Pyrimidinone compounds, and preparation method, pharmaceutical composition and application thereof

Abstract

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound can be used for treating neurodegenerative related diseases, such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), cardiovascular diseases including atherosclerosis and the like, diabetic macular edema (DME), prostate diseases and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a pyrimidone compound, a preparation method thereof, a pharmaceutical composition thereof, and its use in medicine. In particular, the present invention relates to a pyrimidone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as an Lp-PLA2 inhibitor for treating neurodegenerative diseases such as Alzheimer's disease, glaucoma, age-related macular degeneration (AMD), cardiovascular diseases such as atherosclerosis, diabetic macular edema, or prostate disease. Background Art

[0002] Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 superfamily (Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Chem Rev. 2011, 111, 6130-6185). It is mainly secreted by monocytes, macrophages, T lymphocytes and chief cells (Stafforini DM, Elstad MR, McIntyre TM, Zimmerman GA, Prescott SM. J Biol Chem. 1990, 265: 9682-9687; Nakajima K, Murakami M, Yanoshita R, Samejima Y, Karasawa K, Setaka M, Nojima S, Kudo IJ Biol Chem. 1997, 272, 19708-19713). Phosphatidylcholine sn-2 ester is produced during the oxidation of low-density lipoprotein (LDL), and Lp-PLA2 is responsible for hydrolyzing oxidatively modified phosphatidylcholine sn-2 ester, and then producing oxidized fatty acids and lysophosphatidylcholine (LysoPC) (Caslake MJ, Packard CJ, Suckling KE, Holmes SD, Chamberlain P, Macphee CH. Atherosclerosis. 2000, 150, 413-419; MacPhee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, Leake DS, Milliner KJ, Patterson RA, Suckling KE, Tew DG, Hickey DM. Biochem J. 1999, 338, 479-487). Oxidized fatty acids and LysoPC both play a role in activating macrophages, increasing oxidative stress, affecting T lymphocyte function and inducing inflammatory responses (Quinn MT, Parthasarathy S, Steinberg D. Proc Natl Acad Sci US A. 1988, 85, 2805-2809). LysoPC is reported to induce the release of a variety of cytotoxic inflammatory cytokines (Shi, et al. Atherosclerosis, 2007, 191, 54-62). In addition, LysoPC is also involved in leukocyte activation, induction of apoptosis and mediation of endothelial dysfunction (Wilensky, et al. Current Opinion in Lipidology, 2009, 20, 415-420).

[0003] It has been reported in the literature that plasma Lp-PLA2 levels are associated with cardiovascular disease (Fitzpatrick AL, Irizarry MC, Cushman M, Jenny NS, Chi GC, Koro C. Atherosclerosis. 2014, 235, 384-391), diabetic macular edema (DME) (Staurenghi G, Ye L, Magee MH, Danis RP, Wurzelmann J, Adamson P, McLaughlin MM, Darapladib DMESG. Ophthalmology. 2015, 122, 990-996), and prostate cancer (Bertilsson H, Tessem MB, Flatberg A, Viset T, Gribbestad I, Angelsen A, Halgunset J. Clin Cancer Res. 2012, 18, 3261-3269).

[0004] Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes cognitive decline, mood swings, irreversible memory loss, disorientation, language impairment, and loss of self-protection ability (Hardy J, et al. Science 2002, 297, 353-356). Alzheimer's disease usually starts slowly and gradually worsens over time, which is the cause of 60% to 70% of dementia cases and affects about 6% of the population over 65 years old. AD patients will gradually withdraw from their families and society, become increasingly dependent on help, and eventually progress to death. AD is one of the most expensive diseases in developed countries and is also costly in other countries. In particular, as aging becomes an important social issue, these costs will increase dramatically. There is no doubt that AD is a complex disease involving multiple factors. Although the etiology of AD has not been fully elucidated, it is clear that several factors are involved in the occurrence and development of the disease, including aggregated tau protein and Aβ peptide, oxidative stress and neuroinflammation (Echeverria V, Yarkov A, Aliev G. Prog Neurobiol. 2016, 144, 142-157). Current AD drug research and development focuses on targets of Aβ amyloidosis and tau (Chiang K, Koo EH. Annu Rev Pharmacol Toxicol. 2014, 54, 381-405; Awasthi M, Singh S, Pandey VP, Dwivedi UN. J Neurol Sci. 2016, 361, 256-271). However, despite strong preclinical data, the results of late clinical trials have so far failed to demonstrate clinical efficacy. These disappointing results indicate that other neuropathological mechanisms, such as oxidative stress and neuroinflammation, may have to be explored for AD treatment.

[0005] Elevated levels of Lp-PLA2 in plasma increase the risk of dementia, including AD (Van Oijen, et al. Annals of Neurology, 2006, 59, 139). Vascular dementia and mixed dementia, as well as high oxidized LDL levels, have been found in AD patients (Maher-Edwards G, De'Ath J, Barnett C, Lavrov A, Lockhart A, Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2015, 1, 131-140; Kassner, et al. Current Alzheimer Research, 2008, 5, 358-366; Dildar, et al. Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem, et al. Current Alzheimer Research, 2010, 7, 463-469). Neuroinflammation and up-regulated inflammatory cytokines have also been found in AD patients (Colangelo, et al. Journal of Neuroscience Research, 2002, 70, 462-473; Wyss-Coray, Nature Medicine, 2006, 12, Sept.).

[0006] Based on all these findings, Lp-PLA2 is a potential target for the treatment of AD, and the clinical results of the Lp-PLA2 inhibitor Rilapladib in AD patients further confirmed this (Maher-Edwards G, De'Ath J, Barnett C, Lavrov A, Lockhart A, Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2015, 1, 131-140).

[0007] Glaucoma and age-related macular degeneration (AMD) are retinal neurodegenerative diseases. Buschini et al. reported that inflammation, including TNF-α signaling, may play an important role in the pathogenesis of glaucoma and AMD (Buschini, et al. Progress in Neurobiology, 2011, 95, 14-25; Tezel, Progress in Brain Research, vol. 173, ISSN 0079-6123, Chapter 28). In addition, Shi et al. confirmed that Lp-PLA2 inhibitors can block the release of inflammatory cytokines (Shi, et al. Atherosclerosis, 2007, 191, 54-62). The inhibition of Lp-PLA2 is a potential treatment for glaucoma and AMD.

[0008] Many Lp-PLA2 inhibitors have been reported, including β-lactams (Tew DG, Boyd HF, Ashman S, Theobald C, Leach CA. Biochemistry. 1998, 37, 10087-10093), oximes (Jeong TS, Kim MJ, Yu H, Kim HS, Choi JK, Kim SS, Lee WS. Bioorg Med Chem Lett. 2005, 15, 1525-1527; Jeong HJ, Park YD, Park HY, Jeong IY, Jeong TS, Lee WS. Bioorg Med Chem Lett. 2006, 16, 5576-5579), amides of xanthuric acid (Lin EC, Hu Y, Amantea CM, Pham LM, Cajica J, Okerberg E, Brown HE, Fraser A, Du L, Kohno J Y,Ishiyama J,Kozarich JW,Shreder KR.Bioorg MedChem Lett.2012,22,868-871;Hu Y,Lin EC,Pham LM,Cajica J,Amantea CM,Okerberg E,Brown HE,Fraser A,Du L,Kohno Y,Ishiyama J,Kozarich JW,Shreder KR.Bioorg MedChem Lett.2013,23,1553-1556), and carbamates (Nagano JM, Hsu KL, Whitby LR, NiphakisMJ, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Hodder P, Srinivasan P, Gonzalez TD, Rosen H, Bahnson BJ, Cravatt BF.Bioorg Med Chem Lett. 2013, 23, 839-843).

[0009] It is reported that the Lp-PLA2 inhibitor Darapladib is a potential treatment for atherosclerosis and DME (Magrioti V, Kokotos G. Expert Opin Ther Pat. 2013; 23: 333-344). Summary of the invention

[0010] The present invention provides a novel Lp-PLA2 inhibitor, which can be used to treat neurodegenerative diseases, such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), cardiovascular diseases such as atherosclerosis, diabetic macular edema (DME), or prostate diseases.

[0011] The present invention provides a pyrimidone compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0012]

[0013] in,

[0014] n1, n2, n3 are each independently 0, 1 or 2;

[0015] R1, R2, R3, R4, and R5 are each independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen;

[0016] U is: -O-, -S-, -NR6-, or -CHR6-; wherein each R6 is independently -H, alkyl, deuterated alkyl, haloalkyl, or alkanoyl;

[0017] Alternatively, R1 and R2 and the atoms to which they are attached form a 3-6 membered non-aromatic ring;

[0018] Alternatively, R3 and R4 and the atoms to which they are attached form a 3-6 membered non-aromatic ring;

[0019] Alternatively, R1 or R2 and R6 and the atoms connected thereto form a 5-7 membered non-aromatic ring;

[0020] Alternatively, R3 or R4 and R6 and the atoms connected thereto form a 5-7 membered non-aromatic ring, in which case n2 is 0;

[0021] Alternatively, R3 or R4 and R5 and the atoms connected thereto form a 6-7 membered non-aromatic ring or a 6-7 membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S;

[0022] X is: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: H, alkyl, deuterated alkyl, or cycloalkyl;

[0023] Ar is a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene; the substituted arylene or substituted heteroarylene is substituted by one or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, monoalkyl or dialkyl substituted amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0024] Y is -H, halogen, alkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, -OAr', -SAr', -NH-Ar', -NMe-Ar', -NHR", or -R"'-Ar';

[0025] wherein Ar′ is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; the substituted aryl or substituted heteroaryl is substituted by one or more substituents, each of which is independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxyl, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, halosulfanyl, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R″ is alkyl or cycloalkyl; R″′ is alkylene;

[0026] Z is O or S.

[0027] Optionally, the halogen atoms in the "halogen", "haloalkyl", "haloalkoxy" and "halosulfanyl" are each independently selected from F, Cl, Br or I;

[0028] Optionally, the alkyl groups in the “alkyl”, “deuterated alkyl”, “deuterated alkoxy”, “hydroxyalkyl”, “haloalkyl”, “haloalkoxy”, “alkoxy”, “monoalkyl or dialkyl substituted amino” and “alkanoyl” are each independently C1-C 10 linear or branched alkyl; optionally, C1-C7 linear or branched alkyl; optionally, C1-C4 linear or branched alkyl; optionally, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, butyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl;

[0029] Optionally, the "alkylene" is each independently C1-C 10 A straight or branched alkylene group; optionally, a C1-C7 straight or branched alkylene group; optionally, a C1-C5 straight or branched alkylene group; optionally, selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n-heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, or 2,2,3-trimethylbutylene;

[0030] Optionally, the "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

[0031] Optionally, the "heterocyclic group" is a 3-10-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; Optionally, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; Optionally, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; Optionally, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring; Optionally, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring;

[0032] Optionally, the "aryl" is a 6-10 membered aryl; Optionally, it is phenyl or naphthyl; Optionally, it is phenyl, 1-naphthyl, or 2-naphthyl;

[0033] Optionally, the "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group;

[0034] Optionally, the "heteroaryl" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; Optionally, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; Optionally, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group; Optionally, the heteroaromatic group is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazolyl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine yl, pyrazin-2-yl, pyrazin-3-yl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, thieno[2,3-b]furanyl, furano[3,2-b]pyranyl, pyrido[2,3-d]oxazinyl, pyrazolo[4,3-d]oxazolyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl, benzothiophenyl, benzoxazolyl, benzimidazo[2,3-d]pyridazinyl oxazolyl, benzothiazolyl, benzoxazolinyl, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2 -b] pyridazinyl, imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazolo[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl; optionally, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl;

[0035] Optionally, the "heteroaryl group" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; optionally, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; optionally, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group.

[0036] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0037] n1 is 0, 1 or 2; n2 is 0, 1 or 2; n3 is 0 or 1;

[0038] R1, R2, R3, and R4 are each independently -H, C1-C7 alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), C1-C7 alkoxy (optionally, -OCH3, -OC2H5, -OC3H7), C1-C7 deuterated alkoxy (optionally, -OCD3, -OC2D5, or -OC3D7), C1-C7 haloalkoxy (optionally, -OCF3, -OCH2CF3, -OCF2CF3), or halogen (optionally, -F, -Cl, -Br);

[0039] R5 is -H, cyano, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethyl C1-C7 deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), C1-C7 alkoxy (optionally, -OCH3, -OC2H5, -OC3H7), C1-C7 deuterated alkoxy (optionally, -OCD3, -OC2D5, or -OC3D7), C1-C7 haloalkoxy (optionally, -OCF3, -OCH2CF3, -OCF2CF3), or halogen (optionally, -F, -Cl, -Br);

[0040] U is -O-, -NR6-, or -CHR6-; wherein each R6 is independently -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), C1-C7 deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), or C1-C7 alkanoyl (optionally, formyl, acetyl);

[0041] Alternatively, R1 and R2 and the atoms to which they are attached form a 3-5 membered non-aromatic ring;

[0042] Alternatively, R3 and R4 and the atoms connected thereto form a 3-5 membered non-aromatic ring;

[0043] Alternatively, R1 or R2 and R6 and the atoms connected thereto form a 5-6 membered non-aromatic ring;

[0044] Alternatively, R3 or R4 and R6 and the atoms connected thereto form a 5-6 membered non-aromatic ring, in which case n2 is 0;

[0045] Alternatively, R3 or R4 and R5 and the atoms connected thereto form a 6-membered non-aromatic ring or the ring contains 1 or 2 6-membered non-aromatic heterocyclic rings selected from O or S;

[0046] X is: C1-C7 alkylene (optionally, -CH2-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; alternatively, X is -CH2-, or -O-; alternatively, X is -O-; wherein R′ is selected from -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl , 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), or C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane);

[0047] Ar is phenylene or pyridyl, the phenylene or pyridyl is substituted by 0, 1, 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -I, -CN, -Me, -CF3, -C2H5, -C3H7, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3, -OCD3, -OMe, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN;

[0048] Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCD3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2H5, -OC3H7, or -OAr'; alternatively, Y is -H, -F, -Cl, -Br, -I, or -OAr'; alternatively, Y is -H, -F, or -OAr'; wherein Ar' is selected from 0, 1, phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl substituted with 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -CN, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, -OCD3, C1-C7 haloalkyl, -OCH3, -OC2H7, -OC3H7, C1- C7 haloalkoxy, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), hydroxyl, hydroxyalkyl, cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl, or quinolin-7-yl substituted with 0, 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5;

[0049] Z is O.

[0050] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0051] n1 is 0, 1 or 2; n2 is 0, 1 or 2; n3 is 1;

[0052] R1, R2, R3, and R4 are each independently -H, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl), C1-C4 deuterated alkyl, or C1-C4 haloalkyl;

[0053] R5 is -H, cyano, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl), deuterated alkyl (optionally -CD3, -C2D5, or -C3D7), C1-C4 haloalkyl, C1-C4 alkoxy (optionally -OCH3, -OC2H5, -OC3H7), C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, or halogen;

[0054] U is -O-, -NR6-, or -CHR6-; wherein each R6 is independently -H, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl), C1-C4 deuterated alkyl, C1-C4 haloalkyl, or C1-C4 alkanoyl (optionally formyl);

[0055] Alternatively, R1 and R2 and the atoms to which they are attached form a cyclopropane;

[0056] Alternatively, R3 and R4 and the atoms to which they are attached form a cyclopropane;

[0057] Alternatively, R1 or R2 and R6 and the atoms to which they are attached form piperidine, piperidone, tetrahydropyrrole, or cyclohexane;

[0058] Alternatively, R3 or R4 and R6 and the atoms connected thereto form piperidine, piperidone, tetrahydropyrrole, or cyclohexane, in which case n2 is 0;

[0059] Alternatively, R3 or R4 and R5 and the atoms to which they are attached form 3,4-dihydropyran, 3,6-dihydropyran, or cyclohexene;

[0060] X is -O-;

[0061] Ar is a phenylene group, the phenylene group is substituted by 0, 1 or 2 substituents, the substituents are -F or -CN;

[0062] Y is -H, -F, or -OAr'; wherein Ar' is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl substituted with 0, 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5;

[0063] Z is O.

[0064] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the compound of formula (I) is selected from the following compounds:

[0065]

[0066] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt includes an anionic salt or a cationic salt of the compound of formula (I);

[0067] Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound of formula (I); optionally, the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium;

[0068] Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an organic base; Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, or N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine;

[0069] Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an acid; optionally, the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

[0070] In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the above-mentioned compounds of formula (I) or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable carrier.

[0071] Optionally, the dosage form of the pharmaceutical composition includes an oral preparation, a rectal preparation, or a parenteral preparation;

[0072] Optionally, the oral preparation includes a solid preparation or a liquid preparation; Optionally, the solid preparation includes a tablet, a powder, a granule, or a capsule; Optionally, the liquid preparation includes an aqueous or oil suspension, or a syrup;

[0073] Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

[0074] On the other hand, the present invention also provides use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of an Lp-PLA2 inhibitor.

[0075] On the other hand, the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a drug for treating neurodegenerative diseases, cardiovascular diseases, diabetic macular edema (DME) or prostate diseases;

[0076] Optionally, the neurodegeneration-related disease comprises Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD);

[0077] Optionally, the cardiovascular disease comprises atherosclerosis.

[0078] On the other hand, the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention for inhibiting Lp-PLA2.

[0079] On the other hand, the present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention for treating neurodegeneration-related diseases, cardiovascular diseases, diabetic macular edema (DME) or prostate diseases;

[0080] Optionally, the neurodegeneration-related disease includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

[0081] On the other hand, the present invention provides a method for preventing or treating a disease mediated by Lp-PLA2, comprising administering to a subject in need (e.g., a human or an animal) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in an effective amount for preventing or treating the disease. Alternatively, a method for preventing or treating a disease is provided, comprising administering to a subject in need (e.g., a human or an animal) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in an effective amount for preventing or treating the disease, wherein the disease comprises: a neurodegenerative disease, a cardiovascular disease, diabetic macular edema (DME), or a prostate disease; optionally, the neurodegenerative disease comprises Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); the cardiovascular disease comprises atherosclerosis.

[0082] On the other hand, the present invention also provides a method for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention, the method comprising the following preparation route:

[0083] Route 1:

[0084]

[0085] In each structural formula, n1, n2, n3, R1, R2, R3, R4, R5, U, X, Z, Ar and Y are as defined above; W is a halogen or a sulfonate.

[0086] Compound 1A is reacted (for example, with methyl trifluoromethanesulfonate) to generate compound 1B; compound 1B and compound 1C are cyclized (for example, in the presence of triethylamine) to generate compound 1D; compound 1D is chlorinated (for example, with POCl3) or esterified (for example, with sulfonyl chloride) to generate compound 1E (Z=O); compound 1E is sulfided (for example, with Lawesson's reagent) to generate compound 1F (Z=S); compound 1E / 1F and compound 1G are subjected to aromatic nucleophilic substitution or C-heteroatom coupling to obtain compound (I). Alternatively, route 2 is used:

[0087]

[0088] In each structural formula, n1, n2, n3, R1, R2, R3, R4, R5, U, X, Z, Ar and Y are as defined above; W is a halogen or a sulfonate.

[0089] Compound 2A and compound 2B are subjected to substitution reaction (for example, with K2CO3 as base) to generate compound 2C; compound 2C is subjected to intramolecular cyclization (for example, through Mitsunobu reaction) to generate compound 2D; compound 2D is subjected to chlorination (for example, with POCl3) or esterification (for example, with sulfonyl chloride) to generate compound 2E (Z=O); compound 2E is subjected to sulfidation (for example, with Lawesson reagent) to generate compound 2F (Z=S); compound 2E / 2F and compound 2G are subjected to aromatic nucleophilic substitution or C-heteroatom coupling to obtain compound (I).

[0090] Herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention includes tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof of the compound of formula (I).

[0091] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention is a pyrimidone compound, which is a new Lp-PLA2 inhibitor, and can be used to treat neurodegenerative diseases such as Alzheimer's disease (AD), glaucoma and age-related macular degeneration (AMD), including cardiovascular diseases such as atherosclerosis, diabetic macular edema (DME), or prostate diseases. DETAILED DESCRIPTION

[0092] The present invention is further described by the following examples. It should be understood that the examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0093] Example

[0094] The starting materials of the present invention can be synthesized according to methods known in the art, or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

[0095] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0096] In the examples, unless otherwise specified, the reaction temperature is room temperature, for example, 20-30°C.

[0097] Embodiment 1:

[0098] Compound 1: 8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4-dihydropyrimido[6,1-c][1,4]oxazin-6(1H)-one

[0099]

[0100] Synthesis of 1 g of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol:

[0101]

[0102] Compound 3,4,5-trifluorobenzaldehyde 1g-1 (23.0 g, 143.67 mmol), 2-(trifluoromethyl)pyridin-4-ol (25.8 g, 158.04 mmol), potassium carbonate (19.9 g, 143.67 mmol) were dissolved in DMF (200 mL) and reacted at 90°C for 1 h. After cooling to room temperature, the reaction solution was poured into ice water (2 L), extracted with ethyl acetate (500 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:5) to obtain a white solid 1g-2 (22.0 g, 51%).

[0103] LC-MS: [M+H] + :304.0.

[0104] The compound 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 1g-2 (20.0g, 65.97mmol) was dissolved in ethanol (200mL), cooled to 0°C, sodium borohydride (2.5g, 65.97mmol) was added, and the temperature was slowly raised to room temperature and stirred for 1h. The reaction solution was spin-dried, added to water (500mL), extracted with ethyl acetate (300mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:1) to obtain 1g (20.0g, 99%) of white solid.

[0105] LC-MS: [M+H] + :306.1.

[0106] Synthesis of 5-methoxy-3,6-dihydro-2H-1,4-oxazine 1b:

[0107]

[0108] A solution of 3-morpholinone 1a (25.0 g, 0.25 mol) and methyl trifluoromethanesulfonate (52.8 g, 0.32 mol) in dichloromethane (1000.0 mL) was stirred at room temperature for 16 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the crude product was used directly in the next step without further purification. A colorless oily crude product 1b (28 g, yield 98%) was obtained.

[0109] LC-MS: [M+H] + :116.2.

[0110] Synthesis of 6,8-dicarbonyl-1,3,4,6,7,8-hexahydropyrimido[6,1-c][1,4]oxazine-9-carbonitrile 1d:

[0111]

[0112] A mixture of 5-methoxy-3,6-dihydro-2H-1,4-oxazine 1b (28.4 g, 0.25 mol), ethyl (2-cyanoacetyl) carbamate 1c (7.7 g, 0.05 mol) and triethylamine (32.4 g, 0.32 mol) was stirred at 105°C for 2 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and dried, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 1:10) to obtain a yellow solid 1d (6.5 g, yield 68%).

[0113] LC-MS: [MH] - :192.0.

[0114] Synthesis of 3,4-dihydropyrimido[6,1-c][1,4]oxazine-6,8(1H,7H)-dione 1e:

[0115]

[0116] 6,8-Dicarbonyl-1,3,4,6,7,8-hexahydropyrimido[6,1-c][1,4]oxazine-9-carbonitrile 1d (3.0 g, 15.5 mmol) was dissolved in aqueous hydrobromic acid solution (120.0 mL, 8.8 M), and the mixture was stirred at 120°C for 3 days. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was concentrated under reduced pressure and dried, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 1:10) to obtain an orange solid 1e (0.6 g, yield 23%).

[0117] LC-MS: [M+H] + :169.1.

[0118] Synthesis of 6-carbonyl-1,3,4,6-tetrahydropyrimido[6,1-c][1,4]oxazin-8-yl-2,4,6-triisopropylbenzenesulfonate 1f:

[0119]

[0120] 2,4,6-triisopropylbenzenesulfonyl chloride (1080.7 mg, 3.57 mmol) was added to a dichloromethane solution (15.0 mL) of 3,4-dihydropyrimido[6,1-c][1,4]oxazine-6,8(1H,7H)-dione 1e (300.0 mg, 1.78 mmol), triethylamine (541.6 mg, 5.35 mmol) and 4-dimethylaminopyridine (21.8 mg, 0.18 mmol), and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a yellow solid 1f (20.0 mg, yield 3%).

[0121] LC-MS: [M+H] + :435.2.

[0122] Compound 1: Synthesis of 8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4-dihydropyrimido[6,1-c][1,4]oxazin-6(1H)-one:

[0123]

[0124] 6-Carbonyl-1,3,4,6-tetrahydropyrimido[6,1-c][1,4]oxazin-8-yl 2,4,6-triisopropylbenzenesulfonate 1f (20.0 mg, 0.05 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1g (21.1 mg, 0.07 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (4.4 mg, 0.005 mmol) and cesium carbonate (30.0 mg, 0.09 mmol) were dissolved in anhydrous toluene (0.5 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 100°C for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane:methanol=30:1) to obtain a white solid 1 (2.9 mg, yield 14%).

[0125] LC-MS: [M+H] + :456.1.

[0126] 1 H NMR (400MHz, CDCl3) δ8.61 (d, J=5.5Hz, 1H), 7.26–7.25 (m, 1H), 7.14 (d, J=8.1Hz, 2H), 6.99 (d, J= 5.2Hz,1H),5.75(s,1H),5.44(s,2H),4.66(s,2H),4.10(t,J=5.1Hz,2H),3.92(t,J=5.1Hz,2H).

[0127] Embodiment 2:

[0128] Compound 2: 8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-1,2,3,4-tetrahydro-6H-pyrazinyl[1,2-c]pyrimidin-6-one

[0129]

[0130] Synthesis of 6-(((2-hydroxyethyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 2b:

[0131]

[0132] A solution of 6-chloromethylpyrimidine-2,4(1H,3H)-dione 2a (5.0 g, 0.031 mol), 2-(methylamino)ethanol-1-ol (3.7 g, 0.037 mol) and potassium carbonate (6.4 g, 0.046 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane: methanol = 5:1 (100 mL), the insoluble potassium carbonate was filtered off, the filter cake was eluted with methanol, and the filtrate was dried by spin drying. The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10:1) to obtain a white solid 2b (2.9 g, 47%).

[0133] LC-MS: [M+H] + :200.1.

[0134] Synthesis of 2-methyl-1,2,3,4-tetrahydro-6H-pyrazinyl[1,2-c]pyrimidine-6,8(7H)-dione 2c:

[0135]

[0136] Compound 6-(((2-hydroxyethyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 2b (2.5 g, 0.012 mol) and triphenylphosphine (4.9 g, 0.019 mol) were dissolved in tetrahydrofuran (30 mL), the mixture was cooled to 0°C, diisopropyl azodicarboxylate (3.8 g, 0.044 mol) was slowly added dropwise, and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid 2c (1.5 g, 63%).

[0137] LC-MS: [M+H] + :182.1.

[0138] Synthesis of 2-methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrazinyl[1,2-c]pyrimidin-8-yl 2,4,6-triisopropylbenzenesulfonate 2d:

[0139]

[0140] Compound 2-methyl-1,2,3,4-tetrahydro-6H-pyrazinyl[1,2-c]pyrimidine-6,8(7H)-dione 2c (300.0 mg, 1.65 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (1002.9 mg, 3.29 mmol), triethylamine (502.5 mg, 4.98 mmol), 4-dimethylaminopyridine (20.1 mg, 0.17 mmol) were dissolved in 1,2-dichloroethane solution (5.0 mL) and reacted at 50°C for 1 hour. After the reaction was completed, the reaction solution was directly wet-loaded and subjected to silica gel chromatography (dichloromethane: methanol = 10:1) to obtain a crude product, which was then purified on a preparative plate to obtain a crude product 2d (50.0 mg, 7%).

[0141] LC-MS: [M+H] + :448.2.

[0142] Compound 2: Synthesis of 8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-1,2,3,4-tetrahydro-6H-pyrazinyl[1,2-c]pyrimidin-6-one:

[0143]

[0144] Compound 2-methyl-6-oxo-1,3,4,6-tetrahydro-2H-pyrazinyl[1,2-c]pyrimidin-8-yl 2,4,6-triisopropylbenzenesulfonate 2d (50.0 mg, 0.11 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1 g (44.3 mg, 0.15 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (10.6 mg, 0.011 mmol) and cesium carbonate (72.8 mg, 0.22 mmol) were dissolved in anhydrous toluene (5 mL), and the mixture was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by wet loading on silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a crude product, which was then purified on a preparative plate to obtain a white solid 2 (8.7 mg, 17%).

[0145] LC-MS: [M+H] + :469.1.

[0146] 1H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.7Hz,1H),7.67(d,J=2.3Hz,1H),7.49(d,J=8.9Hz,2H),7.33–7.29( m,1H),5.96(s,1H),5.37(s,2H),3.69(t,J=5.6Hz,2H),3.54(s,2H),2.76(d,J=5.2Hz,2H),2.31(s,3H).

[0147] Embodiment 3:

[0148] Compound 3: 3-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidin-1-one

[0149]

[0150] Synthesis of 6-methoxy-2,3,4,5-tetrahydropyridine 3b:

[0151]

[0152] A solution of piperidin-2-one 3a (2.0 g, 0.02 mol) and trimethyloxonium tetrafluoroborate (3.6 g, 0.02 mol) in dichloromethane (30.0 mL) was stirred at 25° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude oil 3b (2.2 g, 96%).

[0153] LC-MS: [M+H] + :114.2.

[0154] Synthesis of 1,3-dicarbonyl-2,3,5,6,7,8-hexahydro-1H-pyrido[1,2-c]pyrimidine-4-carbonitrile 3c:

[0155]

[0156] A mixture of 6-methoxy-2,3,4,5-tetrahydropyridine 3b (2.2 g, 0.02 mol), triethylamine (2.9 g, 0.03 mol) and ethyl (2-cyanoacetyl)carbamate (3.0 g, 0.02 mol) was stirred at 105°C for 3 hours. After the reaction was completed, the reaction mixture was allowed to cool to room temperature, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a gray solid 3c (1.3 g, 36%).

[0157] LC-MS: [MH] - :190.1.

[0158] Synthesis of 5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione 3d:

[0159]

[0160] A solution of 1,3-dicarbonyl-2,3,5,6,7,8-hexahydro-1H-pyrido[1,2-c]pyrimidine-4-carbonitrile 3c (1.3 g, 0.01 mol) in a hydrobromic acid aqueous solution (8.8 M) (35.5 mL) was stirred at 120°C for 3 days. After the reaction was completed, the reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 12: 1) to obtain a white solid 3d (975.0 mg, 86%). LC-MS: [M+H] + :167.1.

[0161] Synthesis of 1-carbonyl-5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidin-3-yl-2,4,6-triisopropylbenzenesulfonate 3e:

[0162]

[0163] At 0°C, 2,4,6-triisopropylbenzenesulfonyl chloride (1458.0 mg, 4.81 mmol) was added to a dichloromethane solution (16.6 mL) of 5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione 3d (400.0 mg, 2.41 mmol), triethylamine (730.7 mg, 0.72 mmol) and 4-dimethylaminopyridine (29.4 mg, 0.24 mmol), and the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to obtain a yellow solid 3e (800.0 mg, 100%).

[0164] LC-MS: [M+H] + :433.2.

[0165] Compound 3: Synthesis of 3-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidin-1-one:

[0166]

[0167] 1-Carbonyl-5,6,7,8-tetrahydro-1H-pyrido[1,2-c]pyrimidin-3-yl-2,4,6-triisopropylbenzenesulfonate 3e (300.0 mg, 0.69 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1 g (318.5 mg, 1.04 mmol), cesium carbonate (451.9 mg, 1.39 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.8 mg, 0.07 mmol) were dissolved in toluene (10.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 100°C for 1 hour. After the reaction was completed, the temperature dropped to room temperature, and water (30.0 mL) was added to the mixture to dilute it, and then extracted twice with ethyl acetate (30.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to obtain a white solid 3 (121.0 mg, 38%).

[0168] LC-MS: [M+H] + :454.1.

[0169] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.7Hz,1H),7.67(d,J=2.4Hz,1H),7.48(d,J=8.9Hz,2H),7.31(dd,J=5.6,2.3Hz ,1H),5.95(s,1H),5.36(s,2H),3.72(t,J=6.3Hz,2H),2.77(t,J=6.6Hz,2H),1.90–1.82(m,2H),1.72–1.64(m,2H).

[0170] Embodiment 4:

[0171] Compound 7: 3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazepan-1-one

[0172]

[0173] Synthesis of 5-methoxy-2,3,6,7-tetrahydro-1,4-oxazine 7b:

[0174]

[0175] Compound 1,4-oxazepan-5-one 7a (7.0 g, 60.86 mmol) and trimethyloxytetrafluoroborate (10.0 g, 73.03 mmol) were dissolved in dichloromethane (105.0 mL), and the mixture was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the obtained crude product 7b (7.0 g) was directly used in the next step.

[0176] LC-MS: [M+H] + :130.2.

[0177] Synthesis of 1,3-dioxo-2,3,5,6,8,9-hexahydro-1H-pyrimido[1,6-d][1,4]oxaazepane-4-carbonitrile 7c:

[0178]

[0179] Compound 5-methoxy-2,3,6,7-tetrahydro-1,4-oxazine 7b (7.0 g, 53.85 mmol) and ethyl (2-cyanoacetyl)carbamate (7.0 g, 44.87 mmol) were dissolved in triethylamine (10.9 g, 107.70 mmol), and the mixture was stirred at 105°C for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid 7c (450.0 mg, 7%).

[0180] LC-MS: [MH] - :206.1.

[0181] Synthesis of 5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazine-1,3(2H)-dione 7d:

[0182]

[0183] The compound 1,3-dioxo-2,3,5,6,8,9-hexahydro-1H-pyrimido[1,6-d][1,4]oxaazepine-4-carbonitrile 7c (450.0 mg, 2.17 mmol) was dissolved in aqueous hydrobromic acid (15.0 mL), and the mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a white solid 7d (120.0 mg, 30%). LC-MS: [M+H] + :183.1.

[0184] Synthesis of 1-oxo-5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazolin-3-yl-2,4,6-triisopropylbenzenesulfonate 7e:

[0185]

[0186] Compound 5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazine-1,3(2H)-dione 7d (120.0 mg, 0.65 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (235.0 mg, 0.78 mmol) and triethylamine (131.0 mg, 1.30 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) were dissolved in dichloromethane solution (3.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a white solid 7e (60.0 mg, 20%).

[0187] LC-MS: [M+H] + :449.2.

[0188] Compound 7: Synthesis of 3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazepan-1-one:

[0189]

[0190] Compound 1-oxo-5,6,8,9-tetrahydro-1H-pyrimido[1,6-d][1,4]oxazolin-3-yl-2,4,6-triisopropylbenzenesulfonate 7e (60.0 mg, 0.13 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)phenyl)methanol 1 g (21.0 mg, 0.07 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (9.0 mg, 0.01 mmol) and cesium carbonate (68.0 mg, 0.21 mmol) were dissolved in anhydrous toluene (3.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and the crude product was purified by silica gel chromatography (dichloromethane:methanol=20:1) to obtain a white solid 7 (20.7 mg, 32%).

[0191] LC-MS: [M+H] + :470.1.

[0192] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.6Hz,1H),7.67(s,1H),7.50(d,J=9.2Hz,2H),7.32(d,J=5.4Hz,1H) ,6.08(s,1H),5.38(s,2H),4.40–4.36(m,2H),3.78–3.74(m,2H),3.72–3.69(m,2H),3.04–3.00(m,2H).

[0193] Embodiment 5:

[0194] Compound 8: 8-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-3,4-dihydropyrimido[6,1-c][1,4]oxazin-6(1H)-one

[0195]

[0196] Synthesis of 3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzaldehyde 8b:

[0197]

[0198] Compound 3-(pentafluorosulfanyl)phenol (1.80 g, 8.20 mmol) and 3,4,5-trifluorobenzaldehyde 8a (1.97 g, 12.30 mmol) were dissolved in N,N-dimethylformamide (54 mL), potassium carbonate (3.40 mg, 24.60 mmol) was added to the mixture, and the mixture was stirred at 90°C for 1 hour. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate twice, the organic phases were combined, the obtained organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate, the organic phases were concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 10:1) to obtain yellow oil 8b (2.0 g, 68%).

[0199] LC-MS: [M+Na] + :383.3.

[0200] Synthesis of (3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)phenyl)methanol 8c:

[0201]

[0202] Compound 3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzaldehyde 8b (2.0 g, 5.60 mmol) was dissolved in ethanol (40.0 mL), sodium borohydride (0.25 g, 6.72 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to obtain a yellow oil 8c (1.4 g, 70%).

[0203] LC-MS: [M+Na] + :385.3.

[0204] Compound 8: Synthesis of 8-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-3,4-dihydropyrimido[6,1-c][1,4]oxazin-6(1H)-one:

[0205]

[0206] Compound 1f (70.0 mg, 0.16 mmol), (3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)phenyl)methanol 8c (46.7 mg, 0.13 mmol), cesium carbonate (105.0 mg, 0.32 mmol) and methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (15.3 mg, 0.016 mmol) were dissolved in toluene (7.0 mL), and the mixture was stirred at 100° C. for 2 hours under argon protection. The reaction solution was concentrated in vacuo, and the crude product was separated by preparative separation to give a white solid 8 (3.3 mg, 4%).

[0207] LC-MS: [M+H] + :512.9.

[0208] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=5.8Hz,1H),7.39(s,2H),7.13–7.08(m,2H),7.04(d,J=7.8Hz, 1H),5.74(s,1H),5.42(d,J=3.2Hz,2H),4.66(s,2H),4.09(t,J=5.3Hz,2H),3.95–3.89(m,2H).

[0209] Embodiment 6:

[0210] Compound 11: 9-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-2-methyl-2,3,4-5-tetrahydropyrimido[1,6-a][1,4]diazepine-7(1H)-one

[0211]

[0212] Synthesis of 6-(((3-hydroxypropyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 11b:

[0213]

[0214] A solution of 6-chloromethylpyrimidine-2,4(1H,3H)-dione (3.0 g, 0.019 mol), 3-(methylamino)propan-1-ol (2.5 g, 0.028 mol) and potassium carbonate (5.2 g, 0.037 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane: methanol = 5:1, the insoluble potassium carbonate was filtered off, the filter cake was eluted with methanol, the filtrate was dried, and the obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10:1) to obtain a white solid 11b (3.6 g, 81%).

[0215] LC-MS: [M+H] + :214.2.

[0216] Synthesis of 2-methyl-2,3,4,5-tetrahydropyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 11c:

[0217]

[0218] Compound 6-(((3-hydroxypropyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 11b (1.5 g, 7.00 mmol) and triphenylphosphine (2.4 g, 9.10 mmol) were dissolved in tetrahydrofuran (20 mL), the mixture was cooled to 0°C, diisopropyl azodicarboxylate (2.1 g, 10.50 mmol) was slowly added dropwise, and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid 11c (1.2 g, 78%).

[0219] LC-MS: [M+H] + :196.2.

[0220] Synthesis of 2-methyl-7-oxo-1,2,3,4,5,7-hexahydropyrimido[1,6-a][1,4]diazepine-9-yl 2,4,6-triisopropylbenzenesulfonate 11d:

[0221]

[0222] Compound 2-methyl-2,3,4,5-tetrahydropyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 11c (300.0 mg, 1.54 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (930.8 mg, 3.07 mmol), triethylamine (311.0 mg, 3.07 mmol), 4-dimethylaminopyridine (37.6 mg, 0.31 mmol) were dissolved in dichloromethane solution (5.0 mL) and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly wet-loaded and subjected to silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a crude product, which was then purified on a preparative plate to obtain a white solid 11d (500.0 mg, 63%).

[0223] LC-MS: [M+H] + :462.2.

[0224] Compound 11: Synthesis of 9-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-2-methyl-2,3,4-5-tetrahydropyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0225]

[0226] The compound 2-methyl-7-oxo-1,2,3,4,5,7-hexahydropyrimido[1,6-a][1,4]diazepine-9-yl 2,4,6-triisopropylbenzenesulfonate 11d (120.0 mg, 0.26 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1 g (95.5 mg, 0.31 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (49.4 mg, 0.052 mmol) and cesium carbonate (254.1 mg, 0.78 mmol) were dissolved in anhydrous toluene (5 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) and then prepared to give a white solid 11 (56.2 mg, 37%).

[0227] LC-MS: [M+H] +:483.1.

[0228] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 5.7 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 5.6, 2.3 Hz, 1H), 6.14 (s, 1H), 5.36 (s, 2H), 4.27 (s, 2H), 3.82 (s, 2H), 2.90 (d, J = 4.8 Hz, 2H), 2.30 (s, 3H), 1.70 (s, 2H). Example 7:

[0229] Compound 12: 8'-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)-2'-methyl-1',2'-dihydro-4'H,6'-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidine]-6'-one

[0230]

[0231] Synthesis of 6-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 12b:

[0232]

[0233] A solution of 6-chloromethylpyrimidine-2,4(1H,3H)-dione 12a (3.0 g, 19 mmol), (1-aminocyclopropyl)methanol (2.7 g, 22 mmol) and potassium carbonate (6.4 g, 47 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained solid was added to a solvent of dichloromethane:methanol = 5:1, the insoluble matter was filtered off, the filter cake was eluted with methanol, and the filtrate was dried by spin drying. The obtained crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain a white solid 12b (2.5 g, 54%).

[0234] LC-MS: [M+H] + :212.1.

[0235] Synthesis of 6-(((1-(hydroxymethyl)cyclopropyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 12c:

[0236]

[0237] Compound 6-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 12b (1.4 g, 6.6 mmol) was dissolved in methanol (15 mL), formaldehyde (0.3 g, 9.9 mmol) and a drop of glacial acetic acid were added, the mixture was placed at 25°C, stirred for 30 minutes, sodium cyanoborohydride (0.8 g, 13 mmol) was slowly added at 0°C, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid 12c (0.7 g, 46%).

[0238] LC-MS: [M+H] + :226.1.

[0239] Synthesis of 2'-methyl-1',2'-dihydro-4'H,6'H-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidine]-6',8'(7'H)-dione 12d:

[0240]

[0241] Compound 6-(((1-(hydroxymethyl)cyclopropyl)(methyl)amino)methyl)pyrimidine-2,4(1H,3H)-dione 12c (770.0 mg, 3.42 mmol) and triphenylphosphine (1.3 g, 5.13 mmol) were dissolved in tetrahydrofuran (10 mL), the mixture was cooled to 0°C, diisopropyl azodicarboxylate (1.0 g, 5.13 mol) was slowly added dropwise, and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to give a white solid 12d (370 mg, 47%).

[0242] LC-MS: [M+H] + :208.1.

[0243] Synthesis of 2'-methyl-6'-oxo-1',6'-dihydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidin]-8'-yl 2,4,6-triisopropylbenzenesulfonate 12e:

[0244]

[0245] Compound 2'-methyl-1',2'-dihydro-4'H,6'H-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidine]-6',8'(7'H)-dione 12d (110.0 mg, 0.53 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (321.5 mg, 1.06 mmol), triethylamine (107.4 mg, 1.06 mmol), 4-dimethylaminopyridine (12.9 mg, 0.11 mmol) were dissolved in dichloromethane solution (5.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, silica gel chromatography (dichloromethane: methanol = 10: 1) was used to purify to give a white solid 12e (130.0 mg, 43%).

[0246] LC-MS: [M+H] + :474.3.

[0247] Compound 12: Synthesis of 8'-(3,5-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)oxy)-2'-methyl-1',2'-dihydro-4'H,6'-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidine]-6'-one:

[0248]

[0249] Compound 2'-methyl-6'-oxo-1',6'-dihydro-2'H,4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-c]pyrimidin]-8'-yl 2,4,6-triisopropylbenzenesulfonate 12e (140.0 mg, 0.30 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1 g (90.5 mg, 0.30 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg, 0.029 mmol) and cesium carbonate (192.6 mg, 0.59 mmol) were dissolved in anhydrous toluene (5 mL), and the mixture was stirred at 25°C for 3 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and the crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give a white solid 12 (10.7 mg, 6%).

[0250] LC-MS: [M+H] + :495.1.

[0251] 1H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.7Hz,1H),7.68(d,J=2.4Hz,1H),7.50(d,J=8.8Hz,2H),7.32(dd,J =5.6,2.3Hz,1H),6.03(s,1H),5.38(s,2H),3.87(s,2H),3.54(s,2H),2.32(s,3H),0.74–0.65(m,4H).

[0252] Embodiment 8:

[0253] Compounds 17 and 18: (S)-8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-10(6H)-one and (R)-8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-10(6H)-one

[0254] Synthesis of 6-((3-(hydroxymethyl)morpholine)methyl)pyrimidine-2,4(1H,3H)-dione 17b:

[0255]

[0256] The compound morpholin-3-ylmethanol (20.0 g, 170.94 mmol) and 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (32.8 g, 205.13 mmol) were dissolved in N,N-dimethylformamide (300.0 mL), potassium carbonate (47.2 g, 341.88 mmol) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid 17b (8.0 g, 36%).

[0257] LC-MS: [M+H] + :242.2.

[0258] Synthesis of (4-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl)morpholin-3-yl)methyl-4-methylbenzenesulfonate 17c:

[0259]

[0260] Compound 6-((3-(hydroxymethyl)morpholine)methyl)pyrimidine-2,4(1H,3H)-dione 17b (6.0 g, 24.79 mmol) was dissolved in tetrahydrofuran (90.0 mL), triethylamine (5.0 g, 49.58 mmol), 4-dimethylaminopyridine (0.3 g, 2.47 mmol) and p-toluenesulfonyl chloride (5.6 g, 29.74 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product 17c (6.0 g, 50%) was directly used in the next step as a white solid.

[0261] LC-MS: [M+H] + :396.1.

[0262] Synthesis of 3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-8,10(6H,9H)-dione 17d:

[0263]

[0264] Compound (4-((2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl)morpholin-3-yl)methyl-4-methylbenzenesulfonate 17c (6.0 g, 15.15 mmol) and cesium carbonate (9.8 g, 30.3 mmol) were dissolved in acetonitrile (90.0 mL), and the mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a white solid 17d (1.4 g, 48%).

[0265] LC-MS: [M+H] + :224.1.

[0266] Synthesis of 10-oxo-3,4,6,10,12,12a-hexahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-8-yl-2,4,6-triisopropylbenzenesulfonate 17e:

[0267]

[0268] Compound 3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazine-8,10(6H,9H)-dione 17d (900.0 mg, 4.01 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (1.8 g, 6.01 mmol) and triethylamine (810.0 mg, 8.02 mmol), 4-dimethylaminopyridine (5.0 mg, 0.04 mmol) were dissolved in dichloromethane solution (15.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a white solid 17e (220.0 mg, 13%).

[0269] LC-MS: [M+H] + :490.3.

[0270] Synthesis of 8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-10(6H)-one 17f:

[0271]

[0272] Compound 10-oxo-3,4,6,10,12,12a-hexahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-8-yl-2,4,6-triisopropylbenzenesulfonate 17e (220.0 mg, 0.45 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)phenyl)methanol 1 g (194.0 mg, 0.54 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (38.0 mg, 0.04 mmol) and cesium carbonate (292.0 mg, 0.90 mmol) were dissolved in anhydrous toluene (5.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and the crude product was purified by silica gel chromatography (dichloromethane:methanol=20:1) to give a white solid 17f (13.0 mg, 8%).

[0273] LC-MS: [M+H] + :511.0.

[0274] Compounds 17 and 18: Synthesis of (S)-8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-10(6H)-one and (R)-8-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,12,12a-tetrahydro-1H-pyrimido[1',6':4,5]pyrazino[2,1-c][1,4]oxazin-10(6H)-one:

[0275]

[0276] 17f (13.0 mg, 0.03 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid 17 (3.3 mg, 25%) and white solid 18 (2.8 mg, 22%).

[0277] Compound 17:

[0278] LC-MS: [M+H] + :511.0.

[0279] RT:4.03min.

[0280] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.6Hz,1H),7.68(d,J=2.4Hz,1H),7.49(d,J=8.8 Hz,2H),7.32(d,J=2.4Hz,1H),6.00(s,1H),5.37(s,2H),3.94–3.79(m,4H),3.56(dd ,J=11.0,9.1Hz,1H),3.23(d,J=11.2Hz,1H),3.03(dd,J=13.8,11.3Hz,1H),2.83(d ,J=11.5Hz,1H),2.67–2.63(m,1H),2.23(dd,J=11.3,8.0Hz,1H),2.03–1.98(m,1H).

[0281] Compound 18:

[0282] LC-MS: [M+H] + :511.2.

[0283] RT:5.23min.

[0284] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.7Hz,1H),7.68(d,J=2.4Hz,1H),7.50(d,J=9.0H z,2H),7.32(d,J=5.9Hz,1H),6.00(s,1H),5.37(s,2H),3.88(ddd,J=21.3,9.1,5.2H z,4H),3.56(t,J=10.3Hz,1H),3.27–3.21(m,1H),3.07–2.98(m,1H),2.83(d,J=11.4 Hz, 1H), 2.66 (d, J = 14.3Hz, 1H), 2.25 (dd, J = 11.6, 3.0Hz, 1H), 2.00 (d, J = 7.8Hz, 1H).

[0285] Biological evaluation

[0286] 1. Recombinant human Lp-PLA2 inhibition assay (rhLp-PLA2)

[0287] Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), hydrolyzes 2-thio-PAF, and its product reacts with DTNB to generate 5-thio-2-Nitrobenzoic Acid again; this substance has a certain absorption of 414nm light waves, and based on this, an experimental method is set up to detect the inhibitory effect of the compound on the activity of Lp-PLA2 in plasma.

[0288] 1. Prepare assay buffer: 50 mM MES (pH 6.5), 150 mM NaCl, 0.1% BSA

[0289] 2. Dissolve the compound powder in DMSO to a 10 mM stock solution and keep at room temperature for later use.

[0290] 3. The compound solution was diluted four-fold with DMSO.

[0291] 4. Use Echo to transfer serial dilutions of compounds to 384-well plate experiments.

[0292] 5. Prepare 2x PLA2G7 in assay buffer.

[0293] 6. Add 15 μl of prepared PLA2G7 to the 384-well plate and place it in a 25°C incubator for incubation.

[0294] 7. Prepare a 2x mixture of 2-Thio-PAF and DTNB in ​​assay buffer.

[0295] 8. Add 15 μl of the mixture of 2x 2-Thio-PAF and DTNB to the plate and incubate in a 25°C incubator.

[0296] 9. Data was read using Envision, ABS 405nm. The results are listed in Table 1.

[0297] Table 1

[0298] Compound No. <![CDATA[rhLp-PLA2(IC 50 ,nM)]]> Compound 1 (Example 1) 1.6 Compound 2 (Example 2) 1.1 Compound 3 (Example 3) 0.5 Compound 7 (Example 4) 1.1 Compound 8 (Example 5) 1.4 Compound 11 (Example 6) 2.5 Compound 12 (Example 7) 1.4 Compound 17 (Example 8) 8.7 Compound 18 (Example 8) 1.6 Darapladib 0.6

[0299] Experimental reagents:

[0300] PLA2G7 (Sino biological, 10848-H08H); 2-Thio-PAF (Cayman, 60945); DTNB (Sigma, D-8130); Darapladib (MCE, HY-10521)

[0301] II: Human plasma Lp-PLA2 inhibition assay

[0302] Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), hydrolyzes 2-thio-PAF, and its product reacts with DTNB to generate 5-thio-2-Nitrobenzoic Acid again; this substance has a certain absorption of 414nm light waves, and based on this, an experimental method is set up to detect the inhibitory effect of the compound on the activity of Lp-PLA2 in plasma.

[0303] Determination method:

[0304] 1. Dilute the test compound with DMSO at a gradient ratio of 1:2; then dilute with Assay Buffer (0.1MTris-HCl, pH 7.5; 0.1mg / ml BSA) at a ratio of 1:99; mix well;

[0305] 2. Take a 96-well transparent plate and use a multi-well pipette to add 8 μl of 1 mM DTNB, 8 μl of the diluted test compound, and 4 μl of human plasma to the 96-well plate. Mix well and centrifuge (500 g, room temperature, 5 min). Place in a 37°C constant temperature incubator and incubate for 30 min. Then transfer to a 25°C constant temperature incubator.

[0306] 3. After 15 min, add 60 μl of 133.33 μM 2-thio-PAF using a multi-well pipette and mix well; centrifuge (500 g, room temperature, 5 min);

[0307] 4. Set the parameters of the microplate reader (Abs414, time interval 1min, recording for 40min).

[0308] 5. The exported data were processed and analyzed using GraphPad Prism7. The results are listed in Table 2.

[0309] Table 2

[0310]

[0311]

[0312] Experimental reagents:

[0313] Human plasma (PreceDo, 20230203EDTA); DTNB (TCI, D0944); 2-thio-PAF (MCE, HY-101263); Darapladib (MCE, HY-10521)

[0314] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, n1, n2, n3 are each independently 0, 1 or 2; R1, R2, R3, R4, and R5 are each independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen; U is: -O-, -S-, -NR6-, or -CHR6-; wherein each R6 is independently -H, alkyl, deuterated alkyl, haloalkyl, or alkanoyl; Alternatively, R1 and R2 and the atoms to which they are attached form a 3-6 membered non-aromatic ring; Alternatively, R3 and R4 and the atoms to which they are attached form a 3-6 membered non-aromatic ring; Alternatively, R1 or R2 and R6 and the atoms connected thereto form a 5-7 membered non-aromatic ring; Alternatively, R3 or R4 and R6 and the atoms connected thereto form a 5-7 membered non-aromatic ring, in which case n2 is 0; Alternatively, R3 or R4 and R5 and the atoms connected thereto form a 6-7 membered non-aromatic ring or a 6-7 membered non-aromatic heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S; X is: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: -H, alkyl, deuterated alkyl, or cycloalkyl; Ar is a substituted or unsubstituted arylene or a substituted or unsubstituted heteroarylene; the substituted arylene or substituted heteroarylene is substituted by one or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, monoalkyl or dialkyl substituted amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Y is -H, halogen, alkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, -OAr', -SAr', -NH-Ar', -NMe-Ar', -NHR", or -R"'-Ar'; wherein Ar′ is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; the substituted aryl or substituted heteroaryl is substituted by one or more substituents, each of which is independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxyl, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, halosulfanyl, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R″ is alkyl or cycloalkyl; R″′ is alkylene; Z is O or S.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The halogen atoms in the "halogen", "haloalkyl", "haloalkoxy" and "halosulfanyl" are each independently selected from F, Cl, Br or I; The alkyl groups in the aforementioned “alkyl”, “deuterated alkyl”, “deuterated alkoxy”, “hydroxyalkyl”, “haloalkyl”, “haloalkoxy”, “alkoxy”, “amino substituted with monoalkyl or dialkyl” and “alkanoyl” are each independently C1-C 10 linear or branched alkyl; optionally, C1-C7 linear or branched alkyl; optionally, C1-C4 linear or branched alkyl; optionally, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, butyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl; The "alkylene" is each independently C1-C 10 A straight or branched alkylene group; optionally, a C1-C7 straight or branched alkylene group; optionally, a C1-C5 straight or branched alkylene group; optionally, selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n-heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, or 2,2,3-trimethylbutylene; The "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; The "heterocyclic group" is a 3-10-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; alternatively, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring; alternatively, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring; The "aryl" is a 6-10 membered aryl; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl; The "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group; The "heteroaryl" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; alternatively, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; alternatively, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group; alternatively, the heteroaromatic group is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazolyl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, yl, pyrazin-2-yl, pyrazin-3-yl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, thieno[2,3-b]furanyl, furano[3,2-b]pyranyl, pyrido[2,3-d]oxazinyl, pyrazolo[4,3-d]oxazolyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl, benzothienyl, benzoxazolyl, benzimidazolyl , benzothiazolyl, benzoxazolinyl, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2- b] pyridazinyl, imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazolo[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl; optionally, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl; The "heteroarylene" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; alternatively, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; alternatively, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein n1 is 0, 1 or 2; n2 is 0, 1 or 2; n3 is 0 or 1; R1, R2, R3, and R4 are each independently -H, C1-C7 alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), C1-C7 alkoxy (optionally, -OCH3, -OC2H5, -OC3H7), C1-C7 deuterated alkoxy (optionally, -OCD3, -OC2D5, or -OC3D7), C1-C7 haloalkoxy (optionally, -OCF3, -OCH2CF3, -OCF2CF3), or halogen (optionally, -F, -Cl, -Br); R5 is -H, cyano, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethyl C1-C7 deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), C1-C7 alkoxy (optionally, -OCH3, -OC2H5, -OC3H7), C1-C7 deuterated alkoxy (optionally, -OCD3, -OC2D5, or -OC3D7), C1-C7 haloalkoxy (optionally, -OCF3, -OCH2CF3, -OCF2CF3), or halogen (optionally, -F, -Cl, -Br); U is -O-, -NR6-, or -CHR6-; wherein each R6 is independently -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), C1-C7 deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), C1-C7 haloalkyl (optionally, -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3), or C1-C7 alkanoyl (optionally, formyl, acetyl); Alternatively, R1 and R2 and the atoms to which they are attached form a 3-5 membered non-aromatic ring; Alternatively, R3 and R4 and the atoms connected thereto form a 3-5 membered non-aromatic ring; Alternatively, R1 or R2 and R6 and the atoms connected thereto form a 5-6 membered non-aromatic ring; Alternatively, R3 or R4 and R6 and the atoms connected thereto form a 5-6 membered non-aromatic ring, in which case n2 is 0; Alternatively, R3 or R4 and R5 and the atoms connected thereto form a 6-membered non-aromatic ring or the ring contains 1 or 2 6-membered non-aromatic heterocyclic rings selected from O or S; X is: C1-C7 alkylene (optionally, -CH2-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; alternatively, X is -CH2-, or -O-; alternatively, X is -O-; wherein R′ is selected from -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl , 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), or C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane); Ar is phenylene or pyridyl, the phenylene or pyridyl is substituted by 0, 1, 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -I, -CN, -Me, -CF3, -C2H5, -C3H7, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3, -OCD3, -OMe, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN; Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCD3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2H5, -OC3H7, or -OAr'; alternatively, Y is -H, -F, -Cl, -Br, -I, or -OAr'; alternatively, Y is -H, -F, or -OAr'; wherein Ar' is selected from 0, 1, phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl substituted with 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -CN, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, -OCD3, C1-C7 haloalkyl, -OCH3, -OC2H7, -OC3H7, C1- C7 haloalkoxy, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), hydroxyl, hydroxyalkyl, cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl, or quinolin-7-yl substituted with 0, 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5; Z is O.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: n1 is 0, 1 or 2; n2 is 0, 1 or 2; n3 is 1; R1, R2, R3, and R4 are each independently -H, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl), C1-C4 deuterated alkyl, or C1-C4 haloalkyl; R5 is -H, cyano, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl), deuterated alkyl (optionally -CD3, -C2D5, or -C3D7), C1-C4 haloalkyl, C1-C4 alkoxy (optionally -OCH3, -OC2H5, -OC3H7), C1-C4 deuterated alkoxy, C1-C4 haloalkoxy, or halogen; U is -O-, -NR6-, or -CHR6-; wherein each R6 is independently -H, C1-C4 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl), C1-C4 deuterated alkyl, C1-C4 haloalkyl, or C1-C4 alkanoyl (optionally formyl); Alternatively, R1 and R2 and the atoms to which they are attached form a cyclopropane; Alternatively, R3 and R4 and the atoms to which they are attached form a cyclopropane; Alternatively, R1 or R2 and R6 and the atoms to which they are attached form piperidine, piperidone, tetrahydropyrrole, or cyclohexane; Alternatively, R3 or R4 and R6 and the atoms connected thereto form piperidine, piperidone, tetrahydropyrrole, or cyclohexane, in which case n2 is 0; Alternatively, R3 or R4 and R5 and the atoms to which they are attached form 3,4-dihydropyran, 3,6-dihydropyran, or cyclohexene; X is -O-; Ar is a phenylene group, the phenylene group is substituted by 0, 1 or 2 substituents, the substituents are -F or -CN; Y is -H, -F, or -OAr'; wherein Ar' is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl substituted with 0, 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5; Z is O.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from the following compounds:

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: The pharmaceutically acceptable salts include anionic salts or cationic salts of the compound of formula (I); Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound of formula (I); optionally, the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium; Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an organic base; Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, or N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine; Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an acid; optionally, the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

7. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, comprising the following synthetic route: Route 1: In each structural formula, n1, n2, n3, R1, R2, R3, R4, R5, U, X, Z, Ar and Y are defined as described in any one of claims 1 to 6; W is a halogen or a sulfonate; Or, take route 2: In each structural formula, n1, n2, n3, R1, R2, R3, R4, R5, U, X, Z, Ar and Y are defined as described in any one of claims 1 to 6; and W is a halogen or a sulfonate.

8. A pharmaceutical composition comprising one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6 and optionally a pharmaceutically acceptable carrier, Optionally, the dosage form of the pharmaceutical composition includes an oral preparation, a rectal preparation, or a parenteral preparation; Optionally, the oral preparation includes a solid preparation or a liquid preparation; Optionally, the solid preparation includes a tablet, a powder, a granule, or a capsule; Optionally, the liquid preparation includes an aqueous or oil suspension, or a syrup; Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

9. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 8 in the preparation of an Lp-PLA2 inhibitor.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating neurodegenerative diseases, cardiovascular diseases, diabetic macular edema (DME) or prostate diseases; Optionally, the neurodegeneration-related disease comprises Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); Optionally, the cardiovascular disease comprises atherosclerosis.

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