Tetrahydropyrrolopyrimidinone compounds and their pharmaceutical uses

Abstract

This invention provides compounds having RIPK1 inhibitory activity. [Solution] The present invention relates to a compound with the following structural formula or a pharmaceutically acceptable salt thereof. JPEG2026062559000385.jpg37161

Description

[Technical Field]

[0001] The present invention relates to tetrahydropyrrolopyrimidinone compounds having RIPK1 inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. [Background technology]

[0002] RIPK1 (Receptor-interacting protein kinase 1) is a serine / threonine kinase belonging to the tyrosine kinase-like (TKL) kinase family and is expressed in a wide range of cell types.

[0003] RIPK1 possesses protein-binding domains such as the death domain and the RHIM (RIP Homotypic Interaction Motif) domain, and is activated through interaction with these domains upon activation of inflammatory signals (TNFR1, FAS, TRADD, TLR3, TLR4, etc.).

[0004] Activated RIPK1 interacts with RIPK3, a RIPK family protein, via its RHIM domain, activating RIPK3 through phosphorylation. Activated RIPK3 phosphorylates MLKL (Mixed Lineage Kinase Domain-Like Protein). Phosphorylated MLKL forms multimers and migrates to the cell membrane, inducing membrane breakdown and necroptosis. Necroptosis is caspase-independent programmed cell death characterized by necrosis-like cell death, including cell swelling and membrane breakdown, and releases damage-associated molecular patterns (DAMPs). DAMPs activate immune cells, inducing inflammatory responses through the production of inflammatory cytokines and chemokines and immune cell migration.

[0005] Furthermore, RIPK1 functions as an adapter protein by activating inflammatory signals, and is involved in regulating the activation of survival and inflammatory signals and the induction of apoptosis through the activation of NFκB and MAPK1. Dysregulation of RIPK1 is thought to be involved in various diseases by inducing excessive inflammation and cell death.

[0006] Increased levels of phosphorylated RIPK1 and phosphorylated RIPK3 have been reported in brain lesions of multiple sclerosis (MS) patients. Furthermore, the detection of phosphorylated MLKL, which induces necroptosis, has been reported in brain lesions of MS patients (Non-Patent Literature 1). A positive correlation has been observed between the amount of RIPK1 protein in brain lesions of MS patients and a decrease in the amount of myelin basic proteins that constitute the myelin sheath (Non-Patent Literature 2). Additionally, in the mouse MOG-EAE model, an autoimmune demyelination model, the administration of the RIPK1 inhibitor Nec-1s has been reported to suppress motor dysfunction (Non-Patent Literature 1). Based on these results, RIPK1 inhibitors are considered potential therapeutic agents for multiple sclerosis.

[0007] It has been reported that the expression of RIPK1-related molecules (RIPK3, MLKL) increases in the inflammatory tissue of patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) (Non-Patent Literature 3). Furthermore, it has been reported that administration of the RIPK1 inhibitor Necrostatin-1 suppresses intestinal pathology in a DSS-induced colitis model (Non-Patent Literature 4). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for inflammatory bowel disease.

[0008] Increased levels of RIPK1, RIPK3, and MLKL proteins have been reported in the brains of Alzheimer's disease (AD) patients (Non-Patent Literature 5). Furthermore, the detection of phosphorylated MLKL that induces necroptosis has been reported in the hippocampus of AD patients (Non-Patent Literature 6). In APP / PS1 mice, an AD model mouse, spatial memory impairment has been suppressed by mice lacking RIPK1 kinase activity (Non-Patent Literature 7). In addition, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, suppresses spatial memory impairment in APP / PS1 mice (Non-Patent Literature 7). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for Alzheimer's disease.

[0009] Increased levels of RIPK1, RIPK3, and MLKL proteins, as well as the detection of phosphorylated proteins of each molecule, have been reported in the spinal cord lesions of patients with amyotrophic lateral sclerosis (ALS) (Non-Patent Literature 8). In addition, increased levels of RIPK1 and phosphorylated MLKL, which induces necroptosis, have been observed in the spinal cords of OPTN-deficient mice, one of the causative genes of familial ALS. Cell death observed in the spinal cords of OPTN-deficient mice is suppressed and motor dysfunction is reduced in mice lacking RIPK1 kinase activity. Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, delays disease progression in SOD1G93A mice, an ALS model mouse (Non-Patent Literature 8). From the above, it is considered that RIPK1 inhibitors may be therapeutic agents for amyotrophic lateral sclerosis.

[0010] Increased levels of RIPK1, RIPK3, and MLKL proteins have been reported in the substantia nigra of Parkinson's disease patients (Non-Patent Literature 9). In an MPTP-induced Parkinson's disease model, administration of the RIPK1 inhibitor Nec-1s has been reported to suppress neuronal cell death in the substantia nigra and striatum (Non-Patent Literature 9). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for Parkinson's disease.

[0011] Increased levels of RIPK1, RIPK3, and MLKL proteins, as well as phosphorylated MLKL that induces necroptosis, have been reported in the lesions of psoriasis patients and imiquimod-induced psoriasis model mice (Non-Patent Literature 10). Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, suppresses the induction of necroptosis and reduces psoriasis-like symptoms in imiquimod-induced psoriasis model mice (Non-Patent Literature 10). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for psoriasis.

[0012] The detection of phosphorylated RIPK1 has been reported in the synovial membrane of rheumatoid arthritis patients (Non-Patent Literature 11). In addition, increased levels of RIPK1, RIPK3, and MLKL proteins have been reported in the joint tissue of mouse collagen-induced arthritis, a model of rheumatoid arthritis (Non-Patent Literature 12). In mouse collagen-induced arthritis, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, suppresses arthritis (Non-Patent Literature 13). From the above, it is considered that RIPK1 inhibitors can be used as therapeutic agents for rheumatoid arthritis.

[0013] Increased levels of RIPK1, RIPK3, and MLKL have been reported in the brain tissue of middle cerebral artery occlusion (MCAO) mice, a model of cerebral infarction (Non-Patent Literature 14). Furthermore, it has been reported that RIPK1 kinase-deficient mice exhibit neuroprotective effects in a mouse MCAO model (Non-Patent Literature 14). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for cerebral infarction.

[0014] It has been reported that the expression of RIPK1-related molecules (RIPK3, MLKL) increases in the brain tissue of a rat model of subarachnoid hemorrhage (Non-Patent Literature 15). It has also been reported that administration of the RIPK1 inhibitor Necrostatin-1 reduces cerebral edema and exhibits neuroprotective effects in a rat model of subarachnoid hemorrhage (Non-Patent Literature 15). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for subarachnoid hemorrhage.

[0015] An increase in phosphorylated MLKL, which induces necroptosis, has been reported in retinal pigment epithelial cells of patients with age-related macular degeneration (Non-Patent Literature 16). In addition, an increase in the expression of RIPK1, RIPK3, and MLKL has been reported in retinal pigment epithelial cells of a sodium iodate-induced retinal injury model, which is a model of age-related macular degeneration (Non-Patent Literature 17). In a sodium iodate-induced retinal injury model, it has been reported that administration of Necrostatin-1, a RIPK1 inhibitor, suppresses the degeneration of retinal pigment epithelial cells (Non-Patent Literature 18). From the above, it is considered that RIPK1 inhibitors may be therapeutic agents for age-related macular degeneration.

[0016] Increased levels of RIPK1 have been reported in the retinal tissue of glaucoma patients (Non-Patent Literature 19). In a retinal ischemia-reperfusion model, a glaucoma model, administration of the RIPK1 inhibitor Necrostatin-1 has been reported to exhibit neuroprotective effects on the retina (Non-Patent Literature 20). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for glaucoma and ischemic retinal damage.

[0017] Increased expression of RIPK1 and RIPK3 has been reported in the retina of rd10 mice, a model of retinitis pigmentosa (Non-Patent Literature 21). Furthermore, it has been reported that administration of Necrostatin-1, a RIPK1 inhibitor, suppresses cone degeneration in rd10 mice (Non-Patent Literature 21). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for retinitis pigmentosa.

[0018] Increased levels of phosphorylated RIPK1 have been reported in the livers of patients with non-alcoholic steatohepatitis (metabolic disorder-associated steatohepatitis, MASH) and in the high-fat diet-induced steatohepatitis model, which is a MASH model (Non-Patent Literature 22). Furthermore, it has been reported that liver damage in the high-fat diet-induced steatohepatitis model is suppressed in mice lacking RIPK1 kinase activity (Non-Patent Literature 22). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for MASH.

[0019] Increased RIPK1 expression has been reported in the serum of patients with chronic kidney disease (Non-Patent Literature 23). Furthermore, a negative correlation has been reported between serum RIPK1 levels and estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (Non-Patent Literature 23). Additionally, in a subtotal nephrectomy model of chronic kidney disease, administration of the RIPK1 inhibitor Necrostatin-1 has been reported to suppress renal damage (Non-Patent Literature 24). Based on these findings, RIPK1 inhibitors are considered promising therapeutic agents for chronic kidney disease.

[0020] Increased levels of RIPK1 and RIPK3 have been reported in the plaques of patients with atherosclerosis (Non-Patent Literature 25). Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, suppresses the progression of lesions in ApoE-deficient mice, a model of atherosclerosis (Non-Patent Literature 26). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for atherosclerosis.

[0021] An increase in phosphorylated RIPK1 levels has been reported in the microglia of MECP2-deficient mice, a model of Rett syndrome (Non-Patent Literature 27). Furthermore, it has been reported that in MECP2-deficient mice, RIPK1 kinase activity deficiency suppresses microglial activation and reduces motor dysfunction (Non-Patent Literature 27). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for Rett syndrome.

[0022] Increased levels of RIPK1 and RIPK3 have been reported in the cerebellum of patients with Niemann-Pick disease type C (Non-Patent Literature 28). Furthermore, in NPC1-deficient mice, a model of Niemann-Pick disease type C, the progression of motor dysfunction has been suppressed in mice lacking RIPK1 kinase activity (Non-Patent Literature 29). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for Niemann-Pick disease type C.

[0023] Increased levels of phosphorylated RIPK1 have been observed in the intestinal lesions of graft-versus-host disease (GVHD) patients, and this has been reported to be positively correlated with the degree of histological damage (Non-Patent Literature 30). Furthermore, in a mouse GVHD model, it has been reported that RIPK1 kinase-deficient mice suppressed intestinal lesions and reduced mortality (Non-Patent Literature 30). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for GVHD.

[0024] In MRL / lpr mice, a model of systemic lupus erythematosus (SLE), administration of the RIPK1 inhibitor ZJU37 has been reported to suppress serum inflammatory cytokines and reduce renal damage (Non-Patent Literature 31). Furthermore, it has been reported that RIPK1 kinase-deficient mice suppress IgG and C3 deposition in the kidneys in a bm12-induced SLE model (Non-Patent Literature 31). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for SLE.

[0025] In TNF-induced systemic inflammatory response syndrome (SIRS), a sepsis model, it has been reported that mice lacking RIPK1 kinase activity suppress serum inflammatory cytokine and chemokine production, improving hypothermia and reduced survival (Non-patent Literature 32). Therefore, RIPK1 inhibitors are considered potential therapeutic agents for sepsis.

[0026] Increased levels of RIPK1, RIPK3, and MLKL have been reported in the muscle tissue of patients with polymyositis. Furthermore, the detection of phosphorylated MLKL that induces necroptosis has been reported (Non-Patent Literature 33). In a C-protein sensitization-induced myositis model, administration of the RIPK1 inhibitor Nec-1s has been reported to suppress muscle weakness (Non-Patent Literature 33). Therefore, RIPK1 inhibitors are considered potential therapeutic agents for polymyositis.

[0027] CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome is an autoinflammatory disease caused by activating mutations in the RIPK1 gene (Non-Patent Literature 34). In CRIA syndrome, the inactivation mechanism of RIPK1 by Caspase-8 does not function properly. Mice expressing RIPK1 mutations associated with CRIA syndrome exhibit enhanced inflammatory symptoms due to TNF-induced systemic inflammatory response syndrome (SIRS) (Non-Patent Literature 35). It has been reported that RIPK1 kinase activity-deficient mice suppress inflammatory symptoms in mice expressing RIPK1 mutations associated with CRIA syndrome (Non-Patent Literature 35). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for CRIA syndrome.

[0028] In myocardial tissue from a myocardial ischemia-reperfusion model, an increase in phosphorylated RIPK1, phosphorylated RIPK3, and phosphorylated MLKL, which induces necroptosis, has been reported (Non-Patent Literature 36). Furthermore, in a myocardial ischemia-reperfusion model, administration of Necrostatin-1, a RIPK1 inhibitor, has been reported to reduce the infarct area of ​​the myocardium (Non-Patent Literature 37). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for ischemic heart diseases such as myocardial infarction.

[0029] It has been reported that phosphorylated RIPK1 is detected in the lung tissue of patients infected with SARS-CoV-2 (Non-Patent Literature 38). Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, suppresses inflammation in the lungs and brain and inhibits the increase in viral load in mice infected with SARS-CoV-2 (Non-Patent Literature 38). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for COVID-19 caused by SARS-CoV-2.

[0030] An increase in phosphorylated RIPK1 levels has been reported in the pancreatic tissue of a sodium taurocholate-induced pancreatitis model, which is a model of acute pancreatitis (Non-Patent Literature 39). Furthermore, it has been reported that administration of necrostatin-1, a RIPK1 inhibitor, suppresses pancreatic tissue damage in pancreatitis models (Non-Patent Literature 39). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for acute pancreatitis.

[0031] OTULIN-associated autoinflammatory syndrome (ORAS) is an autoinflammatory disease caused by a loss-of-function mutation in the OTULIN gene. It has been reported that dermatitis symptoms can be suppressed in mice expressing ORAS-related OTULIN mutations by using mice with RIPK1 kinase activity deficiency (Non-Patent Literature 40). Therefore, RIPK1 inhibitors are considered to be potential therapeutic agents for OTULIN-associated autoinflammatory syndrome.

[0032] The detection of phosphorylated RIPK1 has been reported in the renal tissue of patients with diabetic nephropathy and in the streptozotocin / high-fat diet-induced nephropathy model, which is a model of diabetic nephropathy (Non-Patent Literature 41). Furthermore, it has been reported that administration of necrostatin-1, a RIPK1 inhibitor, suppresses renal inflammation and improves renal function in the diabetic nephropathy model (Non-Patent Literature 41). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for diabetic nephropathy.

[0033] Genetic expression analysis of blood samples from patients with major depressive disorder has identified RIPK1 as a biomarker (Non-Patent Literature 42). Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, improves neurological symptoms in an LPS-induced depression model (Non-Patent Literature 43). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for depression.

[0034] Increased levels of RIPK1 have been reported in the stomachs of gastric cancer patients (Non-Patent Literature 44). Furthermore, a positive correlation between RIPK1 levels and decreased survival has been reported (Non-Patent Literature 44). In gastric cancer cell transplantation models, RIPK1 knockdown has been reported to suppress tumor growth (Non-Patent Literature 44). Therefore, RIPK1 inhibitors are considered potential therapeutic agents for gastric cancer.

[0035] Increased RIPK1 expression has been reported in the pancreas of pancreatic cancer patients (Non-Patent Literature 45). Furthermore, in KC mice, a model of pancreatic cancer, administration of the RIPK1 inhibitor GSK'547 has been reported to reduce pancreatic tumor weight and extend survival time (Non-Patent Literature 45). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for pancreatic cancer.

[0036] It has been reported that increased expression levels of RIPK1, RIPK3, and MLKL are observed in the brain tissue of model mice into which the human mutant gene Tau p301s, one of the causative genes of frontotemporal dementia, has been introduced (Non-Patent Literature 46). Furthermore, it has been reported that administration of Nec-1s, a RIPK1 inhibitor, improves the survival rate and neurological symptoms in Tau p301s-introduced mice (Non-Patent Literature 46). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for frontotemporal dementia.

[0037] In a mouse model of renal ischemia-reperfusion injury, a model of acute kidney injury, increased expression levels of RIPK1, RIPK3, and MLKL have been reported in the renal lesions, and phosphorylated MLKL that induces necroptosis has been detected in the proximal tubules of the same model (Non-Patent Literature 47 and 48). Furthermore, in a mouse model of renal ischemia-reperfusion injury, administration of Necrostatin-1, a RIPK1 inhibitor, suppressed the increase in blood urea and creatinine levels associated with renal injury and improved the histopathological damage of the kidney (Non-Patent Literature 48). From the above, it is considered that RIPK1 inhibitors can be used as therapeutic agents for ischemic acute kidney injury.

[0038] Increased phosphorylated proteins of RIPK1, RIPK3, and MLKL have been reported in lung epithelial cells in lesions of a mouse lung ischemia-reperfusion injury model (Non-Patent Literature 49). Furthermore, in a mouse lung ischemia-reperfusion injury model, administration of the RIPK1 inhibitor Necrostatin-1 suppressed inflammatory cytokine production in the bronchoalveolar lavage fluid and inhibited lung tissue damage (Non-Patent Literature 49). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for ischemic lung diseases such as primary graft failure and pulmonary embolism after lung transplantation.

[0039] In a mouse model of hepatic ischemia-reperfusion injury, mice lacking RIPK1 kinase activity suppressed the increase in serum inflammatory cytokines ALT and AST associated with liver injury, and reduced liver tissue damage (Non-Patent Literature 50). Furthermore, it has been reported that phosphorylated RIPK1 levels are increased in hepatocytes collected from human livers after liver transplantation and reperfusion (Non-Patent Literature 50). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for ischemic liver injury associated with liver transplantation and other related conditions.

[0040] Increased levels of RIPK1, RIPK3, phosphorylated RIPK3, and phosphorylated MLKL proteins have been reported in the intestinal lesions of rodent intestinal ischemia-reperfusion injury models (Non-Patent Literature 51 and 52). Furthermore, in a mouse intestinal ischemia-reperfusion injury model, administration of the RIPK1 inhibitor Necrostatin-1 suppressed serum inflammatory cytokine levels and inhibited intestinal tissue damage (Non-Patent Literature 51). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for ischemic intestinal diseases such as mesenteric artery occlusion.

[0041] Increased phosphorylated proteins of RIPK1, RIPK3, and MLKL have been reported in the lesioned spinal cord of a rat spinal cord ischemia-reperfusion injury model (Non-Patent Literature 53). Furthermore, in a rabbit spinal cord ischemia-reperfusion injury model, administration of the RIPK1 inhibitor Necrostatin-1 suppressed motor neuron cell death and inhibited the progression of neurological symptoms (Non-Patent Literature 54). Based on these findings, RIPK1 inhibitors are considered to be potential therapeutic agents for ischemic spinal cord injuries such as paraplegia caused by spinal cord ischemia after aortic surgery.

[0042] Increased RIPK1 expression has been reported in immune cells in skin lesions of alopecia areata models (Non-Patent Literature 55). Furthermore, in a mouse model of alopecia areata, administration of the RIPK1 inhibitor Nec-1s or GSK2982772 suppressed the number of immune cells in skin lesions and inhibited the onset of alopecia areata symptoms (Non-Patent Literature 55). Based on the above, RIPK1 inhibitors are considered to be potential therapeutic agents for alopecia areata.

[0043] Increased levels of RIPK1 and RIPK3 proteins, as well as phosphorylated MLKL that induces necroptosis, have been reported in the hearts of patients with dilated cardiomyopathy (Non-Patent Literature 56). Furthermore, in TAB2-deficient mice exhibiting dilated cardiomyopathy-like symptoms, RIPK1 kinase activity deficiency suppressed cardiomyocyte cell death and improved decreased cardiac contractility and ventricular dilation (Non-Patent Literature 57). In addition, in TAB2-deficient human iPSC-derived cardiomyocytes, an in vitro model of dilated cardiomyopathy, treatment with the RIPK1 inhibitor Nec-1s improved decreased contractility (Non-Patent Literature 58). From the above, it is considered that RIPK1 inhibitors could be therapeutic agents for dilated cardiomyopathy. [Prior art documents] [Non-patent literature]

[0044] [Non-Patent Document 1] Cell Rep. 2015 Mar 24;10(11):1836-49. [Non-Patent Document 2] Cell Rep. 2021 May 11;35(6):109112. [Non-licensed document 3] Am J Gastroenterol. 2014 Feb;109(2):279-87.

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[0045] The present invention provides tetrahydropyrrolopyrimidinone compounds having RIPK1 inhibitory activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof.

[0046] The present invention includes the following embodiments.

[0047] [Section 1] A compound represented by formula [I-3] (hereinafter also referred to as "compound of formula [I-3]" or "compound [I-3]") or a pharmaceutically acceptable salt thereof.

[0048] [ka]

[0049] [In formula [I-3], R 1 teeth, (1) Hydrogen, (2) Halogen, or (3) Hydroxy and; R 2 'teeth, (1) Phenyl, which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (2) pyridyl optionally substituted by cyano or halogen, or (3) T 4 -substituted pyrazolyl (where the T 4 is (a) C 1-2 alkyl optionally substituted by 1 to 3 halogens, or (b) cyclopropyl); R 3 is (1) C 1 alkyl optionally substituted by 1 to 3 T 1-4 (where the T 1 are each independently (a) hydroxy, (b) halogen, (c) cyano, (d) methoxy optionally substituted by 1 or 2 halogens, (e) methylsulfonyl, (f) phenyl optionally substituted by halogen, (g) phenoxy optionally substituted by 1 or 2 substituents independently selected from the group consisting of cyano and halogen, (h) pyridyl optionally substituted by halogen, (i) pyridyloxy optionally substituted by 1 or 2 substituents independently selected from the group consisting of cyano and halogen, (j) pyrimidinyl oxy optionally substituted by cyano or halogen, (k) a group represented by formula [II]:

[0050]

Chemical formula

[0051] and (l) a group represented by formula [III]:

[0052]

Chemical formula

[0053] a group represented by (selected from (2) cyano, (3) methoxy, (4) cyclopropyl, (5) phenyl, (6) phenoxy, or (7) benzyloxy optionally substituted by one halogen and R 4 is (1) hydrogen, or (2) C 1-2 alkyl optionally substituted by one or two halogens or R 3 and R 4 together with the carbon atom to which they are attached form (1) a C 2 cycloalkane optionally substituted by one or two T 3-7 (where the T 2 are each independently <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by ) Forms, and R 5 teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6 teeth, (1) Hydrogen, or (2) Methyl is it, or R 5 and R 6 They combine with the carbon atoms to which they bond to form cyclopropane; R 3 and R 5 They come together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (here, the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from), (2) Equation [VI]:

[0058] [ka]

[0059] A ring represented by, or (3) Formula [VII]:

[0060] [ka]

[0061] (In the formula, W 2 It forms a ring represented by a pyrimidinyl which may be substituted with a halogen, and R 4 and R 6 Is this synonymous with the above; or R 3 , R 4 , and R 5 They come together, along with the carbon atoms to which they bond, (1) Formula [VIII]:

[0062] [ka]

[0063] A ring represented by, or (2) Formula [IX]:

[0064] [ka]

[0065] It forms a ring represented by, and R 6 This is synonymous with the above.

[0066] [Term 1'] A compound represented by formula [I] (hereinafter also referred to as "compound of formula [I]" or "compound [I]") or a pharmaceutically acceptable salt thereof.

[0067] [ka]

[0068] [In formula [I], R 1 teeth, (1) Hydrogen, (2) Halogen, or (3) Hydroxy and; R 2 teeth, (1) Phenyl, which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (2) Pyridyl which may be substituted with cyano or halogen, (3) Pyrazolyl which may be substituted with difluoromethyl and; R 3 teeth, (1) 1 to 3 T 1 C may be replaced by 1-4 alkyl (where, the T 1 Each of them operates independently. (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Methylsulfonyl, (f) Phenyl which may be substituted with a halogen, (g) A phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (h) Pyridyl which may be substituted with a halogen, (i) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (j) Pyrimidinyl oxy, which may be substituted with cyano or halogen, (k) Formula [II]:

[0069] [ka]

[0070] A group represented by, and (l) Formula [III]:

[0071] [ka]

[0072] The base represented by (Selected from), (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and R 4 teeth, (1) Hydrogen, or (2) C which may be replaced by one or two halogens 1-2 Alkyl is it, or R 3 and R 4 They come together, along with the carbon atoms to which they bond, (1) One or two T 2 C may be replaced by 3-7 Cycloalkane (here, the T 2 Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with 1 to 3 halogens (Selected from), (2) Tetrahydropyran ring, (3) Formula [IV]:

[0073] [ka]

[0074] A ring represented by, or (4) Formula [V]:

[0075] [ka]

[0076] (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by ) Forms, and R 5 teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6 teeth, (1) Hydrogen, or (2) Methyl is it, or R 5 and R 6 They combine with the carbon atoms to which they bond to form cyclopropane; R 3 and R 5 They come together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (here, the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from), (2) Equation [VI]:

[0077] [ka]

[0078] A ring represented by, or (3) Formula [VII]:

[0079] [ka]

[0080] (In the formula, W 2 It forms a ring represented by a pyrimidinyl which may be substituted with a halogen, and R 4 and R 6 Is this synonymous with the above; or R 3 , R 4 , and R 5 They come together, along with the carbon atoms to which they bond, (1) Formula [VIII]:

[0081] [ka]

[0082] A ring represented by, or (2) Formula [IX]:

[0083] [ka]

[0084] It forms a ring represented by R 6 This is synonymous with the above.

[0085] [Section 2] R 1 However, the compound described in item 1 or 1' or a pharmaceutically acceptable salt thereof is fluorine.

[0086] [Section 3] R 3 and R 5 But together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (here, the T 3Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from), (2) Equation [VI]:

[0087] [ka]

[0088] A ring represented by, or (3) Formula [VII]:

[0089] [ka]

[0090] (In the formula, W 2 It forms a ring represented by a pyrimidinyl which may be substituted with a halogen, and R 4 and R 6 However, is it synonymous with item 1? Or R 3 , R 4 , and R 5 But together, along with the carbon atoms to which they bond, (1) Formula [VIII]:

[0091] [ka]

[0092] A ring represented by, or (2) Formula [IX]:

[0093] [ka]

[0094] It forms a ring represented by, and R6 However, the compound described in any one of items 1, 1', and 2, or a pharmaceutically acceptable salt thereof, is synonymous with item 1.

[0095] [Section 4] W 2 However, equation [X]:

[0096] [ka]

[0097] A compound described in item 3 or a pharmaceutically acceptable salt thereof, which is a group represented by .

[0098] [Section 5] The following structural formula:

[0099] [ka]

[0100] A compound according to item 1 or 1', selected from the group consisting of compounds having the property, or a pharmaceutically acceptable salt thereof.

[0101] [Section 6] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 5 and item 1', and a pharmaceutically acceptable carrier.

[0102] [Section 7] A RIPK1 inhibitor comprising any one of the compounds described in items 1 to 5 and item 1', or a pharmaceutically acceptable salt thereof.

[0103] [Section 8] A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 5 and item 1', is included in the treatment of multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disease, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, and graft-versus-host disease (GV). A therapeutic or prophylactic agent for diseases selected from the group consisting of HD, systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

[0104] [Term 8'] The compounds described in any one of items 1 to 5 and item 1', or pharmaceutically acceptable salts thereof, are used for multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disorders, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, and graft pairs. A therapeutic or prophylactic agent for diseases selected from the group consisting of host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, and ischemic spinal cord injury.

[0105] [Section 9] A method for inhibiting RIPK1 in a mammal, comprising administering a pharmaceutically effective amount of any one of the compounds described in items 1 to 5 and item 1' or a pharmaceutically acceptable salt thereof to the mammal.

[0106] [Section 10] The present invention relates to administering a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of items 1 to 5 and item 1' to a mammal, thereby treating in the mammal multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disease, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, and Niemann-Pick disease. A method for treating or preventing diseases selected from the group consisting of disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

[0107] [Section 10'] The treatment involves administering a pharmaceutically effective amount of any one of the compounds described in items 1 to 5 and item 1' or a pharmaceutically acceptable salt thereof to a mammal, for the following conditions in the mammal: multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, A method for treating or preventing diseases selected from the group consisting of Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, and ischemic spinal cord injury.

[0108] [Section 11] Use of any compound described in items 1 to 5 and any one of item 1' or a pharmaceutically acceptable salt thereof for the manufacture of a RIPK1 inhibitor.

[0109] [Section 12] Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorders-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, SA Use of compounds described in any one of claims 1 to 5 and claim 1' or pharmaceutically acceptable salts thereof for the manufacture of therapeutic or prophylactic agents for diseases selected from the group consisting of COVID-19 caused by RS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

[0110] [Section 12'] Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disease, retinitis pigmentosa, metabolic disorders-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, heart Use of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 5 and claim 1' for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, and ischemic spinal cord injury.

[0111] [Section 13] A compound described in any one of items 1 to 5 and item 1', or a pharmaceutically acceptable salt thereof, for use in inhibiting RIPK1.

[0112] [Section 14] Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorders-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, Compounds described in any one of claims 1 to 5 and 1', or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of diseases selected from the group consisting of COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

[0113] [Section 14'] Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome Compounds described in any one of claims 1 to 5 and claim 1', or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of diseases selected from the group consisting of myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, and ischemic spinal cord injury. [Effects of the Invention]

[0114] Compounds of formula [I-3] or formula [I] of the present invention, or pharmaceutically acceptable salts thereof, have RIPK1 inhibitory activity and are therefore used to treat multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus ( It is useful for the treatment or prevention of diseases selected from the group consisting of SLE, sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, OTULIN-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, X-linked adrenoleukodystrophy, Huntington's disease, Pelizaeus-Merzbacher disease, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy. [Modes for carrying out the invention]

[0115] The definitions of terms used in this invention are as follows: In chemical formulas the below described:

[0116] [ka]

[0117] The wavy lines indicated by the symbol represent the bonding sites of the structure or group shown in the chemical formula.

[0118] "C 1-2 "Alkyl" refers to a linear saturated hydrocarbon group with 1 to 2 carbon atoms. 1-2 "Alkyl" includes methyl and ethyl. Preferred "C 1-2 "Alkyl" is either methyl or ethyl.1-2 "Alkyl" may be labeled with isotopic elements. For example, methyl may be -CD3. Another preferred "C 1-2 alkyl" is methyl, -CD3, or ethyl.

[0119] "C 1-4 alkyl" means a straight-chain or branched-chain 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 "C 1-4 alkyl" is methyl, ethyl, isopropyl or isobutyl. More preferred "C 1-4 alkyl" is methyl or ethyl. "C 1-4 alkyl" may be labeled with isotopic elements. For example, methyl may be -CD3. Another preferred "C 1-4 alkyl" is methyl, -CD3, ethyl, isopropyl or isobutyl. Another more preferred "C 1-4 alkyl" is methyl, -CD3, or ethyl.

[0120] "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Preferred "halogen" is fluorine, chlorine, or bromine.

[0121] "C 3-7 cycloalkane" means a saturated hydrocarbon ring having 3 to 7 carbon atoms. "C 3-7 cycloalkane" includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Preferred "C 3-7 cycloalkane" is cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0122] "C 5-6 cycloalkane" means a saturated hydrocarbon ring having 5 to 6 carbon atoms. "C 5-6 cycloalkane" includes cyclopentane and cyclohexane. Preferred "C5-6 The "cycloalkane" is cyclopentane or cyclohexane.

[0123] When α may be "substituted" by β, it means that α is unsubstituted or any replaceable hydrogen of α is replaced by β. For example, "C alkyl optionally substituted by halogen" means that the C alkyl is unsubstituted or any hydrogen in the C alkyl is replaced by halogen. 1-4 The "C alkyl" 1-4 means that the C alkyl is unsubstituted or any hydrogen in the C alkyl is replaced by halogen. 1-4

[0124] The "pharmaceutically acceptable salt" may be any salt without excessive toxicity known in the art. Specifically, salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, etc. may be mentioned. 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 Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). The pharmaceutically acceptable salts can be obtained by reacting the compound of formula [I-3] or formula [I] with an inorganic acid, an organic acid, an inorganic base, or an organic base according to a method known per se.

[0125] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid.

[0126] ​Examples of salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcinol, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, Examples include salts with maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid.

[0127] Examples of salts with inorganic bases include those with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium.

[0128] Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0129] The preferred embodiments of the "pharmaceutically acceptable salt" are as follows: Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, or hydrobromic acid. Examples of salts with organic acids include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid. Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, or zinc. Examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0130] Compounds of formula [I-3] or formula [I], or their pharmaceutically acceptable salts, may exist as solvates. A "solvate" is a compound of formula [I-3] or formula [I], or its pharmaceutically acceptable salt, in which a solvent molecule is coordinated, and this includes hydrates. Pharmaceutically acceptable solvates are preferred, and examples include hydrates, ethanol hydrates, dimethyl sulfoxide hydrates, etc., of compounds of formula [I-3] or formula [I], or their pharmaceutically acceptable salts.

[0131] Specifically, examples include hemihydrates, monohydrates, dihydrates, or monoethanolates of compounds of formula [I-3] or formula [I], or 2 / 3 ethanolates of monohydrates or dihydrochloride salts of sodium salts of compounds of formula [I-3] or formula [I]. These solvates can be obtained by known methods.

[0132] Compounds of formula [I-3] or formula [I] may exist as tautomers. In that case, compounds of formula [I-3] or formula [I] may exist as individual tautomers or as mixtures of tautomers.

[0133] Compounds of formula [I-3] or formula [I] may have a carbon double bond. In that case, compounds of formula [I-3] or formula [I] may exist as the E-isomer, the Z-isomer, or a mixture of the E-isomer and the Z-isomer.

[0134] Compounds of formula [I-3] or formula [I] may have stereoisomers that should be recognized as cis / trans isomers. In such cases, compounds of formula [I-3] or formula [I] may exist as cis isomers, trans isomers, or mixtures of cis and trans isomers.

[0135] Compounds of formula [I-3] or formula [I] may have one or more chiral carbon atoms. In such cases, compounds of formula [I-3] or formula [I] may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0136] Compounds of formula [I-3] or formula [I] may exist as atropisomers. In that case, compounds of formula [I-3] or formula [I] may exist as individual atropisomers or mixtures of atropisomers.

[0137] Compounds of formula [I-3] or formula [I] may simultaneously contain multiple structural features that give rise to the above-mentioned isomers. Furthermore, compounds of formula [I-3] or formula [I] may contain the above-mentioned isomers in any proportion.

[0138] Formulas, chemical structures, or compound names expressed herein without specifying stereochemistry include all possible isomers unless otherwise noted.

[0139] Diastereomer mixtures can be separated into their individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, each diastereomer can be synthesized using stereochemically monolithic starting materials or through stereoselective reactions.

[0140] The separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in the art. For example, a mixture of enantiomers can be reacted with a substantially pure enantiomer known as a chiral auxiliary to form a diastereomer mixture, and a single diastereomer with an increased isomer ratio or substantially pure can be separated by standard methods such as fractional crystallization or chromatography. The separated diastereomer can then be converted to the desired enantiomer by removing the added chiral auxiliary through cleavage. Alternatively, the mixture of enantiomers can be directly separated by chromatography using a chiral stationary phase, a method well known in the art. Or, one of the enantiomers can be obtained by using substantially pure optically active starting materials, or by stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary or an asymmetric catalyst.

[0141] The absolute configuration can be determined by X-ray crystallography of the crystalline product or intermediate. If necessary, a crystalline product or intermediate derived with a reagent having a known chiral center configuration may be used.

[0142] Compounds of formula [I-3] or formula [I] contain isotopic elements ( 2 H(D), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 18 O, 18 F, 35 S, 123They may be labeled with an isotope (e.g., I). For example, if a compound of formula [I-3] or formula [I] has a methyl group, the methyl group may be replaced with a -CD3 group, and compounds obtained in this manner are also included in the present invention. Compounds of formula [I-3] or formula [I] labeled with isotopes may be useful in pharmaceuticals, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostic agents (e.g., positron emission tomography (PET), single-photon emission computed tomography (SPECT)). Compounds of formula [I-3] or formula [I] labeled with isotopes can be prepared using an isotope-labeled compound instead of a non-isotope-labeled compound according to known methods or the methods described herein.

[0143] The compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, are preferably substantially purified compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof. More preferably, the compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, are purified to a purity of 80% or higher.

[0144] The pharmaceutical composition of the present invention may be prepared by appropriately mixing a compound of formula [I-3] or formula [I], or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier, etc., in appropriate amounts, according to methods known in the art of pharmaceutical formulations. The content of the compound of formula [I-3] or formula [I], or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition varies depending on the dosage form, dose, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0145] Pharmaceutical compositions containing a compound of formula [I-3] or formula [I], or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "the pharmaceutical composition of the present invention" in this specification) can take the following dosage forms: oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions; or parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0146] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants, etc. in solid formulations; solvents, solubilizers, suspending agents, isotonic agents, buffers, analgesics, etc. in liquid formulations; and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. in semi-solid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0147] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of "disintegrants" include carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, and crystalline cellulose. Examples of "binding agents" include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of "fluidizing agents" include light anhydrous silicic acid and magnesium stearate. Examples of "lubricants" include magnesium stearate, calcium stearate, and talc. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. Examples of "suspending agents" include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate. Examples of "isotonic agents" include glucose, D-sorbitol, sodium chloride, and D-mannitol. Examples of "buffering agents" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate. Examples of "pain-relieving agents" include benzyl alcohol. Examples of "bases" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, refined lanolin, absorbent ointment, hydrated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogol (macrogol 200 to 600, etc.), and combinations of two or more of these. Examples of "preservatives" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid. Examples of "antioxidants" include sodium sulfite and ascorbic acid. Examples of "coloring agents" include food colorings (such as Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.) and beta-carotene. Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0148] The pharmaceutical compositions of the present invention can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to humans and non-human mammals (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage of the compound of formula [I-3] or formula [I], or its pharmaceutically acceptable salt (hereinafter also referred to as the "pharmaceutical effective dose" in this specification) varies depending on the target of administration, disease, symptoms, dosage form, route of administration, etc. However, for example, the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day as the active ingredient, the compound of formula [I-3] or formula [I]. These amounts can be administered in one to several divided doses.

[0149] Compounds of formula [I-3] or formula [I], or their pharmaceutically acceptable salts, have RIPK1 inhibitory activity, and are therefore expected to improve various diseases or conditions by regulating RIPK1 activity, such as multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorders-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, and graft-versus-host disease (GVH). D) It is useful for the treatment and / or prevention of diseases selected from the group consisting of systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, OTULIN-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, X-linked adrenoleukodystrophy, Huntington's disease, Pelizaeus-Merzbacher disease, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy. Furthermore, compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, are useful for neuroprotection in brain and retinal tissue. In addition, compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, are useful as therapeutic and / or prophylactic agents for ischemia-reperfusion injury. Compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, are useful for the treatment and / or prevention of tissue damage associated with post-ischemia reperfusion in the brain, retina, heart, kidneys, lungs, liver, intestines, spinal cord, and / or other tissues.

[0150] The RIPK1 inhibitor or pharmaceutical composition of the present invention can be used in combination with a pharmaceutically effective amount of one or more agents selected from S1P agonists, anti-CD20 antibodies, Bruton's tyrosine kinase (BTK) inhibitors, and other therapeutic agents for multiple sclerosis. In some embodiments, compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof, can be used in combination with a pharmaceutically effective amount of one or more agents selected from the group consisting of ocrelizumab, natalizumab, siponimod, ofatumumab, fingolimod, dimethyl fumarate, alemtuzumab, natalizumab, teriflunomide, cladribine, trebrutinib, fenebrutinib, and remibrutinib.

[0151] "Inhibiting RIPK1" means inhibiting the function of RIPK1, thereby eliminating or reducing its activity. For example, it means inhibiting the function of RIPK1 based on the conditions of Test Example 1 described later. "Inhibiting RIPK1" preferably means "inhibiting human RIPK1." Inhibition of function or elimination or reduction of activity is preferably performed in a clinical indication in humans.

[0152] "RIPK1 inhibitor" refers to a drug containing a compound that exhibits an inhibitory effect on RIPK1, and preferably refers to a "human RIPK1 inhibitor."

[0153] In this specification, “treatment” includes improvement of symptoms, prevention of worsening, maintenance of remission, prevention of relapse, and prevention of recurrence.

[0154] In this specification, "prevention" means suppressing the onset of symptoms.

[0155] Preferred specific embodiments of the active ingredient in the RIPK1 inhibitor or pharmaceutical composition of the present invention include compounds of formula [I-3] or formula [I], or pharmaceutically acceptable salts thereof.

[0156] Specific embodiments of the substituents of the compound of formula [I-3] of the present invention are illustrated below, but each substituent of the compound of formula [I-3] is not limited to its specific embodiment, and the compound of formula [I-3] also includes embodiments that combine any two or more of the specific embodiments of each substituent.

[0157] First, specific examples of each substituent in the compound of formula [I-3] are given below.

[0158] R 1 The element is preferably a halogen, and more preferably fluorine.

[0159] R 2 ' is preferably the following formula:

[0160] [ka]

[0161] It is a group selected from the group consisting of groups represented by . R 2 'Moreover, (1) Formula [XI]:

[0162] [ka]

[0163] A base represented by, or (2) Equation [XII]:

[0164] [ka]

[0165] It is a base represented by .

[0166] R 3 and R 5 Preferably, together with the carbon atoms to which they are bonded, one or two T 3Cyclopentane (where T may be substituted by) 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl Forms (selected from).

[0167] R 4 Preferably, it is methyl.

[0168] R 6 Preferably, it is methyl.

[0169] Next, preferred embodiments of the compound of formula [I-3] are illustrated below. One preferred embodiment of the compound of formula [I-3] is formula [I]:

[0170] [ka]

[0171] [In formula [I], R 1 teeth, (1) Hydrogen, (2) Halogen, or (3) Hydroxy and; R 2 teeth, (1) Phenyl, which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (2) Pyridyl which may be substituted with cyano or halogen, (3) Pyrazolyl which may be substituted with difluoromethyl and; R 3 teeth, (1) 1 to 3 T 1 C may be replaced by 1-4 alkyl (where, the T 1 Each of them operates independently. (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Methylsulfonyl, (f) Phenyl which may be substituted with a halogen, (g) A phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (h) Pyridyl which may be substituted with a halogen, (i) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (j) Pyrimidinyl oxy, which may be substituted with cyano or halogen, (k) Formula [II]:

[0172] [ka]

[0173] A group represented by, and (l) Formula [III]:

[0174] [ka]

[0175] The base represented by (Selected from), (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and R 4 teeth, (1) Hydrogen, or (2) C which may be replaced by one or two halogens 1-2 Alkyl is it, or R 3 and R 4 They come together, along with the carbon atoms to which they bond, (1) One or two T 2 C may be replaced by 3-7 Cycloalkane (here, the T 2 Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with 1 to 3 halogens (Selected from), (2) Tetrahydropyran ring, (3) Formula [IV]:

[0176] [ka]

[0177] A ring represented by, or (4) Formula [V]:

[0178] [ka]

[0179] (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by ) Forms, and R 5 teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6 teeth, (1) Hydrogen, or (2) Methyl is it, or R 5 and R 6 They combine with the carbon atoms to which they bond to form cyclopropane; R 3 and R 5 They come together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (here, the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from), (2) Equation [VI]:

[0180] [ka]

[0181] A ring represented by, or (3) Formula [VII]:

[0182] [ka]

[0183] (In the formula, W 2 It forms a ring represented by a pyrimidinyl which may be substituted with a halogen, and R 4 and R 6 Is this synonymous with the above; or R 3 , R 4 , and R 5 They come together, along with the carbon atoms to which they bond, (1) Formula [VIII]:

[0184] [ka]

[0185] A ring represented by, or (2) Formula [IX]:

[0186] [ka]

[0187] It forms a ring represented by, and R 6 This is synonymous with the above. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0188] Another preferred embodiment of the compound of formula [I-3] is formula [Ia]:

[0189] [ka]

[0190] [In formula [Ia], R 1 and R 2 This is synonymous with the definition in equation [I]; R 3a teeth, (1) 1 to 3 T 1a C may be replaced by 1-4 alkyl (where, the T 1a Each of them operates independently. (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Methylsulfonyl, (f) Phenyl which may be substituted with a halogen, (g) A phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (h) Pyridyl which may be substituted with a halogen, (i) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (j) Pyrimidinyl oxy, which may be substituted with cyano or halogen, (k) Formula [II]:

[0191] [ka]

[0192] A group represented by, and (l) Formula [III]:

[0193] [ka]

[0194] The base represented by (Selected from), (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and; R 4a teeth, (1) Hydrogen, or (2) C which may be replaced by one or two halogens 1-2 Alkyl and; R 5a teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R6a It is either hydrogen or methyl. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0195] Another preferred embodiment of the compound of formula [I-3] is formula [Ib]:

[0196] [ka]

[0197] [In formula [Ib], R 1 and R 2 This is synonymous with the definition in equation [I]; R 3b teeth, (1) 1 to 3 T 1b C may be replaced by 1-4 alkyl (where, the T 1b Each of them operates independently. (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Methylsulfonyl, (f) Phenyl which may be substituted with a halogen, (g) A phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (h) Pyridyl which may be substituted with a halogen, (i) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (j) Pyrimidinyl oxy, which may be substituted with cyano or halogen, (k) Formula [II]:

[0198] [ka]

[0199] A group represented by, and (l) Formula [III]:

[0200] [ka]

[0201] The base represented by (Selected from), (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and R 4b teeth, (1) Hydrogen, or (2) C which may be replaced by one or two halogens 1-2 Alkyl That is the case. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0202] Another preferred embodiment of the compound of formula [I-3] is formula [Ic]:

[0203] [ka]

[0204] [In formula [Ic], R 1 and R 2 This is synonymous with the definition in equation [I]; R 3c and R 4c They come together, along with the carbon atoms to which they bond, (1) One or two T 2c C may be replaced by 3-7 Cycloalkane (here, the T 2c Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with 1 to 3 halogens (Selected from), (2) Tetrahydropyran ring, (3) Formula [IV]:

[0205] [ka]

[0206] A ring represented by, or (4) Formula [V]:

[0207] [ka]

[0208] (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by ) form; R 5c teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6c It is either hydrogen or methyl. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0209] Another preferred embodiment of the compound of formula [I-3] is formula [Id]:

[0210] [ka]

[0211] [In formula [Id], R 1 and R 2 This is synonymous with the definition in equation [I]; R 3d and R 4d They come together, along with the carbon atoms to which they bond, (1) One or two T 2d C may be replaced by 3-7 Cycloalkane (here, the T 2d Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with 1 to 3 halogens (Selected from), (2) Tetrahydropyran ring, (3) Formula [IV]:

[0212] [ka]

[0213] A ring represented by, or (4) Formula [V]:

[0214] [ka]

[0215] (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by ) [to form.] It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0216] Another preferred embodiment of the compound of formula [I-3] is formula [Ie]:

[0217] [ka]

[0218] [In formula [Ie], R 1 and R 2 This is synonymous with the definition in equation [I]; J 1 It is a single bond, and J 2 is 1 or 2 T 3 -CH2- (where the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from) J 1 is -CH2- substituted with one or two halogens, and J 2 is -CH2- or, J 1 is -CH2- and J 2 teeth, (1) -CH2- which may be substituted with one or two halogens, (2) -O-, or (3) Equation [XIII]:

[0219] [ka]

[0220] It is a base represented by; and R 4e teeth, (1) Hydrogen, or (2) C which may be replaced by one or two halogens 1-2 Alkyl is it, or, J 1 and J 2 The ring containing R 4e Together with, (1) Equation [VIIIe]:

[0221] [ka]

[0222] A ring represented by, or (2) Formula [IXe]:

[0223] [ka]

[0224] It is a ring represented by; and R 6e [is hydrogen or methyl] It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0225] Another preferred embodiment of the compound of formula [I-3] is formula [IF]:

[0226] [ka]

[0227] [In the expression [If], R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 This is equivalent to the definition in equation [I]. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0228] Another preferred embodiment of the compound of formula [I-3] is formula [Ig]:

[0229] [ka]

[0230] [In the formula [Ig], R 1g teeth, (1) Hydrogen, (2) Halogen, or (3) Hydroxy and; R 2g teeth, (1) Phenyl, which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (2) Pyridyl which may be substituted with cyano or halogen, (3) Pyrazolyl which may be substituted with difluoromethyl and; R 3g teeth, (1) 1 to 3 T 1g C may be replaced by 1-4 alkyl (where, the T 1g Each of them operates independently. (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Phenyl which may be substituted with a halogen, (f) A phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (g) Pyridyl which may be substituted with a halogen, (h) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (i) pyrimidinyl oxy which may be substituted with cyano or halogen, and (j) Formula [III]:

[0231] [ka]

[0232] The base represented by (Selected from), (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and R 4g This is a methyl which may be substituted with one or two halogens. is it, or R 3g and R 4g They come together, along with the carbon atoms to which they bond, (1) One or two T 2g C may be replaced by 3-7 Cycloalkane (here, the T 2g Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with 1 to 3 halogens (Selected from), (2) Tetrahydropyran ring, (3) Formula [IV]:

[0233] [ka]

[0234] A ring represented by, or (4) Formula [V]:

[0235] [ka]

[0236] (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano It forms a ring represented by ) and R 5g teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6g teeth, (1) Hydrogen, or (2) Methyl is it, or R 5g and R 6g They combine with the carbon atoms to which they bond to form cyclopropane; R 3g and R 5g They come together, along with the carbon atoms to which they bond, (1) One or two T 3g C may be replaced by 5-6 Cycloalkane (here, the T 3g Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxymethyl (Selected from), (2) Formula [VIg]:

[0237] [ka]

[0238] A ring represented by, or (3) Equation [VIIg]:

[0239] [ka]

[0240] (In the formula, W2 It forms a ring represented by a pyrimidinyl which may be substituted with a halogen, and R 4g and R 6g Is this synonymous with the above; or R 3g , R 4g , and R 5g They come together, along with the carbon atoms to which they bond, (1) Equation [VIIIg]:

[0241] [ka]

[0242] A ring represented by, or (2) Formula [IXg]:

[0243] [ka]

[0244] It forms a ring represented by, and R 6g This is synonymous with the above. It is a compound represented by or a pharmaceutically acceptable salt thereof.

[0245] Preferred specific embodiments of the compound of formula [I-3] (compound [I-3]) or the compound of formula [I] (compound [I]) include the compounds of Examples 1 to 303 listed in the table below.

[0246] A more preferred specific embodiment of the compound of formula [I-3] (compound [I-3]) or the compound of formula [I] (compound [I]) is shown in the following structural formula:

[0247] [ka]

[0248] Examples include compounds selected from the group consisting of compounds having the property, or pharmaceutically acceptable salts thereof.

[0249] [General method for producing compound [I-3] or compound [I], or a pharmaceutically acceptable salt thereof] Examples of general methods for producing compound [I-3] or compound [I], or their pharmaceutically acceptable salts, are given below. However, the methods for producing compound [I-3] or compound [I], or their pharmaceutically acceptable salts, are not limited to these methods. Furthermore, unless otherwise specified, the salts of each compound in the general methods may be appropriately selected from the "pharmaceutically acceptable salts" listed above.

[0250] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, and column chromatography, as needed. However, in some cases, the process can proceed to the next step without isolation and / or purification.

[0251] In this specification, room temperature refers to the temperature in an uncontrolled state, and one embodiment is a range of 1°C to 40°C.

[0252] The abbreviations used are as follows: DBU: 1,8-Diazabicyclo[5.4.0]-7-Undecene DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide KHMDS: Potassium bis(trimethylsilyl)amide LDA: Lithium diisopropylamide LiHMDS: Lithium bis(trimethylsilyl)amide NaHMDS: Sodium bis(trimethylsilyl)amide THF: Tetrahydrofuran WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0253] [Manufacturing Method A1]: Method for producing compound [I-1] or its salt R in compound [I] 1 Compound [I-1] or a salt thereof, in which is hydrogen or a halogen, can be produced, for example, by the production method A1 shown below.

[0254] [ka]

[0255] [In the formula, R 2 , R 3 , R 4 , R 5 , and R 6 This is equivalent to the definition in formula [I] above, and R 1a is hydrogen or halogen, L 1 C may be substituted with phenyl. 1-4 It is an alkyl group, and X is a halogen.

[0256] (Process A1-1) Compound [A1-2] or its salt can be produced by removing the carboxyl protecting group from compound [A1-1] or its salt.

[0257] Removal of the protecting group is L 1 It should be carried out under conditions suitable for the type. For example, L 1 However, if it is ethyl, it can be produced by hydrolyzing the ethoxycarbonyl group of compound [A1-1] or its salt in a solvent in the presence of water and a base.

[0258] Examples of solvents include alcohol-based solvents such as methanol; ether-based solvents such as THF; water; and mixed solvents thereof. Preferred solvents are a mixed solvent of methanol, THF, and water, or THF.

[0259] Examples of suitable bases include sodium hydroxide, potassium trimethylsilanolate, and potassium hydroxide. Preferred bases are sodium hydroxide or potassium trimethylsilanolate.

[0260] The reaction temperature is, for example, room temperature to 100°C, preferably 50°C. Furthermore, the above reaction may be carried out under microwave irradiation conditions if necessary.

[0261] Compound [A1-1] or its salt may be produced from a commercially available product by known methods, for example, by the production methods S1 or S2 described later, or by the methods described in intermediate production examples 3, 8, 10, 17, or 19. Alternatively, compound [A1-2] or its salt may be produced, for example, by the methods described in production examples 4, 9, 11, or 12 described later, or by the method described in intermediate production example 16.

[0262] (Process A1-2) Compound [A1-3] or its salt can be produced by reacting compound [A1-2] or its salt with a halogenating agent in a solvent.

[0263] Examples of solvents include halogenated solvents such as dichloromethane; ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. Dichloromethane is a preferred solvent.

[0264] Examples of halogenating agents include oxalyl chloride, thionyl chloride, and phosphorus(V) oxychloride. The preferred halogenating agent is oxalyl chloride. Additionally, if necessary, DMF may be added as a catalyst to carry out the above reaction.

[0265] The reaction temperature is, for example, 0°C to 50°C, and preferably room temperature.

[0266] (Process A1-3) Compound [A1-5] or its salt can be produced by reacting compound [A1-3] or its salt with compound [A1-4] or its salt in a solvent in the presence of a base.

[0267] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as hexane; and mixed solvents thereof. The preferred solvent is THF.

[0268] Examples of suitable bases include LiHMDS and LDA. LiHMDS is the preferred base.

[0269] The reaction temperature is, for example, from -100°C to room temperature, preferably from -78°C to room temperature.

[0270] Compound [A1-4] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in production method S3 below.

[0271] (Process A1-4) Compound [I-1] or a salt thereof can be produced by carrying out an intramolecular Azawittig reaction of compound [A1-5] or a salt thereof in a solvent in the presence of a triarylphosphine or a trialkylphosphine.

[0272] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. The preferred solvent is THF.

[0273] Examples of triarylphosphines include triphenylphosphine. A preferred triarylphosphine is triphenylphosphine.

[0274] Examples of trialkylphosphines include trimethylphosphine. A preferred trialkylphosphine is trimethylphosphine.

[0275] The reaction temperature is, for example, 0°C to 100°C, preferably room temperature to 50°C.

[0276] [Manufacturing Method S1]: Method for producing compound [A1-1-1] or its salt

[0277] R in compound [A1-1] or its salt 6 Compound [A1-1-1] or a salt thereof, in which hydrogen is present, can be produced, for example, by the following production method S1.

[0278] [ka]

[0279] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above, L 2 [These are halogens or hydroxyls.]

[0280] (Process S1-1) Compound [A1-1-1] or its salt is L of Compound [S1-1] or its salt 2 It can be produced by azidation in a solvent. Azidation is L 2 It should be carried out under conditions suitable for the type. For example, L 2 However, if it is hydroxyl, compound [A1-1-1] or its salt can be produced by substituting the hydroxyl group of compound [S1-1] or its salt with an azidating agent in a solvent in the presence of an activator and a catalyst.

[0281] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. The preferred solvent is THF.

[0282] Examples of activator-catalyst combinations include methanesulfonyl chloride and DMAP, as well as diisopropyl azodicarboxylate and triphenylphosphine. A preferred activator is the combination of diisopropyl azodicarboxylate and triphenylphosphine.

[0283] Diphenyl phosphate azide is an example of an azidating agent.

[0284] The reaction temperature is, for example, 0°C to 50°C, preferably 0°C to 30°C.

[0285] Also, L 2 If is a halogen, compound [A1-1-1] or its salt can be produced under the same conditions as in step (3) of intermediate production example 3.

[0286] Compound [S1-1] or its salt may be a commercially available product or may be produced from a commercially available product by known methods, for example, by the production methods K1, K2, K3, or K4 described later, or by the methods described in intermediate production examples 5, 6, 9, 12, or 14.

[0287] [Manufacturing Method K1]: Method for producing compound [S1-1] or its salt Compound [S1-1] or its salt can be produced, for example, by the following production method K1.

[0288] [ka]

[0289] [In the formula, R 3 , R 4 , R 5 , L 1 , and L 2 This is synonymous with the above.

[0290] (Process K1-1) Compound [K1-2] or its salt is converted to a carboxylic acid halide in the same manner as in step A1-2, and then in a solvent, in the presence of a base, L 1 It can be produced by reacting it with OH to convert it into an ester.

[0291] Examples of solvents include halogenated solvents such as chloroform; hydrocarbon solvents such as toluene; and mixed solvents thereof. The preferred solvent is chloroform. In addition, L may be used as needed. 1 OH can be used as a solvent. In that case, thionyl chloride and L 1 By using a mixed solvent of OH groups, conversion to carboxylic acid halides and conversion to esters can be performed in a single-pot reaction.

[0292] Examples of suitable bases include triethylamine and diisopropylethylamine. The preferred base is triethylamine.

[0293] The reaction temperature is, for example, between 0°C and 85°C.

[0294] Compound [K1-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0295] (Process K1-2) Compound [S1-1] or a salt thereof can be produced by reacting compound [K1-2] or a salt thereof with an alkylating agent in a solvent in the presence of a base.

[0296] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as hexane; and mixed solvents thereof. The preferred solvent is THF.

[0297] As an alkylating agent, R 5 and L 2 You should select the appropriate one for the type. Examples include dibromomethane and 1H-benzotriazole-1-methanol.

[0298] Examples of bases include LDA or LiHMDS. The preferred base is LDA.

[0299] The reaction temperature is, for example, from -100°C to room temperature, preferably from -78°C to room temperature.

[0300] [Manufacturing Method K2]: Method for producing compound [S1-1] or its salt Compound [S1-1] or its salt can be produced, for example, by the production method K2 shown below.

[0301] [ka]

[0302] [In the formula, R 3 , R 4 , R 5 , L 1 , and L 2 This is synonymous with the above.

[0303] (Process K2-1) Compound [S1-1] or its salt is compound [K2-1] or its salt, and L 1 It can be produced by reacting OH or its salts in a solvent in the presence of a base.

[0304] Examples of solvents include halogenated solvents such as chloroform; hydrocarbon solvents such as toluene; and mixed solvents thereof. Chloroform is preferred.

[0305] Examples of suitable bases include triethylamine and diisopropylethylamine. The preferred base is triethylamine.

[0306] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0307] Compound [K2-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0308] [Manufacturing Method K3]: Method for producing compound [S1-1-1] or its salt R in compound [S1-1] or its salt 5 is hydrogen, and L 2 Compound [S1-1-1] or a salt thereof, in which is hydroxyl, can be produced, for example, by the production method K3 shown below.

[0309] [ka]

[0310] [In the formula, R 3 , R 4 , and L 1 This is synonymous with the above.

[0311] (Process K3-1) Compound [S1-1-1] or its salt can be produced by selectively reducing one of the esters of compound [K3-1] or its salt to an alcohol in a solvent using a reducing agent.

[0312] Examples of solvents include ether-based solvents such as THF; alcohol-based solvents such as ethanol; and mixed solvents thereof. THF is preferred.

[0313] Examples of reducing agents include lithium tri-tert-butoxyaluminum hydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, and lithium borohydride. A preferred reducing agent is lithium tri-tert-butoxyaluminum hydride.

[0314] The reaction temperature is, for example, between 0°C and room temperature.

[0315] Compound [K3-1] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in Intermediate Production Example 7 below.

[0316] [Manufacturing Method K4]: Method for producing compound [S1-1-2] or its salt L in compound [S1-1] or its salt 2 Compound [S1-1-2] or a salt thereof, in which is hydroxyl, can be produced, for example, by the production method K4 shown below.

[0317] [ka]

[0318] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above.

[0319] (Process K4-1) Compound [S1-1-2] or its salt can be produced by selectively reducing the formyl group or carbonyl group of compound [K4-1] or its salt in a solvent using a reducing agent.

[0320] Examples of solvents include ether-based solvents such as THF; alcohol-based solvents such as ethanol; and mixed solvents thereof. THF is preferred.

[0321] Examples of reducing agents include sodium borohydride and lithium borohydride. The preferred reducing agent is sodium borohydride.

[0322] The reaction temperature is, for example, between 0°C and room temperature.

[0323] Compound [K4-1] or its salt can be produced, for example, by the production methods M1, M2, M3, or M4 described later, or by the method described in intermediate production example 4.

[0324] [Manufacturing Method M1]: Method for producing compound [K4-1] or its salt R in compound [K4-1] or its salt 3 R 3’ And R 4 R 4’ Compound [K4-1'] or a salt thereof can be produced, for example, by the following production method M1.

[0325] [ka]

[0326] [In the formula, R 3’ This is 1 to 3 T 1 C may be replaced by 1-4 alkyl (where, the T 1 (is the same as the definition in formula [I] above) or cyclopropyl, R 4’ C may be substituted with one or two halogens. 1-2 It is alkyl, and R 5 and L 1 This is synonymous with the above.

[0327] (Process M1-1) Compound [K4-1'] or its salt can be produced by reacting compound [K4-1a'] or its salt with an alkylating agent in a solvent in the presence of a base.

[0328] Examples of solvents include amide solvents such as DMF; ether solvents such as THF; ketone solvents such as acetone; and mixtures thereof. DMF is a preferred solvent.

[0329] As an alkylating agent, R 3 or R 4 You should choose the appropriate one for the type of substance. Examples include iodomethane, iodoethane, and dimethyl sulfate.

[0330] Examples of bases include sodium hydride and potassium carbonate. Sodium hydride is a preferred base.

[0331] The reaction temperature is, for example, 0°C to 100°C, preferably room temperature to 90°C.

[0332] Compound [K4-1a'] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0333] [Manufacturing Method M2]: Method for producing compound [K4-1] or its salt Compound [K4-1] or its salt can be produced, for example, by the production method M2 shown below.

[0334] [ka]

[0335] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above.

[0336] (Process M2-1) Compound [K4-1] or its salt can be produced by reacting compound [K1-2] or its salt with an acylating agent in a solvent in the presence of a base.

[0337] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. The preferred solvent is THF.

[0338] As an acylating agent, R 5 You should select the one that is suitable for the type. For example, acetic anhydride and 2,2-difluoroacetic anhydride are examples.

[0339] Examples of bases include LDA and LiHMDS. The preferred base is LDA.

[0340] The reaction temperature ranges from, for example, -78°C to room temperature.

[0341] [Manufacturing Method M3]: Method for producing compound [K4-1] or its salt Compound [K4-1] or its salt can be produced, for example, by the production method M3 shown below.

[0342] [ka]

[0343] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above.

[0344] (Process M3-1) Compound [K4-1] or its salt can be produced by reacting compound [M3-1] or its salt with a carbonate ester in a solvent in the presence of a base.

[0345] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. The preferred solvent is THF.

[0346] As a carbonate ester, L 1 You should select the one that is appropriate for the type. For example, dimethyl dicarbonate, diethyl dicarbonate, and diisopropyl dicarbonate are examples.

[0347] Examples of bases include sodium hydride and NaHMDS. Sodium hydride is a preferred base.

[0348] The reaction temperature is, for example, between 0°C and 70°C.

[0349] Compound [M3-1] or its salt may be commercially available or may be prepared from a commercially available product by a known method.

[0350] [Manufacturing Method M4]: Method for producing compound [K4-1] or its salt Compound [K4-1] or its salt can be produced, for example, by the following production method M4.

[0351] [ka]

[0352] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above.

[0353] (Process M4-1) Compound [K4-1] or its salt can be produced by oxidizing the hydroxyl group of compound [S1-1-2] or its salt in a solvent using an oxidizing agent.

[0354] Examples of solvents include halogenated solvents such as dichloromethane; sulfoxide solvents such as DMSO; and mixed solvents thereof. Dichloromethane is a preferred solvent.

[0355] Examples of oxidizing agents include des-martin periodinane, 2-iodoxybenzoic acid, and pyridinium chlorochromate. The preferred oxidizing agent is des-martin periodinane.

[0356] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0357] [Manufacturing Method S2]: Method for producing compound [A1-1] or its salt Compound [A1-1] or its salt can be produced, for example, by the following production method S2.

[0358] [ka]

[0359] [In the formula, R 3 , R 4 , R 5 , R 6 , and L 1 This is synonymous with the above.

[0360] (Process S2-1) Compound [A1-1] or its salt can be prepared by reacting the amino group of compound [S2-1] or its salt with a diazotransfer reagent in a solvent in the presence of a copper catalyst and a base (Ethan, DG; Robert, VS Org. Lett., 2007, 9, 3797-3800).

[0361] Examples of solvents include alcohol-based solvents such as methanol; amide-based solvents such as DMF; ether-based solvents such as methyl-tert-butyl ether; sulfoxide-based solvents such as DMSO; water; and mixtures thereof. A preferred solvent is methanol.

[0362] Examples of diazotransfer reagents include imidazole-1-sulfonyl azide hydrochloride and sulfuryl azide fluoride. The preferred diazotransfer reagent is imidazole-1-sulfonyl azide hydrochloride.

[0363] Examples of copper catalysts include copper sulfate pentahydrate and anhydrous copper sulfate. The preferred copper catalyst is copper sulfate pentahydrate.

[0364] Examples of bases include potassium carbonate and potassium bicarbonate. The preferred base is potassium carbonate.

[0365] The reaction temperature is, for example, -10°C to 50°C, preferably room temperature.

[0366] Compound [S2-1] or its salt may be a commercially available product or may be produced from a commercially available product by known methods, for example, by the methods described in production methods K5, K6, K7, or K8 below.

[0367] [Manufacturing Method K5]: Method for producing compound [S2-1-1] or its salt R in compound [S2-1] or its salt 6 Compound [S2-1-1] or a salt thereof, in which the element is hydrogen, can be produced, for example, by the production method K5 shown below.

[0368] [ka]

[0369] [In the formula, R 3 , R 4 , R 5 , and L 1 This is synonymous with the above.

[0370] (Process K5-1) Compound [S2-1-1] or its salt can be produced by catalytic hydrogenation of the azide group of compound [A1-1-1] or its salt in a solvent in the presence of a catalytic amount of palladium-carbon.

[0371] Examples of solvents include ester solvents such as ethyl acetate; alcohol solvents such as methanol; ether solvents such as THF; and mixtures thereof. The preferred solvent is ethyl acetate.

[0372] The reaction temperature is, for example, 0°C to 60°C, preferably room temperature.

[0373] [Manufacturing Method K6]: Method for producing compound [S2-1-2] or its salt R in compound [S2-1] or its salt 5 and R 6Compound [S2-1-2] or a salt thereof, in which hydrogen is present, can be produced, for example, by the production method K6 shown below.

[0374] [ka]

[0375] [In the formula, R 3 , R 4 , and L 1 This is synonymous with the above.

[0376] (Process K6-1) Compound [S2-1-2] or its salt can be produced by catalytic hydrogenation of the cyano group of compound [K6-1] or its salt in a solvent in the presence of a catalytic amount of palladium-carbon.

[0377] Examples of solvents include ester solvents such as ethyl acetate; alcohol solvents such as ethanol; ether solvents such as THF; and mixtures thereof. Ethanol is a preferred solvent.

[0378] The reaction temperature is, for example, 0°C to 60°C, preferably room temperature.

[0379] Compound [K6-1] or its salt may be commercially available or produced from a commercially available product by known methods, for example, by the production method M5 described later, or by the methods described in intermediate production examples 11, 13, 15, 18, 20, or 21.

[0380] [Manufacturing Method K7]: Method for producing compound [S2-1-3] or its salt R in compound [S2-1] or its salt 5 and R 6 However, the compound [S2-1-3] or a salt thereof, which together form cyclopropane with the carbon atoms to which they are bonded, can be produced, for example, by the production method K7 shown below.

[0381] [ka]

[0382] [In the formula, R 3 , R 4 , and L 1 This is synonymous with the above.

[0383] (Process K7-1) Compound [S2-1-3] or its salt can be prepared by reacting the cyano group of compound [K6-1] or its salt with ethylmagnesium halide in a solvent in the presence of titanium(IV) isopropoxide, followed by exposure to Lewis acid conditions (P. Bertus, J. Szymoniak, J. Org. Chem., 2003, 68, 7133-7136).

[0384] Examples of solvents include ether-based solvents such as diethyl ether, and hydrocarbon-based solvents such as toluene. Toluene is a preferred solvent.

[0385] Examples of ethylmagnesium halides include ethylmagnesium bromide. A preferred ethylmagnesium halide is ethylmagnesium bromide.

[0386] Examples of Lewis acids include the boron trifluoride diethyl ether complex.

[0387] The reaction temperature is, for example, -35°C to 10°C, preferably -25°C to 0°C.

[0388] [Manufacturing Method M5]: Method for producing compound [K6-1] or its salt R in compound [K6-1] or its salt 3 R 3’ And R 4 R 4’ Compound [K6-1'] or a salt thereof can be produced, for example, by the production method M5 shown below.

[0389] [ka]

[0390] [In the formula, R 3’ , R 4’ , and L 1 This is synonymous with the above.

[0391] (Process M5-1) Compound [K6-1a'] or a salt thereof can be produced by reacting compound [M5-1] or a salt thereof with an alkylating agent in a solvent in the presence of a base.

[0392] Examples of solvents include amide solvents such as DMF; halogenated solvents such as dichloromethane; and mixed solvents thereof. DMF is a preferred solvent.

[0393] As an alkylating agent, R 3 'or R 4 You should select the one that is suitable for the type of '. Examples include 1,1-difluoro-2-iodomethane, 2,2-difluoroethyltrifluoromethanesulfonate, (bromodifluoromethyl)trimethylsilane, 3,3-difluoropropyl 4-methylbenzenesulfonate, methyl iodide, ethyl iodide, d3-methyl iodide, and dibromomethane.

[0394] Examples of bases include potassium carbonate, potassium hydroxide, DBU, and sodium hydroxide. The preferred base is potassium carbonate.

[0395] The reaction temperature is, for example, -10°C to 40°C, preferably 0°C to room temperature.

[0396] Compound [M5-1] or its salt may be commercially available or may be prepared from a commercially available product by a known method.

[0397] R 3 'and R4 If the groups are the same, steps M5-1 and M5-2 may be carried out in one step using two or more equivalent amounts of alkylating agent.

[0398] Compound [K6-1a'] or its salt contains R in compound [K6-1] or its salt. 3 R 3’ And R 4 The compound contains hydrogen. Therefore, compound [K6-1a'] or its salt can be used as a starting material for production method K6.

[0399] (Process M5-2) Compound [K6-1'] or a salt thereof can be produced by reacting compound [K6-1a'] or a salt thereof in a solvent in the same manner as in step M5-1.

[0400] [Manufacturing Method K8]: Method for producing compound [S2-1] or its salt Compound [S2-1] or its salt can be produced, for example, by the following production method K8.

[0401] [ka]

[0402] [In the formula, R 3 , R 4 , R 5 , R 6 , and L 1 This is synonymous with the above, L 3 This refers to an amine protecting group (e.g., benzyloxycarbonyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, or tert-butoxycarbonyl).

[0403] (Process K8-1) Compound [S2-1] or its salt is a protecting group L of the nitrogen atom of compound [K8-1] or its salt. 3 It can be manufactured by removing the protective group L. 3 The removal of L 3It should be carried out under conditions suitable for the type. For example, L 3 However, if it is benzyloxycarbonyl, the benzyloxycarbonyl group of compound [K8-1] or its salt can be removed by catalytic hydrogenation in a solvent in the presence of a catalytic amount of palladium carbon.

[0404] Examples of solvents include ether-based solvents such as THF; alcohol-based solvents such as methanol; and mixed solvents thereof. A preferred solvent is a mixed solvent of THF and methanol.

[0405] The reaction temperature is, for example, 0°C to 60°C, preferably room temperature.

[0406] Compound [K8-1] or its salt may be a commercially available product or may be produced from a commercially available product by known methods, for example, by the production methods M6, M7, M8, or M9 described later, or by the methods described in intermediate production examples 1, 2, 23, or 24.

[0407] [Manufacturing Method M6]: Method for producing compound [K8-1] or its salt R in compound [K8-1] or its salt 3 R 3’ And R 4 R 4’ Compound [K8-1'] or a salt thereof can be produced, for example, by the production method M6 shown below.

[0408] [ka]

[0409] [In the formula, R 3 ', R 4 ', R 5 , R 6 , L 1 , and L 3 This is synonymous with the above.

[0410] (Process M6-1) Compound [K8-1'] or its salt can be produced by reacting compound [K8-1a'] or its salt with an alkylating agent in a solvent in the presence of a base.

[0411] Examples of solvents include ether-based solvents such as THF; amide-based solvents such as DMF; and mixed solvents thereof. The preferred solvent is THF.

[0412] As an alkylating agent, R 3 'or R 4 You should select one that is suitable for the type of '. Examples include d3-methyl iodide, methyl iodide, 1H-benzotriazole-1-methanol, and fluoroiodomethane.

[0413] Examples of bases include LDA or sodium hydride. The preferred base is LDA.

[0414] The reaction temperature is, for example, from -100°C to room temperature, preferably from -78°C to room temperature.

[0415] Compound [K8-1a'] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in production method E1 below.

[0416] [Manufacturing Method E1]: Method for producing compound [K8-1a'] or its salt Compound [K8-1a'] or its salt can be produced, for example, by the following production method E1.

[0417] [ka]

[0418] [In the formula, R 3 ', R 4 ', R 5 , R 6 , L 1 , and L 3 This is synonymous with the above.

[0419] (Process E1-1) Compound [E1-2] or its salt can be prepared by protecting the amino group of compound [E1-1] or its salt with a protecting reagent in the presence of a base in a solvent.

[0420] As a protective reagent, L 3 You should choose the one that is suitable for the type. For example, L 3 However, in the case of benzyloxycarbonyl, a suitable protective agent is, for example, benzyloxycarbonyl chloride.

[0421] Examples of solvents include ether-based solvents such as THF; halogen-based solvents such as dichloromethane; nitrile-based solvents such as acetonitrile; water; and mixtures thereof. The preferred solvent is THF.

[0422] Examples of suitable bases include sodium bicarbonate and diisopropylethylamine. Sodium bicarbonate is a preferred base.

[0423] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0424] Compound [E1-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0425] (Process E1-2) Compound [K8-1a'] or its salt can be produced by reacting compound [E1-2] or its salt with an alkylating agent in a solvent in the presence of a base.

[0426] Examples of solvents include ether-based solvents such as THF; amide-based solvents such as DMF; and mixed solvents thereof. The preferred solvent is THF.

[0427] As an alkylating agent, R 3 'or R 4You should select the one that is appropriate for the type. For example, methyl iodide or d3-methyl iodide are examples.

[0428] Examples of bases include LDA and LiHMDS. The preferred base is LDA.

[0429] The reaction temperature is, for example, from -100°C to room temperature, preferably from -78°C to room temperature.

[0430] [Manufacturing Method M7]: Method for producing compound [K8-1-1] or its salt L in compound [K8-1] 3 Compound [K8-1-1] or a salt thereof, in which is a carbamate protecting group, can be produced, for example, by the production method M7 shown below.

[0431] [ka]

[0432] [In the formula, R 3 , R 4 , R 5 , R 6 , and L 1 This is synonymous with the above, L 3a is a carbamate protecting group (for example, benzyloxycarbonyl or tert-butoxycarbonyl), L 4 C 1-4 It is alkyl.

[0433] (Process M7-1) Compound [M7-2] or its salt can be produced by selectively hydrolyzing one of the esters of compound [M7-1] or its salt in a solvent, in the presence of water and a base.

[0434] Examples of solvents include alcohol-based solvents such as ethanol; ether-based solvents such as dioxane; sulfoxide-based solvents such as DMSO; water; and mixtures thereof. A preferred solvent is a mixture of dioxane and water.

[0435] Examples of suitable bases include sodium hydroxide, potassium tert-butoxide, and potassium hydroxide. Preferred bases are sodium hydroxide or potassium tert-butoxide.

[0436] The reaction temperature is, for example, room temperature to 60°C, and preferably room temperature.

[0437] Compound [M7-1] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the production method E2 described later, or by the method described in intermediate production examples 22, 25, or 26.

[0438] (Process M7-2) Compound [K8-1-1] or its salt can be produced by reacting compound [M7-2] or its salt with an azidating agent in a solvent in the presence of a base, followed by a Curtius rearrangement, and then reacting with the corresponding alcohol.

[0439] As for alcohol, L 3 You should choose the one that is appropriate for the type. For example, tert-butyl alcohol or benzyl alcohol are options.

[0440] Examples of solvents include hydrocarbon solvents such as toluene; alcoholic solvents such as tert-butyl alcohol; and mixed solvents thereof. Toluene is a preferred solvent.

[0441] Examples of azidating agents include diphenyl phosphate azide. A preferred azidating agent is diphenyl phosphate azide.

[0442] Examples of suitable bases include triethylamine and diisopropylethylamine. Diisopropylethylamine is a preferred base. A catalyst may be added as needed to carry out the above reaction. A preferred catalyst is DMAP.

[0443] The reaction temperature is, for example, 80°C to 130°C, preferably 100°C to 110°C.

[0444] [Manufacturing Method E2]: Method for producing compound [M7-1-2] or its salt R in compound [M7-1] or its salt 4 and R 6 Compound [M7-1-2] or a salt thereof, in which is methyl, can be produced, for example, by the production method E2 shown below.

[0445] [ka]

[0446] [In the formula, R 3 , R 5 , L 1 , and L 4 This is synonymous with the above.

[0447] (Process E2-1) Compound [M7-1-2] or its salt can be produced by reacting compound [M7-1-1] or its salt with a methylating agent in a solvent in the presence of a base.

[0448] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; and mixed solvents thereof. The preferred solvent is THF.

[0449] Examples of methylating agents include methyl iodide.

[0450] Examples of bases include LDA and LiHMDS. The preferred base is LDA.

[0451] The reaction temperature is, for example, from -100°C to room temperature, preferably from -78°C to room temperature.

[0452] Compound [M7-1-1] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in Production Example 9 or 12 below.

[0453] [Manufacturing Method M8]: Method for producing compound [K8-1-2] or its salt R in compound [K8-1] or its salt 6 Compound [K8-1-2] or a salt thereof, in which hydrogen is present, can be produced, for example, by the production method M8 shown below.

[0454] [ka]

[0455] [In the formula, R 3 , R 4 , R 5 , L 1 , and L 3 This is synonymous with the above.

[0456] (Process M8-1) Compound [K8-1-2] or its salt contains the formyl group or carbonyl group of compound [K4-1] or its salt in a solvent, L 3 It can be produced by a reductive amination reaction with NH2 or a salt thereof.

[0457] Examples of solvents include halogenated solvents such as dichloromethane; ether-based solvents such as THF; nitrile-based solvents such as acetonitrile; and mixed solvents thereof. Dichloromethane is preferred.

[0458] Examples of reducing agents include sodium triacetoxyborohydride, tetra(n-butyl)triacetoxyborohydride, and sodium borohydride. A preferred reducing agent is sodium triacetoxyborohydride.

[0459] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0460] Furthermore, the above reaction may be carried out in the presence of an acid, if necessary. A preferred acid is acetic acid.

[0461] L 3 NH2 or its salts may be commercially available or may be produced from commercially available products by known methods.

[0462] [Manufacturing Method M9]: Method for producing compound [K8-1-3] or its salt R in compound [K8-1] or its salt 4 is hydrogen, and L 1 Compound [K8-1-3] or a salt thereof, in which the compound is methyl, can be produced, for example, by the production method M9 shown below.

[0463] [ka]

[0464] [In the formula, R 3 , R 5 , R 6 , and L 3 This is synonymous with the above.

[0465] (Process M9-1) Compound [M9-2] or its salt can be produced by reacting compound [M9-1] or its salt with an oxidizing agent in a solvent.

[0466] Examples of oxidizing agents include combinations of chromium trioxide and concentrated sulfuric acid, ruthenium tetroxide and sodium periodate, and pyridinium dichromate. Preferred oxidizing agents are combinations of chromium trioxide and concentrated sulfuric acid, or ruthenium tetroxide and sodium periodate.

[0467] As for the solvent, one should be selected that is suitable for the type of oxidizing agent. For example, when the oxidizing agent is a combination of chromium trioxide and concentrated sulfuric acid, examples of solvents include ketone solvents such as acetone; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of acetone and water. When the oxidizing agent is a combination of ruthenium tetroxide and sodium periodate, examples of solvents include nitrile solvents such as acetonitrile; halogenated solvents such as dichloromethane; ester solvents such as ethyl acetate; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of ethyl acetate, dichloromethane, and water.

[0468] The reaction temperature is, for example, 0°C to room temperature, preferably room temperature.

[0469] Compound [M9-1] or a salt thereof may be commercially available or may be produced from a commercially available product by a known method, for example, by the method described in production method E3 below.

[0470] (Process M9-2) Compound [K8-1-3] or its salt can be produced by reacting compound [M9-2] or its salt with trimethylsilyldiazomethane in a solvent.

[0471] Examples of solvents include hydrocarbon solvents such as toluene; alcohol solvents such as methanol; halogenated solvents such as dichloromethane; and mixed solvents thereof. Preferably, a mixed solvent of toluene and methanol is used.

[0472] The reaction temperature is, for example, -10°C to room temperature, preferably room temperature.

[0473] [Manufacturing Method E3]: Method for producing compound [M9-1-1] or its salt R in compound [M9-1] or its salt 5 R 5’ And R 6 R 6’ and L 3Compound [M9-1-1'] or a salt thereof, in which is a carbamate protecting group, can be produced, for example, by the production method E3 shown below.

[0474] [ka]

[0475] [In the formula, R 5 ' is a methyl which may be substituted with one or two halogens, R 6 ' is methyl, R 3 , and L 4 This is synonymous with the above, L 3a This is a carbamate protecting group (for example, benzyloxycarbonyl or tert-butoxycarbonyl).

[0476] (Process E3-1) Compound [E3-1'] or a salt thereof can be produced by reacting compound [E3-1a'] or a salt thereof with an alkylating agent in a solvent in the presence of a base.

[0477] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; alcohol-based solvents such as methanol; ketone-based solvents such as acetone; and mixtures thereof. The preferred solvent is acetone.

[0478] As an alkylating agent, R 5 'or R 6 You should select one that is suitable for the type of '. For example, methyl iodide is one option.

[0479] Examples of bases include sodium hydride, sodium methoxide, NaHMDS, and potassium carbonate. Potassium carbonate is a preferred base.

[0480] The reaction temperature is, for example, 0°C to 70°C, preferably 0°C to 56°C.

[0481] Compound [E3-1a'] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0482] (Process E3-2) Compound [E3-2'] or a salt thereof can be produced by Wittig reaction of compound [E3-1] or a salt thereof with a phosphorus ylide prepared from a phosphonium salt in a solvent in the presence of a base.

[0483] Examples of solvents include ether-based solvents such as THF; hydrocarbon-based solvents such as toluene; halogen-based solvents such as dichloromethane; and mixtures thereof. The preferred solvent is THF.

[0484] Examples of suitable bases include potassium tert-butoxide, KHMDS, and sodium hydride. The preferred base is potassium tert-butoxide.

[0485] Examples of phosphonium salts include methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide. The preferred phosphonium salt is methyltriphenylphosphonium bromide.

[0486] The reaction temperature is, for example, -20°C to room temperature, preferably 0°C to room temperature.

[0487] (Process E3-3) Compound [E3-3'] or its salt can be produced by hydrolyzing an ester of compound [E3-2'] or its salt in a solvent in the presence of water and a base.

[0488] Examples of solvents include alcohol-based solvents such as methanol; ether-based solvents such as THF; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of methanol, THF, and water.

[0489] Examples of suitable bases include sodium hydroxide, potassium tert-butoxide, and potassium hydroxide. The preferred base is sodium hydroxide.

[0490] The reaction temperature is, for example, room temperature to 50°C, and preferably room temperature.

[0491] (Process E3-4) Compound [E3-4'] or its salt can be produced by reacting compound [E3-3'] or its salt with an azidating agent in a solvent in the presence of a base, as in step M7-2, followed by a Curtius rearrangement, and then reacting with the corresponding alcohol.

[0492] (Process E3-5) Compound [M9-1-1'] or its salt can be produced by reacting compound [E3-4'] or its salt with a borane complex in a solvent using a brown hydroboration reaction, then reacting it with hydrogen peroxide in the presence of a base, and finally reacting it with water.

[0493] Examples of solvents include ether-based solvents such as THF. THF is a preferred solvent.

[0494] Examples of borane complexes include borane-tetrahydrofuran complexes and borane-dimethyl sulfide complexes. The preferred borane complex is the borane-tetrahydrofuran complex.

[0495] Examples of suitable bases include sodium peroxoborate and sodium hydroxide. Sodium hydroxide is a preferred base.

[0496] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0497] [Manufacturing Method S3]: Method for producing compounds [A1-4] or their salts Compounds [A1-4] or their salts can be produced, for example, by the following production method S3.

[0498] [ka]

[0499] [In the formula, R 1 and R 2 This is synonymous with the above, L 5 This is an amine protecting group (e.g., benzyloxycarbonyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, or tert-butoxycarbonyl).

[0500] (Process S3-1) Compound [A1-4] or its salt is a protecting group L for the nitrogen atom of compound [S3-1] or its salt. 5 It can be manufactured by removing the protective group L. 5 The removal of L 5 It should be carried out under conditions suitable for the type. For example, L 5 However, if it is p-methoxybenzyl, the p-methoxybenzyl group of compound [S3-1] or its salt can be removed by reacting it with an oxidizing agent in a solvent.

[0501] Examples of solvents include nitrile solvents such as acetonitrile; halogenated solvents such as dichloromethane; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of acetonitrile and water.

[0502] Examples of oxidizing agents include ammonium hexanitratocerium(IV) and 2,3-dichloro-5,6-dicyano-p-benzoquinone. The preferred oxidizing agent is ammonium hexanitratocerium(IV).

[0503] The reaction temperature is, for example, 0°C to 50°C, and preferably room temperature.

[0504] Compound [S3-1] or its salt may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in production methods K9 or K10 below.

[0505] [Manufacturing Method K9]: Method for producing compound [S3-1-1] or its salt R in compound [S3-1] or its salt 1 Compound [S3-1-1] or a salt thereof, in which is a halogen, can be produced, for example, by the production method K9 shown below.

[0506] [ka]

[0507] [In the formula, R 2 and L 5 This is synonymous with the above, where X is a halogen and L 6 This is a hydroxyl protecting group (for example, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, or tert-butyldiphenylsilyl).

[0508] (Process K9-1) Compound [K9-3] or its salt can be prepared by reductive cross-electrophilic coupling reaction using nickel catalyst and light with compound [K9-1] or its salt and compound [K9-2] or its salt in a solvent in the presence of Hantchu ester (diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylate) and a base (Viktor CP, Shorouk OB, Sebastian K, Anais J, and Gary AM, Org. Lett. 2021, 23, 4828-4833, James TB, Samuel DR, John K., Cole C., Richard S., Eugene T., and Ronald JH, Org. Lett. 2022, 24, 9123-9129).

[0509] Examples of solvents include amide solvents such as DMA; nitrile solvents such as acetonitrile; and mixed solvents thereof. DMA is a preferred solvent.

[0510] Examples of nickel catalysts include combinations of divalent nickel salts and ligands. For example, combinations of dichloro(dimethoxyethane)nickel and 4,4'-di-tert-butyl-2,2'-bipyridyl, and combinations of dibromo(dimethoxyethane)nickel and 4,4'-di-tert-butyl-2,2'-bipyridyl are exemplified. A preferred nickel catalyst is the combination of dichloro(dimethoxyethane)nickel and 4,4'-di-tert-butyl-2,2'-bipyridyl.

[0511] Examples of suitable bases include 2,6-lutidine, sodium bicarbonate, and 2,4,6-collidine. The preferred base is 2,6-lutidine.

[0512] The wavelength of the irradiated light is exemplified by a range of 365 nM to 450 nM. A preferred wavelength is in the range of 405 nM to 420 nM.

[0513] The reaction temperature is, for example, 20°C to 35°C, preferably 28°C to 33°C.

[0514] Furthermore, the above reactions can be carried out using a flow synthesis apparatus as needed (Maria G., David FF, Juan AR, Mario B., Oscar F., Carlos M., Susana G., Javier A., ​​David WC, ACS Cent. Sci. 2021, 7, 1126-1134). Compound [K9-1] or its salt may be commercially available or produced from a commercially available product by a known method. Compound [K9-2] or its salt may also be produced from a commercially available product by a known method, for example, by the method described in production method M10 below.

[0515] (Process K9-2) Compound [K9-4] or its salt protects the hydroxyl group L of compound [K9-3] or its salt. 6 It can be manufactured by removing the protective group L. 6 The removal of L 6 It should be carried out under conditions suitable for the type. For example, L 6 However, if it is tert-butyldimethylsilyl, the tert-butyldimethylsilyl group of compound [K9-3] or its salt can be removed by reacting it with tetra-n-butylammonium fluoride in a solvent.

[0516] Examples of solvents include ether-based solvents such as THF; halogen-based solvents such as dichloromethane; and mixed solvents thereof. The preferred solvent is THF.

[0517] The reaction temperature is, for example, -10°C to 50°C, preferably room temperature.

[0518] (Process K9-3) Compound [K9-5] or its salt can be produced by halogenating the hydroxyl group of compound [K9-4] or its salt in a solvent.

[0519] Examples of solvents include halogenated solvents such as dichloromethane; ether-based solvents such as THF; and mixed solvents thereof. Dichloromethane is a preferred solvent.

[0520] For halogenation, a reagent suitable for the type of X should be selected. Examples include (diethylamino)sulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, a combination of tetrachloromethane and triphenylphosphine, a combination of tetrabromomethane and triphenylphosphine, and a combination of methyl iodide and triphenylphosphine.

[0521] The reaction temperature is, for example, -100°C to 50°C, preferably -78°C to 30°C.

[0522] (Process K9-4) Compound [S3-1-1] or its salt can be produced by reacting compound [K9-5] or its salt with an oxidizing agent in a solvent.

[0523] Examples of solvents include ester-based solvents such as ethyl acetate; nitrile-based solvents such as acetonitrile; water; and mixed solvents thereof. A preferred solvent is a mixed solvent of ethyl acetate and water.

[0524] Examples of oxidizing agents include a combination of ruthenium tetroxide and sodium periodate, and dichromate. The preferred oxidizing agent is a combination of ruthenium tetroxide and sodium periodate.

[0525] The reaction temperature is, for example, -10°C to 50°C, preferably 10°C to room temperature.

[0526] [Manufacturing Method M10]: Method for producing compound [K9-2] or its salt Compound [K9-2] or its salt can be produced, for example, by the production method M10 shown below.

[0527] [ka]

[0528] [In the formula, L 5 and L 6 This is synonymous with the above.

[0529] (Process M10-1) Compound [K9-2] or its salt can be produced by reacting the carboxyl group of compound [M10-1] or its salt with N-hydroxyphthalimide in a solvent in the presence of a condensing agent and a catalyst.

[0530] Examples of solvents include amide solvents such as DMF; halogenated solvents such as dichloromethane; and mixed solvents thereof. DMF is a preferred solvent.

[0531] Examples of condensing agents include N,N'-dicyclohexylcarbodiimide and WSC. The preferred condensing agent is WSC.

[0532] As an example of a catalyst, DMAP is one such example.

[0533] The reaction temperature is, for example, -10°C to 50°C, preferably room temperature.

[0534] Compound [M10-1] or a salt thereof may be commercially available or may be prepared from a commercially available product by known methods.

[0535] [Manufacturing Method K10]: Method for producing compound [S3-1-1] or its salt R in compound [S3-1] or its salt 1 Compound [S3-1-1] or a salt thereof, in which is a halogen, can be produced, for example, by the production method K10 shown below.

[0536] [ka]

[0537] [In the formula, R 2 and L 5 This is synonymous with the above, and X is a halogen.

[0538] (Process K10-1) Compound [S3-1-2] or its salt can be prepared by protecting the nitrogen atom of compound [A1-4-1] or its salt in a solvent in the presence of a base using a protecting reagent.

[0539] As a protective reagent, L 5 You should choose the one that is suitable for the type. For example, L 5If the substance is p-methoxybenzyl, a suitable protective reagent is, for example, p-methoxybenzyl chloride.

[0540] Examples of solvents include amide solvents such as DMF; ether solvents such as THF; and mixed solvents thereof. A preferred solvent is a mixed solvent of DMF and THF.

[0541] Examples of suitable bases include sodium hydride and potassium hydride. Sodium hydride is a preferred base.

[0542] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0543] Compound [A1-4-1] or its salt may be commercially available or may be prepared from a commercially available product by known methods.

[0544] (Process K10-2) Compound [K10-1] or its salt can be prepared by oxidizing the α-position of the carbonyl group of compound [S3-1-2] or its salt in a solvent in the presence of a base using Davis's reagent (N-sulfonyl oxaziridine).

[0545] Examples of solvents include ether-based solvents such as THF. THF is a preferred solvent.

[0546] Examples of suitable bases include NaHMDS and LDA. LDA is the preferred base.

[0547] The reaction temperature is, for example, -100°C to -50°C, preferably -78°C to -60°C.

[0548] (Process K10-3) Compound [S3-1-1] or its salt can be produced by halogenating the hydroxyl group of compound [K10-1] or its salt in a solvent.

[0549] Examples of solvents include hydrocarbon solvents such as toluene; ether solvents such as THF; halogen solvents such as dichloromethane; and mixtures thereof. Toluene is a preferred solvent.

[0550] For halogenation, a reagent suitable for the type of X should be selected. Examples include a combination of pyridine-2-sulfonyl fluoride and DBU, a combination of tetrachloromethane and triphenylphosphine, a combination of tetrabromomethane and triphenylphosphine, and a combination of methyl iodide and triphenylphosphine.

[0551] The reaction temperature is, for example, -10°C to 50°C, preferably room temperature.

[0552] [Manufacturing Method A2]: Method for producing compound [I-1] or its salt R in compound [I] or its salt 1 Compound [I-1] or a salt thereof, in which is hydrogen or a halogen, can be produced, for example, by the production method A2 shown below.

[0553] [ka]

[0554] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , and R 1a This is synonymous with the above.

[0555] (Process A2-1) Compound [I-1] or a salt thereof can be produced by reacting compound [S2-1] or a salt thereof with compound [A2-1] or a salt thereof in a solvent.

[0556] Examples of solvents include hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; and mixed solvents thereof. Toluene is a preferred solvent.

[0557] The reaction temperature is, for example, room temperature to 150°C, preferably 110°C.

[0558] If necessary, a base may be added to carry out the above reaction. A preferred base is triethylamine. Furthermore, if necessary, the above reaction may be carried out under microwave irradiation conditions.

[0559] Compound [A2-1] or its salt may be produced from a commercially available product by a known method, for example, by the method described in production method S4 below.

[0560] [Manufacturing Method S4]: Method for producing compound [A2-1] or its salt Compound [A2-1] or its salt can be produced, for example, by the production method S4 shown below.

[0561] [ka]

[0562] [In the formula, R 1a and R 2 This is synonymous with the above.

[0563] (Process S4-1) Compound [A2-1] or its salt can be produced by methylating the carbonyl oxygen of compound [A1-4] or its salt in a solvent using Meyerwein's reagent (trimethyloxonium tetrafluoroborate).

[0564] Examples of solvents include halogenated solvents such as dichloromethane. Dichloromethane is a preferred solvent.

[0565] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0566] [Manufacturing Method A3]: Method for producing compound [I-2] or its salt R in compound [I] or its salt 1 Compound [I-2] or a salt thereof, wherein the compound is hydroxyl, can be produced, for example, by the following production method A3.

[0567] [ka]

[0568] [In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , L 6 , and X are synonymous with the above.

[0569] (Process A3-1) Compound [A3-2] or a salt thereof can be produced by reacting compound [A1-3] or a salt thereof with compound [A3-1] or a salt thereof in the same manner as in step A1-3.

[0570] Compound [A3-1] or a salt thereof may be a commercially available product or may be produced from a commercially available product by a known method, for example, by the method described in production method S5 below.

[0571] (Process A3-2) Compound [A3-3] or a salt thereof can be produced by subjecting compound [A3-2] or a salt thereof to an intramolecular Azawittig reaction in the same manner as in step A1-4.

[0572] (Process A3-3) Compound [I-2] or its salt is compound [A3-3] or its salt, similar to step K9-2, with a hydroxyl protecting group L 6 It can be manufactured by removing it.

[0573] [Manufacturing Method S5]: Method for producing compound [A3-1] or its salt Compound [A3-1] or its salt can be produced, for example, by the production method S5 shown below.

[0574] [ka]

[0575] [In the formula, R 2 , L 5 , and L 6 This is synonymous with the above.

[0576] (Process S5-1) Compound [S5-1] or its salt can be prepared by protecting the hydroxyl group of compound [K10-1] or its salt in a solvent in the presence of a base using a protecting reagent.

[0577] As a protective reagent, L 6 You should choose the one that is suitable for the type. For example, L 6 However, in the case of tert-butyldimethylsilyl, a suitable protecting agent is, for example, tert-butyldimethylsilyl chloride.

[0578] Examples of solvents include ether-based solvents such as THF; amide-based solvents such as DMF; hydrocarbon-based solvents such as toluene; and mixtures thereof. DMF is a preferred solvent.

[0579] Examples of suitable bases include imidazole and 2,6-lutidine. The preferred base is imidazole.

[0580] The reaction temperature is, for example, -10°C to room temperature, preferably 0°C to room temperature.

[0581] (Process S5-2) Compound [A3-1] or its salt is a protecting group L of the nitrogen atom of compound [S5-1] or its salt.5 This can be manufactured by removing it in the same manner as in process S3-1.

[0582] In compound [I-3] or its salt, R 2 'ga T 4 Pyrazolyl (where the T may be substituted by) 4 A compound or salt thereof is defined as R in formula [I-3] above (which is the same as the definition in formula [I-3] above). 2 By using suitable raw materials and reagents, it can be manufactured by the same method as described above. [Examples]

[0583] The following provides a specific example of the production of compound [I-3] of the present invention or a pharmaceutically acceptable salt thereof. However, the production methods for compound [I-3] of the present invention or a pharmaceutically acceptable salt thereof are not limited to these.

[0584] The compounds obtained in each step can be isolated and / or purified by known methods such as distillation, recrystallization, and column chromatography, as needed. However, in some cases, the process can proceed to the next step without isolation and / or purification.

[0585] In this specification, room temperature refers to the temperature in an uncontrolled state, and one embodiment is a range of 1°C to 40°C.

[0586] The abbreviations used are as follows: DBU: 1,8-Diazabicyclo[5.4.0]-7-Undecene DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DIBAL: Diisobutylaluminum hydride DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide LDA: Lithium diisopropylamide LiHMDS: Lithium bis(trimethylsilyl)amide THF: Tetrahydrofuran

[0587] [Manufacturing Example 1] Synthesis of 1-(5-chloropyrimidine-2-yl)-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one (Example No. 6)

[0588] [ka]

[0589] (1) tert-butyl 4'-oxo-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-1-carboxylate

[0590] [ka]

[0591] To a solution of 5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole (0.20 g), obtained from a commercially available product by the same method as in manufacturing method S4, in toluene (5 ml), 1-(tert-butyl) 4-ethyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (0.425 g) was added at room temperature and stirred overnight at 125°C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.387 g). 1H-NMR (CDCl3) δ: 7.37-7.31 (2H, m), 7.30-7.24 (1H, m), 7.18-7.13 (2H, m), 5.28 (1H, dd, J = 8.6, 2.4 Hz), 3.69-3.39 (6H, m), 2.90-2.78 (1H, m), 2.72-2.61 (1H, m), 2.54-2.38 (1H, m), 2.05-1.88 (2H, m), 1.86-1.76 (1H, m), 1.52-1.37 (11H, m).

[0592] (2) 6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one 2-hydrochloride

[0593] [ka]

[0594] To a methanol solution (8 ml) of tert-butyl 4'-oxo-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-1-carboxylate (0.378 g), 2.96 ml of 2 M hydrogen chloride-methanol solution was added at room temperature, and the mixture was stirred for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.36 g). The number of hydrochloride salts is an estimate. 1 H-NMR (DMSO-D6) δ: 9.31 (1H, br s), 9.10 (1H, br s), 7.44-7.29 (5H, m), 5.41-5.36 (1H, m), 4.13-4.05 (1H, m), 3.93-3.84 (1H, m), 3.49-3.31 (1H, m), 3.27-3.02 (4H, m), 3.02-2.91 (1H, m), 2.74-2.60 (1H, m), 2.17-2.07 (1H, m), 2.05-1.93 (3H, m), 1.84-1.75 (1H, m).

[0595] (3) 1-(5-chloropyrimidine-2-yl)-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one

[0596] [ka]

[0597] 6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one dihydrochloride (0.026 g) was dissolved in ethanol (0.78 ml), to which 2,5-dichloropyrimidine (0.016 g) and diisopropylethylamine (0.127 ml) were added. The mixture was stirred at 100°C for 40 minutes under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.019 g). 1 H-NMR (CDCl3) δ: 8.19 (2H, br s), 7.37-7.30 (2H, m), 7.30-7.25 (1H, m), 7.20-7.15 (2H, m), 5.36-5.24 (1H, m), 3.95-3.81 (4H, m), 3.72-3.55 (2H, m), 2.93-2.79 (1H, m), 2.74-2.63 (1H, m), 2.56-2.42 (1H, m), 2.06-1.96 (2H, m), 1.95-1.86 (1H, m), 1.57-1.46 (2H, m).

[0598] The compounds of Examples 12, 13, 14, and 15 were obtained from commercially available products by the same method as in Production Example 1.

[0599] [Manufacturing Example 2] Synthesis of 1-acetyl-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one (Example No. 7)

[0600] [ka]

[0601] 1-Acetyl-6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one

[0602] [ka]

[0603] To a chloroform solution of 6'-phenyl-2',6',7',8'-tetrahydro-4'H-spiro[piperidine-4,3'-pyrrolo[1,2-a]pyrimidine]-4'-one dihydrochloride (0.028 g), diisopropylethylamine (0.137 ml) and acetyl chloride (0.006 ml) were added at room temperature, and the mixture was stirred for 40 minutes. The reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.016 g). 1 H-NMR (CDCl3) δ: 7.38-7.31 (2H, m), 7.31-7.25 (1H, m), 7.20-7.14 (2H, m), 5.34-5.23 (1H, m), 3.88-3.72 (1H, m), 3.72-3.60 (1H, m), 3.56-3.43 (2H, m), 3.03-2.76 (2H, m), 2.76-2.62 (1H, m), 2.56-2.41 (1H, m), 2.08-2.05 (3H, m), 2.05-1.87 (2H, m), 1.87-1.70 (2H, m), 1.53-1.38 (2H, m).

[0604] [Manufacturing Example 3] Synthesis of 4-(4'-oxo-2',6',7',8'-tetrahydro-4'H-spiro[cyclohexane-1,3'-pyrrolo[1,2-a]pyrimidine]-6'-yl)benzonitrile (Example No. 21)

[0605] [ka]

[0606] 4-(4'-oxo-2',6',7',8'-tetrahydro-4'H-spiro[cyclohexane-1,3'-pyrrolo[1,2-a]pyrimidine]-6'-yl)benzonitrile

[0607] [ka]

[0608] To a solution of 6'-(4-bromophenyl)-2',6',7',8'-tetrahydro-4'H-spiro[cyclohexane-1,3'-pyrrolo[1,2-a]pyrimidine]-4'-one (0.087 g) in N-methylpyrrolidone (0.87 ml), potassium hexacyanoferrate(II) trihydrate (0.102 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.039 g) and sodium carbonate (0.026 g) were added at room temperature, and the mixture was stirred at 130°C for 4 hours under an argon atmosphere. The reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.018 g). 1H-NMR (CDCl3) δ: 7.66-7.62 (2H, m), 7.31-7.27 (2H, m), 5.26 (1H, dd, J = 8.8, 3.5 Hz), 3.75-3.67 (1H, m), 3.58-3.49 (1H, m), 2.85-2.63 (2H, m), 2.57-2.45 (1H, m), 1.99-1.89 (1H, m), 1.88-1.77 (1H, m), 1.70-1.55 (3H, m), 1.56-1.41 (5H, m), 1.41-1.32 (1H, m).

[0609] [Manufacturing Example 4] Synthesis of (3S,6S,8S)-8-fluoro-3-(hydroxymethyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (Example No. 177)

[0610] [ka]

[0611] (1) Ethyl 2-cyano-3-hydroxy-2-methylpropanoate

[0612] [ka]

[0613] To a solution of ethyl 2-cyanopropanoate (5 g) in acetonitrile (10 ml), triethylamine (0.548 ml), and 37% formaldehyde aqueous solution (8.78 ml), triethylamine (0.548 ml) was added under ice cooling and the mixture was stirred at 50°C for 3 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the title compound (6.1 g) was obtained by azeotropic distillation in toluene. 1H-NMR (CDCl3) δ: 4.34-4.27 (2H, m), 3.99-3.84 (2H, m), 2.40 (1H, t, J = 7.0 Hz), 1.59 (3H, s), 1.37-1.32 (3H, m).

[0614] (2) Ethyl 3-((tert-butyldiphenylsilyl)oxy)-2-cyano-2-methylpropanoate

[0615] [ka]

[0616] To a solution of ethyl 2-cyano-3-hydroxy-2-methylpropanoate (6.1 g) in DMF (30.5 ml) and imidazole (5.28 g), tert-butyldiphenylchlorosilane (11.96 ml) was added and mixed under ice cooling. After stirring at room temperature for 20 hours, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (14.7 g). 1 H-NMR (CDCl3) δ: 7.72-7.64 (4H, m), 7.46-7.38 (6H, m), 4.29 (2H, q, J = 7.1 Hz), 3.95 (1H, d, J = 9.5 Hz), 3.82 (1H, d, J = 9.5 Hz), 1.53 (3H, s), 1.34 (3H, t, J = 7.1 Hz), 1.06 (9H, s).

[0617] (3) Ethyl 3-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropanoate

[0618] [ka]

[0619] Ethyl 3-((tert-butyldiphenylsilyl)oxy)-2-cyano-2-methylpropanoate (4.4 g) was mixed with methanol (59.4 ml) and cobalt(II) chloride hexahydrate (2.73 g). Sodium borohydride (1.184 g) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. 10 ml of 1 N hydrochloric acid was added to the reaction mixture at room temperature, neutralized with 28% aqueous ammonia (7 ml), and then ethyl acetate (150 ml) was added. The mixture was filtered using Celite. The filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure to obtain the title compound (4 g). 1 H-NMR (CDCl3) δ: 7.67-7.60 (4H, m), 7.44-7.35 (6H, m), 4.17-4.11 (2H, m), 3.77 (1H, d, J = 9.8 Hz), 3.69 (1H, d, J = 9.8 Hz), 3.03 (1H, d, J = 12.5 Hz), 2.78 (1H, d, J = 12.5 Hz), 1.46 (2H, br s), 1.31-1.21 (3H, m), 1.18 (3H, s), 1.05 (9H, s).

[0620] (4) Ethyl 3-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropanoate

[0621] [ka]

[0622] Ethyl 3-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropanoate (1.2 g) was mixed with potassium carbonate (0.649 g), methanol (24.0 ml), imidazole-1-sulfonyl azide hydrochloride (0.984 g), and copper(II) sulfate pentahydrate (0.039 g) at room temperature and stirred for 20 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (830 mg). 1 H-NMR (CDCl3) δ: 7.64-7.62 (4H, m), 7.46-7.37 (6H, m), 4.23-4.10 (2H, m), 3.82-3.79 (1H, m), 3.71-3.68 (1H, m), 3.64-3.61 (2H, m), 1.26 (3H, t, J = 7.1 Hz), 1.17 (3H, s), 1.04 (9H, s).

[0623] (5) 3-Azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionic acid

[0624] [ka]

[0625] Ethyl 3-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropanoate (830 mg) was mixed with THF (8.3 ml), methanol (8.3 ml), and 2 N aqueous sodium hydroxide solution (2.027 ml) at room temperature and stirred at 60°C for 5 hours. Water and chloroform were added to the reaction mixture and separated. 2 N hydrochloric acid (0.772 ml) was added to the aqueous layer and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (780 mg). 1H-NMR (CDCl3) δ: 7.66-7.62 (4H, m), 7.45-7.38 (6H, m), 3.80 (1H, d, J = 10.0 Hz), 3.68-3.64 (3H, m), 1.20 (3H, s), 1.06 (9H, s).

[0626] (6) 3-Azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionate salt

[0627] [ka]

[0628] 3-Azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionic acid (780 mg) was mixed with dichloromethane (10 ml), DMF (0.016 ml), and oxalyl chloride (0.268 ml) at room temperature and stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound (818 mg), which was then used in the next step.

[0629] (7)(3S,5S)-1-((S)-3-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionyl)-3-fluoro-5-phenylpyrrolidine-2-one

[0630] [ka]

[0631] To a solution of (3S,5S)-3-fluoro-5-phenylpyrrolidine-2-one (340 mg), obtained from commercially available (S)-5-phenylpyrrolidine-2-one by the same method as in production methods K10 and S3, in THF (5.1 ml), 1.678 ml of 1.15 M LiHMDS-n-hexane solution was added at -78°C, and the mixture was stirred for 10 minutes under ice cooling. To the reaction mixture, a solution of 3-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionate chloride (835 mg) in THF (1.7 ml) was added at -78°C, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous ammonium chloride solution (2 ml) and water (2 ml) were added at -78°C, and after stirring at room temperature, the mixture was extracted with ethyl acetate (40 ml). The organic layer was washed with water (5 ml) and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (320 mg). The stereochemistry of the title compound was estimated by tracing back from the NOESY in step (8) of this manufacturing example 4. 1 H-NMR (CDCl3) δ: 7.61-7.57 (4H, m), 7.43-7.34 (6H, m), 7.27-7.17 (5H, m), 5.16-4.99 (2H, m), 4.01-3.95 (2H, m), 3.85-3.80 (2H, m), 2.92-2.80 (1H, m), 2.22-2.09 (1H, m), 1.37 (3H, s), 1.01 (9H, s).

[0632] Furthermore, a diastereomer (410 mg) of the title compound was obtained.

[0633] (8)(3S,6S,8S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-8-fluoro-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0634] [ka]

[0635] (3S,5S)-1-((S)-3-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylpropionyl)-3-fluoro-5-phenylpyrrolidine-2-one (320 mg) was added to a solution of THF (9.6 ml) and, under ice cooling, 3 mmol / g polymer-supported triphenylphosphine (491 mg) was added and the mixture was stirred at room temperature for 17 hours. Insoluble matter was filtered off the reaction mixture, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (270 mg). The stereochemistry of the title compound was determined by NOESY. 1 H-NMR (CDCl3) δ: 7.65-7.62 (4H, m), 7.44-7.31 (8H, m), 7.30-7.26 (3H, m), 5.34-5.21 (2H, m), 4.07 (1H, dd, J = 16.6, 4.6 Hz), 3.82 (1H, d, J = 9.8 Hz), 3.66 (1H, dd, J = 16.6, 6.4 Hz), 3.46 (1H, d, J = 9.8 Hz), 2.71-2.57 (1H, m), 2.32-2.21 (1H, m), 1.15 (3H, s), 1.04 (9H, s).

[0636] (9)(3S,6S,8S)-8-fluoro-3-(hydroxymethyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0637] [ka]

[0638] (3S,6S,8S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-8-fluoro-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (270 mg) was mixed with THF (5.4 ml) and acetic acid (0.037 ml) and 1 M tetrabutylammonium fluoride-THF solution (0.65 ml) at room temperature. The mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to obtain the title compound (130 mg). 1 H-NMR (CDCl3) δ: 7.38-7.27 (5H, m), 5.42-5.41 (0.5H, m), 5.32-5.26 (1.5H, m), 3.87 (1H, dd, J = 17.0, 7.4 Hz), 3.74 (1H, dd, J = 11.5, 7.4 Hz), 3.63 (1H, dd, J = 17.0, 4.8 Hz), 3.48 (1H, dd, J = 11.5, 6.4 Hz), 2.84-2.67 (1H, m), 2.39-2.27 (2H, m), 1.19 (3H, s).

[0639] [Manufacturing Example 5] Synthesis of (3S,6S,8S)-8-fluoro-3-methyl-6-phenyl-3-((pyridine-3-yloxy)methyl)-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (Example No. 187)

[0640] [ka]

[0641] (1)((3S,6S,8S)-8-fluoro-4-oxo-6-phenyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine-3-yl)methyl ethanesulfonate

[0642] [ka]

[0643] (3S,6S,8S)-8-fluoro-3-(hydroxymethyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (40 mg), obtained in step (9) of Production Example 4, was mixed with THF (0.6 ml) and triethylamine (0.023 ml). Ethanesulfonyl chloride (0.012 ml) was added under ice cooling and the mixture was stirred for 90 minutes. Water was added at room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (40 mg). This product was used directly in the next step without measuring NMR.

[0644] (2)(3S,6S,8S)-8-fluoro-3-methyl-6-phenyl-3-((pyridine-3-yloxy)methyl)-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0645] [ka]

[0646] ((3S,6S,8S)-8-fluoro-4-oxo-6-phenyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine-3-yl)methylethanesulfonate (40 mg) was mixed with DMF (0.4 ml) and potassium carbonate (45.0 mg), potassium iodide (33.2 mg), and 3-hydroxypyridine (20.65 mg). After stirring at 90°C for 9 hours, the reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (19 mg). 1H-NMR (CDCl3) δ: 8.30-8.28 (1H, m), 8.24-8.21 (1H, m), 7.37-7.26 (5H, m), 7.21-7.15 (2H, m), 5.47-5.46 (0.5H, m), 5.35-5.29 (1.5H, m), 4.26 (1H, d, J = 7.6 Hz), 4.14-4.06 (1H, m), 3.86-3.77 (2H, m), 2.85-2.69 (1H, m), 2.42-2.29 (1H, m), 1.29 (3H, s).

[0647] The compounds of Examples 224, 236, 239, 243, 249, 253, 265, and 277 were synthesized using commercially available products in the same manner as described above.

[0648] [Manufacturing Example 6] Synthesis of (3S,6S,8S)-8-fluoro-3-methyl-6-phenyl-3-((pyridine-2-yloxy)methyl)-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (Example No. 223)

[0649] [ka]

[0650] (3S,6S,8S)-8-fluoro-3-methyl-6-phenyl-3-((pyridine-2-yloxy)methyl)-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0651] [ka]

[0652] ((3S,6S,8S)-8-fluoro-4-oxo-6-phenyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine-3-yl)methyl ethanesulfonate (26 mg), obtained by the same method as in step (1) of Production Example 5, was mixed with potassium carbonate (29.3 mg), 1H-pyridine-2-one (6.71 mg), and potassium iodide (33.2 mg) in a DMA (0.52 ml) solution. After stirring at 90°C for 9 hours, the reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (5 mg). The stereochemistry of this compound was determined by NMR-HMBC and NOESY. 1 H-NMR (CDCl3) δ: 8.10 (1H, s), 7.56-7.54 (1H, m), 7.34-7.25 (5H, m), 6.88-6.85 (1H, m), 6.71-6.69 (1H, m), 5.45-5.43 (0.5H, m), 5.32-5.30 (0.5H, m), 5.27-5.22 (1H, m), 4.46 (1H, d, J = 10.6 Hz), 4.27 (1H, d, J = 10.6 Hz), 4.09-4.03 (1H, m), 3.73-3.68 (1H, m), 2.79-2.66 (1H, m), 2.40-2.27 (1H, m), 1.28 (3H, s).

[0653] In addition, the isomer compound ((3S,6S,8S)-8-fluoro-3-methyl-3-((2-oxopyridine-1(2H)-yl)methyl)-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one, Example No. 222) (6 mg) was obtained at the same time.

[0654] [ka]

[0655] 1H-NMR (CDCl3) δ: 7.29 (7H, t, J = 12.0 Hz), 6.52-6.48 (1H, m), 6.14-6.10 (1H, m), 5.51-5.50 (0.5H, m), 5.38-5.36 (0.5H, m), 5.21-5.17 (1H, m), 4.72 (1H, d, J = 13.5 Hz), 3.80-3.69 (2H, m), 3.43 (1H, d, J = 13.5 Hz), 2.97-2.86 (1H, m), 2.33-2.22 (1H, m), 1.26 (3H, s).

[0656] [Manufacturing Example 7] Synthesis of (3S,6S,8S)-8-fluoro-3-(((3-fluoropyridine-4-yl)oxy)methyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (Example No. 229)

[0657] [ka]

[0658] (3S,6S,8S)-8-fluoro-3-(((3-fluoropyridine-4-yl)oxy)methyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0659] [ka]

[0660] ((3S,6S,8S)-8-fluoro-4-oxo-6-phenyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine-3-yl)methyl ethanesulfonate (26 mg) was mixed with DMA (0.52 ml) in a solution of ((3S,6S,8S)-8-fluoro-4-oxo-6-phenyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine-3-yl)methyl ethanesulfonate (26 mg) and potassium carbonate (29.3 mg), 3-fluoropyridine-4-ol (15.96 mg), and potassium iodide (33.2 mg). After stirring at 90°C for 11 hours, the reaction solution was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (15 mg). 1 H-NMR (CDCl3) δ: 8.33 (1H, d, J = 3.3 Hz), 8.26 (1H, d, J = 5.5 Hz), 7.40-7.27 (5H, m), 6.87-6.83 (1H, m), 5.51-5.49 (0.5H, m), 5.37-5.28 (1.5H, m), 4.30 (1H, d, J = 8.8 Hz), 4.08 (1H, dd, J = 16.8, 6.6 Hz), 3.91 (1H, d, J = 8.8 Hz), 3.83 (1H, dd, J = 16.8, 5.3 Hz), 2.91-2.74 (1H, m), 2.42-2.30 (1H, m), 1.29 (3H, s).

[0661] In addition, the isomer compound ((3S,6S,8S)-8-fluoro-3-((3-fluoro-4-oxopyridine-1(4H)-yl)methyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one, Example No. 230) (3 mg) was obtained at the same time.

[0662] [ka]

[0663] 1H-NMR (CDCl3) δ: 7.37-7.26 (8H, m), 5.42-5.41 (0.5H, m), 5.30-5.26 (1.5H, m), 3.87 (1H, dd, J = 17.0, 7.5 Hz), 3.77-3.69 (1H, m), 3.63 (1H, dd, J = 17.0, 4.6 Hz), 3.50-3.44 (1H, m), 2.83-2.67 (1H, m), 2.38-2.26 (1H, m), 1.20 (3H, s).

[0664] [Manufacturing Example 8] Synthesis of (3S,6S,8S)-8-fluoro-3-(((5-fluoropyrimidine-2-yl)oxy)methyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (Example No. 198)

[0665] [ka]

[0666] (3S,6S,8S)-8-fluoro-3-(((5-fluoropyrimidine-2-yl)oxy)methyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one

[0667] [ka]

[0668] To a solution of (3S,6S,8S)-8-fluoro-3-(hydroxymethyl)-3-methyl-6-phenyl-2,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-4(3H)-one (20 mg) obtained in step (9) of Production Example 4, 2-chloro-5-fluoropyrimidine (11.51 mg) was added. A 60% sodium hydride-mineral oil mixture (3.47 mg) was added to the reaction mixture under ice cooling and a nitrogen atmosphere, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by silica gel column chromatography (eluent: acetonitrile / water) to obtain the title compound (12 mg). 1 H-NMR (CDCl3) δ: 8.34 (2H, s), 7.36-7.27 (5H, m), 5.46-5.45 (0.5H, m), 5.32-5.26 (1.5H, m), 4.58 (1H, d, J = 10.8 Hz), 4.22 (1H, d, J = 10.8 Hz), 4.13 (1H, dd, J = 16.9, 6.1 Hz), 3.76 (1H, dd, J = 16.9, 4.9 Hz), 2.87-2.70 (1H, m), 2.39-2.28 (1H, m), 1.29 (3H, s).

[0669] The compounds of Examples 200, 201, and 202 were synthesized using commercially available products in the same manner as described above.

[0670] [Manufacturing Example 9] Synthesis of 5-((2S,3aS,5S,7S,9aS)-2-(difluoromethoxy)-5-fluoro-3a,9a-dimethyl-9-oxo-2,3,3a,5,6,7,9,9a-octahydro-1H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-7-yl)nicotinonitrile (Example No. 248)

[0671] [ka]

[0672] (1) trans-dimethyl 1,4-dioxaspiro[4,4]nonane-7,8-dicarboxylate

[0673] [ka]

[0674] To a solution of trans-dimethyl 4-oxocyclopentane-1,2-dicarboxylate (25 g) in toluene (125 ml), 4-toluenesulfonic acid monohydrate (2.4 g) and 1,2-bis(trimethylsiloxy)ethane (46.4 g) were added at room temperature and stirred overnight at room temperature. Water was added to the reaction mixture, extracted with toluene, and the organic layer was dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the title compound (29.8 g). 1 H-NMR (CDCl3) δ: 3.96-3.85 (4H, m), 3.71 (6H, s), 3.34-3.22 (2H, m), 2.30-2.21 (2H, m), 2.14-2.04 (2H, m).

[0675] (2) trans-dimethyl 7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7,8-dicarboxylate

[0676] [ka]

[0677] To a 200 ml solution of THF in a 149 ml solution of 2 M LDA-THF-heptane-ethylbenzene, a 100 ml solution of trans-dimethyl-1,4-dioxaspiro[4,4]nonane-7,8-dicarboxylate (29.8 g) in THF was added at -78°C. After stirring for 20 minutes, methyl iodide (30.9 ml) was added, and the mixture was stirred at room temperature and allowed to stand overnight. Saturated aqueous ammonium chloride solution and 1 N hydrochloric acid were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (22.5 g). 1 H-NMR (CDCl3) δ: 3.96-3.80 (4H, m), 3.70 (6H, s), 2.89 (2H, d, J = 14.5 Hz), 1.91 (2H, d, J = 14.1 Hz), 1.30 (6H, s).

[0678] (3) trans-8-(methoxycarbonyl)-7,8-dimethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid

[0679] [ka]

[0680] To a solution of trans-dimethyl 7,8-dimethyl-1,4-dioxaspiro[4.4]nonane-7,8-dicarboxylate (1.02 g) in DMSO (7 ml), potassium tert-butoxide (0.503 g) was added under ice cooling. DMSO (3 ml) was added to the reaction mixture, and after sonication, the mixture was stirred under water cooling for 1 hour. Potassium tert-butoxide (0.084 g) was added to the reaction mixture and the mixture was stirred under water cooling for 2.5 hours. A further potassium tert-butoxide (0.042 g) was added to the reaction mixture and stirred for 10 minutes. Ice was added to the reaction mixture, diethyl ether was added, and the mixture was stirred to remove the organic layer. 1 N hydrochloric acid (4 ml) was added to the aqueous layer and extracted with a mixed solvent of ethyl acetate and n-hexane. The organic layer was washed with water and dried over sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the title compound (0.652 g). 1 ¹H-NMR (CDCl3) δ: 3.97-3.81 (7H, m), 2.85-2.78 (1H, m), 2.74-2.67 (1H, m), 2.14-2.07 (1H, m), 2.06-1.99 (1H, m), 1.44 (3H, s), 1.39 (3H, s). Protons of the carboxylic acid were not detected.

[0681] (4) trans-methyl 8-(((benzyloxy)carbonyl)amino)-7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate

[0682] [ka]

[0683] To a solution of trans-8-(methoxycarbonyl)-7,8-dimethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid (4.79 g) in toluene (47.9 ml), diisopropylethylamine (4.86 ml) and diphenyl phosphoryl azide (5.18 ml) were added at room temperature and the mixture was stirred at 110°C for 20 minutes. Benzyl alcohol (2.87 ml) and DMAP (0.453 g) were added to the reaction mixture and stirred overnight at 110°C. After returning to room temperature, saturated ammonium chloride aqueous solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (4.18 g). 1 H-NMR (CDCl3) δ: 7.40-7.30 (5H, m), 5.69 (1H, br s), 5.06 (2H, s), 3.94-3.82 (4H, m), 3.72 (3H, s), 2.70-2.62 (2H, m), 2.48-2.43 (1H, m), 1.97-1.90 (1H, m), 1.37 (3H, s), 1.32 (3H, s).

[0684] (5) trans-methyl 2-(((benzyloxy)carbonyl)amino)-1,2-dimethyl-4-oxocyclopentane-1-carboxylate

[0685] [ka]

[0686] To a solution of trans-methyl 8-(((benzyloxy)carbonyl)amino)-7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate (4.18 g) in acetone (41.8 ml), 2 N hydrochloric acid (8.63 ml) was added at room temperature and the mixture was stirred at 60°C for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with saturated sodium bicarbonate aqueous solution and water. The mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.82 g). 1 H-NMR (CDCl3) δ: 7.54-7.30 (5H, m), 5.60-5.52 (1H, m), 5.10-5.05 (2H, m), 3.82-3.75 (3H, m), 3.04-2.87 (3H, m), 2.40-2.27 (1H, m), 1.37 (3H, s), 1.32 (3H, s).

[0687] (6)rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate

[0688] [ka]

[0689] To a methanol (18.2 ml) solution of trans-methyl 2-(((benzyloxy)carbonyl)amino)-1,2-dimethyl-4-oxocyclopentane-1-carboxylate (1.82 g), sodium borohydride (0.237 g) was added under ice cooling and the mixture was stirred for 18 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (first title compound) and the crude product. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (second title compound). The first and second title compounds were combined to obtain the title compound (0.704 g). The relative stereochemistry of this compound was estimated from the results of NOESY analysis of compounds synthesized by the same method as described above. 1 H-NMR (CDCl3) δ: 7.41-7.29 (5H, m), 5.60 (1H, br s), 5.07 (2H, s), 4.52-4.43 (1H, m), 3.70 (3H, s), 2.77-2.66 (2H, m), 2.24-2.15 (1H, m), 2.07-2.01 (1H, m), 1.70-1.64 (1H, m), 1.40 (3H, s), 1.22 (3H, s).

[0690] Furthermore, a diastereomer (0.94 g) of the title compound was obtained.

[0691] rac-methyl (1S,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate

[0692] [ka]

[0693] 1H-NMR (CDCl3) δ: 7.39-7.29 (5H, m), 5.42 (1H, br s), 5.06 (2H, s), 4.52-4.42 (1H, m), 3.73 (3H, s), 2.76-2.62 (1H, m), 2.31-2.22 (2H, m), 2.21-2.11 (1H, m), 1.99 (1H, br s), 1.38 (3H, s), 1.21 (3H, s).

[0694] (7)rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0695] [ka]

[0696] rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate (0.704 g) was mixed with dichloromethane (7.0 ml) and water (1.4 ml). Potassium fluoride (0.684 g) and (bromodifluoromethyl)trimethylsilane (1.36 ml) were added at room temperature, and the mixture was stirred for two nights at room temperature. Potassium fluoride (0.684 g), (bromodifluoromethyl)trimethylsilane (1.36 ml), dichloromethane (5 ml), and water (0.7 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for three days. The reaction mixture was extracted with chloroform, the organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.581 g). 1H-NMR (CDCl3) δ: 7.40-7.30 (5H, m), 6.16 (1H, t, J = 74.3 Hz), 5.57 (1H, br s), 5.07 (2H, s), 4.77-4.68 (1H, m), 3.72 (3H, s), 2.93-2.82 (1H, m), 2.80-2.70 (1H, m), 2.40-2.31 (1H, m), 1.87-1.81 (1H, m), 1.39 (3H, s), 1.22 (3H, s).

[0697] (8)rac-methyl (1S,2S,4S)-2-amino-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0698] [ka]

[0699] To a solution of rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (0.581 g) in methanol (6 ml) and THF (1 ml), 10% Pd-C (0.250 g) was added at room temperature under an argon atmosphere, and the mixture was stirred at room temperature under a hydrogen atmosphere (atmospheric pressure) for 2 hours. After purging the reaction mixture with nitrogen, 10% Pd-C was filtered off using a Hyfloo Supercell as a filter aid, and the mixture was washed with methanol. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using InterSep SCX (GL Sciences Inc.) (eluent: methanol to 1 M ammonia-methanol solution) to obtain the title compound (0.334 g). 1¹H-NMR (CDCl3) δ: 6.17 (1H, t, J = 74.6 Hz), 4.81-4.71 (1H, m), 3.68 (3H, s), 2.82 (1H, dd, J = 14.9, 8.8 Hz), 2.27 (1H, dd, J = 14.3, 8.1 Hz), 1.93 (1H, dd, J = 14.5, 4.4 Hz), 1.85 (1H, dd, J = 15.2, 3.3 Hz), 1.33 (3H, s), 1.06 (3H, s). Protons of the amine were not detected.

[0700] (9)rac-methyl (1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0701] [ka]

[0702] To a methanol (6.6 ml) solution of rac-methyl (1S,2S,4S)-2-amino-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (0.33 g), potassium carbonate (0.288 g), imidazole-1-sulfonyl azide hydrochloride (0.437 g), and copper(II) sulfate pentahydrate (0.017 g) were added at room temperature and the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.327 g). 1H-NMR (CDCl3) δ: 6.19 (1H, t, J = 74.3 Hz), 4.92-4.84 (1H, m), 3.70 (3H, s), 2.68 (1H, dd, J = 14.5, 8.3 Hz), 2.33 (1H, dd, J = 15.2, 8.1 Hz), 2.19-2.15 (1H, m), 1.91 (1H, dd, J = 14.5, 4.4 Hz), 1.35 (3H, s), 1.31 (3H, s).

[0703] (10)rac-(1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid

[0704] [ka]

[0705] To a solution of rac-methyl (1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (0.326 g) in THF (3.3 ml), potassium trimethylsilanolate (0.212 g) was added at room temperature and the mixture was stirred at 60°C for 1 hour. Potassium trimethylsilanolate (0.106 g) and THF (1 ml) were added to the reaction mixture and the mixture was stirred at 60°C for 40 minutes. Potassium trimethylsilanolate (0.053 g) and THF (1 ml) were further added to the reaction mixture and the mixture was stirred at 60°C for 20 minutes. Ice water was added to the reaction mixture at room temperature and stirred for 10 minutes, then diethyl ether was added and the mixture was separated. Under ice cooling, 2 N hydrochloric acid was added to the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.304 g). 1¹H-NMR (CDCl3) δ: 6.20 (1H, t, J = 76.2 Hz), 4.92-4.85 (1H, m), 2.69 (1H, dd, J = 14.5, 8.3 Hz), 2.40 (1H, dd, J = 15.2, 8.6 Hz), 2.21 (1H, dd, J = 15.2, 2.9 Hz), 1.95 (1H, dd, J = 14.5, 4.8 Hz), 1.40 (3H, s), 1.38 (3H, s). Protons of the carboxylic acid were not detected.

[0706] (11)rac-(1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid chloride

[0707] [ka]

[0708] To a solution of rac-(1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid (0.304 g) in dichloromethane (3 ml) and DMF (0.0095 ml), oxalyl chloride (0.160 ml) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.325 g). 1 H-NMR (CDCl3) δ: 6.19 (1H, t, J = 73.6 Hz), 4.84-4.76 (1H, m), 2.80 (1H, dd, J = 14.9, 8.3 Hz), 2.38 (1H, dd, J = 14.9, 8.3 Hz), 2.25 (1H, dd, J = 14.9, 4.0 Hz), 2.03 (1H, dd, J = 14.9, 4.0 Hz), 1.54 (3H, s), 1.48 (3H, s).

[0709] (12)(2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid

[0710] [ka]

[0711] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (100 g) in DMF (800 ml), DBU (65.2 ml), triethylamine (151 ml), and tert-butylchlorodimethylsilane (71.7 g) in DMF (200 ml) were sequentially added dropwise under ice cooling and a nitrogen atmosphere. The mixture was stirred at room temperature. The reaction mixture was stirred at room temperature for 2.5 days. Water (1000 ml) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was washed three times with a mixed solvent of ethyl acetate and hexane (mixing ratio: 1 / 1). To the resulting aqueous layer, 6 N hydrochloric acid (72.1 ml) was added dropwise under ice cooling to adjust the pH to 2.5, and ethyl acetate and hexane were added and separated. The aqueous layer was extracted twice with a mixed solvent of ethyl acetate and hexane (mixing ratio: 1 / 1). The organic layers were washed three times with 0.01 N hydrochloric acid, once with water, and once with saturated saline solution. After drying the organic layers over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (134.67 g), which was then used directly in the next step.

[0712] (13) 1-(tert-butyl) 2-(1,3-dioxoindolin-2-yl) (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

[0713] [ka]

[0714] (2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (107.24 g) and 2-hydroxyisoindoline-1,3-dione (55.7 g) were mixed in DMF (1609 ml). The reaction mixture was cooled on ice, and under a nitrogen atmosphere, DMAP (3.79 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71.4 g) were added and the mixture was stirred at room temperature. Water (107 ml) was added dropwise to the reaction mixture under ice cooling, and a seed crystal of the title compound (0.100 g) was inoculated to crystallize. The mixture was stirred under ice cooling for 45 minutes. Water (1287 ml) was added dropwise to the reaction mixture, and the resulting suspension was stirred under ice cooling for 1 hour. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound (140.68 g). Seed crystals of the title compound can also be obtained by carrying out this reaction and adding water to induce crystallization. 1 H-NMR (CDCl3) δ: 7.91-7.86 (2H, m), 7.81-7.77 (2H, m), 4.73-4.49 (2H, m), 3.67-3.47 (2H, m), 2.44-2.36 (2H, m), 1.56 (9H, br s), 0.89 (9H, s), 0.11 (3H, s), 0.10 (3H, s).

[0715] (14) tert-butyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(5-cyanopyridine-3-yl)pyrrolidine-1-carboxylate

[0716] [ka]

[0717] A DMA (200 ml) solution of nickel(II) chloride ethylene glycol dimethyl ether complex (0.879 g) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.29 g) was bubbling with argon gas for 10 minutes at room temperature. 5-bromonicotinonitrile (3.66 g), 1-(tert-butyl) 2-(1,3-dioxoindolin-2-yl)(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (14.72 g), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-carboxylate (10.13 g), and 2,6-lutidine (2.33 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. A reductive cross-electrophile coupling reaction was carried out using a Vapourtec flow synthesizer (UV-150) with a holding time of 40 minutes, a set temperature of 30°C, a light output of 99%, a lamp wavelength of 405 nm, and a flow rate of 0.250 ml / min. The same reaction was carried out a total of six times. The resulting reaction solutions were combined and separated by adding 5% aqueous lithium chloride, ethyl acetate, and hexane. The aqueous layer was extracted twice with a mixed solvent of ethyl acetate and hexane (mixing ratio: 1 / 1). The organic layers were washed five times with 1 N aqueous sodium hydroxide solution and twice with saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain the title compound (first title compound) and the crude product. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 75 / 25) to obtain the title compound (second title compound). The first and second title compounds were combined to obtain the title compound (27.68 g). 1H-NMR (CDCl3) δ: 8.76 (1H, br s), 8.69 (1H, d, J = 2.2 Hz), 7.80 (1H, br s), 5.07-4.87 (1H, m), 4.42 (1H, br s), 3.77-3.57 (2H, m), 2.39-2.32 (1H, m), 1.84 (1H, br s), 1.47-1.16 (9H, m), 0.90 (9H, s), 0.09 (6H, s).

[0718] (15) tert-butyl (2S,4R)-2-(5-cyanopyridine-3-yl)-4-hydroxypyrrolidine-1-carboxylate

[0719] [ka]

[0720] To a solution of tert-butyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(5-cyanopyridine-3-yl)pyrrolidine-1-carboxylate (27.68 g) in THF (277 ml), 137 ml of 1 M tetrabutylammonium fluoride solution was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate, water, and saturated sodium bicarbonate aqueous solution were added to the reaction mixture and separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed twice with saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (18.13 g). 1H-NMR (CDCl3) δ: 8.77 (1H, br s), 8.69 (1H, d, J = 2.2 Hz), 7.80 (1H, br s), 5.10-4.95 (1H, m), 4.55 (1H, br s), 3.87-3.68 (2H, m), 2.51-2.43 (1H, m), 1.96-1.89 (1H, m), 1.74 (1H, br s), 1.44-1.19 (9H, m).

[0721] (16) tert-butyl (2S,4S)-2-(5-cyanopyridine-3-yl)-4-fluoropyrrolidine-1-carboxylate

[0722] [ka]

[0723] To a solution of tert-butyl (2S,4R)-2-(5-cyanopyrrolidine-3-yl)-4-hydroxypyrrolidine-1-carboxylate (18.13 g) in dichloromethane (501.6 ml), 59.2 ml of 2.33 M bis(2-methoxyethyl)aminosulfur trifluoride-THF solution was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours. It was stirred overnight at room temperature. Saturated sodium bicarbonate aqueous solution and water were added dropwise to the reaction mixture under ice cooling, and it was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and liquid-liquid was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were sequentially washed twice with saturated sodium bicarbonate aqueous solution and once with saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 30 / 70) to obtain the title compound (first title compound) and the crude product. The crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 0 to 30 / 70) to obtain the title compound (second title compound). The first and second title compounds were combined to obtain the title compound (15.95 g). 1H-NMR (CDCl3) δ: 8.78-8.70 (2H, m), 7.92-7.84 (1H, m), 5.31 (1H, dt, J = 52.6, 3.7 Hz), 5.17-4.98 (1H, m), 4.10-3.66 (2H, m), 2.72-2.53 (1H, m), 2.35-2.26 (1H, m), 1.47-1.25 (9H, m).

[0724] (17) tert-butyl (3S,5S)-5-(5-cyanopyridine-3-yl)-3-fluoro-2-oxopyrrolidine-1-carboxylate

[0725] [ka]

[0726] A solution of sodium periodate (41.0 g) in water (478 ml) was stirred under an argon atmosphere at room temperature for 20 minutes. Ruthenium tetroxide monohydrate (1.654 g) was added to the reaction mixture and stirred at room temperature for 10 minutes. Then, a solution of tert-butyl (2S,4S)-2-(5-cyanopyridine-3-yl)-4-fluoropyrrolidine-1-carboxylate (15.95 g) in ethyl acetate (159 ml) was added dropwise and the mixture was stirred at room temperature for 3 days. Saturated sodium bicarbonate aqueous solution (63.8 ml) and sodium thiosulfate (17.31 g) were added to the reaction mixture and stirred at room temperature for 20 minutes. Celite (12.3 g) and ethyl acetate (319 ml) were added to the reaction mixture and stirred at room temperature for 50 minutes. The reaction mixture was filtered through Celite, and the residue was washed with ethyl acetate (500 ml) to obtain the first filtrate. Next, the residue was washed with ethyl acetate, and the residue was suspended in ethyl acetate once more, then filtered again with Celite and washed with ethyl acetate to obtain a second filtrate. The second filtrate was washed with saturated saline solution and dried with sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the title compound (first title compound) (3.34 g). The first filtrate was separated to obtain the first aqueous layer and the first organic layer. The first aqueous layer was extracted with ethyl acetate and washed together with saturated saline solution to obtain the second organic layer. The emulsified portion of the first aqueous layer was filtered with Celite solution, the filtrate was extracted twice with ethyl acetate, and the resulting organic layer was washed with saturated saline solution to obtain the third organic layer. The second and third organic layers were dried together with sodium sulfate. After filtering off the sodium sulfate, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and after stirring at room temperature for 20 minutes, the resulting solid was filtered off and sequentially washed with ethyl acetate and a mixed solvent of ethyl acetate and diisopropyl ether (mixing ratio: ethyl acetate / diisopropyl ether = 1 / 5) to obtain the title compound (second title compound) (3.62 g). 1H-NMR (CDCl3) δ: 8.86 (1H, d, J = 2.2 Hz), 8.79 (1H, d, J = 2.2 Hz), 7.92 (1H, dd, J = 2.2, 2.2 Hz), 5.24-5.08 (2H, m), 2.99-2.85 (1H, m), 2.23-2.11 (1H, m), 1.38 (9H, s).

[0727] (18) 5-((2S,4S)-4-fluoro-5-oxopyrrolidine-2-yl)nicotinonitrile

[0728] [ka]

[0729] 6.96 g of tert-butyl (3S,5S)-5-(5-cyanopyrrolidine-3-yl)-3-fluoro-2-oxopyrrolidine-1-carboxylate was mixed with chloroform (69.6 ml) and acetonitrile (6.96 ml). Trifluoroacetic acid (34.8 ml) was added to the mixture under cooling in a water bath and stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue. This process of concentration under reduced pressure was repeated a total of two times. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 95 / 5 to 0 / 100) to obtain the trifluoroacetate of the title compound. Water was added to the trifluoroacetate of the title compound and neutralized with saturated sodium bicarbonate aqueous solution. A portion of the solution was purified by reverse-phase column chromatography (water / acetonitrile = 95 / 5 to 0 / 100) to obtain the title compound (first title compound) (0.789 g). The remaining solution was allowed to stand at room temperature. The obtained suspension was concentrated under reduced pressure, some of the water was removed, and the mixture was stirred at room temperature for 20 minutes. The resulting solid was filtered and sequentially washed with water and a mixed solvent of acetonitrile and water (mixing ratio: acetonitrile / water = 5 / 95), and dried under reduced pressure to obtain the crude product. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (water / acetonitrile = 95 / 5 to 0 / 100) to obtain the title compound (second title compound) (0.957 mg). The crude product was purified by reverse-phase column chromatography (water / acetonitrile = 95 / 5 to 0 / 100) to obtain the title compound (third title compound) (1.46 g). 1 H-NMR (DMSO-D6) δ: 8.99 (1H, d, J = 2.2 Hz), 8.85 (1H, d, J = 2.2 Hz), 8.75 (1H, br s), 8.32 (1H, dd, J = 2.2, 2.2 Hz), 5.23 (1H, ddd, J = 53.2, 7.6, 7.6 Hz), 4.75 (1H, td, J = 5.6, 2.7 Hz), 3.04-2.94 (1H, m), 2.10-1.96 (1H, m).

[0730] (19) 5-((2S,4S)-1-((1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-4-fluoro-5-oxopyrrolidine-2-yl)nicotinonitrile

[0731] [ka]

[0732] To a solution of 5-((2S,4S)-4-fluoro-5-oxopyrrolidine-2-yl)nicotinonitrile (0.15 g) in THF (4 ml), 1.3 M LiHMDS-THF (0.73 ml) was added at -78°C. After stirring the reaction mixture at 0°C for 10 minutes, a solution of rac-(1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carboxylic acid chloride (0.215 g) obtained in (10) in THF (3 ml) was added at -78°C. The reaction mixture was raised to room temperature over 1 hour and then stirred for 30 minutes. Under ice cooling, saturated ammonium chloride aqueous solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.0597 g). 1 H-NMR (CDCl3) δ: 8.84 (1H, d, J = 1.8 Hz), 8.76 (1H, d, J = 2.2 Hz), 7.85-7.83 (1H, m), 6.19 (1H, t, J = 73.6 Hz), 5.32-5.12 (2H, m), 4.66-4.56 (1H, m), 3.06-2.90 (1H, m), 2.72 (1H, dd, J = 15.2, 8.6 Hz), 2.43-2.34 (2H, m), 2.33-2.19 (1H, m), 2.10 (1H, dd, J = 14.5, 4.4 Hz), 1.53 (3H, s), 1.19 (3H, s).

[0733] Furthermore, a diastereomer (0.104 g) of the title compound was obtained. The stereochemistry of the title compound was estimated by tracing back from the difference in polarity between the title compound and its diastereomer, and from the NOESY results of the compound of Example No. 248 obtained by the same method as in this Production Example 9. Of the title compound and its diastereomer, the one with higher polarity was the title compound, and the one with lower polarity was the diastereomer.

[0734] 5-((2S,4S)-1-((1R,2R,4R)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-4-fluoro-5-oxopyrrolidine-2-yl)nicotinonitrile

[0735] [ka]

[0736] 1 H-NMR (CDCl3) δ: 8.86-8.84 (2H, m), 7.96 (1H, dd, J = 2.2, 2.2 Hz), 6.18 (1H, t, J = 73.6 Hz), 5.33-5.10 (2H, m), 4.62-4.54 (1H, m), 3.08-2.95 (1H, m), 2.70-2.63 (1H, m), 2.43-2.22 (2H, m), 2.09 (2H, d, J = 7.9 Hz), 1.64-1.51 (6H, m).

[0737] Using the diastereomer of the title compound as a starting material, the compound of Example No. 247 was obtained by the same method as in step (20) of Production Example 9.

[0738] (20)5-((2S,3aS,5S,7S,9aS)-2-(difluoromethoxy)-5-fluoro-3a,9a-dimethyl-9-oxo-2,3,3a,5,6,7,9,9a-octahydro-1H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-7-yl)nicotinonitrile

[0739] [ka]

[0740] 5-((2S,4S)-1-((1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-4-fluoro-5-oxopyrrolidine-2-yl)nicotinonitrile (0.0589 g) was dissolved in toluene (0.589 ml) at room temperature. 1 M trimethylphosphine-THF solution (0.405 ml) was added, and the mixture was stirred for 10 minutes. Acetic acid (0.0019 ml) was added, and the mixture was stirred at 50°C for 1 hour and 40 minutes. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.0281 g). The absolute stereochemistry of the title compound was determined from the NOESY of the compound obtained by the same method as described above, the stereochemistry of the commercially available starting material (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid, and the estimated absolute stereochemistry of the compound in Example No. 287. 1 H-NMR (CDCl3) δ: 8.87 (1H, d, J = 2.2 Hz), 8.84 (1H, d, J = 2.2 Hz), 7.95 (1H, dd, J = 2.2, 2.2 Hz), 6.19 (1H, t, J = 73.8 Hz), 5.53 (1H, ddd, J = 53.1, 6.7, 1.6 Hz), 5.27 (1H, d, J = 9.2 Hz), 4.85 (1H, q, J = 7.5 Hz), 2.98-2.81 (1H, m), 2.50-2.29 (4H, m), 1.87 (1H, d, J = 15.1 Hz), 1.27 (3H, s), 1.06 (3H, s).

[0741] [Manufacturing Example 10] Synthesis of (2S,3aS,5S,7S,9aS)-5-fluoro-7-(5-fluoropyridine-3-yl)-2-hydroxy-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one (Example No. 266)

[0742] [ka]

[0743] (1)(1S,3S,4S)-3-azido-4-((3S,5S)-3-fluoro-5-(5-fluoropyridine-3-yl)-2-oxopyrrolidine-1-carbonyl)-3,4-dimethylcyclopentyl formate

[0744] [ka]

[0745] When rac-(1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid chloride (0.111 g) obtained in step (11) of Production Example 9 was stored in a refrigerator (4 to 5°C), some of the difluoromethyl ether groups were converted to formyl ether groups. The commercially available (2S,4R)-1-(tert-butoxy To a solution of (3S,5S)-3-fluoro-5-(5-fluoropyrrolidine-3-yl)pyrrolidine-2-one (0.075 g), obtained from carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid by the same method as in production method S3, in THF (2.475 ml), 0.378 ml of 1.3 M LiHMDS-n-hexane solution was added at -78 °C, and the mixture was stirred at 0 °C for 10 minutes. To the reaction mixture, a solution of rac-(1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid chloride and rac-(1S,3S,4S)-3-azido-4-(chlorocarbonyl)-3,4-dimethylcyclopentyl formate (0.111 g) in THF (2 ml) was added at -78°C. After raising the temperature to room temperature over 2 hours, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain a mixture (0.038 g) of the title compound and (3S,5S)-1-((1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-3-fluoro-5-(5-fluoropyridine-3-yl)pyrrolidine-2-one. In addition, a mixture (0.0609 g) of the diastereomer of the title compound and (3S,5S)-1-((1R,2R,4R)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-3-fluoro-5-(5-fluoropyridine-3-yl)pyrrolidine-2-one was obtained.

[0746] The stereochemistry of the title compound was estimated by the difference in polarity between the title compound and its diastereomer, and by working backward from the stereochemistry estimation performed in step (3) of this manufacturing example 10. Of the mixture containing the title compound and the mixture containing the diastereomer of the title compound, the one with higher polarity was the mixture containing the title compound. The mixture containing the title compound was used as is in the next reaction.

[0747] (2)(2S,3aS,5S,7S,9aS)-5-fluoro-7-(5-fluoropyridine-3-yl)-3a,9a-dimethyl-9-oxo-2,3,3a,5,6,7,9,9a-octahydro-1H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-2-yl formate

[0748] [ka]

[0749] A mixture of (1S,3S,4S)-3-azido-4-((3S,5S)-3-fluoro-5-(5-fluoropyridine-3-yl)-2-oxopyrrolidine-1-carbonyl)-3,4-dimethylcyclopentyl formate and (3S,5S)-1-((1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-3-fluoro-5-(5-fluoropyridine-3-yl)pyrrolidine-2-one (0.0382 g) was dissolved in toluene (0.382 ml), to which 1 M trimethylphosphine-THF solution (0.267 ml) and acetic acid (0.0013 ml) were added at room temperature. The mixture was stirred at 50°C for 1 hour and 30 minutes. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.0184 g) and (2S,3aS,5S,7S,9aS)-2-(difluoromethoxy)-5-fluoro-7-(5-fluoropyridine-3-yl)-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one (Example No. 261) (0.0049 g). 1H-NMR (CDCl3) δ: 8.44 (1H, br s), 8.37 (1H, d, J = 2.7 Hz), 7.94 (1H, s), 5.56-5.32 (2H, m), 5.23-5.17 (1H, m), 2.91-2.73 (1H, m), 2.51-2.43 (1H, m), 2.43-2.30 (2H, m), 2.20-2.12 (1H, m), 1.74-1.67 (1H, m), 1.20 (3H, s), 1.05-1.02 (3H, m).

[0750] (3)(2S,3aS,5S,7S,9aS)-5-fluoro-7-(5-fluoropyridine-3-yl)-2-hydroxy-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9one

[0751] [ka]

[0752] (2S,3aS,5S,7S,9aS)-5-fluoro-7-(5-fluoropyridine-3-yl)-3a,9a-dimethyl-9-oxo-2,3,3a,5,6,7,9,9a-octahydro-1H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-2-yl formate (0.019 g) was dissolved in THF (1 ml) and potassium trimethylsilanolate (0.011 g) was added and the mixture was stirred at room temperature for 27 minutes. Ice water was added and the mixture was stirred, and ethyl acetate and methanol were added for extraction. The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / ethyl acetate) to obtain the title compound (0.0105 g). The stereochemistry of the title compound was estimated from the difference in polarity between the compounds of Example No. 247 and 248, and from the polarity of the compound of Example No. 261 obtained in step (2) of this production example 10. Of the compounds of Example No. 247 and 248, the compound with higher polarity was the compound of Example No. 248, and the compound with lower polarity was the compound of Example No. 247. 1 H-NMR (CDCl3) δ: 8.50-8.45 (1H, m), 8.40 (1H, d, J = 2.6 Hz), 7.42-7.35 (1H, m), 5.60-5.39 (1H, m), 5.27-5.20 (1H, m), 4.61-4.52 (1H, m), 2.94-2.75 (1H, m), 2.47-2.35 (2H, m), 2.34-2.26 (1H, m), 2.18-2.10 (1H, m), 1.79-1.51 (2H, m), 1.29 (3H, d, J = 0.9 Hz), 1.04 (3H, d, J = 0.9 Hz).

[0753] [Manufacturing Example 11] Synthesis of (2S,3aS,5S,7S,9aS)-2-(difluoromethoxy)-7-(1-(difluoromethyl)-1H-pyrazole-4-yl)-5-fluoro-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one (Example No. 287)

[0754] [ka]

[0755] (1) trans-8-(methoxycarbonyl)-7,8-dimethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid

[0756] [ka]

[0757] To a solution of trans-dimethyl 7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7,8-dicarboxylate (10.0 g), obtained by the same method as in step (2) of Production Example 9, in 1,4-dioxane (100 ml) and water (70.0 ml), 20.2 ml of 2 N sodium hydroxide aqueous solution was added under ice cooling, and the mixture was stirred at 60°C for two nights. After concentrating the reaction mixture under reduced pressure, water and chloroform were added and the mixture was separated. 2 N hydrochloric acid was added to the aqueous layer to adjust the pH to 4, and ethyl acetate was added for extraction. The organic layers were washed together with saturated brine, dried over sodium sulfate, and the sodium sulfate was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (3.51 g). The title compound (1.02 g) was obtained by carrying out a reaction similar to this one. These were used together in the following reaction. 1 ¹H-NMR (CDCl3) δ: 3.97-3.81 (7H, m), 2.85-2.78 (1H, m), 2.74-2.67 (1H, m), 2.14-2.07 (1H, m), 2.06-1.99 (1H, m), 1.44 (3H, s), 1.39 (3H, s). Protons of the carboxylic acid were not detected.

[0758] (2) trans-methyl 8-(((benzyloxy)carbonyl)amino)-7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate

[0759] [ka]

[0760] To a solution of trans-8-(methoxycarbonyl)-7,8-dimethyl-1,4-dioxaspiro[4.4]nonane-7-carboxylic acid (4.51 g) in toluene (45.1 ml), diisopropylethylamine (4.57 ml) and diphenyl phosphoryl azide (4.05 ml) were added at room temperature. The reaction mixture was stirred at 110°C for 1 hour and 30 minutes, then benzyl alcohol (2.70 ml) and DMAP (0.427 g) were added, and the mixture was stirred at 110°C for two days. The reaction solution was concentrated under reduced pressure, and water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (6.12 g). 1 H-NMR (CDCl3) δ: 7.41-7.28 (5H, m), 5.68 (1H, br s), 5.06 (2H, s), 3.95-3.80 (4H, m), 3.72 (3H, s), 2.69-2.62 (2H, m), 2.45 (1H, d, J = 14.5 Hz), 1.93 (1H, d, J = 14.9 Hz), 1.37 (3H, s), 1.32 (3H, s).

[0761] (3) trans-methyl 2-(((benzyloxy)carbonyl)amino)-1,2-dimethyl-4-oxocyclopentane-1-carboxylate

[0762] [ka]

[0763] To a solution of trans-methyl 8-(((benzyloxy)carbonyl)amino)-7,8-dimethyl-1,4-dioxaspiro[4,4]nonane-7-carboxylate (6.12 g) in acetone (61.2 ml), 12.62 ml of 2 N hydrochloric acid was added at room temperature, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was mixed with saturated sodium bicarbonate aqueous solution and water, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (3.39 g). 1 H-NMR (CDCl3) δ: 7.41-7.31 (5H, m), 5.55 (1H, s), 5.07 (2H, s), 3.77 (3H, s), 2.97-2.90 (3H, m), 2.36-2.30 (1H, m), 1.37 (3H, s), 1.32 (3H, s).

[0764] (4)rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate

[0765] [ka]

[0766] To a solution of trans-methyl 2-(((benzyloxy)carbonyl)amino)-1,2-dimethyl-4-oxocyclopentane-1-carboxylate (3.39 g) in methanol (33.9 ml), sodium borohydride (0.481 g) was added at 0°C. After stirring at 0°C for 1 hour, saturated ammonium chloride aqueous solution was added. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.18 g). The relative stereochemistry of this compound was estimated by measuring the NOESY of the title compound prepared by the same method as described above. 1 ¹H-NMR (CDCl3) δ: 7.38-7.30 (5H, m), 5.60 (1H, br s), 5.07 (2H, s), 4.50-4.44 (1H, m), 3.70 (3H, s), 2.76-2.68 (2H, m), 2.23-2.16 (1H, m), 1.73-1.62 (1H, m), 1.40 (3H, s), 1.22 (3H, s). Protons of alcohol were not detected.

[0767] Furthermore, a diastereomer (0.863 g) of the title compound was obtained.

[0768] rac-methyl (1S,2S,4R)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate

[0769] [ka]

[0770] 1H-NMR (CDCl3) δ: 7.38-7.30 (5H, m), 5.43 (1H, br s), 5.06 (2H, s), 4.51-4.42 (1H, m), 3.73 (3H, s), 2.73-2.64 (1H, m), 2.29-2.14 (3H, m), 2.05-1.95 (1H, m), 1.38 (3H, s), 1.22 (3H, s).

[0771] (5)rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0772] [ka]

[0773] To a solution of rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-hydroxy-1,2-dimethylcyclopentane-1-carboxylate (1.15 g) in dichloromethane (11.5 ml) and water (2.3 ml), potassium hydrogen fluoride (1.40 g) and (bromodifluoromethyl)trimethylsilane (2.77 ml) were added at room temperature and the mixture was stirred overnight at room temperature. Potassium hydrogen fluoride (1.40 g), (bromodifluoromethyl)trimethylsilane (2.77 ml), dichloromethane (5.0 ml), and water (1.0 ml) were added to the reaction mixture and stirred at room temperature for 3 days. The mixture was then extracted with chloroform and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.07 g). 1H-NMR (CDCl3) δ: 7.40-7.30 (5H, m), 6.16 (1H, t, J = 74.3 Hz), 5.57 (1H, br s), 5.07 (2H, s), 4.77-4.68 (1H, m), 3.72 (3H, s), 2.93-2.82 (1H, m), 2.80-2.70 (1H, m), 2.40-2.31 (1H, m), 1.87-1.81 (1H, m), 1.39 (3H, s), 1.22 (3H, s).

[0774] (6)rac-methyl (1S,2S,4S)-2-amino-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0775] [ka]

[0776] To a solution of rac-methyl (1S,2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (1.07 g) in methanol (10.7 ml), 10% Pd-C (0.214 g) was added at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere (atmospheric pressure) for 2 hours. After purging the reaction mixture with nitrogen, 10% Pd-C was filtered off using a Hyfloo Supercell as a filter aid, and the mixture was washed with methanol. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using InterSep SCX (GL Sciences) (eluent: methanol to 1 M ammonia-methanol solution) to obtain the title compound (0.550 g). 1¹H-NMR (CDCl3) δ: 6.17 (1H, t, J = 74.6 Hz), 4.79-4.72 (1H, m), 3.68 (3H, s), 2.82 (1H, dd, J = 15.1, 8.6 Hz), 2.27 (1H, dd, J = 14.5, 8.1 Hz), 1.93 (1H, dd, J = 14.5, 4.3 Hz), 1.85 (1H, dd, J = 15.1, 3.2 Hz), 1.33 (3H, s), 1.05 (3H, s). No amine protons were detected.

[0777] (7)rac-methyl (1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate

[0778] [ka]

[0779] To a methanol (22 ml) solution of rac-methyl (1S,2S,4S)-2-amino-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (0.550 g), imidazole-1-sulfonyl azide (0.729 g), potassium carbonate (0.481 g), and copper(II) sulfate pentahydrate (0.0289 g) were added at room temperature and the mixture was stirred for 3 days. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.533 g). 1H-NMR (CDCl3) δ: 6.19 (1H, t, J = 74.1 Hz), 4.91-4.85 (1H, m), 3.70 (3H, s), 2.68 (1H, dd, J = 14.5, 8.1 Hz), 2.33 (1H, dd, J = 15.1, 8.6 Hz), 2.17 (1H, dd, J = 15.1, 2.7 Hz), 1.91 (1H, dd, J = 14.5, 4.8 Hz), 1.35 (3H, s), 1.31 (3H, s).

[0780] (8)rac-(1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid

[0781] [ka]

[0782] To a solution of rac-methyl (1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylate (0.282 g) in THF (2.8 ml), potassium trimethylsilanolate (0.306 g) was added at room temperature and the mixture was stirred at 60°C for 1 hour. Water and diethyl ether were added to the reaction mixture at room temperature and stirred. After separating the aqueous layer, the organic layer was extracted again with water. Hydrochloric acid (2 N) was added to the combined aqueous layer to adjust the pH to 1, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.255 g). 1H-NMR (DMSO-D6) δ: 12.73 (1H, br s), 6.66 (1H, t, J = 75.7 Hz), 4.79-4.73 (1H, m), 2.62 (1H, dd, J = 14.3, 8.4 Hz), 2.35 (1H, dd, J = 14.8, 8.4 Hz), 2.03 (1H, dd, J = 15.1, 3.2 Hz), 1.71 (1H, dd, J = 14.5, 4.3 Hz), 1.32 (3H, s), 1.24 (3H, s).

[0783] (9)rac-(1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid chloride

[0784] [ka]

[0785] To a solution of rac-(1S,2S,4S)-2-azide-4-(difluoromethoxy)-1,2-dimethylcyclopentane-1-carboxylic acid (0.205 g) in chloroform (2.0 ml), DMF (0.0064 ml) and oxalyl chloride (0.106 ml) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.220 g), which was then used directly in the next step.

[0786] (10)(3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl 4-nitrobenzoate

[0787] [ka]

[0788] To a mixture of (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one (0.566 g), 4-nitrobenzoic acid (0.421 g), and triphenylphosphine (0.660 g) obtained in step (19) of Production Example 12, toluene (8.49 ml) was added under an argon atmosphere. Bis(2-methoxyethyl)(E)-diazene-1,2-dicarboxylate (0.589 g) was added to this solution under ice cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes, then allowed to stand overnight. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.733 g). 1 H-NMR (CDCl3) δ: 8.33-8.25 (4H, m), 7.67 (1H, s), 7.55 (1H, s), 7.19 (1H, t, J = 60.3 Hz), 7.15-7.11 (2H, m), 6.90-6.86 (2H, m), 5.80 (1H, t, J = 8.1 Hz), 5.06 (1H, d, J = 15.1 Hz), 4.64 (1H, dd, J = 8.6, 3.2 Hz), 3.82 (3H, s), 3.71 (1H, d, J = 15.1 Hz), 2.62-2.45 (2H, m).

[0789] (11)(3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one

[0790] [ka]

[0791] (3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-1-(4-methoxybenzyl)-2-oxopyrrolidine-3-yl 4-nitrobenzoate (0.733 g) was mixed with THF (7.33 ml) and methanol (7.33 ml), and 2 N aqueous sodium hydroxide solution (0.979 ml) was added at room temperature. The mixture was stirred at 50°C for 2 hours. 2 N aqueous sodium hydroxide solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.532 g). 1 H-NMR (CDCl3) δ: 7.60 (1H, s), 7.48 (1H, s), 7.17 (1H, t, J = 60.2 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 4.98 (1H, d, J = 14.5 Hz), 4.62 (1H, t, J = 7.9 Hz), 4.52 (1H, dd, J = 7.9, 3.1 Hz), 3.80 (3H, s), 3.67 (1H, d, J = 14.5 Hz), 3.20 (1H, br s), 2.39-2.27 (2H, m).

[0792] (12)(3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoro-1-(4-methoxybenzyl)pyrrolidine-2-one

[0793] [ka]

[0794] To a solution of (3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one (0.508 g) in toluene (5.08 ml), pyridine-2-sulfonyl fluoride (0.485 g) in toluene (2.54 ml) and DBU (0.567 ml) were added and stirred for 1 hour, then allowed to stand overnight. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, sodium sulfate was added and dried, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.444 g). 1 H-NMR (CDCl3) δ: 7.69 (1H, s), 7.58 (1H, s), 7.18 (1H, t, J = 60.3 Hz), 7.02 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 9.2 Hz), 5.17 (1H, ddd, J = 52.3, 7.5, 4.8 Hz), 4.97 (1H, d, J = 15.1 Hz), 4.44-4.40 (1H, m), 3.80 (3H, s), 3.64 (1H, dd, J = 14.5, 2.7 Hz), 2.84-2.71 (1H, m), 2.27-2.13 (1H, m).

[0795] (13)(3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one

[0796] [ka]

[0797] (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoro-1-(4-methoxybenzyl)pyrrolidine-2-one (0.444 g) was mixed with acetonitrile (7.99 ml) and water (0.888 ml), and ammonium hexanitratocerium(IV) (3.59 g) was added under ice cooling. The mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and 1 N hydrochloric acid (30 ml) was added to the residue and washed with diethyl ether (30 ml). The organic layer was extracted with 1 N hydrochloric acid (25 ml), and 4 N aqueous sodium hydroxide solution was added to the combined aqueous layer to adjust the pH to >11, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound. The crude product (0.158 g) of the title compound obtained by the same method as in steps (19) to (21) of Production Example 12 was mixed with diisopropyl ether, and the slurry was purified to obtain the title compound (0.370 g). 1 H-NMR (DMSO-D6) δ: 8.64 (1H, br s), 8.25 (1H, s), 7.83 (1H, s), 7.78 (1H, t, J = 59.3 Hz), 5.18 (1H, dt, J = 53.0, 7.7 Hz), 4.61 (1H, td, J = 5.6, 2.7 Hz), 2.94-2.84 (1H, m), 2.12-1.98 (1H, m).

[0798] (14)(3S,5S)-1-((1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one

[0799] [ka]

[0800] To a solution of (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one (0.114 g) in THF (3.06 ml), 1.3 M LiHMDS-THF solution (0.46 ml) was added at -78 °C, and the mixture was stirred at 0 °C for 10 minutes. To the reaction mixture, a solution of rac-(1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carboxylic acid chloride (0.153 g) obtained in (9) above in THF (1 ml) was added at -78 °C, and the mixture was stirred at -78 °C for 30 minutes, followed by stirring at 0 °C for 1 hour. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.0831 g). 1 H-NMR (CDCl3) δ: 7.85 (1H, s), 7.68 (1H, s), 7.15 (1H, t, J = 60.3 Hz), 6.17 (1H, t, J = 73.8 Hz), 5.32-5.28 (1H, m), 5.16 (1H, ddd, J = 51.5, 7.5, 5.1 Hz), 4.65-4.58 (1H, m), 2.94-2.80 (2H, m), 2.52-2.33 (2H, m), 2.28-2.06 (2H, m), 1.39 (3H, s), 1.18 (3H, s).

[0801] Furthermore, a diastereomer (0.075 g) of the title compound was obtained. The stereochemistry of the title compound and its diastereomer was estimated by tracing back from the difference in polarity between the title compound and its diastereomer, and from the stereochemistry of the compound of Example No. 287, which was estimated in step (15) of this production example 11. Of the title compound and its diastereomer, the one with higher polarity was the title compound, and the one with lower polarity was the diastereomer.

[0802] (15)(2S,3aS,5S,7S,9aS)-2-(difluoromethoxy)-7-(1-(difluoromethyl)-1H-pyrazole-4-yl)-5-fluoro-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one

[0803] [ka]

[0804] (3S,5S)-1-((1S,2S,4S)-2-azido-4-(difluoromethoxy)-1,2-dimethylcyclopentan-1-carbonyl)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one (0.083 g) was dissolved in toluene (0.83 ml), to which 1 M trimethylphosphine-THF solution (0.553 ml) was added at room temperature and the mixture was stirred for 30 minutes. Acetic acid (0.0026 ml) was added to the reaction mixture and the mixture was stirred at 60°C for 1 hour and 30 minutes. The reaction mixture was returned to room temperature, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.0468 g). The absolute stereochemistry of the title compound was estimated from the NOESY of the compound obtained by the same method as described above, and from the results of X-ray crystal structure analysis of the compound of Example No. 298. 1 H-NMR (CDCl3) δ: 7.88 (1H, s), 7.75 (1H, s), 7.14 (1H, t, J = 60.4 Hz), 6.18 (1H, t, J = 73.8 Hz), 5.48 (1H, dd, J = 53.1, 5.7 Hz), 5.34 (1H, d, J = 9.2 Hz), 4.82 (1H, q, J = 7.5 Hz), 2.79-2.25 (5H, m), 1.86 (1H, d, J = 15.1 Hz), 1.25 (3H, s), 0.90 (3H, s).

[0805] [Production Example 12] Synthesis of (3aS,5S,7S,9aS)-7-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2,2,5-trifluoro-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one (Example No. 298)

[0806] [ka]

[0807] (1) Dimethyl 4,4-difluorocyclopentane-1,2-dicarboxylate

[0808] [ka]

[0809] Diethylaminosulfur trifluoride (48.3 g) was added to a solution of dimethyl 4-oxocyclopentane-1,2-dicarboxylate (20 g) in dichloromethane (200 ml) under ice cooling, and the mixture was stirred at room temperature for 96 hours. The reaction mixture was added dropwise to a 9% sodium bicarbonate aqueous solution (760 ml) under ice cooling, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). The fraction containing impurities was purified again in the same manner to obtain the title compound (18.6 g). 1 H-NMR (CDCl3) δ: 3.74 (6H, s), 3.40-3.32 (2H, m), 2.60-2.31 (4H, m).

[0810] (2) A mixture of three stereoisomers containing dimethyl (1S,2S)-4,4-difluoro-1,2-dimethylcyclopentane-1,2-dicarboxylate

[0811] [ka]

[0812] To a 134 ml solution of THF in a 2.0 M LDA-THF-heptane-ethylbenzene solution (72.5 ml), a 67 ml THF solution of dimethyl 4,4-difluorocyclopentane-1,2-dicarboxylate (13.4 g) was added dropwise over 30 minutes at -78°C. After stirring at -78°C for 30 minutes, methyl iodide (15.1 ml) was added dropwise over 30 minutes. After stirring at -78°C for 1 hour, the mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the stereoisomer mixture (15.2 g, dr=3:1) of the title compound. 1 H-NMR (CDCl3) δ: 3.73 (4.5H, s), 3.69 (1.5H, s), 3.10 (1.5H, q, J = 16.7 Hz), 3.00-2.87 (0.5H, m), 2.28-2.15 (2H, m), 1.40 (1.5H, s), 1.30 (4.5H, s).

[0813] In this reaction, d3-methyl iodide (CAS number: 865-50-9) is used instead of methyl iodide, and then the same reaction as in (3) to (23) of Production Example 12 is carried out to obtain the compound of Example No. 303.

[0814] (3) A mixture of four diastereomers containing (1S,2S)-4,4-difluoro-2-(methoxycarbonyl)-1,2-dimethylcyclopentane-1-carboxylic acid

[0815] [ka]

[0816] Dimethyl 4,4-difluoro-1,2-dimethylcyclopentane-1,2-dicarboxylate (15.2 g) was mixed with 1,4-dioxane (137 ml) and water (91 ml). Under ice cooling, 33.4 ml of 2 N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The organic solvent was removed from the reaction mixture under reduced pressure, water was added, and the mixture was washed with chloroform. 6 N hydrochloric acid was added to the aqueous layer to adjust the pH to 4, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound, a mixture of diastereomers (5.57 g, trans / cis = 1 / 1). 1 H-NMR (DMSO-D6) δ: 12.70 (1H, br s), 3.64 (1.5H, s), 3.58 (1.5H, s), 3.01-2.72 (2H, m), 2.35-2.15 (2H, m), 1.33 (1.5H, s), 1.30 (1.5H, s), 1.26 (1.5H, s), 1.17 (1.5H, s).

[0817] (4) A mixture of four diastereomers containing methyl (1S,2S)-2-(((benzyloxy)carbonyl)amino)-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate

[0818] [ka]

[0819] To a solution of 4,4-difluoro-2-(methoxycarbonyl)-1,2-dimethylcyclopentane-1-carboxylic acid (6.02 g) in toluene (60.2 ml), diisopropylethylamine (6.68 ml) and benzyl alcohol (3.94 ml) were added at room temperature. Diphenyl phosphoryl azide (5.91 ml) was added to the reaction mixture at 110 °C and stirred overnight at the same temperature. The reaction mixture was returned to room temperature, saturated ammonium chloride aqueous solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound, a mixture of diastereomers (8.16 g, trans / cis = 1 / 1). 1 H-NMR (CDCl3) δ: 7.40-7.30 (5H, m), 5.60 (0.5H, s), 5.49 (0.5H, s), 5.10-5.03 (2H, m), 3.75 (1.5H, s), 3.74 (1.5H, s), 3.24-2.75 (2.5H, m), 2.44-2.32 (0.5H, m), 2.25-2.12 (1H, m), 1.50 (1.5H, s), 1.38 (1.5H, s), 1.35 (1.5H, s), 1.32 (1.5H, s).

[0820] (5) Hydrobromide of a mixture of four diastereomers containing methyl (1S,2S)-2-amino-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate

[0821] [ka]

[0822] 1.00 g of methyl 2-(((benzyloxy)carbonyl)amino)-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate was added to 5.0 ml of a 25% hydrobromide-acetic acid solution at room temperature. After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. Diisopropyl ether was added to the resulting residue, and the slurry was purified to obtain the title compound, a mixture of diastereomers (0.773 g, trans / cis = 1 / 1). 1 H-NMR (DMSO-D6) δ: 8.30 (3H, br s), 3.73 (1.5H, s), 3.71 (1.5H, s), 3.16-3.04 (0.5H, m), 2.96-2.84 (0.5H, m), 2.79-2.51 (2H, m), 2.46-2.31 (1H, m), 1.42 (1.5H, s), 1.37 (1.5H, s), 1.34 (1.5H, s), 1.29 (1.5H, s).

[0823] (6) trans-methyl 2-azide-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate

[0824] [ka]

[0825] To a methanol (16 ml) solution of methyl 2-amino-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate hydrobromide (0.800 g), imidazole-1-sulfonyl azide hydrochloride (0.873 g), potassium carbonate (0.959 g), and copper(II) sulfate pentahydrate (0.035 g) were added at room temperature and the mixture was stirred overnight. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). The same reaction was carried out in another container on the same scale, and the purified fractions were combined to obtain the title compound (0.569 g). 1 H-NMR (CDCl3) δ: 3.76 (3H, s), 2.94-2.80 (1H, m), 2.52-2.34 (2H, m), 2.30-2.20 (1H, m), 1.44 (3H, s), 1.41 (3H, s).

[0826] Furthermore, a cis-diastereomer (0.523 g) of the title compound was obtained.

[0827] cis-methyl 2-azide-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate

[0828] [ka]

[0829] 1 H-NMR (CDCl3) δ: 3.75 (3H, s), 3.08 (1H, td, J = 17.8, 15.1 Hz), 2.55 (1H, td, J = 12.6, 5.7 Hz), 2.45-2.33 (1H, m), 2.23-2.13 (1H, m), 1.60 (3H, s), 1.32 (3H, s).

[0830] The title compound and its cis-diastereomer are both racemic. The relative stereochemistry of the title compound was determined by comparing the NMR spectrum of a compound obtained by azidating trans-methyl (1S,2S)-2-amino-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate, whose relative stereochemistry was estimated by NOESY, using the same method as in step (6) of this production example. The above trans-methyl (1S,2S)-2-amino-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate was obtained by hydrogenation using the same method as in step (5) of this production example, and then purified by silica gel column chromatography.

[0831] (7) trans-2-azide-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylic acid

[0832] [ka]

[0833] To a solution of trans-methyl 2-azido-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylate (0.568 g) in THF (5.7 ml), potassium trimethylsilanolate (0.521 g) was added at room temperature. The reaction mixture was stirred at 50°C for 25 minutes, then returned to room temperature, and stirred with ice water for 10 minutes. Diethyl ether was added to the reaction mixture and the mixture was separated. Hydrochloric acid was added to the aqueous layer under ice cooling to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.420 g). 1 ¹H-NMR (CDCl3) δ: 2.77-2.64 (1H, m), 2.41-2.25 (2H, m), 2.17-2.06 (1H, m), 1.37 (3H, s), 1.29 (3H, s). Protons of the carboxylic acid were not detected.

[0834] (8) trans-2-azide-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylic acid chloride

[0835] [ka]

[0836] To a solution of trans-2-azide-4,4-difluoro-1,2-dimethylcyclopentane-1-carboxylic acid (0.127 g) in chloroform (1.3 ml) and DMF (0.0045 ml), oxalyl chloride (0.075 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, the crude product of the title compound (0.138 g) was obtained by azeotropic reaction with toluene and used directly in the next step.

[0837] (9) 1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide

[0838] [ka]

[0839] To a suspension of 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (10 g) and N,O-dimethylhydroxyamine hydrochloride (18.1 g) in DMF (50 ml), n-propylphosphonic anhydride (54.4 ml) and triethylamine (43 ml) were added dropwise under ice cooling. The mixture was stirred at room temperature and allowed to stand for 2 days. After that, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (first title compound). The aqueous layer was further extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was similarly purified by silica gel column chromatography to obtain the title compound (second title compound). The first and second title compounds were combined to obtain the title compound (10.3 g). 1H-NMR (CDCl3) δ: 8.35 (1H, s), 8.12 (1H, s), 7.21 (1H, t, J = 60.6 Hz), 3.74 (3H, s), 3.36 (3H, s).

[0840] (10) 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde

[0841] [ka]

[0842] To a solution of 1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (2.88 g) in THF (40 ml), 1.0 M DIBAL-toluene solution (17.6 ml) was added dropwise at -78 °C and the mixture was stirred for 30 minutes. Methanol (20 ml) and ethyl acetate were added to the reaction mixture, and the mixture was concentrated under reduced pressure. Rochelle salt aqueous solution and ethyl acetate were added to the resulting residue and stirred. Insoluble matter was filtered off, the filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.62 g). 1 H-NMR (CDCl3) δ: 9.97 (1H, s), 8.36 (1H, s), 8.11 (1H, s), 7.24 (1H, t, J = 60.3 Hz).

[0843] (11)(R,E)-N-((1-(difluoromethyl)-1H-pyrazole-4-yl)methylene)-2-methylpropane-2-sulfinamide

[0844] [ka]

[0845] To a solution of 1-(difluoromethyl)-1H-pyrazole-4-carboaldehyde (1.62 g) in THF (27 ml), (R)-(+)-tert-butylsulfinamide (2.02 g) and tetraethyl orthotitanate (containing ≤35% tetraisopropyl orthotitanate) (7.15 ml) were added at room temperature and stirred overnight at room temperature. Saturated saline and ethyl acetate were added to the reaction mixture, the precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.53 g). 1 H-NMR (CDCl3) δ: 8.55 (1H, s), 8.23 ​​(1H, s), 8.08 (1H, s), 7.23 (1H, t, J = 60.3 Hz), 1.25 (9H, s).

[0846] (12)(R)-N-((S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)-2-methylpropane-2-sulfinamide

[0847] [ka]

[0848] To a solution of (R,E)-N-((1-(difluoromethyl)-1H-pyrazole-4-yl)methylene)-2-methylpropane-2-sulfinamide (4.07 g) in dichloromethane (80 ml), 16.3 ml of 2 M allyl magnesium chloride-THF solution was added dropwise over 15 minutes at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture. Extraction was performed with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane). The crude product (4.73 g) obtained was purified by preparative HPLC (Daicel CHIRALPAK IC, hexane / ethanol = 9 / 1) to obtain the title compound (3.24 g), which was used in the next step without measuring NMR. The stereochemistry of this compound was estimated from the description in non-patent literature (Synlett 2012; 23(9): 1374-1378).

[0849] (13) Benzyl (S)-(1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)carbamate

[0850] [ka]

[0851] To a methanol (30 ml) solution of (R)-N-((S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)-2-methylpropane-2-sulfinamide (3.0 g), 4 M hydrogen chloride-cyclopentyl methyl ether solution (7.72 ml) was added at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in THF (30 ml) and water (9 ml), and then sodium carbonate (3.6 g) and benzyl chloroformate (3.86 g) were added at room temperature. After stirring the reaction mixture for 3 hours, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (3.53 g). 1 H-NMR (CDCl3) δ: 7.71 (1H, s), 7.59 (1H, s), 7.38-7.31 (5H, m), 7.13 (1H, t, J = 60.5 Hz), 5.79-5.67 (1H, m), 5.18-5.10 (4H, m), 5.00-4.84 (2H, m), 2.63-2.50 (2H, m).

[0852] (14) Benzyl (S)-(1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)(4-methoxybenzyl)carbamate

[0853] [ka]

[0854] To a solution of benzyl (S)-(1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)carbamate (3.53 g) in DMF (35.3 ml), 4-methoxybenzyl chloride (2.24 ml) and a 55% sodium hydride-mineral oil mixture (0.719 g) were added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour, then saturated ammonium chloride aqueous solution and water were added under ice cooling, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane (mixing ratio: 1 / 1). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (4.52 g), which was used directly in the next step.

[0855] (15) Benzyl ((1S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3,4-dihydroxybutyl)(4-methoxybenzyl)carbamate

[0856] [ka]

[0857] Benzyl (S)-(1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-buten-1-yl)(4-methoxybenzyl)carbamate (4.52 g) was mixed with THF (22.6 ml), tert-butyl alcohol (22.6 ml), N-methylmorpholine N-oxide (1.26 g), and water (4.52 ml), and 13.01 ml of 2% osmium tetroxide aqueous solution was added under ice cooling. The reaction mixture was stirred at room temperature for 1.5 hours, then saturated sodium thiosulfate aqueous solution was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the crude product of the title compound (4.86 g), which was used directly in the next reaction.

[0858] (16) Benzyl ((1S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-4-oxobutyl)(4-methoxybenzyl)carbamate

[0859] [ka]

[0860] Benzyl ((1S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3,4-dihydroxybutyl)(4-methoxybenzyl)carbamate (6.19 g) was mixed with dichloromethane (61.9 ml) and saturated sodium bicarbonate aqueous solution (61.9 ml). Under ice cooling, 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (0.407 g), potassium bromide (0.31 g), and sodium hypochlorite pentahydrate (2.78 g) were added, and the mixture was stirred for 20 minutes. Then saturated sodium thiosulfate aqueous solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (6.22 g), which was then used in the next step.

[0861] (17)(4S)-4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2-hydroxybutanoic acid

[0862] [ka]

[0863] Benzyl ((1S)-1-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-4-oxobutyl)(4-methoxybenzyl)carbamate (6.16 g) was mixed with 2-methyl-2-butene (13.8 ml) and tert-butyl alcohol (185 ml). A mixed solution of sodium dihydrogen phosphate dihydrate (3.05 g) and water (30.8 ml) was added at room temperature, and a mixed solution of sodium chlorite (4.42 g) and water (30.8 ml) was added, and the mixture was stirred overnight. Saturated sodium sulfite aqueous solution and 6N hydrochloric acid were added to the reaction mixture to adjust the pH to 1, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (6.37 g), which was then used directly in the next step.

[0864] (18) Methyl (4S)-4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2-hydroxybutanoate

[0865] [ka]

[0866] To a solution of (4S)-4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2-hydroxybutanoic acid (6.37 g) in dichloromethane (96 ml) and methanol (32 ml), 43.7 ml of 10% trimethylsilyldiazomethane-hexane solution was added at room temperature and stirred for 15 minutes. Another 43.7 ml of 10% trimethylsilyldiazomethane-hexane solution was added to the reaction mixture and stirred for 30 minutes, after which the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue and washed sequentially with saturated sodium bicarbonate aqueous solution and saturated brine. After drying with sodium sulfate, the sodium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (5.14 g), which was then used directly in the next step.

[0867] (19)(3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one

[0868] [ka]

[0869] 5.14 g of methyl (4S)-4-(((benzyloxy)carbonyl)(4-methoxybenzyl)amino)-4-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2-hydroxybutanoate (5.14 g) was dissolved in methanol (51 ml) and THF (51 ml). 10% Pd-C (1.09 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere (1 atm) for 4 hours. 10% Pd-C was removed from the reaction mixture using Celite as a filter agent, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in THF (51 ml), heated and stirred at 60°C for 1 hour, allowed to stand overnight at room temperature, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the crude product of the title compound (2.52 g). This was purified by preparative HPLC (Daicel CHIRALPAK OJ-H, hexane / ethanol = 7 / 3) to obtain the title compound (0.862 g). The stereochemistry of the title compound was estimated from the NOESY of the compound obtained by the same method as above. 1 H-NMR (CDCl3) δ: 7.60 (1H, s), 7.48 (1H, s), 7.17 (1H, t, J = 60.2 Hz), 7.08 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8 Hz), 4.98 (1H, d, J = 14.5 Hz), 4.62 (1H, t, J = 7.9 Hz), 4.52 (1H, dd, J = 7.9, 3.1 Hz), 3.80 (3H, s), 3.67 (1H, d, J = 14.5 Hz), 3.06 (1H, s), 2.39-2.27 (2H, m).

[0870] Furthermore, a diastereomer (1.28 g) of the title compound was obtained. Of the title compound and its diastereomer, the one with the longer retention time in preparative HPLC was the title compound, and the one with the shorter retention time was the diastereomer.

[0871] (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one

[0872] [ka]

[0873] 1 H-NMR (CDCl3) δ: 7.69 (1H, s), 7.58 (1H, s), 7.18 (1H, t, J = 60.6 Hz), 6.97 (2H, d, J = 7.0 Hz), 6.82 (2H, d, J = 6.6 Hz), 4.91 (1H, d, J = 14.5 Hz), 4.44-4.36 (2H, m), 3.80 (3H, s), 3.62 (1H, d, J = 14.9 Hz), 3.16 (1H, s), 2.81-2.74 (1H, m), 2.01-1.93 (1H, m).

[0874] The compound of Example No. 302 was obtained by using (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one obtained in this reaction and carrying out the same reaction as in (20) to (23) of Production Example 12. (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one could also be obtained by stereochemically inverting the hydroxyl group of the title compound using the Mitsunobu reaction, which is well known to those skilled in the art.

[0875] (20)(3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoro-1-(4-methoxybenzyl)pyrrolidine-2-one

[0876] [ka]

[0877] To a solution of (3R,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-hydroxy-1-(4-methoxybenzyl)pyrrolidine-2-one (0.496 g) in toluene (4.96 ml), pyridine-2-sulfonyl fluoride (0.474 g) in toluene (2.48 ml) and DBU (0.554 ml) were added and stirred at room temperature for 1 hour, then allowed to stand overnight. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.418 g), which was used directly in the next reaction.

[0878] (21)(3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one

[0879] [ka]

[0880] (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoro-1-(4-methoxybenzyl)pyrrolidine-2-one (0.418 g) was mixed with acetonitrile (7.52 ml) and water (0.836 ml), and ammonium hexanitratocerium(IV) (3.38 g) was added under ice cooling. The mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was left to stand overnight in a refrigerator (4 to 5°C) and concentrated under reduced pressure. 1 N hydrochloric acid (30 ml) was added to the residue, and it was washed with diethyl ether (30 ml). The organic layer was extracted with 1 N hydrochloric acid (25 ml). 4 N aqueous sodium hydroxide solution was added to the combined aqueous layer to adjust the pH to >11, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was mixed with diisopropyl ether, and the slurry was purified to obtain the title compound (0.194 g). 1H-NMR (DMSO-D6) δ: 8.64 (1H, s), 8.25 (1H, s), 7.83 (1H, s), 7.78 (1H, t, J = 60.0 Hz), 5.18 (1H, dt, J = 53.1, 7.6 Hz), 4.61 (1H, td, J = 5.7, 2.7 Hz), 2.93-2.84 (1H, m), 2.12-1.97 (1H, m).

[0881] (22) Diastereomer mixture containing (3S,5S)-1-((1S,2S)-2-azido-4,4-difluoro-1,2-dimethylcyclopentan-1-carbonyl)-5-(1(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one

[0882] [ka]

[0883] To a solution of (3S,5S)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one (0.114 g) in THF (2.72 ml), 1.3 M LiHMDS-THF solution (0.46 ml) was added at -78°C and the mixture was stirred at 0°C for 10 minutes. To the reaction mixture, a solution of trans-2-azido-4,4-difluoro-1,2-dimethylcyclopentan-1-carboxylic acid chloride (0.136 g) obtained in step (8) above in THF (1 ml) was added at -78°C. After stirring at -78°C for 30 minutes, the mixture was stirred at 0°C for 1 hour. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain a mixture of the title compound and its diastereomer (0.156 g, dr=1:1). This mixture was used in the following reaction without isolation. 1H-NMR (CDCl3) δ: 7.93 (0.5H, s), 7.86 (0.5H, s), 7.73 (0.5H, s), 7.69 (0.5H, s), 7.15 (1H, t, J = 60.1 Hz), 5.39-5.32 (1H, m), 5.26-5.04 (1H, m), 3.03-2.81 (2H, m), 2.74-2.57 (1H, m), 2.48-2.28 (2.5H, m), 2.12 (0.5H, td, J = 15.0, 4.5 Hz), 1.52 (1.5H, s), 1.38 (1.5H, s), 1.34 (1.5H, s), 0.90 (1.5H, s).

[0884] (23)(3aS,5S,7S,9aS)-7-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2,2,5-trifluoro-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one

[0885] [ka]

[0886] A diastereomer mixture (0.145 g) containing (3S,5S)-1-((1S,2S)-2-azido-4,4-difluoro-1,2-dimethylcyclopentan-1-carbonyl)-5-(1-(difluoromethyl)-1H-pyrazole-4-yl)-3-fluoropyrrolidine-2-one was dissolved in toluene (1.45 ml) at room temperature. 1.04 ml of 1 M trimethylphosphine-THF solution was added and the mixture was stirred for 10 minutes. Then, 0.005 ml of acetic acid was added, and the mixture was stirred at 60°C for 2 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse-phase column chromatography (eluent: acetonitrile / water) followed by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the crude product (0.0867 g) of the title compound and its diastereomer mixture. This was purified by preparative HPLC (Daicel CHIRALPAK IG / SFC, carbon dioxide / methanol) to obtain the title compound (0.0366 g). The title compound (2.33 g) obtained by the same method as above was dissolved in ethyl acetate (4.66 ml), irradiated with sonication, then n-hexane (18.64 ml) was added, and sonication was irradiated again. The precipitated crystals were filtered off, washed with a mixed solvent of ethyl acetate and n-hexane (mixing ratio: ethyl acetate / n-hexane = 1 / 7), and dried under reduced pressure to obtain crystals of the title compound (2.15 g). The absolute configuration of the title compound was determined by X-ray crystallography. 1 H-NMR (CDCl3) δ: 7.89 (1H, s), 7.76 (1H, s), 7.15 (1H, t, J = 60.4 Hz), 5.50 (1H, ddd, J = 53.2, 6.6, 0.9 Hz), 5.36 (1H, d, J = 8.8 Hz), 2.80-2.38 (5H, m), 2.27 (1H, td, J = 15.5, 1.6 Hz), 1.22 (3H, s), 1.06 (3H, s).

[0887] Furthermore, a diastereomer (0.0316 g) of the title compound was obtained. Of the title compound and its diastereomer, the one with the shorter retention time in preparative HPLC was the title compound, and the one with the longer retention time was the diastereomer.

[0888] (3aR,5S,7S,9aR)-7-(1-(difluoromethyl)-1H-pyrazole-4-yl)-2,2,5-trifluoro-3a,9a-dimethyl-1,2,3,3a,5,6,7,9a-octahydro-9H-cyclopenta[d]pyrrolo[1,2-a]pyrimidine-9-one (Example No. 297)

[0889] [ka]

[0890] 1 H-NMR (CDCl3) δ: 7.89 (1H, s), 7.74 (1H, s), 7.14 (1H, t, J = 60.6 Hz), 5.42-5.28 (2H, m), 2.79-2.37 (5H, m), 2.22-2.12 (1H, m), 1.19 (3H, s), 1.10 (3H, s).

[0891] [Example of intermediate product manufacturing 1] Synthesis of methyl 1-benzoyl-4-(((tert-butoxycarbonyl)amino)methyl)piperidine-4-carboxylate

[0892] [ka]

[0893] Methyl 1-benzoyl-4-(((tert-butoxycarbonyl)amino)methyl)piperidine-4-carboxylate

[0894] [ka]

[0895] To a chloroform solution (10 ml) of methyl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-4-carboxylate (0.80 g), triethylamine (0.614 ml) was added at room temperature, followed by benzoyl chloride (0.372 ml) at 0°C. The reaction mixture was stirred at room temperature and then allowed to stand overnight. Sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated to obtain the title compound (1.817 g), which was then used in the next step. 1 H-NMR (CDCl3) δ: 7.43-7.35 (5H, m), 4.81-4.71 (1H, m), 4.28-4.11 (1H, m), 3.75 (3H, s), 3.69-3.53 (1H, m), 3.48-3.21 (4H, m), 2.84-2.64 (1H, m), 2.26-2.10 (1H, m), 2.11-1.96 (1H, m), 1.40 (9H, s), 1.22-1.11 (1H, m).

[0896] [Example of intermediate product manufacturing 2] Synthesis of methyl 4-(((tert-butoxycarbonyl)amino)methyl)-1-(5-chloropyrimidine-2-yl)piperidine-4-carboxylate

[0897] [ka]

[0898] Methyl 4-(((tert-butoxycarbonyl)amino)methyl)-1-(5-chloropyrimidine-2-yl)piperidine-4-carboxylate

[0899] [ka]

[0900] To a solution of methyl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-4-carboxylate (0.30 g) in acetonitrile (3.0 ml), 2,5-dichloropyrimidine (0.197 g) and diisopropylethylamine (0.577 ml) were added at room temperature, and the mixture was stirred at 100°C for 40 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting solid was filtered, washed with water, and dried to obtain the title compound (0.393 g). 1 H-NMR (DMSO-D6) δ: 8.39 (2H, s), 7.02 (1H, t, J = 6.4 Hz), 4.36-4.27 (2H, m), 3.62 (3H, s), 3.09 (2H, d, J = 6.6 Hz), 3.07-2.97 (2H, m), 2.02-1.93 (2H, m), 1.41-1.29 (11H, m).

[0901] [Example of intermediate product manufacturing 3] Synthesis of ethyl (1R,4R)-1-(azidomethyl)-4-cyanocyclohexane-1-carboxylate

[0902] [ka]

[0903] (1) Ethyl 8-(bromomethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate

[0904] [ka]

[0905] To a 10 ml THF solution in a 2 M LDA-THF-heptane-ethylbenzene solution (5.13 ml), a 10 ml THF solution containing 1,4-dioxaspiro[4.5]decane-8-carboxylate ethyl (2.0 g) was added over 10 minutes at -78°C, and the mixture was stirred for 30 minutes. Then, 3.38 ml of dibromomethane was added over 10 minutes, and the mixture was stirred for 45 minutes. The reaction mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.31 g). 1 H-NMR (CDCl3) δ: 4.21 (2H, q, J = 6.7 Hz), 3.94 (4H, s), 3.49 (2H, s), 2.25 (2H, d, J = 11.9 Hz), 1.70-1.60 (6H, m), 1.28 (3H, t, J = 7.0 Hz).

[0906] (2) Ethyl 1-(bromomethyl)-4-oxocyclohexane-1-carboxylate

[0907] [ka]

[0908] To a solution of ethyl 8-(bromomethyl)-1,4-dioxaspiro[4,5]decane-8-carboxylate (2.31 g) in acetone (15 ml), 7.51 ml of 2 N hydrochloric acid was added at room temperature, and the mixture was stirred at 60°C for 2 hours. After standing overnight at room temperature, the mixture was stirred at 60°C for 1 hour. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.70 g). 1 H-NMR (CDCl3) δ: 4.29 (2H, q, J = 7.0 Hz), 3.56 (2H, s), 2.55-2.46 (4H, m), 2.40-2.34 (2H, m), 1.84-1.75 (2H, m), 1.33 (3H, t, J = 7.0 Hz).

[0909] (3) Ethyl 1-(azidomethyl)-4-oxocyclohexane-1-carboxylate

[0910] [ka]

[0911] To a solution of ethyl 1-(bromomethyl)-4-oxocyclohexane-1-carboxylate (1.89 g) in N-methylpyrrolidone (9.45 ml), potassium azide (1.17 g) was added at room temperature and the mixture was stirred overnight at 100°C. The reaction mixture was allowed to return to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.56 g). 1 H-NMR (CDCl3) δ: 4.28 (2H, q, J = 7.2 Hz), 3.52 (2H, s), 2.54-2.31 (6H, m), 1.78-1.69 (2H, m), 1.33 (3H, t, J = 7.3 Hz).

[0912] (4) Ethyl (1R,4R)-1-(azidomethyl)-4-cyanocyclohexane-1-carboxylate

[0913] [ka]

[0914] To a solution of ethyl 1-(azidomethyl)-4-oxocyclohexane-1-carboxylate (1.56 g) in 1,2-dimethoxyethane (15.6 ml) and methanol (0.56 ml), p-toluenesulfonylmethyl isocyanide (1.63 g) and potassium tert-butoxide (1.56 g) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.187 g). The relative stereochemistry of the title compound was determined by NOESY. 1 H-NMR (CDCl3) δ: 4.21 (2H, q, J = 7.2 Hz), 3.44 (2H, s), 2.90-2.85 (1H, m), 2.14 (2H, d, J = 14.1 Hz), 1.93-1.86 (2H, m), 1.81-1.73 (2H, m), 1.66-1.59 (2H, m), 1.29 (3H, t, J = 7.0 Hz).

[0915] [Example of intermediate product manufacturing 4] Synthesis of methyl 4-fluoro-2-oxobicyclo[2.2.2]octane-1-carboxylate

[0916] [ka]

[0917] (1) Dimethyl 2-oxobicyclo[2.2.2]octane-1,4-dicarboxylate

[0918] [ka]

[0919] To a solution of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (5 g) in acetic acid (50 ml), chromium trioxide (4.42 g) was added at room temperature and the mixture was stirred overnight at 90°C. Water was added to the reaction mixture at room temperature, and the mixture was extracted twice with a mixed solvent of ethyl acetate and n-hexane (mixing ratio: ethyl acetate / n-hexane = 1 / 3). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.52 g). 1 H-NMR (CDCl3) δ: 3.75-3.75 (3H, m), 3.71-3.71 (3H, m), 2.58 (2H, s), 2.34-2.27 (2H, m), 2.10-1.82 (6H, m).

[0920] (2) 4-(methoxycarbonyl)-3-oxobicyclo[2.2.2]octane-1-carboxylic acid

[0921] [ka]

[0922] To a solution of dimethyl 2-oxobicyclo[2.2.2]octane-1,4-dicarboxylate (1.86 g) in THF (14.9 ml) and methanol (3.71 ml), an aqueous solution of lithium hydroxide monohydrate (0.298 g) (3.71 ml) was added under ice cooling and stirred overnight at room temperature. After concentrating the reaction mixture under reduced pressure, water (10 ml) was added to the residue and washed with diethyl ether (10 ml). 6 N hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.35 g). 1 H-NMR (DMSO-D6) δ: 12.50 (1H, s), 3.63 (3H, s), 2.17-1.74 (10H, m).

[0923] (3) Methyl 4-fluoro-2-oxobicyclo[2.2.2]octane-1-carboxylate

[0924] [ka]

[0925] Water (40 ml) was bubbling with argon for 2 hours. 4-(methoxycarbonyl)-3-oxobicyclo[2.2.2]octane-1-carboxylic acid (1.68 g), silver(I) nitrate (0.252 g), and N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) (4.74 g) were added, and the mixture was heated and stirred overnight at 55°C. The reaction mixture was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.717 g). 1 H-NMR (DMSO-D6) δ: 3.63 (3H, s), 2.74 (2H, d, J = 5.3 Hz), 2.14-1.87 (8H, m).

[0926] [Example of intermediate product manufacturing 5] Synthesis of methyl 1-(hydroxymethyl)-3-methylcyclobutane-1-carboxylate

[0927] [ka]

[0928] (1) Methyl 1-(hydroxymethyl)-3-methylenecyclobutane-1-carboxylate

[0929] [ka]

[0930] To a 15 ml solution of THF in a 2 M LDA-THF-heptane-ethylbenzene solution (7.93 ml), a 5 ml solution of THF containing methyl-3-methylenecyclobutane-1-carboxylate (1.0 g) was added dropwise over 6 minutes at -78°C, and the mixture was stirred for 15 minutes. 1.30 g of 1H-benzotriazole-1-methanol was added to the reaction mixture, and the mixture was stirred at -78°C for 1 hour, then stirred at room temperature for 2 hours. After stirring, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.491 g). 1 H-NMR (DMSO-D6) δ: 5.01 (1H, t, J = 5.7 Hz), 4.84-4.81 (2H, m), 3.62 (3H, s), 3.61 (2H, d, J = 5.7 Hz), 2.93-2.87 (2H, m), 2.62-2.56 (2H, m).

[0931] (2) Methyl 1-(hydroxymethyl)-3-methylcyclobutane-1-carboxylate

[0932] [ka]

[0933] To a solution of methyl 1-(hydroxymethyl)-3-methylenecyclobutane-1-carboxylate (0.491 g) in methanol (3.4 ml), 10% Pd-C (73.7 mg) was added at room temperature and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). From the reaction mixture, 10% Pd-C was removed using Celite as a filter agent, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (0.449 g). 1H-NMR (DMSO-D6) δ: 4.90-4.84 (1H, m), 3.63-3.60 (2.4H, m), 3.58 (1.6H, s), 3.52 (1H, d, J = 5.7 Hz), 2.36-2.21 (2H, m), 2.09-2.04 (1H, m), 1.82-1.77 (1H, m), 1.65-1.60 (1H, m), 1.02-0.98 (3H, m).

[0934] [Intermediate product manufacturing example 6] Synthesis of benzyl 3-fluoro-2-(hydroxymethyl)-2-methylpropanoate

[0935] [ka]

[0936] (1) Benzyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

[0937] [ka]

[0938] To a solution of 2,2-bis(hydroxymethyl)propionic acid (1.0 g) in DMF (10 ml), potassium carbonate (1.55 g) was added at room temperature, and the mixture was stirred for 30 minutes. Then, benzyl bromide (1.3 ml) was added, and the mixture was stirred for 18 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.16 g). 1H-NMR (DMSO-D6) δ: 7.39-7.28 (5H, m), 5.09 (2H, s), 4.71 (2H, t, J = 5.7 Hz), 3.54 (2H, dd, J = 10.2, 5.4 Hz), 3.45 (2H, dd, J = 10.2, 5.4 Hz), 1.08 (3H, s).

[0939] (2) Benzyl 3-fluoro-2-(hydroxymethyl)-2-methylpropanoate

[0940] [ka]

[0941] To a solution of benzyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (860 mg) in dichloromethane (8.6 ml), ethanol (22.39 μL) was added at room temperature, followed by the addition of diethylaminosulfur trifluoride (659 μL) at 0°C. The mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (267 mg). 1 H-NMR (DMSO-D6) δ: 7.40-7.30 (5H, m), 5.14 (2H, s), 5.08 (1H, t, J = 5.4 Hz), 4.66-4.42 (2H, m), 3.58-3.49 (2H, m), 1.13 (3H, d, J = 1.2 Hz).

[0942] [Intermediate Product Manufacturing Example 7] Synthesis of diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate

[0943] [ka]

[0944] Diisopropyl 3,3-difluorocyclobutane-1,1-dicarboxylate

[0945] [ka]

[0946] Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (5 g) was mixed with dichloromethane (50 ml) and ethanol (0.121 ml), and diethylaminosulfur trifluoride (8.18 ml) was added dropwise at 0°C. The mixture was stirred at room temperature for 72 hours. Saturated sodium bicarbonate aqueous solution was added dropwise to the reaction mixture at 0°C until the foaming subsided, and the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried with sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (4.57 g). 1 H-NMR (DMSO-D6) δ: 5.03-4.94 (2H, m), 3.11 (4H, t, J = 12.1 Hz), 1.20 (12H, d, J = 5.9 Hz).

[0947] [Intermediate product manufacturing example 8] Synthesis of methyl 1-(azidomethyl)-3-(fluoromethyl)cyclobutane-1-carboxylate

[0948] [ka]

[0949] (1) Methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(hydroxymethyl)cyclobutane-1-carboxylate

[0950] [ka]

[0951] To a solution of tetrahydrofuran (22.5 ml) in 2M LDA-THF / heptane / ethylbenzene (2.96 ml), a solution of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutane-1-carboxylate (1.5 g) in a solution of tetrahydrofuran (7.5 ml) was added dropwise over 7 minutes at -78°C. The mixture was stirred at -78°C for 30 minutes, 1H-benzotriazole-1-methanol (0.952 g) was added, and the temperature was raised to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain a diastereomer mixture of the title compound (1.361 g), which was then used to proceed to the next step.

[0952] (2) Methyl 1-(azidomethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutane-1-carboxylate

[0953] [ka]

[0954] To a solution of methyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-1-(hydroxymethyl)cyclobutane-1-carboxylate (1.631 g) in tetrahydrofuran (16.31 ml), triphenylphosphine (2.97 g) was added, and after cooling on ice, diisopropyl azodicarboxylic acid (1.979 ml) and diphenyl phosphate azide (2.192 ml) were added. To the reaction mixture, tetrahydrofuran (7 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound (1.397 g), which was then used to proceed to the next step.

[0955] (3) Methyl 1-(azidomethyl)-3-(hydroxymethyl)cyclobutane-1-carboxylate

[0956] [ka]

[0957] To a solution of methyl 1-(azidomethyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutane-1-carboxylate (1.397 g) in THF (13.97 ml), 1 M tetrabutylammonium fluoride-THF solution (4.9 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain a diastereomer mixture of the title compound (0.799 g). 1 ¹H-NMR (CDCl3) δ: 3.80-3.73 (3H, m), 3.69-3.56 (4H, m), 2.71-2.42 (2H, m), 2.33-2.22 (1H, m), 2.13-2.03 (1H, m), 1.97-1.85 (1H, m). Protons of the alcohol were not detected.

[0958] (4) Methyl 1-(azidomethyl)-3-(fluoromethyl)cyclobutane-1-carboxylate

[0959] [ka]

[0960] To a solution of methyl 1-(azidomethyl)-3-(hydroxymethyl)cyclobutane-1-carboxylate (0.401 g) in dichloromethane (8.02 ml), bis(2-methoxyethyl)aminosulfate trifluoride (approximately 50% THF solution) (2.162 ml) was added under ice cooling and stirred at room temperature. After allowing the reaction mixture to stand at room temperature for 2 days, saturated sodium bicarbonate aqueous solution and chloroform were added under ice cooling and extracted with chloroform. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound (0.169 g). 1 H-NMR (CDCl3) δ: 4.48-4.40 (1H, m), 4.36-4.27 (1H, m), 3.82-3.74 (3H, m), 3.69-3.66 (1H, m), 3.59-3.56 (1H, m), 2.89-2.56 (1H, m), 2.55-2.45 (1H, m), 2.40-2.32 (1H, m), 2.17-1.97 (2H, m).

[0961] [Intermediate Manufacturing Example 9] Synthesis of ethyl 3-bromo-2-cyano-2-methylpropanoate

[0962] [ka]

[0963] Ethyl 3-bromo-2-cyano-2-methylpropanoate

[0964] [ka]

[0965] To a solution of ethyl 2-cyanopropionate (2 g) in DMF (10 ml), dibromomethane (2.2 ml) and potassium carbonate (2.4 g) were added and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (3.3 g). 1 H-NMR (DMSO-D6) δ: 4.26 (2H, q, J = 7.0 Hz), 3.97 (1H, d, J = 10.8 Hz), 3.89 (1H, d, J = 10.8 Hz), 1.68 (3H, s), 1.25 (3H, t, J = 7.0 Hz).

[0966] [Intermediate Product Manufacturing Example 10] Synthesis of cis-methyl 2-azido-5,5-difluoro-1-methylcyclohexane-1-carboxylate

[0967] [ka]

[0968] (1) Methyl 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate

[0969] [ka]

[0970] 2 g of methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate was mixed with 30 ml of THF, 1.478 ml of DBU, and 0.613 ml of iodomethane. The mixture was stirred at room temperature for 70 hours, then 0.613 ml of iodomethane and 0.75 ml of DBU were added, and the mixture was stirred at room temperature for 20 hours. 0.613 ml of iodomethane and 1.478 ml of DBU were added to the reaction mixture, and the mixture was stirred at 50°C for 6 hours. 0.613 ml of iodomethane and 1.478 ml of DBU were added, and the mixture was allowed to stand at room temperature for 120 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (760 mg). 1 H-NMR (CDCl3) δ: 4.06-3.94 (4H, m), 3.73 (3H, s), 3.06-2.97 (1H, m), 2.68 (1H, d, J = 14.0 Hz), 2.51 (1H, dt, J = 14.8, 4.1 Hz), 2.04-1.98 (2H, m), 1.73 (1H, d, J = 14.0 Hz), 1.29 (3H, s).

[0971] (2) cis-methyl 8-((4-methoxybenzyl)amino)-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate

[0972] [ka]

[0973] Methyl 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (760 mg) was mixed with THF (7.6 ml), 4-methoxybenzylamine (0.862 ml), and acetic acid (0.191 ml). The mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (1.059 g) was added, and the mixture was stirred at room temperature for 20 hours. Saturated sodium bicarbonate aqueous solution (7 ml) was added to the reaction mixture, and it was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (aminosilica, developing solvent: ethyl acetate / n-hexane) to obtain the title compound (680 mg). The relative stereochemistry of the title compound was estimated by NOESY. 1 H-NMR (DMSO-D6) δ: 7.21 (2H, d, J = 8.3 Hz), 6.85 (2H, d, J = 8.3 Hz), 3.88-3.74 (5H, m), 3.72 (3H, s), 3.55 (3H, s), 3.51-3.45 (1H, m), 2.37 (1H, br s), 2.15 (1H, d, J = 14.0 Hz), 1.99-1.83 (2H, m), 1.74-1.64 (2H, m), 1.50-1.44 (1H, m), 1.38 (1H, d, J = 14.0 Hz), 1.21 (3H, s).

[0974] (3) cis-methyl 8-amino-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate

[0975] [ka]

[0976] 680 mg of cis-methyl 8-((4-methoxybenzyl)amino)-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate was added at room temperature with 3.4 ml of THF, 3.4 ml of methanol, and 10% Pd-C (104 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 20 hours. Pd-C was filtered off the reaction mixture by Celite filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (440 mg). 1 H-NMR (CDCl3) δ: 3.99-3.82 (4H, m), 3.67 (3H, s), 2.57 (1H, dd, J = 10.5, 3.8 Hz), 2.33 (1H, dd, J = 13.8, 2.5 Hz), 2.07-1.98 (1H, m), 1.86-1.73 (2H, m), 1.69-1.65 (1H, m), 1.65 (2H, br s), 1.44 (1H, d, J = 13.8 Hz), 1.31 (3H, s).

[0977] (4) cis-methyl 8-azido-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate

[0978] [ka]

[0979] 440 mg of cis-methyl 8-amino-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate was added at room temperature to potassium carbonate (398 mg), methanol (8.8 ml), imidazole-1-sulfonyl azide hydrochloride (603 mg), and copper(II) sulfate pentahydrate (23.96 mg), and the mixture was stirred for 20 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (450 mg). 1H-NMR (CDCl3) δ: 3.98-3.85 (4H, m), 3.73 (3H, s), 3.61-3.57 (1H, m), 2.18 (1H, d, J = 14.3 Hz), 2.14-2.07 (1H, m), 2.03-1.97 (1H, m), 1.86-1.78 (1H, m), 1.66-1.59 (2H, m), 1.33 (3H, s).

[0980] (5) cis-methyl 2-azide-1-methyl-5-oxocyclohexane-1-carboxylate

[0981] [ka]

[0982] 450 mg of cis-methyl 8-azido-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate was added to 13.5 ml of THF and 6.75 ml of 2N hydrochloric acid at room temperature. After stirring for 18 hours, 6 ml of THF and 3 ml of 2N hydrochloric acid were added, and the mixture was stirred for 24 hours. To the reaction mixture, 4 ml of acetone and 1 ml of 2N hydrochloric acid were added, and after stirring for 24 hours, potassium carbonate was added to adjust the pH from 8 to 9, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (310 mg). 1 H-NMR (CDCl3) δ: 4.07-4.04 (1H, m), 3.77 (3H, s), 2.88 (1H, d, J = 14.5 Hz), 2.62-2.53 (1H, m), 2.36 (1H, d, J = 14.5 Hz), 2.31-2.09 (3H, m), 1.22 (3H, s).

[0983] (6) cis-methyl 2-azide-5,5-difluoro-1-methylcyclohexane-1-carboxylate

[0984] [ka]

[0985] 310 mg of cis-methyl 2-azido-1-methyl-5-oxocyclohexane-1-carboxylate was mixed with 3.1 ml of dichloromethane and 0.582 ml of diethylaminosulfur trifluoride under ice cooling. The mixture was stirred at room temperature for 4 hours and then allowed to stand for 40 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture under ice cooling and extracted with deuterated chloroform. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (144 mg). 1 H-NMR (CDCl3) δ: 3.94-3.86 (1H, m), 3.76 (3H, s), 2.43-2.26 (2H, m), 2.11-1.94 (4H, m), 1.32 (3H, s).

[0986] [Intermediate Product Manufacturing Example 11] Synthesis of ethyl 2-cyano-3-(difluoromethoxy)-2-methylpropanoate

[0987] [ka]

[0988] (1) Ethyl 2-cyano-3-hydroxy-2-methylpropanoate

[0989] [ka]

[0990] To a solution of ethyl 2-cyanopropionate (2 g) in acetonitrile (20 ml), 3.51 ml of 37% formaldehyde aqueous solution was added, followed by the addition of triethylamine (0.219 ml) at 0°C. The mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.21 g). 1 H-NMR (DMSO-D6) δ: 5.82 (1H, t, J = 5.7 Hz), 4.20 (2H, q, J = 7.3 Hz), 3.74 (1H, dd, J = 10.5, 5.7 Hz), 3.66 (1H, dd, J = 10.5, 5.7 Hz), 1.45 (3H, s), 1.23 (3H, t, J = 6.8 Hz).

[0991] (2) Ethyl 2-cyano-3-(difluoromethoxy)-2-methylpropanoate

[0992] [ka]

[0993] Ethyl 2-cyano-3-hydroxy-2-methylpropanoate (2 g) was mixed with dichloromethane (10 ml) and water (20 ml). At room temperature, (bromodifluoromethyl)trimethylsilane (5.92 ml) and potassium hydrogen fluoride were added, and the mixture was stirred at room temperature for 72 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (468 mg). 1H-NMR (CDCl3) δ: 6.28 (1H, t, J = 72.5 Hz), 4.32 (2H, q, J = 7.2 Hz), 4.20 (1H, d, J = 9.7 Hz), 4.06 (1H, d, J = 10.2 Hz), 1.64 (3H, s), 1.35 (3H, t, J = 7.0 Hz).

[0994] [Intermediate Production Example 12] Synthesis of methyl 3-hydroxy-2-methoxy-2-methylpropanoate

[0995] [ka]

[0996] (1) Methyl 3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-2-methylpropanoate

[0997] [ka]

[0998] 1-(benzyloxy)propan-2-one (1 g) was mixed with THF (10 ml) and 2-((tert-butyldimethylsilyl)oxy)malonitrile (1.888 ml), and methanol (0.739 ml) and DMAP were added at 0°C. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.4 g). 1 H-NMR (DMSO-D6) δ: 7.38-7.25 (5H, m), 4.51 (2H, dd, J = 18.9, 12.4 Hz), 3.65 (3H, s), 3.56 (1H, d, J = 9.7 Hz), 3.48 (1H, d, J = 9.2 Hz), 1.34 (3H, s), 0.84 (9H, s), 0.06 (3H, s), 0.04 (3H, s).

[0999] (2) Methyl 3-(benzyloxy)-2-hydroxy-2-methylpropanoate

[1000] [ka]

[1001] Methyl 3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-2-methylpropanoate (1.48 g) was mixed with THF (14.8 ml), and at room temperature, 1.0 M tetrabutylammonium fluoride-THF solution (6.56 ml) was added and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (861 mg), which was then used in the next step.

[1002] (3) Methyl 3-(benzyloxy)-2-methoxy-2-methylpropanoate

[1003] [ka]

[1004] 761 mg of methyl 3-(benzyloxy)-2-hydroxy-2-methylpropanoate was mixed with 7.61 ml of DMF, and at 0°C, 143 mg of 60% sodium hydride-mineral oil mixture was added and the mixture was stirred for 5 minutes. 233 μL of iodomethane was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. At 0°C, 27.1 mg of 60% sodium hydride was added and the mixture was stirred for 5 minutes. 42 μL of iodomethane was added to the reaction mixture and the mixture was stirred at room temperature for 18 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture at room temperature and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (621 mg). 1 H-NMR (CDCl3) δ: 7.36-7.26 (5H, m), 4.57 (2H, t, J = 13.2 Hz), 3.75 (3H, s), 3.65-3.57 (2H, m), 3.34 (3H, s), 1.43 (3H, s).

[1005] (4) Methyl 3-hydroxy-2-methoxy-2-methylpropanoate

[1006] [ka]

[1007] Methyl 3-(benzyloxy)-2-methoxy-2-methylpropanoate (621 mg) was mixed with methanol (19 ml), 10% palladium carbon (hydrated, 186 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen (2 L) atmosphere. The reaction mixture was filtered through Celite at room temperature, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (347 mg). 1H-NMR (CDCl3) δ: 3.78 (3H, s), 3.76 (1H, dd, J = 11.4, 7.5 Hz), 3.68 (1H, dd, J = 11.4, 5.7 Hz), 3.38 (3H, s), 2.19-2.14 (1H, m), 1.41 (3H, s).

[1008] [Intermediate Production Example 13] Synthesis of ethyl 1-cyanospiro[2,4]heptane-1-carboxylate

[1009] [ka]

[1010] (1) Ethyl 2-cyano-2-cyclopentylidene acetate

[1011] [ka]

[1012] Ethyl 2-cyanoacetate (2 g) was mixed with toluene (20 ml), and at room temperature, cyclopentanone (1.649 ml), acetic acid (0.911 ml), and ammonium acetate (409 mg) were added, and the mixture was stirred at 135°C for 3 hours. The water produced in the reaction system was removed using a Dean-Stark apparatus. Water was added to the reaction mixture at room temperature, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.936 g). 1 H-NMR (DMSO-D6) δ: 4.21 (2H, q, J = 7.2 Hz), 2.91 (2H, t, J = 6.7 Hz), 2.75 (2H, t, J = 6.7 Hz), 1.82-1.69 (4H, m), 1.25 (3H, t, J = 7.3 Hz).

[1013] (2) Ethyl 1-cyanospiro[2,4]heptane-1-carboxylate

[1014] [ka]

[1015] Ethyl 2-cyano-2-cyclopentylidene acetate (2.936 g) was mixed with acetonitrile (73.4 ml), nitromethane (4.42 ml) and DBU (2.469 ml) were added, and the mixture was stirred at room temperature for 18 hours. At room temperature, 2 N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.43 g). 1 H-NMR (DMSO-D6) δ: 4.19 (2H, q, J = 7.4 Hz), 1.97-1.89 (1H, m), 1.86-1.80 (2H, m), 1.77-1.63 (7H, m), 1.23 (3H, t, J = 7.3 Hz).

[1016] [Intermediate Production Example 14] Synthesis of benzyl 4-fluoro-3-hydroxy-2,2-dimethylbutanoate

[1017] [ka]

[1018] (1) Benzyl 2,2-dimethyl-3-butenoate

[1019] [ka]

[1020] To a solution of benzyl tiglic acid (2g) in THF (20ml), N,N'-dimethylpropylene urea (6.34ml) was added, followed by the addition of 2M LDA-THF-heptane-ethylbenzene solution (6.31ml) at -78°C, and the mixture was stirred at -78°C for 2 hours. Iodomethane (1.315ml) was added to the reaction mixture, and the mixture was stirred at -78°C for 1 hour, followed by stirring at room temperature for 20 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.9g). 1 H-NMR (CDCl3) δ: 7.37-7.30 (5H, m), 6.05 (1H, dd, J = 17.4, 10.6 Hz), 5.13-5.03 (4H, m), 1.33 (6H, s).

[1021] (2) Benzyl 2-methyl-2-(oxiran-2-yl)propanoate

[1022] [ka]

[1023] To a solution of benzyl 2,2-dimethyl-3-butenoate (1.9 g) in dichloromethane (28.5 ml), 3-chloroperbenzoic acid (6.88 g) was added and the mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution and 16.7% sodium bisulfate aqueous solution (30 ml) were added to the reaction mixture at room temperature and stirred for 30 minutes. The reaction mixture was then extracted with dichloromethane. The combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.0 g). 1H-NMR (CDCl3) δ: 7.39-7.30 (5H, m), 5.16 (2H, s), 3.21-3.18 (1H, m), 2.72-2.65 (2H, m), 1.23 (3H, s), 1.15 (3H, s).

[1024] (3) Benzyl 4-fluoro-3-hydroxy-2,2-dimethylbutanoate

[1025] [ka]

[1026] Benzyl 2-methyl-2-(oxiran-2-yl)propanoate (2 g) was mixed with tetrabutylammonium trihydrogen trifluoride (5.47 g) and potassium hydrogen fluoride (0.709 g) and stirred at 120°C for 9 hours. Saturated sodium bicarbonate solution was added to the reaction mixture at room temperature and stirred for 30 minutes. The mixture was then extracted with ethyl acetate, the organic layer was washed with water, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.7 g). 1 H-NMR (CDCl3) δ: 7.39-7.32 (5H, m), 5.15 (2H, s), 4.60-4.50 (1H, m), 4.48-4.38 (1H, m), 3.98-3.88 (1H, m), 2.90 (1H, d, J = 6.5 Hz), 1.29 (3H, s), 1.27 (3H, s).

[1027] [Intermediate Product Manufacturing Example 15] Synthesis of ethyl 1-cyano-2,2-dimethylcyclopropane-1-carboxylate

[1028] [ka]

[1029] (1) Ethyl 2-cyano-3-methylbuta-2-enoate

[1030] [ka]

[1031] Ethyl 2-cyanoacetate (3 g) was mixed with acetone (3.89 ml), then piperidine (131 μL) was added, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.2 g). 1 H-NMR (DMSO-D6) δ: 4.21 (2H, q, J = 7.0 Hz), 2.35 (3H, s), 2.26 (3H, s), 1.25 (3H, t, J = 7.0 Hz).

[1032] (2) Ethyl 1-cyano-2,2-dimethylcyclopropane-1-carboxylate

[1033] [ka]

[1034] Ethyl 2-cyano-3-methylbuta-2-enoate (2.2 g) was mixed with acetonitrile (55 ml), nitromethane (3.87 ml) and DBU (2.165 ml) were added, and the mixture was stirred at room temperature for 18 hours. At room temperature, 2 N hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.72 g). 1H-NMR (CDCl3) δ: 4.26 (2H, q, J = 7.2 Hz), 1.82 (1H, d, J = 4.8 Hz), 1.49 (3H, s), 1.46 (1H, d, J = 5.4 Hz), 1.34 (3H, t, J = 7.3 Hz), 1.30 (3H, s).

[1035] [Intermediate Product Manufacturing Example 16] Synthesis of 3-azido-2-methyl-2-phenoxypropanoic acid

[1036] [ka]

[1037] (1) Benzyl 2,3-dihydroxy-2-methylpropanoate

[1038] [ka]

[1039] To a solution of benzyltriethylammonium chloride (5.47 g) in acetone (40 ml) at room temperature, potassium permanganate (3.79 g) was added and the mixture was stirred for 3 hours. Then, under ice cooling, a solution of benzyl methacrylate (3.39 ml) in acetone (8 ml) was added dropwise over 30 minutes while maintaining a temperature below 5°C. The reaction mixture was stirred at a temperature below 5°C for 1 hour and 30 minutes, after which saturated sodium bicarbonate aqueous solution was added. The precipitate was filtered off with Celite, the filtrate was extracted with ethyl acetate, the organic layer was dried with sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.72 g). 1H-NMR (CDCl3) δ: 7.40-7.33 (5H, m), 5.25 (2H, s), 3.84 (1H, dd, J = 10.8, 9.9 Hz), 3.59 (1H, ddd, J = 11.2, 4.6, 1.1 Hz), 3.49 (1H, s), 2.14-2.10 (1H, m), 1.37 (3H, s).

[1040] (2) 5-benzyl 3-methyl 5-methyl-1,2,3-oxathiazolidine-3,5-dicarboxylate 2,2-dioxide

[1041] [ka]

[1042] 7.09 g of Burgess reagent was added to a solution of benzyl 2,3-dihydroxy-2-methylpropanoate (2.72 g) in THF (272 ml) at room temperature, stirred for 7.5 hours, and allowed to stand overnight. Water was then added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.33 g). 1 H-NMR (CDCl3) δ: 7.42-7.34 (5H, m), 5.28 (2H, dd, J = 13.2, 12.3 Hz), 4.58 (1H, d, J = 10.5 Hz), 3.91 (3H, s), 3.91 (1H, d, J = 10.5 Hz), 1.81 (3H, s).

[1043] (3) Benzyl 3-((methoxycarbonyl)amino)-2-methyl-2-phenoxypropanoate

[1044] [ka]

[1045] To a solution of 5-benzyl 3-methyl 5-methyl-1,2,3-oxathiazolidine-3,5-dicarboxylate 2,2-dioxide (2.33 g) in DMF (23.3 ml), sodium phenoxide trihydrate (1.565 g) was added and heated at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 20% sulfuric acid (20 ml) and dichloromethane (20 ml) were added to the residue. The mixture was stirred at room temperature for 3.5 hours and allowed to stand overnight. The aqueous layer and organic layer were separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (2.02 g). 1 H-NMR (CDCl3) δ: 7.38-7.26 (6H, m), 7.19 (2H, t, J = 7.0 Hz), 6.99 (1H, t, J = 7.3 Hz), 6.80 (2H, d, J = 7.9 Hz), 5.20 (2H, s), 3.77-3.61 (5H, m), 1.52 (3H, s).

[1046] (4) 3-amino-2-methyl-2-phenoxypropanoate

[1047] [ka]

[1048] Benzyl 3-((methoxycarbonyl)amino)-2-methyl-2-phenoxypropanoate (1 g) was mixed with 35% hydrochloric acid (20 ml) and stirred overnight at 100°C. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (eluent: acetonitrile / water) to obtain the title compound (0.332 g). 1H-NMR (DMSO-D6) δ: 13.82 (1H, s), 8.20 (2H, s), 7.35-7.30 (2H, m), 7.07 (1H, t, J = 7.3 Hz), 7.01-6.97 (2H, m), 3.34-3.27 (2H, m), 1.48 (3H, s).

[1049] (5) 3-Azido-2-methyl-2-phenoxypropanoic acid

[1050] [ka]

[1051] To a methanol (16 ml) solution of 3-amino-2-methyl-2-phenoxypropane hydrochloride (332 mg), imidazole-1-sulfonyl azide hydrochloride (451 mg), potassium carbonate (495 mg), and copper(II) sulfate pentahydrate (17.9 mg) were added at room temperature and the mixture was stirred for 15 hours at room temperature. 0.1 N aqueous sodium hydroxide solution was added to the reaction mixture and extracted with chloroform. 6 N hydrochloric acid was added to the aqueous layer to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (185 mg). 1 H-NMR (DMSO-D6) δ: 13.49 (1H, s), 7.30 (2H, t, J = 8.1 Hz), 7.02 (1H, t, J = 7.3 Hz), 6.90 (2H, d, J = 8.3 Hz), 3.77 (1H, d, J = 13.2 Hz), 3.64 (1H, d, J = 12.7 Hz), 1.46 (3H, s).

[1052] [Intermediate Product Manufacturing Example 17] Synthesis of benzyl 3-azido-2-((4-fluorobenzyl)oxy)-2-methylpropanoate

[1053] [ka]

[1054] (1) Benzyl 2-methyloxirane-2-carboxylate

[1055] [ka]

[1056] Benzyl methacrylate (2 g) was mixed with dichloromethane (20 ml), and 3-chloroperbenzoic acid (4.20 g) was added at room temperature. The mixture was stirred at 55°C for 7 hours. At room temperature, saturated sodium bicarbonate aqueous solution and saturated sodium thiosulfate aqueous solution were added to the reaction mixture, and the liquid-liquid was separated. The aqueous layer was extracted with chloroform. The combined organic layers were sequentially washed with water and saturated brine, dried with sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (1.5515 g). 1 H-NMR (CDCl3) δ: 7.39-7.32 (5H, m), 5.23 (1H, d, J = 12.3 Hz), 5.15 (1H, d, J = 12.3 Hz), 3.12 (1H, d, J = 6.2 Hz), 2.76 (1H, d, J = 5.7 Hz), 1.60 (3H, s).

[1057] (2) Benzyl 3-azido-2-hydroxy-2-methylpropanoate

[1058] [ka]

[1059] Benzyl 2-methyloxirane-2-carboxylate (500 mg) was mixed with DMF (7.5 ml), and at room temperature, ammonium chloride (153 mg) and potassium azide (253 mg) were added, and the mixture was stirred at 80°C for 18 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (363 mg). 1 H-NMR (CDCl3) δ: 7.41-7.34 (5H, m), 5.25 (2H, s), 3.49-3.42 (3H, m), 1.42 (3H, s).

[1060] (3) Benzyl 3-azide-2-((4-fluorobenzyl)oxy)-2-methylpropanoate

[1061] [ka]

[1062] Benzyl 3-azido-2-hydroxy-2-methylpropanoate (360 mg) was mixed with DMF (5.4 ml) and 1-(bromomethyl)-4-fluorobenzene (0.229 ml). At 0°C, 60% sodium hydride-mineral oil mixture (64.3 mg) was added, and the mixture was stirred at room temperature for 2 hours. At room temperature, saturated ammonium chloride aqueous solution was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (385.3 mg). 1H-NMR (CDCl3) δ: 7.38-7.34 (5H, m), 7.31-7.26 (2H, m), 7.01-6.95 (2H, m), 5.22 (2H, s), 4.53 (1H, d, J = 10.8 Hz), 4.47 (1H, d, J = 10.2 Hz), 3.58 (1H, d, J = 12.9 Hz), 3.49 (1H, d, J = 12.9 Hz), 1.56 (3H, s).

[1063] [Intermediate Product Manufacturing Example 18] Synthesis of ethyl 2-cyano-3-(4-fluorophenoxy)-2-methylpropanoate

[1064] [ka]

[1065] Ethyl 2-cyano-3-(4-fluorophenoxy)-2-methylpropanoate

[1066] [ka]

[1067] Ethyl 2-cyano-3-bromo-2-methylpropanoate (1 g) was mixed with DMF (10 ml), 4-fluorophenol (0.611 g), and potassium carbonate (0.942 g), and the mixture was stirred at 70°C for 3 hours, followed by 90°C for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to obtain the title compound (960 mg). 1H-NMR (CDCl3) δ: 7.00-6.87 (4H, m), 4.16-4.12 (2H, m), 3.72 (1H, d, J = 10.5 Hz), 3.59 (1H, d, J = 10.5 Hz), 1.73 (3H, s), 1.36-1.33 (3H, m).

[1068] [Intermediate Production Example 19] Synthesis of trans-methyl 4-azido-1-(5-fluoropyrimidine-2-yl)-3-methylpiperidine-3-carboxylate

[1069] [ka]

[1070] (1) trans-1-(tert-butyl) 3-methyl 4-((4-methoxybenzyl)amino)-3-methylpiperidine-1,3-dicarboxylate

[1071] [ka]

[1072] To a solution of 1-(tert-butyl)3-methyl3-methyl-4-oxopiperidine-1,3-dicarboxylate (5.0 g) in THF (50 ml), 4-methoxybenzylamine (4.77 ml) and acetic acid (1.055 ml) were added and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (5.86 g) was added and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified twice by silica gel column chromatography (eluent: ethyl acetate / hexane) to obtain the title compound (3.11 g). The relative stereochemistry of the title compound was estimated by tracing back from the NOESY of the compound obtained from Example No. 175 using the title compound as a starting material. 1H-NMR (CDCl3) δ: 7.20-7.18 (2H, m), 6.86-6.83 (2H, m), 4.20-3.91 (1H, m), 3.80 (3H, s), 3.78-3.71 (1H, m), 3.66 (3H, s), 3.63-3.58 (1H, m), 3.33-2.98 (2H, m), 2.84-2.64 (1H, m), 1.92-1.76 (1H, m), 1.66-1.49 (1H, m), 1.44 (9H, s), 1.42-1.30 (2H, m), 1.15 (3H, s).

[1073] Furthermore, the diastereomer, the cis-isomer (3.38 g), was obtained. Of the trans-isomer and the cis-isomer, the less polar one was the cis-isomer.

[1074] (2) trans-1-(tert-butyl) 3-methyl 4-amino-3-methylpiperidine-1,3-dicarboxylate

[1075] [ka]

[1076] To a solution of trans-1-(tert-butyl)3-methyl4-((4-methoxybenzyl)amino)-3-methylpiperidine-1,3-dicarboxylate (3.11 g) in methanol (31.1 ml), 10% Pd-C (1.687 g) was added and stirred overnight at room temperature under a hydrogen atmosphere (1 atm). After purging the reaction mixture with nitrogen, 10% Pd-C was filtered off using a Hyfloo Supercell as a filter aid, and the mixture was washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product of the title compound (2.447 g), which was then used directly in the next step.

[1077] (3) trans-1-(tert-butyl) 3-methyl 4-azido-3-methylpiperidine-1,3-dicarboxylate

[1078] [ka]

[1079] To a methanol (43.2 ml) solution of trans-1-(tert-butyl) 3-methyl 4-amino-3-methylpiperidine-1,3-dicarboxylate (2.159 g), imidazole-1-sulfonyl azide hydrochloride (2.492 g), potassium carbonate (1.643 g), and copper(II) sulfate pentahydrate (0.099 g) were added at room temperature and the mixture was stirred for 3 days. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered off the sodium sulfate, and the filtrate was con...

Claims

1. A compound of formula [I-3] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In formula [I-3], R 1 teeth, (1) Hydrogen, (2) Halogen, or (3) Hydroxy And; R 2 'teeth, (1) Phenyl, which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (2) Pyridyl which may be substituted with cyano or halogen, (3) T 4 Pyrazolyl (where the T may be substituted by) 4 teeth, (a) C which may be substituted with one to three halogens 1-２ Alkyl, or (b) Cyclopropyl (is) and; R 3 teeth, (1) 1 to 3 Ts 1 C which may be replaced by 1-4 alkyl (where the Ts 1 are each independently (a) Hydroxy, (b) Halogen, (c) Cyano, (d) Methoxy, which may be substituted with one or two halogens (e) Methylsulfonyl, (f) Phenyl which may be substituted with a halogen, (g) Phenoxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (h) Pyridyl which may be substituted with a halogen, (i) Pyridyloxy which may be substituted with one or two substituents independently selected from the group consisting of cyano and halogens, (j) Pyrimidinyl oxy, which may be substituted with cyano or halogen, (k) Formula [II]: 【Chemistry 2】 A group represented by, and (l) Formula [III]: 【Transformation 3】 The base represented by (Selected from) (2) Cyano, (3) Methoxy, (4) Cyclopropyl, (5) Phenyl, (6) Phenoxy, or (7) Benzyloxy which may be substituted with one halogen and R 4 teeth, (1) Hydrogen, or (2) C which may be substituted with one or two halogens 1-2 Alkyl is it, or R 3 and R 4 They come together, along with the carbon atoms to which they bond, (1) One or two T 2 C may be replaced by 3-7 Cycloalkane (where, the T 2 Each of them operates independently. (a) Halogen, (b) Cyano, and (c) Methyl which may be substituted with one to three halogens (Selected from) (2) Tetrahydropyran ring, (3) Formula [IV]: 【Chemistry 4】 A ring represented by, or (4) Formula [V]: 【Transformation 5】 (In the formula, W 1 teeth, (a) tert-butoxycarbonyl, (b) Acetyl, (c) Benzoyl, or (d) Pyrimidinyl which may be substituted with a halogen or cyano The ring represented by (is) Forms, and R 5 teeth, (1) Hydrogen, or (2) Methyl which may be substituted with one or two halogens and R 6 teeth, (1) Hydrogen, or (2) Methyl is it, or R 5 and R 6 They combine with the carbon atoms to which they bond to form cyclopropane; R 3 and R 5 They come together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (where, the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxyphosphate which may be substituted with one to three halogens (Selected from) (2) Equation [VI]: 【Transformation 6】 A ring represented by, or (3) Formula [VII]: 【Transformation 7】 (In the formula, W 2 is a pyrimidinyl which may be substituted with a halogen. It forms a ring represented by ) and R 4 and R 6 Is this synonymous with the above; or R 3 , R 4 , and R 5 They come together, along with the carbon atoms to which they bond, (1) Formula [VIII]: 【Transformation 8】 A ring represented by, or (2) Formula [IX]: 【Chemistry 9】 It forms a ring represented by, and R 6 This is synonymous with the above.

2. R 1 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is fluorine.

3. R 3 and R 5 But together, along with the carbon atoms to which they bond, (1) One or two T 3 C may be replaced by 5-6 Cycloalkane (where, the T 3 Each of them operates independently. (a) Hydroxy, (b) Halogens, and (c) Methoxyphosphate which may be substituted with one to three halogens (Selected from) (2) Equation [VI]: 【Chemistry 10】 A ring represented by, or (3) Formula [VII]: 【Chemistry 11】 (In the formula, W 2 is a pyrimidinyl which may be substituted with a halogen. It forms a ring represented by ) and R 4 and R 6 However, is it equivalent to claim 1; or R 3 , R 4 , and R 5 But together, along with the carbon atoms to which they bond, (1) Formula [VIII]: 【Chemistry 12】 A ring represented by, or (2) Formula [IX]: 【Chemistry 13】 It forms a ring represented by, and R 6 However, the compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is synonymous with claim 1.

4. The following structural formula: 【Chemistry 14】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds having the above.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A RIPK1 inhibitor comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, comprising multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, and graft-versus-host disease (GVHD). A therapeutic or prophylactic agent for diseases selected from the group consisting of systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

8. A method for inhibiting RIPK1 in a mammal, comprising administering a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 4 to the mammal.

9. The present invention involves administering a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 4 to a mammal, thereby treating multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disease, retinitis pigmentosa, metabolic disorder-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, and Niemann-Pick disease C in the mammal. A method for treating or preventing a disease selected from the group consisting of type 1, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

10. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the production of a RIPK1 inhibitor.

11. Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal damage, retinitis pigmentosa, metabolic-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction, Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

12. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, for use in inhibiting RIPK1.

13. Multiple sclerosis, inflammatory bowel disease, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, psoriasis, rheumatoid arthritis, cerebral infarction, subarachnoid hemorrhage, age-related macular degeneration, glaucoma, ischemic retinal disease, retinitis pigmentosa, metabolic disorders-associated steatohepatitis (MASH), chronic kidney disease, atherosclerosis, Rett syndrome, Niemann-Pick disease type C, graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), sepsis, polymyositis, CRIA syndrome, myocardial infarction A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from the group consisting of nephrosis, COVID-19 caused by SARS-CoV-2, acute pancreatitis, otulin-associated autoinflammatory syndrome, diabetic nephropathy, depression, gastric cancer, pancreatic cancer, frontotemporal dementia, ischemic acute kidney injury, ischemic lung disease, ischemic liver injury, ischemic bowel disease, ischemic spinal cord injury, alopecia areata, and dilated cardiomyopathy.

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