]

[0687] Among them, R 14 and R15 Each independently is C 1-4 Alkyl or C 1-4 haloalkyl,

[0688] R 16 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0689] R 1 for

[0690] (1) Hydrogen,

[0691] (2) cyano,

[0692] (3)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0693] (4)C 1-4 haloalkyl, or

[0694] (5)-CO-C 1-4 alkyl;

[0695] R 2 、R 3 and R 4 Each independently

[0696] (1) Hydrogen,

[0697] (2) hydroxyl groups,

[0698] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0699] (a) hydroxyl groups,

[0700] (b)C 1-4 alkoxy, and

[0701] (c)-SO2-C 1-4 alkyl,

[0702] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0703] (a) hydroxyl groups,

[0704] (b) phenyl, or

[0705] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0706] (5) halogens,

[0707] (6)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0708] (7)-OC 1-4 haloalkyl,

[0709] (8)-OR 17 , where R 17 is a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0710] (9)C 3-6 Cycloalkyl,

[0711] (10) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocycloalkyl group may be optionally substituted with oxo, or

[0712] (11) A group represented by the following formula:

[0713] or

[0714] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0715] (a) cyano group,

[0716] (b)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0717] (1) cyano,

[0718] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0719] (3)C 1-4 Alkoxy,

[0720] (4) Halogen, and

[0721] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0722] (c) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0723] (1) hydroxyl groups,

[0724] (2)C 1-4 alkyl,

[0725] (3)C 1-4 Alkoxy, and

[0726] (4) Halogen, or

[0727] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0728] (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the fused heterocyclic group may be optionally substituted by 1 or 2 halogen atoms,

[0729] (e) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0730] (f) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally substituted by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0731] (g)C 5-6 Cycloalkenyl,

[0732] (h) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0733] (i) a group represented by the following formula:

[0734]

[0735] Among them, R 20 for

[0736] (1)C 1-4 Alkyl, or

[0737] (2)-NR 21 R 22 , where R 21 and R 22 Each independently

[0738] (a) Hydrogen,

[0739] (b)C 1-4 alkyl,

[0740] (c)C 1-4 haloalkyl, or

[0741] (d) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom.

[0742] Another preferred embodiment of the compound of formula [I] is the compound of formula [II]:

[0743]

[0744] Among them, R 9 and R 10 Each independently

[0745] (a) Hydrogen,

[0746] (b)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0747] (c)C 1-4 Alkoxy,

[0748] (d) halogens,

[0749] (e)C 1-4 haloalkyl, or

[0750] (f)-OC 1-4 alkyl halide;

[0751] R 11 and R 12 Each independently

[0752] (a) Hydrogen,

[0753] (b)C 1-4 Alkyl, or

[0754] (c)C 1-4 alkyl halide;

[0755] R 13 for

[0756] (a) Hydrogen,

[0757] (b)C 1-4 alkyl,

[0758] (c)C 1-4 Alkoxy,

[0759] (d)C 1-6 haloalkyl, or

[0760] (e)-OC 1-4 a haloalkyl group, or

[0761] R 13 With R 11 or R 12 Together with the carbon atoms to which they are attached, they form:

[0762] (a)C 5-6 Cyclic olefins, or

[0763] (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms;

[0764] R 2 、R 3 and R 4 Each independently

[0765] (1) Hydrogen,

[0766] (2) hydroxyl groups,

[0767] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0768] (a) hydroxyl groups,

[0769] (b)C 1-4 alkoxy, and

[0770] (c)-SO2-C 1-4 alkyl,

[0771] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0772] (a) hydroxyl groups,

[0773] (b) phenyl, or

[0774] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0775] (5) halogens,

[0776] (6)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0777] (7)-OC 1-4 haloalkyl,

[0778] (8)-OR 17 , where R17 is a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0779] (9)C 3-6 Cycloalkyl,

[0780] (10) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocycloalkyl group may be optionally substituted with oxo, or

[0781] (11) A group represented by the following formula:

[0782] or

[0783] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0784] (a) cyano group,

[0785] (b)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0786] (1) cyano group,

[0787] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0788] (3)C 1-4 Alkoxy,

[0789] (4) halogen, and

[0790] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0791] (c) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0792] (1) hydroxyl groups,

[0793] (2)C 1-4 alkyl,

[0794] (3)C 1-4 Alkoxy, and

[0795] (4) Halogen, or

[0796] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0797] (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the fused heterocyclic group may be optionally substituted by 1 or 2 halogen atoms,

[0798] (e) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0799] (f) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally substituted by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0800] (g)C 5-6 Cycloalkenyl,

[0801] (h) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0802] (i) a group represented by the following formula:

[0803]

[0804] Among them, R 20 for

[0805] (1)C 1-4 Alkyl, or

[0806] (2)-NR 21 R 22 , where R 21 and R 22 Each independently

[0807] (a) Hydrogen,

[0808] (b)C 1-4 alkyl,

[0809] (c)C 1-4 haloalkyl, or

[0810] (d) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom.

[0811] A preferred embodiment of the compound of formula [II] is a compound of formula [III]:

[0812]

[0813] Among them, R 9 and R 10 Each independently

[0814] (a) Hydrogen,

[0815] (b)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0816] (c)C 1-4 Alkoxy,

[0817] (d) halogens,

[0818] (e)C 1-4 a haloalkyl group, or

[0819] (f)-OC 1-4 alkyl halide;

[0820] R 13 for

[0821] (a) Hydrogen,

[0822] (b)C 1-4 alkyl,

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

[0824] (d)C 1-6 haloalkyl, or

[0825] (e)-OC 1-4 a haloalkyl group, or

[0826] R 13 With R 11 or R 12 Together with the carbon atoms to which they are attached, they form:

[0827] (a)C 5-6 Cyclic olefins, or

[0828] (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms;

[0829] R 2 、R 3 and R 4 Each independently

[0830] (1) Hydrogen,

[0831] (2) hydroxyl groups,

[0832] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0833] (a) hydroxyl groups,

[0834] (b)C 1-4 Alkoxy, and

[0835] (c)-SO2-C 1-4 alkyl,

[0836] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0837] (a) hydroxyl groups,

[0838] (b) phenyl, or

[0839] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0840] (5) halogens,

[0841] (6)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0842] (7)-OC 1-4 haloalkyl,

[0843] (8)-OR 17 , where R 17 is a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0844] (9)C 3-6 Cycloalkyl,

[0845] (10) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocycloalkyl group may be optionally substituted with oxo, or

[0846] (11) A group represented by the following formula:

[0847] or

[0848] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR2 R 3 R 4 The group is formed as:

[0849] (a) cyano group,

[0850] (b)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0851] (1) cyano,

[0852] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0853] (3)C 1-4 Alkoxy,

[0854] (4) Halogen, and

[0855] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0856] (c) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0857] (1) hydroxyl groups,

[0858] (2)C 1-4 alkyl,

[0859] (3)C 1-4 Alkoxy, and

[0860] (4) Halogen, or

[0861] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0862] (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the fused heterocyclic group may be optionally substituted by 1 or 2 halogen atoms,

[0863] (e) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0864] (f) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally substituted by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0865] (g)C 5-6 Cycloalkenyl,

[0866] (h) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0867] (i) a group represented by the following formula:

[0868]

[0869] Among them, R 20 for

[0870] (1)C 1-4 Alkyl, or

[0871] (2)-NR 21 R 22 , where R 21 and R 22 Each independently

[0872] (a) Hydrogen,

[0873] (b)C 1-4 alkyl,

[0874] (c)C 1-4 haloalkyl, or

[0875] (d) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom.

[0876] In a preferred embodiment of the compound of formula [III],

[0877] R 9 and R 10 Each independently

[0878] (a)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution,

[0879] (b)C 1-4 Alkoxy,

[0880] (c) halogens,

[0881] (d)C 1-4 haloalkyl, or

[0882] (e)-OC 1-4 alkyl halide;

[0883] R 13 C 1-6 Haloalkyl or -OC 1-4 alkyl halide;

[0884] R 2 、R 3 and R 4 Each independently

[0885] (1) Hydrogen,

[0886] (2) hydroxyl groups,

[0887] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0888] (a) hydroxyl groups,

[0889] (b)C 1-4 Alkoxy, and

[0890] (c)-SO2-C 1-4 alkyl,

[0891] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0892] (a) hydroxyl groups,

[0893] (b) phenyl, or

[0894] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms,

[0895] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution,

[0896] (6)-OC 1-4 haloalkyl, or

[0897] (7)C 3-6 Cycloalkyl, or

[0898] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0899] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0900] (1) cyano,

[0901] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0902] (3)C 1-4 Alkoxy,

[0903] (4) Halogen, and

[0904] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0905] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0906] (1) hydroxyl groups,

[0907] (2)C 1-4 alkyl,

[0908] (3)C 1-4 Alkoxy, and

[0909] (4) Halogen, or

[0910] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups.

[0911] (c) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen,

[0912] (d) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally replaced by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group,

[0913] (e) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or

[0914] (f) a group represented by the following formula:

[0915]

[0916] Among them, R 21 and R 22 Each independently

[0917] (1) Hydrogen,

[0918] (2)C 1-4 alkyl,

[0919] (3)C 1-4 a haloalkyl group, or

[0920] (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

[0921] In a more preferred embodiment of the compound of formula [III],

[0922] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0923] R 13 C 1-6 Haloalkyl or -OC 1-4 alkyl halide;

[0924] R 2 、R 3 and R 4 Each independently

[0925] (1) Hydrogen,

[0926] (2) hydroxyl groups,

[0927] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0928] (a) hydroxyl groups,

[0929] (b)C 1-4 Alkoxy, and

[0930] (c)-SO2-C 1-4 alkyl,

[0931] (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with:

[0932] (a) hydroxyl groups,

[0933] (b) phenyl, or

[0934] (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or

[0935] (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substituted, or

[0936] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed as:

[0937] (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0938] (1) cyano,

[0939] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0940] (3)C 1-4 Alkoxy,

[0941] (4) Halogen, and

[0942] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl,

[0943] (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0944] (1) hydroxyl groups,

[0945] (2)C 1-4 alkyl,

[0946] (3)C 1-4 Alkoxy, and

[0947] (4) Halogen, or

[0948] Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups, or

[0949] (c) a group represented by the following formula:

[0950]

[0951] Among them, R 21 and R 22 Each independently

[0952] (1) Hydrogen,

[0953] (2)C 1-4 alkyl,

[0954] (3)C 1-4 haloalkyl, or

[0955] (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

[0956] In a more preferred embodiment of the compound of formula [III],

[0957] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0958] R 13 C 1-6 Haloalkyl or -OC 1-4 alkyl halide;

[0959] R 2 、R 3 and R 4 Each independently

[0960] (1) Hydrogen,

[0961] (2) hydroxyl groups,

[0962] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0963] (a) hydroxyl groups,

[0964] (b)C 1-4 Alkoxy, and

[0965] (c)-SO2-C 1-4 Alkyl, or

[0966] R 2 、R 3 and R 4together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed into C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0967] (1) cyano,

[0968] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0969] (3)C 1-4 Alkoxy,

[0970] (4) Halogen, and

[0971] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.

[0972] In a more preferred embodiment of the compound of formula [III],

[0973] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0974] R 13 C 1-6 alkyl halide;

[0975] R 2 、R 3 and R 4 Each independently

[0976] (1) Hydrogen,

[0977] (2) hydroxyl groups, or

[0978] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0979] (a) hydroxyl groups,

[0980] (b)C 1-4 Alkoxy, and

[0981] (c)-SO2-C 1-4 Alkyl, or

[0982] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed into C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0983] (1) cyano,

[0984] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[0985] (3)C 1-4 Alkoxy,

[0986] (4) Halogen, and

[0987] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.

[0988] In a more preferred embodiment of the compound of formula [III],

[0989] R 9 and R 10 Each independently is C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution;

[0990] R 13 For-OC 1-4 alkyl halide;

[0991] R 2 、R 3 and R 4 Each independently

[0992] (1) Hydrogen,

[0993] (2) hydroxyl groups, or

[0994] (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups:

[0995] (a) hydroxyl groups,

[0996] (b)C1-4 Alkoxy, and

[0997] (c)-SO2-C 1-4 Alkyl, or

[0998] R 2 、R 3 and R 4 together with the carbon atom to which they are attached, and -CR 2 R 3 R 4 The group is formed into C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups:

[0999] (1) cyano,

[1000] (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution,

[1001] (3)C 1-4 Alkoxy,

[1002] (4) Halogen, and

[1003] (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl.

[1004] Another preferred embodiment of the compound of formula [I] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X] or [XI]:

[1005]

[1006] Among them, R 9 、R 10 、R 12 、R 14 、R 15 and R 16 Same as the above definition.

[1007] The term "pharmaceutically acceptable salt" as used herein may be any salt known in the art that is not associated with excessive toxicity. Such pharmaceutically acceptable salts specifically include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references:

[1008] (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977),

[1009] (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

[1010] (c) Paulekuhn et al., J. Med. Chem., 50, pp. 6665-6672 (2007).

[1011] The compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se to obtain its corresponding pharmaceutically acceptable salt.

[1012] Such salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid. Such salts preferably include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

[1013] Such salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric 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, glycolylparaaminophenylarsanilic acid, hexylresorcinol acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, The salts of the present invention include salts of oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid.

[1014] Such salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth and ammonium. Such salts preferably include salts with sodium, potassium, calcium, magnesium and zinc.

[1015] Such salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine and lysine. Such salts preferably include salts with tris(hydroxymethyl)methylamine, N-methylglucamine and lysine.

[1016] Compound [I] may exist in the form of a solvate thereof. The term "solvate" refers to a compound in which a solvent molecule is coordinated with, for example, Compound [I]. The solvate may be any pharmaceutically acceptable solvate; and includes, for example, hydrates, acetates, acetonides, ethanolates, and dimethylsulfoxides of Compound [I]. Such solvates specifically include hemihydrates, monohydrates, dihydrates, monoacetonides, monoacetonides, and monoethanolates of the compound of formula [I]; as well as the monohydrate and monoacetonide of the sodium salt of the compound of formula [I], and the 2 / 3 ethanolate of its dihydrochloride salt. These solvates can be obtained according to any known method.

[1017] Compound [I] may exist as tautomers. In this case, compound [I] may exist as a single tautomer or a mixture of tautomers. For example, unless otherwise specified, the structure represented by the following formula:

[1018]

[1019] It means that the compound can exist and / or be represented by the following formula: (1)

[1021] (2)

[1023] (3)

[1025] (4)

[1027] or

[1028] (5) A mixture of these structures.

[1029] Compound [I] may have a carbon-carbon double bond. In this case, compound [I] may exist as an E-isomer, a Z-isomer, or a mixture of E- and Z-isomers.

[1030] Compound [I] may exist as stereoisomers, which should be identified as cis / trans isomers. In this case, compound [I] may exist as cis isomers, trans isomers, or a mixture of cis and trans isomers.

[1031] Compound [I] may have one or more asymmetric carbon atoms. In this case, compound [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[1032] Compound [I] may exist as an atropisomer. In this case, compound [I] may exist as a single atropisomer or a mixture of atropisomers.

[1033] Compound [I] may simultaneously have multiple structural features that can provide the above-mentioned isomers. Compound [I] may also contain the above-mentioned isomers in any ratio.

[1034] Unless otherwise stated, formulas, chemical structures or chemical names that do not specify stereochemistry are intended to encompass all such isomers that may exist.

[1035] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography or crystallization.Individual diastereomers can also be prepared by using starting materials that are stereochemically single isomers or by synthetic methods that use stereoselective reactions.

[1036] A mixture of enantiomers can be separated into various single enantiomers by methods well known in the art. For example, a mixture of enantiomers can react with a substantially pure enantiomer known as a chiral auxiliary to form a mixture of diastereomers, which can then be separated into diastereomers or substantially pure single diastereomers with an increased isomer ratio by conventional methods such as fractional crystallization or chromatography. The added chiral auxiliary can be removed from the separated diastereomers by a cleavage reaction to obtain the desired enantiomer. A mixture of enantiomers can also be directly separated by chromatography well known in the art using a chiral stationary phase. Alternatively, any one of the enantiomers can also be obtained by stereoselective synthesis (i.e., asymmetric induction) of a protochiral intermediate using substantially pure and optically active raw materials or by employing a chiral auxiliary or an asymmetric catalyst.

[1037] The absolute configuration can be determined by X-ray crystallographic analysis of crystalline products or intermediates. In this case, if desired, crystalline products or intermediates induced by reagents having asymmetric centers of known configuration can be used.

[1038] Compound [I] can be modified with isotopic atoms such as2 H(D), 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 18 O. 18 F. 35 S and 123 I labeling. For example, in the case where the compound of formula [I] has a methyl group, the methyl group can be replaced by a -CD3 group. The compounds thus obtained are also included in the present invention. Compounds [I] labeled with isotopic atoms can be used for pharmaceuticals, pharmacokinetic studies, in vitro and / or in vivo assays and / or diagnostics such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). Compounds [I] labeled with isotopic atoms can be prepared using isotope-labeled compounds instead of the corresponding unlabeled compounds according to known methods or methods described herein.

[1039] Compound [I] is preferably substantially purified Compound [I], and more preferably purified Compound [I] with a purity of 80% or higher.

[1040] The pharmaceutical composition of the present invention can be prepared by optionally mixing Compound [I] with at least one or more pharmaceutically acceptable carriers in a certain amount according to known methods in the field of pharmaceutical preparations. The content of Compound [I] in the pharmaceutical composition varies depending on the dosage form and dosage, and is, for example, 0.1 to 100% by weight of the composition.

[1041] Dosage forms of compound [I] include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions; and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[1042] As used herein, the term "pharmaceutically acceptable carrier" includes various organic or inorganic carrier substances conventionally used for formulation components. Such substances include, for example, excipients, disintegrants, binders, fluidizers, and lubricants for solid formulations; solvents, cosolvents, suspending agents, tonicity agents, buffers, and soothing agents for liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plasticizers, pH regulators, absorption promoters, gelling agents, preservatives, extenders, solubilizers, cosolvents, and suspending agents for semisolid formulations. If necessary, additives such as preservatives, antioxidants, colorants, and sweeteners may be further used.

[1043] Such excipients include, for example, lactose, soft sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic.

[1044] Such disintegrants include, for example, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, cross-linked carboxymethylcellulose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and crystalline cellulose.

[1045] Such binders include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, caster sugar, dextrin, starch, gelatin, sodium carboxymethyl cellulose, and gum arabic.

[1046] Such fluidizing agents include, for example, light anhydrous silicic acid and magnesium stearate.

[1047] Such lubricants include, for example, magnesium stearate, calcium stearate and talc.

[1048] Such solvents include, for example, purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.

[1049] Such solubilizing agents include, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate and sodium citrate.

[1050] Such suspending agents include, for example, benzalkonium chloride, carboxymethylcellulose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose and glyceryl monostearate.

[1051] Such tonicity agents include, for example, dextrose, D-sorbitol, sodium chloride, and D-mannitol.

[1052] Such buffers include, for example, sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.

[1053] Such soothing agents include, for example, benzyl alcohol.

[1054] Such bases include, for example, water, oils of animal or plant origin (such as olive oil, corn oil, peanut oil, sesame oil and castor oil), lower alcohols (such as ethanol, propanol, propylene glycol, 1,3-butylene glycol and phenol), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (such as white petrolatum, liquid paraffin and paraffin), hydrophilic petrolatum, purified lanolin, water-absorbing ointments, aqueous lanolin, hydrophilic ointments, starch, pullulan, gum arabic, gum tragacanth, gelatin, dextran, cellulose derivatives (such as methylcellulose, carboxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose), synthetic polymers (such as carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol and polyvinylpyrrolidone), propylene glycol, polyethylene glycol (such as Macrogol 200 to 600), and combinations of two or more thereof.

[1055] Such preservatives include, for example, ethylparaben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.

[1056] Such antioxidants include, for example, sodium sulfite and ascorbic acid.

[1057] Such coloring agents include, for example, food colorings (eg, food red No. 2 or No. 3, food yellow No. 4 or No. 5) and beta-carotene.

[1058] Such sweeteners include, for example, sodium saccharin, dipotassium glycyrrhizate, and aspartame.

[1059] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topically, rectally, intravenously, intramuscularly, and subcutaneously) to humans and non-human mammals such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, and monkeys. Although the dosage (sometimes referred to herein as "therapeutically effective amount") may vary depending on the subject, disease, symptoms, dosage form, administration route, and the like, for example, when orally administered to adult patients, the dosage of the compound of formula [I] or a pharmaceutically acceptable salt thereof as the active ingredient is generally about 0.01 mg to 1 g per day, which can be administered in one or several divided doses.

[1060] Compound [I] has inhibitory activity of NLRP3 inflammasome and can be used to treat and / or prevent various diseases or conditions that are expected to be improved by regulating NLRP3 inflammasome activity. Various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include, for example, diseases selected from the group consisting of multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-associated periodic syndromes (e.g., familial cold autoinflammatory syndrome, Mueller-Weiss syndrome, chronic infantile neurocutaneous arthritis, and neonatal onset multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, relapsing pericarditis, adult-onset Still's disease (e.g., Hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, interleukin-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

[1061] The expression "inhibiting the NLRP3 inflammasome" refers to inhibiting the function of the NLRP3 inflammasome to eliminate or reduce its activity; for example, it refers to inhibiting the function of the NLRP3 inflammasome based on the conditions of Test Example 1 described below. By inhibiting the function of the NLRP3 inflammasome, the production of IL-1β and / or IL-18 is suppressed, and preferably the production of IL-1β and IL-18 is suppressed. Preferably, "inhibiting the NLRP3 inflammasome" refers to "inhibiting the human NLRP3 inflammasome."

[1062] Compound [I] has NLRP3 inflammasome inhibitory activity, and compound [I] or a pharmaceutically acceptable salt thereof can be used alone as an NLRP3 inflammasome inhibitor or, if necessary, after formulation as an NLRP3 inflammasome inhibitor.

[1063] As used herein, the term "treating" includes ameliorating symptoms, preventing worsening, maintaining remission, preventing exacerbations, and preventing relapses.

[1064] As used herein, the term "preventing" includes both inhibiting and delaying the onset of symptoms.

[1065] To the extent that the embodiments disclosed herein are compatible with other embodiments disclosed in another part of the specification, any combination of two or more of these embodiments is also intended to be included in the present invention.

[1066] General preparation method

[1067] The general method for preparing the compound of formula [I] or a pharmaceutically acceptable salt thereof is shown below. However, the method for preparing the compound of formula [I] or a pharmaceutically acceptable salt thereof is not limited thereto.

[1068] Each compound obtained in each step may be isolated and / or purified according to any known method such as distillation, recrystallization and column chromatography, where necessary, or may optionally be subjected to the subsequent step without isolation and / or purification.

[1069] As used herein, the term "room temperature" refers to temperatures that are uncontrolled and include, as one embodiment, temperatures from 1°C to 40°C.

[1070] The abbreviations used herein are as follows.

[1071] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[1072] Preparation method A1: Preparation method of compound [IA] or its salt

[1073] Compound [IA] or a salt thereof can be produced by, for example, the following Production Method A1.

[1074]

[1075] In this diagram, R 2 、R 3 、R 4 and the ring group Cy are the same as defined above,

[1076] R A11 Each independently is C 1-4 alkyl,

[1077] R A12 is boric acid, a boric acid ester (such as pinacol borate), a trifluoroborate or tributyltin, and

[1078] L A11 、L A12 and L A13 Each is independently a leaving group (eg, halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).

[1079] (Step A1-1)

[1080] 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 the presence of an acid in a solvent.

[1081] The acid here includes, for example, sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid and p-toluenesulfonic acid. The acid is preferably sulfuric acid or p-toluenesulfonic acid.

[1082] The solvent includes, for example, toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixed solvents thereof. The solvent is preferably toluene.

[1083] The reaction temperature here is, for example, in the range of 0°C to 150°C, preferably 5°C to 40°C.

[1084] The compound [A1-1] or a salt thereof may be commercially available, or may be prepared from any commercially available product according to a known method.

[1085] Compound [A1-2] may be commercially available, or may be prepared from any commercially available product according to a known method.

[1086] (Step A1-2)

[1087] 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.

[1088] The base includes, for example, triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene and N,N-diisopropylethylamine. The base is preferably triethylamine or N,N-diisopropylethylamine.

[1089] The solvent includes, for example, toluene, methanol, ethanol, tetrahydrofuran and mixed solvents thereof. The solvent is preferably toluene or methanol.

[1090] The reaction temperature here is, for example, in the range of -78°C to 100°C, preferably 0°C to 40°C.

[1091] The compound [A1-4] or a salt thereof may be commercially available, or may be prepared from any commercially available product according to a known method.

[1092] (Steps A1-3)

[1093] 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.

[1094] The acid here includes, for example, trifluoroacetic acid, sulfuric acid, hydrochloric acid and triethylsilyl trifluoromethanesulfonate. The acid is preferably trifluoroacetic acid.

[1095] The solvent includes, for example, toluene, tetrahydrofuran, ethyl acetate, cyclopentyl methyl ether, dichloromethane and mixed solvents thereof. The solvent is preferably toluene.

[1096] The reaction temperature here is, for example, in the range of -78°C to 60°C, preferably 0°C to 40°C.

[1097] (Steps A1-4)

[1098] 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.

[1099] The alkali herein includes, for example, sodium hydroxide and potassium hydroxide. The alkali is preferably sodium hydroxide.

[1100] The solvent includes, for example, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, chloroform, and mixed solvents thereof. The solvent is preferably tetrahydrofuran.

[1101] The reaction temperature here is, for example, in the range of 0°C to 150°C, preferably 50°C to 100°C.

[1102] (Steps A1-5)

[1103] Compound [IA] 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.

[1104] The catalysts include, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bis(triphenylphosphine)dichloropalladium(II), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). The catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct.

[1105] The base here includes, for example, tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. The base is preferably tripotassium phosphate.

[1106] When R A12 For example, when the solvent is boric acid, boric acid ester (including pinacol borate) or trifluoroborate, the solvent includes water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide and mixed solvents thereof. The solvent is preferably a mixed solvent of toluene and water.

[1107] When R A12For example, when tributyltin is used, the solvent includes toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide, and preferably N,N-dimethylacetamide.

[1108] The reaction temperature here is, for example, in the range of 10°C to 200°C, preferably 50°C to 150°C.

[1109] Compound [A1-8] or a salt thereof is commercially available, or can be prepared from any commercially available product according to a known method.

[1110] In the preparation method herein, any compound having any functional group or any protected functional group that can be converted into compound [A1-8] or a salt thereof by any known reaction, or a salt thereof, can be used instead of compound [A1-8] or a salt thereof to obtain a compound corresponding to compound [IA] or a salt thereof, and then compound [IA] or a salt thereof can be prepared by conversion of the functional group.

[1111] In the preparation method herein, any compound or its salt having any functional group or any protected substituent that can be converted into any of various substituents on the benzene ring by any known reaction may be used in place of compound [A1-4] or its salt to obtain a compound or its salt corresponding to compound [IA], and then the functional group or protected substituent is converted into various substituents to prepare compound [IA] or its salt. For example, in the preparation method herein, a compound having L as described below may be used. A41 The phenyl-substituted hydrazine compound or its salt is used to replace the compound [A1-4] or its salt to obtain the compound corresponding to the compound [IA], that is, the compound [IB] or its salt, and then L is added according to the preparation method A4. A41 Converted to cycloCy A41 , to obtain compound [IC] or a salt thereof.

[1112] Preparation method A2: Preparation method of compound [IA] or its salt

[1113] Compound [IA] or a salt thereof can also be produced by, for example, the following production method A2.

[1114]

[1115] In this diagram, R 2 、R 3 、R 4 、L A11 、L A12 、R A12 and the cyclic group Cy are the same as defined above, and

[1116] R A21is a protecting group for hydroxy (e.g., benzyl, 4-methoxybenzyl, and 2-methoxybenzyl) and R A21 Preferred is benzyl.

[1117] (Step A2-1)

[1118] 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.

[1119] The alcohol herein includes, for example, benzyl alcohol, 4-methoxybenzyl alcohol and 2-methoxybenzyl alcohol. The alcohol is preferably benzyl alcohol.

[1120] The base here includes, for example, sodium hydride, potassium tert-butoxide and sodium tert-butoxide. The base is preferably sodium hydride.

[1121] The solvent includes, for example, tetrahydrofuran, N,N-dimethylformamide and mixed solvents thereof, preferably tetrahydrofuran.

[1122] The reaction temperature here is, for example, in the range of -20°C to 100°C, preferably 0°C to 50°C.

[1123] (Step A2-2)

[1124] 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.

[1125] The catalysts include, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), bis(triphenylphosphine)dichloropalladium(II), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). The catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct.

[1126] The base here includes, for example, tripotassium phosphate, cesium carbonate, potassium carbonate and lithium chloride. The base is preferably tripotassium phosphate.

[1127] When R A12 For example, when the solvent is boric acid, boric acid ester (including pinacol borate) or trifluoroborate, the solvent includes water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylacetamide and mixed solvents thereof. The solvent is preferably a mixed solvent of toluene and water.

[1128] When R A12For example, when tributyltin is used, the solvent includes toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide, and preferably N,N-dimethylacetamide.

[1129] The reaction temperature here is, for example, in the range of 10°C to 200°C, preferably 50°C to 150°C.

[1130] (Step A2-3)

[1131] Compound [IA] or a salt thereof can be prepared by removing R from compound [A2-2] or a salt thereof in a deprotection reaction. A21 To prepare. The deprotection reaction can be carried out according to R A21 Under suitable conditions.

[1132] For example, when R A21 In the case of a benzyl group, compound [IA] or a salt thereof can be prepared by reacting compound [A2-2] or a salt thereof in the presence of an acid. A solvent may be optionally added during the reaction.

[1133] The acid here includes, for example, formic acid, trifluoroacetic acid and hydrochloric acid. The acid is preferably formic acid.

[1134] The reaction temperature here is, for example, in the range of 0°C to 120°C, and preferably in the range of 10°C to 100°C.

[1135] The solvent here includes, for example, toluene, tetrahydrofuran and 1,4-dioxane.

[1136] In the preparation method herein, any compound having any functional group or any protected functional group that can be converted into compound [A1-8] or a salt thereof by any known reaction, or a salt thereof, can be used instead of compound [A1-8] or a salt thereof to obtain a compound corresponding to compound [IA] or a salt thereof, followed by conversion of the functional group to prepare compound [IA] or a salt thereof.

[1137] Preparation method A3: Preparation method of compound [IA] or its salt

[1138] Compound [IA] or a salt thereof can also be produced by, for example, the following production method A3.

[1139]

[1140] In this diagram, R 2 、R 3 、R 4 and the cyclic group Cy are the same as defined above,

[1141] R A31 C 1-4 alkyl,

[1142] R A32 is a protecting group for hydrogen or amino (e.g., tert-butoxycarbonyl), and

[1143] R A33 is hydrogen or C 1-4 alkyl.

[1144] (Step A3-1)

[1145] The compound [A3-3] or a salt thereof can be produced by reacting the compound [A3-1] or a salt thereof with the compound [A3-2] or a salt thereof in a solvent in the presence of an oxidizing agent, an acid and an additive.

[1146] The oxidizing agent includes, for example, sodium nitrite, butyl nitrite and isoamyl nitrite. The oxidizing agent is preferably sodium nitrite.

[1147] The acid here includes, for example, concentrated hydrochloric acid, concentrated sulfuric acid and nitric acid. The acid is preferably concentrated hydrochloric acid.

[1148] The additives include, for example, sodium acetate and potassium acetate, preferably sodium acetate.

[1149] The solvent includes, for example, ethanol, methanol, butanol, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1150] The reaction temperature here is, for example, in the range of -40°C to 50°C, preferably -10°C to 40°C.

[1151] The compound [A3-1] or a salt thereof is commercially available, or can be prepared from any commercially available product according to a known method.

[1152] The compound [A3-2] or a salt thereof is commercially available, or can be prepared from any commercially available product according to a known method.

[1153] (Step A3-2)

[1154] 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.

[1155] The base includes, for example, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene, preferably triethylamine.

[1156] The solvent includes, for example, chloroform, 1,2-dichloroethane, dichloromethane and mixed solvents thereof, preferably chloroform.

[1157] The reaction temperature here is, for example, in the range of 20°C to 120°C, preferably 50°C to 100°C.

[1158] Compound [A3-4] is a marketed product.

[1159] (Step A3-3)

[1160] Compound [A3-6] or a salt thereof can be prepared by reacting compound [A3-5] or a salt thereof in a solvent in the presence of a base.

[1161] The alkali herein includes, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide. The alkali is preferably sodium hydroxide.

[1162] The solvent includes, for example, ethanol, methanol, butanol, tetrahydrofuran, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1163] The reaction temperature here is, for example, in the range of 0°C to 100°C, preferably 5°C to 50°C.

[1164] (Step A3-4)

[1165] The compound [A3-7] or a salt thereof can be produced by reacting the compound [A3-6] or a salt thereof in the presence of a reactant and a base in a solvent.

[1166] The reactants include, for example, sodium azide and diphenylphosphoryl azide, preferably diphenylphosphoryl azide.

[1167] The base includes, for example, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene, preferably triethylamine.

[1168] The solvent includes, for example, tert-butyl alcohol, benzyl alcohol, tetrahydrofuran and mixed solvents thereof. The solvent is preferably tert-butyl alcohol.

[1169] The reaction temperature here is, for example, in the range of 0°C to 150°C, preferably 50°C to 120°C.

[1170] (Steps A3-5)

[1171] The compound [A3-8] or a salt thereof can be produced by reacting the compound [A3-7] or a salt thereof in the presence of an oxidizing agent and a base in a solvent.

[1172] The oxidant herein includes, for example, hydrogen peroxide solution, ferrosoferric oxide and manganese dioxide, and the oxidant is preferably hydrogen peroxide solution.

[1173] The alkali herein includes, for example, sodium hydroxide, potassium hydroxide and barium hydroxide. The alkali is preferably sodium hydroxide.

[1174] The solvent includes, for example, ethanol, dimethyl sulfoxide, water and mixed solvents thereof. The solvent is preferably a mixed solvent of dimethyl sulfoxide and water, or ethanol.

[1175] The reaction temperature here is, for example, in the range of -20°C to 50°C, preferably 10°C to 40°C.

[1176] (Step A3-6)

[1177] Compound [A3-9] or a salt thereof can be prepared by removing R from compound [A3-8] or a salt thereof in a deprotection reaction. A32 The deprotection reaction can be prepared according to R A32 Implement under appropriate conditions.

[1178] For example, when R A32 In the case of a tert-butoxycarbonyl group, the compound [A3-9] or a salt thereof can be produced by reacting the compound [A3-8] or a salt thereof in a solvent in the presence of an acid.

[1179] The acid here includes, for example, hydrogen chloride, trifluoroacetic acid and sulfuric acid. The acid is preferably hydrogen chloride.

[1180] The solvent includes, for example, ethyl acetate, cyclopentyl methyl ether and mixed solvents thereof. The solvent is preferably ethyl acetate.

[1181] The reaction temperature here is, for example, in the range of 0°C to 80°C, preferably 10°C to 50°C.

[1182] Compound [A3-9] or a salt thereof can also be produced by reversing the order of steps A3-5 and A3-6.

[1183] (Steps A3-7)

[1184] 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.

[1185] The condensing agent herein includes, for example, HATU, WSC and propylphosphoric anhydride. The condensing agent is preferably HATU.

[1186] The base includes, for example, sodium methoxide, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene. The base is preferably N,N-diisopropylethylamine.

[1187] The solvent includes, for example, methanol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide and mixed solvents thereof, preferably N-methylpyrrolidone.

[1188] The reaction temperature here is, for example, in the range of 0°C to 120°C, preferably 50°C to 100°C.

[1189] Compound [A3-10] or a salt thereof is commercially available, or can be prepared from any commercially available product according to a known method.

[1190] (Step A3-8)

[1191] Compound [IA] or a salt thereof can be produced by reacting compound [A3-11] or a salt thereof in the presence of a base in a solvent.

[1192] The base includes, for example, sodium methoxide, sodium tert-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene. Preferably, the base is 1,8-diazabicyclo[5,4,0]-7-undecene.

[1193] The solvent includes, for example, ethanol, methanol, butanol, water and mixed solvents thereof. The solvent is preferably a mixed solvent of ethanol and water.

[1194] The reaction temperature here is, for example, in the range of 0°C to 180°C, preferably 50°C to 150°C.

[1195] In the preparation method herein, any compound having any functional group or any protected functional group that can be converted into compound [A3-10] or a salt thereof by any known reaction, or a salt thereof, can be used instead of compound [A3-10] or a salt thereof to obtain a compound corresponding to compound [IA] or a salt thereof, followed by conversion of the functional group to prepare compound [IA] or a salt thereof.

[1196] In the preparation method herein, any compound or its salt having any functional group or any protected substituent that can be converted into any of various substituents on the benzene ring by any known reaction may be used in place of compound [A3-1] or its salt to obtain a compound or its salt corresponding to compound [IA], and then the functional group or protected substituent is converted into a respective substituent to prepare compound [IA] or its salt. For example, in the preparation method herein, a compound having an amino group on the benzene ring and L as described below may be used. A41 or a salt thereof to replace compound [A3-1] or a salt thereof to obtain a compound corresponding to compound [IA], ie, compound [IB] or a salt thereof, and then L is converted into A41 Converted to cycloCy A41 , to obtain compound [IC] or a salt thereof.

[1197] In the preparation method herein, any compound or its salt having any functional group or any protected substituent that can be converted into any of various substituents on the benzene ring by any known reaction can be used in place of compound [A3-1] or its salt to obtain a compound or its salt corresponding to compound [A3-8], and then the functional group or protected substituent is converted into various substituents to prepare compound [A3-8] or its salt. For example, in the preparation method herein, a compound having an amino group on the benzene ring and L as described below can be used. A41 or a salt thereof to replace compound [A3-1] or a salt thereof to obtain a compound corresponding to compound [A3-8], ie, compound [A3-8-A] or a salt thereof, and then L is converted into A41 Converted to cycloCy A41 , to obtain compound [A3-8-B] or a salt thereof.

[1198] Preparation method A4: Preparation method of compound [IC] or its salt

[1199] Compound [IC] or a salt thereof can be produced by, for example, the following Production Method A4.

[1200]

[1201] In this diagram, R 2 、R 3 and R 4 Same as the above definition,

[1202] Cy A41 C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 or 2 halogens, and

[1203] L A41 is a leaving group (such as halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy), provided that the leaving group is attached to the ortho- or para-position of the phenyl ring.

[1204] (Step A4-1)

[1205] Compound [IC] or a salt thereof can be prepared by reacting compound [IB] or a salt thereof with compound [A4-1] or a derivative thereof (eg, cyclopropylboronic acid pinacol ester and cyclopropyltrifluoroborate potassium) in a solvent in the presence of a catalyst and a base.

[1206] The catalyst includes, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).

[1207] The base here includes, for example, tripotassium phosphate, cesium carbonate and potassium carbonate. The base is preferably tripotassium phosphate.

[1208] The solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixed solvents thereof. The solvent is preferably a mixed solvent of toluene and water.

[1209] The reaction temperature here is, for example, in the range of 10°C to 200°C, preferably 50°C to 150°C.

[1210] Compound [IB] or a salt thereof can be prepared from any commercially available product according to a known method. Compound [IB] or a salt thereof can be prepared, for example, by the above-mentioned preparation method.

[1211] The compound [A4-1] or a derivative thereof is commercially available, or can be produced from any commercially available product according to a known method.

[1212] Preparation method A5: Preparation method of compound [A3-8-B] or its salt

[1213] Compound [A3-8-B] or a salt thereof can be produced by, for example, the following production method A5.

[1214]

[1215] In this diagram, the symbols have the same definitions as above.

[1216] (Step A5-1)

[1217] Compound [A3-8-B] or a salt thereof can be prepared by reacting compound [A3-8-A] or a salt thereof with compound [A4-1] or a derivative thereof (e.g., cyclopropylboronic acid pinacol ester and cyclopropyltrifluoroborate potassium) in the presence of a catalyst and a base in a solvent.

[1218] The catalyst includes, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). The catalyst is preferably [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II).

[1219] The base here includes, for example, tripotassium phosphate, cesium carbonate and potassium carbonate. The base is preferably tripotassium phosphate.

[1220] The solvent includes, for example, water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixed solvents thereof. The solvent is preferably a mixed solvent of toluene and water.

[1221] The reaction temperature here is, for example, in the range of 10°C to 200°C, preferably 50°C to 150°C.

[1222] Compound [A3-8-A] or a salt thereof can be produced from any commercially available product according to a known method. Compound [A3-8-A] or a salt thereof can be produced, for example, by the above-mentioned production method.

[1223] Preparation method A6: Preparation method of compound [ID] or its salt, or compound [IE] or its salt

[1224] Compound [ID] or a salt thereof, or compound [IE] or a salt thereof can also be produced by, for example, the following Production Method A6.

[1225]

[1226] In this diagram, R 2 、R 3 、R 4 、R 8 and the cyclic group Cy are the same as defined above,

[1227] R A61 C 1-4 Alkyl, and

[1228] L A61 is a leaving group (eg, halogen, methanesulfonyloxy, and p-toluenesulfonyloxy).

[1229] (Step A6-1)

[1230] Compound [ID] or a salt thereof, or compound [IE] or a salt thereof can be produced by reacting compound [IA] or a salt thereof with compound [A6-1] in the presence of a base in a solvent.

[1231] The base here includes, for example, cesium carbonate, sodium methoxide, sodium hydride and potassium carbonate. The base is preferably sodium hydride.

[1232] The solvent includes, for example, methanol, N,N-dimethylformamide and tetrahydrofuran, preferably N,N-dimethylformamide.

[1233] The reaction temperature here is, for example, in the range of 0°C to 100°C, preferably 10°C to 50°C.

[1234] Compound [A6-1] is commercially available, or can be produced from any commercially available product according to a known method.

[1235] Example

[1236] The following preparation examples specifically describe the preparation methods of the compound of formula [I] or its pharmaceutically acceptable salt. However, the preparation methods of the compound of formula [I] or its pharmaceutically acceptable salt are not intended to be limited thereto.

[1237] Unless otherwise specified, % refers to weight %. Unless otherwise specified, the ratios described in mixed solvents refer to volume ratios.

[1238] NMR was measured at 400 MHz.

[1239] [Preparation Example 1]: Synthesis of 2-(2,4-dimethylphenyl)-5,6-dimethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 13)

[1240]

[1241] Step 1-1: 4-chloro-2-(2,4-dimethylphenyl)-6-methyl-2H-pyrazolo[3,4-d]pyrimidine

[1242]

[1243] Under an argon atmosphere, 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde (2.0 g) was added to a mixture of (2,4-dimethylphenyl)hydrazine hydrochloride (2.0 g), triethylamine (3.2 mL) and ethanol (40 mL) at 0°C, and the mixture was stirred at 100°C for 3 hours. The solvent was then removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 10% to 70% by volume ethyl acetate / hexane) to give the title compound (1.6 g).

[1244] 1 H-NMR(CDCl3)δ:8.19(1H,s),7.29(1H,d,J=8.1Hz),7.19(1H,t,J=0.6Hz),7.15-7.13(1H,m),2.81(3H,s),2.41(3H,s),2.25(3H,s).

[1245] Step 1-2: 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1246]

[1247] To a mixture of 4-chloro-2-(2,4-dimethylphenyl)-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (1.6 g) and 1,2-dimethoxyethane (13 mL) was added 4 M aqueous sodium hydroxide solution (6.3 mL), and the mixture was stirred at 110° C. for 6 hours. 2 M hydrochloric acid was then added to the mixture for neutralization. The residue was purified by column chromatography (elution solvent: 10% to 100% by volume ethyl acetate / hexane) to give the title compound (1.2 g).

[1248] 1 H-NMR(DMSO-D6)δ:11.71(1H,br s),8.68(1H,s),7.31(1H,d,J=8.1Hz),7.23(1H,s),7.17(1H,d,J=8.1Hz),2.34(3H,s),2.31(3H,s),2.15(3H,s).

[1249] LC-MS(MH+):255.

[1250] Step 1-3: 2-(2,4-dimethylphenyl)-5,6-dimethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1251]

[1252] To a mixture of 2-(2,4-dimethylphenyl)-6-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (50 mg) and N,N-dimethylformamide (0.5 mL) was added cesium carbonate (130 mg) and iodomethane (0.024 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed under reduced pressure. The residue was purified by column chromatography to give the title compound (32 mg).

[1253] 1 H-NMR(DMSO-d6)δ:8.74(1H,s),7.33(1H,d,J=7.9Hz),7.25-7.25(1H,m),7.19-7.17(1H,m),3.48(3H,s),2.56(3H,s),2.36(3H,s),2.16(3H,s).

[1254] LC-MS(MH+):269.

[1255] [Preparation Example 2]: Synthesis of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 83) and 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-methoxymethyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 88)

[1256]

[1257] Step 2-1: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine

[1258]

[1259] Under nitrogen atmosphere, to the mixture of 2,4,6-trichloropyrimidine-5-carboxaldehyde (170g) and toluene (1.0L), trimethyl orthoformate (500mL) and sulfuric acid (1.1mL) were added, and the mixture was stirred at room temperature for 2.5 hours. Basic silica gel (Fuji Silysia Chemical Ltd., 330g) was added to the reaction mixture, the mixture was stirred for 1.5 hours, and the added silica gel was then collected by filtration. The silica gel was washed with ethyl acetate, and then the solvent was removed under reduced pressure to obtain the title compound (175g).

[1260] 1 H-NMR(CDCl3)δ:5.68(1H,s),3.49(6H,s).

[1261] Step 2-2: 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazino)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine

[1262]

[1263] Under a nitrogen atmosphere, 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (82 g) was added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (80 g) and methanol (560 mL), and the mixture was then cooled in an ice bath. Triethylamine (133 mL) was slowly added to the reaction mixture, and the mixture was stirred at the same temperature for 1.5 hours. The resulting solid was collected by filtration and washed sequentially with methanol (150 mL) and hexane (100 mL) to give the title compound (120 g).

[1264] 1H-NMR(CDCl3)δ:8.28(1H,d,J=4.4Hz),7.10(2H,s),6.14(1H,d,J=4.9Hz),5.56(1H,s),3.45(6H,s),2.43(6H,s).

[1265] LC-MS(MH+):436.

[1266] Step 2-3: 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine

[1267]

[1268] To a mixture of 4-(2-(4-bromo-2,6-dimethylphenyl)hydrazine)-2,6-dichloro-5-(dimethoxymethyl)pyrimidine (121 g) and toluene (970 mL) was slowly added trifluoroacetic acid (43 mL) at 0°C under a nitrogen atmosphere over 10 minutes. The reaction mixture was slowly added dropwise to an ice-cooled mixture of tripotassium phosphate (120 g), water (400 mL) and tetrahydrofuran (640 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. All organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to give a crude product (109 g) of the title compound.

[1269] LC-MS(MH+):372.

[1270] Step 2-4: 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1271]

[1272] To a mixture of a crude product of 2-(4-bromo-2,6-dimethylphenyl)-4,6-dichloro-2H-pyrazolo[3,4-d]pyrimidine (109g) and tetrahydrofuran (830mL) was added 4M aqueous sodium hydroxide solution (210mL) at room temperature, and the mixture was stirred at 65°C for 5 hours. The reaction mixture was cooled in an ice bath, and then 2M hydrochloric acid (280mL) was slowly added dropwise thereto. The reaction mixture was extracted with ethyl acetate, and the aqueous layer was extracted again with a mixed solution of ethyl acetate / tetrahydrofuran (v / v=1 / 4). All organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Diisopropyl ether (550mL) and ethyl acetate (150mL) were added to the resulting crude product, the mixture was stirred for 1 hour, and the solid was then collected by filtration to give the title compound (79g).

[1273] 1 H-NMR(DMSO-D6)δ:12.88(1H,br s),8.81(1H,s),7.53(2H,s),1.95(6H,s).

[1274] LC-MS(MH+):354.

[1275] Step 2-5: 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1276]

[1277] Under an argon atmosphere, 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.37 g) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-chloro-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1.0 g), cyclopropylboronic acid (1.2 g), toluene (15 mL), and a 2M aqueous solution of potassium phosphate (7.1 mL), and the mixture was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 30% to 80% by volume ethyl acetate / hexane) to give the title compound (740 mg).

[1278] 1 H-NMR(DMSO-D6)δ:11.98(1H,s),8.57(1H,s),6.94(2H,s),1.99-1.89(8H ,m),1.08(2H,t,J=3.7Hz),1.02-0.95(4H,m),0.72(2H,dt,J=8.6,3.2Hz).

[1279] LC-MS(MH+):321.

[1280] Step 2-6: 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde

[1281]

[1282] To a mixture of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (100 mg) and tetrahydrofuran (1.0 mL) was added bis(trimethylsilyl)amide lithium (1.1 M tetrahydrofuran solution, 1.1 mL) at 0 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 10 minutes. N,N-dimethylformamide (0.12 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed under reduced pressure to give a crude product (110 mg) of the title compound.

[1283] LC-MS(MH+):349.

[1284] Step 2-7: 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 83)

[1285]

[1286] Under water bath cooling, sodium borohydride (35 mg) was added to a mixture of the crude product (110 mg) of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-d]pyrimidine-3-carboxaldehyde, methanol (1.1 mL) and tetrahydrofuran (1.1 ml), and the mixture was stirred for 2 hours at the same temperature. Saturated aqueous ammonium chloride solution 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. The residue was purified by column chromatography (elution solvent: 20% by volume to 80% by volume ethyl acetate / hexane) to give the title compound (60 mg).

[1287] 1 H-NMR (DMSO-D6) δ: 12.04 (1H, s), 6.92 (2H, s), 4.46 (2H, d, J = 4.9 Hz), 1.98-1.90 (2H, m), 1.84 (6H, s), 1.09-1.05 (2H, m), 1.01-0.97 (4H, m), 0.75-0.72 (2H, m). (One peak is missing (OH))

[1288] LC-MS(MH+):351.

[1289] Step 2-8: 3-(Bromomethyl)-6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1290]

[1291] To a mixture of 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(hydroxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (30 mg) and deuterated chloroform (1.5 mL) was added phosphorus tribromide (8.1 μL) at 0°C under an argon atmosphere, and the mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution 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 to obtain a crude product of the title compound (36 mg).

[1292] LC-MS(MH+):413.

[1293] Step 2-9: 6-cyclopropyl-2-(4-cyclopropyl-2,6-dimethylphenyl)-3-(methoxymethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 88)

[1294]

[1295] At 0 ° C, to a mixture of the crude product (36 mg) of 3- (bromomethyl) -6-cyclopropyl -2- (4-cyclopropyl -2,6-dimethylphenyl) -2,5-dihydro -4H- pyrazolo [3,4-d] pyrimidin-4-one and tetrahydrofuran (1.1 mL) was added 5M methanol solution of sodium methoxide (0.086 mL), and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride solution 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. The residue was purified by column chromatography (elution solvent: 20% to 60% by volume ethyl acetate / hexane) and then by reverse phase column chromatography (elution solution: 10% to 100% by volume acetonitrile / water) to give the title compound (5.7 mg).

[1296] 1 H-NMR(DMSO-D6)δ:12.04(1H,s),6.94(2H,s),4.39(2H,s),3.15(3H,s),1.99-1. 90(2H,m),1.82(6H,s),1.09-1.07(2H,m),1.02-0.96(4H,m),0.76-0.72(2H,m).

[1297] LC-MS(MH+):365.

[1298] [Preparation Example 3]: Synthesis of 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 147) and 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146)

[1299]

[1300] Step 3-1: methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazide}-2-chloroacetate

[1301]

[1302] Water (54 mL) and concentrated hydrochloric acid (47.3 mL) were added to a mixture of 4-bromo-2,6-dimethylaniline (45 g) and ethanol (72 mL) at room temperature. The reaction mixture was cooled to -10 ° C or lower, and then, while the reaction temperature was maintained at 0 ° C or lower, an aqueous solution (54 mL) of sodium nitrite (17.1 g) was slowly added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes, and then an aqueous solution (315 mL) of methyl 2-chloro-3-oxobutanoate (27.1 mL) and sodium acetate (55.4 g) was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and then washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product of the title compound.

[1303] Step 3-2: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid methyl ester

[1304]

[1305] To a mixture of the crude product of methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazide}-2-chloroacetate and chloroform (575 mL) were added fumaric acid nitrile (20.2 g) and triethylamine (36.1 mL), and the mixture was stirred at 80 ° C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, and anhydrous magnesium sulfate and silica gel (200 g) were added thereto. The resultant was stirred at room temperature for 1 hour and filtered through an alkaline silica gel column (Fuji Silysia Chemical Ltd., 200 g) (eluting solvent: ethyl acetate), and then the solvent was removed under reduced pressure. The obtained solid was stirred with a mixed solution of ethyl acetate (50 mL) and hexane (50 ml), and the solid was collected by filtration. The obtained solid was washed with a mixed solution of ethyl acetate (50 mL) and hexane (50 ml) to obtain the title compound (38.9 g).

[1306] 1 H-NMR(DMSO-D6)δ:9.00(1H,s),7.57(2H,s),3.90(3H,s),1.96(6H,s).

[1307] Step 3-3: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid

[1308]

[1309] To a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-formic acid methyl ester (36g) and methanol (360mL) was added 2M aqueous sodium hydroxide solution (108mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 2M hydrochloric acid and then stirred at room temperature for 30 minutes. Water (200mL) was added to the reaction mixture, and the mixture was stirred for another 2 hours. The resulting solid was collected by filtration and then washed with water and hexane to obtain the title compound (33.8g).

[1310] 1 H-NMR(DMSO-D6)δ:13.85(1H,br s),8.95(1H,s),7.56(2H,s),1.97(6H,s).

[1311] Step 3-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

[1312]

[1313] Under a nitrogen atmosphere, diphenylphosphoryl azide (34.0 mL) was added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (33.8 g), triethylamine (29.4 mL) and tert-butanol (507 mL), and the mixture was stirred at 90 ° C for 8 hours. Then, the solvent was removed under reduced pressure. Trifluoroacetic acid (24.4 mL) was added to a mixture of the residue and chloroform (200 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (elution solvent: 1% by volume to 40% by volume ethyl acetate / hexane) to obtain the title compound (30.7 g).

[1314] 1 H-NMR(DMSO-D6)δ:8.31(1H,s),7.46(2H,s),5.76(2H,s),2.01(6H,s).

[1315] LC-MS(MH+):291.

[1316] Step 3-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide

[1317]

[1318] Under ice bath cooling, sodium hydroxide (12.7 g) and 30% hydrogen peroxide solution (43.1 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (30.7 g), ethanol (184 mL) and dimethyl sulfoxide (46 mL). The reaction mixture was stirred at room temperature for 1 hour, and then a 10% aqueous sodium sulfite solution was added thereto. The mixture was acidified with 6M hydrochloric acid and then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 30% by volume to 100% by volume ethyl acetate / hexane) to give the title compound (8.11 g).

[1319] 1 H-NMR(DMSO-D6)δ:7.97(1H,s),7.45(2H,s),7.30(1H,br s),6.91(1H,br s),5.53(2H,br s),2.02(6H,s).

[1320] Step 3-6: 2-(4-bromo-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1321]

[1322] Under an argon atmosphere, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (922 mg) and N,N-diisopropylethylamine (627 mg) were added to a mixture of trans-2-fluorocyclopropane-1-carboxylic acid (252 mg) and N,N-dimethylformamide (3.0 mL), and the mixture was stirred at room temperature for 5 minutes. 3-Amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (300 mg) was added to the reaction mixture, and the mixture was stirred at 50°C for 3 hours. The mixture was then cooled to room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with water. The mixture was then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added ethanol (4.8 mL), water (4.8 mL) and 1,8-diazabicyclo [5.4.0] 11-7-ene (1.17 mL), and the mixture was stirred at 90 ° C for 24 hours. Then, 1,8-diazabicyclo [5.4.0] 11-7-ene (0.5 mL) was added to the mixture. The mixture was stirred at 100 ° C for 14 hours. The reaction mixture was cooled, and ethyl acetate was then added thereto. The mixture was washed with water and saturated brine in sequence. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 33% by volume to 50% by volume ethyl acetate / hexane) to obtain the title compound (237 mg).

[1323] 1 H-NMR(CDCl3)δ:9.91(1H,br s),8.07(1H,s),7.34(2H,s),5.19-4.98(1H,m),2.31-2.16(1H,m),2.02(6H,s),1.83-1.64(2H,m).

[1324] Step 3-7: 2-[4-(1-ethoxyvinyl)-2,6-dimethylphenyl]-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1325]

[1326] Under an argon atmosphere, a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (237 mg), tributyl(1-ethoxyvinyl)tin (340 mg), bis(triphenylphosphine)palladium(II) dichloride (44.1 mg), and toluene (4.7 mL) was stirred at 120° C. for 1 hour. The reaction mixture was cooled and then purified by column chromatography (elution solvent: 20% to 50% by volume ethyl acetate / hexane) to give the title compound (149 mg).

[1327] 1 H-NMR(CDCl3)δ:10.46(1H,br s),8.08(1H,s),7.43(2H,s),5.20-5.00(1H,m),4.68(1H,d,J=2.8Hz),4.27(1H,d,J=2.8Hz),3 .94(2H,q,J=7.0Hz),2.36-2.24(1H,m),2.05(6H,s),1.83-1.63(2H,m),1.45(3H,t,J=7.0Hz).

[1328] Step 3-8: 2-(4-acetyl-2,6-dimethylphenyl)-6-{(1RS,2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1329]

[1330] Under an argon atmosphere, a mixture of 2-[4-(1-ethoxyvinyl)-2,6-dimethylphenyl]-6-{(1RS, 2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (149 mg), 2M hydrochloric acid (1.0 mL) and tetrahydrofuran (2.0 mL) was stirred at 50 ° C for 1 hour. The reaction mixture was cooled and ethyl acetate was added thereto. The mixture was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed under reduced pressure to give the title compound (138 mg).

[1331] 1 H-NMR(CDCl3)δ:10.22(1H,br s),8.11(1H,s),7.76(2H,s),5.20-4.99(1H,m),2.64(3H,s),2.34-2.23(1H,m),2.12(6H,s),1.84-1.64(2H,m).

[1332] Step 3-9: 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1RS,2SR)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 142)

[1333]

[1334] Under an argon atmosphere, a mixture of 2-(4-acetyl-2,6-dimethylphenyl)-6-{(1RS, 2SR)-2-fluorocyclopropyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (110 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (1.1 mL) was stirred at 70 ° C for 4 hours. The reaction mixture was slowly added dropwise to a saturated aqueous sodium bicarbonate solution stirred under ice cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 20% to 50% by volume ethyl acetate / hexane) to give the title compound (89 mg).

[1335] 1 H-NMR(CDCl3)δ:10.14(br s,1H),8.10(s,1H),7.32(s,2H),5.20-5.16(m,0.5H),5.04-5.00(m,0.5H) ,2.33-2.22(m,1H),2.08(s,6H),1.95(t,3H,J=18.3Hz),1.84-1.63(m,2H).

[1336] LC-MS(MH+):363.

[1337] Step 3-10: 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 147) and 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146)

[1338]

[1339] 2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1RS,2SR)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (89 mg) was optically resolved by column chromatography with a chiral column {Instrument: Japan Analytical Industry; Automatic recovery preparative HPLC LaboACE LC-7080; Column: Daicel CHIRALPAKI H, 20 mm (ID) x 250 mm (L), 5 μm; Guard column: Daicel CHIRALPAKI H, 10 mm (ID) x 20 mm (L), 5 μm; column temperature: 30 ° C; mobile phase flow rate: 20 mL / min; mobile phase mixing ratio: isocratic, hexane / ethanol = 80 / 20}, to obtain 2- [4- (1,1-difluoroethyl) -2,6-dimethylphenyl] -6- [(1R, 2S) -2-fluorocyclopropyl] -2,5-dihydro-4H-pyrazole as the first peak fraction (24.2 to 32.0 min) pyrimidin-4-one (Example 147 compound, 38 mg), and 2-[4-(1,1-difluoroethyl)-2,6-xylyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 146 compound, 38 mg) as the second peak fraction (34.3 to 44.0 minutes). The absolute configuration of Example 147 compound was determined by X-ray crystallography.

[1340] [2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1R,2S)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 147]

[1341] 1 H-NMR(CDCl3)δ:10.47(br s,1H),8.10(s,1H),7.32(s,2H),5.21-5.00(m,1H),2.37-2.24(m,1H),2.09(s,6H),1.95(t,3H,J=18.1Hz),1.83-1.65(m,2H).

[1342] LC-MS(MH+):363.

[1343] [2-[4-(1,1-difluoroethyl)-2,6-dimethylphenyl]-6-[(1S,2R)-2-fluorocyclopropyl]-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 146]

[1344] 1H-NMR(CDCl3)δ:10.21(br s,1H),8.10(s,1H),7.32(s,2H),5.20-5.00(m,1H),2.34-2.23(m,1H),2.08(s,6H),1.95(t,3H,J=18.1Hz),1.83-1.65(m,2H).

[1345] LC-MS(MH+):363.

[1346] [Preparation Example 4]: Synthesis of (R)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 154) and (S)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 155)

[1347]

[1348] Step 4-1: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-ol

[1349]

[1350] Under an argon atmosphere, 1.56M n-butyllithium in hexane (13.8mL) was added dropwise to a mixture of 2,5-dibromo-1,3-dimethylbenzene (6.0g) and tetrahydrofuran (120mL) at -78°C for 5 minutes. The mixture was stirred at the same temperature for 15 minutes, and acetaldehyde (3.0g) was added thereto. Then, the mixture was stirred for 15 minutes under ice cooling. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with a mixed solution of ethyl acetate / hexane. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain a crude product (7.4g) of the title compound.

[1351] Step 4-2: 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one

[1352]

[1353] To a mixture of a crude product of 1-(4-bromo-3,5-dimethylphenyl)ethan-1-ol (3.7 g) and dichloromethane (30 mL) was slowly added Dess-Martin reagent (5.8 g) under water bath cooling, and the mixture was stirred at room temperature for 30 minutes. Isopropyl alcohol (1.0 mL) was added to the reaction mixture, and the mixture was purified by column chromatography (elution solvent: 10% by volume ethyl acetate / hexane) to obtain the title compound (2.1 g).

[1354] 1 H-NMR(CDCl3)δ:7.64(2H,s),2.57(3H,s),2.47(6H,s).

[1355] Step 4-3: 2-Bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene

[1356]

[1357] Under an argon atmosphere, a mixture of 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one (3.2 g) and bis(2-methoxyethyl)aminosulfur trifluoride (12.5 g) synthesized in a similar manner to step 4-2 was stirred at 85 ° C for 2 hours. The reaction mixture was added dropwise to a stirred saturated aqueous sodium bicarbonate solution under ice cooling, and the mixture was extracted with a mixed solution of hexane / ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: 0 volume % to 10 volume % ethyl acetate / hexane) to obtain the title compound (1.6 g).

[1358] 1 H-NMR(CDCl3)δ:7.20(2H,s),2.45(6H,s),1.89(3H,t,J=18.1Hz).

[1359] Step 4-4: Di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate

[1360]

[1361] At -78 ° C, under an argon atmosphere, 1.56M n-butyllithium in hexane (2.3mL) was added dropwise to a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (750mg) and tetrahydrofuran (15mL), and the mixture was stirred at the same temperature for 10 minutes. Di-tert-butyl azodicarboxylate (1.0g) was then added thereto. The mixture was stirred at the same temperature for 15 minutes, and acetic acid (0.3mL) was added thereto. The mixture was then diluted with ethyl acetate. The reaction mixture was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (eluting solvent: 5% by volume to 20% by volume ethyl acetate / hexane) to obtain the title compound (854mg).

[1362] 1 H-NMR(CDCl3)δ:7.19(2H,d,J=4.6Hz),6.59(1H,br s),2.38(6H,s),1.95-1.82(3H,m),1.49-1.37(18H,br m).

[1363] Step 4-5: {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride

[1364]

[1365] A mixture of di-tert-butyl 1-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine-1,2-dicarboxylate (854 mg) and a 4M solution of hydrogen chloride in ethyl acetate (17.1 mL) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the resultant was dried at room temperature under reduced pressure for 1 hour to obtain the title compound (497 mg).

[1366] 1 H-NMR(DMSO-D6)δ:9.60(3H,s),7.30(2H,s),6.85(1H,br s),2.41(6H,s),1.93(3H,t,J=18.8Hz).

[1367] Step 4-6: 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine

[1368]

[1369] Under nitrogen atmosphere, to 2,4,6-trichloropyrimidine-5-carboxaldehyde (165g) in toluene (990mL), add trimethyl orthoformate (500mL) and sulfuric acid (1.0mL), and at room temperature stir this mixture 1.5 hours.In reaction mixture, add basic silica gel (Fuji Silysia Chemical Ltd., 330g), and stir this mixture 1.5 hours.Then, collect the silica gel added by filtration.Wash silica gel with ethyl acetate (1.3L), then remove solvent under reduced pressure, obtain title compound (177g).

[1370] 1 H-NMR(CDCl3)δ:5.68(1H,s),3.49(6H,s).

[1371] Step 4-7: 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazino]-5-(dimethoxymethyl)pyrimidine

[1372]

[1373] To a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (541 mg), triethylamine (0.88 mL), and methanol (9.9 mL) was added {4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine hydrochloride (497 mg) at 0°C, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was stirred. The resulting solid was then collected by filtration, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (885 mg).

[1374] 1 H-NMR(CDCl3)δ:8.35(1H,d,J=4.6Hz),7.12(2H,s),6.28(1H,d,J=4.9Hz),5.58(1H,s),3.48(6H,s),2.50(6H,s),1.88(3H,t,J=18.1Hz).

[1375] Step 4-8: 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1376]

[1377] To a mixture of the crude product of 2,4-dichloro-6-[2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}hydrazine]-5-(dimethoxymethyl)pyrimidine (885 mg) and toluene (8.9 mL) was added trifluoroacetic acid (0.40 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, and a 2M aqueous potassium phosphate solution (4.0 mL) was added thereto. The mixture was then extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 5% by volume to 33% by volume ethyl acetate / hexane) to give the title compound (441 mg).

[1378] 1 H-NMR(CDCl3)δ:8.21(1H,s),7.37(2H,s),2.07(6H,s),1.95(3H,t,J=18.1Hz).

[1379] Step 4-9: 4-(Benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1380]

[1381] Under an argon atmosphere, benzyl alcohol (0.15 mL) was added to a mixture of sodium hydride (60% oil, 52 mg) and tetrahydrofuran (8.8 mL), and the mixture was stirred at 50 ° C for 30 minutes. The reaction mixture was ice-cooled, and then 4,6-dichloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (440 mg) was added thereto. The mixture was then stirred at the same temperature for 30 minutes. 2M hydrochloric acid (0.75 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained solid was stirred with a mixed solution of hexane / ethyl acetate (v / v=4 / 1), and then collected by filtration to obtain the title compound (470 mg).

[1382] 1 H-NMR(CDCl3)δ:8.04(1H,s),7.54(2H,d,J=6.5Hz),7.46-7.39(3H,m),7.32(2H,s),5.66(2H,s),2.04(6H,s),1.93(3H,t,J=18.1Hz).

[1383] Step 4-10: 1-[4-(Benzyloxy)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidin-6-yl]ethan-1-one

[1384]

[1385] Under an argon atmosphere, a mixture of 4-(benzyloxy)-6-chloro-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine (200 mg), tributyl(1-ethoxyvinyl)tin (253 mg), bis(triphenylphosphine)palladium dichloride(II) (33 mg) and toluene (4.0 mL) was stirred at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature, and then 2M hydrochloric acid (4.0 mL) was added thereto. The mixture was then stirred at 50 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 10% to 50% by volume ethyl acetate / hexane) to obtain a crude product (85 mg) of the title compound.

[1386] 1 H-NMR(DMSO-D6)δ:9.06(1H,d,J=10.9Hz),7.62(2H,t,J=4.3Hz),7.53(2H,s),7.45-7.36(3H,m),5.73(2H,s),2.74(3H,s),2.07-1.98(9H,m).

[1387] Step 4-11: 6-acetyl-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1388]

[1389] A mixture of the crude product of 1-[4-(benzyloxy)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidin-6-yl]ethan-1-one (85 mg) and formic acid (0.85 mL) was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature, and then the solvent was removed under reduced pressure. Ethyl acetate, water and a saturated aqueous sodium bicarbonate solution were added to the residue, and the mixture was separated. The resulting aqueous layer was then extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the title compound (68 mg).

[1390] 1H-NMR(DMSO-D6)δ:11.80(1H,s),8.91(1H,s),7.52(2H,s),2.63(3H,s),2.05-1.99(9H,m).

[1391] Step 4-12: (RS)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 144)

[1392]

[1393] Under ice cooling, sodium borohydride (47 mg) was added to a mixture of 6-acetyl-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (142 mg) and methanol (2.8 mL) synthesized in a manner similar to step 4-11, and the mixture was stirred at the same temperature for 30 minutes. Then, the solvent was removed under reduced pressure. Ethyl acetate, water and a saturated aqueous ammonium chloride solution were added to the residue and the mixture was separated. The resulting aqueous layer was then extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by reverse phase column chromatography (eluting solvent: 10% by volume to 100% by volume acetonitrile / water) to give the title compound (87 mg).

[1394] 1 H-NMR(DMSO-D6)δ:11.32(1H,s),8.75(1H,s),7.49(2H,s),5.65(1H,s),4.58 (1H,dd,J=13.6,6.2Hz), 2.01(9H,dd,J=21.4,16.5Hz), 1.43(3H,d,J=6.5Hz).

[1395] LC-MS(MH+):349.

[1396] Step 4-13: (R)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 154), and (S)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 155)

[1397]

[1398] (RS)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (85 mg) was optically resolved by supercritical fluid chromatography {instrument: Waters SFCPrep 15 system; column: Daicel CHIRALPAK IH / SFC, 10 mm (ID) x 250 mm (L), 5 μm; column temperature: 40°C; flow rate of the mobile phase: 15 mL / min; mixing ratio of the mobile phase: isocratic, carbon dioxide / methanol = 92 / 8}, to obtain (R)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 154 compound, 33.4 mg) as the first peak fraction (8.0 to 9.5 minutes), and (S)-2-(4-(1,1-difluoroethyl)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (35.6 mg) as the second peak fraction (11.2 to 13.3 minutes). The absolute configuration of the compound of Example 154 was determined by X-ray crystallography.

[1399] [(R)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 154]

[1400] 1 H-NMR(DMSO-D6)δ:11.35(1H,s),8.76(1H,s),7.49(2H,s),5.64(1H,d,J=5.1Hz ),4.61-4.55(1H,m),2.04-1.98(9H,m),1.44(3H,d,J=6.5Hz).LC-MS(MH+):349.

[1401] [(S)-2-{4-(1,1-difluoroethyl)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 155]

[1402] 1 H-NMR(DMSO-D6)δ:11.37(1H,s),8.74(1H,s),7.49(2H,s),5.67(1H,s),4.58(1H,q,J=6.6Hz),2.04-1.98(9H,m),1.43(3H,d,J=6.5Hz).

[1403] LC-MS(MH+):349.

[1404] [Preparation Example 5]: Synthesis of (R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 165), and (S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 166)

[1405]

[1406] Step 5-1: 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene

[1407]

[1408] At -18 ° C, 8M potassium hydroxide aqueous solution (59.8 mL) and (bromodifluoromethyl) diethyl phosphonate (38.3 mL) were added to a mixture of 3,5-dimethyl-4-nitrophenol (20 g) and acetonitrile (120 mL). The mixture was then stirred at the same temperature for 30 minutes, then heated to room temperature and subsequently stirred for another 30 minutes. Concentrated hydrochloric acid (20 mL) was added to the reaction mixture at 0 ° C, and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 0 volume % to 11 volume % ethyl acetate / hexane) to obtain the title compound (23.1 g).

[1409] 1 H-NMR (CDCl3) δ: 6.88 (2H, s), 6.52 (1H, t, J = 73.1Hz), 2.33 (6H, s).

[1410] Step 5-2: 4-(difluoromethoxy)-2,6-dimethylaniline hydrochloride

[1411]

[1412] 10% palladium on carbon (566 mg) is added to a mixture of 5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene (23.1 g) and ethanol (130 mL), and the mixture is stirred overnight at room temperature under a hydrogen atmosphere (at normal pressure). The palladium catalyst is filtered out through diatomaceous earth, and the solvent is then removed under reduced pressure. 4M hydrogen chloride in ethyl acetate (35 mL) and a mixed solution of hexane / ethyl acetate (v / v=3 / 1, 100 mL) are added to the residue under ice cooling. The resulting solid is collected by filtration and then washed with a mixed solution of hexane / ethyl acetate (v / v=3 / 1) to give the title compound (19.9 g).

[1413] 1 H-NMR(DMSO-D6)δ:7.14(1H,t,J=74.3Hz),6.93(2H,s),2.32(6H,s).

[1414] LC-MS(MH+):188.

[1415] Step 5-3: {4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazine hydrochloride

[1416]

[1417] To a mixture of 4-(difluoromethoxy)-2,6-dimethylaniline hydrochloride (19.5 g) and 6 M hydrochloric acid (98 mL) was added concentrated hydrochloric acid (59 mL), and the mixture was then cooled to -10°C. An aqueous solution (19.5 mL) of sodium nitrite (6.3 g) was slowly added dropwise at the same temperature over 10 minutes. The mixture was then stirred for an additional 2 hours. A mixture of tin (II) chloride dihydrate (29.5 g) and concentrated hydrochloric acid (33 mL) was added to the reaction mixture at the same temperature, and the mixture was stirred for 1.5 hours while heating to room temperature. The resulting solid was collected by filtration and then washed sequentially with 2 M hydrochloric acid and diisopropyl ether to obtain the title compound (10 g).

[1418] 1 H-NMR(DMSO-D6)δ:9.61(3H,s),7.20(1H,t,J=74.4Hz),6.93(2H,s),6.77(1H,brs),2.39(6H,s).

[1419] Step 5-4: 2,4-dichloro-6-[2-{4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazino]-5-(dimethoxymethyl)pyrimidine

[1420]

[1421] To a mixture of {4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazine hydrochloride (7.9 g), 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (10 g) synthesized in a manner similar to Preparation Method 4, Step 4-6, and methanol (100 mL) was added triethylamine (16.2 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and the resulting salt was filtered off. The solvent was then removed under reduced pressure to obtain a crude product of the title compound.

[1422] Step 5-5: 4,6-dichloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine

[1423]

[1424] To a mixture of the crude product of 2,4-dichloro-6-[2-{4-(difluoromethoxy)-2,6-dimethylphenyl}hydrazine]-5-(dimethoxymethyl)pyrimidine and toluene (278 mL) was added trifluoroacetic acid (12.7 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was allowed to stand overnight, and the solvent was then removed under reduced pressure. The residue was neutralized by adding a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed under reduced pressure to give a crude product of the title compound.

[1425] Step 5-6: 6-chloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1426]

[1427] To a mixture of the crude product of 4,6-dichloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2H-pyrazolo[3,4-d]pyrimidine and tetrahydrofuran (118 mL) was added 2M aqueous sodium hydroxide solution (32.9 mL) and stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2M hydrochloric acid and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 25% to 55% by volume ethyl acetate / hexane). The obtained solid was stirred with a mixed solution of diisopropyl ether / ethyl acetate (v / v=2 / 1) and then collected by filtration to give the title compound (4.83 g).

[1428] 1H-NMR(DMSO-D6)δ:12.88(1H,s),8.81(1H,s),7.32(1H,t,J=73.9Hz),7.12(2H,s),1.98(6H,s).

[1429] Step 5-7: 2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1430]

[1431] Under an argon atmosphere, a mixture of 6-chloro-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (300 mg), (1-ethoxyvinyl)tributyltin (477 mg), bis(triphenylphosphine)palladium(II) dichloride (62 mg), and toluene (6.0 mL) was stirred at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature, separated after addition of water, and the resulting aqueous layer was extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (331 mg).

[1432] LC-MS(MH+):377.

[1433] Step 5-8: 6-acetyl-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1434]

[1435] To a mixture of the crude product of 2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-ethoxyvinyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (332 mg) and tetrahydrofuran (5.0 mL) was added 2M hydrochloric acid (5.0 mL), and the mixture was stirred at room temperature for 30 minutes and then stirred at 50 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and then separated after adding ethyl acetate, water and saturated sodium bicarbonate aqueous solution. The resulting aqueous layer was then extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 30% by volume to 80% by volume ethyl acetate / hexane) to give the title compound (271 mg).

[1436] 1H-NMR(DMSO-D6)δ:11.79(1H,s),8.88(1H,s),7.33(1H,t,J=73.8Hz),7.15(2H,s),2.63(3H,s),1.99(6H,s).

[1437] Step 5-9: (RS)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 141)

[1438]

[1439] To a mixture of 6-acetyl-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (271 mg), methanol (5.4 mL) and tetrahydrofuran (2.7 mL) was added sodium borohydride (59 mg) at 0 ° C, and the mixture was stirred at the same temperature for 45 minutes. The solvent was removed under reduced pressure, and the residue was separated after adding ethyl acetate, water and saturated aqueous ammonium chloride solution. The resulting aqueous layer was then extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 60% to 100% by volume ethyl acetate / hexane, followed by 0% to 10% by volume methanol / ethyl acetate) to give the title compound (98 mg).

[1440] 1 H-NMR (DMSO-D6) δ: 11.33 (1H, s), 8.72 (1H, d, J = 0.5Hz), 7.32 (1H, t, J = 73.9Hz), 7. 12(2H,s),5.64(1H,s),4.58(1H,d,J=5.5Hz),1.98(6H,s),1.43(3H,d,J=6.5Hz).

[1441] LC-MS(MH+):351.

[1442] Step 5-10: (R)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 165), and (S)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 166)

[1443]

[1444] (RS)-2-(4-(difluoromethoxy)-2,6-dimethylphenyl)-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (98 mg) was optically resolved by column chromatography using a chiral column {instrument: Japan Analytical Industry Co., Ltd.; automatic recovery preparative HPLC LaboACE LC-7080; column: Daicel CHIRALPAKIJ, 20 mm (ID) x 250 mm (L), 5 μm; column temperature: room temperature; flow rate of mobile phase: 15 mL / min; mixing ratio of mobile phase: isocratic, water / acetonitrile = 70 / 30] to give (R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one as the first peak fraction (23.2 to 28.5 minutes). The following was added: (S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound of Example 165, 42.9 mg) and (S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound of Example 166, 42.6 mg) as the second peak fraction (28.9 to 34.5 minutes). The absolute configuration of the compound of Example 165 was determined by X-ray crystallography.

[1445] [(R)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 165]

[1446] 1 H-NMR(DMSO-D6)δ:11.30(1H,s),8.71(1H,s),7.32(1H,t,J=73.9Hz),7.12(2 H,s),5.61(1H,s),4.57(1H,q,J=6.6Hz),1.98(6H,s),1.43(3H,d,J=6.7Hz).

[1447] LC-MS(MH+):351.

[1448] [(S)-2-{4-(difluoromethoxy)-2,6-dimethylphenyl}-6-(1-hydroxyethyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one: Example 166]

[1449] 1H-NMR(DMSO-D6)δ:11.31(1H,br s),8.71(1H,s),7.32(1H,t,J=73.9Hz),7.12(2H,s),5.65(1H,br s), 4.57 (1H, q, J = 6.5Hz), 1.98 (6H, s), 1.43 (3H, d, J = 6.7Hz).

[1450] LC-MS(MH+):351.

[1451] [Preparation Example 6]: Synthesis of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 163, racemate) and its various optically active substances (Examples 178, 179)

[1452]

[1453] Step 6-1: methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene}-2-chloroacetate

[1454]

[1455] To a mixture of 4-bromo-2,6-dimethylaniline (45 g), ethanol (72 mL) and water (25 mL) was added concentrated hydrochloric acid (47 mL), and the mixture was cooled to -10 ° C. An aqueous solution (54 mL) of sodium nitrite (17.1 g) was slowly added dropwise to the reaction mixture at the same temperature for 30 minutes, and the mixture was stirred for another 30 minutes. An aqueous solution (315 mL) of methyl 2-chloro-3-oxobutanoate (27 mL) and sodium acetate (55.4 g) was added dropwise to the reaction mixture at the same temperature. The reaction mixture was stirred for another 2 hours, and the resulting aqueous layer was then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed under reduced pressure to obtain a crude product of the title compound.

[1456] Step 6-2: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid methyl ester

[1457]

[1458] Under an argon atmosphere, triethylamine (36 mL) and fumaric acid nitrile (20 g) were added to a mixture of the crude product of methyl 2-{2-(4-bromo-2,6-dimethylphenyl)hydrazide}-2-chloroacetate and chloroform (580 mL). The reaction mixture was heated to 80 ° C and stirred for 40 minutes. The reaction mixture was cooled to room temperature and silica gel (250 g) was then added thereto. The mixture was then stirred for 30 minutes. The added silica gel was collected by filtration and washed with ethyl acetate. The solvent was removed under reduced pressure and the resulting solid was washed with ethyl acetate to give the title compound (36.7 g).

[1459] 1 H-NMR(DMSO-D6)δ:9.01(1H,s),7.57(2H,s),3.90(3H,s),1.96(6H,s).

[1460] Step 6-3: 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid

[1461]

[1462] To a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid methyl ester (36g) and methanol (360mL) was added 2M aqueous sodium hydroxide solution (110mL), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was neutralized with 6M hydrochloric acid, and the resulting solid was collected by filtration. 1M hydrochloric acid, saturated brine and ethyl acetate were added to the resulting solid, and the mixture was separated. The resulting aqueous layer was extracted with ethyl acetate. All organic layers were mixed, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to obtain the desired product 1. The mother liquor after filtering the solid was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the desired product 2. The desired products 1 and 2 were combined, stirred in a mixed solution of ethyl acetate / diisopropyl ether / hexane, and the resulting solid was collected by filtration to obtain the title compound (30g).

[1463] 1 H-NMR(DMSO-D6)δ:13.86(1H,s),8.95(1H,s),7.56(2H,s),1.97(6H,s).

[1464] Step 6-4: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile

[1465]

[1466] Under an argon atmosphere, triethylamine (26 mL) and diphenylphosphoryl azide (30 mL) were added to a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (30 g) and tert-butanol (450 mL), and the mixture was stirred at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature and then the solvent was removed under reduced pressure. The residue was diluted with chloroform (180 mL), and trifluoroacetic acid (22 mL) was then added thereto. The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to 0 ° C, neutralized with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (elution solvent: 1 volume % to 40 volume % ethyl acetate / hexane). The obtained solid was washed with ethyl acetate / diisopropyl ether to obtain the title compound (11 g).

[1467] 1 H-NMR(DMSO-D6)δ:8.31(1H,s),7.46(2H,s),5.76(2H,s),2.01(6H,s).

[1468] Step 6-5: 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide

[1469]

[1470] Under an argon atmosphere, sodium hydroxide (4.5 g) and 30% hydrogen peroxide solution (15 mL) were added to a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (11 g), ethanol (66 mL) and dimethyl sulfoxide (17 mL) at 0 ° C. The mixture was stirred at room temperature for 40 minutes, and then a saturated aqueous sodium sulfite solution and concentrated hydrochloric acid were added thereto. The reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The crude product was washed with ethyl acetate / diisopropyl ether to obtain the title compound (10 g).

[1471] 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).

[1472] Step 6-6: Dimethyl 2,2'-[1,2-ethanediylbis(oxy)]diacetate

[1473]

[1474] Under an argon atmosphere, sulfuric acid (0.15 mL) was added to a mixture of 2,2'-[1,2-ethanediylbis(oxy)]diacetic acid (10 g) and methanol (50 mL) at room temperature. The reaction mixture was stirred at 80 ° C for 24 hours. The reaction mixture was cooled to room temperature, and then a saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto. The obtained organic layer was separated, and the obtained aqueous layer was extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography (elution solvent: 29% by volume to 50% by volume hexane / ethyl acetate) to obtain the title compound (9.5 g).

[1475] 1 H-NMR(DMSO-D6)δ:4.14(4H,s),3.65(6H,s),3.61(4H,s).

[1476] Step 6-7: Methyl 6-oxo-1,4-dioxepane-5-carboxylate

[1477]

[1478] Under an argon atmosphere, at 100 ° C, a mixture of 2,2'-[1,2-ethanediylbis(oxy)]dimethyl diacetate (9.5 g) and tetrahydrofuran (150 mL) was added dropwise to a mixture of sodium tert-butoxide (9.8 g) and tetrahydrofuran (150 mL) for 1 hour. The mixture was stirred at the same temperature for 3 hours and then stirred overnight after cooling to room temperature. Acetic acid (6.6 mL) was added to the reaction mixture, and the solvent was removed under reduced pressure. Water and ethyl acetate were added to the residue, and the mixture was separated. The obtained aqueous layer was then extracted with ethyl acetate. All organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography (eluting solvent: 5% by volume to 60% by volume hexane / ethyl acetate) to obtain the title compound (3.2 g).

[1479] 1 H-NMR (DMSO-D6) δ: 5.10 (1H, s), 4.35 (1H, d, J = 17.6Hz), 4.25 (1H, d, J = 17.8Hz), 4.10-4.00 (2H, m), 3.92-3.85 (1H, m), 3.72-3.65 (4H, m).

[1480] Step 6-8: Methyl 6-[{(trifluoromethyl)sulfonyl}oxy]-2,3-dihydro-5H-1,4-dioxepene 7-carboxylate

[1481]

[1482] Under an argon atmosphere, N, N-diisopropylethylamine (7.1 mL) and trifluoromethanesulfonic anhydride (3.4 mL) were added to a mixture of 6-oxo-1,4-dioxepane-5-methyl formate (3.0 g) and deuterated chloroform (35 mL) at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate aqueous solution, water and ethyl acetate were added to the reaction mixture. Then, the mixture was separated and the resulting aqueous layer was extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (elution solvent: 0 volume % to 30 volume % hexane / ethyl acetate) to obtain the title compound (4.8 g).

[1483] 1 H-NMR(DMSO-D6)δ:4.49(2H,s),4.21-4.18(2H,m),3.89-3.87(2H,m),3.77(3H,s).

[1484] Steps 6-9: Methyl 1,4-dioxepane-5-carboxylate

[1485]

[1486] To a mixture of methyl 6-[{(trifluoromethyl)sulfonyl}oxy]-2,3-dihydro-5H-1,4-dioxepene 7-carboxylate (4.8 g) and methanol (71 mL) was added nickel (II) chloride (0.6 g) at 0°C. Sodium borohydride (2.1 g) was added to the reaction mixture in 4 portions at the same temperature, and the mixture was then heated to room temperature and stirred for another hour. Saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture. The obtained organic layer was separated, and the obtained aqueous layer was extracted with ethyl acetate. All the organic layers were combined, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography (elution solvent: 5% to 60% by volume hexane / ethyl acetate) to obtain the title compound (1.7 g).

[1487] 1 H-NMR (DMSO-D6) δ: 4.36 (1H, dd, J = 9.7, 5.4Hz), 3.87-3.84 (1H, m), 3.71-3.64 (8H, m), 2.27-2.19 (1H, m), 2.07-1.97 (1H, m).

[1488] Step 6-10: 2-(4-bromo-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

[1489]

[1490] Under microwave irradiation, a mixture of 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (600 mg), 1,4-dioxepane-5-methylformate (370 mg), sodium methoxide (5M methanol solution, 1.6 mL) and methanol (3.6 mL) was stirred at 120 ° C for 2 hours. The reaction mixture was cooled to room temperature, and then 1M hydrochloric acid, water and ethyl acetate were added thereto. The organic layer obtained was separated, and the aqueous layer obtained was extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The crude product obtained was purified by column chromatography (eluting solvent: 20% by volume to 100% by volume hexane / ethyl acetate) to obtain the title compound (380 mg).

[1491] 1 H-NMR(DMSO-D6)δ:11.65(1H,s),8.75(1H,s),7.54(2H,s),4.69(1H,dd,J=9.5,4.9Hz), 4.02-3.96(1H,m),3.78-3.68(5H,m),2.43-2.39(1H,m),2.33-2.29(1H,m),1.96(6H,s).

[1492] Step 6-11: (RS)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 163)

[1493]

[1494] Under an argon atmosphere, a 2M aqueous solution of potassium phosphate (0.55 mL) was added to a mixture of 2-(4-bromo-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (155 mg), cyclopropylboronic acid (95 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (24 mg), and toluene (3.0 mL), and the mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, and water was then added. The resulting organic layer was separated, and the resulting aqueous layer was extracted with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography (elution solvent: 20% to 80% by volume hexane / ethyl acetate) and then by reverse phase column chromatography (elution solvent: 20% to 100% by volume acetonitrile / water) to give the title compound (96 mg).

[1495] 1 H-NMR(DMSO-D6)δ:11.61(1H,s),8.67(1H,s),6.96(2H,s),4.69(1H,dd,J=9.4,5.0Hz),4.01-3.98(1H,m),3.87-3. 69(5H,m),2.45-2.40(1H,m),2.32-2.29(1H,m),1.97-1.91(7H,m),1.01-0.96(2H,m),0.74(2H,dt,J=8.3,3.2Hz).

[1496] LC-MS(MH+):381.

[1497] Step 6-12: Optically active substances of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Examples 178, 179)

[1498]

[1499] (RS)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1,4-dioxepan-5-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (97 mg) was optically resolved by supercritical fluid chromatography {instrument: Waters SFC Prep15 system; column: Daicel CHIRALPAK IG / SFC, 10 mm (inner diameter) x 250 mm (L), 5 μm; column temperature: 40°C; mobile phase flow rate: 15 mL / min; mixing ratio of mobile phase: isocratic, carbon dioxide / methanol = 60 / 40} to give Example 178 compound (37 mg) as the first peak fraction (6.4 to 7.7 minutes) and Example 179 compound (40 mg) as the second peak fraction (9.2 to 11.5 minutes).

[1500] [Example 178]

[1501] 1 H-NMR(DMSO-D6)δ:11.61(1H,s),8.66(1H,s),6.96(2H,s),4.68(1H,dd,J=9.2,4.8Hz),4.01-3.98(1H,m) ,3.83-3.73(5H,m),2.38-2.32(2H,m),1.95-1.92(7H,m),0.98(2H,td,J=7.1,4.7Hz),0.76-0.72(2H,m).

[1502] LC-MS(MH+):381.

[1503] [Example 179]

[1504] 1 H-NMR(DMSO-D6)δ:11.62(1H,s),8.66(1H,s),6.96(2H,s),4.68(1H,dd,J=9.4,4.6Hz),4.00(1H,t,J=8.1Hz) ,3.84-3.69(5H,m),2.43-2.29(2H,m),1.94-1.91(7H,m),0.98(2H,dd,J=13.2,5.1Hz),0.73(2H,q,J=4.8Hz).

[1505] LC-MS(MH+):381.

[1506] [Preparation Example 7]: Synthesis of 2-(4-bromo-2,6-dimethylphenyl)-4-methoxy-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (Example 210)

[1507]

[1508] Step 7-1: 2-(4-bromo-2,6-dimethylphenyl)-4-chloro-6-methyl-2H-pyrazolo[3,4-d]pyrimidine

[1509]

[1510] Under an argon atmosphere, 4,6-dichloro-2-methylpyrimidine-5-carboxaldehyde (150 mg) was added to a mixture of (4-bromo-2,6-dimethylphenyl) hydrazine hydrochloride (200 mg), triethylamine (0.44 mL), tetrahydrofuran (1.5 mL) and water (0.75 mL) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 10% by volume to 70% by volume ethyl acetate / hexane) to give the title compound (100 mg).

[1511] 1 H-NMR(CDCl3)δ:8.11(1H,s),7.39(2H,s),2.84(3H,s),2.01(6H,s).

[1512] LC-MS(MH+):353.

[1513] Step 7-2: 2-(4-bromo-2,6-dimethylphenyl)-4-methoxy-6-methyl-2H-pyrazolo[3,4-d]pyrimidine

[1514]

[1515] Under an argon atmosphere, a mixture of 2-(4-bromo-2,6-dimethylphenyl)-4-chloro-6-methyl-2H-pyrazolo[3,4-d]pyrimidine (100 mg) and methanol (1.5 mL) was added 5 M methanol solution of sodium methoxide (0.28 mL), and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (elution solvent: 10% by volume to 80% by volume ethyl acetate / hexane) to give the title compound (15 mg).

[1516] 1 H-NMR(DMSO-D6)δ:8.82(1H,s),7.56(2H,s),4.09(3H,s),2.58(3H,s),1.93(6H,s).

[1517] LC-MS(MH+):347.

[1518] In addition to the above compounds, example compounds were obtained in a manner similar to the above preparation methods and preparation examples, or if necessary, by known methods. The structures and physical property data of each example compound are shown in the following table.

[1519]

[1520]

[1521]

[1522]

[1523]

[1524]

[1525]

[1526]

[1527]

[1528]

[1529]

[1530]

[1531]

[1532]

[1533]

[1534]

[1535]

[1536]

[1537]

[1538]

[1539]

[1540]

[1541]

[1542]

[1543]

[1544]

[1545]

[1546]

[1547]

[1548]

[1549]

[1550]

[1551]

[1552]

[1553]

[1554]

[1555]

[1556]

[1557]

[1558]

[1559]

[1560]

[1561]

[1562]

[1563]

[1564]

[1565]

[1566]

[1567]

[1568]

[1569]

[1570]

[1571]

[1572]

[1573]

[1574]

[1575]

[1576]

[1577]

[1578]

[1579]

[1580]

[1581]

[1582]

[1583]

[1584] Test Example 1: Evaluation of NLRP3 inflammasome inhibitory activity

[1585] The NLRP3 inflammasome inhibitory activity of the test compound was evaluated based on the inhibitory activity of IL-1β production in THP1-Null cells (Product No.: thp-null, InvivoGen). Cells were maintained in RPMI-1640 medium containing 10% (v / v) fetal bovine serum, 25 mmol / L HEPES, 100 U / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL normocin, and 200 μg / mL hygromycin B (set at 37°C, 5% CO2 / 95% air).

[1586] The cells were 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. The suspended cells were seeded onto Corning (registered trademark) 384-well clear flat-bottom black polystyrene TC-treated microplates (25,000 cells / 25 μL / well) and incubated overnight (at 37°C, 5% CO2 / 95% air). The culture supernatant was removed, and assay medium (25 μL / well) containing 1 μg / mL lipopolysaccharide (Product No. L2654, Sigma-Aldrich (registered trademark)) was added. The cultures were then incubated for a further 3 hours (at 37°C, 5% CO2 / 95% air). The culture supernatant was removed. Then, the vehicle solution prepared by Opti-MEM (trademark) culture medium (product number: 31985-070, Invitrogen) is added to the blank setting well and the control setting well (20 μ L / well), then incubated for 15 minutes (set at 37 ° C, 5% CO2 / 95% air). The solution containing the test compound (20 μ L / well) is added to the test compound setting well. In addition, the Opti-MEM (trademark) culture medium containing nigericin (Nigericin) (product number: N7143, Sigma-Aldrich (registered trademark)) is added to the control setting well and the test compound setting well (5 μ L / well), then incubated for 1.5 hours (set at 37 ° C, 5% CO2 / 95% air). The final concentration of nigericin is adjusted to 7.5 μ mol / L. The Opti-MEM (trademark) culture medium of 5 μ L / well is added to the blank setting well. The supernatant of the culture is stored frozen (set at -20 ° C) until IL-1 β is measured.

[1587] The amount of IL-1β in the culture supernatant was quantified using the AlphaLISA (registered trademark) Human IL-1β Detection Kit (Product No. AL220C, PerkinElmer). Fluorescence intensity was measured using a microplate reader, EnSpier (Model No. 2300-00J, PerkinElmer) or EnSight (Model No. HH34000000, Perkin Elmer), according to the accompanying operating instructions. The inhibition rate of the test compound wells was calculated based on the blank wells being set as 100% and the control wells being set as 0%. The IC value of the test compound was 0. 50 The values ​​(ie, 50% inhibition concentration) were calculated by logistic regression analysis. The results for each example compound are shown in the table below.

[1588]

[1589]

[1590]

[1591]

[1592]

[1593]

[1594]

[1595]

[1596] Formulation examples of the present invention include the following formulations, but are not intended to be limited thereto.

[1597] Preparation Example 1: Preparation of Capsules

[1598]

[1599] Ingredients (1), (2), (3) and (4) are mixed to fill into gelatin capsules.

[1600] Formulation Example 2: Preparation of tablets

[1601]

[1602] The entire amount of ingredients (1), (2), and (3) and 30 g of ingredient (4) were combined with water, vacuum dried, and then granulated. The resulting granules were mixed with 14 g of ingredient (4) and 1 g of ingredient (5) and compressed using a tablet press. In this manner, 1000 tablets were obtained, each containing 10 mg of the compound of Example 1.

[1603] Industrial Applicability

[1604] The compound of formula [I] or a pharmaceutically acceptable salt thereof has NLRP3 inflammasome inhibitory activity and is thus expected to be useful for treating or preventing a disease selected from the group consisting of: multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), arteriosclerosis, cold inflammation-related periodic syndromes (e.g., familial cold autoinflammatory syndrome, Mueller-Weiss syndrome, chronic infantile neurocutaneous arthritis, and neonatal multisystem inflammatory disease), nonalcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g., acute myocardial infarction), systemic lupus erythematosus, systemic juvenile idiopathic arthritis, recurrent pericarditis, adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation syndrome), Schnitzler syndrome, IL-1 receptor antagonist deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behçet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, intracranial hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-associated periodic syndrome.

Claims

1. Compounds of formula [I]: or a pharmaceutically acceptable salt thereof, wherein the partial structure is: yes: (1) The structure shown in the following formula: in, R 5 is hydrogen or C 1-4 Alkyl, wherein the alkyl may be optionally substituted with: (a) carboxyl, (b)-CO-C 1-4 Alkoxy, or (c)-CO-NR 6 R 7 , where R 6 and R 7 are each independently hydrogen or C 1-4 Alkyl, or (2) The structure shown in the following formula: Among them, R 8 C 1-4 alkyl; The ring group Cy is: (1) A group represented by the following formula: Among them, R 9 and R 10 Each independently (a) Hydrogen, (b)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution, (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-4 haloalkyl, or (f)-OC 1-4 haloalkyl, R 11 and R 12 Each independently (a) Hydrogen, (b)C 1-4 Alkyl, or (c)C 1-4 haloalkyl, R 13 for (a) Hydrogen, (b)C 1-4 alkyl, (c)C 1-4 Alkoxy, (d) halogens, (e)C 1-6 Halogenated alkyl, (f)-OC 1-4 haloalkyl, or (g)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted by 1 or 2 halogen atoms, or R 13 Can be used with R 11 or R 12 Together with the carbon atom to which it is attached, it forms: (a)C 5-6 Cyclic olefins, or (b) a 5- to 7-membered heterocyclic olefin containing 1 or 2 oxygen atoms, or (2) A group represented by the following formula: Among them, R 14 and R 15 Each independently is C 1-4 Alkyl or C 1-4 haloalkyl, R 16 C 1-6 Alkyl or C 3-6 Cycloalkyl, R 1 for: (1) Hydrogen, (2) cyano, (3)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution, (4)C 1-4 haloalkyl, or (5)-CO-C 1-4 alkyl, R 2 、R 3 and R 4 Each independently (1) Hydrogen, (2) hydroxyl groups, (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (a) hydroxyl groups, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with: (a) hydroxyl groups, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, (5) halogens, (6)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution, (7)-OC 1-4 haloalkyl, (8)-OR 17 , where R 17 is a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, (9)C 3-6 Cycloalkyl, (10) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, wherein the heterocycloalkyl group may be optionally substituted with oxo, or (11) A group represented by the following formula: or R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R 3 R 4 Groups can be formed as: (a) cyano group, (b)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups: (1) cyano, (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution, (3)C 1-4 Alkoxy, (4) Halogen, and (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl, (c) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (1) hydroxyl groups, (2)C 1-4 alkyl, (3)C 1-4 Alkoxy, and (4) Halogen, or Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups. (d) a 7- to 9-membered saturated fused heterocyclic group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the fused heterocyclic group may be optionally substituted by 1 or 2 halogen atoms, (e) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen, (f) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally substituted by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group, (g)C 5-6 Cycloalkenyl, (h) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or (i) a group represented by the following formula: Among them, R 20 for: (1)C 1-4 Alkyl, or (2)-NR 21 R 22 , where R 21 and R 22 Each independently (a) Hydrogen, (b)C 1-4 alkyl, (c)C 1-4 haloalkyl, or (d) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom and an oxygen atom.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Partial structure: for (1) The structure shown in the following formula: Among them, R 5 Same as defined in claim 1.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 5 For hydrogen.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein The ring group Cy is: (1) A group represented by the following formula: Among them, R 9 、R 10 、R 11 、R 12 and R 13 Same as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which is represented by formula [II], in, R 2 、R 3 、R 4 、R 9 、R 10 、R 11 、R 12 and R 13 Same as defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 For hydrogen.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is represented by formula [III], in, R 2 、R 3 、R 4 、R 9 、R 10 and R 13 Same as defined in claim 1.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 At least one of: (1)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by C 1-4 Alkoxy substitution, (2)C 1-4 Alkoxy, (3) Halogen, (4)C 1-4 haloalkyl, or (5)-OC 1-4 Halogenated alkyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 3 and R 4 Each independently (1) Hydrogen, (2) hydroxyl groups, (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (a) hydroxyl groups, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with: (a) hydroxyl groups, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substitution, (6)-OC 1-4 a haloalkyl group, or (7)C 3-6 Cycloalkyl, or R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R 3 R 4 Groups can be formed as: (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups: (1) cyano, (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution, (3)C 1-4 Alkoxy, (4) Halogen, and (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl, (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (1) hydroxyl groups, (2)C 1-4 alkyl, (3)C 1-4 Alkoxy, and (4) Halogen, or Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups. (c) a 5- to 8-membered bridged cycloalkyl group, wherein the bridged cycloalkyl group may be optionally substituted with halogen, (d) a 5- to 8-membered bridged heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, wherein the bridged heterocycloalkyl group may be optionally replaced by C 1-4 Alkyl substituted, the C 1-4 The alkyl group is optionally substituted with a hydroxy group, (e) a 5-membered or 6-membered heterocycloalkenyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms, or (f) a group represented by the following formula: Among them, R 21 and R 22 are each independently (1) hydrogen, (2)C 1-4 alkyl, (3)C 1-4 haloalkyl, or (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 、R 3 and R 4 Each independently (1) Hydrogen, (2) hydroxyl groups, (3)C 1-6 Alkyl, wherein the alkyl may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (a) hydroxyl groups, (b)C 1-4 Alkoxy, and (c)-SO2-C 1-4 alkyl, (4)C 1-6 Alkoxy, wherein the alkoxy may be optionally substituted with: (a) hydroxyl groups, (b) phenyl, or (c) a 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen atoms, or (5)C 1-4 Haloalkyl, wherein the haloalkyl may be optionally replaced by hydroxy or C 1-4 Alkoxy substituted, or R 2 、R 3 and R 4 can combine with the carbon atom to which they are attached, and -CR 2 R 3 R 4 Groups can be formed as: (a)C 3-6 Cycloalkyl, wherein the cycloalkyl may be optionally substituted with 1 to 3 substituents independently selected from the following groups: (1) cyano, (2)C 1-4 Alkyl, wherein the alkyl group may be optionally replaced by a hydroxyl group or a C 1-4 Alkoxy substitution, (3)C 1-4 Alkoxy, (4) Halogen, and (5)-CO-NR 18 R 19 , where R 18 and R 19 are each independently hydrogen or C 1-4 alkyl, (b) a 4- to 7-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the following groups: (1) hydroxyl groups, (2)C 1-4 alkyl, (3)C 1-4 Alkoxy, and (4) Halogen, or Any ring-forming atom of the heterocycloalkyl group may be optionally substituted by 1 or 2 oxo groups, or (c) a group represented by the following formula: Among them, R 21 and R 22 are each independently (1) hydrogen, (2)C 1-4 alkyl, (3)C 1-4 haloalkyl, or (4) A 4- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms independently selected from nitrogen atoms and oxygen atoms.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following formula:

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following formula:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. An NLRP3 inflammasome inhibitor comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. A medicament comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cytokine-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

17. The medicament according to claim 16, wherein The inflammatory bowel disease is ulcerative colitis or Crohn's disease.

18. The medicament according to claim 16, wherein The cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal multisystem inflammatory disease.

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

20. A method for treating or preventing a disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cytokine-associated periodic syndrome, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury.

21. The method according to claim 20, wherein The inflammatory bowel disease is ulcerative colitis or Crohn's disease.

22. The method according to claim 20, wherein The cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal multisystem inflammatory disease.

23. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of an NLRP3 inflammasome inhibitor.

24. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease selected from the group consisting of: multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cytokine-associated periodic syndrome, non-alcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury.

25. The use according to claim 24, wherein The inflammatory bowel disease is ulcerative colitis or Crohn's disease.

26. The use according to claim 24, wherein The cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous arthritis syndrome, or neonatal multisystem inflammatory disease.

27. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 inflammasome.

28. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease selected from the group consisting of multiple sclerosis, inflammatory bowel disease, arteriosclerosis, cytokine-associated periodic syndromes, nonalcoholic steatohepatitis, gout, ischemic heart disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein For use, the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein For use, the cold inflammatory factor-associated periodic syndrome is familial cold autoinflammatory syndrome, Muir-Weid syndrome, chronic infantile neurocutaneous and articular syndrome, or neonatal multisystem inflammatory disease.

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