WO2024048519A1 - ピラゾロピリミジン化合物及びその医薬用途 - Google Patents

ピラゾロピリミジン化合物及びその医薬用途 Download PDF

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WO2024048519A1
WO2024048519A1 PCT/JP2023/030980 JP2023030980W WO2024048519A1 WO 2024048519 A1 WO2024048519 A1 WO 2024048519A1 JP 2023030980 W JP2023030980 W JP 2023030980W WO 2024048519 A1 WO2024048519 A1 WO 2024048519A1
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disease
compound
pharmaceutically acceptable
syndrome
salt
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French (fr)
Japanese (ja)
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雄介 大場
馨 足達
健太朗 櫻井
晋平 佐藤
俊哉 伊東
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority to US18/705,065 priority Critical patent/US20250114361A1/en
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Priority to KR1020257009740A priority patent/KR20250056233A/ko
Priority to CN202380062735.4A priority patent/CN119790055A/zh
Priority to AU2023334673A priority patent/AU2023334673A1/en
Priority to PE2025000467A priority patent/PE20251551A1/es
Priority to EP23860281.7A priority patent/EP4582428A1/en
Priority to IL319000A priority patent/IL319000A/en
Publication of WO2024048519A1 publication Critical patent/WO2024048519A1/ja
Priority to ZA2025/01724A priority patent/ZA202501724B/en
Priority to CONC2025/0002359A priority patent/CO2025002359A2/es
Priority to MX2025002450A priority patent/MX2025002450A/es
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Definitions

  • the present invention relates to a pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is a pattern recognition receptor that belongs to the NLR (NOD-like receptors) family, and is used not only in phagocytic cells such as macrophages and microglia, but also in glomerular epithelial cells and It is also expressed in non-immune cells such as renal tubular epithelial cells.
  • NLR NOD-like receptors
  • NLRP3 is a molecular pattern specific to DAMPs (Danger Associated Molecular Patterns), which are cytotoxic factors (ATP, HMGB1, S100, uric acid crystals, silica, etc.) and pathogenic microorganisms (viruses, bacteria, fungi, etc.). It recognizes PAMPs (Pathogen Associated Molecular Patterns), binds to these molecules, and becomes activated.
  • DAMPs Dannger Associated Molecular Patterns
  • PAMPs Pathogen Associated Molecular Patterns
  • Activated NLRP3 associates with the adapter protein ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine protease caspase 1 through protein-protein interaction, and forms an intracellular protein complex called NLRP3.
  • ASC Apoptosis-associated speck-like protein containing a caspase recruitment domain
  • cysteine protease caspase 1 through protein-protein interaction
  • Forms an inflammasome By forming the NLRP3 inflammasome, caspase 1 within the complex is converted to the active form, and active caspase 1 converts proIL-1 ⁇ , a precursor of the pro-inflammatory cytokine IL-1 ⁇ , into active IL-1 ⁇ and IL-1 ⁇ . -18 precursor proIL-18 is converted to active IL-18.
  • Activated IL-1 ⁇ secreted outside the cell induces an inflammatory response by inducing production of inflammatory cytokines and
  • Non-patent Document 1 In the brain and cerebrospinal fluid of multiple sclerosis patients, an increase in the amount of DAMPs (Non-patent Document 1), an increase in the expression level of caspase 1 in lesions, and an increase in the amount of IL-1 ⁇ in the cerebrospinal fluid were observed (Non-Patent Document 1). Reference 2).
  • activated microglia are present in the lesions in the chronic advanced stage of this disease (Non-Patent Document 3), and activated microglia stimulated by DAMPs produce inflammatory cytokines such as IL-1 ⁇ and cause neuroinflammation. and induce neurological disorders (Non-Patent Document 4). Therefore, the NLRP3 inflammasome is considered to be involved in the pathological manifestation of multiple sclerosis.
  • the MOG 35-55 EAE model mouse created by sensitizing mice to Myelin Oligodendrocyte Glycoprotein (MOG), develops motor dysfunction similar to multiple sclerosis.
  • MOG Myelin Oligodendrocyte Glycoprotein
  • NLRP3 knockout mice the onset of motor dysfunction is suppressed in the MOG 35-55 EAE model.
  • cuprizone model mice created by administering the copper chelate compound cuprizone to mice demyelination of the central nervous system similar to multiple sclerosis develops, but in NLRP3 knockout mice, demyelination progresses in the cuprizone model. is delayed (Non-patent Document 6).
  • JC-171 an NLPR3 inflammasome inhibitor, suppressed motor dysfunction in the MOG 35-55 EAE model when administered after onset (Non-Patent Document 7). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for multiple sclerosis.
  • Non-patent Documents 8, 9 Increased expression of NLRP3 inflammasome-related genes has been reported in the kidneys of patients with chronic kidney disease. Furthermore, it has been reported that NLRP3 knockout suppresses proteinuria and tubulointerstitial fibrosis in a 5/6 nephrectomy model, which is a non-clinical chronic kidney disease model (Non-Patent Document 10). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for chronic kidney disease.
  • Non-Patent Document 11 Increased expression of NLRP3 inflammasome-related genes has been reported in the intestines of patients with inflammatory bowel diseases (eg, ulcerative colitis and Crohn's disease) (Non-Patent Document 11). IL-1 ⁇ produced by activation of NLRP3 is increased in the intestinal mucosa of IBD patients, and increased IL-1 ⁇ secretion from the large intestine is positively correlated with worsening of the disease condition. It has been reported (Non-Patent Document 11). Additionally, it has been reported that dysfunction of CARD8, which negatively regulates inflammasome activity, increases susceptibility to Crohn's disease, and that NLRP3 inflammasome is activated and IL-1 ⁇ production from monocytes is increased.
  • CARD8 which negatively regulates inflammasome activity
  • Non-patent Document 12 It has been reported that NLRP3 deficiency suppresses intestinal pathology in a TNBS-induced colitis model, which is a colitis model (Non-Patent Document 13). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for inflammatory bowel diseases.
  • Non-Patent Document 14 Increased expression of NLRP3 inflammasome-related genes has been reported in arteriosclerotic sites of coronary arteries of patients with myocardial infarction. Furthermore, in low-density lipoprotein receptor (LDL) receptor-deficient mice fed a high-fat diet, which is an arteriosclerosis model, it has been reported that NLRP3 knockout suppresses lesion formation (Non-Patent Document 15). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for arteriosclerosis.
  • LDL low-density lipoprotein receptor
  • Cryopyrin-associated periodic fever syndrome is a general term for autoinflammatory diseases caused by activating mutations in the NLRP3 gene, and is a mild form of familial cold autoinflammatory syndrome (FCAS). syndrome), moderate Muckle-Wells Syndrome MWS, severe Chronic infantile neurologic cutaneous, and articular syndrome (CINCA), or neonatal-onset multisystem inflammatory disease (NOMID). It is classified into three types: neonatal onset multisystem inflammatory disease (Non-Patent Document 16). In CAPS, more than 200 mutations in the NLRP3 gene have been reported (Non-Patent Document 17). These NLRP3 gene mutations result in the formation and activation of the NLRP3 inflammasome even in the absence of activation signals.
  • FCAS familial cold autoinflammatory syndrome
  • CINCA severe Chronic infantile neurologic cutaneous, and articular syndrome
  • NOMID neonatal-onset multisystem inflammatory disease
  • Non-Patent Document 18 Mice expressing CAPS-associated NLRP3 mutations exhibit systemic lethal inflammation dependent on the NLRP3 inflammasome and the downstream signaling molecules IL-1 ⁇ and IL-18 (Non-Patent Document 18).
  • a mouse strain expressing a CAPS-related NLRP3 mutation CY-09, an NLRP3 inflammasome inhibitor, suppressed systemic lethal inflammation and improved survival rate (Non-Patent Document 19). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for CAPS.
  • Non-patent Document 20 Increased expression of NLRP3 inflammasome-related genes has been reported in liver tissues of nonalcoholic steato-hepatitis (NASH) patients (Non-patent Document 20). Furthermore, in a choline-deficient amino acid substituted diet loaded model, which is a NASH model, NLRP3 knockout has been reported to suppress liver fibrosis (Non-Patent Document 20). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for NASH.
  • NASH nonalcoholic steato-hepatitis
  • Non-Patent Document 21 In gout/gouty arthritis, uric acid crystals deposited in joints and periarticular tissues cause inflammation (Non-Patent Document 21). Uric acid crystals activate NLRP3 in macrophages to produce IL-1 ⁇ and IL-18 (Non-Patent Document 22). OLT1177, an NLRP3 inflammasome inhibitor, suppressed arthritis in an intra-articular uric acid injection arthritis model (Non-Patent Document 23). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for gout and gouty arthritis.
  • Non-Patent Document 24 Increased expression of NLRP3 inflammasome-related genes has been reported in the joint synovium and peripheral blood mononuclear cells of patients with rheumatoid arthritis. Furthermore, in collagen-induced arthritis, which is a rheumatoid arthritis model, increased expression of NLRP3 inflammasome-related genes in the synovium has been reported (Non-Patent Document 25). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for rheumatoid arthritis.
  • Trinitrochlorobenzene which induces contact dermatitis, increases IL-1 ⁇ production from human skin keratinocytes through NLRP3 activation, and NLRP3 knockout also occurs in the trinitrochlorobenzene-induced dermatitis model, which is a contact dermatitis model. It has been reported that the onset of dermatitis is suppressed by (Non-Patent Document 26). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for contact dermatitis.
  • Non-patent Documents 27, 28 Increased expression of NLRP3 inflammasome-related genes has been reported in the tear fluid and ocular surface of dry eye patients.
  • Non-patent Documents 27, 28 when cultured human corneal epithelial cells were subjected to hyperosmotic stress to induce dry eye condition, increased expression of NLRP3 inflammasome-related genes and increased production of IL-1 ⁇ were observed, and knockdown of the NLRP3 gene resulted in increased IL-1 ⁇ production. It has been reported that the production is suppressed (Non-Patent Document 28). Based on the above results, NLRP3 inflammasome inhibitors are considered to be a therapeutic drug for dry eye.
  • Non-Patent Document 29 Increased expression of the ASC domain of the NLRP3 inflammasome has been reported in macrophages and neutrophils infiltrated into the myocardial tissue of patients with acute myocardial infarction. Furthermore, in the ischemia-reperfusion model, which is a myocardial infarction model, increased expression of NLRP3 inflammasome-related genes was observed at the infarcted site, and knockdown of the NLRP3 gene suppressed the reduction in infarct area and the decline in myocardial contractility. has been reported (Non-Patent Document 30). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for ischemic heart diseases such as acute myocardial infarction.
  • Non-Patent Documents 31, 32 The expression of IL-1 ⁇ or IL-18 is increased in the serum and glomeruli of patients with systemic lupus erythematosus (SLE) (Non-Patent Documents 31, 32), and the expression of the NLRP3 gene and IL-18 are increased in macrophages. It has been reported that 1 ⁇ production increases (Non-Patent Document 33). Furthermore, in Nlrp3-R258W mice that have an activating mutation in the NLRP3 gene, lupus nephritis-like symptoms expressed by pristane administration are exacerbated (Non-Patent Document 34). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for SLE.
  • Non-patent Document 35 systemic juvenile idiopathic arthritis
  • Non-Patent Document 36 recurrent pericarditis
  • adult Onset Still's disease e.g.
  • Non-patent document 37 hemophagocytic lymphohistiocytosis and macrophage activation syndrome
  • Non-patent document 38 Schnitzler syndrome
  • Non-patent document 39 IL-1 receptor antagonist molecule deficiency
  • Familial Mediterranean fever Non-patent document 40
  • mevalonate kinase deficiency Non-patent document 40
  • hyper-IgD syndrome Non-patent document 40
  • TNF receptor-related periodic syndrome Non-patent document 40
  • Behcet's disease Examples include non-patent literature 41) and lung cancer (non-patent literature 42).
  • NLRP3 inflammasome is involved in the production of inflammatory cytokines such as IL-1 ⁇ , NLRP3 inflammasome inhibitors are considered to be therapeutic agents for these diseases.
  • Non-Patent Document 43 It has been reported that the NLRP3 rs10733113 genotype is significantly increased in psoriasis patients, leading to increased susceptibility to psoriasis. Furthermore, it has been reported that NLRP3 deficiency suppresses psoriasis symptoms in an IL-23-induced psoriasis model, which is a psoriasis model (Non-Patent Document 44). Based on the above results, NLRP3 inflammasome inhibitors are considered to be a therapeutic agent for psoriasis.
  • NLRP3 inflammasome inhibitors are considered to be therapeutic agents for hypertension.
  • Non-Patent Document 47 It has been reported that the expression of NLRP3 is enhanced in the proliferative membranes of patients with diabetic retinopathy (Non-Patent Document 47). Furthermore, in an STZ-induced retinopathy model, which is a diabetic retinopathy model, the expression of NLRP3 is increased (Non-Patent Document 48). In this model, it has been reported that decreased NLRP3 expression by NLRP3 shRNA decreases IL-1 ⁇ and VEGF secretion, increases ganglion cell mass, and recovers from retinal damage (Non-Patent Document 49). Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for diabetic retinopathy.
  • NLRP3 inflammasome activation occurs in the brain in Alzheimer's disease patients, MCI (mild cognitive impairment) patients, and APP/PS1 mice, which are Alzheimer's disease model mice, and NLRP3 deficiency in APP/PS1 mice causes spatial memory impairment. is suppressed (Non-Patent Document 50).
  • MCC950 an NLRP3 inhibitor, suppresses NLRP3 activation in microglia and improves cognitive dysfunction in APP/PS1 mice (Non-Patent Document 51). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for Alzheimer's disease and MCI.
  • NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for Parkinson's disease.
  • Non-Patent Document 53 In Huntington's disease patients, the cerebrospinal fluid concentration of IL-1 ⁇ , an NLRP3 inflammasome-related cytokine, increases (Non-Patent Document 53). In R6/2 mice, which are a pathological model of Huntington's disease, the expression level of NLRP3 inflammasome in the striatum increases (Non-Patent Document 54). MCC950, an NLRP3 inhibitor, suppresses NLRP3 inflammasome activation in the striatum of R6/2 mice, suppresses neuronal death in the striatum, and suppresses symptom progression (Non-Patent Document 55). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for Huntington's disease.
  • Non-Patent Document 56 In the spinal cord of patients with amyotrophic lateral sclerosis (ALS), the expression of NLRP3 inflammasome, IL-18, and active caspase 1 increases (Non-Patent Document 56). In the spinal cords of ALS model mice, SOD1G93A mice and TDP-43Q331K mice, mRNA expression of IL-1 ⁇ , Nlrp3, Pycard, and Casp1 increases (Non-Patent Document 57). MCC950, an NLRP3 inhibitor, suppresses NLRP3 activation in microglia induced by SOD1G93A and TDP-43 protein, and reduces IL-1 ⁇ production (Non-Patent Document 57).
  • ALS amyotrophic lateral sclerosis
  • Non-Patent Document 58 NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for ALS.
  • Non-Patent Documents 59, 60 The expression level of NLRP3 inflammasome increases in the brain tissue and cerebrospinal fluid of traumatic brain injury (TBI) patients (Non-Patent Documents 59, 60). In the brain tissues of TBI model rats, the expression level of NLRP3 inflammasome increases, and the expression levels of IL-1 ⁇ and IL-18 also increase (Non-Patent Document 61). MCC950, an NLRP3 inhibitor, suppresses IL-1 ⁇ production in TBI model mice and suppresses the expression of neurological symptoms after brain trauma (Non-Patent Document 62). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for TBI.
  • NLRP3 inflammasome, IL-1 ⁇ , and IL-18 were found in the brain tissues of cerebral infarction patients, middle cerebral artery occlusion (MCAO) mice, and intracerebral hemorrhage model rats. expression increases (Non-Patent Documents 63, 64). Furthermore, MCC950, an NLRP3 inhibitor, showed neuroprotective effects in MCAO model and intracerebral hemorrhage model rats. Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for cerebral infarction and cerebral hemorrhage.
  • Non-Patent Documents 65, 66 The expression of NLRP inflammasome is increased in brain tissue of patients with temporal lobe epilepsy and in Pilocarpine-induced epilepsy model mice (Non-Patent Documents 65, 66). Furthermore, in pilocarpine-induced epilepsy model mice, deletion of the NLRP3 inflammasome and administration of MCC950, an NLRP3 inhibitor, suppresses apoptosis of hippocampal neurons, which causes epilepsy (Non-Patent Document 66). Therefore, NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for epilepsy.
  • Non-Patent Document 67 Increased expression levels of NLRP3 inflammasome, IL-1 ⁇ , or IL-18 in brain tissue and NLRP3 inflammasome activity in LPS-induced model, chronic stress-induced model, or social defeat model, which are pathological models of depression.
  • Non-patent Documents 68, 69, 70 Furthermore, in pathological models, administration of MCC950, an NLRP3 inhibitor, or NLRP3 deficiency shows an improvement effect on depressive symptoms (Non-Patent Documents 69, 70). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for depression.
  • Non-Patent Document 71 In the peripheral blood of patients with autism spectrum disorder (ASD), the expression level of NLRP3 inflammasome and the concentration of IL-1 ⁇ and IL-18 increase (Non-Patent Document 71).
  • MIA maternal immune activation
  • MCC950 an NLRP3 inhibitor
  • NLRP3 inflammasome inhibitors are considered to be potential therapeutic agents for ASD.
  • Non-Patent Documents 73, 74 In the spinal cord of mice with spinal cord injury, NLRP3 inflammasome or IL-1 ⁇ expression increases, and NLRP3 activation is observed (Non-Patent Documents 73, 74). Furthermore, when MCC950, an NLRP3 inhibitor, is administered to mice after spinal cord injury, NLRP3 activation and IL-1 ⁇ expression in the spinal cord are suppressed, and recovery of motor function is promoted (Non-Patent Document 73). Therefore, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for spinal cord injury.
  • Non-Patent Documents 75, 76 When MCC950, an NLRP3 inhibitor, is administered to an 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 therapeutic agents for septic encephalopathy.
  • Non-Patent Document 77 In the chronic constriction injury (CCI) model, which is a neuropathic pain model animal, the expression levels of IL-1 ⁇ and NLRP3 inflammasome-related molecules increase in intraspinal glial cells and neurons (Non-Patent Document 77). In addition, in the paclitaxel-induced pain model, which is a neuropathic pain model for anticancer drug-induced neuropathy, the expression level of NLRP3 inflammasome-related molecules increases in the spinal dorsal root ganglion and sciatic nerve (Non-patent Document 78).
  • CCI chronic constriction injury
  • NLRP3 inflammasome inhibitors are considered to be therapeutic agents for neuropathic pain.
  • NLRP3 inflammasome inhibitors are considered to be therapeutic agents for COVID-19 caused by SARS-CoV-2.
  • Non-Patent Document 81 An increase in the ASC domain of the NLRP3 inflammasome and mature IL-1 ⁇ protein has been reported in the cerebral cortex of frontotemporal dementia patients with tau protein mutations.
  • Non-Patent Document 81 An increase in the ASC domain of the NLRP3 inflammasome and caspase1 after cleavage was reported in the cerebral cortex of Tau22 mice (mice expressing human mutant tau protein), which is a frontotemporal dementia model, and NLRP3 knockout inhibits tau lesion formation. Suppressive effects and suppressive effects on cognitive function decline have also been reported (Non-Patent Document 81). Based on the above results, NLRP3 inflammasome inhibitors are considered to be a therapeutic agent for frontotemporal dementia.
  • Drusen formation which is thought to be a causative agent of age-related macular degeneration (AMD)
  • AMD age-related macular degeneration
  • NLRP3-AID NLRP3-related autoinflammatory disease
  • Non-patent Document 82 NLRP3-AID-related autoinflammatory disease
  • the NLRP3 inhibitor suppressed retinal pigment epithelial cell degeneration (Non-Patent Document 83).
  • Non-Patent Document 83 NLRP3 inhibitors suppressed neovascularization. Based on the above results, NLRP3 inflammasome inhibitors are considered to be therapeutic agents for age-related macular degeneration.
  • Non-Patent Document 84 MCC950, an NLRP3 inhibitor, improved increased retinal vascular permeability in STZ-induced diabetic mice (Non-Patent Document 85). Therefore, NLRP inflammasome inhibitors are considered to be therapeutic agents for diabetic macular edema.
  • Hereditary transient keratitis is one of the cryopyrin-associated periodic fever syndromes caused by activating mutations in the NLRP3 gene (Non-Patent Document 86). Therefore, NLRP inflammasome inhibitors are considered to be therapeutic agents for hereditary transient corneal endotheliitis.
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  • Non-patent Document 3 Politis, M et al., Increased PK11195 PET binding in the cortex of patients with MS correlates with disability. Neurology, 2012, Vol 79(6), p523-30.
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  • Non-patent Document 7 Guo, C et al., Development and Characterization of a Hydroxyl-Sulfonamide Analogue, 5-Chloro-N-[2-(4-hydroxysulfamoyl-phenyl)-ethyl]-2-methoxy-benzamide, as a Novel NLRP3 Inflammasome Inhibitor for Potential Treatment of Multiple Sclerosis. ACS Chem Neurosci., 2017, Vol 8(10), p2194-2201 [Non-Patent Document 8] Akosua Vilaysane et al., The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD.
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  • Non-Patent Document 47 Zhang Y et al., Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction. Cell Death Dis. 2017 Jul 20; 8(7):e2941.
  • Non-patent Document 48 Sheng Li et al., Protective effects of sulforaphane on diabetic retinopathy: activation of the Nrf2 pathway and inhibition of NLRP3 inflammasome formation. Exp Anim. 2019 May 8;68(2):221-231.
  • Non-patent Document 49 Guangrui Chai et al., NLRP3 Blockade Suppresses Pro-Inflammatory and Pro-Angiogenic Cytokine Secretion in Diabetic Retinopathy. Diabetes Metab Syndr Obes. 2020 Aug 25;13:3047-3058.
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  • Non-Patent Document 53 Rodrigues FB et al., Cerebrospinal Fluid Inflammatory Biomarkers Reflect Clinical Severity in Huntington's Disease. PLoS One. 2016 Sep 22;11(9):e0163479.
  • Non-patent Document 54 Paldino E et al., Pyroptotic cell death in the R6/2 mouse model of Huntington's disease: new insight on the inflammasome. Cell Death Discov. 2020 Jul 31;6:69.
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  • Non-Patent Document 56 Johann S et al., NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients.
  • Non-patent Document 57 Deora V et al., The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020 Feb;68(2):407-421.
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  • Non-Patent Document 59 Lin C et al., Omega-3 fatty acids regulate NLRP3 inflammasome activation and prevent behavior deficits after traumatic brain injury. Exp Neurol. 2017 Apr;290:115-122.
  • Non-Patent Document 60 Wallisch JS et al., Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children. Neurocrit Care. 2017 Aug;27(1):44-50.
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  • Non-Patent Document 63 Fann DY et al., Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013 Sep 5;4(9):e790.
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  • Non-Patent Document 75 Ding H et al., Fisetin ameliorates cognitive impairment by activating mitophagy and suppressing neuroinflammation in rats with sepsis-associated encephalopathy. CNS Neurosci Ther. 2022 Feb;28(2):247-258.
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  • Non-Patent Document 77 Xu L et al., MiR-34c Ameliorates Neuropathic Pain by Targeting NLRP3 in a Mouse Model of Chronic Constriction Injury. Neuroscience. 2019 Feb 10;399:125-134.
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  • Non-Patent Document 86 Joni A Turunen, et al., Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene, Am J Ophthalmol. 2018 Apr;188:41-50.
  • the present invention provides a pyrazolopyrimidine compound having NLRP3 inflammasome inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof. That is, the present invention includes the embodiments illustrated below.
  • a compound of formula [I] or a pharmaceutically acceptable salt thereof (hereinafter, in the present specification, "a compound of formula [I] or a pharmaceutically acceptable salt thereof” is also referred to as “compound [I]”).
  • R 1 and R 2 are each independently, (1) Hydrogen, (2) Hydroxy, (3) Cyano, (4) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (5) C 1-6 alkoxy (wherein the alkoxy may be substituted with C 3-6 cycloalkyl), (6) halogen, (7) C 1-4 haloalkyl, (8)-CHO, (9) -OC 1-4 haloalkyl, (10) -O-C 3-6 cycloalkyl, (11) -CO
  • An NLRP3 inflammasome inhibitor comprising the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • Treatment 7 Multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, containing the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • cryopyrin-associated periodic fever syndrome e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome, and neonatal-onset multisystem inflammatory disease
  • nonalcoholic steatohepatitis e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint 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
  • recurrent pericarditis adult-onset Still's disease (e.g., hemophagocytosis).
  • lymphohistiocytosis and macrophage activation syndrome Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetes mellitus sexual retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, sepsis A therapeutic or prophylactic agent for a disease selected from the group consisting of encephalopathy, neuropathic pain, COVID-19, and TNF receptor-related periodic syndrome.
  • ischemic heart disease e.g.
  • ulcerative colitis and Crohn's disease arteriosclerosis
  • cryopyrin-associated periodic fever syndrome e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile syndrome
  • neurocutaneous joint syndrome and neonatal-onset multisystem inflammatory disease non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye
  • ischemic heart disease e.g.
  • cryopyrin-related periodic fever syndrome e.g. Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis e.g., Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis e.g., Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis e.g., Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis e.g., gouty arthritis, rheumatoid arthritis, contact dermatitis , dry eye
  • ischemic heart disease
  • Schnitzler syndrome IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild dementia disability, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID- 19.
  • a commercial package comprising a statement regarding said pharmaceutical composition, which states that said pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of 19 and TNF receptor-associated periodic syndrome.
  • the pharmaceutical composition according to item 5 and the pharmaceutical composition can be used to treat multiple sclerosis, chronic kidney disease, inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-related periodic fever syndrome (e.g.
  • Familial cold autoinflammatory syndrome Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis gout, gouty arthritis, rheumatoid arthritis, contact dermatitis , dry eye
  • ischemic heart disease e.g., acute myocardial infarction
  • systemic lupus erythematosus systemic juvenile idiopathic arthritis
  • recurrent pericarditis adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation).
  • Schnitzler syndrome IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild dementia disability, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID- 19.
  • a commercial kit comprising a description of the pharmaceutical composition, which describes that the pharmaceutical composition can be used for the treatment or prevention of a disease selected from the group consisting of 19 and TNF receptor-associated periodic syndrome.
  • a compound of formula [IA] or a pharmaceutically acceptable salt thereof (hereinafter, in the present specification, "a compound of formula [IA] or a pharmaceutically acceptable salt thereof” is also referred to as “compound [IA]").
  • bond is a single bond or a double bond
  • R 1 and R 2 are each independently, (1) Hydrogen, (2) Hydroxy, (3) Cyano, (4) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (5) C 1-6 alkoxy (wherein the alkoxy may be substituted with C 3-6 cycloalkyl), (6) halogen, (7) C 1-4 haloalkyl, (8)-CHO, (9) -OC 1-4 haloalkyl, (10) -O-C 3-6 cycloalkyl, (11) -CO-C 1-4 alkyl, (12) -CO-C 3-6 cycloalkyl, (13)-NR 7 R 8 (where R 7 and R 8 are each independently hydrogen or 2,4-dimethoxybenzyl, or R 7 and R 8
  • n is 0 or 1
  • X 1 , X 2 , X 3 and X 4 are each independently carbon, nitrogen, oxygen or sulfur atoms (wherein nitrogen, oxygen and sulfur atoms as X 1 , X 2 , X 3 or (the total number of oxygen and sulfur atoms is 1, 2, or 3, and the total number of oxygen and sulfur atoms is 0 or 1)
  • X 1 , X 2 , X 3 and X 4 are adjacent to each other with X 1 and X 4 together with a carbon atom to form a heteroaryl
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently carbon or nitrogen atoms (wherein, the total number of nitrogen atoms as X 1 , is 1 or 2), X 1 , X 2 , X 3 , X
  • [Section 11A] The compound according to any one of Items 1A to 10A, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
  • [Section 12A] At least one of R 1 and R 2 is C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; or halogen; A compound according to any one of Items 1A to 11A or a pharmaceutically acceptable salt thereof.
  • [Section 13A] Structural formula below: A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • cryopyrin-associated periodic fever syndrome e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome, and neonatal-onset multisystem inflammatory disease
  • nonalcoholic steatohepatitis e.g., familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint 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
  • recurrent pericarditis adult-onset Still's disease (e.g., hemophagocytosis).
  • lymphohistiocytosis and macrophage activation syndrome Schnitzler syndrome, IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetes mellitus sexual retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, sepsis Selected from the group consisting of encephalopathy, neuropathic pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient keratitis, and TNF receptor-related periodic syndrome therapeutic or prophylactic agents for diseases.
  • FIG. 17A The therapeutic or preventive agent according to item 16A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • FIG. 18A 16A.
  • the therapeutic or preventive agent according to item 16A, wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome, or neonatal onset multisystem inflammatory disease.
  • Diseases include multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, and depression.
  • ischemic heart disease e.g.
  • FIG. 22A 21A, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
  • 21A wherein the cryopyrin-associated periodic fever syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome, or neonatal onset multisystem inflammatory disease.
  • Diseases include multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, and depression.
  • ischemic heart disease e.g.
  • ischemic heart disease e.g.
  • Treatment 34A Diseases include multiple sclerosis, dry eye, diabetic retinopathy, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, and depression. , autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, and hereditary transient corneal endotheliitis. 31A, or a pharmaceutically acceptable salt thereof.
  • Familial cold autoinflammatory syndrome Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis gout, gouty arthritis, rheumatoid arthritis, contact dermatitis , dry eye
  • ischemic heart disease e.g., acute myocardial infarction
  • systemic lupus erythematosus systemic juvenile idiopathic arthritis
  • recurrent pericarditis adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation).
  • Schnitzler syndrome IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild dementia disability, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID- 19.
  • a disease selected from the group consisting of frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-related periodic syndrome.
  • Familial cold autoinflammatory syndrome Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal onset multisystem inflammatory disease
  • non-alcoholic steatohepatitis gout, gouty arthritis, rheumatoid arthritis, contact dermatitis , dry eye
  • ischemic heart disease e.g., acute myocardial infarction
  • systemic lupus erythematosus systemic juvenile idiopathic arthritis
  • recurrent pericarditis adult-onset Still's disease (e.g., hemophagocytic lymphohistiocytosis and macrophage activation).
  • Schnitzler syndrome IL-1 receptor antagonist molecule deficiency, familial Mediterranean fever, mevalonate kinase deficiency, hyper-IgD syndrome, Behcet's disease, lung cancer, psoriasis, hypertension, diabetic retinopathy, Alzheimer's disease, mild dementia disability, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neuropathic pain, COVID- 19.
  • a disease selected from the group consisting of frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-related periodic syndrome.
  • C 1-4 alkyl means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms.
  • C 1-4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferred are methyl and ethyl. More preferred is methyl.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • C 1-6 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, 1, Includes 1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.
  • Preferred are methyl and ethyl. More preferred is methyl.
  • C 2-6 alkenyl means a straight or branched unsaturated hydrocarbon group containing 2 to 6 carbon atoms and at least one double bond.
  • C 2-6 alkenyl includes, for example, vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 3-methyl-2 -butenyl, 1,1-dimethyl-2-propenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, and 1-methyl-2-butenyl.
  • C 2-5 alkynyl means a straight or branched unsaturated hydrocarbon group containing 2 to 5 carbon atoms and at least one triple bond.
  • C 2-5 alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 2-pentynyl.
  • C 1-4 alkoxy means a group in which the above “C 1-4 alkyl” is bonded to an oxygen atom.
  • C 1-4 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy. Preferably it is methoxy.
  • C 1-6 alkoxy means a group in which the above “C 1-6 alkyl” is bonded to an oxygen atom.
  • C 1-6 alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2- Includes methylbutoxy, 1,1-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, and 2-ethylbutoxy It will be done.
  • Halogen includes, for example, fluorine, chlorine, bromine, and iodine. Preferred are fluorine, chlorine, and bromine.
  • C 1-4 haloalkyl means the above “C 1-4 alkyl” substituted with 1 to 7 halogens independently selected from the group of “halogen” above.
  • 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. Preferred are difluoromethyl and trifluoro
  • C 1-6 haloalkyl means the above “C 1-6 alkyl” substituted with 1 to 9 halogens independently selected from the group of “halogen” above.
  • 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
  • C 2-6 haloalkenyl means the above “C 2-6 alkenyl” substituted with 1 to 9 halogens independently selected from the group of “halogen” above.
  • C 2-6 haloalkenyl includes, for example, 2-fluoroethenyl, 3-chloropropenyl, 2-fluoropropenyl, 1-trifluoromethylethenyl, and 4,4,4-trifluoro-2-butenyl. is included.
  • C 3-6 cycloalkyl means a monocyclic saturated hydrocarbon ring group having 3 to 6 carbon atoms.
  • C 3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferably it is cyclopropyl.
  • C 5-6 cycloalkene means a monocyclic partially unsaturated hydrocarbon ring having 5 to 6 carbon atoms and containing at least one double bond.
  • C 5-6 cycloalkene includes, for example, cyclopentene, cyclopentadiene, cyclohexene, and cyclohexadiene. Preferably it is cyclopentene.
  • C 5-6 cycloalkenyl means a monocyclic partially unsaturated hydrocarbon ring group having 5 to 6 carbon atoms and at least one double bond.
  • C 5-6 cycloalkenyl includes, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.
  • "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms” means, in addition to carbon atoms, nitrogen and oxygen atoms as ring constituent atoms. means a 4- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of: "4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms” includes, for example, azetidinyl, oxetanyl, diazetidinyl, dioxetanyl, pyrrolidinyl, Includes tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diaza
  • "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms” means, in addition to carbon atoms, nitrogen and oxygen atoms as ring constituent atoms. means a 5- to 6-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms independently selected from the group consisting of: "5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms” includes, for example, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, Included are isoxazolidinyl, dioxolanyl, piperidinyl, tetrahydropyranyl, 1,3-diazacyclohexanyl, piperazinyl, morpholinyl, tetrahydro-1,2-oxazin
  • a 5- to 7-membered heterocycloalkane containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms means, in addition to carbon atoms, nitrogen and oxygen atoms as ring constituent atoms. means a 5- to 7-membered monocyclic saturated heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of.
  • a 5- to 7-membered heterocycloalkane containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms includes, for example, pyrrolidine, tetrahydrofuran, imidazolidine, pyrazolidine, dioxolane, Oxazolidine, isoxazolidine, piperidine, tetrahydropyran, 1,2-diazacyclohexane, 1,3-diazacyclohexane, piperazine, dioxane, morpholine, tetrahydro-1,2-oxazine, tetrahydro-1,3-oxazine, azepane, oxepane , diazepanes (eg, 1,4-diazepane), dioxepane (eg, 1,4-dioxepane), and oxazepanes (eg, 1,4-oxazepane and 1,2-oxaze
  • a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms refers to a 5- to 7-membered heterocycloalkene containing 1 or 2 oxygen atoms in addition to carbon atoms as ring constituent atoms, and at least one double bond.
  • Examples of "5- to 7-membered heterocycloalkenes containing 1 or 2 oxygen atoms" include dihydrofuran, dioxole, dihydropyran, dihydrodioxine, pyran, tetrahydroxepine, dihydrodioxepine, dihydroxepine, Includes cepin, and dioxepin. Preferably it is dihydropyran.
  • a 5- to 7-membered heterocycloalkene containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms means, in addition to carbon atoms, nitrogen and oxygen atoms as ring constituent atoms. means a 5- to 7-membered monocyclic partially unsaturated heterocycle containing one or two heteroatoms independently selected from the group consisting of at least one double bond.
  • a 5- to 7-membered heterocycloalkene containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms includes, for example, pyrroline, pyrazoline, imidazoline, dihydrofuran, dioxole, Oxazoline, Isoxazoline, Tetrahydropyridine, Tetrahydropyrimidine, Tetrahydropyridazine, Tetrahydropyrazine, Dihydropyridine, Dihydropyran, Dihydrodioxine, Pyran, Dihydroxazine, Tetrahydroazepine, Tetrahydrodiazepine, Dihydroazepine, Dihydrodiazepine, Tetrahydroxepine, Dihydrodi Includes xepin, dihydroxepine, dioxepine, tetrahydroxazepine, and dihydroxazepine. Preferred are pyrroline and dihydroxazine.
  • n in formula [I] and formula [IA] is 0, and X 1 , X 2 , X 3 and X 4 are each independently a carbon, nitrogen, oxygen or sulfur atom. and X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and the mutually adjacent carbon atoms form a heteroaryl (wherein The total number of nitrogen, oxygen and sulfur atoms as X 4 is 1, 2, or 3, and the total number of oxygen and sulfur atoms is 0 or 1).
  • the heteroaryl contains, in addition to carbon atoms, 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring constituent atoms, and the total number of oxygen and sulfur atoms means a 5-membered monocyclic aromatic heterocyclic group in which is 0 or 1.
  • Such heteroaryls include, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl (e.g.
  • n in formula [I] and formula [IA] is 1, and X 1 , X 2 , X 3 , X 4 and X 5 are each independently a carbon or nitrogen atom. and X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and the mutually adjacent carbon atoms form a heteroaryl (here, X 1 , X 2 , The total number of nitrogen atoms as X 3 , X 4 or X 5 is 1 or 2). That is, the heteroaryl means a 6-membered monocyclic aromatic heterocyclic group containing one or two nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • heteroaryls include, for example, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl.
  • Preferred are pyrimidyl and pyridazinyl. More preferably, the following groups: It is.
  • a substructure of formula [IA] is, when two adjacent R 6As form a ring structure together with two adjacent ones of X 1 , X 2 , X 3 , X 4 and X 5 to which they are bonded, the nitrogen as a whole , forming an 8- to 11-membered partially unsaturated fused ring group containing 1 to 5 heteroatoms independently selected from the group consisting of oxygen and sulfur atoms.
  • the fused ring group include the following groups: can be mentioned.
  • a substructure of formula [IA]: is 9 to 11, which may contain 1 or 2 oxygen atoms as a whole, when R 5A is combined with R 3A or R 4A and the carbon atom to which they are bonded to form a ring structure.
  • R 1 and R 2 form a fused ring group substituted with R 3A or R 4A .
  • Examples of the fused ring group include the following groups: can be mentioned.
  • ⁇ “may be substituted” with ⁇ means that ⁇ is unsubstituted or that any substitutable hydrogen of ⁇ is replaced with ⁇ .
  • C 1-6 alkyl which may be substituted with hydroxy means that C 1-6 alkyl is unsubstituted or any hydrogen in C 1-6 alkyl is substituted with hydroxy. .
  • each substituent of the compound of formula [I] and formula [IA] is illustrated below, but each substituent of the compound of formula [I] and formula [IA] is limited to the specific embodiment. Moreover, the compounds of formula [I] and formula [IA] also include embodiments in which two or more of the specific embodiments of each substituent are combined.
  • R 1 and R 2 are preferably each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (3) C 1-6 alkoxy (wherein the alkoxy may be substituted with C 3-6 cycloalkyl), (4) Halogen, (5) C 1-4 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl.
  • R 1 and R 2 are preferably each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, or (3) halogen. , is.
  • R 1 and R 2 are more preferably each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy).
  • R 3 and R 4 are preferably hydrogen.
  • R 5 is preferably (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl (wherein the cycloalkyl may be substituted with 1 to 3 halogens or C 1-4 haloalkyl) , is.
  • Substructure is preferably, R 1 and R 2 are each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (3) C 1-6 alkoxy (wherein the alkoxy may be substituted with C 3-6 cycloalkyl), (4) Halogen, (5) C 1-4 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; R 3 and R 4 are preferably hydrogen; R5 is (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl (wherein the cycloalkyl may be substituted with 1
  • R 3A and R 4A are preferably each independently hydrogen or C 1-4 alkyl.
  • R 3A and R 4A are more preferably hydrogen.
  • R 5A is preferably (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, or R 5A is R 3A or R 4A and together with the carbon atoms to which they are bonded, Forms (1) a C 5-6 cycloalkene, or (2) a 5- to 7-membered heterocycloalkene containing one or two oxygen atoms.
  • R 5A is more preferably (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 5A is more preferably, (1) halogen, or (2) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 5A is even more preferably C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • Substructure is preferably, R 1 and R 2 are each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, or (3) halogen.
  • R 3A and R 4A are each independently hydrogen or C 1-4 alkyl
  • R5A is (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, or R 5A is R 3A or R 4A and together with the carbon atoms to which they are bonded, Forms (1) a C 5-6 cycloalkene, or (2) a 5- to 7-membered heterocycloalkene containing one or two oxygen atoms.
  • Substructure is more preferably, R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy); R 3A and R 4A are hydrogen; R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy); R 3A and R 4A are hydrogen; R5A is (1) halogen, or (2) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy); R 3A and R 4A are hydrogen; R 5A is C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 6 is preferably (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 alkoxy, (3) halogen, or (4) C 1-4 haloalkyl.
  • R 6A is preferably independently: (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 alkoxy, (3) halogen, or (4) C 1-4 haloalkyl.
  • R 6A is more preferably independently C 1-4 alkyl, where said alkyl may be substituted with C 1-4 alkoxy.
  • m is preferably 0 or 1.
  • X 1 is preferably a carbon, nitrogen, or oxygen atom. X 1 is more preferably carbon or nitrogen atom.
  • X 2 is preferably a carbon or nitrogen atom.
  • X 3 is preferably a carbon, nitrogen, or sulfur atom.
  • X 4 is preferably a carbon, nitrogen, or sulfur atom. X 4 is more preferably a carbon atom.
  • X 5 is preferably a carbon atom.
  • n is preferably 0.
  • Substructure is preferably when n is 0, m is 0 or 1;
  • R6A is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;
  • X 1 is a carbon, nitrogen or oxygen atom;
  • X 2 is a carbon or nitrogen atom;
  • X 3 is a carbon, nitrogen, oxygen or sulfur atom;
  • X 4 is a carbon, nitrogen or sulfur atom (wherein the total number of nitrogen, oxygen and sulfur atoms as X 1 , X 2 , X 3 or X 4 is 1, 2 or 3, and and the total number of sulfur atoms is 0 or 1);
  • X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a
  • R6A is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;
  • X 1 is a carbon, nitrogen or oxygen atom;
  • X 2 is a carbon or nitrogen atom;
  • X 3 is a carbon, nitrogen, oxygen or sulfur atom;
  • X 4 is a carbon, nitrogen or sulfur atom (here, the total number of nitrogen, oxygen and sulfur atoms as X 1 , X 2 , X 3 or X 4 is 2 or 3, and total number of atoms is 0 or 1);
  • X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a heteroaryl.
  • Substructure is more preferably when n is 0, m is 0 or 1;
  • R 6A is C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy);
  • X 1 is a nitrogen atom;
  • X 2 is a carbon or nitrogen atom;
  • X 3 is a carbon, nitrogen, or sulfur atom;
  • X 4 is a carbon atom (where the total number of nitrogen and sulfur atoms as X 1 , X 2 or X 3 is 2);
  • X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a heteroaryl.
  • Substructure Even more preferably, when n is 0, formula: ,formula: , or the expression: , and m is 0 or 1; R 6A is C 1-4 alkyl, where the alkyl may be substituted with C 1-4 alkoxy.
  • Substructure When n is 1, preferably, m is 0 or 1; R6A is (1) C 1-4 alkoxy, (2) halogen, or (3) C 1-4 haloalkyl; X 1 , X 2 , X 3 , and X 4 are each independently carbon or nitrogen atoms (here, the total number of nitrogen atoms as X 1 , X 2 , X 3 , or X 4 is 1 or 2). ); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and adjacent carbon atoms form a heteroaryl.
  • Substructure is more preferably when n is 1, m is 0; X 1 and X 2 are each independently a carbon or nitrogen atom; X 3 is a nitrogen atom (where the total number of nitrogen atoms as X 1 , X 2 or X 3 is 2); X 4 and X 5 are carbon atoms; X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and adjacent carbon atoms form a heteroaryl.
  • Substructure: is more preferably when n is 1, formula: , or formula: , is.
  • Substructure is preferably, m is 0 or 1;
  • R6A is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;
  • X 1 is a carbon, nitrogen or oxygen atom;
  • X 2 is a carbon or nitrogen atom;
  • X 3 is a carbon, nitrogen, oxygen or sulfur atom;
  • X 4 is a carbon, nitrogen or sulfur atom (here, the total number of nitrogen, oxygen and sulfur atoms as X 1 , X 2 , X 3 or X 4 is 2 or 3, and total number of atoms is 0 or 1);
  • X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a heteroaryl.
  • Substructure is more preferably, m is 0 or 1; R 6A is C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy); X 1 is a carbon, nitrogen or oxygen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, oxygen or sulfur atom; X 4 is a carbon, nitrogen or sulfur atom (here, the total number of nitrogen, oxygen and sulfur atoms as X 1 , X 2 , X 3 or X 4 is 2 or 3, and total number of atoms is 0 or 1); X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a heteroaryl.
  • Substructure More preferably, m is 0 or 1; R 6A is C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy); X 1 is a nitrogen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, or sulfur atom; X 4 is a carbon atom (where the total number of nitrogen and sulfur atoms as X 1 , X 2 or X 3 is 2); X 1 , X 2 , X 3 and X 4 together with X 1 and X 4 and adjacent carbon atoms form a heteroaryl.
  • Substructure Even more preferably, formula: ,formula: , or the expression: , and m is 0 or 1; R 6A is C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy).
  • Substructure is preferably, m is 0 or 1; R6A is (1) C 1-4 alkoxy, (2) halogen, or (3) C 1-4 haloalkyl; X 1 , X 2 , X 3 , and X 4 are each independently carbon or nitrogen atoms (here, the total number of nitrogen atoms as X 1 , X 2 , X 3 , or X 4 is 1 or 2). ); X 5 is a carbon atom; X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and adjacent carbon atoms form a heteroaryl.
  • Substructure is more preferably, m is 0; X 1 and X 2 are each independently a carbon or nitrogen atom; X 3 is a nitrogen atom (where the total number of nitrogen atoms as X 1 , X 2 or X 3 is 2); X 4 and X 5 are carbon atoms; X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and the mutually adjacent carbon atoms form a heteroaryl.
  • Substructure More preferably, formula: , or formula: , is.
  • R 1 and R 2 are each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (3) C 1-6 alkoxy (wherein the alkoxy may be substituted with C 3-6 cycloalkyl), (4) Halogen, (5) C 1-4 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl; R 3 and R 4 are preferably hydrogen; R5 is (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, or (7) C 3-6 cycloalkyl (wherein the cycloal
  • R 1 and R 2 are each independently, (1) Hydrogen, (2) C 1-6 alkyl ⁇ wherein the alkyl is (a) hydroxy, (b) C 1-4 alkoxy, and (c) C 3-6 cycloalkyl, optionally substituted with one or two substituents independently selected from the group consisting of; (3) halogen; R 3A and R 4A are each independently, (1) hydrogen, or (2) C 1-4 alkyl; R5A is (1) Hydrogen, (2) C 1-6 alkyl, (3) C 1-4 alkoxy, (4) Halogen, (5) C 1-6 haloalkyl, (6) -O-C 1-4 haloalkyl, (7) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, or R 5A is R 3A or R 4A and together with the carbon atoms to which they are
  • X 5 is a carbon atom
  • X 1 , X 2 , X 3 , X 4 and X 5 are compounds of formula [IA] that form a heteroaryl together with X 1 and X 5 and mutually adjacent carbon atoms.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy); R 3A and R 4A are hydrogen; R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of; m is 0 or 1; R 6A is C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy); n is 0 or 1; When n is 0, X 1 is a nitrogen atom; X 2 is a carbon or nitrogen atom; X 3 is a carbon, nitrogen, or sulfur atom; X 4 is a carbon atom (where the total number of nitrogen and sulfur atom
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R6A is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;
  • X 1 is a carbon, nitrogen or oxygen atom
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R6A is (1) C 1-4 alkoxy, (2) halogen, or (3) C 1-4 haloalkyl;
  • X 1 , X 2 , X 3 , and X 4 are each independently carbon or nitrogen atoms (here, the total number of nitrogen atoms as X 1 , X 2 , X 3 , or X 4 is 1 or 2).
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R6A is (1) C 1-4 alkyl (wherein the alkyl may be substituted with C 1-4 alkoxy), (2) C 1-4 haloalkyl, or (3) a 4- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms; X 1 , X 2 , X 3 and X 4 together with X 1 and X
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R 6A is C 1-4 alkyl, where the alkyl may be substituted with C 1-4 alkoxy.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R 6A is C 1-4 alkyl, where the alkyl may be substituted with C 1-4 alkoxy.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0 or 1;
  • R 6A is C 1-4 alkyl, where the alkyl may be substituted with C 1-4 alkoxy.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of;
  • m is 0; X 1 , X 2 , X 3 , X 4 and X 5 together with X 1 and X 5 and adjacent carbon atoms form pyridazinyl or pyrimidyl.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • R 1 and R 2 are each independently C 1-6 alkyl (wherein the alkyl may be substituted with hydroxy or C 1-4 alkoxy);
  • R5A is (1) Halogen, (2) C 1-6 haloalkyl, or (3) C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen; and (c) C 1-4 haloalkyl.
  • Another preferred embodiment of the compound of formula [IA] is a compound of formula [IV], [V], [VI], [VII], [VIII], [IX], [X], or [XI]: [In the formula, R 1 , R 2 , R 3A , and R 4A have the same meanings as in term 1A] This is a compound represented by
  • the pharmaceutically acceptable salt may be any salt known in the art that does not cause excessive toxicity. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases.
  • Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci. , 66, p1-19 (1977), (b) Stahl et al., “Handbook of Pharmaceutical Salt: Properties, Selection, and Use” (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem. , 50, p6665-6672 (2007).
  • a pharmaceutically acceptable salt thereof can be obtained by reacting a compound of formula [I] or formula [IA] with an inorganic acid, an organic acid, an inorganic base, or an organic base according to a method known per se. .
  • salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid. Preferred are salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid or hydrobromic acid.
  • Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, and citric acid.
  • Acid edetic acid, ethane-1,2-disulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxy- Naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methyl sulfuric acid, methyl nitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfone Acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid
  • oxalic acid maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid , p-toluenesulfonic acid or 2-hydroxy-1-ethanesulfonic acid.
  • salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Preferred are salts with sodium, potassium, calcium, magnesium or zinc.
  • salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine or lysine. Preferred examples include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.
  • Compound [I] or compound [IA] may exist as a solvate.
  • a solvate is, for example, compound [I] or compound [IA] coordinated with a solvent molecule.
  • the solvate may be any pharmaceutically acceptable solvate, such as hydrate, acetate, acetonate, ethanolate, dimethyl sulfoxide, etc. of compound [I] or compound [IA]. can be mentioned.
  • solvates can be obtained according to known methods.
  • Compound [I] or compound [IA] may exist as tautomers.
  • compound [I] or compound [IA] may exist as an individual tautomer or a mixture of tautomers.
  • the following expression The structure described in is, unless otherwise mentioned in annotation, (1) (2) (3) (4) , or (5) a mixture thereof.
  • Compound [I] or compound [IA] may have a carbon-carbon double bond.
  • compound [I] or compound [IA] may exist as E form, Z form, or a mixture of E form and Z form.
  • Compound [I] or compound [IA] may have stereoisomers that should be recognized as cis/trans isomers.
  • compound [I] or compound [IA] may exist as a cis form, a trans form, or a mixture of a cis form and a trans form.
  • Compound [I] or compound [IA] may have one or more asymmetric carbon atoms.
  • compound [I] or compound [IA] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.
  • Compound [I] or compound [IA] may exist as an atropisomer.
  • compound [I] or compound [IA] may exist as an individual atropisomer or a mixture of atropisomers.
  • Compound [I] or compound [IA] may simultaneously contain multiple structural features that give rise to the above-mentioned isomers.
  • compound [I] or compound [IA] may contain the above-mentioned isomers in any ratio.
  • Diastereomeric mixtures can be separated into their respective diastereomers by commonly used methods such as chromatography and crystallization.
  • the respective diastereomers can also be made by using stereochemically uniform starting materials or by synthetic methods using stereoselective reactions.
  • each single enantiomer from a mixture of enantiomers can be carried out by methods well known in the art.
  • diastereomeric mixtures formed by reacting mixtures of enantiomers with compounds that are substantially pure enantiomers, known as chiral auxiliaries can be synthesized by fractional crystallization or chromatography.
  • Enriched or substantially pure single diastereomers can be separated using standard methods.
  • the separated diastereomers can be converted to the desired enantiomer by removing the added chiral auxiliary by cleavage.
  • Enantiomeric mixtures can also be separated directly by chromatographic methods using chiral stationary phases, which are well known in the art.
  • either enantiomer can be synthesized stereoselectively by using substantially pure optically active starting materials or by using chiral auxiliaries or asymmetric catalysts for prochiral intermediates. It can also be obtained by performing a simultaneous induction).
  • the absolute configuration can be determined by X-ray crystallography of the crystalline product or intermediate.
  • a crystalline product or intermediate derivatized with a reagent having an asymmetric center whose steric configuration is known may be used.
  • Compound [I] or compound [IA] is an isotopic element ( 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 18 O, 18 F, 35 S , 123 I, etc.).
  • the compound of formula [I] or formula [IA] has a methyl group
  • the methyl group can be replaced with a -CD 3 group, and the compounds thus obtained are also included in the present invention.
  • Compound [I] or compound [IA] labeled with an isotope can be used in pharmaceuticals, pharmacokinetic tests, in vitro and/or in vivo assays, and/or diagnostic agents (positron emission tomography (PET), single photon emission computer It may be useful for imaging (SPECT, etc.).
  • Isotope-labeled compound [I] or compound [IA] can be produced using an isotope-labeled compound instead of a non-isotope-labeled compound according to a known method or the method described herein. .
  • Compound [I] or compound [IA] is preferably substantially purified compound [I] or compound [IA]. More preferred is Compound [I] or Compound [IA] purified to a purity of 80% or more.
  • the pharmaceutical composition of the present invention can be prepared by mixing Compound [I] or Compound [IA] with at least one pharmaceutically acceptable carrier in an appropriate amount according to a method known in the technical field of pharmaceutical formulation. It may be manufactured by The content of compound [I] or compound [IA] in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the entire composition.
  • Dosage forms of compound [I] or compound [IA] include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, or external preparations, suppositories, and injections. , parenteral preparations such as eye drops, nasal preparations, and pulmonary preparations.
  • “Pharmaceutically acceptable carriers” include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, flow agents, lubricants, etc. in solid formulations, and liquid formulations. Solvents, solubilizing agents, suspending agents, isotonic agents, buffering agents, soothing agents, etc. in semi-solid preparations, bases, emulsifiers, wetting agents, stabilizers, stabilizers, dispersants, plasticizers, Examples include pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizers, suspending agents, and the like. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as necessary.
  • Excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, Examples include gum arabic.
  • examples of the "disintegrant” include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, white sugar, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like.
  • plasticizer examples include light silicic anhydride, magnesium stearate, and the like.
  • lubricating agent examples include magnesium stearate, calcium stearate, and talc.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.
  • Examples of the "solubilizing agent” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like.
  • Examples of the "suspending agent” include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate, and the like.
  • Examples of the “isotonizing agent” include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like.
  • Examples of the “buffer” include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like.
  • the "alleviating agent” examples include benzyl alcohol and the like.
  • the “base” includes water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher Fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, water-absorbing ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic , gum tragacanth, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidon
  • Examples of the "preservative” include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like.
  • Examples of “antioxidants” include sodium sulfite, ascorbic acid, and the like.
  • Examples of the "coloring agent” include food pigments (Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.), ⁇ -carotene, and the like.
  • Examples of the “sweetening agent” include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally to mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. It can be administered orally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.).
  • the dosage (also referred to herein as "therapeutically effective amount”) varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when orally administered to adult patients is:
  • the amount of the active ingredient, the compound of formula [I] or formula [IA], or a pharmaceutically acceptable salt thereof, is usually in the range of about 0.01 mg to 1 g per day. These amounts can be administered in one or several divided doses.
  • Compound [I] or Compound [IA] has an NLRP3 inflammasome inhibitory effect, it is useful for the treatment and/or prevention of various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity.
  • Various diseases or conditions that can be expected to be improved by regulating NLRP3 inflammasome activity include, for example, multiple sclerosis, chronic kidney disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), arteriosclerosis, and cryopyrin Associated periodic fever syndromes (e.g.
  • ischemic heart disease e.g. acute myocardial infarction
  • systemic lupus erythematosus systemic juvenile idiopathic arthritis
  • recurrent pericarditis adult-onset Still's disease
  • hemophagocytic lymphoid tissue bulbar disease and macrophage activation syndrome
  • Schnitzler syndrome IL-1 receptor antagonist molecule deficiency
  • familial Mediterranean fever mevalonate kinase deficiency
  • hyper-IgD syndrome Behcet's disease
  • lung cancer psoriasis
  • hypertension diabetic retinopathy , Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral infarction, cerebral hemorrhage, epilepsy, depression, autism spectrum disorder, spinal cord injury, septic encephalopathy, neurology
  • a disease selected from the group consisting of disabling pain, COVID-19, frontotemporal dementia, age-related macular degeneration, diabetic macular edema, hereditary transient corneal endotheliitis, and TNF receptor-related periodic syndrome. can be mentioned.
  • “Inhibiting the NLRP3 inflammasome” means inhibiting the function of the NLRP3 inflammasome to eliminate or attenuate its activity. It means to inhibit the function of some. By inhibiting the function of the NLRP3 inflammasome, the amount of IL-1 ⁇ and/or IL-18 produced is suppressed, preferably the amount of IL-1 ⁇ and IL-18 produced is suppressed. "Inhibiting the NLRP3 inflammasome” preferably means “inhibiting the human NLRP3 inflammasome.”
  • Compound [I] or Compound [IA] has NLRP3 inflammasome inhibitory activity
  • Compound [I] or Compound [IA] or a pharmaceutically acceptable salt thereof may be used as it is or in an appropriate formulation to inhibit NLRP3 inflammasome.
  • treatment includes improvement of symptoms, prevention of aggravation, maintenance of remission, prevention of relapse, and further prevention of recurrence.
  • prevention includes suppressing and delaying the onset of symptoms.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • WSC 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide hydrochloride
  • Production method A1 Production method of compound [I] or its salt
  • Compound [I] or its salt can be produced, for example, by production method A1 shown below.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above, each R A11 is independently C 1-4 alkyl;
  • R A12 is a boronic acid, a boronic ester (e.g., boronic acid pinacol ester), trifluoroborate, or tributyltin;
  • L A11 , L A12 , and L A13 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy) ⁇
  • Step A1-1 Compound [A1-3] or a salt thereof can be produced by reacting compound [A1
  • acids include sulfuric acid, hydrochloric acid, formic acid, perchloric acid, methanesulfonic acid, and p-toluenesulfonic acid. Preferred acids are sulfuric acid or p-toluenesulfonic acid.
  • the solvent include toluene, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, and mixed solvents thereof.
  • a preferred solvent is toluene.
  • the reaction temperature is, for example, 0°C to 150°C, preferably 5°C to 40°C.
  • Compound [A1-1] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Compound [A1-2] is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A1-2 Compound [A1-5] or a salt thereof can be produced by reacting compound [A1-3] or a salt thereof with compound [A1-4] or a salt thereof in a solvent in the presence of a base.
  • a base include triethylamine, 1,8-diazabicyclo[5,4,0]-7-undecene, and N,N-diisopropylethylamine.
  • Preferred bases are triethylamine or N,N-diisopropylethylamine.
  • the solvent include toluene, methanol, ethanol, tetrahydrofuran, and mixed solvents thereof. Preferred solvents are toluene or methanol.
  • reaction temperature is, for example, -78°C to 100°C, preferably 0°C to 40°C.
  • Compound [A1-4] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A1-3 Compound [A1-6] or a salt thereof can be produced by reacting compound [A1-5] or a salt thereof in a solvent in the presence of an acid.
  • acids include trifluoroacetic acid, sulfuric acid, hydrochloric acid, and triethylsilyl trifluoromethanesulfonate.
  • a preferred acid is trifluoroacetic acid.
  • the solvent include toluene, tetrahydrofuran, ethyl acetate, cyclopentyl methyl ether, dichloromethane, and mixed solvents thereof.
  • a preferred solvent is toluene.
  • the reaction temperature is, for example, -78°C to 60°C, preferably 0°C to 40°C.
  • Step A1-4 Compound [A1-7] or a salt thereof can be produced by reacting compound [A1-6] or a salt thereof in a solvent in the presence of a base.
  • the base include sodium hydroxide and potassium hydroxide.
  • a preferred base is sodium hydroxide.
  • the solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, chloroform, and mixed solvents thereof.
  • a preferred solvent is tetrahydrofuran.
  • the reaction temperature is, for example, 0°C to 150°C, preferably 50°C to 100°C.
  • Step A1-5 Compound [I] or a salt thereof can be produced by reacting compound [A1-7] or a salt thereof with compound [A1-8] or a salt thereof in a solvent in the presence of a catalyst and a base.
  • the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis( Mention may be made of di-tert-butylphosphino)ferrocene]palladium(II) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).
  • a preferred catalyst is [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct.
  • the base include tripotassium phosphate, cesium carbonate, potassium carbonate, and lithium chloride.
  • a preferred base is tripotassium phosphate.
  • R A12 is, for example, boronic acid, boronic acid ester (boronic acid pinacol ester, etc.), trifluoroborate
  • examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N -dimethylacetamide and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of toluene and water.
  • R A12 is, for example, tributyltin
  • examples of the solvent include toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylsulfoxide.
  • a preferred solvent is N,N-dimethylacetamide.
  • the reaction temperature is, for example, 10°C to 200°C, preferably 50°C to 150°C.
  • Compound [A1-8] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Manufacturing method A1A Manufacturing method of compound [IA] or a salt thereof Compound [A1-4] or a salt thereof in place of compound [A1-4] or a salt thereof, and compound in place of compound [A1-8] or a salt thereof
  • [A1A-8] or a salt thereof compound [IA] or a salt thereof can be produced in the same manner as production method A1.
  • each symbol has the same meaning as the definition above
  • Compound [A1A-4] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Compound [A1A-8] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Production method A2 Production method of compound [I] or its salt
  • Compound [I] or its salt can also be produced, for example, by production method A2 shown below.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m, n, L A11 , L A12 , and R A12 is the same as the definition above
  • R A21 is a hydroxy-protecting group (e.g., benzyl, 4-methoxybenzyl, and 2-methoxybenzyl), and R A21 is preferably benzyl ⁇
  • Step A2-1 Compound [A2-1] or a salt thereof can be produced by reacting compound [A1-6] or a salt thereof in a solvent in the presence of an alcohol and a base.
  • Examples of the alcohol include benzyl alcohol, 4-methoxybenzyl alcohol, and 2-methoxybenzyl alcohol.
  • a preferred alcohol is benzyl alcohol.
  • Examples of the base include sodium hydride, potassium tert-butoxy, and sodium tert-butoxy.
  • a preferred base is sodium hydride.
  • Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and mixed solvents thereof. A preferred solvent is tetrahydrofuran.
  • the reaction temperature is, for example, -20°C to 100°C, preferably 0°C to 50°C.
  • Step A2-2 Compound [A2-2] or a salt thereof can be produced by reacting compound [A2-1] or a salt thereof with compound [A1-8] or a salt thereof in a solvent in the presence of a catalyst and a base.
  • the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), [1,1'-bis( Mention may be made of di-tert-butylphosphino)ferrocene]palladium(II) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).
  • Preferred catalysts are [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).
  • Examples of the base include tripotassium phosphate, cesium carbonate, potassium carbonate, and lithium chloride.
  • Preferred bases are tripotassium phosphate or lithium chloride.
  • R A12 is, for example, boronic acid, boronic acid ester (boronic acid pinacol ester, etc.), trifluoroborate
  • examples of the solvent include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, N,N -dimethylacetamide and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of toluene and water.
  • examples of the solvent include toluene, N,N-dimethylacetamide, N,N-dimethylformamide and dimethylsulfoxide.
  • a preferred solvent is N,N-dimethylacetamide.
  • the reaction temperature is, for example, 10°C to 200°C, preferably 50°C to 150°C.
  • Step A2-3) Compound [I] or a salt thereof can be produced by reacting compound [A2-2] or a salt thereof in the presence of an acid.
  • acids include formic acid, trifluoroacetic acid, and hydrochloric acid.
  • a preferred acid is formic acid.
  • the reaction temperature is, for example, 0°C to 120°C, preferably 10°C to 100°C.
  • Manufacturing method A2A Method for manufacturing compound [IA] or a salt thereof
  • Compound [IA] or a salt thereof can also be manufactured by, for example, manufacturing method A2A shown below. (In the formula, each symbol has the same meaning as the definition above)
  • Step A2A-1 By using compound [A1A-6] or a salt thereof instead of compound [A1-6] or a salt thereof, compound [A2A-1] or a salt thereof can be produced in the same manner as in step A2-1. .
  • Step A2A-2 Compound [A2A-2] or a salt thereof can be produced in the same manner as step A2-2 by using compound [A1A-8] or a salt thereof instead of compound [A1-8] or a salt thereof. .
  • Step A2A-3 Compound [IA] or a salt thereof can be produced by removing R A21 of compound [A2A-2] or a salt thereof by a deprotection reaction.
  • the deprotection reaction may be carried out under conditions suitable for the type of R A21 .
  • R A21 is benzyl
  • compound [IA] or a salt thereof can be produced by reacting compound [A2A-2] or a salt thereof in the presence of an acid.
  • a solvent may be added if necessary.
  • acids include formic acid, trifluoroacetic acid, and hydrochloric acid.
  • a preferred acid is formic acid.
  • the solvent include toluene, tetrahydrofuran, and 1,4-dioxane.
  • the reaction temperature is, for example, 0°C to 120°C, preferably 10°C to 100°C.
  • Production method A3 Production method of compound [I] or its salt Compound [I] or its salt can also be produced, for example, by production method A3 shown below.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above, R A31 is C 1-4 alkyl, R A32 is an amino group protecting group (e.g.
  • Step A3-1 Compound [A3-3] or a salt thereof can be prepared by reacting compound [A3-1] or a salt thereof with compound [A3-2] or a salt thereof in a solvent in the presence of an oxidizing agent, an acid, and an additive.
  • an oxidizing agent examples include sodium nitrite, butyl nitrite, and isoamyl nitrite.
  • a preferred oxidizing agent is sodium nitrite.
  • acids include concentrated hydrochloric acid, concentrated sulfuric acid, and nitric acid.
  • a preferred acid is concentrated hydrochloric acid.
  • additives include sodium acetate and potassium acetate.
  • a preferred additive is sodium acetate.
  • the solvent include ethanol, methanol, butanol, water, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of ethanol and water.
  • the reaction temperature is, for example, -40°C to 50°C, preferably -10°C to 40°C.
  • Compound [A3-1] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Compound [A3-2] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A3-2 Compound [A3-5] or a salt thereof can be produced by reacting compound [A3-3] or a salt thereof and compound [A3-4] in a solvent in the presence of a base.
  • a base include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • a preferred base is triethylamine.
  • the solvent include chloroform, 1,2-dichloroethane, dichloromethane, and mixed solvents thereof.
  • a preferred solvent is chloroform.
  • the reaction temperature is, for example, 20°C to 120°C, preferably 50°C to 100°C.
  • Compound [A3-4] is a commercially available product.
  • Step A3-3 Compound [A3-6] or a salt thereof can be produced by reacting compound [A3-5] or a salt thereof in a solvent in the presence of a base.
  • a base include sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.
  • a preferred base is sodium hydroxide.
  • the solvent include ethanol, methanol, butanol, tetrahydrofuran, water, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of ethanol and water.
  • the reaction temperature is, for example, 0°C to 100°C, preferably 5°C to 50°C.
  • Step A3-4 Compound [A3-7] or a salt thereof can be produced by reacting compound [A3-6] or a salt thereof in a solvent in the presence of a reactant and a base.
  • the reactant include sodium azide and diphenylphosphoryl azide.
  • a preferred reactant is diphenylphosphoryl azide.
  • the base include triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • a preferred base is triethylamine.
  • the solvent include tert-butanol, benzyl alcohol, tetrahydrofuran, and mixed solvents thereof.
  • a preferred solvent is tert-butanol.
  • the reaction temperature is, for example, 0°C to 150°C, preferably 50°C to 120°C.
  • Step A3-5 Compound [A3-8] or a salt thereof can be produced by reacting compound [A3-7] or a salt thereof in a solvent in the presence of an oxidizing agent and a base.
  • the oxidizing agent include hydrogen peroxide, triiron tetroxide, and manganese dioxide.
  • a preferred oxidizing agent is hydrogen peroxide.
  • the base include sodium hydroxide, potassium hydroxide, and barium hydroxide.
  • a preferred base is sodium hydroxide.
  • the solvent include ethanol, dimethyl sulfoxide, water, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of ethanol, dimethyl sulfoxide and water.
  • the reaction temperature is, for example, -20°C to 50°C, preferably 10°C to 40°C.
  • Step A3-6 Compound [A3-9] or a salt thereof can be produced by removing R A32 of compound [A3-8] or a salt thereof by a deprotection reaction.
  • the deprotection reaction may be carried out under conditions suitable for the type of RA32 .
  • R A32 is tert-butoxycarbonyl
  • compound [A3-9] or a salt thereof can be produced by reacting compound [A3-8] or a salt thereof in a solvent in the presence of an acid.
  • Acids include, for example, hydrogen chloride, trifluoroacetic acid and sulfuric acid. A preferred acid is hydrogen chloride.
  • the solvent include ethyl acetate, cyclopentyl methyl ether, and mixed solvents thereof.
  • a preferred solvent is ethyl acetate.
  • the reaction temperature is, for example, 0°C to 80°C, preferably 10°C to 50°C.
  • Compound [A3-9] or a salt thereof may be produced by reversing steps A3-5 and A3-6.
  • Step A3-7 Compound [A3-11] or a salt thereof can be produced by reacting compound [A3-9] or a salt thereof with compound [A3-10] or a salt thereof in a solvent in the presence of a condensing agent and a base.
  • a condensing agent include HATU, WSC, and propylphosphonic anhydride.
  • a preferred condensing agent is HATU.
  • the base include sodium methoxide, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxy and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • a preferred base is N,N-diisopropylethylamine.
  • the solvent include methanol, N-methylpyrrolidone, N,N-dimethylacetamide, and mixed solvents thereof.
  • a preferred solvent is N-methylpyrrolidone.
  • the reaction temperature is, for example, 0°C to 120°C, preferably 50°C to 100°C.
  • Compound [A3-10] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A3-8 Compound [I] or a salt thereof can be produced by reacting compound [A3-11] or a salt thereof in a solvent in the presence of a base.
  • a base include sodium methoxide, sodium-tert-butoxide and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • a preferred base is 1,8-diazabicyclo[5,4,0]-7-undecene.
  • the solvent include ethanol, methanol, butanol, water, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of ethanol and water.
  • the reaction temperature is, for example, 0°C to 180°C, preferably 50°C to 150°C.
  • Manufacturing method A3A Method for manufacturing compound [IA] or a salt thereof Compound [IA] or a salt thereof can also be manufactured by, for example, manufacturing method A3A shown below.
  • R 1 , R 2 , R 3A , R 4A , R 5A , R 6A , R A31 , R A33 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are the above-mentioned is synonymous with definition
  • R A32A is hydrogen or an amino group protecting group (e.g.
  • Step A3A-1 By using compound [A3A-1] or a salt thereof instead of compound [A3-1] or a salt thereof, compound [A3A-3] or a salt thereof can be produced in the same manner as in step A3-1. .
  • Compound [A3A-1] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A3A-2 By using compound [A3A-3] or its salt instead of compound [A3-3] or its salt, compound [A3A-5] or its salt can be produced in the same manner as step A3-2. .
  • Step A3A-3 By using compound [A3A-5] or its salt instead of compound [A3-5] or its salt, compound [A3A-6] or its salt can be produced in the same manner as step A3-3. .
  • Step A3A-4 By using compound [A3A-6] or its salt instead of compound [A3-6] or its salt, compound [A3A-7] or its salt can be produced in the same manner as step A3-4. .
  • Step A3A-5 By using compound [A3A-7] or a salt thereof instead of compound [A3-7] or a salt thereof, compound [A3A-8] or a salt thereof can be produced in the same manner as in step A3-5. .
  • Step A3A-6 Compound [A3A-9] or a salt thereof can be produced by removing R A32A of compound [A3A-8] or a salt thereof by a deprotection reaction.
  • the deprotection reaction may be carried out under conditions suitable for the type of RA32A .
  • R A32A is tert-butoxycarbonyl
  • compound [A3A-9] or a salt thereof can be produced by reacting compound [A3A-8] or a salt thereof in a solvent in the presence of an acid.
  • Acids include, for example, hydrogen chloride, trifluoroacetic acid and sulfuric acid. A preferred acid is hydrogen chloride.
  • the solvent examples include ethyl acetate, cyclopentyl methyl ether, and mixed solvents thereof.
  • a preferred solvent is ethyl acetate.
  • the reaction temperature is, for example, 0°C to 80°C, preferably 10°C to 50°C.
  • Compound [A3A-9] or a salt thereof may be produced by subjecting compound [A3A-7] or a salt thereof to step A3A-5 after step A3A-6.
  • Step A3A-7 By using compound [A3A-9] or a salt thereof in place of compound [A3-9] or a salt thereof, and compound [A3A-10] or a salt thereof in place of compound [A3-10] or a salt thereof, the step Compound [A3A-11] or a salt thereof can be produced in the same manner as A3-7.
  • Compound [A3A-10] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A3A-8 By using compound [A3A-11] or a salt thereof instead of compound [A3-11] or a salt thereof, compound [IA] or a salt thereof can be produced in the same manner as in step A3-8.
  • compound [A3A-1] or its salt in place of compound [A3A-1] or its salt, a compound having a functional group or a protected substituent that can be converted into various substituents on the benzene ring by a known reaction or a salt thereof is used. After carrying out this production method to obtain a compound corresponding to compound [IA] or a salt thereof, converting the functional group or protected substituent into the various substituents, compound [IA] or The salt may be manufactured.
  • the present production method is carried out using a compound having an amino group on the benzene ring and L A41 (described below) or a salt thereof, and a compound corresponding to compound [IA] is obtained.
  • compound [IA-B] or a salt thereof may be produced by converting L A41 to ring Cy A41A according to production method A4A.
  • the present production method is carried out using a compound having an amino group on the benzene ring and L A41 (described below) or its salt, and compound [A3A-8] After obtaining the corresponding compound, that is, compound [A3A-8-A] or its salt, compound [A3A-8-B] or its salt is produced by converting L A41 to ring Cy A41A according to production method A5A. It's okay.
  • Production method A4 Production method of compound [IB] or its salt
  • Compound [IB] or its salt can be produced, for example, by production method A4 shown below.
  • R 6 , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above
  • Cy A41 is C 3-6 cycloalkyl, where the cycloalkyl is optionally substituted with 1 to 3 halogen or C 1-4 haloalkyl
  • L A41 is a leaving group (eg, halogen, methanesulfonyloxy, and trifluoromethanesulfonyloxy).
  • Step A4-1 Compound [IB] or a salt thereof is prepared by combining compound [IA] or a salt thereof and compound [A4-1] or a derivative thereof (for example, cyclopropylboronic acid pinacol ester and potassium cyclopropyl trifluoroborate) in a solvent. It can be produced by reacting in the presence of a catalyst and a base.
  • Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis (di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • a preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • Examples of the base include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate.
  • the solvent examples include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of toluene and water.
  • the reaction temperature is, for example, 10°C to 200°C, preferably 50°C to 150°C.
  • Compound [IA] or a salt thereof may be produced from a commercially available product by a known method.
  • Compound [IA] or a salt thereof may be produced, for example, by the above-mentioned production method.
  • Compound [A4-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Manufacturing method A4A Manufacturing method for compound [IA-B] or its salt Replace compound [IA] or its salt with compound [IA-A] or its salt, and replace with compound [A4-1] or its salt
  • compound [IA-B] or a salt thereof can be produced in the same manner as production method A4.
  • Cy A41A is C 3-6 cycloalkyl ⁇ wherein the cycloalkyl is (a) hydroxy, (b) halogen, and (c) C 1-4 haloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of Compound [IA-A] or a salt thereof may be produced from a commercially available product by a known method.
  • Compound [IA-A] or a salt thereof may be produced, for example, by the above-mentioned production method.
  • Compound [A4A-1] or a derivative thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Production method A5 Production method of compound [A3-9-B] or its salt
  • Compound [A3-9-B] or its salt can be produced, for example, by production method A5 shown below.
  • Step A5-1 Compound [A3-9-B] or a salt thereof is a combination of compound [A3-9-A] or a salt thereof and compound [A4-1] or a derivative thereof (for example, cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate).
  • a solvent in the presence of a catalyst and a base.
  • Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis (di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • a preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • Examples of the base include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate.
  • the solvent examples include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of toluene and water.
  • the reaction temperature is, for example, 10°C to 200°C, preferably 50°C to 150°C.
  • Compound [A3-9-A] or a salt thereof may be produced from a commercially available product by a known method.
  • Compound [A3-9-A] or a salt thereof may be produced, for example, by the above-mentioned production method.
  • Production method A5A Production method of compound [A3A-8-B] or its salt Compound [A3A-8-B] or its salt can be produced, for example, by production method A5A shown below. (In the formula, each symbol has the same meaning as the definition above) (Step A5A-1) Compound [A3A-8-B] or a salt thereof is a combination of compound [A3A-8-A] or a salt thereof and compound [A4A-1] or a derivative thereof (for example, cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluoroborate). ) in a solvent in the presence of a catalyst and a base.
  • Step A5A-1 Compound [A3A-8-B] or a salt thereof is a combination of compound [A3A-8-A] or a salt thereof and compound [A4A-1] or a derivative thereof (for example, cyclopropylboronic acid pinacol ester and potassium cyclopropyltrifluorobo
  • Examples of the catalyst include [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and [1,1'-bis (di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • a preferred catalyst is [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride.
  • Examples of the base include tripotassium phosphate, cesium carbonate, and potassium carbonate. A preferred base is tripotassium phosphate.
  • the solvent examples include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of toluene and water.
  • the reaction temperature is, for example, 10°C to 200°C, preferably 50°C to 150°C.
  • Compound [A3A-8-A] or a salt thereof may be produced from a commercially available product by a known method.
  • Compound [A3A-8-A] or a salt thereof may be produced, for example, by the above-mentioned production method.
  • Production method A6 Production method of compound [IA] or its salt Compound [IA] or its salt can be produced, for example, by production method A6 shown below. ⁇ wherein R 1 , R 2 , R 3A , R 4A , R 5A , R 6A , X 1 , X 2 , X 3 , X 4 , X 5 , m and n are as defined above, R A61 is hydrogen or an amino group protecting group (e.g.
  • R A62 and R A63 are each independently C 1-4 alkyl
  • L A61 and L A62 are each independently a leaving group (e.g., halogen, methanesulfonyloxy, and p-toluenesulfonyloxy) ⁇
  • Step A6-1 Compound [A6-2] or a salt thereof can be produced by reacting compound [A6-1] or a salt thereof in a solvent in the presence of a reactant.
  • An acid may be added if necessary.
  • Reactants include lithium bis(trimethylsilyl)amide, ammonia, and ammonium chloride.
  • a preferred reactant is lithium bis(trimethylsilyl)amide.
  • acids include hydrogen chloride and sulfuric acid.
  • the solvent examples include methanol, tetrahydrofuran, 1,4-dioxane, and mixed solvents thereof.
  • a preferred solvent is tetrahydrofuran.
  • the reaction temperature is, for example, -78°C to 40°C, preferably -10°C to 10°C.
  • Compound [A6-1] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A6-2 Compound [A6-4] or a salt thereof can be produced by reacting compound [A6-2] or a salt thereof with compound [A6-3] or a salt thereof in a solvent.
  • the solvent include methanol, ethanol, isopropanol, tetrahydrofuran, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of tetrahydrofuran and methanol.
  • the reaction temperature is, for example, from room temperature to 120°C, preferably from 60°C to 100°C.
  • Compound [A6-3] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A6-3 Compound [A6-5] or a salt thereof is prepared by reacting compound [A6-4] or a salt thereof in a solvent in the presence of a Vilsmeier reagent, then adding phosphorus oxychloride and heating (the reaction temperature is, for example, 80°C).
  • the solvent include N,N-dimethylformamide, toluene, benzene, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of N,N-dimethylformamide and toluene.
  • the reaction temperature is, for example, -20°C to 100°C, preferably -10°C to 90°C.
  • Vilsmeier reagent is made, for example, from phosphorous oxychloride and N,N-dimethylformamide.
  • Step A6-4 Compound [A6-7] or a salt thereof can be produced by reacting compound [A6-5] or a salt thereof with compound [A6-6] or a salt thereof in a solvent in the presence of a base.
  • a base include triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]-7-undecene.
  • a preferred base is triethylamine.
  • the solvent include methanol, ethanol, tetrahydrofuran, toluene, cyclopentyl methyl ether, acetonitrile, water, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of tetrahydrofuran and water.
  • the reaction temperature is, for example, -20°C to 80°C, preferably 0°C to room temperature.
  • Compound [A6-6] or a salt thereof is a commercially available product, or may be produced from a commercially available product by a known method.
  • Step A6-5 Compound [IA] or a salt thereof can be produced by reacting compound [A6-7] or a salt thereof in a solvent in the presence of an acid.
  • acids include formic acid, trifluoroacetic acid, and hydrochloric acid.
  • a preferred acid is trifluoroacetic acid.
  • the solvent include water, acetonitrile, tetrahydrofuran, and mixed solvents thereof.
  • a preferred solvent is a mixed solvent of acetonitrile and water.
  • the reaction temperature is, for example, 0°C to 100°C, preferably 50°C to 70°C.
  • compound [A6-6] or its salt instead of compound [A6-6] or its salt, a compound having a functional group or a protected substituent that can be converted into various substituents on the benzene ring by a known reaction or a salt thereof is used. After carrying out this production method to obtain a compound corresponding to compound [IA] or a salt thereof, converting the functional group or protected substituent into the various substituents, compound [IA] or The salt may be manufactured.
  • the present production method is carried out using a phenyl group-substituted hydrazine compound having L A41 or a salt thereof, and a compound corresponding to compound [IA], i.e.
  • compound [IA-B] or a salt thereof may be produced by converting L A41 to ring Cy A41A according to production method A4A.
  • Step 1-2 Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate Under an argon atmosphere, tripotassium phosphate (190 g) was dissolved in water (357 mL), toluene (715 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate ( 89.3 g), cyclopropylboronic acid (61.7 g) and [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (4.18 g) were added, and the mixture was heated at 105°C for 4 hours.
  • Step 1-3 (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride Under a nitrogen atmosphere, add 4 M to a mixture of benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate (133 g) and ethanol (798 mL) synthesized in the same manner as Step 1-2. Aqueous sodium hydroxide solution (536 mL) was added, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled with ice, acetic acid (73.6 mL) was added, and then extracted with toluene (1 L).
  • Step 1-4 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine Under a nitrogen atmosphere, trimethyl orthoformate (750 mL) and sulfuric acid (1.6 mL) were added to a mixture of 2,4,6-trichloropyrimidine-5-carbaldehyde (250 g) and toluene (1.5 L), and the mixture was stirred at room temperature. Stirred for 1.5 hours.
  • Basic silica gel (Fuji Silicia, 500 g) was added to the reaction mixture, and after stirring for 2 hours, the added silica gel was filtered off. After washing the silica gel with ethyl acetate (1.0 L), the solvent was distilled off under reduced pressure to obtain the title compound (268 g).
  • Step 1-5 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (4-Cyclopropyl-2,6-dimethylphenyl) was added to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (94 g) and toluene (1160 mL) under ice cooling under a nitrogen atmosphere. Hydrazine hydrochloride (83 g) and triethylamine (102 mL) were added, and the mixture was stirred at the same temperature for 40 minutes.
  • Trifluoroacetic acid (98 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was slowly added dropwise to an aqueous solution (776 mL) of tripotassium phosphate (310 g) under an ice bath, and the mixture was stirred at room temperature for 10 minutes. After layer separation, the aqueous layer was extracted with toluene. All the organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (162 g) of the title compound.
  • Step 1-6 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  • the crude product of 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (162 g) and tetrahydrofuran (970 mL) ) 2M aqueous sodium hydroxide solution (913 mL) was added to the mixture, and the mixture was stirred at 75°C for 3 hours. After cooling the reaction mixture on ice, 6 M hydrochloric acid (243 mL) was added.
  • Step 1-7 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one Under an argon atmosphere, tripotassium phosphate (148 g) was dissolved in water (510 mL), then toluene (880 mL), 6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2, 5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (73 g), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-pyrazole (57.9 g) and [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (4
  • silica gel 70 g
  • basic silica gel Fuji Silicia, 70 g
  • Acetone 180 mL was added to the obtained solid, and the mixture was stirred for 30 minutes under ice cooling.
  • Step 1-8 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one monohydrate 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- Crystals of 4-one ( ⁇ crystal, 16.0 g) were dissolved in methanol (100 mL) under heating at 80°C.
  • Step 2-2 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene
  • a solution of 50% bis(2-methoxyethyl)aminosulfur trifluoride in tetrahydrofuran (48.7 g) was added to 1-(4-bromo-3,5-dimethylphenyl)ethan-1-one (5.0 g) at 0 °C under an argon atmosphere.
  • mL) and methanol (0.089 mL) were added, and the mixture was stirred at 80°C for 7 hours.
  • the reaction mixture was added dropwise to a saturated aqueous sodium bicarbonate solution, and then extracted with ethyl acetate.
  • Step 2-3 Di-tert-butyl 1- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine-1,2-dicarboxylate n-Butyllithium was added to a mixture of 2-bromo-5-(1,1-difluoroethyl)-1,3-dimethylbenzene (3.58 g) and tetrahydrofuran (72 mL) at -78 °C under an argon atmosphere. -Hexane solution (1.56 M, 11 mL) was added, and the mixture was stirred at the same temperature for 30 minutes.
  • Step 2-4 ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride di-tert-butyl 1- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine-1,2-dicarboxylate (3.38 g) in 4 M hydrogen chloride in ethyl acetate (34 mL ) solution was added and stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure to obtain the title compound (2.0 g).
  • Step 2-5 2,4-dichloro-6-[2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine
  • ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride 2.0 g
  • triethylamine 3.53 mL
  • methanol 40 mL
  • Step 2-6 4,6-dichloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine Under an argon atmosphere, the crude product of 2,4-dichloro-6-[2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine (3.56 Trifluoroacetic acid (1.62 mL) was slowly added dropwise to a mixture of g) and toluene (36 mL), and the mixture was stirred at room temperature for 1 hour.
  • Step 2-7 6-chloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4 -on of 4,6-dichloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine (1.89 g) and tetrahydrofuran (19 mL). A 2M aqueous sodium hydroxide solution (5.29 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 hours.
  • ISOLUTE Si-TMT metal scavenged silica gel, manufactured by Biotage, 0.47 mmol TMT/g, 3 g
  • ISOLUTE Si-TMT metal scavenged silica gel, manufactured by Biotage, 0.47 mmol TMT/g, 3 g
  • the added ISOLUTE Si-TMT was filtered off, washed with ethyl acetate, and then the solvent was distilled off under reduced pressure.
  • the residue was purified by column chromatography (developing solvent: hexane/ethyl acetate).
  • Step 3-1 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3, Synthesis of 4-d]pyrimidin-4-one (Example 39)
  • Step 3-1 Benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate N,N-diisopropylethylamine (220 mL) and chloroformin were added to a mixture of (4-bromo-2,6-dimethylphenyl)hydrazine hydrochloride (150 g) and tetrahydrofuran (1.0 L) at 0°C under a nitrogen atmosphere.
  • Step 3-2 Benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate Under a nitrogen atmosphere, tripotassium phosphate (380 g) was dissolved in water (710 mL), toluene (1400 mL), benzyl 2-(4-bromo-2,6-dimethylphenyl)hydrazine-1-carboxylate ( 180 g), cyclopropylboronic acid (110 g) and [1,1'-bis(di-phenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (8.3 g) were added, and the mixture was heated at 110 °C for 5 hours.
  • Step 3-3 (4-cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride Under nitrogen atmosphere, add 4 M aqueous sodium hydroxide solution (400 mL) to a mixture of benzyl 2-(4-cyclopropyl-2,6-dimethylphenyl)hydrazine-1-carboxylate (100 g) and ethanol (600 mL). The mixture was added and stirred at 80°C for 3 hours. After the reaction mixture was allowed to cool, acetic acid (55 mL) was added, and then extracted with toluene. The obtained organic layer was dried over anhydrous magnesium sulfate, and then concentrated until the liquid volume became approximately 1/4.
  • Step 3-4 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine Under ice cooling under a nitrogen atmosphere, to a mixture of 2,4,6-trichloro-5-(dimethoxymethyl)pyrimidine (63 g) synthesized in the same manner as Step 1-4 of Production Example 1 and toluene (780 mL), (4-Cyclopropyl-2,6-dimethylphenyl)hydrazine hydrochloride (54 g) and triethylamine (68 mL) were added, and the mixture was stirred at the same temperature for 40 minutes.
  • Trifluoroacetic acid (66 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was slowly added dropwise to a solution of tripotassium phosphate (210 g) in water (470 mL) under an ice bath, and the mixture was stirred at room temperature for 10 minutes. After separating the organic layer, the aqueous layer was extracted with toluene. All the organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (102 g) of the title compound. A part of the obtained crude product was purified by column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound (1.6 g).
  • Step 3-5 4-(benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine
  • Benzyl alcohol 630 mg was added to a mixture of sodium hydride (60% in oil, 200 mg) and tetrahydrofuran (24 mL) under an argon atmosphere, and the mixture was stirred at 50°C for 30 minutes. After cooling the reaction mixture in an ice bath, 4,6-dichloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (1.6 g) was added. The mixture was stirred at room temperature for 30 minutes.
  • Step 3-6 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4 -d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one mixture Under an argon atmosphere, 4-(benzyloxy)-6-chloro-2-(4-cyclopropyl-2,6-dimethylphenyl)-2H-pyrazolo[3,4-d]pyrimidine (70 mg) and N,N- To a mixture of dimethylacetamide (1.0 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II
  • the reaction mixture was purified by column chromatography (developing solvent: methanol/ethyl acetate) to give 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H).
  • -imidazol-4-yl)-2H-pyrazolo[3,4-d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl )-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one mixture was obtained.
  • Step 3-7 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one Under an argon atmosphere, 4-(benzyloxy)-2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2H-pyrazolo[3,4- d]pyrimidine and 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H-pyrazolo[3,4- Formic acid (1.0 mL) was added to a mixture of d]pyrimidin-4-one (110 mg), and the mixture was stirred at 90°C for 1 hour, and then the solvent was distilled off under reduced pressure.
  • Step 4-2 Ethyl 2-[4- ⁇ (tert-butoxycarbonyl)amino) ⁇ -3,5-dimethylphenyl]-2,2-difluoroacetate Under a nitrogen atmosphere, add ethyl 2-bromo-2,2-difluoroacetate (21 mL) to a mixture of tert-butyl (4-iodo-2,6-dimethylphenyl) carbamate (29 g) and dimethyl sulfoxide (230 mL). and copper (16 g) were added, and the mixture was stirred at 70°C for 4 hours.
  • Step 4-3 tert-butyl ⁇ 4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl ⁇ carbamate Under a nitrogen atmosphere, ethyl 2-[4- ⁇ (tert-butoxycarbonyl)amino) ⁇ -3,5-dimethylphenyl]-2,2-difluoroacetate (30 g) synthesized in the same manner as in Step 4-2 and ethanol. (240 mL) was slowly added sodium borohydride (2.7 g) over 16 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then cooled in an ice bath.
  • Step 4-4 2-[4- ⁇ (tert-butoxycarbonyl)amino ⁇ -3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate tert-Butyl ⁇ 4-(1,1-difluoro-2-hydroxyethyl)-2,6-dimethylphenyl ⁇ carbamate (16 g), pyridine (5.6 mL) and toluene (130 mL) under ice cooling under nitrogen atmosphere. ) To the mixture, trifluoromethanesulfonic anhydride (9.4 mL) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour.
  • Step 4-5 tert-butyl ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ carbamate Under nitrogen atmosphere, to a mixture of 2-[4- ⁇ (tert-butoxycarbonyl)amino ⁇ -3,5-dimethylphenyl]-2,2-difluoroethyl trifluoromethanesulfonate (21 g) and dimethyl sulfoxide (150 mL). , sodium borohydride (2.7 g) was added slowly. After stirring the reaction mixture at room temperature overnight, 1 M hydrochloric acid (60 mL) and water (140 mL) were added under a water bath.
  • Step 4-6 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride A 4 M solution of hydrogen chloride in ethyl acetate ( 140 mL) and stirred at room temperature for 2 hours. The obtained solid was collected by filtration and washed with ethyl acetate to obtain the title compound (11 g).
  • 1 H-NMR (DMSO-D 6 ) ⁇ : 7.15 (2H, s), 7.10 (3H, br s), 2.24 (6H, s), 1.90 (3H, t, J 19.1 Hz).
  • Step 4-7 ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride Concentrated hydrochloric acid (9.0 mL) and 6 M hydrochloric acid (15 mL) were added to 4-(1,1-difluoroethyl)-2,6-dimethylaniline hydrochloride (2.0 g), and then cooled to -20°C. A solution of sodium nitrite (690 mg) in water (3.0 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0° C. for 40 minutes.
  • Step 4-8 2,4-dichloro-6-[2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine into a mixture of ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazine hydrochloride (500 mg), triethylamine (0.88 mL) and methanol (10 mL) at 0 °C under an argon atmosphere.
  • Step 4-9 4,6-dichloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine Under an argon atmosphere, the crude product of 2,4-dichloro-6-[2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ hydrazinyl]-5-(dimethoxymethyl)pyrimidine (890 Trifluoroacetic acid (0.40 mL) was added to a mixture of 2.0 mg) and toluene (8.9 mL), stirred at room temperature for 1 hour, and then added dropwise to a 2M aqueous tripotassium phosphate solution.
  • Step 4-10 4-(benzyloxy)-6-chloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine Under an argon atmosphere, sodium hydride (60% in oil, 61 mg) was added to a mixture of benzyl alcohol (0.18 mL) and tetrahydrofuran (10 mL), and the mixture was stirred at 50°C for 30 minutes.
  • Step 4-11 2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -6-(1-methyl-1H-imidazol-4-yl)-2,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one Under an argon atmosphere, 4-(benzyloxy)-6-chloro-2- ⁇ 4-(1,1-difluoroethyl)-2,6-dimethylphenyl ⁇ -2H-pyrazolo[3,4-d]pyrimidine (80 mg ) and N,N-dimethylacetamide (1.0 mL), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (13 mg), lithium chloride (7.9 mg), and 1-Methyl-4-(tributylstannyl)-1H-imidazole (0.12 mL) was added, and the
  • Step 5-2 Methyl 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylate Under an argon atmosphere, triethylamine (36 mL) was added to a mixture of crude methyl 2- ⁇ 2-(4-bromo-2,6-dimethylphenyl)hydrazinylidene ⁇ -2-chloroacetate (81 g) and chloroform (580 mL). ) and fumaronitrile (20 g) were added, and the mixture was stirred at 80°C for 40 minutes. After the reaction mixture was allowed to cool to room temperature, silica gel (250 g) was added and stirred at room temperature for 30 minutes.
  • Step 5-3 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid
  • methanol 360 mL
  • 2 M aqueous sodium hydroxide 110 mL
  • 6 M hydrochloric acid was added to the reaction mixture to adjust the pH to 1, followed by extraction with ethyl acetate. After drying the obtained organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Step 5-4 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile into a mixture of 1-(4-bromo-2,6-dimethylphenyl)-4-cyano-1H-pyrazole-3-carboxylic acid (30 g) and t-butanol (450 mL) at room temperature under an argon atmosphere. After adding triethylamine (26 mL) and diphenylphosphoryl azide (30 mL), the mixture was stirred at 90°C for 3 hours.
  • Step 5-5 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide 3-Amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (11 g), dimethylsulfoxide (17 mL), and ethanol ( Sodium hydroxide (4.5 g) and 30% hydrogen peroxide solution (15 mL) were added to the mixture (66 mL), and the mixture was stirred at room temperature for 40 minutes. After cooling the reaction mixture to 0°C, saturated aqueous sodium sulfite solution was added.
  • Step 5-6 N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide HATU (180 mg) and N,N-diisopropylethylamine (160 mg) were added to a mixture of pyrimidine-4-carboxylic acid (60 mg) and N,N-dimethylformamide (1.5 mL), and the mixture was heated at room temperature for 5 minutes. Stirred. Then, 3-amino-1-(4-bromo-2,6-dimethylphenyl)-1H-pyrazole-4-carboxamide (75 mg) was added, and the mixture was stirred at 50°C for 2 hours.
  • Step 5-7 2-(4-bromo-2,6-dimethylphenyl)-6-(pyrimidin-4-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4- on Under an argon atmosphere, the crude product of N-(1-(4-bromo-2,6-dimethylphenyl)-4-carbamoyl-1H-pyrazol-3-yl)pyrimidine-4-carboxamide (100 mg), ethanol ( 1.0 mL) and water (1.0 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mL) was added, and the mixture was stirred at 110°C for 2 hours.
  • the reaction mixture was allowed to cool to room temperature, water was added, and then extracted with ethyl acetate.
  • the obtained organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the residue was purified by column chromatography (developing solvent: 50 vol% to 100 vol% ethyl acetate/hexane) to obtain the title compound (47 mg).
  • Step 6-1 (6-chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride Concentrated hydrochloric acid (3.0 mL) was added to a mixture of 6-chloro-2,3-dihydro-1H-inden-5-amine (1.0 g) and 6 M hydrochloric acid (5.0 mL), and the mixture was cooled to 0°C.
  • Step 6-2 Lithium 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4-oleate
  • a solution of 1.2 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (500 mL) was added to a mixture of 1-methyl-1H-pyrazole-3-carbonitrile (53 g) and tetrahydrofuran (11 mL) at 0 °C under an argon atmosphere. The mixture was added and stirred at room temperature for 2 hours. After cooling the reaction mixture to 5°C, dimethyl malonate (110 mL) and methanol (320 mL) were added, and the mixture was stirred at 80°C for 24 hours.
  • Step 6-3 4,6-dichloro-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-5-carbaldehyde Phosphorus oxychloride (64 mL) was added to N,N-dimethylformamide (270 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The prepared mixture was cooled to 0 °C, then lithium 6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4-oleate (90 g) and toluene (270 mL) cooled to 0 °C. ) was slowly added dropwise to the mixture.
  • Step 6-4 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo [3,4-d]pyrimidine (6-chloro-2,3-dihydro-1H-inden-5-yl)hydrazine hydrochloride (100 mg), N,N-diisopropylethylamine (0.40 mL), tetrahydrofuran (1.5 mL) and water (0.50 mL).
  • Step 6-5 2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one Under an argon atmosphere, 4-chloro-2-(6-chloro-2,3-dihydro-1H-inden-5-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2H-pyrazolo[ Trifluoroacetic acid (0.033 mL) was added to a mixture of 3,4-d]pyrimidine (55 mg), acetonitrile (0.55 mL) and water (0.28 mL), and the mixture was stirred at 60°C for 1 hour.
  • Test Example 1 Evaluation of NLRP3 inflammasome inhibitory effect The NLRP3 inflammasome inhibitory effect of the test substance was evaluated using the inhibitory effect on IL-1 ⁇ production in THP1-Null cells (product number thp-null, InvivoGen) as an index.
  • Cells were maintained in RPMI-1640 medium containing 10% (v/v) fetal bovine serum, 25 mmol/L HEPES, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, 100 ⁇ g/mL normocin, and 200 ⁇ g/mL hygromycin B. (37°C setting, 5%CO 2 /95% air).
  • Opti-MEM (trademark) medium containing Nigericin (product number N7143, Sigma-Aldrich (registered trademark)) was added (5 ⁇ L/well) to the control setting well and the test substance setting well, and cultured for 1.5 hours (set at 37°C, 5%CO 2 /95% air). The final nigericin concentration was 7.5 ⁇ mol/L.
  • Opti-MEM (trademark) medium was added to the blank setting wells (5 ⁇ L/well). The culture supernatant was stored frozen (set at -20°C) until IL-1 ⁇ was measured.
  • AlphaLISA Human IL-1 ⁇ Detection Kit
  • product number AL220C Perkin Elmer
  • the method was to measure fluorescence intensity using a microplate reader EnSpier (model number 2300-00J, Perkin Elmer) or EnSight (model number HH34000000, Perkin Elmer) according to the attached instruction manual.
  • the inhibition rate of the test substance setting well was calculated by setting the blank setting well as 100% and the control setting well as 0%.
  • the IC 50 value (50% inhibitory concentration) of the test substance was calculated by logistic regression analysis. The results for each example compound are shown in the table below.
  • formulations of the present invention include the following formulations. However, the present invention is not limited to these formulation examples.
  • Formulation example 1 (manufacture of capsules) (1) Compound of Example 1 30 mg (2) Microcrystalline cellulose 10mg (3) Lactose 19mg (4) Magnesium stearate 1mg (1), (2), (3) and (4) are mixed and filled into gelatin capsules.
  • Formulation example 2 (manufacture of tablets) (1) 10 g of the compound of Example 1 (2) Lactose 50g (3) Corn starch 15g (4) Carmellose calcium 44g (5) Magnesium stearate 1g The total amount of (1), (2), and (3) and 30 g of (4) are kneaded with water, dried in vacuum, and then sized. 14 g of (4) and 1 g of (5) are mixed with this sized powder and compressed into tablets using a tablet machine. In this way, 1000 tablets each containing 10 mg of the compound of Example 1 are obtained.
  • the compound of formula [I] or a pharmaceutically acceptable salt thereof, or the compound of formula [IA] or a pharmaceutically acceptable salt thereof has an NLRP3 inflammasome inhibitory effect, and thus is effective against multiple sclerosis and chronic kidney disease.
  • disease inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), arteriosclerosis, cryopyrin-associated periodic fever syndrome (e.g. familial cold autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous joint syndrome and neonatal period) multisystem inflammatory disease), non-alcoholic steatohepatitis, gout, gouty arthritis, rheumatoid arthritis, contact dermatitis, dry eye, ischemic heart disease (e.g.

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WO2024214046A1 (en) 2023-04-14 2024-10-17 Takeda Pharmaceutical Company Limited Pyrazolopyrimidine derivatives as inhibitors of nlrp3
WO2025140708A1 (zh) * 2023-12-31 2025-07-03 杭州百新生物医药科技有限公司 吡唑并嘧啶类化合物及其医药用途
WO2025153532A1 (en) 2024-01-16 2025-07-24 NodThera Limited Nlrp3 inhibitors and glp-1 agonists combination therapies

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