Tricyclic dihydroimidazopyrimidone derivative, preparation method therefor, pharmaceutical composition and use thereof

Abstract

Disclosed are a compound as represented by general formula (I), a cis-trans isomer thereof, an enantiomer thereof, a diastereoisomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof or a prodrug thereof, a preparation method therefor, a pharmaceutical composition comprising the compound and the use of the compound as an Lp-PLA2 inhibitor.

Description

Tricyclic dihydroimidazopyrimidinone derivatives, their preparation methods, pharmaceutical compositions and uses Technical Field: This invention relates to novel tricyclic dihydroimidazole pyrimidinone compounds, methods for their preparation, pharmaceutical compositions comprising the compounds, and their use in the treatment of Lp-PLA2-mediated diseases. Background technology: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a phospholipase A2 enzyme involved in the hydrolysis of lipoprotein lipids or phospholipids, also known as platelet-activating factor acetylhydrolase (PAF-AH). Lp-PLA2 migrates with low-density lipoprotein (LDL) and rapidly cleaves oxidized phosphatidylcholine molecules obtained from LDL oxidation. Lp-PLA2 hydrolyzes the sn-2 ester of oxidized phosphatidylcholine to yield the lipid mediator lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (NEFA). Literature reports that lysoPC and NEFA can induce inflammatory responses; therefore, Lp-PLA2 mediates oxidative inflammatory responses in vivo. (Zalewski A et al., Arterioscler. Thromb. Vasc. Biol., 25, 5, 923-31 (2005)) Documents (WO96 / 13484, WO96 / 19451, WO97 / 02242, WO97 / 12963, WO97 / 21675, WO97 / 21676, WO97 / 41098, WO97 / 41099, WO99 / 2442, WO00 / 10980, WO00 / 66 566. WO00 / 66567, WO00 / 68208, WO01 / 60805, WO02 / 30904, WO02 / 30911, WO03 / 015786, WO03 / 016287, WO03 / 041712, WO03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 87088, WO08 / 04886, US2008 / 0103156, US2008 / 0090851, US2008 / 0090852, WO08 / 048866, W005 / 003118, W006 / 063811、W006 / 063813、WO2008 / 141176、WO2013013503A1、WO2013014185A1、WO2014114248A1、WO2014114694A1、WO2016011930A1、JP200188847 US2008 / 0279846A1, US 2010 / 0239565A1, and US 2008 / 0280829A1 describe a number of Lp-PLA2 inhibitors and / or their uses for the treatment of diseases involving or related to vascular endothelial dysfunction, diseases involving lipid oxidation associated with Lp-PLA2 activity (e.g., associated with the formation of lysophosphatidylcholine and oxidized free fatty acids), and diseases involving or associated with increased involvement of activated monocytes, macrophages, or lymphocytes. Specific examples of diseases include neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric disorders such as schizophrenia and autism, peripheral and cerebral arteriosclerosis, stroke, metabolic bone diseases (such as myelospermia), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (such as macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy), diabetic peripheral neuropathy pain, inflammatory pain, neuropathic pain, various cancers (such as prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sclerosis. Scientific research has further demonstrated that Lp-PLA2 inhibitors can be used to treat atherosclerosis. Wilensky et al. demonstrated the effect of Lp-PLA2 inhibitors on atherosclerotic plaque components in a pig model of diabetes and hypercholesterolemia that accelerates coronary atherosclerosis (Wilensky et al., Nature Medicine, 10, 1015-1016 (2008)). Clinical studies have also found that Lp-PLA2 inhibitors can stabilize atherosclerotic plaques in patients and prevent further plaque development and rupture (Serruys et al., Circulation 118: 1172-1182 (2008)). Studies have shown that high Lp-PLA2 activity is associated with a high risk of dementia, including Alzheimer's disease (AD) and mixed dementia (Van Oijen et al., Annals of Neurology, 59, 139 (2006); Fitzpatrick et al., Atherosclerosis 235: 384-391 (2014)). Higher levels of oxidized LDL have been observed in AD patients (Kassner et al., Current Alzheimer Research, 5, 358-366 (2008); Dildar et al., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem et al., Current Alzheimer Research, 7, 463-469 (2010)). Furthermore, US2008 / 0279846 describes Lp-PLA2 inhibitors as reducing blood-brain barrier leakage and cerebral amyloid (Abeta) load, which can be used to treat diseases associated with blood-brain barrier leakage, such as Alzheimer's disease and vascular dementia. In clinical studies, Lp-PLA2 inhibitors have shown significant effects in preventing further cognitive decline in Alzheimer's patients (Maher-Edwards et al., Alzheimer's & Dementia: Translational Research & Clinical Interventions 1, 131-140 (2015)). Neuroinflammation (including the release of various cytotoxic cytokines) is a common feature of all neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease (Perry, Acta Neuropathol, 120, 277-286 (2010)). Lp-PLA2 inhibitors reduce the release of various cytokines by inhibiting lysoPC production (Shi et al., Atherosclerosis 191, 54-62 (2007)). Therefore, inhibiting Lp-PLA2 is a potential treatment for neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease. LysoPC is also involved in leukocyte activation, induction of apoptosis, and mediation of vascular endothelial cell dysfunction (Wilensky et al., Current Opinion in Lipidology, 20, 415-420, (2009)). Therefore, Lp-PLA2 inhibitors are thought to be useful for treating diabetes-related tissue damage by reducing lysoPC production. High Lp-PLA2 activity is associated with a high risk of diabetic retinopathy (Siddiqui et al., Diabetologia, 61, 1344-1353 (2018)). Lp-PLA2 inhibitors can suppress the major pathological changes in retinopathy in a diabetic rat model (Canning et al., PNAS 113, 7213-7218 (2016). Clinical studies have also shown that Lp-PLA2 inhibitors can improve macular edema symptoms and visual acuity in patients with diabetic retinopathy (Staurenghi et al., Ophthalmology 122, 990-996 (2015). These studies demonstrate that Lp-PLA2 inhibitors can be used for diabetic retinopathy. Studies have shown that Lp-PLA2 activity is higher in diabetic patients than in healthy individuals (Serban et al. J.Cell.Mol.Med.6:643-647, (2002); Garg et al. Indian J.Med.Res.141:107-114, (2015)). As mentioned above, Lp-PLA2 activity mediates oxidative inflammatory responses, suggesting that inhibiting Lp-PLA2 activity could be used to treat various complications in diabetic patients caused by oxidative inflammatory responses, such as diabetic nephropathy, diabetic peripheral neuropathy, and diabetic skin ulcers. Glaucoma and age-related macular degeneration (AMD) are neurodegenerative diseases of the retina. Inflammation plays an important role in the pathogenesis of glaucoma and AMD (Buschini et al., Progress in Neurobiology, 95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173, ISSN 0079-6123, Chapter 28). Therefore, Lp-PLA2 inhibitors may have potential therapeutic applications for glaucoma and AMD. In men with erectile dysfunction, the activity of Lp-PLA2 in the body is significantly higher than that in normal individuals, and it is believed that high Lp-PLA2 activity can predict early erectile dysfunction in men (Otunctemur et al., Andrologia 47:706-710 (2015)), suggesting that Lp-PLA2 inhibitors can be used to treat erectile dysfunction in men. Lp-PLA2 is highly expressed in prostate cancer tissues. Reducing Lp-PLA2 can decrease prostate cell carcinogenesis and promote prostate cancer cell apoptosis in in vitro experiments (Vainio et al., Oncotarget, 2:1176-1190 (2011)), suggesting that Lp-PLA2 inhibitors may be used to treat prostate cancer. However, there remains a strong demand for new Lp-PLA2 inhibitors in existing technologies. Summary of the Invention The purpose of this invention is to provide a pyrimidinone compound and a pharmaceutical composition thereof, which can be used as an Lp-PLA2 inhibitor. In a first aspect, the present invention relates to a compound of formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, or a pharmaceutically acceptable salt thereof or a prodrug thereof. in n is 0, 1 or 2, and when n is 0, R2 is methyl or ethyl, and when n is 1 or 2, R2 does not exist; R1 is H, halogen, cyano, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, R1 may optionally be substituted by one or more of the following substituents: halogen, cyano, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic or 6-10 membered heteroaryl; R a Independently, it is either H or D; m is 1 or 2; Rx H, halogen, hydroxyl, carboxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 6-10 membered heteroaryl, -C(O)NR b R c -S(O)2NR b R c R x It may be optionally substituted with one or more of the following substituents: halogen, hydroxyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl or 6-10 membered heteroaryl; Q is -O-, -S-, -CH2-, or -NR b -; X is -O-, -CH2-, -NR c -, -OCH2- or not present; R b For H, C 1-6 Alkyl or C 3-8 cycloalkyl or 3-8 membered heterocyclic groups; R c The values ​​are L, LC(O)-, L-CH2-, or LS(O)2-, where L is H or C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8-membered heterocyclic, 6-10-membered aryl or 6-10-membered heteroaryl, L may be optionally substituted by one or more of the following groups: halogen, hydroxyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl or 6-10 membered heteroaryl; Y is -CH2-, -CH2CH2-, or does not exist; U is -CH2-, -C(O)-, or does not exist; X and U do not exist simultaneously; Y and U can be optionally substituted by one or more of the following substituents: halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl or 6-10 membered heteroaryl; A is Z is N or CR 3； Z' is N or CR 4； R3, R4, R5, and R6 are independently H, cyano, halogen, or C. 1-3 Haloalkyl; V is N or CR9, where R9 is H, cyano, halogen, or C. 1-3 Alkyl, C 1-3 Haloalkyl or -OW; W is phenyl or 5 or 6-membered heteroaryl, which may optionally be substituted by one or more of the following substituents: halogen, cyano, C 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl groups and C 1-3 Halogenated alkoxy groups. In some implementations, n is 0; R1 is H, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or C 1-3 Halogenated alkyl; R a Rx is H, cyano, fluorine, difluoromethyl, amino. R2 is methyl or ethyl; Q is -O-; X is -O-, -CH2 or absent-; Y is -CH2-; U is -CH2- or absent; X and U are not absent at the same time. Furthermore, R1 is H and Rx is H. In some implementations, where n = 1 or 2, R2 does not exist. Further, where R... x H. Further, X is -O- or -CH2-. In some implementations, n is 1; R x R1 is H; cyano, amino, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkyl group. In some implementations, U is -CH2-; X is -CH2- or -O- and Q is -O-. In some implementations, U is -CH2-; X is -NR c -, R c It is methyl, oxetyl, trifluoroethyl, benzoyl, cyclobutyl, benzyl. In some implementations, U is -C(O)-; R1 and R x Both are H, Y is -CH2-; X is -NR c -, R c It is L or LC(O)-, where L is methyl, trifluoroethyl, benzoyl, oxetane, cyclobutane, benzyl. Furthermore, L stands for methyl. In some implementations, n is 1; X is -CH2-; U does not exist; R x H, hydroxyl, halogen, cyano, amino, C 1-3 Alkoxy, C 1-3 Haloalkyl, 3-8 membered heterocyclic, R x It may be optionally substituted with one or more of the following substituents: halogen, hydroxyl, C 1-6 Alkoxy, cyano, 3-8 membered heterocyclic, 6-10 membered aryl or 6-10 membered heteroaryl. In some implementations, Y is -CH2-; R1 is H, cyano, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-6 Alkoxy group; Q is -O-. In some implementations, R x H, halogen, cyano, amino, difluoromethyl In some implementations, Y is -CH2CH2-; R x H, halogen, cyano, amino, difluoromethyl R1 is H, cyano, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkyl group; Q is -O-. Further, Rx is H. In some implementations, n is 2; U is -CH2-; X is -CH2- or -O-; Y is -CH2- or does not exist; R x H, halogen, cyano, amino, difluoromethyl R1 is H, cyano, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkyl group; and Q is -O-. Further, Rx is H and R1 is H. In some implementations, m = 2; R1 is H, cyano, or C. 1-3 Halogenated alkyl; and R x For H. In some implementations, m = 1, R1 is H, cyano, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkoxy; and R x For H. In some implementation schemes, A is R5,R 6, R7, R8, and R9 are independently H, F, or cyano groups. In some implementation schemes, A is R5,R 6, R7 and R8 are independently H, F, or cyano; R9 is -OW, W is a 5- or 6-membered heteroaryl or phenyl group, which may be optionally substituted by one or more of the following substituents: C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, cyanohalogens and C 1-6 alkyl. In some implementation schemes, A is R7 and R8 are independently H, F, or cyano; R9 is -OW; W is pyridyl, pyrimidinyl, pyrazolyl, or phenyl, which may be optionally substituted by one or more substituents independently selected from the following: halogen, cyano, CF3, -OCF3, CHF2, and CH3. In some embodiments, the compound has formula I' Where R1 is H, cyano, halogen, C 1-6 Alkyl, C 1-3 Alkoxy or C 1-3 Haloalkyl; X is -O-, -CH2-, -NRc- or absent; R c It can be L or LC(O)-, where L is H or C. 1-3 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C1-3 haloalkyl, or benzyl; Y is -CH2- or absent; n, R2, R a A and m are as defined in equation (I) above. In some implementations, n is 0, R2 is methyl or ethyl; R1 is H; R a H is 1; m is 1; X is -O- or -CH2-. In some embodiments, the compound is the following compound Wherein, R1 is H, halogen, cyano, C 1-6 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkoxy (furthermore, the halogen is fluorine or chlorine, the C 1-6 The alkyl group is methyl, ethyl, or isopropyl, and the C group is... 1-3The haloalkyl group is trifluoromethyl, and the C... 1-6 alkoxy group is methoxy group); R2 is methyl or ethyl group; R c C 1-6 Alkyl, 3-8 membered heterocyclic group, C 1-3 Halogenated alkyl, benzoyl, C 3-8 cycloalkyl, benzyl or (Furthermore, the C) 1-6 The alkyl group is methyl, the 3-8 membered heterocyclic group is oxocyclic butyl, and the C 1-3 The haloalkyl group is trifluoroethyl and the C 3-8 cycloalkyl is cyclobutyl); R x H, cyano, halogen, C 1-3 Halogenated alkyl, amino (Furthermore, the halogen is fluorine and the C 1-3 The haloalkyl group is difluoromethyl. Furthermore, the compound is the following compound Wherein, R1 is H, halogen, cyano, C 1-6 Alkyl, C 1-3 Halogenated alkyl or C 1-6 Alkoxy (furthermore, the halogen is fluorine or chlorine, the C 1-6 The alkyl group is methyl, ethyl, or isopropyl, and the C group is... 1-3 The haloalkyl group is trifluoromethyl, and the C... 1-6 alkoxy group is methoxy group); R2 is methyl or ethyl group; R c C 1-6 Alkyl, 3-8 membered heterocyclic group, C 1-3 Halogenated alkyl, benzoyl, C 3-8 cycloalkyl, benzyl or (Furthermore, the C) 1-6 The alkyl group is methyl, the 3-8 membered heterocyclic group is oxocyclic butyl, and the C 1-3 The haloalkyl group is trifluoroethyl and the C 3-8 cycloalkyl is cyclobutyl); R x H, cyano, halogen, C 1-3 Halogenated alkyl, amino (Furthermore, the halogen is fluorine and the C 1-3 The haloalkyl group is difluoromethyl. In some embodiments, in compounds of general formula (I) above, A is selected from the following groups: In some embodiments, the compound of general formula (I) is the following compound: In a second aspect, the present invention relates to a compound of formula I', its cis-trans isomer, its enantiomer, its diastereomer, its racemic mixture, its solvate, its hydrate, or a pharmaceutically acceptable salt thereof or a prodrug thereof. in When n is 0, 1, or 2, and when n is 0, R2 is methyl or ethyl; when n is not 0, R2 does not exist. R1 is H, a halogen, and C. 1-6 Alkyl or C 3-6 cycloalkyl; R a Independently, it is either H or D; m is 1 or 2; X is -O-, -CH2-, -NR-, or does not exist; R is LC(O)-, L-CH2-, or LS(O)2-, where L is H or C. 1-3 Alkyl, C 3-6 cycloalkyl or phenyl; Y is -CH2- or does not exist; A is Z is N or CR 3； Z' is N or CR 4； R3, R4, R5, and R6 are independently H, CN, halogen, or C. 1-3 Halogenated alkyl groups; V is N or CR 9，R9 represents H, CN, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups or -OW; W is a 5- or 6-membered heteroaromatic ring or a phenyl group, which may optionally be substituted by one or more of the following substituents: C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, CN, halogens and C 1-5 alkyl. In some embodiments, the compound of the above general formula (I') is not 0 and has one or more of the following characteristics: (1) R1 is H, R a For H; (2) X is 0 or does not exist, Y is -CH2-, and n is 1; (3) X is -CH2-, Y is -CH2- or does not exist, and n is 2; (4) m is 1. In some embodiments, the compound of general formula (I') has n = 0 and has one or more of the following characteristics: (1) R1 is H, R a For H; (2) R2 is a methyl group; (3) X is non-existent, -O-, -CH2-; (4) m is 1. In one implementation, A is... Where R5, R 6, R7, R8, and R9 are independently represented by H, F, or CN. In one embodiment, A is Where R5, R 6, R7 and R8 are independently H, F, or CN; R9 is -OW; W is a 5- or 6-membered heteroaryl or phenyl group, wherein the heteroaryl or phenyl group is optionally substituted by one or more of the following substituents: C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, CN, halogens and C 1-5 alkyl. In one embodiment, A is Wherein R7 and R8 are independently H, F, or CN; R9 is -OW; W is pyridyl, pyrimidinyl, pyrazolyl, or phenyl, wherein the pyridyl, pyrimidinyl, pyrazolyl, or phenyl is optionally substituted by one or more of the following substituents: halogen, CN, CF3, -OCF3, and CH3. In some embodiments, A is... In one embodiment, the compound is any one of the following compounds: The compounds of the above formula, and their salts (e.g., pharmaceutically acceptable salts), may exist in stereoisomer form (e.g., containing one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are all included within the scope of this invention. This invention also includes various deuterated forms of compounds of the above formula and their salts (e.g., pharmaceutically acceptable salts). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art will understand how to synthesize deuterated forms of compounds of the above formula and their salts (e.g., pharmaceutically acceptable salts). Commercially available deuterated raw materials can be used in the preparation of deuterated forms of compounds of the above formula and their salts (e.g., pharmaceutically acceptable salts), or these compounds can be synthesized using conventional techniques employing deuterating agents (such as lithium aluminum deuteride). In addition to the free base or free acid forms of the compounds described herein, the salt forms of the compounds are also within the scope of this invention. Salts or pharmaceutically acceptable salts of the compounds of this invention may be prepared in situ during the final separation and purification of the compounds, or by reacting the purified compounds in their free acid or free base forms separately with suitable bases or acids. For a review of suitable pharmaceutically acceptable salts, see Berge et al., J. Pharm, Sci., 66, 1-19, 1977; PL Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al., Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc, New York 1996, Volume 13, pages 453-497. The compounds described herein, their salts (e.g., pharmaceutically acceptable salts), deuterated forms, solvates, or hydrates may exist in one or more polymorphs. Therefore, in another aspect, the present invention provides polymorphs of the compounds defined herein, their salts (e.g., pharmaceutically acceptable salts), or solvates or hydrates of the compounds described herein or their salts (e.g., pharmaceutically acceptable salts). This invention also includes isotopically labeled compounds and salts equivalent to compounds or salts of the above formulas, but with one or more atoms replaced by atoms whose atomic mass or mass number differs from the most frequently found atomic mass or mass number in nature. Examples of isotopes that can be incorporated into compounds or salts of the above formulas are isotopes of hydrogen, carbon, nitrogen, and deuterium, such as... 3 H, 11 C 14 C and 18 F These isotopically labeled compounds of the above formula, or their salts, can be used for drug and / or substrate tissue distribution assays. For example, 11 C and 18 The F isotope can be used in PET (positron emission tomography). PET can be used for brain imaging. In some embodiments, the compound of the above formula or its salt is non-isotopically labeled. Therefore, the compounds of the present invention include compounds of the above formula, or salts thereof, such as pharmaceutically acceptable salts thereof. Representative compounds of the present invention include the specific compounds described above. In a third aspect, the present invention also relates to pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable excipients. In a fourth aspect, the invention also relates to methods for treating or preventing diseases associated with Lp-PLA2 activity, comprising administering a therapeutically effective amount of the compound of the invention described herein to a subject in need. The disease may be associated with: increased lysophosphatidylcholine and oxidized free fatty acid formation through the involvement of monocytes, macrophages, or lymphocytes; lipid oxidation associated with Lp-PLA2 activity; or endothelial dysfunction. In some embodiments, the present invention also provides methods for treating or preventing diseases by inhibiting Lp-PLA2 activity. Exemplary diseases include, but are not limited to: neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric disorders such as schizophrenia and autism, peripheral and cerebral arteriosclerosis, stroke, metabolic bone diseases (e.g., myelodysplastic syndromes), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (e.g., macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy), diabetic peripheral neuropathy pain, inflammatory pain, neuropathic pain, various cancers (e.g., prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sclerosis. The method involves administering a therapeutically effective amount of the compound of the present invention to a subject in need. The present invention is not intended to be limited to any particular stage of disease (e.g., early or late). In some embodiments, the present invention also provides a method for treating or preventing Alzheimer's disease. This method includes administering a therapeutically effective amount of the compound of the present invention to a subject in need. In some embodiments, the present invention also provides a method for treating or preventing atherosclerosis. This method includes administering a therapeutically effective amount of the compound of the present invention to a subject in need. In some embodiments, the present invention also provides a method for treating or preventing eye diseases by administering a compound of the present invention. In some embodiments, the present invention provides a method for treating macular edema, comprising administering a therapeutically effective amount of a compound of the present invention to a subject. In some embodiments, the macular edema is associated with diabetic eye disease (e.g., diabetic macular edema or diabetic retinopathy). In one embodiment, the macular edema is associated with posterior uveitis. In a fifth aspect, the present invention also provides the use of the compounds of the present invention in the preparation of medicaments for the treatment or prevention of diseases associated with Lp-PLA2. Exemplary diseases include, but are not limited to: neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, vascular dementia), various neuropsychiatric disorders such as schizophrenia and autism, peripheral and cerebral arteriosclerosis, stroke, metabolic bone diseases (e.g., myelodysplastic syndromes), dyslipidemia, Paget's disease, type II diabetes, hypertension, angina pectoris, myocardial infarction, ischemia, reperfusion injury, metabolic syndrome, insulin resistance and hyperparathyroidism, diabetic complications (e.g., macular edema, diabetic retinopathy and posterior uveitis, diabetic ulcers and diabetic nephropathy), diabetic peripheral neuropathy pain, inflammatory pain, neuropathic pain, various cancers (e.g., prostate cancer, colon cancer, breast cancer, kidney cancer, lung cancer and ovarian cancer, etc.), macular edema, wound healing, male erectile dysfunction, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), sepsis, acute and chronic inflammation, psoriasis and multiple sclerosis. The method includes administering a therapeutically effective amount of the compound of the present invention to a subject in need. This invention is not intended to be limited to any particular stage of a disease (such as early or late stage). In a sixth aspect, the present invention also provides compounds of the present invention for the treatment or prevention of the diseases described herein. As used herein, “and / or” means any and all possible combinations including one or more associated enumerated items. It can be further understood that the terms “comprising” and / or “including” as used in this specification indicate the presence of the referred feature, whole, step, operation, element, and / or component, but do not exclude the presence or inclusion of one or more other features, wholes, steps, operations, elements, components, and / or combinations thereof. Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and biology described herein are well-known and commonly used in the field. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Where multiple definitions exist for terms used herein, the definitions in this section shall prevail unless otherwise stated. Invention Details definition As used herein, unless otherwise stated, the term “disease” means any alteration in the state of the body or organs that interrupts or interferes with the performance of functions and / or causes symptoms (such as discomfort, dysfunction, adverse stress, or even death) in a person who is ill or in contact with such a person. As used herein, unless otherwise stated, “diabetic retinopathy” refers to the result of chronic, progressive microvascular leakage and obstruction of the retina caused by diabetes. “Diabetic macular edema” refers to retinal thickening or hard exudate deposits caused by extracellular fluid accumulation within one optic disc diameter of the fovea due to diabetes. As used herein, unless otherwise stated, “neurodegenerative disease” refers to various types of central nervous system disorders characterized by progressive loss of neural tissue and / or neural function. Neurodegenerative diseases are a class of neurological disorders characterized by progressive loss of neural tissue and / or altered neural function, typically resulting from progressive loss of neural tissue leading to a decline in neural function. In some embodiments, the neurodegenerative diseases described herein include those with a defective blood-brain barrier (e.g., a permeable blood-brain barrier). Examples of neurodegenerative diseases with a defective blood-brain barrier include, but are not limited to, Alzheimer's disease, Huntington's disease, Parkinson's disease, and vascular dementia. As used herein, unless otherwise stated, "vascular dementia" is also known as "multiple infarct dementia," and refers to a group of syndromes caused by different mechanisms, all of which lead to damage to blood vessels in the brain. For example, the main subtypes of vascular dementia are vascular mild cognitive impairment, multiple infarct dementia, vascular dementia due to a large single infarction (affecting the thalamus, anterior cerebral artery, parietal lobe, or cingulate gyrus), vascular dementia due to hemorrhagic damage, small vessel disease (including, for example, vascular dementia due to lacunar damage and Binswanger disease), and mixed dementia. As used herein, unless otherwise stated, “neuropathic pain” is pain caused or induced by primary damage and dysfunction of the nervous system. As used herein, unless otherwise stated, "inflammatory pain" is pain caused by localized acute or chronic inflammation irritating nerves. As used herein, unless otherwise stated, “diabetic peripheral neuropathy pain” refers to pain caused by nerve damage resulting from diabetes, which is at least partly due to reduced blood flow and hyperglycemia. As used herein, unless otherwise stated, the terms "blood-brain barrier" or "BBB" are used interchangeably to refer to the permeable barrier present in the blood vessels that pass through brain tissue, which strictly restricts and closely regulates the exchange of substances between the blood and brain tissue. Components of the blood-brain barrier include the endothelial cells that form the innermost lining of all blood vessels, the tight junctions between adjacent endothelial cells that act as structural linkers of the BBB, the basement membrane of the endothelial cells, and the enlarged foot processes of nearby astrocytes that cover almost all exposed outer surfaces of the blood vessels. As used herein, unless otherwise stated, “metabolic bone disease” refers to various types of bone diseases characterized by progressive and gradual loss of bone tissue. Metabolic bone diseases as described herein are bone metabolic disorders in which there is a diffuse decrease in bone mineral density and / or a reduction in bone strength. These diseases are characterized by their histological appearance. Exemplary metabolic bone diseases include, but are not limited to, osteoporosis characterized by a reduction in mineral content and bone matrix, and osteomalacia characterized by a reduction in mineral content but with intact bone matrix. As used herein, unless otherwise stated, “osteoreduction disease” or “osteoreduction” may be used interchangeably herein to refer to a condition with decreased calcification and / or bone mineral density, and is a descriptive term used to represent all skeletal systems in which decreased calcification and / or bone mineral density is observed. Osteopenia also refers to a reduction in bone due to insufficient osteoid synthesis. As used herein, unless otherwise stated, "osteoporosis" means a condition in which there is a reduction in mineral and / or bone matrix and / or a decrease in bone matrix. As used herein, unless otherwise stated, "alkyl" is a monovalent, saturated alkyl chain having a specified number of carbon atoms. For example, C 1-3 Alkyl groups are alkyl groups having 1 to 3 carbon atoms. (C) 1-5 Alkyl groups are alkyl groups having 1 to 5 carbon atoms. (C) 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be straight-chain or branched. In some embodiments, a branched alkyl group may have one, two, or three branches. Exemplary alkyl groups include, but are not limited to, methyl, methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl, and hexyl. As used herein, unless otherwise stated, an "alkoxy" substituent is a group of the formula "RO-", where R is an alkyl group as defined above. For example, C 1-3 An alkoxy group refers to an alkoxy substituent containing 1 to 3 carbons. Exemplary alkoxy substituents include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy, and neopentoxy. As used herein, "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, including bridged rings and spiro rings, preferably having 3-8 cyclic carbon atoms (C). 3-8 cycloalkyl groups), 3-7 cyclic carbon atoms (C 3-7 cycloalkyl groups or 3-6 cyclic carbon atoms (C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or [1,1,1]spiroalkyl, and those groups specifically exemplified below. Unless otherwise stated, "C 3-6 "Cycloalkyl" is a monovalent group obtained by removing a hydrogen atom from a 3, 4, 5, or 6-membered monocyclic cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, unless otherwise stated, "aryl" means a hydrocarbon group containing one or more aromatic rings, such as phenyl or naphthyl. As used herein, in some embodiments, "heteroaryl" is a monovalent group obtained by removing a hydrogen atom from a monocyclic 5- or 6-membered heteroaryl ring, the ring consisting of a ring-carbon atom and a ring-heteroatom selected from nitrogen, oxygen, and sulfur, and the ring being aromatic. For example, a heteroaryl is a monocyclic heteroaryl consisting of 5 or 6 ring atoms, wherein 1 to 3 are ring-heteroatoms. Exemplary heteroaryl groups include, but are not limited to, furanyl, thiopheneyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, pyridinyl, pyrazinyl, triazinyl, and azazolyl. Basic, oxygen and nitrogen Basic, sulfur-nitrogen alkyl and diaza In other embodiments, "heteroaryl" means a stable monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, wherein at least one ring is aromatic and at least one ring contains one to four heteroatoms selected from O, N, and S. The heteroaryl groups within this defined range include, but are not limited to, acridinel, carbazolyl, cenolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indole, isoindole, 1H,3H-1-oxoisoindole, benzotriazolyl, furanyl, thiophene, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothiophene, benzofuranyl, benzodioxane, benzodioxane, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridinyl, pyrimidine, pyrrolidinyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3, 5-Triazinyl, 1,2,4-Triazinyl, 1,2,4,5-Tetraazinyl, Tetrazolyl, Xanthonyl, Phenazinyl, Phenithiazinyl, Phenoxazinyl, Azazolyl, Oxazolyl, and Thiozonyl. Particularly, heteroaryl groups have 5- or 6-membered rings, such as furanyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isozolyl, oxazolyl, diazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, and pyridopyrroleylalkyl. As used herein, in some embodiments, a "heterocyclic group" is a monovalent group obtained by removing a hydrogen atom from a 3, 4, 5, or 6-membered saturated monocyclic heterocycle, the ring consisting of a ring-carbon atom and a ring-heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary monocyclic saturated heterocyclic substituents include, but are not limited to, pyrrolidinyl, dioxacyclopentyl, imidazoalkyl, pyrazolyl, piperidinyl, dioxyl, morpholino, dithiaalkyl, thiomorpholino, and piperazinyl. In other embodiments, "heterocycle" or "heterocyclic group" refers to a cyclic hydrocarbon in which one to four carbon atoms have been replaced by heteroatoms independently selected from N, N(R), S, S(O), S(O), and O. The heterocycle may be saturated or unsaturated, but not aromatic. The heterocyclic group may also contain one, two, or three rings, including bridged rings and spirocyclic structures. Examples of suitable heterocyclic groups include, but are not limited to: azahexacyclobutane, oxacyclobutane, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, 2-oxopyrrolyl, pyrrolinyl, pyranyl, dioxopentyl, piperidinyl, 2-oxopyridinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiocyclopentadienyl, oxathiocyclopentadienyl, dioxalkyl, dioxenyl, dioxazolyl, oxathiozolyl, oxazolone, piperazine, morpholinyl, thiomorpholinyl, 3-oxomorpholinyl, dithiaalkyl, trithiaalkyl, and oxazine. As used herein, unless otherwise stated, a "bridged ring compound" refers to one or more atoms (i.e., C, O, N, or S) connected to two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. Notably, a bridge always converts a monocyclic ring into a tricyclic ring. Substituents on the ring can also appear on the bridge in a bridged ring. The term "spirocyclic compound" refers to a polycyclic compound in which two monocyclic rings share a single carbon atom, which is called a spiro atom. As used herein, unless otherwise stated, "halogen" means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). "Halogenated" refers to a halogen group: fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I). As used herein, unless otherwise stated, "haloalkyl" means an alkyl group substituted with one or more halogen substituents, which may be the same or different. For example, C 1-3 A haloalkyl group refers to a haloalkyl substituent containing 1 to 3 carbons. Exemplary haloalkyl substituents include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, trifluoropropyl, 3-fluoropropyl, and 2-fluoroethyl. As used herein, unless otherwise stated, a ring can be either spiro-fused or unilaterally fused when two substituents on a ring, together with their interconnected atoms, combine to form another ring. A spiro-fused ring system consists of two rings that share only one common carbon atom. A unilaterally fused ring system consists of two rings that share only two atoms and one bond. As used herein, unless otherwise stated, “optionally substituted” means that the group or ring may be unsubstituted, or that the group or ring may be substituted with one or more substituents as defined herein. As used herein, unless otherwise stated, "a 4, 5, or 6-membered saturated ring, which optionally contains a heteroatom selected from N or O" means a 4, 5, or 6-membered saturated carbon ring in which one carbon atom ring member may optionally be replaced by a heteroatom selected from N or O, such as cyclobutyl, cyclopentyl, cyclohexyl, azitidinyl, pyrrolidinyl, piperidinyl, oxadienoyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl. As used herein, unless otherwise stated, “treatment,” “cure,” or “management” in relation to a disease means: (1) alleviating the disease or reducing one or more biological manifestations of the disease; (2) interfering with (a) one or more points in a biological cascade that causes or creates the disease or (b) one or more biological manifestations of the disease; (3) mitigating one or more symptoms or effects associated with the disease; and / or (4) slowing the progression of the disease or one or more biological manifestations of the disease; and / or (5) reducing the likelihood of the severity of the disease or the biological manifestations of the disease. As used herein, unless otherwise stated, “prevention” means the prophylactic administration of a drug to reduce the likelihood of or delay the occurrence of a disease or its biological manifestations. As used herein, unless otherwise stated, “subject” means mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and especially human subject. As used herein, unless otherwise stated, a "pharmaceutically acceptable salt" means a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, separately with a suitable base or acid. As used herein, unless otherwise stated, the term "therapeutic effective amount" means an amount that, compared to a corresponding subject who did not receive that amount, results in the treatment or prevention of disease, but is sufficiently low, within the range of reasonable medical judgment, to avoid serious side effects (at a reasonable benefit / risk ratio). Therapeutic effective amounts of compounds will vary depending on the specific compound chosen (e.g., taking into account the compound's potency, efficacy, and half-life); the chosen route of administration; the disease being treated; the severity of the disease being treated; the age, body type, weight, and physical condition of the patient being treated; the patient's medical history; the duration of treatment; the nature of concurrent treatments; the desired therapeutic effect, etc., but can still be determined by those skilled in the art in a conventional manner. Compound Synthesis Those skilled in the art will understand that if a substituent described herein is incompatible with the synthetic method described herein, the substituent can be protected with a suitable protecting group that is stable under the reaction conditions. The protecting group can be removed at an appropriate point in the reaction sequence to yield the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of this can be found in I. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd Edition), John Wiley & Sons, NY (1999). In some cases, substituents that are reactive under the reaction conditions used can be specifically selected. In these cases, the reaction conditions change the selected substituent to another substituent that can be used as an intermediate compound or another substituent for a desired substituent in the target compound. General solution: The general scheme provides general synthetic routes for compounds of formulas 1.5 and 2.5, where R1, R2, R x U, X, Y, m, n, Q, A are defined as in equation (I). Step (i) can be used as S N The Ar reaction, using a suitable reagent, such as triethylamine in a suitable solvent, such as acetonitrile, at a suitable temperature, such as room temperature, reacts compounds 1.1 and 1.2 to give compound 1.3. Step (ii) can be achieved by reacting compound 1.3 with a suitable reagent, such as triethylamine and methanesulfonyl chloride or sulfonyl chloride, at a suitable temperature, such as 0°C or room temperature, to convert the hydroxyl group to a methanesulfonate or chlorinated compound, followed by cyclization without purification in a base, such as potassium carbonate, and a suitable solvent, such as acetonitrile, to give compound 1.4. Step (iii) reacts 1.4 with the corresponding alcohol or amine HQ-(CH2). m -A(Q is either -O- or -NR) b -) The reaction is carried out under suitable base conditions such as NaH or DIPEA in a suitable solvent such as acetonitrile or 1,4-dioxane to give the final product 1.5. Compound 2.5 is prepared from alcohol 2.1 and R1-substituted trichloropyrimidine. Variations in reaction conditions and reactants will be readily apparent to those skilled in the art. For the specific synthetic scheme when Q is -CH2-, see Example 170. In addition, the general scheme provides general synthetic routes for compounds of formulas 1.5 and 2.5, wherein R1, R2, X, Y, m, n, A are as defined in formula (I'). Step (i) can be used as S NThe Ar reaction, using a suitable reagent, such as triethylamine in a suitable solvent such as acetonitrile, at a suitable temperature such as room temperature, reacts compounds 1.1 and 1.2 to give compound 1.3. Step (ii) can be achieved by reacting compound 1.3 with a suitable reagent such as triethylamine and methanesulfonyl chloride or sulfonyl chloride at a suitable temperature such as 0°C or room temperature to convert the hydroxyl group to a methanesulfonate or chlorinated compound, followed by cyclization without purification in a base such as potassium carbonate and a suitable solvent such as acetonitrile to give compound 1.4. Step (iii) reacts 1.4 with the corresponding alcohol HO-(CH2). m -A reacts under suitable base conditions, such as NaH, in a suitable solvent, such as acetonitrile, to give the final product 1.5. Compound 2.5 is prepared from alcohol 2.1 and R1-substituted trichloropyrimidine. Variations in reaction conditions and reactants will be readily apparent to those skilled in the art. use The compounds of this invention are Lp-PLA2 inhibitors. Therefore, these compounds can be used for treatment, such as treating or preventing diseases related to Lp-PLA2 activity, including treating a subject requiring such treatment with a therapeutically effective amount of an Lp-PLA2 inhibitor. Therefore, one aspect of this invention relates to a method of treating or preventing diseases related to Lp-PLA2 activity. Those skilled in the art will understand that a particular disease or its treatment may involve one or more potential mechanisms related to Lp-PLA2 activity, including one or more mechanisms described herein. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating or preventing any of the diseases disclosed in the following patent applications: WO96 / 13484, WO96 / 19451, WO97 / 02242, WO97 / 12963, WO97 / 21675, WO97 / 21676, WO97 / 41098, WO97 / 41099, WO99 / 24420, WO00 / 10980, WO00 / 66566, WO00 / 66567, WO00 / 68208, WO01 / 60 805, WO02 / 30904, WO02 / 30911, WO03 / 015786, WO03 / 016287, WO03 / 041712, WO03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 87088, WO08 / 048867, US2008 / 0103156, US2008 / 0090851, US2008 / 0090852, WO08 / 048866, WO05 / 003118(CA 2530816Al), WO06 / 063811, WO06 / 063813, WO2008 / 141176, WO2013013503A1, WO2013014185A1, WO2014114248A1, WO2014114694A1, WO2016011930A1, JP 200188847, US 2008 / 0279846 A1, US 2010 / 0239565 A1, and US 2008 / 0280829 A1. In some embodiments, the present invention provides the use of the compounds of the invention in the preparation of medicaments for treating eye diseases. Eye diseases applicable to this invention may be related to disruption of the blood-retinal inner barrier (iBRB). Exemplary eye diseases involve diabetic eye diseases, including macular edema, diabetic retinopathy, posterior uveitis, retinal vein occlusion, etc. More eye diseases include, but are not limited to, central retinal vein occlusion, branch retinal vein occlusion, I-G syndrome (post-cataract and post-operative), retinitis pigmentosa, pars plana inflammation, shotgun retinal choroidal disease, outer retinal membrane, choroidal tumor, cystic macular edema, parafoveal telangiectasia, traction macular disease, vitreomacular traction syndrome, retinal detachment, optic nerve retinitis, idiopathic macular edema, etc. More detailed information on the treatment of eye diseases using Lp-PLA2 inhibitors is provided in WO2012 / 080497, which is incorporated herein by reference. Furthermore, some embodiments of the present invention provide the use of the compounds of the present invention in the preparation of a medicament for treating or preventing diabetic macular edema in a subject. In some embodiments, the present invention provides the use of the compounds of the present invention for treating diabetic macular edema in a subject. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of a medicament for treating or preventing macular edema in a subject who has macular edema or is at risk of developing macular edema. In other embodiments, the macular edema is associated with diabetic eye disease, such as diabetic macular edema or diabetic retinopathy. In still other embodiments, the macular edema is associated with posterior uveitis. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating or preventing glaucoma or macular degeneration. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of a medicament for treating or preventing diseases related to disruption of the blood-retinal inner barrier in subjects requiring such treatment. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for the treatment or prevention of any of the following diseases involving endothelial dysfunction, such as atherosclerosis (e.g., peripheral vascular atherosclerosis and cerebral vascular atherosclerosis), diabetes, hypertension, angina pectoris, and conditions following ischemia and reperfusion. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for the treatment or prevention of any of the following diseases involving lipid oxidation associated with enzyme activity, for example, diseases other than those such as atherosclerosis and diabetes, such as rheumatoid arthritis, stroke, inflammatory diseases of the brain (e.g., Alzheimer's disease), various neuropsychiatric disorders (e.g., schizophrenia, autism), myocardial infarction, ischemia, reperfusion injury, sepsis, and acute and chronic inflammation. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of a medicament for reducing the likelihood of cardiovascular events (e.g., heart attack, myocardial infarction, or stroke) in patients with coronary artery disease. In some embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating or preventing diseases involving activated monocytes, macrophages, or lymphocytes, because all such cell types express Lp-PLA2, including diseases involving activated macrophages (such as M1, dendritic, and / or other oxidative stress-generating macrophages). Exemplary conditions include, but are not limited to, psoriasis, rheumatoid arthritis, wound healing disorders, chronic obstructive pulmonary disease (COPD), cirrhosis, atopic dermatitis, emphysema, chronic pancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis, Alzheimer's disease, and autoimmune diseases such as lupus. In other embodiments, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for primary or secondary prevention of acute coronary events (e.g., caused by atherosclerosis); adjunctive therapy for the prevention of restenosis; or for delaying the development of diabetes or hypertensive renal insufficiency. Prevention includes treating subjects at risk for such conditions. In some embodiments, the present invention provides a method for treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) ​​function, inflammation, and / or microglial activation in a subject requiring such treatment. In some embodiments, the present invention provides a method for treating or preventing neurological disorders associated with abnormal blood-brain barrier (BBB) ​​function, inflammation, and / or microglial activation in a subject requiring such treatment. The method includes administering a therapeutically effective amount of the compound of the present invention to the subject. In other embodiments, the abnormal BBB is a permeable BBB. In other embodiments, the disease is a neurodegenerative disease. Such neurodegenerative diseases include, but are not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In some embodiments, the present invention provides a method for treating or preventing a disease in a subject associated with blood-brain barrier (BBB) ​​leakage. In some embodiments, the present invention provides a method for treating a disease in a subject associated with blood-brain barrier (BBB) ​​leakage. Exemplary diseases include, but are not limited to, cerebral hemorrhage and cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is Alzheimer's disease. In a specific implementation, the neurodegenerative disease is vascular dementia. In some implementations, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the compounds of the present invention can be used to treat or prevent neurodegenerative diseases in a subject. The method includes administering the compounds of the present invention (e.g., in the form of a pharmaceutical composition comprising the compounds of the present invention) to a subject in need of this treatment. In some embodiments, the compounds of the present invention can be used to treat a neurodegenerative disease in a subject. Exemplary neurodegenerative diseases include, but are not limited to, Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. In one specific embodiment, the neurodegenerative disease described in this invention is related to an abnormal blood-brain barrier. In some embodiments, the subject to which the agent inhibiting Lp-PLA2 activity is administered is a human. In some embodiments, the present invention provides a method for treating or preventing vascular dementia in a subject who has vascular dementia or is at risk of developing vascular dementia. The method includes administering a compound of the present invention (e.g., a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention) to the subject. In some embodiments, the present invention provides a method for treating a subject who has vascular dementia or is at risk of developing vascular dementia. In one specific embodiment, the vascular dementia is associated with Alzheimer's disease. In some embodiments, the present invention relates to a method of treating or preventing metabolic bone diseases by administering a therapeutically effective amount of a compound of the present invention to a subject in need of such treatment. Exemplary metabolic bone diseases include diseases related to bone and bone mineral density loss, including but not limited to osteoporosis and osteopenia. Exemplary osteoporosis and osteopenia include, but are not limited to, myelodisc disorders, dyslipidemia, Paget's disease, type II diabetes, metabolic syndrome, insulin resistance, hyperparathyroidism, and related diseases. In other embodiments, the subject in need of such treatment is a human being. It is believed that methods for preventing osteoporosis and / or osteopenia as described herein may be affected by inhibiting the expression of Lp-PLA2 and / or inhibiting the protein activity of Lp-PLA2. Therefore, some embodiments of the present invention provide methods for inhibiting Lp-PLA2 by blocking enzyme activity. In other embodiments, methods are provided for inhibiting Lp-PLA2 by reducing and / or downregulating the expression of Lp-PLA2 RNA. In still other embodiments, prevention and / or reduction of bone loss and / or bone mineral density loss result in prevention or reduction of symptoms associated with metabolic bone diseases such as osteoporosis and / or osteopenia. In a specific implementation, the method further includes administering other therapeutic agents for treating metabolic bone diseases to the subject requiring treatment. For example, when the metabolic bone disease is osteoporosis, other therapeutic agents may be used, such as bisphosphates (e.g., alendronate, ibandronate, riseapyridine, calcitonin, raloxifene), selective estrogen modulators (SERMs), estrogen therapy, hormone replacement therapy (ET / HRT), and teriparin. In some embodiments, systemic inflammatory diseases such as juvenile rheumatoid arthritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis, reactive arthritis, systemic lupus erythematosus, Voeux-Koyanagi-Harada syndrome, Lyme disease, Behçet's disease, ankylosing spondylitis, chronic granulomatous disease, and enthesitis may be the underlying cause of posterior uveitis affecting the retina and can lead to macular edema. This invention relates to a method of treating or preventing posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of the compound of the invention. In some embodiments, the invention provides a method of treating posterior uveitis or any of these systemic inflammatory diseases by administering a therapeutically effective amount of the compound of the invention. Treatment and / or prevention of diseases associated with Lp-PLA2 activity can be achieved using the compounds of the present invention in monotherapy or in dual or multiple combinations of therapy. For example, the compounds of the present invention can be used in combination with anti-hyperlipidemia agents, anti-atherosclerotic agents, antidiabetic agents, antianginal agents, anti-inflammatory agents, or antihypertensive agents, or agents for lowering lipoprotein(a) (Lp(a)), to treat or prevent the diseases described in the present invention. Examples of such agents include, but are not limited to, cholesterol synthesis inhibitors, such as statins; antioxidants, such as propofol; insulin sensitizers; calcium channel antagonists; and anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs). Agents for lowering Lp(a) include aminophosphates as described in WO 97 / 02037, WO 98 / 28310, WO 98 / 28311, and WO98 / 28312. In some embodiments, the compounds of the present invention can be used with one or more statins. Statins are well-known cholesterol-lowering agents, including atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, and rosuvastatin. In some embodiments, the compounds of the present invention may be used in conjunction with antidiabetic drugs or insulin sensitizers. In some embodiments, the compounds of the present invention may be used in conjunction with PPARγ activators, such as GI262570 (GlaxoSmithKline), and glitazone compounds such as rosiglitazone, troglitazone, and pioglitazone. The agent may be administered, for example, at a therapeutically effective amount known in the art, or at a smaller or greater amount than the dose known in the art that provides effective treatment. Combination therapy includes the administration of therapeutic agents in separate dosage forms or together in a single dosage form. Combination therapy may include simultaneously or separately administered therapeutic agents, which may be substantially simultaneous or substantially separate. Typically, combination therapy involves administering each agent such that a therapeutically effective amount of each agent is present in the subject's body for at least an overlapping period of time. How to use The therapeutically effective dose of the compounds of this invention will depend on many factors, including the age and weight of the intended recipient, the exact condition requiring treatment and its severity, the nature of the formulation and the route of administration, and will ultimately depend on the judgment of the prescribing physician. However, the therapeutically effective dose of the compounds of this invention for treating the diseases described herein will generally range from 0.1 to 100 mg / kg body weight / day, more typically from 1 to 10 mg / kg body weight / day. Thus, for example, for a 70 kg adult mammal, the actual daily dose is typically 70 to 700 mg, and this dose may be given as a single dose / day or multiple sub-dose daily, such as two, three, four, five, or six doses daily. Alternatively, administration may be intermittent, such as every other day, once a week, or once a month. Similar doses are expected to be suitable for treating other conditions described above. The pharmaceutical compositions of the present invention may comprise one or more of the compounds of the present invention. In some embodiments, the pharmaceutical composition may comprise more than one compound of the present invention. For example, in some embodiments, the pharmaceutical composition may comprise two or more compounds of the present invention. Furthermore, the pharmaceutical composition may optionally comprise one or more other pharmaceutically active compounds. As used in this invention, "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable raw material, component, or carrier that participates in imparting the morphology or consistency of the pharmaceutical composition. When mixed, each excipient is compatible with the other components of the pharmaceutical composition, thereby avoiding interactions that would significantly reduce the potency of the compounds of this invention when administered to a subject, and avoiding interactions that would result in pharmaceutically unacceptable pharmaceutical components. The compounds of the present invention and one or more pharmaceutically acceptable excipients can be formulated into dosage forms suitable for administration to a subject via the desired route of administration. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration (including sublingual or sublingual), such as tablets, capsules, sachets, pills, lozenges, powders, syrups, infusions, suspensions, solutions, emulsions, sachets, and capsules; (2) parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal), such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) nasal inhalation, such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration (including sublingual, sublingual, or transdermal), such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Such compositions can be prepared by any method known in the pharmaceutical field, for example by conjugating a compound of the above formula with a carrier or excipient. Pharmaceutical compositions suitable for oral administration may exist as discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquid form; edible foams (foams or whisks); or oil-in-water or water-in-oil liquid emulsions. Suitable pharmaceutically acceptable excipients may vary depending on the specific dosage form chosen. Furthermore, appropriate pharmaceutically acceptable excipients may be selected based on their specific function in the composition. For example, some pharmaceutically acceptable excipients may be selected because they have the ability to promote the production of a homogeneous dosage form. Some pharmaceutically acceptable excipients may be selected because they have the ability to promote the production of a stable dosage form. Some pharmaceutically acceptable excipients may be selected because they facilitate the delivery or translocation of one or more compounds of the invention from one organ or part of the body to another organ or part of the body when administered to a subject. Some pharmaceutically acceptable excipients may be selected because they increase patient compliance. Suitable pharmaceutically acceptable excipients include the following types: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will understand that some pharmaceutically acceptable excipients can provide more than one function, and that additional functions may be provided depending on the amount of the excipient present in the formulation and what other components are present in the formulation. Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in this invention. Furthermore, those skilled in the art have access to numerous resources describing pharmaceutically acceptable excipients and which can be used to select appropriate pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Company), and the Handbook of Pharmaceutical Excipients (American Pharmaceutical Association and Pharmaceutical Press). The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington Pharmaceutical Sciences (Mack Publishing). In one aspect, the present invention relates to solid oral dosage forms, such as tablets or capsules, comprising a therapeutically effective amount of the compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, glycosides, glucose, mannitol, sorbitol, starch (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and calcium hydrogen phosphate. The oral solid dosage form may also include a binder. Suitable binders include starch (e.g., corn starch, potato starch, and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, xanthan gum, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose). The oral solid dosage form may also include a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginate, and sodium carboxymethyl cellulose. The oral solid dosage form may also include a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc. In a specific embodiment, the present invention relates to a pharmaceutical composition comprising 0.01 mg to 1000 mg of one or more compounds of the above formulas described herein or pharmaceutically acceptable salts thereof, and 0.01 g to 5 g of one or more pharmaceutically acceptable excipients. Intermediate 1 (1S,4R)-4-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester Methyl (1S,4S)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-4-carboxylic acid (0.88 g, 3.4 mmol, Chemistry Letters, 2017, 566-568) was added to anhydrous tetrahydrofuran (30 mL), cooled to 0 °C, and lithium borohydride (222 mg, 10.2 mmol) was slowly added. The mixture was stirred overnight at room temperature. The reaction solution was cooled to 0 °C and quenched with sodium sulfate decahydrate. The reaction solution was poured into dichloromethane, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed with dichloromethane / methanol (20 / 1). The filtrate was concentrated to give the crude product of the title compound (1.5 g). LC-MS:m / z[M+H-tBu] + =174. ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol hydrochloride (1S,4R)-4-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (1.5 g crude) was dissolved in a mixed solvent of dichloromethane (5 mL) and methanol (5 mL), and ethyl hydrogen chloride solution (4.0 M, 5 mL) was added. The reaction mixture was stirred overnight at 40-50 °C. The reaction solution was concentrated to the crude product of the title compound (900 mg). LC-MS: m / z [M+H] + =130. ((1S,4R)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol hydrochloride (0.9 g, 5.4 mmol) was dissolved in dichloromethane (50 mL), cooled to 0 °C, and triethylamine (1.1 g, 1.5 mL, 10.8 mmol) and 2,4,6-trichloropyrimidine (1.2 g, 5.76 mmol) were added sequentially. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated the organic phase, and purified by silica gel column chromatography to give the title compound (0.36 g, 38% yield in three steps). LC-MS:m / z[M+H] + =276. (3S,11aR)-7-chloro-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazo[5,1-C][1,4]oxazin-9-one ((1S,4R)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol (360 mg, 1.3 mmol) and triethylamine (395 mg, 3.9 mmol) were added to anhydrous tetrahydrofuran (10 mL) and cooled to 0 °C. Methylsulfonyl chloride (229 mg, 2.0 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was concentrated and potassium carbonate (898 mg, 6.5 mmol) and acetonitrile (15 mL) were added. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated, and thin-layer chromatography (dichloromethane / methanol = 20 / 1) was used to separate the compound into the title compound (230 mg, 74%). LC-MS:m / z[M+H] + =240. 1 H NMR (400MHz, CDCl3) δ5.60 (s, 1H), 4.78 (br.s, 1H), 4.49 (d, J = 13.2Hz, 1H), 4.09-3.88 (m, 3H) ,3.61(d,J=9.8Hz,1H),3.32(d,J=9.8Hz,1H),2.10(d,J=10.8Hz,1H),1.84(d,J=10.3Hz,1H). Intermediate 2 (1R,4S)-4-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester Methyl (1R,4R)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-4-carboxylic acid (430 mg, 1.67 mmol, Chemistry Letters, 2017, 566-568) was added to anhydrous tetrahydrofuran (10 mL), cooled to 0 °C, and lithium borohydride (430 mg, 1.67 mmol) was slowly added. The mixture was stirred overnight at room temperature. The reaction solution was cooled to 0 °C and quenched with water. The reaction solution was diluted with ethyl acetate and dried with anhydrous sodium sulfate. The mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated. The residue was dissolved in dichloromethane, filtered, and the filtrate was concentrated to give the crude title compound (380 mg, 99%). LC-MS:m / z[M+H-tBu] + =174. ((1R,4S)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol (1R,4S)-4-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (380 mg, 1.67 mmol) was added to dichloromethane (10 mL) and trifluoroacetic acid (5 mL) and stirred overnight at room temperature. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1 to 2 / 1) to give the crude title compound (800 mg). LC-MS:m / z[M+H] + =130. ((1R,4S)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol 2,4,6-Trichloropyrimidine (1055 mg, 5.76 mmol) was added to acetonitrile (30 mL) and cooled to 0 °C. A solution of ((1R,4S)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol (700 mg, 2.88 mmol) and triethylamine (872 mg, 8.64 mmol) in acetonitrile (30 mL) was added dropwise, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give the title compound (120 mg, 15%). LC-MS:m / z[M+H] + =276. (3R,11aS)-7-chloro-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazo[5,1-C][1,4]oxazin-9-one ((1R,4S)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol (110 mg, 0.40 mmol) and triethylamine (121 mg, 1.20 mmol) were added to anhydrous tetrahydrofuran (3 mL) and cooled to 0 °C. Methylsulfonyl chloride (69 mg, 0.60 mmol) was added dropwise, and the mixture was stirred at 0 °C for 10 minutes. The reaction mixture was concentrated and potassium carbonate (166 mg, 1.20 mmol) and acetonitrile (2 mL) were added. The mixture was stirred at 90 °C for 5 hours. The reaction mixture was concentrated, and the solution was separated by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (50 mg, 52%). LC-MS:m / z[M+H] + =240. 1 H NMR (400MHz, CDCl3) δ5.60 (s, 1H), 4.78 (br.s, 1H), 4.49 (d, J = 12.7Hz, 1H), 4.07-3.98 (m, 3H) ,3.60(d,J=10.3Hz,1H),3.32(d,J=9.8Hz,1H),2.10(d,J=9.8Hz,1H),1.87(d,J=10.3Hz,1H). Intermediate 3 (2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (2-azabicyclo[2.1.1]hex-1-yl)methanol (3.5 g, 30.98 mmol, Journal of Organic Chemistry, 2018, 83, 14350-14361) was dissolved in acetonitrile (100 mL), and sodium carbonate (12.6 g, 93 mmol) was added. The reaction solution was cooled to below 0 °C, and 2,4,6-trichloropyrimidine (28.3 g, 154.9 mmol) was added dropwise. The reaction solution was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the white solid title compound (5.7 g, 71%) was obtained by silica gel column chromatography. LC-MS:m / z[M+H] + =260. 3-Chloro-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (5.1 g, 19.6 mmol) was dissolved in dichloromethane (100 mL), and sulfoxide (7 g, 58.8 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated, the residue was dissolved in acetonitrile (100 mL), and potassium carbonate (8.11 g, 58.8 mmol) was added. The mixture was stirred at 85 °C overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography to obtain the title compound (3.9 g, 89%). LC-MS:m / z[M+H] + =224. 1 H NMR (400MHz, DMSO-d6) δ5.93(s,1H),3.92(s,2H),3.40(s,2H),2.93(br.s,1H),2.06(br.s,2H),1.66-1.61(m,2H). Intermediate 4 (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]hept-1-yl)methanol 1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester (4.3 g, 18.9 mmol, Tetrahedron Letters, 2010, 51, 6741–6744) was dissolved in a mixed solvent of dichloromethane (20 mL) and methanol (20 mL), and ethyl hydrochloride solution (4.0 M, 20 mL) was added. The mixture was stirred overnight at 40–50 °C. The reaction solution was concentrated. The residue was dissolved in dichloromethane (80 mL), cooled to 0 °C, and triethylamine (5.7 g, 7.8 mL, 56.7 mmol) and 2,4,6-trichloropyrimidine (6.9 g, 4.3 mL, 37.8 mmol) were added sequentially. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated in the organic phase, and purified by silica gel column chromatography to give the title compound (1.13 g, 21%). LC-MS:m / z[M+H] + =274. 3-Chloro-7,8-dihydro-1H,6H,9H-6,8a-ethbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]hept-1-yl)methanol (360 mg, 1.3 mmol) was dissolved in dichloromethane (30 mL) and cooled to 0 °C. Thionyl chloride (4.56 g, 38.35 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue and potassium carbonate (3.18 g, 23.01 mmol) were added to acetonitrile (30 mL), and the mixture was stirred overnight at 80 °C. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed several times with ethyl acetate. The filtrates were combined and concentrated to give the title compound (0.76 g, 94%). LC-MS:m / z[M+H] + =238. 1 H NMR (400MHz, CDCl3) δ5.68(s,1H),4.19(t,J=4.6Hz,1H),4.03(s,2H),2.10(dd,J=4.6,10.5Hz,2H),1.87-1.76(m,6H).. Intermediate 5 (2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.2.2]oct-1-yl)methanol 2,4,6-Trichloropyrimidine (584 mg, 3.19 mmol) was added to acetonitrile (5 mL) and cooled to 0 °C. A solution of (2-azabicyclo[2.2.2]oct-1-yl)methanol (300 mg, 2.12 mmol, J. Org. Chem., 2007, 72, 3112-3115) and triethylamine (429 mg, 4.25 mmol) in acetonitrile (5 mL) was added dropwise, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give the title compound (198 mg, 32%). LC-MS:m / z[M+H] + =288. 3-Chloro-6,7,8,9-Tetrahydro-1H,10H-7,9a-Ethyl-bridged pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.2.2]oct-1-yl)methanol (198 mg, 0.69 mmol) was added to dichloromethane (5 mL) and cooled to 0 °C. Thionyl chloride (409 mg, 3.44 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and potassium carbonate (379 mg, 2.75 mmol) and acetonitrile (5 mL) were added. The mixture was stirred overnight at 90 °C. The reaction mixture was concentrated, and thin-layer chromatography (dichloromethane / methanol = 20 / 1) was used to obtain the title compound (170 mg, 98%). LC-MS:m / z[M+H] + =252. Intermediate 6 Benzylproline methyl ester Methyl 1-Boc-2-pyrrolidinecarboxylate (25 g, 109.04 mmol) was added to ethyl hydrochloride solution (4.0 M, 100 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue, benzyl bromide (22.38 g, 130.85 mmol), and anhydrous potassium carbonate (30.1 g, 218.08 mmol) were added to acetonitrile (100 mL), and the mixture was heated to reflux and stirred overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the combined organic phases were concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1 to 80 / 1) to give the title compound (18 g, 75%). LC-MS:m / z[M+H] + =220. 1-Benzyl-2-methylpyrrolidine-2-carboxylic acid methyl ester Benzylproline methyl ester (8 g, 36.48 mmol) was added to tetrahydrofuran (100 mL) and cooled to -20 °C under argon protection. Iodomethane (15.5 g, 109.44 mmol) was added to the reaction solution, and the temperature was lowered to -50 °C. A tetrahydrofuran solution of diisopropylaminolithium (2.0 M, 63.84 mL, 127.68 mmol) was added dropwise at -50 °C to -40 °C. After the addition was completed, the mixture was stirred at -50 °C to -40 °C for 3 hours. The reaction solution was quenched with methanol (50 mL), and then poured into water. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1 to 100 / 1) to give the title compound (5 g, 59%). LC-MS:m / z[M+H] + =234. (1-Benzyl-2-methylpyrrolidone-2-yl)methanol Lithium aluminum hydride (1.63 g, 42.90 mmol) was added to anhydrous tetrahydrofuran (25 mL), and the mixture was cooled to 0 °C under argon protection. A solution of methyl 1-benzyl-2-methylpyrrolidine-2-carboxylate (5 g, 21.45 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction was quenched by adding sodium sulfate decahydrate (20 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound (3.8 g, 86%). LC-MS:m / z[M+H] + =206. (2-Methylpyrrolidone-2-yl)methanol (1-Benzyl-2-methylpyrrolidone-2-yl)methanol (3.8 g, 18.52 mmol) and Pd / C (10%, 400 mg) were added to methanol (40 mL). Hydrogenation was carried out overnight at 50 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (2.16 g, 101%). LC-MS:m / z[M+H] + =116. (1-(2,6-dichloropyrimidin-4-yl)-2-methylpyrrolidine-2-yl)methanol 2,4,6-Trichloropyrimidine (5.16 g, 28.15 mmol) and triethylamine (3.8 g, 37.54 mmol) were added to acetonitrile (80 mL). The reaction mixture was cooled to 0 °C, and (2-methylpyrrolidone-2-yl)methanol (2.16 g, 18.77 mmol) was added. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give the title compound (2 g, 41%). LC-MS:m / z[M+H] + =262. 3-Chloro-8a-methyl-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (1-(2,6-dichloropyrimidin-4-yl)-2-methylpyrrolidine-2-yl)methanol (2 g, 7.67 mmol) was added to dichloromethane (30 mL), and the mixture was cooled to 0 °C. Thionyl chloride (4.56 g, 38.35 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the concentrated residue, along with potassium carbonate (3.18 g, 23.01 mmol), was added to acetonitrile (30 mL). The mixture was stirred overnight at 90 °C. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate and dichloromethane, respectively. The combined organic phases were concentrated to give the title compound (1.5 g, 88%). 1 H NMR(400MHz,DMSO-d6)δ5.96(s,1H),4.06(d,J=12.2Hz,1H),3.79(d,J=12.2H z,1H),3.48-3.35(m,2H),2.10-1.89(m,2H),1.87-1.68(m,2H),1.32(s,3H). Intermediate 7 1-Benzyl-2-ethylpyrrolidine-2-carboxylic acid methyl ester Benzylproline methyl ester (8 g, 36.48 mmol) was added to tetrahydrofuran (100 mL) and cooled to -20 °C under argon protection. Iodethane (17.1 g, 109.45 mmol) was added to the reaction solution, and the mixture was cooled to -50 °C. A solution of diisopropylaminolithium in tetrahydrofuran (2.0 M, 63.84 mL, 127.68 mmol) was added dropwise at -50 °C to -40 °C. After the addition was complete, the mixture was stirred at -50 °C to -40 °C for 3 hours. The reaction solution was quenched with methanol, poured into water, and extracted with ethyl acetate. The combined organic phases were concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 200 / 1 to 100 / 1) to give the title compound (4.9 g, 54%). LC-MS:m / z[M+H] + =248. (1-Benzyl-2-ethylpyrrolidine-2-yl)methanol Lithium aluminum hydride (1.51 g, 39.66 mmol) was added to anhydrous tetrahydrofuran (25 mL), and the mixture was cooled to 0 °C under argon protection. A solution of methyl 1-benzyl-2-ethylpyrrolidine-2-carboxylate (4.9 g, 19.83 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise. The mixture was stirred overnight at room temperature. Sodium sulfate decahydrate (5 g) was added to quench the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound (3.5 g, 81%). LC-MS:m / z[M+H] + =220. (2-Ethylpyrrolidone-2-yl)methanol (1-Benzyl-2-ethylpyrrolidone-2-yl)methanol (3.5 g, 15.97 mmol) and Pd / C (10%, 350 mg) were added to methanol (50 mL). Hydrogenation was carried out overnight at 50 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (2.1 g, 100%). LC-MS:m / z[M+H] + =130. (1-(2,6-dichloropyrimidin-4-yl)-2-ethylpyrrolidine-2-yl)methanol 2,4,6-Trichloropyrimidine (3.5 g, 19.16 mmol) and triethylamine (3.23 g, 31.94 mmol) were added to acetonitrile (80 mL) and cooled to 0 °C. (2-Ethylpyrrolidone-2-yl)methanol (2.1 g, 15.97 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give the title compound (1.5 g, 28%). LC-MS:m / z[M+H] + =276. 3-Chloro-8a-ethyl-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (1-(2,6-dichloropyrimidin-4-yl)-2-ethylpyrrolidine-2-yl)methanol (1.5 g, 5.45 mmol) was added to dichloromethane (30 mL), and the mixture was cooled to 0 °C. Thionyl chloride (3.24 g, 27.27 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the concentrated residue, along with potassium carbonate (2.26 g, 16.35 mmol), was added to acetonitrile (30 mL), and the mixture was stirred overnight at 90 °C. The reaction solution was poured into water (30 mL), and extracted with ethyl acetate and dichloromethane, respectively. The combined organic phases were concentrated, and thin-layer chromatography (dichloromethane / methanol = 20 / 1) was performed to obtain the title compound (260 mg, 20%). LC-MS:m / z[M+H] + =240. Intermediate 8 Methyl N-Boc-2-methylpiperidine-2-carboxylate Methyl N-BOC-piperidine-2-carboxylate (10.0 g, 41.15 mmol) and iodomethane (16.2 g, 123.4 mmol) were added to tetrahydrofuran (60 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium diisopropylaminoacetate (61.7 mL, 2.0 M, 123.4 mmol) was added dropwise. After stirring for 3 hours, the reaction mixture was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (10.0 g, 95%). LC-MS:m / z[M+H-Boc] + =158. (2-Methylpiperidin-2-yl)methanol Methyl N-Boc-2-methylpiperidin-2-carboxylate (5.0 g, 19.45 mmol) was dissolved in dichloromethane (15 mL), and ethyl hydrogen chloride solution (30 mL) was added. After 20 minutes, the reaction solution was concentrated. Dichloromethane (20 mL) and sodium carbonate solid were added to adjust the pH to 7-8. The mixture was filtered, and the filtrate was concentrated to obtain crude methyl 2-methylpiperidin-2-carboxylate, which was dissolved in tetrahydrofuran (20 mL). This solution was added dropwise to a tetrahydrofuran solution of lithium aluminum hydride (30 mL, 23.3 mmol) at 0 °C. After stirring at 0 °C for 2 hours, the reaction was quenched with sodium sulfate decahydrate. After stirring at room temperature for 30 minutes, the mixture was filtered, and the filtrate was concentrated to obtain the title compound (1.8 g, 72%). LC-MS:m / z[M+H] + =130. (1-(2,6-dichloropyrimidin-4-yl)-2-methylpiperidin-2-yl)methanol 2,4,6-Trichloropyrimidine (3.8 g, 20.93 mmol) was added to acetonitrile (60 mL) and cooled to 0 °C. Sodium carbonate (2.95 g, 27.90 mmol) was added and stirred for 10 minutes. Then, a solution of (2-methylpiperidin-2-yl)methanol (1.8 g, 13.95 mmol) in acetonitrile (20 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the title compound (1.8 g, 47%). LC-MS:m / z[M+H] + =276. 3-Chloro-9a-methyl6,7,8,9,9a,10-hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (1-(2,6-dichloropyrimidin-4-yl)-2-methylpiperidin-2-yl)methanol (1.8 g, 6.54 mmol) was added to dichloromethane (20 mL), and thionyl chloride (1.56 g, 13.0 mmol) was added dropwise at room temperature. After stirring at room temperature for 10 minutes, the reaction solution was concentrated and potassium carbonate (2.7 g, 19.62 mmol) and acetonitrile (40 mL) were added. The mixture was stirred overnight at 85 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (1.2 g, 77%). LC-MS:m / z[M+H] + =240. 1 H NMR (400MHz, CDCl3) δ5.47(s,1H),3.91-3.78(m,2H),3.40(dd,J=3.2,13.5Hz,1H),3.25-3.07(m,1H),1.98-1.56(m,7H),1.51(dd,J=4.2,9.0Hz,2H). Intermediate 9 Methyl N-Boc-2-ethylpiperidine-2-carboxylate Methyl N-BOC-piperidine-2-carboxylate (5.1 g, 20.98 mmol) and iodoethane (3.2 mL, 41.0 mmol) were added to tetrahydrofuran (60 mL), cooled to 0 °C, and a tetrahydrofuran solution of lithium diisopropylaminoacetate (21.0 mL, 2.0 M, 42.0 mmol) was added. After stirring at 0 °C for 0.5 hours, the reaction mixture was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give the crude title compound (4.0 g, 70%). LC-MS:m / z[M+H-Boc] + =172. 2-Ethyl-2-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester Methyl N-Boc-2-ethylpiperidine-2-carboxylate (3.0 g, 11.0 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (970 mg, 25.5 mmol) was added in portions at 0 °C. After stirring at this temperature for 15 minutes, sodium sulfate decahydrate was added to quench the reaction. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (300 mg, 11%). LC-MS:m / z[M+H-Boc] + =144. (1-(2,6-dichloropyrimidin-4-yl)-2-ethylpiperidin-2-yl)methanol 400 mg (1.65 mmol) of tert-butyl 2-ethyl-2-hydroxymethylpiperidin-1-carboxylate was added to 3 mL of dichloromethane, and 6 mL of ethyl hydrochloride solution was added. After stirring at room temperature for 10 minutes, the mixture was concentrated to give 320 mg of (2-ethylpiperidin-2-yl)methanol. 320 mg (1.10 mmol) of (2-ethylpiperidin-2-yl)methanol and 600 mg (3.33 mmol) of 2,4,6-trichloropyrimidine were added sequentially to 16 mL of acetonitrile, and the mixture was cooled to 0 °C. 530 mg (5.01 mmol) of sodium carbonate and the obtained (2-ethylpiperidin-2-yl)methanol were added, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) was performed to give the title compound (200 mg, 41%). LC-MS:m / z[M+H] + =290. 3-Chloro-9a-ethyl 6,7,8,9,9a,10-hexahydro-1H-pyrido[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (1-(2,6-dichloropyrimidin-4-yl)-2-ethylpiperidin-2-yl)methanol (50 mg, 0.17 mmol) was added to dichloromethane (6 mL), and thionyl chloride (40 mg, 0.34 mmol) was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and potassium carbonate (70 mg, 0.51 mmol) and acetonitrile (6 mL) were added. The mixture was stirred overnight at 85 °C. The reaction mixture was filtered, and the filtrate was concentrated. Thin-layer chromatography (dichloromethane / methanol = 10 / 1) was used to separate the compound into the title compound (30 mg, 77%). LC-MS:m / z[M+H] + =254. 1 H NMR (400MHz, CDCl3): δ5.49 (s, 1H), 3.95 (d, J = 12.2Hz, 1H), 3.75 (d, J = 12.2Hz, 1H), 3.41 (d, J = 13. 7Hz,1H),3.13(t,J=13.0Hz,1H),1.70-2.05(m,6H),1.52(d,J=12.7Hz,2H),0.89(t,J=7.3Hz,3H); Intermediate 10 Methyl N-Boc-morpholino-3-carboxylate N-Boc-morpholino-3-carboxylic acid (10 g, 43.3 mmol) was dissolved in dichloromethane (200 mL) and methanol (20 mL), and trimethylsilazomethane (43 mL, 2.0 M n-hexane solution, 86.7 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was then directly concentrated to obtain the crude product of the title compound (11.4 g). LC-MS:m / z[M+H-Boc] + =146. Methyl N-Boc-3-methylmorpholino-3-carboxylate Methyl N-Boc-morpholino-3-carboxylate (11 g, 44.9 mmol) was dissolved in tetrahydrofuran (120 mL). Under argon protection, iodomethane (10.5 g, 67.3 mmol) was added, and the reaction solution was cooled to below 0 °C. A tetrahydrofuran solution of sodium bis(trimethylsilyl)aminoacetate (2.0 M, 45 mL, 89.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction solution was quenched dropwise with methanol, poured into water, extracted with ethyl acetate, and the combined organic phases were dried, filtered, and the filtrate was concentrated. The filtrate was separated by column chromatography to obtain the title compound (8.6 g, 74%). LC-MS:m / z[M+H-Boc] + =160. 3-Hydroxymethyl-3-methylmorpholine-4-carboxylic acid tert-butyl ester Methyl N-Boc-3-methylmorpholine-3-carboxylate (1 g, 3.86 mmol) was dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to below 0 °C, and lithium aluminum hydride (220 mg, 5.8 mmol) was added in portions. The mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 0.5 hours, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the title compound (550 mg, 61%). LC-MS:m / z[M+H-Boc] + =132. (3-Methylmorpholino-3-yl)methanol hydrochloride 3-hydroxymethyl-3-methylmorpholine-4-carboxylic acid tert-butyl ester (3.2 g, 13.85 mmol) was dissolved in dichloromethane (50 mL) under argon protection, and ethyl hydrogen chloride solution (4.0 M, 50 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated to obtain the crude product of the title compound (1.7 g). LC-MS:m / z[M+H] + =132. (4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholin-3-yl)methanol (3-Methylmorpholino-3-yl)methanol hydrochloride (1.5 g, 11.45 mmol) was dissolved in acetonitrile (50 mL), and sodium carbonate (3.64 g, 34.35 mmol) was added. The reaction solution was cooled to below 0 °C, and 2,4,6-trichloropyrimidine (10.5 g, 57.25 mmol) was added dropwise. The mixture was stirred overnight at 50 °C. After filtration through diatomaceous earth, the filtrate was concentrated and purified by column chromatography to obtain the title compound (2.1 g, 66%). LC-MS:m / z[M+H] + =278. 7-Chloro-11a-methyl-3,4,11,11a-tetrahydro-1H,9H-pyrimidino[6',1':2,3]imidazo[5,1-c][1,4]oxazin-9-one (4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholin-3-yl)methanol (1.6 g, 5.76 mmol) was dissolved in dichloromethane (50 mL), and sulfoxide (2.05 g, 17.3 mmol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction solution was concentrated. The concentrated residue was dissolved in acetonitrile (50 mL), and potassium carbonate (2.1 g, 15.2 mmol) was added. The mixture was stirred at 85 °C overnight. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.2 g, 98%). LC-MS:m / z[M+H] + =242. 1 H NMR (400MHz, DMSO-d6) δ5.99(s,1H),3.79(d,J=7.3Hz,1H),3.73(s,2H),3.66-3.58(m,2H),3.57-3.50(m,1H),3.47-3.39(m,2H),1.47(s,3H); Intermediate 11 ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methane-d2-ol (1S,4S)-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane-4-carboxylic acid methyl ester (470 mg, 1.83 mmol, Chemistry Letters, 2017, 566-568) was added to ethyl hydrochloride solution (4.0 M, 10 mL), and the reaction mixture was stirred at room temperature for 5 hours. After concentration, acetonitrile (20 mL) and sodium carbonate (1 g) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated. Anhydrous tetrahydrofuran (15 mL) and lithium aluminum hydride deuterated (138.9 mg, 3.66 mmol) were added to the residue, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated to give the crude title compound (200 mg). LC-MS:m / z[M+H] + =132. (((1S,4R)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methane-d2-ol Triethylamine (307 mg, 3.04 mmol) and 2,4,6-trichloropyrimidine (335.6 mg, 1.83 mmol) were added to acetonitrile (20 mL) and cooled to 0 °C. ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methane-d2-ol (200 mg, 1.52 mmol) was slowly added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel column chromatography to give the title compound (130 mg, 31%). LC-MS:m / z[M+H] + =278. (3S,11aR)-7-chloro-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidin [6',1':2,3]imidazol [5,1-c][1,4]oxazin-9-one-11,11-d2 ((1S,4R)-5-(2,6-dichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methane-d2-ol (130 mg, 0.47 mmol) was added to dichloromethane (10 mL) and cooled to 0 °C. Thionyl chloride (279.6 mg, 2.35 mmol) was added dropwise, and the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was concentrated and potassium carbonate (194.6 mg, 1.41 mmol) and acetonitrile (15 mL) were added, and the mixture was refluxed and stirred overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (63 mg, 74%). LC-MS:m / z[M+H] + =242. Intermediate 12 ((1S,4R)-5-(2,6-dichloro-5-fluoropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol 2,4,6-Trichloro-5-fluoropyrimidine (872 mg, 4.4 mmol) and triethylamine (795 mg, 7.9 mmol) were added to tetrahydrofuran (10 mL) and cooled to 0 °C. ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol (650 mg, 4.0 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give the title compound (700 mg, 60%). LC-MS:m / z[M+H] + =294. (3S,11aR)-7-chloro-6-fluoro-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazol[5,1-c][1,4]oxazin-9-one ((1S,4R)-5-(2,6-dichloro-5-fluoropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol (700 mg, 2.4 mmol) was added to thionyl chloride (10 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and potassium carbonate (660 mg, 4.8 mmol) and acetonitrile (20 mL) were added. The mixture was stirred overnight at 80 °C. The reaction mixture was concentrated, and the title compound (560 mg, 91%) was obtained by thin-layer chromatography. LC-MS:m / z[M+H] +=258. 1 H NMR (400MHz, CDCl3) δ4.80 (br.s, 1H), 4.53 (d, J = 12.7Hz, 1H), 4.15-4.06 (m, 1H), 4.05-3.95 ( m,2H),3.80(d,J=10.3Hz,1H),3.67(d,J=10.8Hz,1H),2.22-2.13(m,1H),2.12-2.05(m,1H). Intermediate 13 ((1S,4R)-5-(2,5,6-trichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol Perchloropyrimidine (333 mg, 1.71 mmol) was dissolved in acetonitrile (16 mL), followed by the addition of sodium carbonate solid (362 mg, 3.42 mmol) and ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol hydrochloride (200 mg, 1.14 mmol). The mixture was stirred overnight at room temperature. The solution was filtered, concentrated, and purified by thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (280 mg). LC-MS:m / z[M+H] + =310. (3S,11aR)-6,7-dichloro-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazo[5,1-c][1,4]oxazin-9-one ((1S,4R)-5-(2,5,6-trichloropyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol (280 mg, 0.9 mmol) and thionyl chloride (650 mg, 4.5 mmol) were added to dichloromethane (8 mL) and stirred for 30 minutes. The reaction mixture was concentrated and potassium carbonate (620 mg, 4.8 mmol) and acetonitrile (16 mL) were added, and the mixture was stirred overnight at 90 °C. The reaction mixture was filtered, the filtrate was concentrated, and thin-layer chromatography (dichloromethane / methanol = 25 / 1) was used to purify the title compound (160 mg, 65%). LC-MS:m / z[M+H] + =274. 1H NMR (400MHz, CDCl3) δ4.78 (br.s, 1H), 4.51 (d, J = 13.2Hz, 1H), 4.08 (d, J = 7.3Hz, 1H), 3.95-4.04 (m, 2H), 3.89 (s, 2H), 1.96-2.29 (m, 2H). Intermediate 14 ((1S,4R)-5-(2,6-dichloro-5-methylpyrimidin)-4-yl-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol 2,4,6-Trichloro-5-methylpyrimidine (113 mg, 0.4 mmol) was dissolved in acetonitrile (8 mL), and sodium carbonate solid (130 mg, 1.2 mmol) and ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol hydrochloride (70 mg, 0.6 mmol) were added separately. The mixture was stirred overnight at room temperature. The solution was filtered, the filtrate was concentrated, and the solution was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (80 mg). LC-MS:m / z[M+H] + =290. (3S,11aR)-7-chloro-6-methyl-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazo[5,1-c][1,4]oxazin-9-one ((1S,4R)-5-(2,6-dichloro-5-methylpyrimidin)-4-yl-2-oxa-5-azabicyclo[2.2.1]heptyl-4-yl)methanol (80 mg, 0.27 mmol) and thionyl chloride (160 mg, 1.35 mmol) were added to dichloromethane (3 mL) and stirred for 30 minutes. The reaction solution was concentrated and potassium carbonate (112 mg, 0.81 mmol) and acetonitrile (12 mL) were added, and the mixture was stirred overnight at 90 °C. The reaction solution was filtered, the filtrate was concentrated, and thin-layer chromatography (dichloromethane / methanol = 25 / 1) was used to separate the compound into the title compound (20 mg, 29%). LC-MS:m / z[M+H] + =254. Intermediate 15 5-Formyl-2-(3-(trifluoromethyl)phenoxy)benzylnitrile 2-Fluoro-5-formylbenzylnitrile (15.0 g, 0.1 mol), 3-(trifluoromethyl)phenol (16.0 g, 0.1 mol), and potassium carbonate (13.8 g, 0.1 mol) were added to N,N-dimethylformamide (100.0 mL), and the mixture was reacted at 105 °C for 8 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated. The concentrated residue was slurried with ethanol to give the title compound (22.1 g, 75.5%). 1 H NMR (400MHz, DMSO-d6) δ9.96(s,1H),8.49(s,1H),8.14(br.s,1H),7.88(br.s,2H),7.47(br.s,2H),7.19(br.s,1H). 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzylnitrile 5-Formyl-2-(3-(trifluoromethyl)phenoxy)benzyl nitrile (24.3 g, 83.44 mmol) was added to methanol (250.0 mL), and sodium borohydride (4.86 g, 127.9 mmol) was added in portions. The mixture was reacted at room temperature for 0.5 h, the reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (24.2 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ7.80(s,1H),7.73-7.53(m,3H),7.52-7.27(m,2H),7.09(s,1H),5.41(s,1H),4.51(s,2H). Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 15. Intermediate 34 4-(benzyloxy)-2-(trifluoromethoxy)pyridine 4-(benzyloxy)pyridin-2-ol (1.91 g, 9.48 mmol) and 1-trifluoromethyl-1,2-benzyl-3(H)-one (1 g, 3.16 mmol) were added to nitromethane (25 mL) and stirred overnight at 100 °C. The reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (530 mg, 47%). LC-MS:m / z[M+H] + =270. 2-(trifluoromethoxy)pyridine-4-ol 4-(benzyloxy)-2-(trifluoromethoxy)pyridine (530 mg, 1.97 mmol) and Pd / C (10%, 125 mg) were added to methanol (20 mL), and the mixture was stirred overnight at 60 °C and 3.0 bar under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give the crude title compound (330 mg, 94%). LC-MS:m / z[M+H] + =180. (3,5-Difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 3,4,5-Trifluorobenzaldehyde (294.4 mg, 1.84 mol), 2-(trifluoromethoxy)pyridin-4-ol (330 mg, 1.84 mol), and potassium carbonate (330.6 mg, 2.39 mol) were added to N,N-dimethylformamide (10 mL). The mixture was stirred at 120 °C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated to obtain crude 3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzaldehyde. This crude product was added to ethanol (250.0 mL), and sodium borohydride (69.61 mg, 1.84 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to give the title compound (400 mg, 68%). LC-MS:m / z[M+H] + =322. 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=5.9Hz,1H),7.29(d,J=9.3Hz,2H),7.07(d,J=3.9Hz,1H),6.95(s,1H),5.56(br.s,1H),4.56(d,J=4.9Hz,2H). Intermediate 35 4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 2-(trifluoromethyl)pyridine-4-ol (1.0 g, 5.6 mmol), 4-fluorobenzaldehyde (0.7 g, 5.5 mmol), and potassium carbonate (1.7 g, 12.0 mmol) were added to N,N-dimethylformamide (10.0 mL), stirred at 120 °C for 14 h, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography to give the title compound (0.8 g, 54%). LC-MS:m / z[M+H] + =268. 2-(trifluoromethyl)-4-(4-vinylphenoxy)pyridine 4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde (0.8 g, 2.9 mmol) and methyltriphenylphosphine bromide (1.28 g, 3.6 mmol) were added to tetrahydrofuran (20 mL), and sodium hydride (173 mg, 7.2 mmol, 60%) was added to the system. The mixture was stirred for 16 h under argon protection. The reaction solution was poured into ice water, extracted with dichloromethane, concentrated in the organic phase, and purified by column chromatography to give the title compound (0.2 g, 26%). LC-MS:m / z[M+H] + =266. 2-(4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)ethanol-1-ol At 0 °C, 2-(trifluoromethyl)-4-(4-vinylphenoxy)pyridine (0.2 g, 0.75 mmol) was dissolved in tetrahydrofuran (2 mL), and a tetrahydrofuran solution of 9-boronbicyclo[3.3.1]nonane (0.5 M, 15 mL, 7.5 mmol) was added. The mixture was naturally heated to room temperature and stirred for 16 h. Water (1 mL), hydrogen peroxide (30%, 5 mL), and sodium hydroxide aqueous solution (3.0 M, 10 mL) were added to the reaction solution, and the reaction was carried out at 50 °C for 2 h. The reaction solution was diluted with water, extracted with dichloromethane, and the combined organic phases were concentrated. Thin-layer chromatography was used to separate the title compound (116 mg, 55%). LC-MS:m / z[M+H] + =284. 1H NMR(400MHz,DMSO-d6)δ8.61(d,J=5.4Hz,1H),7.38(br.s,2H),7.35(br.s,1H),7.16(d,J=8.3 Hz,2H),7.12(d,J=3.4Hz,1H),4.67(t,J=4.9Hz,1H),3.71-3.55(m,2H),2.77(t,J=6.6Hz,2H). Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 35. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 13. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 15. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 34. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 35. Intermediate 63 2,4-Dichloro-6-((1S,4R)-4-((hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptyl-5-yl)pyrimidin-5-nitrile 2,4,6-Trichloropyrimidin-5-onitrile (400 mg, 1.94 mmol) was dissolved in acetonitrile (12 mL), and sodium carbonate solid (318 mg, 3.0 mmol) and ((1S,4R)-2-oxa-5-azabicyclo[2.2.1]hept-4-yl)methanol hydrochloride (166 mg, 1.0 mmol) were added sequentially. The mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and the solution was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (40 mg, 13%). LC-MS:m / z[M+H] + =301. (3S,11aR)-7-chloro-9-oxo-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidine[6',1':2,3]imidazol[5,1-c][1,4]oxazine-6-nitrile 2,4-Dichloro-6-((1S,4R)-4-((hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptyl-5-yl)pyrimidin-5-onitrile (40 mg, 0.12 mmol) and thionyl chloride (0.2 mL) were added to dichloromethane (3 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated and sodium carbonate (40 mg, 0.37 mmol) and acetonitrile (6 mL) were added, and the mixture was stirred overnight at 85 °C. The reaction mixture was filtered, the filtrate was concentrated, and thin-layer chromatography (dichloromethane / methanol = 25 / 1) was used to separate the compound into the title compound (30 mg, 91%). LC-MS:m / z[M+H] + =265. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 63. Intermediate 65 (2-(2,6-dichloro-5-methoxypyrimidin-4-yl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (2-azabicyclo[2.1.1]hex-1-yl)methanol (500 mg, 4.42 mmol, Journal of Organic Chemistry, 2018, 83, 14350-14361) was dissolved in acetonitrile (10 mL), sodium carbonate (3.64 g, 34.35 mmol) was added, the reaction solution was cooled to 0 °C, and 2,4,6-trichloro-5-methoxypyrimidine (1.4 g, 6.46 mmol) was added. The reaction solution was reacted overnight at room temperature. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the white solid title compound (1.1 g, 72%) was obtained by silica gel chromatography. LC-MS:m / z[M+H] + =290. 3-Chloro-4-methoxy-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(2,6-dichloro-5-methoxypyrimidin-4-yl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (1.1 g, 3.79 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (1.35 g, 11.38 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated and dissolved in acetonitrile (10 mL), and potassium carbonate (1.5 g, 10.9 mmol) was added. The mixture was stirred overnight at 85 °C. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filtrate was concentrated and purified by column chromatography to obtain the solid title compound (230 mg, 25%). LC-MS:m / z[M+H] + =254. 1 H NMR (400MHz, CDCl3) δ4.03 (s, 2H), 3.74 (s, 3H), 3.67 (s, 2H), 3.07 (br.s, 1H), 2.13 (br.s, 2H), 1.75 (d, J = 4.4Hz, 2H). Intermediate 66 (3-oxa-8-azabicyclo[3.2.1]octane-1-yl)methanol hydrochloride 1-(hydroxymethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 0.82 mmol, Tetrahedron Letters, 2016, 57, 599–602) was dissolved in dichloromethane (5 mL), and under argon protection, an ethyl acetate solution of hydrogen chloride (4.0 M, 50 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to give the crude title compound (140 mg). LC-MS:m / z[M+H] + =144. (8-(2,6-dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-1-yl)methanol (3-oxa-8-azabicyclo[3.2.1]octane-1-yl)methanol hydrochloride (140 mg, 0.98 mmol) was dissolved in acetonitrile (10 mL), and sodium carbonate (311 mg, 2.94 mmol) was added with stirring. The reaction solution was cooled to below 0 °C, and 2,4,6-trichloropyrimidine (537 mg, 2.94 mmol) was added dropwise. The mixture was stirred overnight at 50 °C. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography to give the title compound (190 mg, 67%). LC-MS: m / z [M+H] + =290. 7-Chloro-3,4-dihydro-1H,9H,11H-4,11a-ethionidinido[6',1':2,3]imidazo[5,1-c][1,4]oxazin-9-one (8-(2,6-dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]oct-1-yl)methanol (110 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL), and sulfoxide (209 mg, 1.76 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and acetonitrile (10 mL) and potassium carbonate (243 mg, 1.76 mmol) were added to the residue sequentially. The mixture was stirred overnight at 85 °C. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (85 mg, 57%). LC-MS:m / z[M+H] + =254. 1 H NMR (400MHz, CDCl3) δ5.69(s,1H),4.27(d,J=12.2Hz,1H),4.05(d,J=6.4Hz,1H),3.95(d,J=10.3Hz,1H) ,3.75(br.s,4H),2.41-2.26(m,1H),2.20-2.05(m,1H),1.94(td,J=6.2,12.0Hz,1H),1.82-1.68(m,1H). Intermediate 67 (1R,4S)-1-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester 2-Benzyl-1-methyl(1R,4S)-2-azabicyclo[2.2.1]heptane-1,2-dicarboxylic acid ester (300 mg, 1.04 mmol, Tetrahedron, 2009, 1433–1436) was added to a mixture of anhydrous tetrahydrofuran (10 mL) and methanol (1 mL), followed by slow addition of sodium borohydride (117.8 mg, 3.11 mmol). The mixture was stirred at room temperature for 2 hours. Lithium borohydride (67.74 mg, 3.11 mmol) was then added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 1–1 / 1) to give the title compound (230 mg, 85%). LC-MS:m / z[M+H] + =262. ((1R,4S)-2-azabicyclo[2.2.1]heptyl-1-yl)methanol (1R,4S)-1-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (230 mg, 0.88 mmol) and Pd / C (10%, 25 mg) were added to methanol (1 mL) and hydrogenated at room temperature and atmospheric pressure for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (230 mg). LC-MS:m / z[M+H] + =128. ((1R,4S)-2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.2.1]heptyl-1-yl)methanol ((1R,4S)-2-azabicyclo[2.2.1]heptyl-1-yl)methanol (125 mg, crude) was added to acetonitrile (10 mL). The mixture was cooled to 0 °C with stirring, and triethylamine (197.96 mg, 1.96 mmol) and 2,4,6-trichloropyrimidine (215.7 mg, 1.18 mmol) were added sequentially to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) was performed to give the title compound (140 mg, two-step yield 58%). LC-MS:m / z[M+H] + =274. (7S,9aR)-3-chloro-6,7,8,9-tetrahydro-1H,10H-7,9a-methyl-bridged pyridino[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one ((1R,4S)-2-(2,6-dichloropyrimidin-4-yl)-2-azabicyclo[2.2.1]heptyl-1-yl)methanol (140 mg, 0.51 mmol) was added to dichloromethane (5 mL) and cooled to 0 °C. Thionyl chloride (303.77 mg, 0.19 mL, 2.0 mmol) was added dropwise, and the mixture was stirred at 0 °C for 1 hour. The reaction solution was concentrated, and potassium carbonate (422.28 mg, 3.06 mmol) and acetonitrile (10 mL) were added sequentially to the residue, and the mixture was refluxed and stirred overnight. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phase was concentrated. Thin-layer chromatography (dichloromethane / methanol = 25 / 1) was used to obtain the title compound (110 mg, 91%). LC-MS:m / z[M+H] + =238. 1H NMR (400MHz, CDCl3) δ5.54(s,1H),4.37(d,J=12.7Hz,1H),3.92(d,J=12.7Hz,1H),3.21(s,2H),2.77(br.s,1H),2.04-1.86(m,3H),1.69-1.54(m,3H). Intermediate 68 (2-Benzyl-4-fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol Methyl 2-benzoyl-4-fluoro-2-azabicyclo[2.1.1]hexane-1-carboxylate (880 mg, 3.35 mmol, Journal of Organic Chemistry, 2017, 8831-8841) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and lithium aluminum hydride (381 mg, 10.04 mmol) was added in portions. After the addition was complete, the mixture was stirred at 50 °C for 3 hours. The reaction solution was quenched with sodium sulfate decahydrate. The mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain the title compound (370 mg, 50%). LC-MS:m / z[M+H] + =222. (4-Fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol (2-Benzyl-4-fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol (370 mg, 1.67 mmol) was dissolved in methanol (100 mL), and Pd / C (10%, 74 mg) was added. The mixture was hydrogenated overnight at 50 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (220 mg, 100%). LC-MS:m / z[M+H] + =132. (2-(2,6-dichloropyrimidin-4-yl)-4-fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol (4-fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol (210 mg, 1.59 mmol), 4,6-dichloro-2-methoxypyrimidine (427 mg, 2.39 mmol), and sodium carbonate solid (674 mg, 6.36 mmol) were added to isopropanol (10 mL) and stirred at 85 °C for 3 days. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give the title compound (432 mg, 99%). LC-MS:m / z[M+H]+ =275. 3-Chloro-7-fluoro-7,8-dihydro-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(2,6-dichloropyrimidin-4-yl)-4-fluoro-2-azabicyclo[2.1.1]hex-1-yl)methanol (332 mg, 1.21 mmol) was added to dichloromethane (5 mL), and sulfoxide (288 mg, 2.42 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was added to water. The pH was adjusted to 14 with 15% sodium hydroxide aqueous solution with stirring. The mixture was stirred at room temperature for 10 minutes. The solution was extracted with dichloromethane, the organic phase was concentrated, and purified by silica gel column chromatography to give the title compound (213 mg, 73%). LC-MS:m / z[M+H] + =242. Intermediate 69 (5-Chloromethyl-2-oxo-3-oxabicyclo[3.1.1]hept-1-yl)tert-butyl carbamate 5-Chloromethyl-2-oxo-3-oxabicyclo[3.1.1]heptane-1-carboxylic acid (4.0 g, 19.5 mmol, Tetrahedron Letters, 2014, 466–468) was added to toluene (60 mL), followed by the addition of triethylamine (3.9 g, 39.0 mmol) and diphenyl azidophosphate (8.0 g, 29.2 mmol) with stirring. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow oil (3.8 g). The oil was added to tert-butanol (80 mL), followed by the addition of di-tert-butyl dicarbonate (21.9 g, 97.5 mmol) with stirring. The mixture was stirred overnight at 90 °C. The reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (2.8 g, 52%). LC-MS: m / z [M+H-Boc] + =176. 2-(tert-Butoxycarbonyl)-4-hydroxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (5-chloromethyl-2-oxo-3-oxabicyclo[3.1.1]hept-1-yl)tert-butyl carbamate (4.5 g, 16.3 mmol) was added to dichloromethane (20 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 40 mL) was added with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and an aqueous sodium hydroxide solution (0.6 M, 140 mL) was added to the residue. The mixture was stirred at 95 °C for 0.5 hours. The reaction solution was cooled to room temperature and the pH was adjusted to 7 with hydrochloric acid (6.0 M). The reaction solution was concentrated, and tetrahydrofuran (40 mL) and an aqueous sodium hydroxide solution (5%, 35 mL) were added to the residue. Di-tert-butyl dicarbonate (10.6 g, 48.9 mmol) was added with stirring. The mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was poured into water, the pH of the reaction solution was adjusted to 2 with concentrated hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give the title compound (1.6 g, 38%). LC-MS:m / z[M+H-Boc] + =158. 2-tert-Butoxycarbonyl-4-hydroxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester 2-(tert-Butoxycarbonyl)-4-hydroxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (1.6 g, 6.22 mmol) and potassium carbonate solid (2.57 g, 18.66 mmol) were added to N,N-dimethylformamide (30 mL) and stirred at room temperature for 15 minutes under argon protection. Iodomethane (2.65 g, 18.66 mmol) was added to the reaction solution and stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to give the title compound (1.1 g, 65%). LC-MS:m / z[M+H-Boc] + =172. 2-tert-Butoxycarbonyl-4-methoxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (400 mg, 1.47 mmol) was added to N,N-dimethylformamide (16 mL). Sodium hydride (60%, 177 mg, 4.43 mmol) was added with stirring at room temperature. After stirring for 15 minutes at room temperature, methyl iodoform (630 mg, 4.43 mmol) was added, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (290 mg, 69%). LC-MS:m / z[M+H-Boc] + =186. (4-(methoxymethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol Methyl 2-tert-butoxycarbonyl-4-methoxymethyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (290 mg, 1.02 mmol) was added to dichloromethane (2 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 6 mL) was added with stirring. The mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated, and tetrahydrofuran (6 mL) and lithium aluminum hydride (76 mg, 2.0 mmol) were added to the residue. The mixture was stirred at room temperature for 1 h. The reaction solution was quenched with sodium sulfate decahydrate, stirred at room temperature for 0.5 h, filtered, and the filtrate was concentrated to give the title compound (155 mg, 97%). LC-MS:m / z[M+H] + =158. (2-(6-chloro-2-methoxypyrimidin-4-yl)-4-(methoxymethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (4-(methoxymethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (155 mg, 1.0 mmol), 4,6-dichloro-2-methoxypyrimidine (267 mg, 1.5 mmol), and sodium carbonate solid (318 mg, 3.0 mmol) were added to isopropanol (10 mL) and stirred under reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. Preparative thin-layer chromatography (dichloromethane / methanol = 50 / 1) yielded the title compound (260 mg, 87%). LC-MS:m / z[M+H] + =300. 3-Chloro-7-(methoxymethyl)-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(6-chloro-2-methoxypyrimidin-4-yl)-4-(methoxymethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (260 mg, 0.87 mmol) was added to dichloromethane (4 mL), and thionyl chloride (154 mg, 1.3 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and water (4 mL) and sodium hydroxide aqueous solution (1.0 M, 4 mL) were added to the residue sequentially. The mixture was stirred at room temperature for 0.5 hours. The residue was extracted with dichloromethane, and the organic phases were combined and concentrated to give the title compound (180 mg, 78%). LC-MS:m / z[M+H] + =268. Intermediate 70 2-tert-Butoxycarbonyl-4-formyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-tert-butoxycarbonyl-4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylate (400 mg, 1.47 mmol) was added to dichloromethane (20 mL), and Dys-Martin reagent (1.23 g, 2.94 mmol) was added with stirring. The mixture was stirred overnight at room temperature. The solution was filtered, and the filtrate was poured into a saturated sodium bicarbonate solution. Extraction was performed with dichloromethane, and the organic phase was concentrated. Purification was achieved by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give the title compound (250 mg, 63%). LC-MS: m / z [M+H-Boc] + =170. 2-tert-Butoxycarbonyl-4-(difluoromethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-(tert-butoxycarbonyl)-4-formyl-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (250 mg, 0.86 mmol) was added to dichloromethane (12 mL), cooled to 0 °C, and diethylaminosulfur trifluoride (741 mg, 4.6 mmol) was added. The mixture was stirred at 0 °C for 2 hours and then stirred overnight at room temperature. The reaction mixture was poured into a saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (150 mg, 56%). LC-MS:m / z[M+H-Boc] + =192. (4-(difluoromethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol Methyl 2-(tert-butoxycarbonyl)-4-(difluoromethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (150 mg, 0.51 mmol) was added to dichloromethane (4 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 6 mL) was added with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and tetrahydrofuran (6 mL) and lithium aluminum hydride (286 mg, 0.75 mmol) were added to the residue sequentially. The mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with sodium sulfate decahydrate, and stirred at room temperature for 0.5 hours. The mixture was filtered, and the filtrate was concentrated to give the crude title compound (100 mg). LC-MS:m / z[M+H] + =164. 2-(6-chloro-2-methoxypyrimidin-4-yl)-1-(difluoromethyl)-4-(methoxymethyl)-2-azabicyclo[2.1.1]hexane (4-(difluoromethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (100 mg, 0.61 mmol), 4,6-dichloro-2-methoxypyrimidine (163 mg, 0.92 mmol), and sodium carbonate solid (190 mg, 1.83 mmol) were added to isopropanol (10 mL) and stirred under reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. Thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) was performed to obtain the title compound (60 mg, two-step yield: 38%). LC-MS:m / z[M+H] + =306. 3-Chloro-7-(difluoromethyl)-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 2-(6-chloro-2-methoxypyrimidin-4-yl)-1-(difluoromethyl)-4-(methoxymethyl)-2-azabicyclo[2.1.1]hexane (60 mg, 0.20 mmol) was added to dichloromethane (4 mL), and thionyl chloride (47 mg, 0.40 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and water (2 mL) and sodium hydroxide aqueous solution (1.0 M, 0.5 mL) were added sequentially to the residue. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (45 mg, 82%). LC-MS:m / z[M+H] + =274. Intermediate 71 2-(tert-Butoxycarbonyl)-4-(((methanesulfonyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-(tert-butoxycarbonyl)-4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (270 mg, 1.0 mmol) and triethylamine (300 mg, 3.0 mmol) were added to dichloromethane (10 mL), cooled to 0 °C, and methanesulfonyl chloride (3434 mg, 3.0 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The reaction solution was poured into a saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated. Thin-layer chromatography (dichloromethane / methanol = 20 / 1) was used to purify the compound to the title compound (180 mg, 52%). LC-MS:m / z[M+H-Boc] + =250 2-(tert-Butoxycarbonyl)-4-(morpholinomethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-(tert-butoxycarbonyl)-4-((((methanesulfonyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxylate (180 mg, 0.52 mmol), morpholine (226 mg, 2.6 mmol), potassium carbonate solid (215 mg, 1.56 mmol), and potassium iodide (17 mg, 0.1 mmol) were added to acetonitrile (12 mL) and stirred overnight at 85 °C. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (140 mg, 80%). LC-MS:m / z[M+H] + =341 (4-(morpholinomethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol Methyl 2-(tert-butoxycarbonyl)-4-(morpholinomethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (140 mg, 0.41 mmol) was added to dichloromethane (3 mL), and ethyl acetate (4.0 M, 3 mL) of hydrogen chloride was added with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and tetrahydrofuran (6 mL) and lithium aluminum hydride (31 mg, 0.82 mmol) were added to the residue sequentially. The mixture was stirred at room temperature for 0.5 hours. Sodium sulfate decahydrate was added to quench the reaction solution, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, and the filtrate was concentrated to give the crude title compound (80 mg). LC-MS:m / z[M+H]+ =213. (2-(6-chloro-2-methoxypyrimidin-4-yl)-4-(morpholinomethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (4-(morpholinomethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (80 mg, 0.38 mmol), 4,6-dichloro-2-methoxypyrimidine (135 mg, 0.76 mmol), and sodium carbonate solid (120 mg, 1.14 mmol) were added to isopropanol (12 mL) and stirred under reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. Thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) was performed to obtain the title compound (80 mg, two-step yield: 55%). LC-MS:m / z[M+H] + =355. 3-Chloro-7-(morpholinomethyl)-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (2-(6-chloro-2-methoxypyrimidin-4-yl)-4-(morpholinomethyl)-2-azabicyclo[2.1.1]hex-1-yl)methanol (80 mg, 0.23 mmol) was added to dichloromethane (3 mL), and thionyl chloride (81 mg, 0.69 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and water (3 mL) and sodium hydroxide aqueous solution (1.0 M, 3 mL) were added to the residue sequentially. The mixture was stirred at room temperature for 0.5 hours. The residue was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (45 mg, 61%). LC-MS:m / z[M+H] + =323. Intermediate 72 2-(tert-Butoxycarbonyl)-4-((((tert-Butyldimethylsilyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid methyl ester Methyl 2-(tert-Butoxycarbonyl)-4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid (1.0 g, 3.69 mmol) was added to dichloromethane (10 mL), and imidazole (0.5 g, 7.35 mmol) and tert-butyldimethylchlorosilane (0.66 g, 4.37 mmol) were added sequentially with stirring at room temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1.2 g, 84%). LC-MS:m / z[M+H-Boc] + =286. 4-((((tert-butyldimethylsilyl)oxy)methyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1.2 g (3.11 mmol) of methyl 2-(tert-butoxycarbonyl)-4-((((tert-butyldimethylsilyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-1-carboxylic acid was added to methanol (15 mL). The reaction mixture was heated to 65 °C, and sodium borohydride (1.18 g, 31.16 mmol) was added in portions. The mixture was stirred at 65 °C for 0.5 h. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1 g, 90%). LC-MS:m / z[M+H-Boc] + =258. 1-((benzyloxy)methyl)-4-((((tert-butyldimethylsilyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1.0 g (2.80 mmol) of 4-((((tert-butyldimethylsilyl)oxy)methyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester was added to N,N-dimethylformamide (16 mL). The mixture was cooled to 0 °C under argon protection, and sodium hydride (60%, 224 mg, 5.60 mmol) was added with stirring. After stirring at room temperature for 10 minutes, benzyl bromide (718 mg, 4.20 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (1.2 g, 96%). LC-MS:m / z[M+H-Boc] + =348. 1-((benzyloxy)methyl)-4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1-((benzyloxy)methyl)-4-((((tert-butyldimethylsilyl)oxy)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1.2 g, 2.68 mmol) was added to tetrahydrofuran (10 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0 M, 4 mL) was added with stirring. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (600 mg, 67%). LC-MS:m / z[M+H-Boc] + =234. 1-((benzyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 1-((benzyloxy)methyl)-4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (600 mg, 1.80 mmol) was dissolved in acetone (6 mL) at room temperature, and slowly added dropwise to Jones' reagent (2.0 M, 2 mL). The mixture was stirred at room temperature for 0.5 hours. Isopropanol (6 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in water, and the pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution. The pH was then adjusted to 2 with hydrochloric acid (6.0 M). The mixture was extracted with ethyl acetate, and the organic phase was concentrated. Thin-layer chromatography was used to purify the crude title compound (400 mg, 64%). LC-MS:m / z[M+H-Boc] + =248. 2-(tert-Butoxycarbonyl)-1-((benzyloxy)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid methyl ester 1-((benzyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (400 mg, 1.15 mmol) and potassium carbonate solid (476 mg, 3.45 mmol) were added to N,N-dimethylformamide (5 mL). After stirring at room temperature for 10 minutes, iodomethane (326 mg, 2.30 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated. Thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) was used to purify the compound to the title compound (230 mg, 56%). LC-MS:m / z[M+H-Boc] + =262. 2-(tert-Butoxycarbonyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid methyl ester Methyl 2-(tert-butoxycarbonyl)-1-((benzyloxy)methyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (230 mg, 0.64 mmol) and Pd / C (10%, 25 mg) were added to methanol (10 mL) and hydrogenated overnight at room temperature and atmospheric pressure. The mixture was filtered, and the filtrate was concentrated to give the title compound (150 mg, 96%). LC-MS:m / z[M+H-Boc] + =172. 2-(2,6-Dichloropyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid methyl ester Methyl 2-(tert-butoxycarbonyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (80 mg, 0.29 mmol) was added to a solution of dioxane in hydrogen chloride (4.0 M, 6 mL) and stirred at 50 °C for 30 min. The reaction solution was concentrated, and 4,6-dichloro-2-methoxypyrimidine (103 mg, 0.58 mmol), sodium carbonate solid (92 mg, 0.87 mmol), and acetonitrile (6 mL) were added sequentially to the residue, and the mixture was stirred at 85 °C overnight. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and purified by thin-layer chromatography (dichloromethane / methanol = 30 / 1) to give the title compound (60 mg, 66%). LC-MS:m / z[M+H] + =314. 3-Chloro-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid methyl ester Methyl 2-(2,6-dichloropyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (60 mg, 0.87 mmol) was added to dichloromethane (3 mL), followed by dropwise addition of thionyl chloride (154 mg, 1.3 mmol), and the mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated. Water (4 mL) and sodium hydroxide aqueous solution (1.0 M, 2 mL) were added sequentially to the residue, and the mixture was stirred at room temperature for 0.5 h. The mixture was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (30 mg, 56%). LC-MS:m / z[M+H] + =282. 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid methyl ester Methyl 3-chloro-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-7(8H)-carboxylic acid (30 mg, 0.106 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (45 mg, 0.156 mmol), and cesium carbonate (103 mg, 0.318 mmol) were added to toluene (6 mL) and stirred at 130 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. Preparative thin-layer chromatography purification (dichloromethane / methanol = 20 / 1) yielded the title compound (20 mg, 35%). LC-MS:m / z[M+H] + =533. 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid Methyl 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid (1.1 g, 2.07 mmol) was added to acetonitrile (10 mL) and sodium hydroxide aqueous solution (1.0 M, 20 mL), and stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 3-4 with hydrochloric acid aqueous solution (1.0 M). The mixture was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (1.07 g, 100%). LC-MS:m / z[M+H] + =519. (3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-7(8H)-yl)tert-butyl carbamate 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid (1.07 g, 2.07 mmol) and triethylamine (418 mg, 4.14 mmol) were added to dichloromethane (20 mL), cooled to 0 °C, and diphenyl azidophosphate (628 mg, 2.28 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and di-tert-butyl dicarbonate (1.35 g, 6.21 mmol) and tert-butanol (20 mL) were added sequentially to the residue. The mixture was stirred overnight at 90 °C. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 200 / 1 to 50 / 1) to give the title compound (350 mg, 29%). LC-MS:m / z[M+H] + =590. Intermediate 73 4-Carbamoyl-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 200 mg (0.74 mmol) of 4-methoxycarbonyl-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester was added to methanol (3 mL) and ammonia (6 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated to give the title compound (120 mg, 63%). LC-MS:m / z[M+H-Boc] + =157. 4-Cyano-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 4-Carbamoyl-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (220 mg, 0.86 mmol) was added to dichloromethane (16 mL), and triethylamine (434 mg, 4.30 mmol) and trifluoroacetic anhydride (722 mg, 3.44 mmol) were added sequentially with stirring at room temperature for 1 hour. The reaction solution was poured into ethyl acetate, and the organic phase was washed sequentially with saturated ammonium chloride solution and saturated sodium carbonate solution. The organic phase was concentrated and purified by thin-layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (100 mg, 49%). LC-MS:m / z[M+H-Boc] + =139. 2-(6-chloro-2-methoxypyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-nitrile 100 mg (0.42 mmol) of 4-cyano-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester was added to dichloromethane (4 mL), and hydrochloric acid / dioxane (4.0 M, 3 mL) was added with stirring. The mixture was stirred at 50 °C for 30 minutes. The reaction solution was concentrated, and 4,6-dichloro-2-methoxypyrimidine (146 mg, 0.82 mmol), sodium carbonate solid (133 mg, 1.26 mmol), and acetonitrile (8 mL) were added to the residue sequentially. The mixture was stirred at 90 °C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. Thin-layer chromatography (petroleum ether / ethyl acetate = 4 / 1) was used to purify the title compound (20 mg, 17%). LC-MS:m / z[M+H] + =281. 3-Chloro-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-7(8H)-nitriles 2-(6-chloro-2-methoxypyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-onitrile (20 mg, 0.07 mmol) was added to dichloromethane (2 mL), and thionyl chloride (42 mg, 0.35 mmol) was added with stirring. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated, and the residue was added to water. The pH was adjusted to 10 with potassium carbonate solid, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (12 mg, 69%). LC-MS:m / z[M+H] + =249. Intermediate 74 4-(benzylcarbamoyl)-1-((benzyloxy)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 1-((benzyloxy)methyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (750 mg, 2.16 mol), benzylamine (347.4 mg, 3.24 mmol), HATU (1.64 g, 4.32 mmol), and triethylamine (873 mg, 8.64 mmol) were added to dichloromethane (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (800 mg, 85%). LC-MS:m / z[M+H] + =437. 4-(benzylcarbamoyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 4-(benzylcarbamoyl)-1-((benzyloxy)methyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (800 mg, 1.83 mmol) and Pd / C (10%, 80 mg) were added to methanol (10 mL), and the reaction solution was hydrogenated overnight at 60 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude title compound (480 mg). LC-MS:m / z[M+H-tBu] + =291. N-Benzyl-2-(2,6-dichloropyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide 4-(benzylcarbamoyl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (480 mg, 1.39 mmol) was added to hydrochloric acid / dioxane (4.0 M, 5 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and 2,4,6-trichloropyrimidine (254.5 mg, 1.39 mmol), sodium carbonate solid (294.7 mg, 2.78 mmol), and acetonitrile (10 mL) were added to the residue sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (150 mg, two-step yield: 27%). LC-MS:m / z[M+H] + =393. N-Benzyl-3-chloro-1-oxo-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxamide N-Benzyl-2-(2,6-dichloropyrimidin-4-yl)-1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-4-carboxamide (150 mg, 0.38 mmol) was added to dichloromethane (6 mL), and sulfoxide (2 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and potassium carbonate (263.4 mg, 1.91 mmol) and acetonitrile (15 mL) were added to the residue sequentially. The mixture was refluxed and stirred overnight. The reaction solution was poured into water, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (25 mg, 18%). LC-MS:m / z[M+H] + =357. Intermediate 75 1-(tert-Butoxycarbonyl)-(4R)-4-((trimethylsilyl)oxy)pyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-Butoxycarbonyl)-(4R)-4-hydroxypyrrolidine-2-dicarboxylic acid (5 g, 20.39 mmol) and triethylamine (2.88 g, 28.55 mmol) were added to dichloromethane (50 mL). The mixture was cooled to 0 °C under argon protection, and trimethylchlorosilane (2.88 g, 26.51 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The reaction solution was poured into dichloromethane, and the organic phase was washed successively with water and saturated sodium bicarbonate solution. The organic phase was concentrated to give the title compound (6.34 g, 98%). LC-MS:m / z[M+H-tBu] + =262. 1-(tert-Butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-((trimethylsilyl)oxy)pyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-Butoxycarbonyl)-(4R)-4-((trimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (6.5 g, 20.5 mmol) and benzylchloromethyl ether (6.4 g, 41 mmol) were dissolved in tetrahydrofuran (100 mL). Under argon protection, the mixture was cooled to 0 °C and a tetrahydrofuran solution of lithium diisopropylamino in 20 mL (40 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with methanol and then poured into water, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography to give the title compound (3.6 g, 40%). LC-MS:m / z[M+H] + =438. 1-(tert-Butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-((trimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (3 g, 6.86 mmol) was added to a 10% citric acid-methanol solution (10 mL) and stirred at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (2.3 g, 89%). LC-MS:m / z[M+H] + =366. 1-(tert-Butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-((methylsulfonyl)oxy)pyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-Butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.3 g, 6.3 mmol) and triethylamine (1.28 g, 12.6 mmol) were added sequentially to dichloromethane (15 mL). The reaction mixture was cooled to 0 °C, and methanesulfonic anhydride (2.2 g, 10.1 mmol) dissolved in dichloromethane (15 mL) was added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction mixture was then poured into a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was concentrated to give the title compound (2.6 g, 100%). LC-MS:m / z[M+H] + =444. 1-(tert-Butoxycarbonyl)-(4S)-4-(benzylamino)-2-((benzyloxy)methyl)pyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-((methanesulfonyl)oxy)pyrrolidine-2-carboxylic acid (2.6 g, 5.87 mmol) was dissolved in benzylamine (5 mL) and stirred overnight at 85 °C. The title compound (2.32 g, 87%) was purified by silica gel column chromatography. LC-MS:m / z[M+H-Boc] + =355. (1R,4S)-5-benzyl-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester Methyl 1-(tert-butoxycarbonyl)-(4S)-4-(benzylamino)-2-((benzyloxy)methyl)pyrrolidine-2-carboxylic acid (519 mg, 114 mmol) and lithium hydroxide (54.8 mg, 2.28 mmol) were added to water (2 mL) and methanol (10 mL), and stirred at 30 °C for 2 days. The reaction solution was concentrated, and HATU (865 mg, 2.28 mmol), triethylamine (460 mg, 4.56 mmol), and N,N-dimethylformamide (35 mL) were added to the residue sequentially, and the mixture was stirred overnight at room temperature. The reaction solution was poured into ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated. Purification was performed by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the title compound (150 mg, 31%). LC-MS:m / z[M+H-Boc] + =323. (1S,4R)-2-benzyl-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptatri-3-one (1R,4S)-5-benzyl-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.36 mmol) and Pd / C (10%, 20 mg) were added to methanol (10 mL) and hydrogenated overnight at 40 °C under normal pressure. The reaction solution was filtered and concentrated. A solution of dioxane chloride (4.0 M, 5 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude title compound, which was used directly in the next step. LC-MS:m / z[M+H] + =233. (1S,4R)-2-benzyl-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]hepta-3-one (1S,4R)-2-benzyl-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptatri-3-one (crude) was dissolved in acetonitrile (10 mL) and cooled to 0 °C. Triethylamine (71 mg, 0.71 mmol) and 2,4,6-trichloropyrimidine (98 mg, 0.53 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, and thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) was performed to give the title compound (40 mg, 30% yield in two steps). LC-MS:m / z[M+H] + =379. (3S,11aR)-2-benzyl-7-chloro-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-1,9(2H)-dione (1S,4R)-2-benzyl-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]hepta-3-one (40 mg, 0.11 mmol) was added to dichloromethane (5 mL). After cooling to 0 °C, sulfoxide (0.5 mL) was added dropwise, and the mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was concentrated and potassium carbonate (45.54 mg, 0.33 mmol) and acetonitrile (5 mL) were added. The mixture was refluxed and stirred overnight. The reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was concentrated. Thin-layer chromatography (dichloromethane / methanol = 25 / 1) was used to separate the compound into the title compound (15 mg, 40%). LC-MS:m / z[M+H] + =343. Intermediate 76 1-(tert-Butoxycarbonyl)-(4S)-2-((benzyloxy)methyl)-4-((3,5-dimethoxybenzyl)amino)pyrrolidine-2-carboxylic acid methyl ester Methyl 1-(tert-butoxycarbonyl)-(4R)-2-((benzyloxy)methyl)-4-((methanesulfonyl)oxy)pyrrolidine-2-carboxylic acid (100 g, 0.23 mol) was added to 2,4-dimethoxybenzylamine (200 mL) and stirred overnight at 90 °C. The reaction solution was directly purified by column chromatography to give the title compound (75.8 g, 64%). LC-MS:m / z[M+H] + =515. (1R,4S)-1-((benzyloxy)methyl)-5-(3,5-dimethoxybenzyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester Methyl 1-(tert-Butoxycarbonyl)-(4S)-2-((benzyloxy)methyl)-4-((3,5-dimethoxybenzyl)amino)pyrrolidine-2-carboxylic acid (75.8 g, 0.148 mol) and sodium hydroxide (17.76 g, 0.444 mol) were added to a mixed solvent of water (28 mL) and methanol (280 mL), and stirred overnight at 40 °C. The reaction solution was concentrated to dryness, and HATU (112.26 g, 0.296 mol), triethylamine (59.8 g, 0.592 mol), and N,N-dimethylformamide (90 mL) were added sequentially to the residue, and stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (23 g, 32%). LC-MS:m / z[M+H-Boc] + =383. (1R,4S)-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-5-(3,5-dimethoxybenzyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (21 g, 0.044 mol) and DDQ (29.63 g, 0.13 mol) were added to dichloromethane (100 mL) and water (5 mL) and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (5.6 g, 38%). LC-MS:m / z[M+H-Boc] + =233. (1R,4S)-1-((benzyloxy)methyl)-5-methyl-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.8 g, 5.42 mmol) was added to tetrahydrofuran (20 mL) and cooled to 0 °C under argon protection. Sodium hydrogen (325 mg, 8.12 mmol) was added to the reaction solution with stirring, and the mixture was stirred at 0 °C for 30 minutes. Iodomethane (1.15 g, 8.12 mmol) was added dropwise to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give the title compound (800 mg, 43%). LC-MS:m / z[M+H] + =247. (1R,4S)-1-(hydroxymethyl)-5-methyl-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-5-methyl-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (800 mg, 2.3 mmol) and Pd / C (10%, 80 mg) were added to methanol (8 mL), and the reaction solution was hydrogenated overnight at 60 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude title compound (700 mg). LC-MS:m / z[M+H] + =257. (1S,4R)-5-(6-chloro-2-methoxypyrimidin-4-yl)-4-(hydroxymethyl)-2-methyl-2,5-diazabicyclo[2.2.1]hepta-3-one (1R,4S)-1-(hydroxymethyl)-5-methyl-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (700 mg, 2.7 mmol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 2 hours. The reaction solution was concentrated, and 4,6-dichloro-2-methoxypyrimidine (489.4 mg, 2.7 mmol), sodium carbonate solid (1.43 g, 13.5 mmol), and acetonitrile (15 mL) were added sequentially to the residue, and the mixture was refluxed and stirred for 3 days. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave the title compound (520 mg, 75% yield in two steps). LC-MS:m / z[M+H] + =299. (3R,10aR)-6-chloro-2-methyl-2,3,4,4a-tetrahydro-10H-3,10a-methoxypyrido[4',3':3,4]pyrrolo[1,2-c]pyrimidin-1,8-dione (1S,4R)-5-(6-chloro-2-methoxypyrimidin-4-yl)-4-(hydroxymethyl)-2-methyl-2,5-diazabicyclo[2.2.1]hepta-3-one (420 mg, 1.4 mmol) was added to dichloromethane (7 mL), and sulfoxide (836 mg, 7.0 mmol) was slowly added dropwise to the system. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was added to a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (220 mg, 59%). LC-MS:m / z[M+H] + =267. Intermediate 77 (1R,4S)-1-((benzyloxy)methyl)-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 g, 3 mmol) and 3-(chloromethyl)-1-methyl-1H-pyrazole (600 mg, 4.5 mmol) were added to tetrahydrofuran (20 mL). Sodium hydrogen (200 mg, 4.5 mmol) was added to the reaction mixture with stirring, and the mixture was stirred at 50 °C for 3 days. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (800 mg, 62%). LC-MS:m / z[M+H-Boc] + =327. (1R,4S)-1-(hydroxymethyl)-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (800 mg, 1.88 mmol) and Pd / C (10%, 180 mg) were added to methanol (15 mL), and the reaction solution was hydrogenated overnight at 60 °C under normal pressure. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (600 mg). LC-MS:m / z[M+H-Boc] + =237. (1S,4R)-5-(6-chloro-2-methoxypyrimidin-4-yl)-4-(hydroxymethyl)-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2,5-diazabicyclo[2.2.1]hepta-3-one (1R,4S)-1-(hydroxymethyl)-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.88 mmol) was added to hydrochloric acid / ethyl acetate (4.0 M, 6 mL) and ethyl acetate (5 mL), and stirred at room temperature for 3 hours. The reaction solution was concentrated, and 4,6-dichloro-2-methoxypyrimidine (159.3 mg, 0.89 mmol), sodium carbonate solid (471.7 mg, 4.45 mmol), and acetonitrile (15 mL) were added sequentially to the residue, and the mixture was refluxed and stirred for 3 days. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was concentrated. The solution was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (220 mg, two-step yield: 65%). LC-MS:m / z[M+H] + =379. (3R,10aR)-6-chloro-2-((1-methyl-1H-pyrazol-4-yl)methyl)-2,3,4,4a-tetrahydro-10H-3,10a-methylaminopyridine[4',3':3,4]pyrrolo[1,2-c]pyrimidine-1,8-dione (1S,4R)-5-(6-chloro-2-methoxypyrimidin-4-yl)-4-(hydroxymethyl)-2-((1-methyl-1H-pyrazol-3-yl)methyl)-2,5-diazabicyclo[2.2.1]hepta-3-one (220 mg, 1.4 mmol) was added to dichloromethane (10 mL), and methanesulfonyl chloride (99.65 mg, 0.87 mmol) was slowly added dropwise to the system. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was added to a saturated aqueous solution of sodium bicarbonate, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (120 mg, 60%). LC-MS:m / z[M+H] + =347. Intermediate 78 (1R,4S)-1-((benzyloxy)methyl)-5-(bicyclo[1.1.1]pent-1-ylmethyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 g, 3 mmol) and 1-(chloromethyl)bicyclo[1.1.1]pentane (1.05 g, 9.0 mmol) were added to tetrahydrofuran (20 mL). Sodium hydrogen (600 mg, 15 mmol) was added to the reaction mixture with stirring, and the mixture was stirred at 50 °C for 3 days in a sealed container. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (780 mg, 63%). LC-MS:m / z[M+H-Boc] + =313. (1R,4S)-5-(bicyclo[1.1.1]pent-1-ylmethyl)-1-(hydroxymethyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1R,4S)-1-((benzyloxy)methyl)-5-(bicyclo[1.1.1]pent-1-ylmethyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (780 mg, 1.9 mmol) and Pd / C (10%, 200 mg) were added to methanol (20 mL), and the reaction solution was hydrogenated (70 °C, 0.5 MPa) overnight. The reaction solution was filtered, and the filtrate was concentrated to give the crude title compound (430 mg). LC-MS:m / z[M+H-tBu] + =267. (1S,4R)-2-(bicyclo[1.1.1]pentyl-1-ylmethyl)-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-3-one (1R,4S)-5-(bicyclo[1.1.1]pent-1-ylmethyl)-1-(hydroxymethyl)-6-oxo-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (480 mg, 1.88 mmol) was added to hydrochloric acid / dioxane (4.0 M, 5 mL) and dichloromethane (5 mL), and stirred at room temperature for 30 minutes. The reaction solution was concentrated, and 2,4,6-trichloropyrimidine (372.2 mg, 1.44 mmol), sodium carbonate solid (458 mg, 4.32 mmol), and acetonitrile (15 mL) were added to the residue sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (175 mg, two-step yield: 33%). LC-MS:m / z[M+H] + =369. (3S,11aR)-2-(bicyclo[1.1.1]pentyl-1-ylmethyl)-7-chloro-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-1,9(2H)-dione (1S,4R)-2-(bicyclo[1.1.1]pentyl-1-ylmethyl)-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-3-one (50 mg, 1.4 mmol) was added to dichloromethane (6 mL), and sulfoxide (2 mL) was added dropwise with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and sodium carbonate (43.2 mg, 0.41 mmol) and acetonitrile (10 mL) were added to the residue sequentially. The mixture was refluxed and stirred overnight. The reaction solution was poured into water, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give the title compound (42 mg, 93%). LC-MS:m / z[M+H] + =333. Intermediate 79 (1S,4S)-2-benzyl-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-1-carboxylic acid (1S,4S)-5-benzyl-4-cyano-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (6.3 g, 20 mmol, Synthesis, 2015, 1123-1130), sodium hydroxide aqueous solution (1.0 M, 50 mL), and solid sodium hydroxide (8.3 g, 207 mmol) were added to methanol (150 mL) and stirred overnight at 100 °C. The reaction solution was concentrated to remove methanol, and the pH of the residue was adjusted to 3.8–4.4 with hydrochloric acid aqueous solution (1.0 M). The residue was extracted with dichloromethane, and the organic phase was concentrated to give the title compound (5.4 g, 81%). LC-MS:m / z[M+H] + =333. (1S,4S)-5-benzyl-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester A solution of (1S,4S)-2-benzyl-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane-1-carboxylic acid (3.0 g, 9 mmol) and borane dimethyl sulfide in tetrahydrofuran (2.0 M, 9 mL, 18 mmol) was added to tetrahydrofuran (30 mL), and the mixture was stirred overnight at 80 °C. The reaction solution was quenched with methanol and concentrated, and purified by silica gel column chromatography to give the title compound (2.0 g, 70%). LC-MS:m / z[M+H] + =319. (1S,4S)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1S,4S)-5-benzyl-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.7 g 5.3 mmol) and Pd / C (10% 100 mg) were added to methanol (17 mL) and hydrogenated overnight at room temperature and atmospheric pressure. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude title compound (1.4 g 115%), which was used directly in the next step without further purification. (1S,4S)-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1S,4S)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.4 g, 6.1 mmol), sodium carbonate solid (1.3 g, 12 mmol), and 2,4,6-trichloropyrimidine (1.5 g, 8.0 mmol) were added to acetonitrile (14 mL) and stirred overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give the title compound (1.3 g, 56%). LC-MS:m / z[M+H] + =374. (3S,11aR)-7-chloro-9-oxo-3,4-dihydro-9H,11H-3,11-aminopyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-2(1H)-carboxylic acid tert-butyl ester (1S,4S)-5-(2,6-dichloropyrimidin-4-yl)-4-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.3 g, 3.5 mmol) and triethylamine (700 mg, 7.0 mmol) were added to dichloromethane (13 mL), cooled to 0 °C, and then methanesulfonic anhydride (900 mg, 5.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue and potassium carbonate solid (970 mg, 7.0 mmol) were added to acetonitrile (13 mL). The mixture was stirred overnight at 80 °C. The reaction solution was poured into water, extracted with dichloromethane, and concentrated to give the title compound (1.1 g, 97%). LC-MS:m / z[M+H] + =339. 1 H NMR(400MHz, CDCl3)δ5.59(br.s,1H),4.45(d,J=12.7Hz,1H),3.99(br.s,1H),3.65-3.54(m,3H),3 .32(d,J=8.8Hz,1H),3.17-3.06(m,1H),2.09-1.98(m,1H),1.86(d,J=9.3Hz,1H),1.49(br.s,9H). (3S,11aR)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-9-oxo-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidin-2(1H)-tert-butyl carboxylate (3S,11aR)-7-chloro-9-oxo-3,4-dihydro-9H,11H-3,11aminopyrazino[1',2':3,4]imidazo[1,2-c]pyrimidin-2(1H)-carboxylic acid tert-butyl ester (1.1 g, 3.4 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (1.2 g, 4.4 mmol), and cesium carbonate solid (3.3 g, 10 mmol) were added to toluene (11 mL), and the mixture was stirred overnight at 120 °C. The reaction mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give the title compound (1.3 g, 65%). LC-MS:m / z[M+H] + =590. 1H NMR (400MHz, CDCl3) δ8.58(d,J=5.4Hz,1H),7.33(d,J=11.2Hz,1H),7.27-7.16(m,3H),6.96(d,J=4.9Hz,1H),5.44(d,J=4.9Hz,2H),5.15-5.06(m,1H ),4.43(d,J=12.7Hz,1H),4.02-3.90(m,1H),3.66-3.47(m,4H),3.23(d,J= 9.8Hz,1H),1.96(d,J=10.3Hz,1H),1.71(d,J=9.8Hz,1H),1.49(br.s,9H). Intermediate 80 2-Fluoro-4-(2-hydroxyethyl)phenol 2-(3-fluoro-4-hydroxyphenyl)acetic acid (2 g, 11.6 mmol) was added to tetrahydrofuran (10 mL), and borane dimethyl sulfide (3.5 mL, 34.8 mmol) was added with stirring. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated and diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to give the crude product of the title compound (2.2 g, 120%). LCMS:m / z[M+H] + =157. 2-(3-fluoro-4-(((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)ethanol-1-ol 2-Fluoro-4-(2-hydroxyethyl)phenol (2.1 g, 13.29 mmol), 4-chloro-2-(trifluoromethyl)pyridine (2.35 g, 13.29 mmol), and potassium carbonate (3.67 g, 26.58 mmol) were added to N,N-dimethylformamide (20 mL), and the mixture was stirred at 120 °C for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and the solution was separated by silica gel column chromatography to obtain the title compound (1.63 g, 40.6%). LCMS:m / z[M+H] + =302. Intermediate 81 4-Bromo-2-(difluoromethyl)pyridine 10 g (53.76 mmol) of 4-bromopyridinecarboxaldehyde was added to 100 mL of dichloromethane and cooled to 0 °C. Diethylaminosulfur trifluoride (17.3 g, 107.52 mmol) was added dropwise to the reaction mixture with stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was then slowly added dropwise to water, extracted with dichloromethane, and the organic phase was concentrated to obtain the crude title compound, which was used directly in the next reaction step. LC-MS:m / z[M+H] + =208. 2-(difluoromethyl)-4-methoxypyridine 4-Bromo-2-(difluoromethyl)pyridine (11.18 g, 53.76 mmol) and sodium methoxide (5.81 g, 107.52 mmol) were added to methanol (100 mL). The mixture was stirred overnight at 90 °C. The reaction solution was cooled to room temperature and poured into water (300 mL), then extracted with ethyl acetate. The organic phase was concentrated to obtain the crude title compound, which was used directly in the next reaction. LC-MS:m / z[M+H] + =160. 2-(difluoromethyl)pyridine-4-ol 2-(difluoromethyl)-4-methoxypyridine (9.54 g, 59.95 mmol) was added to hydrobromic acid (40% aqueous solution, 58 mL). The mixture was stirred at 90 °C for 2 days. The reaction solution was concentrated, and the residue was diluted with water. Sodium bicarbonate solid was added with stirring until no more bubbles were generated. The mixture was extracted with ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound (2.5 g, overall yield of 26%). LC-MS:m / z[M+H] + =146. 4-((2-(difluoromethyl)pyridin-4-yl)oxy)benzaldehyde 4-Fluorobenzaldehyde (200 mg, 1.6 mmol), 2-(difluoromethyl)carbon-4-ol (289 mg, 1.8 mmol), and potassium carbonate solid (441 mg, 3.2 mmol) were added to N,N-dimethylformamide (5 mL) and stirred overnight at 100 °C. The title compound (180 mg, 45%) was obtained by preparative thin-layer chromatography. LC-MS:m / z[M+H] + =250. (4-((2-(difluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 4-((2-(difluoromethyl)pyridin-4-yl)oxy)benzaldehyde (180 mg, 0.7 mmol) was added to anhydrous ethanol (5 mL), and sodium borohydride (41 mg, 1 mmol) was added with stirring. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, and the organic phase was concentrated to give the title compound (100 mg, 62%). LC-MS:m / z[M+H] + =252. Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, the following intermediates are prepared according to the preparation method of intermediate 81. Intermediate 84: 4-(4-bromophenoxy)-2-(trifluoromethyl)pyridine 4-Bromophenol (9.4 g, 54.53 mmol), 4-chloro-2-(trifluoromethyl)pyridine (9 g, 49.58 mmol), and potassium carbonate (13.7 g, 99.16 mmol) were added to N,N-dimethylformamide (100 mL), and stirred at 120 °C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, concentrated the organic phase, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (4.3 g, 25%). LCMS:m / z[M+H] + =318. 2-(trifluoromethyl)-4-(4-((trimethylsilyl)ethynyl)phenoxy)pyridine 4-(4-bromophenoxy)-2-(trifluoromethyl)pyridine (4.3 g, 13.52 mmol), ethynyltrimethylsilane (3.32 g, 33.8 mmol), tetrakis(triphenylphosphine)palladium (1.56 g, 1.352 mmol), and cuprous iodide (275 mg, 1.352 mmol) were added to a mixed solvent of diisopropylethylamine (15 mL) and toluene (30 mL), and the reaction was carried out overnight at 80 °C in a sealed container. The reaction solution was filtered, the filtrate was poured into water, extracted with ethyl acetate, the organic phase was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give the title compound (1.5 g, 33%). LCMS:m / z[M+H] + =336. 4-(4-ethynylphenoxy)-2-(trifluoromethyl)pyridine 2-(trifluoromethyl)-4-(4-((trimethylsilyl)ethynyl)phenoxy)pyridine (1 g, 2.98 mmol) and potassium carbonate (822.9 mg, 5.96 mmol) were added to methanol (10 mL) and stirred overnight at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated to give the title compound (750 mg, 96%). LCMS:m / z[M+H] + =264. Intermediate 85: (3,4-Difluorobenzyl) tert-butyl carbamate (3,4-Difluorophenyl)methylamine (1.0 g, 6.99 mmol), di-tert-butyl dicarbonate (2.3 g, 10.5 mmol), and triethylamine (1.4 g, 14.0 mmol) were added to dichloromethane (10 mL) and stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel column chromatography to give the title compound (1.6 g, 94%). LCMS:m / z[M+H-Boc] + =144. 1-(3,4-Difluorophenyl)-N-methylmethylamine (3,4-Difluorobenzyl)carbamate tert-butyl ester (300 mg, 1.2 mmol) and lithium aluminum hydride (47 mg, 1.2 mmol) were added to tetrahydrofuran (3 mL), and the mixture was heated to reflux and stirred for 1 hour. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filtrate was concentrated to give the title compound (170 mg, 88%). 1 H NMR (400MHz, DMSO-d6) δ7.63(t,J=9.5Hz,1H),7.56-7.45(m,1H),7.37(br.s,1H),4.15(br.s,1H),3.88(s,2H),2.52(s,3H). Example Example 1 Method A (3S,11aR)-7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,5-difluorobenzyl)oxy)-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6'-,1':2,3]imidazo[5,1-c][1,4]oxazin-9-one (3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (51 mg, 0.167 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), and hexamethyldisilamide lithium (0.167 mL, 1.0 M tetrahydrofuran solution, 0.167 mmol) was added at room temperature. The mixture was stirred for 15 minutes. (3S,11aR)-7-chloro-3,4-dihydro-1H,9H,11H-3,11a-methyl-bridged pyrimidino[6',1':2,3]imidazo[5,1-C][1,4]oxazin-9-one (20 mg, 0.083 mmol) was added, and the reaction mixture was stirred at 120 °C for 16 hours. The reaction was quenched with methanol, and the title compound (10.7 mg, 25%) was obtained by preparative thin-layer chromatography. LC-MS:m / z[M+H] + =509. 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=4.4Hz,1H),7.65(br.s,1H),7.45(d,J=8.8Hz,2H),7.30(br.s,1H),5.34(br.s,2H),5.31(br.s ,1H),4.68(br.s,1H),4.29(d,J=11.7Hz,1H),3.99-3.76(m,3H),3.32-3.22(m,2H),1.90(d,J=9.3Hz,1H),1.79(d,J=9.8Hz,1H). Example 2 Method B 5-(((1-oxo-7,8-dihydro-1H,6H,9H-6,8a-ethbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzylnitrile 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzyl nitrile (233 mg, 0.80 mmol) was dissolved in acetonitrile (12 mL), cooled to 0 °C, and sodium hydride (42 mg, 1.06 mmol, 60%) and 3-chloro-7,8-dihydro-1H,6H,9H-6,8a-ethbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (125 mg, 0.53 mmol) were added. The mixture was stirred for 0.5 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by preparative thin-layer chromatography (dichloromethane / methanol = 25 / 1) to give the title compound (128 mg, 49%). LC-MS:m / z[M+H] + =495. 1 H NMR (400MHz, DMSO-d6) δ7.98 (s, 1H), 7.79-7.40 (m, 5H), 7.10 (d, J = 8.8Hz, 1H), 5.44 (s, 1 H),5.27(s,2H),4.27(br.s,1H),3.88(s,2H),1.92(d,J=7.8Hz,2H),1.81-1.55(m,6H). The examples listed in the table below, 4-168, were prepared by steps similar to those described in Examples 1-2, starting from the respective intermediates: Example 169 Method C 3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenethoxy)-7,8-dihydro-1H,6H,9H-7,8a-methylaminopyrrole[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 3-Chloro-7,8-dihydro-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazol[1,2-c]pyrimidin-1-one (80 mg, 0.359 mmol), 2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)ethanol-1-ol (137 mg, 0.43 mmol), and cesium carbonate (233 mg, 0.718 mmol) were added to toluene (10 mL) and stirred at 120 °C for 16 hours. The reaction mixture was concentrated and purified by thin-layer chromatography to give the title compound (68 mg, 37%). LC-MS:m / z[M+H] + =507. 1 H NMR (400MHz, CDCl3) δ8.58(d,J=5.4Hz,1H),7.24(br.s.,1H),6.96(d,J=8.3Hz,3H),5.04(s,1H),4.57 (t,J=5.9Hz,2H),3.96(s,2H),3.31(s,2H),3.03(t,J=6.4Hz,3H),2.04(br.s.,2H),1.81(br.s.,2H). Example 170 Method D (3S,11aR)-6-methoxy-7-((4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)ethynyl)-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazol[5,1-c][1,4]oxazin-9-one 4-(4-ethynylphenoxy)-2-(trifluoromethyl)pyridine (195.66 mg, 0.74 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and the mixture was cooled to -50 °C under argon protection. A tetrahydrofuran solution of n-butyllithium (2 M, 0.74 mL, 1.44 mmol) was added dropwise. After stirring the reaction mixture for 15 minutes, the temperature was raised to 0 °C, and zinc chloride (150.96 mg, 1.11 mmol) was added. After stirring the reaction solution for 30 minutes, (3S,11aR)-7-chloro-6-methoxy-3,4-dihydro-1H,9H,11H-3,11a-methyl-bridged pyrimidinido[6',1':2,3]imidazole[5,1-c][1,4]oxazin-9-one (200 mg, 0.742 mmol), Pd2(dba)3 (67.76 mg, 0.074 mmol) and 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (70.6 mg, 0.148 mmol) were added. The reaction solution was heated to 120 °C and stirred for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was concentrated. Preparative thin-layer chromatography purification (dichloromethane / methanol = 20 / 1) yielded the title compound (25 mg, 7%). LCMS:m / z[M+H] + =497. (3S,11aR)-6-methoxy-7-(4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenethyl)-3,4-dihydro-1H,9H,11H-3,11a-methylpyrimidino[6',1':2,3]imidazol[5,1-c][1,4]oxazin-9-one (3S,11aR)-6-methoxy-7-((4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)ethynyl)-3,4-dihydro-1H,9H,11H-3,11a-methyl-bridged pyrimidino[6',1':2,3]imidazol[5,1-c][1,4]oxazin-9-one (25 mg, 0.05 mmol) and Pd / C (10%, 5 mg) were added to methanol (5 mL) and hydrogenated at room temperature and atmospheric pressure for 1 hour. The reaction solution was filtered, and the filtrate was concentrated. Preparative thin-layer chromatography purification (dichloromethane / methanol = 20 / 1) yielded the title compound (8 mg, 32%). LCMS:m / z[M+H] + =501. 1H NMR (400MHz, CDCl3) δ8.55(d,J=5.4Hz,1H),7.34(d,J=7.8Hz,2H),7.19(s,1H),7.02(d,J=8.3Hz,2H),6.96(d,J=3.9Hz,1H),4.74(br.s.,1H),4.52 (d,J=12.7Hz,1H),4.09-3.96(m,3H),3.72(s,2H),3.57(s,3H),3.18-3.0 3(m,2H),2.98-2.84(m,2H),2.09(d,J=9.8Hz,1H),1.86(d,J=9.8Hz,1H). Example 171 Method E (3S,11aS)-7-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-1,2,3,4-tetrahydro-9H,11H-3,11a-methylpyrazine[1',2':3,4]imidazol[1,2-c]pyrimidin-9-one (3S,11aR)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-9-oxo-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-2(1H)-carboxylic acid tert-butyl ester (36 mg, 0.06 mmol) and trifluoroacetic acid (8.4 mg, 0.07 mmol) were added to dichloromethane (1 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated, and formaldehyde aqueous solution (37%, 5 mg, 0.06 mmol), sodium cyanoborohydride (12 mg, 0.18 mmol), and methanol (1 mL) were added to the residue and stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by thin-layer chromatography to obtain (13 mg, 41%). LCMS:m / z[M+H] + =504. 1H NMR(400MHz, CDCl3)δ8.59(br.s.,1H),7.27(br.s.,4H),6.97(br.s.,1H),5.45(br.s.,2H),5.11(br.s.,1H),4.37(br.s.,1H),3 .84(br.s.,1H),3.75-3.57(m,2H),3.19(d,J=1.5Hz,1H),2.73(br.s.,1H),2.50(br.s.,3H),2.00(br.s.,1H),0.87(br.s.,2H). Example 172 Method F (3S,11aS)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-(oxacyclobut-3-yl)-1,2,3,4-tetrahydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidin-9-one (3S,11aR)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-9-oxo-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-2(1H)-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was added to ethyl hydrochloride solution (4.0 M, 1 mL) and dichloromethane (11 mL), and stirred at room temperature for 1 hour. The reaction solution was concentrated, and oxetane (20 mg, 0.28 mmol), sodium cyanoborohydride (17 mg, 0.28 mmol), and methanol (1 mL) were added to the residue, and stirred at room temperature for 1 hour. The reaction solution was concentrated, and thin-layer chromatography was performed to obtain (60 mg, 81%). LCMS:m / z[M+H] + =546. 1H NMR (400MHz, CDCl3) δ8.57(d,J=5.4Hz,1H),7.32(d,J=10.8Hz,1H),7.27-7.16(m,3H),6.96(d,J=4.4Hz,1H) ,5.49-5.38(m,2H),5.09(s,1H),4.75(t,J=6.4Hz,2H),4.62(t,J=5.6Hz,1H),4.56(t,J=5.9Hz,1H),4.40(d ,J=12.2Hz,1H),4.04(t,J=5.9Hz,1H),3.89(d,J=12.2Hz,1H),3.62(br.s.,1H),3.43(d,J=9.8Hz,1H),3.16 (d,J=9.3Hz,1H),3.10(d,J=9.8Hz,1H),3.00(d,J=9.3Hz,1H),1.97(d,J=9.8Hz,1H),1.62(d,J=9.8Hz,1H). Example 173 Method G (3S,11aS)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidin-9-one (3S,11aR)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-9-oxo-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidin-2(1H)-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was added to ethyl hydrogen chloride solution (4.0 M, 1 mL). The mixture was stirred in dichloromethane (1 mL) at room temperature for 1 hour. The reaction solution was concentrated, and 2,2,2-trifluoroethyltrifluoromethanesulfonate (49 mg, 0.21 mmol), triethylamine (140 mg, 1.4 mmol), and toluene (1 mL) were added to the residue. The mixture was stirred overnight at 80 °C. The reaction solution was poured into a saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was concentrated. Thin-layer chromatography was used to purify the product to obtain (25 mg, 32%). LCMS:m / z[M+H] + =572. 1H NMR (400MHz, CDCl3) δ8.58(d,J=5.4Hz,1H),7.33(d,J=10.8Hz,1H),7.25-7.16(m,3H),6.96(br.s.,1H),5.49-5.41(m,2H),5.11(s,1H),4.40(d,J= 12.2Hz,1H),3.88(d,J=12.7Hz,1H),3.78(br.s.,1H),3.61(d,J=10.3Hz,1H),3.44(d,J=9.3H z,1H),3.26-3.13(m,3H),2.90(d,J=9.3Hz,1H),2.04(d,J=9.3Hz,1H),1.67(d,J=9.8Hz,1H). Example 174 Method H (3S,11aS)-2-benzoyl-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1,2,3,4-tetrahydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazol[1,2-c]pyrimidin-9-one (3S,11aR)-7-(((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-9-oxo-3,4-dihydro-9H,11H-3,11a-methylpyrazino[1',2':3,4]imidazo[1,2-c]pyrimidine-2(1H)-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) was added to ethyl hydrogen chloride solution (4.0 M, 1 mL) and dichloromethane (1 mL), and stirred at room temperature for 1 hour. The reaction solution was concentrated, and triethylamine (42 mg, 0.42 mmol), benzoyl chloride (29.4 mg, 0.21 mmol), and dichloromethane (1 mL) were added to the residue, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was concentrated. Thin-layer chromatography was performed to obtain (52 mg, 65%). LCMS:m / z[M+H] + =594. 1H NMR (400MHz, CDCl3) δ8.57(d,J=5.4Hz,1H),8.08(d,J=7.3Hz,1H),7.55(d,J=5.4Hz,2H),7.50-7.44 (m,1H),7.32(d,J=10.8Hz,1H),7.27-7.14(m,4H),6.95(d,J=3.9Hz,1H),5.46-5.38(m,2H),5.14(d, J=7.3Hz,1H),4.61(br.s.,1H),4.51-4.42(m,1H),4.08(d,J=12.2Hz,1H),3.96(d,J=10.8Hz,1H),3. 82(d,J=9.3Hz,1H),3.69-3.58(m,1H),3.32(d,J=10.3Hz,1H),2.12-2.03(m,1H),1.86-1.75(m,1H). Example 175 Method I (3S,11aR)-7-((3,4-difluorobenzyl)amino)-6-methoxy-3,4-dihydro-1H,9H,11H-3,11a-methylaminopyrimidine[6',1':2,3]imidazol[5,1-c][1,4]oxazin-9-one (3S,11aR)-7-chloro-6-methoxy-3,4-dihydro-1H,9H,11H-3,11a-methylaminopyrimidine [6',1':2,3]imidazole [5,1-c][1,4]oxazin-9-one (100 mg, 0.37 mmol), (3,4-difluorophenyl)methylamine (110 mg, 0.74 mmol), and diisopropylethylamine (480 mg, 3.7 mmol) were added to 1,4-dioxane (1 mL), and stirred overnight at 120 °C. The reaction mixture was poured into dichloromethane, washed with saturated ammonium chloride aqueous solution, and the organic phase was concentrated. Thin-layer chromatography purification yielded the title compound (120 mg, 86%). LCMS:m / z[M+H] + =377. 1H NMR (400MHz, CDCl3) δ7.20-7.03(m,3H),5.52(br.s.,1H),4.79-4.68(m,2H),4.66-4.57(m,1H),4.42(d,J=12.2Hz,1H),4.0 4-3.95(m,2H),3.86(d,J=12.2Hz,1H),3.70-3.65(m,1H),3.64-3.59(m,4H),2.02(d,J=9.8Hz,1H),1.82(d,J=10.3Hz,1H). The Examples 176-200 listed in the table below were prepared by steps similar to those described in Examples 169-175, starting from the respective intermediates: Example 201 3-((3-fluoro-4-((2-trifluoromethylpyridin-4-yl)oxy)benzyl)oxy)-7-(2-hydroxypropyl-2-yl)-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one Methyl 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidine-7(8H)-carboxylic acid (20 mg, 0.038 mmol) was added to tetrahydrofuran (4 mL). The mixture was cooled to 0 °C under argon protection, and a tetrahydrofuran solution of methyl magnesium chloride (3.0 M, 0.13 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was concentrated. Preparative thin-layer chromatography purification (dichloromethane / methanol = 10 / 1) yielded the title compound (1 mg, 5%). LC-MS:m / z[M+H] + =533. 1H NMR(400MHz, CDCl3)δ8.58(d,J=5.4Hz,1H),7.34(d,J=10.8Hz,1H),7.30-7.28(m,1H),7.24(br.s.,1H),7.22-7.15(m,1H),6.96(d,J=5.4Hz,1H),5 .45(s,2H),5.17(br.s.,1H),4.03(s,2H),3.82-3.74(m,1H),3.35(d,J=3 .9Hz,2H),2.07-1.99(m,2H),1.76(br.s.,2H),1.44(s,3H),1.31(s,3H). Example 202 7-Amino-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8-dihydro-1H,6H,9H-7,8a-methylbridged pyrrolo[1',2':3,4]imidazol[1,2-c]pyrimidin-1-one 90 mg (0.15 mmol) of tert-butyl (3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-1-oxo-1H,6H,9H-7,8a-methylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-7(8H)-yl)carbamate was added to ethyl acetate (4 mL). A solution of ethyl acetate containing hydrogen chloride (4.0 M, 2 mL) was added with stirring. The mixture was stirred at room temperature for 10 minutes. The pH of the reaction solution was adjusted to 8 with sodium carbonate solid, filtered, and the filtrate was concentrated. Preparative thin-layer chromatography purification (dichloromethane / methanol = 10 / 1) yielded the title compound (6 mg, 7%). LC-MS:m / z[M+H] + =490. 1 H NMR(400MHz, CDCl3)δ8.58(d,J=5.9Hz,1H),7.34(d,J=11.2Hz,2H),7.25-7.15(m,2H), 6.96(d,J=3.4Hz,1H),5.44(s,2H),5.15(s,1H),4.04(s,2H),3.25(s,2H),1.97(s,4H). Biological testing and data The compounds of this invention are Lp-PLA2 inhibitors and can be used for the treatment and prevention of Lp-PLA2-mediated diseases. The bioactivity of the compounds of this invention can be determined using any suitable test to determine the activity of the compounds as Lp-PLA2 inhibitors, as well as in tissue and in vivo models. Bioactivity data for each compound are reported as the average of at least one experiment or multiple experiments. It should be understood that the data described in this invention can vary reasonably depending on the specific conditions and methods used by the person conducting the experiments. Lipoprotein-associated phospholipase A2 (Lp-PLA2) assay in human plasma. The human plasma assay utilizes a thioester analog of PAF (phosphatidylcholine), in which hydrolysis results in the formation of a phospholipid containing free thiol groups. The amount of thiol groups is sequentially determined by reaction with CPM (7-diethylamino-3-(4'-maleiminophenyl)-4-methylcoumarin), a maleimide whose fluorescence increases upon Michael addition of the thiol group. This assay can detect the activity of Lp-PLA2 in human plasma, as determined by specific inhibition by an Lp-PLA2 inhibitor. The Thio-PAF assay was performed as a quenched 75 μL assay. Compound source plates were prepared by serially diluting each compound in pure DMSO at a 1:3 (volume) ratio on a 96-well microplate. 3 μL of the compound from the source plate was transferred 20-fold to a 96-well microplate pre-filled with 57 μL of assay buffer using a Rainin multichannel pipette. The assay buffer consisted of 50 mM HEPES, pH 7.4, 150 mM NaCl, and 1 mM CHAPS. 1 μL of the 20-fold diluted compound was transferred 1 μL to a 96-well Greiner 655076 (black) microplate pre-filled with aliquots and thawed 40 μL of mixed human plasma using a Rainin multichannel pipette. The plate was shaken for 20 seconds on a microplate shaker to mix. After a 30-minute pre-incubation at room temperature, 10 μL of substrate solution was added to a 96-well Greiner 655076 (black) microplate using a Rainin multichannel pipette. The substrate solution contained 2.5 mM 2-thio-PAF (from ethanol stock), 32 μM CPM (from DMSO stock), and 3.2 mM NEM (N-ethylmaleimide) (freshly prepared in DMSO for each experiment) in an assay buffer consisting of 50 mM HEPES, pH 7.4, 150 mM NaCl, and 1 mM CHAPS. The reaction was quenched with 25 μL of 5% trifluoroacetic acid (TFA) aqueous solution after 2 minutes. The plate was centrifuged at 2000 rpm for 1 minute. The plates were read using a Biotek Synergy H1 (H1MF) microplate reader at ex:380 / em:485. IC50 was performed using GraphPad Prism 6.0 and Excel. 50 Data, curves, and QC analysis. Example: Activity determination Comparison of Activity Data (Part 1) The comparative data shows that the compound in this patent has significantly higher activity compared to the compounds in the prior art.

Claims

1. A compound of formula I, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates, or its pharmaceutically acceptable salts or its prodrugs, wherein n is 0, 1 or 2; and when n is 0, R2 is methyl or ethyl; when n is 1 or 2, R2 is absent; R1 is H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group, and R1 may optionally be substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkoxy, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group or a 6- to 10-membered heteroaryl; R a Independently H or D; m is 1 or 2; R x is H, halogen, hydroxyl, carboxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl group, 6- to 10-membered heteroaryl group, -C(O)NR b R c or -S(O)2NR b R c ; R x may optionally be substituted with one or more of the following substituents: halogen, hydroxyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl group or 6- to 10-membered heteroaryl group; Q is -O-, -S-, -CH2- or -NR b -; X is -O-, -CH2-, -NR c -, -OCH2- or absent; R b is H, C 1-6 alkyl or C 3-8 cycloalkyl or 3- to 8-membered heterocyclic group; R c is L, L-C(O)-, L-CH2- or L-S(O)2-, where L is H, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, 6-10 membered aryl or 6-10 membered heteroaryl, and L may optionally be substituted by one or more of the following groups: halogen, hydroxy, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 6-10 membered aryl or 6-10 membered heteroaryl; Y is -CH2-, -CH2CH2- or absent; U is -CH2-, -C(O)- or absent; X and U are not both absent; Y and U may optionally be substituted by one or more of the following substituents: halogen, hydroxy, C 1-6 alkyl, C 1- 6-alkoxy, cyano, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl or 6- to 10-membered heteroaryl; A is Z is N or CR3; Z’ is N or CR4; R3, R4, R5, and R6 are each independently H, cyano, halogen, or C 1-3 haloalkyl; V is N or CR9, where R9 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or -O-W; W is phenyl or a 5- or 6-membered heteroaryl, which may optionally be substituted by one or more of the following substituents: halogen, cyano, C 1-6 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and C 1-3 haloalkoxy.

2. The compound according to claim 1, said compound having formula I’ wherein R1 is H, cyano, halogen, C 1-6 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl; X is -O-, -CH2-,-NRc- or absent; R c is L or L-C(O)-, where L is H, C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C1-3 haloalkyl, or benzyl; Y is -CH2- or absent; n, R2, R a , A and m are as defined in claim 1.

3. The compound according to claim 2, wherein n is 0, R2 is methyl or ethyl; R1 is H; R a is H; m is 1; X is -O- or -CH2-.

4. The compound according to claim 1, wherein n is 0; R1 is H, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-3 haloalkyl; R a is H; Rx is H, cyano, fluoro, difluoromethyl, amino, R2 is methyl or ethyl; Q is -O-; X is -O-, -CH2 or absent-; Y is -CH2-; U is -CH2-, or absent; X and U are not both absent.

5. The compound according to claim l, wherein n = 1 or 2; and R2 is absent.

6. The compound according to claim 4, wherein R x is H.

7. The compound according to claim 6, wherein X is -O- or -CH2-.

8. The compound according to claim 5, wherein n is 1; R x is H; R1 is H, cyano, amino, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy.

9. The compound according to claim 8, wherein U is -CH2-; X is -CH2- or -O-; and Q is -O-.

10. The compound according to claim 8, wherein U is -CH2-; X is -NR c -; R c is methyl, oxetanyl, trifluoroethyl, benzoyl, cyclobutyl, benzyl, 11. The compound according to claim 8, wherein U is -C(O)-; R1 and R x are both H; Y is -CH2-; X is -NR c -; R c is L or L-C(O)-, where L is methyl, trifluoroethyl, benzoyl, oxetane, cyclobutane, benzyl, 12. The compound according to claim 5, wherein n is 1; X is -CH2-; U is absent; R x is H, hydroxy, halogen, cyano, amino, C 1-3 alkoxy, C 1-3 haloalkyl or a 3- to 8-membered heterocyclic group, and R x may optionally be substituted by one or more of the following substituents: halogen, hydroxy, C 1-6 alkoxy, cyano, a 3- to 8-membered heterocyclic group, a 6- to 10-membered aryl or a 6- to 10-membered heteroaryl.

13. The compound according to claim 12, wherein Y is -CH2-; R1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy; and Q is -O-.

14. The compound according to claim 13, wherein R x is H, halogen, cyano, amino, difluoromethyl, 15. The compound according to claim 12, wherein Y is -CH2CH2-; R x is H, halogen, cyano, amino, difluoromethyl, R1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy and Q is -O-.

16. The compound according to claim 5, wherein n is 2; U is -CH2-; X is -CH2- or -O-; Y is -CH2- or absent; R x is H, halogen, cyano, amino, difluoromethyl, R1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy; and Q is -O-.

17. The compound according to any one of claims 1-2, 4-10, 12-16, wherein m = 2; R1 is H, cyano or C 1-3 haloalkyl; and R x is H.

18. A compound according to any one of claims 1-2, 4-10, 12-16, wherein m = 1; R1 is H, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy; R x is H.

19. The compound according to any one of claims l to 18, wherein A is and R5, R 6, R7, R8, and R9 are each independently H, F, or cyano.

20. The compound according to any one of claims l to 18 or its pharmaceutically acceptable salt or its prodrug, wherein A is R5, R 6, Each of R7 and R8 is independently H, F or cyano; R9 is -O-W; W is a 5- or 6-membered heteroaryl or phenyl, which may optionally be substituted by one or more of the following substituents: C 1-3 haloalkyl, C 1-3 haloalkoxy, cyano halogen and C 1-6 alkyl.

21. The compound according to any one of claims l to 18, wherein A is R7 and R8 are each independently H, F or cyano; R9 is -O-W; and W is pyridyl, pyrimidinyl, pyrazolyl or phenyl, which may be optionally substituted by one or more substituents independently selected from: halogen, cyano, CF3, -OCF3, CHF2 and CH3.

22. The compound according to any one of claims 1 to 21, said compound being the following compound Among them, R1 is H, halogen, cyano, C 1-6 alkyl, C 1-3 haloalkyl or C 1-6 alkoxy; R c is C 1- 6-alkyl, 3- to 8-membered heterocyclic group, C 1-3 haloalkyl, benzoyl, C 3-8 cycloalkyl, benzyl or R x is H, cyano, halogen, C 1-3 haloalkyl, amino, 23. The compound according to claim 22, wherein R1 is H, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl or methoxy; R2 is methyl or ethyl; R c is methyl, oxetanyl, trifluoroethyl, benzoyl, cyclobutyl, benzyl or R x is H, cyano, fluorine, difluoromethyl, amino, 24. The compound according to any one of claims l to 18 and 22 to 23, wherein A is selected from the following groups:

25. The compound according to any one of claims 1 to 24, said compound being the following compound:

26. Composition, characterized in that Comprising the compound according to any one of claims 1 to 25, its cis-trans isomers, its enantiomers, its diastereoisomers, its racemates, its solvates, its hydrates, or its pharmaceutically acceptable salts or its prodrugs and a pharmaceutically acceptable excipient.

27. Use of the compound according to any one of claims 1 to 25 or the composition according to claim 26 in the preparation of a drug for the treatment or prevention of a disease associated with Lp-PLA2.

28. Use of a compound according to any one of claims 1 to 25 or a composition according to claim 26 in the manufacture of a medicament for treating or preventing the following diseases: diabetic complications, Alzheimer's disease or atherosclerosis.

29. A method for treating or preventing diabetic complications, neuroinflammation-related diseases or atherosclerosis, characterized in that Administering to a patient an effective dose of a compound according to any one of claims 1 to 25 or a composition according to claim 26.

30. The method according to claim 29, wherein The diabetic complications are diabetic retinopathy / diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathic pain or diabetic foot.

31. The method according to claim 29, wherein Neuroinflammation-related diseases are Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson's disease.