Lp-PLA2 inhibitor as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to an Lp-PLA2 inhibitor as well as a preparation method, a pharmaceutical composition and application thereof. A compound represented by formula (I) as an Lp-PLA2 inhibitor 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 an Lp-PLA2 inhibitor, a preparation method thereof, a pharmaceutical composition thereof, and its use in medicine. In particular, the present invention relates to tricyclic pyrimidone derivatives, a preparation method thereof, a pharmaceutical composition containing the derivatives, 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 diseases. 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).

[0010] Chinese patent application CN 113861220A discloses tricyclic pyrimidone compounds of the following formula, which can be used to treat neurodegenerative diseases and cardiovascular diseases.

[0011] Summary of the invention

[0012] 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.

[0013] The present invention provides a tricyclic pyrimidone compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0014]

[0015] in,

[0016] n1 and n2 are each independently 0, 1 or 2;

[0017] R1 and R2 are each independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen;

[0018] Cy is a 3-8 membered saturated heterocyclic ring or a non-aromatic unsaturated heterocyclic ring;

[0019] X1 and X2 are each independently: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: H, alkyl, deuterated alkyl, or cycloalkyl;

[0020] Ar is an arylene or heteroarylene group; the arylene or heteroarylene group is optionally substituted by 0, 1 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;

[0021] 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 aryl or heteroaryl; the aryl or heteroaryl is optionally substituted with 0, 1 or more substituents, each of which is independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R" is alkyl or cycloalkyl; R"' is alkylene;

[0022] Z is O or S;

[0023] The halogen atoms in the "halogen", "haloalkyl" and "haloalkoxy" are each independently selected from F, Cl, Br or I;

[0024] The alkyl groups in the aforementioned “alkyl”, “deuterated alkyl”, “deuterated alkoxy”, “hydroxyalkyl”, “haloalkyl”, “haloalkoxy”, “alkoxy”, and “amino substituted with monoalkyl or dialkyl” 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;

[0025] The "alkylene" is each independently C1-C 10A 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;

[0026] The "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

[0027] 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;

[0028] The "Cy" is a 3-8 membered saturated heterocyclic ring or a non-aromatic unsaturated heterocyclic ring containing 0-2 heteroatoms selected from N, O, and S in addition to the common N atom on the ring; alternatively, the Cy is a 3-8 membered saturated heterocyclic ring containing 0 or 1 O atom in addition to the common N atom on the ring; alternatively, the Cy is an oxaziridine ring, an oxaziridine ring, an oxaziridine ring, an aziridine ring, an azetidine ring, an azopentane ring, an azohexane ring, an azoheptane ring, an azooctane ring;

[0029] The "aryl" is a 6-10 membered aryl; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl;

[0030] The "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group;

[0031] 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, pyrazol-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-4-yl, pyridin-5-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, benzimidazolyl, benzothiazolyl, benzoxapinyl, 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[1,5-a]pyridinyl, pyrimidinyl, pyrido[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, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl;

[0032] The "heteroaryl group" 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.

[0033] According to the tricyclic pyrimidone compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, optionally,

[0034] n1 is 0 or 2, and optionally, n2 is 1 or 2;

[0035] Cy is a 3-8 membered saturated heterocyclic ring; optionally, it is an oxazahexane ring (containing 1 oxygen atom and 1 nitrogen atom), an oxazaheptan ring (containing 1 oxygen atom and 1 nitrogen atom), an oxazahexane ring (containing 1 oxygen atom and 1 nitrogen atom), an aziridine ring (containing 1 nitrogen atom), an azetidine ring (containing 1 nitrogen atom), an azopentane ring (containing 1 nitrogen atom), an azohexane ring (containing 1 nitrogen atom), an azoheptane ring (containing 1 nitrogen atom), an azooctane ring (containing 1 nitrogen atom);

[0036] R1 and R2 are each independently selected from: -H, or C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 Straight or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); optionally, R1 is -H, or -CH3; optionally, R2 is -H, or -CH3; optionally, R1 is -H; optionally, R2 is -H;

[0037] X1 and X2 are each independently: C1-C7 alkylene (optionally, -CH2-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; optionally, X1 is -CH2-, or -O-; optionally, X1 is -O-; optionally, X2 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);

[0038] Ar is phenylene or pyridyl, the phenylene or pyridyl is optionally 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;

[0039] 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 -F, or -OAr'; wherein Ar' is selected from 1, 2 or 3 substituted phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl, 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-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), -CD3, -OCD3, C1-C6 haloalkyl, -OCH3, -OC2H7, -OC3H7, C1-C6 haloalkyl Ar′ is selected from phenyl, pyridyl, pyrimidinyl or pyrazolyl, which are optionally substituted with 1 or 2 substituents; Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl or pyrazol-4-yl, which are optionally substituted with 1 or 2 substituents, wherein the substituents are selected from -F, -Cl, -CH3, -CF3, -CH2CF3, or -OCF3;

[0040] Z is O.

[0041] According to the tricyclic pyrimidone compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, optionally,

[0042] n1 is 0 or 2, n2 is 1;

[0043] R1 and R2 are each independently -H;

[0044] Cy is an oxaziridine ring, an oxaziridine ring, an oxazirocidine ring, an aziridine ring, an azetidine ring, an azopentane ring, an azohexane ring, an azepane ring, an azooctane ring;

[0045] X1 is -O- or -CH2-, and X2 is -O-;

[0046] Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN;

[0047] Y is -F, or -OAr'; wherein Ar' is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl or pyrazol-4-yl optionally substituted by 1 or 2 substituents selected from -Cl, -CH3, -CF3, -OCF3 or -CH2CF3;

[0048] Z is O.

[0049] According to the tricyclic pyrimidone compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, optionally, the compound of formula (I) is selected from the following compounds:

[0050]

[0051] According to the tricyclic pyrimidone compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, wherein the pharmaceutically acceptable salt comprises an anionic salt or a cationic salt of the compound of formula (I);

[0052] 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;

[0053] 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;

[0054] 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.

[0055] On the other hand, the present invention also provides a pharmaceutical composition comprising one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable carrier.

[0056] According to the pharmaceutical composition provided by the present invention, optionally, the dosage form of the pharmaceutical composition includes an oral preparation, a rectal preparation, or a parenteral preparation;

[0057] 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;

[0058] Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

[0059] 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.

[0060] 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;

[0061] Optionally, the neurodegeneration-related disease includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

[0062] 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 1 or route 2:

[0063] Route 1:

[0064]

[0065] In each structural formula, n1, n2, R1, R2, Cy, X1, X2, Z, Ar and Y are as defined above.

[0066] In route 1, the reaction process is as follows: Compound 1A and compound 1B (for example, under the condition of Et3N as a base) undergo aromatic nucleophilic substitution to generate compound 1C; compound 1C undergoes esterification reaction (for example, with methanesulfonic acid) to generate compound 1D, and compound 1D undergoes internal ring closure reaction (for example, under the action of K2CO3) to generate compound 1E (Z=O). In some cases, the reaction from 1C to 1D can directly generate 1E. Compound 1E can react with, for example, Lawesson's reagent to generate compound 1F (Z=S), and compound 1E / 1F undergoes aromatic nucleophilic substitution or CX coupling to obtain compound 1G.

[0067] Route 2:

[0068]

[0069] In each structural formula, n1, n2, R1, R2, Cy, X1, X2, Z, Ar and Y are as defined above.

[0070] In route 2, the reaction process is as follows: compound 2A and compound 2B are reacted by Mitsunobu reaction to generate compound 2C, compound 2C is deprotected (for example, using TFA), and then (for example, under the condition of Et3N as a base) intramolecular cyclization is performed to generate compound 2D, compound 2D is chlorinated (for example, by reaction with POCl3) or esterified (for example, by p-toluenesulfonic acid) to generate 2E (Z=O), compound 2E can react with Lawesson reagent to generate compound 2F (Z=S), and compound 2E / 2F is reacted by aromatic nucleophilic substitution or CX coupling to obtain compound 2G.

[0071] 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).

[0072] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention is a tricyclic 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), cardiovascular diseases such as atherosclerosis, diabetic macular edema (DME), or prostate diseases. DETAILED DESCRIPTION

[0073] 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.

[0074] Example

[0075] 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.

[0076] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0077] In the examples, unless otherwise specified, the reaction temperature is room temperature, for example, 20-30°C.

[0078] Embodiment 1:

[0079] Compounds 1 and 2: (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0080] Synthesis of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol Int-1

[0081]

[0082] Compound 3,4,5-trifluorobenzaldehyde Int-1-1 (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 column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain a white solid compound Int-1-2 (22.0 g, 51%).

[0083] LC-MS: [M+H] + :304.0.

[0084] The compound 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde Int-1-2 (20.0 g, 65.97 mmol) was dissolved in ethanol (200 mL), cooled to 0°C, sodium borohydride (2.5 g, 65.97 mmol) was added, and the temperature was slowly raised to room temperature and stirred for 1 h. The reaction solution was spin-dried, added to water (500 mL), extracted with ethyl acetate (300 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain a white solid compound Int-1 (20.0 g, 99%).

[0085] LC-MS: [M+H] + :306.1.

[0086] Synthesis of Benzyl 5-Oxo-1,4-Oxaazepane-4-carboxylate 1b

[0087]

[0088] Compound 1,4-oxazacycloheptane-5-one 1a (1.0 g, 8.69 mmol) was dissolved in tetrahydrofuran (20.0 mL). The system was cooled to -78 °C, and n-butyl lithium (3.8 mL, 9.56 mmol, 2.5 M dissolved in tetrahydrofuran solution) was slowly added dropwise. After the addition, the mixture was stirred at -78 °C for 30 minutes. Benzyl chloroformate (1.6 g, 9.12 mmol) was continued to be added dropwise to the system. After the addition, the mixture was stirred at -78 °C for 1 hour. The ice bath was removed and the mixture was warmed to room temperature. A saturated ammonium chloride solution (20.0 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The compound 1b (1.0 g, 46%) was obtained as a colorless oily liquid by column chromatography (petroleum ether: ethyl acetate = 20:1).

[0089] Synthesis of 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylic acid benzyl ester 1c:

[0090]

[0091] Dissolve the compound 5-oxo-1,4-oxazacycloheptane-4-carboxylic acid benzyl ester 1b (500.0 mg, 2.01 mmol) in tetrahydrofuran (20.0 mL). Cool the system to -70 ° C, slowly add potassium bis(trimethylsilyl)amide (2.4 mL, 2.41 mmol, 1.0 M dissolved in tetrahydrofuran). After the addition, keep the system at -70 ° C and stir for 1.5 hours. Dissolve diphenyl chlorophosphate (646.5 mg, 2.41 mmol) in tetrahydrofuran (5.0 mL) and slowly add it to the system. After the addition, keep the system at -70 ° C and stir for 1 hour. After the reaction is complete, remove the ice bath, add 5% sodium hydroxide solution (10.0 mL) to quench the reaction, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine, and finally dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. After separation by column chromatography (petroleum ether:ethyl acetate=20:1), a colorless oily liquid compound 1c (700.0 mg, 72%) was obtained.

[0092] LC-MS: [M+H] + :482.2.

[0093] Synthesis of 4-benzyl-5-methyl-2,3-dihydro-1,4-oxaazepine-4,5(7H)-dicarboxylate 1d:

[0094]

[0095] Compound 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-1,4-oxazacycloheptene-4(7H)-carboxylic acid benzyl ester 1c (570.0 mg, 1.18 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and palladium acetate (26.7 mg, 0.12 mmol) and triphenylphosphine (62.0 mg, 0.24 mmol) were added. The system was replaced with a carbon monoxide atmosphere, and the reaction was stirred at room temperature for 0.5 hours. Triethylamine (239.6 mg, 2.37 mmol) and methanol (1517.4 mg, 47.36 mmol) were added to the system, and the reaction was stirred at 45°C for 1 hour. After the reaction was complete, the excess solvent was concentrated to obtain a crude product. After column chromatography separation (petroleum ether: ethyl acetate = 20:1), a colorless oily liquid compound 1d (220.0 mg, 64%) was obtained.

[0096] LC-MS: [M+H] + :292.1

[0097] Synthesis of 1,4-oxaazepane-5-carboxylic acid methyl ester 1e:

[0098]

[0099] Compound 4-benzyl-5-methyl-2,3-dihydro-1,4-oxazacycloheptene-4,5(7H)-dicarboxylate 1d (220.0 mg, 0.76 mmol) and palladium carbon (50.0 mg, 0.05 mmol) were mixed in a methanol solution (3.0 mL), and the system was replaced with a hydrogen atmosphere, and the reaction was repeated three times. The system was stirred at room temperature for 12 hours. After the reaction was complete, the solid was filtered out, and the excess solvent was concentrated to obtain a colorless oily liquid compound 1e (120.0 mg, 100%).

[0100] LC-MS: [M+H] + :160.2

[0101] Synthesis of (1,4-oxaazepan-5-yl)methanol 1f:

[0102]

[0103] Compound 1,4-oxazacycloheptane-5-carboxylic acid methyl ester 1e (121.0 mg, 0.76 mmol) was dissolved in tetrahydrofuran solution (3.0 mL), the system was cooled to 0°C, and lithium aluminum hydride (57.8 mg, 1.52 mmol) was slowly added. After the addition, the ice bath was removed and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium sulfate decahydrate was added, stirred for 0.5 hours, filtered, and after sufficient drying, the excess solvent was concentrated to obtain a colorless oily liquid compound 1f (60.0 mg, 60%).

[0104] LC-MS: [M+H] + :132.3.

[0105] Synthesis of 1 g of (4-(2,6-dichloropyrimidin-4-yl)-1,4-oxazepane-5-yl)methanol:

[0106]

[0107] Dissolve the compound 2,4,6-trichloropyrimidine (69.9 mg, 0.38 mmol) in acetonitrile solution (2.0 mL), cool the system to 0°C, slowly add triethylamine (38.5 mg, 0.38 mmol), and stir at room temperature for 5 minutes after the addition. Then add (1,4-oxazacycloheptane-5-yl)methanol 1f (50.0 mg, 0.38 mmol) to the system, and stir at room temperature for 1 hour. After the reaction is complete, concentrate to remove excess solvent to obtain a crude product. After column chromatography separation (petroleum ether: ethyl acetate = 2:1), a colorless oily liquid compound 1g (50.0 mg, 47%) is obtained.

[0108] LC-MS: [M+H] + : 278.1, 280.1.

[0109] Synthesis of 3-chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxaazepan-1-one 1h:

[0110]

[0111] Dissolve 1g (57.0mg, 0.21mmol) of the compound (4-(2,6-dichloropyrimidin-4-yl)-1,4-oxazepan-5-yl)methanol and triethylamine (62.2mg, 0.62mmol) in a dichloromethane solution (2.0mL), cool the system to 0°C, and slowly add methylsulfonyl chloride (47.0mg, 0.41mmol). After the addition, remove the ice bath and stir at room temperature for 2 hours. When the reaction is complete, add water (10.0mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Separate by column chromatography (dichloromethane: methanol = 20:1) to obtain a colorless oily liquid compound 1h (40.0mg, 79%).

[0112] LC-MS: [M+H] + : 242.1, 244.1.

[0113] Synthesis of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,11,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 1i:

[0114]

[0115] The compound (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol Int-1 (66.5 mg, 0.22 mmol) was dissolved in tetrahydrofuran (2.0 mL), the system was cooled to 0°C, sodium hydride (24.4 mg, 0.61 mmol) was slowly added, and the mixture was stirred at 0°C for 10 minutes after the addition. 3-Chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazacycloheptane-1-one 1h (35.0 mg, 0.14 mmol) was then added to the system, and the mixture was stirred at 0°C for 3 hours after the addition. After the reaction was complete, water (10.0 mL) was added to quench the reaction, extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. White solid compound 1i (40.0 mg, 56%) was obtained by preparative separation.

[0116] LC-MS: [M+H] + :511.2.

[0117] 1 H NMR (400MHz, CD3OD) δ8.61(d,J=5.6Hz,1H),7.42(d,J=2.4Hz,1H),7.31(d,J=8.4Hz,2H),7.17-7.15(m,1H),5.39(s,2H),5.26(s,1H),4.53 -4.16(m,1H),4.28(dd,J=11.2,10.0Hz,1H),4.03-3.90(m,2H),3.84-3.77(m,1H),3.74-3.56(m,3H),3.39-3.34(m,1H),2.13-1.94(m,2H).

[0118] Compounds 1 and 2: Synthesis of (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0119]

[0120] 40.0 mg of racemate 1i was separated and purified by SFC (chromatographic column: CHIRALPAK IA 100*4.6 mm5 μm; mobile phase: A: CO2, B: MeOH (0.05% DEA v / v); gradient: AB.Conc: 40.0%, 8.0 min) to obtain white solid compound 1 (12.7 mg) and white solid compound 2 (13.4 mg).

[0121] Compound 1: (Chiral analysis conditions: chromatographic column: CHIRALPAK IA 5μm 4.6*100mm, mobile phase: A: CO2, B: MeOH (0.05% DEA v / v); gradient: AB.Conc: 40.0%, retention time 2.619 minutes, chiral purity = 100%)

[0122] 1 H NMR (400MHz, CD3OD) δ8.61(d,J=5.7Hz,1H),7.42(d,J=2.4Hz,1H),7.31(d,J=8.6Hz,2H),7.22-7.09(m,1H),5.39(s,2H),5.26(s,1H) ,4.53-4.44(m,1H),4.37-4.22(m,1H),4.07-3.88(m,2H),3.86-3.75(m,1H),3.73-3.55(m,3H),3.42-3.32(m,1H),2.09-1.89(m,2H).

[0123] LC-MS: [M+H] + :511.2.

[0124] Compound 2: (Chiral analysis conditions: chromatographic column: CHIRALPAK IA 5μm 4.6*100mm, mobile phase: A: CO2, B: MeOH (0.05% DEA v / v); gradient: A B.Conc: 40.0%, retention time 4.059 minutes, chiral purity = 100%)

[0125] 1H NMR (400MHz, CD3OD) δ8.61(d,J=5.7Hz,1H),7.42(d,J=2.5Hz,1H),7.31(d,J=8.7Hz,2H),7.16(dd,J=5.7,2.4Hz,1H),5.39(s,2H),5.26(s,1H),4.50- 4.35(m,1H),4.28(d,J=11.5,9.9Hz,1H),4.02-3.93(m,2H),3.86-3.77(m, 1H),3.71-3.54(m,3H),3.39-3.34(m,1H),2.14-1.90(m,2H).LC-MS:[M+H] + :511.2.

[0126] Embodiment 2:

[0127] Compounds 7 and 8: (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azacyclooctan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azacyclooctan-1-one

[0128]

[0129] Synthesis of 2-oxoazacyclooctane-1-carboxylic acid benzyl ester 7b:

[0130]

[0131] Dissolve compound 2-azacyclooctanone 7a (20.0 g, 157.25 mmol) in tetrahydrofuran (400 mL), cool to -78 °C, slowly add n-butyl lithium (69.2 mL, 172.97 mmol), stir at -78 °C for 30 min, continue to drop benzyl chloroformate (23.24 mL, 165.11 mmol) into the system, stir at -78 °C for 1 h. Remove the ice bath and warm to room temperature, add saturated ammonium chloride (500 mL) to quench the reaction, extract with ethyl acetate (300 mL*2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate, pass through a column (ethyl acetate: petroleum ether = 1:2), and spin dry to obtain a colorless oily liquid compound 7b (12.0 g, 29%). LC-MS: [M+H] + :262.2.

[0132] Synthesis of (E)-8-((diphenoxyphosphoryl)oxy)-3,4,5,6-tetrahydroazocine-1(2H)-carboxylic acid benzyl ester 7c:

[0133]

[0134] Compound 2-oxoazacyclooctane-1-carboxylic acid benzyl ester 7b (12.0 g, 45.92 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to -70°C, potassium bis(trimethylsilyl)amide (55.1 mL, 55.11 mmol) was slowly added, stirred at -70°C for 1.5 h, diphenyl chlorophosphate (14.8 g, 55.11 mmol) was added dropwise to the system, stirred at -70°C for 1 h. The ice bath was removed and the temperature was raised, saturated ammonium chloride (500 mL) was added to quench the reaction, ethyl acetate (300 mL*2) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column (ethyl acetate: petroleum ether = 1:5), and the colorless oily liquid compound 7c (12.0 g, 53%) was obtained after spin drying.

[0135] LC-MS: [M+H] + :494.0.

[0136] Synthesis of 2-methyl (Z)-5,6,7,8-tetrahydroazocine-1,2(4H)-dicarboxylic acid 1-benzyl ester 7d:

[0137]

[0138] Compound (E)-8-((diphenoxyphosphoryl)oxy)-3,4,5,6-tetrahydroazocene-1(2H)-carboxylic acid benzyl ester 7c (12.0 g, 24.32 mmol) was dissolved in N,N-dimethylformamide (120 mL), replaced with CO 3 times and stirred at room temperature for 0.5 h. Triethylamine (4.9 g, 48.63 mmol), palladium acetate (0.55 g, 2.43 mmol), triphenylphosphine (1.28 g, 2.86 mmol) and methanol (39.4 mL, 972.64 mmol) were added dropwise to the system. After the addition, the temperature was raised to 60°C and stirred for 2 h. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:4). After concentration, a colorless oily liquid compound 7d (5.5 g, 75%) was obtained. LC-MS: [M+H] + :304.2.

[0139] Synthesis of 1-azacyclooctane-2-carboxylic acid methyl ester 7e:

[0140]

[0141] Compound 2-methyl (Z)-5,6,7,8-tetrahydroazocine-1,2(4H)-dicarboxylic acid 1-benzyl ester 7d (5.0 g, 16.48 mmol) was dissolved in methanol (50 mL), palladium carbon (1.0 g, 1.65 mmol) was added, and the mixture was replaced with H2 three times and stirred at room temperature for 16 h. The reaction solution was filtered with diatomaceous earth, and the mother liquor was concentrated to obtain a crude colorless oily liquid compound 7e (2.2 g, crude).

[0142] LC-MS: [M+H] + :172.4.

[0143] Synthesis of (1-azacyclooctan-2-yl)methanol 7f:

[0144]

[0145] Compound 1-azacyclooctane-2-carboxylic acid methyl ester 7e (2.0 g, 11.68 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0°C, and lithium aluminum hydride (890.0 mg, 23.36 mmol) was slowly added. After the addition, the temperature was slowly raised to room temperature and stirred for 1 hour. The reaction solution was quenched, filtered, and the mother liquor was concentrated to obtain a crude colorless oily liquid compound 7f (1.1 g, crude).

[0146] LC-MS: [M+H] + :144.2.

[0147] Synthesis of 7 g of (1-(2,6-dichloropyrimidin-4-yl)azocane-2-yl)methanol:

[0148]

[0149] Compound (1-azacyclooctan-2-yl)methanol 7f (1.0 g, 6.98 mmol) and 2,4,6-trichloropyrimidine (1.3 g, 6.98 mmol) were dissolved in acetonitrile (20 mL), triethylamine (710.0 mg, 6.98 mmol) was added, and stirred at room temperature for 1 h. The reaction solution was concentrated and column chromatography (ethyl acetate: petroleum ether = 1:2) was performed to obtain a colorless oily liquid compound 7g (320.0 mg, 16%).

[0150] LC-MS: [M+H] + :290.0.

[0151] Synthesis of (1-(2,6-dichloropyrimidin-4-yl)azoctan-2-yl)methyl methanesulfonate 7h:

[0152]

[0153] Dissolve 7 g (300.0 mg, 1.03 mmol) of the compound (1-(2,6-dichloropyrimidin-4-yl)azocane-2-yl)methanol and triethylamine (313.2 mg, 3.10 mmol) in dichloromethane (10 mL), cool to 0°C, add methylsulfonyl chloride (236.8 mg, 2.07 mmol), and stir for 1 h. The reaction solution was concentrated to obtain a crude product 7h (380.0 mg, crude).

[0154] Synthesis of 3-chloro-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azocantane-1-one 7i:

[0155]

[0156] Compound (1-(2,6-dichloropyrimidin-4-yl)azoctan-2-yl)methyl methanesulfonate 7h (380 mg, crude) and potassium carbonate (427.8 mg, 3.10 mmol) were dissolved in dioxane (5 mL) and water (5 mL), and the temperature was raised to 90°C and stirred for 2 h. The reaction solution was cooled and filtered, and the reaction solution was spin-dried. Methanol (10 mL) and dichloromethane (100 mL) were added to dissolve the residual salt, and the mother liquor was concentrated and column chromatography (methanol: dichloromethane = 1:10) was performed to obtain white solid compound 7i (110.0 mg, 42%, two-step yield).

[0157] LC-MS: [M+H] + :254.2.

[0158] Synthesis of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azocantane-1-one 7j

[0159]

[0160] Compound 3-chloro-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azacyclooctan-1-one 7i (100.0 mg, 0.39 mmol), (3,5-difluoro-4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)methanol Int-1 (120.3 mg, 0.39 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (37.4 mg, 0.04 mmol), and cesium carbonate (256.8 mg, 0.79 mmol) were dissolved in dioxane (5 mL), the temperature was raised to 100° C. and stirred for 2 h. The reaction mixture was cooled and filtered. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated (formic acid system). After freeze-drying, white solid compound 7j (40.0 mg, 19%) was obtained.

[0161] LC-MS: [M+H] + :523.0.

[0162] Compounds 7 and 8: (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azacyclooctan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azacyclooctan-1-one:

[0163]

[0164] Compound 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,10,11,11a,12-octahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-a]azocantane-1-one 7j (40.0 mg, 0.08 mmol) was prepared and separated by SFC to give white solid compound 7 (6.7 mg, 17%) and white solid compound 8 (14.0 mg, 35%).

[0165] SFC Conditions:

[0166] Equipment: Waters UPCC system equipped with a PDA detector

[0167] Column: Daicel_ChiralPAK-IBN_100x3.0mm_3μm

[0168] Column temperature: 35 °C

[0169] Flow rate: 2.0 ml / min

[0170] Wavelength: 210 nm Mobile phase: CO2:MeOH(0.1% DEA) = 80:20

[0171] Compound 7:

[0172] RT: 1.747 min LC-MS: [M+H] + : 523.2.

[0173] 1 H NMR(400 MHz, CDCl3) δ 8.60(d, J=5.6 Hz, 1H), 7.26(s, 1H), 7.15 - 7.12(m, 2H), 6.99 - 6.97(m, 1H), 5.46 - 5.38(m, 2H), 4.99(s, 1H), 4.26 - 4.20(m, 1H), 4.08 - 4.03(m, 1H), 3.83 - 3.78(m, 1H), 3.57 - 3.53(m, 1H), 3.24 - 3.18(m, 1H), 2.05 - 2.01(m, 1H), 1.86 - 1.85(m, 1H), 1.77 - 1.74(m, 2H), 1.70 - 1.61(m, 4H), 1.36 - 1.24(m, 2H).

[0174] Compound 8:

[0175] RT: 2.351 min LC-MS: [M+H] + : 523.2.

[0176] 1H NMR (400MHz, CDCl3) δ8.60 (d, J = 5.6Hz, 1H), 7.26 (s, 1H), 7.16-7.10 (m, 2H), 6. 99-6.97(m,1H),5.46-5.35(m,2H),4.99(s,1H),4.26-4.20(m,1H),4.08-4.06( m,1H),3.83-3.78(m,1H),3.57-3.53(m,1H),3.24-3.17(m,1H),2.05-2.02(m,1 H),1.95-1.85(m,1H),1.77-1.74(m,2H),1.69-1.62(m,4H),1.33-1.25(m,2H).

[0177] Embodiment 3:

[0178] Compounds 19 and 20: (R)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0179] Synthesis of 3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 19b:

[0180]

[0181] 3,4-difluorobenzaldehyde 19a (10.0 g, 70.37 mmol), 2-(trifluoromethyl)pyridin-4-ol (11.5 g, 70.37 mmol) and cesium carbonate (45.9 g, 140.75 mmol) were dissolved in N,N-dimethylformamide (100 mL), heated to 80°C and stirred for 3 h. The reaction solution was cooled to room temperature and filtered. The filtrate was added with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined and washed with water (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The yellow oil 19b (5.3 g, 26%) was purified by column chromatography (petroleum ether: ethyl acetate = 1:1).

[0182] LC-MS: [M+H] + :286.0.

[0183] Synthesis of (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 19c:

[0184]

[0185] 3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 19b (1.0 g, 3.51 mmol) was dissolved in methanol (10 mL), and the temperature was lowered to 0°C under nitrogen protection. Sodium borohydride (199.0 mg, 5.26 mmol) was added in batches, and the reaction was stirred at room temperature for 3 h. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the methanol was spin-dried. The solution was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The white solid compound 19c (600.0 mg, 60%) was purified by column chromatography (petroleum ether: ethyl acetate = 1:1).

[0186] LC-MS: [M+H] + :288.4.

[0187] Synthesis of 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 19d:

[0188]

[0189] 3-Chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 1h (90.0 mg, 0.37 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 19c (107.0 mg, 0.37 mmol), cesium carbonate (242.7 mg, 0 .75mmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3.9mg, 0.04mmol) were dissolved in dioxane (3mL), replaced with nitrogen three times, heated to 100°C and stirred for 2h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative purification (formic acid system) to obtain white solid compound 19d (85.0mg, 46%).

[0190] LC-MS: [M+H] + :493.4.

[0191] Compounds 19 and 20: Synthesis of (R)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0192]

[0193] 3-((3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 19d (85.0 mg, 0.17 mmol) was separated by SFC to give white solid compound 19 (12.7 mg, 30%) and white solid compound 20 (13.8 mg, 32%).

[0194] SFC Conditions:

[0195] Instrument:Waters Prep SFC 150Mgm-02

[0196] Column:ChiralPak AD,250×40mm ID,10μm

[0197] Mobile phase:A for CO2 and B for MeOH

[0198] Gradient: B 50%

[0199] Flow rate: 130mL / min

[0200] Back pressure:100bar

[0201] Column temperature:40℃

[0202] Wavelength:210nm / 254nm

[0203] Compound 19:

[0204] RT:1.338minLC-MS:[M+H] +:493.2.

[0205] 1 H NMR (400MHz, CDCl3) δ8.56 (d, J=5.6Hz, 1H), 7.32 (dd, J=10.8, 1.6Hz, 1H), 7.28-7.24 (m, 1H ),7.22(d,J=2.4Hz,1H),7.18(t,J=8.0Hz,1H),6.95(dd,J=5.6,2.4Hz,1H),5.43(s,2H),4 .97(s,1H),4.42-4.31(m,2H),4.05-3.98(m,2H),3.80-3.73(m,2H),3.67-3.60(m,1H),3. 58-3.52(m,1H),3.32(ddd,J=13.2,5.2,2.4Hz,1H),2.14-2.04(m,1H),2.03-1.95(m,1H).

[0206] Compound 20:

[0207] RT:2.456minLC-MS:[M+H] + :493.2.

[0208] 1 H NMR (400MHz, CDCl3) δ8.56 (d, J=5.6Hz, 1H), 7.32 (dd, J=10.8, 1.6Hz, 1H), 7.28-7.24 (m, 1H ),7.22(d,J=2.4Hz,1H),7.18(t,J=8.0Hz,1H),6.95(dd,J=5.6,2.4Hz,1H),5.43(s,2H),4 .97(s,1H),4.42-4.31(m,2H),4.05-3.98(m,2H),3.80-3.73(m,2H),3.67-3.60(m,1H),3. 58-3.52(m,1H),3.32(ddd,J=13.2,5.2,2.4Hz,1H),2.14-2.04(m,1H),2.03-1.95(m,1H).

[0209] Embodiment 4:

[0210] Compounds 21 and 22: (R)-5-(((1-oxo-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-3-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile and (S)-5-(((1-oxo-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-3-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile

[0211]

[0212] Synthesis of 5-formyl-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 21b:

[0213]

[0214] 2-Fluoro-5-formylbenzonitrile 21a (10.0 g, 67.06 mmol), 2-(trifluoromethyl)pyridin-4-ol (10.9 g, 67.06 mmol), cesium carbonate (32.8 g, 100.60 mmol) were dissolved in N,N-dimethylformamide (100 mL), stirred at 90°C for 2 h. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 21b (10.0 g, 51%).

[0215] LC-MS: [M+H] + :293.0.

[0216] Synthesis of 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 21c:

[0217]

[0218] 5-Formyl-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 21b (1.0 g, 3.42 mmol) was dissolved in methanol (20 mL), cooled to 0°C, and sodium borohydride (194.1 mg, 5.13 mmol) was slowly added. The reaction was stirred at room temperature for 2 h, and water (10 mL) was added to quench the reaction. The solvent was concentrated under reduced pressure and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 21c (1.0 g, 99%) as a white solid.

[0219] LC-MS: [M+H] + :295.0.

[0220] Synthesis of (R)-3-chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 1h-1 and 1h-2

[0221]

[0222] 3-Chloro-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one 1h (1.5 g, 6.21 mmol) was separated by SFC to give white solid compounds 1h-1 (RT = 4.985 min, 650.0 mg, 43%) and 1h-2 (RT = 7.529 min, 640.0 mg, 43%).

[0223] SFC conditions:

[0224] Instrument:YMC K-PrepLAB100G

[0225] Column:ChiralPak AD,250×50mm ID,10μm

[0226] Mobile phase:A for n-Hexane and B for EtOH

[0227] Gradient: B 65%

[0228] Flow rate: 80mL / min

[0229] Column temperature:25℃

[0230] Wavelength:214nm

[0231] Compounds 21 and 22: Synthesis of (R)-5-(((1-oxo-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-3-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile and (S)-5-(((1-oxo-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-3-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile:

[0232]

[0233] Compound 1h-1 (50.0 mg, 0.21 mmol), 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 21c (67.0 mg, 0.23 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (19.6 mg, 0.02 mmol) was added, and nitrogen was replaced three times. The mixture was heated to 100°C for 2 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain white solid compound 21 (6.7 mg, 6%).

[0234] LC-MS: [M+H] + :500.2.

[0235] 1H NMR (400MHz, CDCl3) δ8.65(d,J=5.6Hz,1H),7.80(d,J=2.0Hz,1H),7.71(dd,J=8.8,2.4Hz, 1H),7.29(d,J=2.4Hz,1H),7.17(d,J=8.4Hz,1H),7.04(dd,J=5.6,2.4Hz,1H),5.47(s,2H), 4.98(s,1H),4.43-4.32(m,2H),4.07-3.99(m,2H),3.81-3.74(m,2H),3.67-3.61(m,1H),3 .60-3.54(m,1H),3.33(ddd,J=13.2,5.2,2.4Hz,1H),2.15-2.05(m,1H),2.04-1.97(m,1H).

[0236] Compound 1h-2 (50.0 mg, 0.21 mmol), 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 21c (67.0 mg, 0.23 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (19.6 mg, 0.02 mmol) was added, and nitrogen was replaced three times. The mixture was heated to 100°C for 2 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a white solid compound 22 (9.5 mg, 9%).

[0237] LC-MS: [M+H] + :500.2.

[0238] 1 H NMR (400MHz, CDCl3) δ8.65(d,J=5.6Hz,1H),7.80(d,J=2.0Hz,1H),7.71(dd,J=8.8,2.4Hz, 1H),7.29(d,J=2.4Hz,1H),7.17(d,J=8.4Hz,1H),7.04(dd,J=5.6,2.4Hz,1H),5.47(s,2H), 4.98(s,1H),4.43-4.32(m,2H),4.07-3.99(m,2H),3.81-3.74(m,2H),3.67-3.61(m,1H),3 .60-3.54(m,1H),3.33(ddd,J=13.2,5.2,2.4Hz,1H),2.15-2.05(m,1H),2.04-1.97(m,1H).

[0239] Embodiment 5:

[0240] Compounds 23 and 24: (R)-3-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0241]

[0242] Synthesis of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzaldehyde 23b:

[0243]

[0244] Compound 4-chloro-3-(trifluoromethyl)phenol 23a (25.0 g, 127.19 mmol), 3,4,5-trifluorobenzaldehyde (20.4 g, 127.19 mmol) and potassium carbonate (26.4 g, 190.79 mmol) were dissolved in N,N-dimethylformamide (200 mL), replaced with nitrogen three times, and slowly heated to 90°C for 4 hours. The reaction solution was filtered and concentrated under reduced pressure to remove N,N-dimethylformamide, and the residue was purified by column (petroleum ether: ethyl acetate = 8:1) to obtain yellow solid compound 23b (28.5 g, 67%).

[0245] Synthesis of (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol 23c:

[0246]

[0247] Compound 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzaldehyde 23b (1.0 g, 2.97 mmol) was dissolved in methanol (15 mL), cooled to 0°C, sodium borohydride (0.17 g, 4.46 mmol) was slowly added, and the temperature was slowly restored to room temperature for 3 h. Saturated ammonium chloride solution was added dropwise at 0°C, and the methanol was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column (petroleum ether: ethyl acetate = 8:1) to obtain white solid compound 23c (710.0 mg, 71%).

[0248] Compounds 23 and 24: Synthesis of (R)-3-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0249]

[0250] Compound (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol 23c (63.1 mg, 0.19 mmol), compound 1h-1 (45.0 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.7 mg, 0.02 mmol) and cesium carbonate (121.3 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 23 (22.7 mg, 22%).

[0251] LC-MS: [M+H] + :544.0.

[0252] 1 H NMR (400MHz, CDCl3) δ7.41(d,J=8.8Hz,1H),7.30(d,J=3.2Hz,1H),7.11-7.05(m,2H),7.01(dd,J=8.8,2.8Hz,1H),5.40(s,2H),4.98(s,1H),4.42 -4.32(m,2H),4.06-3.98(m,2H),3.81-3.74(m,2H),3.67-3.53(m,2H),3 .33(ddd,J=13.2,5.2,2.4Hz,1H),2.15-2.05(m,1H),2.04-1.96(m,1H).

[0253] Compound (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol 23c (63.1 mg, 0.19 mmol), compound 1h-2 (45.0 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.7 mg, 0.02 mmol) and cesium carbonate (121.3 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 24 (21.6 mg, 21%).

[0254] LC-MS: [M+H] + :544.0.

[0255] 1 H NMR (400MHz, CDCl3) δ7.41(d,J=8.8Hz,1H),7.30(d,J=3.2Hz,1H),7.11-7.05(m,2H),7.01(dd,J=8.8,2.8Hz,1H),5.40(s,2H),4.98(s,1H),4.42 -4.32(m,2H),4.06-3.98(m,2H),3.81-3.74(m,2H),3.67-3.53(m,2H),3 .33(ddd,J=13.2,5.2,2.4Hz,1H),2.15-2.05(m,1H),2.04-1.96(m,1H).

[0256] Embodiment 6:

[0257] Compounds 25 and 26: (R)-3-((3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0258] Synthesis of 3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzaldehyde 25b:

[0259]

[0260] (()) 3-(Trifluoromethoxy)phenol 25a (25.0 g, 140.36 mmol), 3,4,5-trifluorobenzene-1-carboxaldehyde (22.5 g, 140.36 mmol), potassium carbonate (29.1 g, 210.54 mmol) were dissolved in N,N-dimethylformamide (400 mL) and stirred at 90°C for 2 h. Water (200 mL) was added, and the reaction solution was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil 25b (25.0 g, 56%).

[0261] Synthesis of (3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)phenyl)methanol 25c:

[0262]

[0263] 3,5-Difluoro-4-(3-(trifluoromethoxy)phenoxy)benzaldehyde 25b (25.0 g, 78.57 mmol) was dissolved in methanol (400 mL), sodium borohydride (4.5 g, 117.85 mmol) was added to the mixture at 0°C and stirred at room temperature for 2 h. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give a colorless oil 25c (20.0 g, 79%).

[0264] Compounds 25 and 26: Synthesis of (R)-3-((3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0265]

[0266] Compound 1h-1 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)phenyl)methanol 25c (66.3 mg, 0.21 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19.6 mg, 0.02 mmol) was added, and nitrogen was replaced three times. The mixture was heated to 100°C and reacted for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a white solid compound 25 (23.7 mg, 22%).

[0267] LC-MS: [M+H] + :526.4.

[0268] 1 H NMR (400MHz, CDCl3) δ7.30 (t, J = 8.4Hz, 1H), 7.10-7.03 (m, 2H), 6.96-6.91 (m,1H),6.87-6.80(m,2H),5.39(s,2H),4.98(s,1H),4.42-4.32(m,2H),4 .06-3.98(m,2H),3.80-3.73(m,2H),3.67-3.60(m,1H),3.59-3.53(m,1H) ,3.32(ddd,J=13.2,5.2,2.4Hz,1H),2.14-2.05(m,1H),2.03-1.96(m,1H).

[0269] Compound 1h-2 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)phenyl)methanol 25c (66.3 mg, 0.21 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19.6 mg, 0.02 mmol) was added, and nitrogen was replaced three times. The mixture was heated to 100°C and reacted for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain white solid compound 26 (26.1 mg, 24%).

[0270] LC-MS: [M+H] + :526.4.

[0271] 1H NMR (400MHz, CDCl3) δ7.30 (t, J = 8.4Hz, 1H), 7.10-7.03 (m, 2H), 6.96-6.91 (m,1H),6.87-6.80(m,2H),5.39(s,2H),4.98(s,1H),4.42-4.32(m,2H),4 .06-3.98(m,2H),3.80-3.73(m,2H),3.67-3.60(m,1H),3.59-3.53(m,1H) ,3.32(ddd,J=13.2,5.2,2.4Hz,1H),2.14-2.05(m,1H),2.03-1.96(m,1H).

[0272] Embodiment 7:

[0273] Compounds 27 and 28: (R)-3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0274] Synthesis of 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde 27b:

[0275]

[0276] 2-Methylpyridin-4-ol 27a (25.0 g, 229.06 mmol), 3,4,5-trifluorobenzaldehyde (40.3 g, 251.99 mmol) and potassium carbonate (47.5 g, 343.63 mmol) were dissolved in N,N-dimethylformamide (300 mL), replaced with nitrogen three times, and slowly heated to 90°C and stirred for 3 h. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow oily product 27b (19.0 g, 33%).

[0277] LC-MS: [M+H] + :250.4.

[0278] Synthesis of (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol 27c:

[0279]

[0280] 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde 27b (18.0 g, 72.23 mmol) was dissolved in methanol (200 mL), cooled to 0°C, sodium borohydride (4.1 g, 108.34 mmol) was slowly added, and the temperature was slowly restored to room temperature for 2 h. Saturated ammonium chloride solution (200 mL) was added dropwise at 0°C to quench the reaction, the solvent was concentrated under reduced pressure, extracted with ethyl acetate (200 mL x 2), the organic phases were combined, and dried over anhydrous sodium sulfate, and the residue was purified by column (petroleum ether: ethyl acetate = 7:1) to obtain white solid compound 27c (14.0 g, 77%).

[0281] Compounds 27 and 28: Synthesis of (R)-3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0282]

[0283] Compound 1h-1 (45.0 mg, 0.19 mmol), (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol 27c (46.8 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.6 mg, 0.02 mmol) and cesium carbonate (121.1 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 h. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 27 (16.5 mg, 19%).

[0284] LC-MS: [M+H] + :457.2.

[0285] 1H NMR (400MHz, CDCl3) δ8.36 (d, J=5.6Hz, 1H), 7.11-7.05 (m, 2H), 6.69 (d, J=2 .0Hz,1H),6.67(dd,J=5.6,2.4Hz,1H),5.41(s,2H),4.98(s,1H),4.42-4.32 (m,2H),4.06-3.98(m,2H),3.81-3.74(m,2H),3.67-3.53(m,2H),3.33(ddd, J=13.2,5.2,2.4Hz,1H),2.51(s,3H),2.14-2.05(m,1H),2.04-1.95(m,1H).

[0286] Compound 1h-2 (45.0 mg, 0.19 mmol), (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol 27c (46.8 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.7 mg, 0.02 mmol) and cesium carbonate (121.3 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 28 (11.2 mg, 13%).

[0287] LC-MS: [M+H] + :457.2.

[0288] 1 H NMR (400MHz, CDCl3) δ8.36 (d, J=5.6Hz, 1H), 7.11-7.05 (m, 2H), 6.69 (d, J=2 .0Hz,1H),6.67(dd,J=5.6,2.4Hz,1H),5.41(s,2H),4.98(s,1H),4.42-4.32 (m,2H),4.06-3.98(m,2H),3.81-3.74(m,2H),3.67-3.53(m,2H),3.33(ddd, J=13.2,5.2,2.4Hz,1H),2.51(s,3H),2.14-2.05(m,1H),2.04-1.95(m,1H).

[0289] Embodiment 8:

[0290] Compounds 29 and 30: (R)-3-((3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0291]

[0292] Synthesis of 4-(benzyloxy)-2-(trifluoromethoxy)pyridine 29b:

[0293]

[0294] Compound 4-(benzyloxy)pyridin-2-ol 29a (1.0 g, 4.97 mmol) and 1-(trifluoromethyl)-1,2-benzimidoyl-3(1H)-one (1.6 g, 4.97 mmol) were dissolved in nitromethane (25 mL), replaced with nitrogen three times, and heated to 100°C for 18 h. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil 29b (540 mg, 40%).

[0295] LC-MS: [M+H] + :270.4.

[0296] Synthesis of 2-(trifluoromethoxy)pyridin-4-ol 29c:

[0297]

[0298] 4-(Benzyloxy)-2-(trifluoromethoxy)pyridine 29b (340.0 mg, 1.26 mmol) and palladium carbon (10%, 81.0 mg) were dissolved in methanol (10 mL) and stirred at 60°C under 3 MPa hydrogen pressure for 18 h. The reaction solution was filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain white solid compound 29c (170.0 mg, 75%).

[0299] LC-MS: [M+H] + :180.4.

[0300] Synthesis of 3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzaldehyde 29d:

[0301]

[0302] Compound 2-(trifluoromethoxy)pyridin-4-ol 29c (260.0 mg, 1.45 mmol), 3,4,5-trifluorobenzaldehyde (232.4 mg, 1.45 mmol) and potassium carbonate (300.9 mg, 2.18 mmol) were dissolved in N,N-dimethylformamide (8 mL), replaced with nitrogen three times, and slowly heated to 90°C for 4 h. The reaction solution was filtered and concentrated under reduced pressure to remove N,N-dimethylformamide, and the residue was purified by column (petroleum ether: ethyl acetate = 5:1) to obtain colorless oil 29d (300.0 mg, 65%).

[0303] LC-MS: [M+H] + :320.0.

[0304] Synthesis of (3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 29e:

[0305]

[0306] Compound 3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzaldehyde 29d (300.0 mg, 0.94 mmol) was dissolved in methanol (10 mL), cooled to 0°C, sodium borohydride (53.3 mg, 1.41 mmol) was slowly added, and the temperature was slowly restored to room temperature for 2 h. Saturated aqueous ammonium chloride solution (30 mL) was added dropwise at 0°C, the reaction solution was concentrated under reduced pressure, extracted three times with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 29e (160 mg, 53%).

[0307] LC-MS: [M+H] + :322.0.

[0308] Compounds 29 and 30: Synthesis of (R)-3-((3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0309]

[0310] Compound 1h-1 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 29e (66.5 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)) (19.6 mg, 0.02 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100 °C and stirred for 2 h. The reaction mixture was cooled and filtered, and water (100 mL) and ethyl acetate (30 mL*2) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (methanol: dichloromethane = 1:20). After concentration, the mixture was freeze-dried to obtain compound 29 (33.0 mg, 30%) as a white solid.

[0311] LC-MS: [M+H] + :527.0.

[0312] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=5.6Hz,1H),7.14-7.10(m,2H),6.82(dd,J=5.8,2.4Hz,1H),6.49(d,J=2.0Hz,1H),5.41(s,2H), 4.98(s,1H),4.43-4.32(m,2H),4.06-3.99(m,2H),3.81-3.74(m,2H),3.68-3.54(m,2H),3.36-3.31(m,1H),2.14-1.97(m,2H).

[0313] Compound 1h-2 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 29e (66.5 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)) (19.6 mg, 0.02 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100 °C and stirred for 2 h. The reaction mixture was cooled and filtered, and water (100 mL) and ethyl acetate (30 mL*2) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (methanol: dichloromethane = 1:20). After concentration, the mixture was freeze-dried to obtain compound 30 (38.8 mg, 36%) as a white solid.

[0314] LC-MS: [M+H] + :527.0.

[0315] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=6.0Hz,1H),7.12-7.10(m,2H),6.81(dd,J=5.8,2.0Hz,1H),6.49(d,J=2.0Hz,1H),5.41(s,2H), 4.98(s,1H),4.40-4.32(m,2H),4.07-3.99(m,2H),3.81-3.74(m,2H),3.67-3.54(m,2H),3.36-3.30(m,1H),2.11-1.98(m,2H).

[0316] Embodiment 9:

[0317] Compounds 31 and 32: (R)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0318]

[0319] Synthesis of 3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde 31b:

[0320]

[0321] Compound 6-(trifluoromethyl)pyridin-3-ol 31a (5.0 g, 30.66 mmol), 3,4,5-trifluorobenzaldehyde (4.9 g, 30.66 mmol), potassium carbonate (6.4 g, 45.98 mmol) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 90°C for 2 h. Water (50 mL) was added, and the reaction solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a colorless oil 31b (5.0 g, 54%).

[0322] LC-MS: [M+H] + :304.0.

[0323] Synthesis of (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol 31:

[0324]

[0325] Compound 3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde 31b (5.0 g, 16.49 mmol) was dissolved in methanol (100 mL), sodium borohydride (935.73 mg, 24.74 mmol) was added to the mixture at 0°C and stirred at room temperature for 2 h. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give a colorless oil 31c (4.0 g, 79%).

[0326] LC-MS: [M+H] + :306.0.

[0327] Compounds 31 and 32: Synthesis of (R)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0328]

[0329] Compound 1h-1 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol 31c (63.2 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (15.6 mg, 0.02 mmol), cesium carbonate (134.9 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100°C and stirred for 2 h. The reaction solution was cooled and filtered, extracted with water (100 mL) and ethyl acetate (30 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, column chromatographed (methanol: dichloromethane = 1:20), concentrated and freeze-dried to obtain white solid compound 31 (29.0 mg, 27%).

[0330] LC-MS: [M+H] + :511.0.

[0331] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=2.8Hz,1H),7.61(d,J=8.8Hz,1H),7.29-7.25(m,1H),7.11-7.09(m,2H),5.40(s,2H),4.97 (s,1H),4.39-4.31(m,2H),4.05-3.97(m,2H),3.80-3.72(m,2H),3.66-3.52(m,2H),3.34-3.29(m,1H),2.10-2.96(m,2H).

[0332] Compound 1h-2 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol 31c (63.1 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (19.6 mg, 0.02 mmol), cesium carbonate (134.9 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100°C and stirred for 2 h. The reaction mixture was cooled and filtered, and water (100 mL) and ethyl acetate (30 mL*2) were added to the reaction solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (methanol: dichloromethane = 1:20). After concentration, the mixture was freeze-dried to obtain a white solid compound 32 (17.0 mg, 16%).

[0333] LC-MS: [M+H] + :511.0.

[0334] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=2.8Hz,1H),7.61(d,J=8.4Hz,1H),7.29-7.25(m,1H),7.11-7.09(m,2H),5.40(s,2H),4.97 (s,1H),4.39-4.30(m,2H),4.05-3.97(m,2H),3.80-3.72(m,2H),3.66-3.52(m,2H),3.34-3.29(m,1H),2.10-1.96(m,2H).

[0335] Embodiment 10:

[0336] Compounds 33 and 34: (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyloxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyloxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0337]

[0338] Synthesis of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde 33b:

[0339]

[0340] 2-(Trifluoromethyl)pyrimidin-5-ol 33a (1.0 g, 6.09 mmol), 3,4,5-trifluorobenzaldehyde (1.2 g, 7.31 mmol), potassium carbonate (1.1 g, 7.92 mmol) were dissolved in N,N-dimethylformamide (15 mL) and stirred at 90°C for 2 h. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain yellow solid compound 33b (1.1 g, 59%).

[0341] LC-MS: [M+H] + :305.0.

[0342] Synthesis of (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol 33c:

[0343]

[0344] 3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde 33b (950.0 mg, 3.12 mmol) was dissolved in methanol (10 mL), cooled to 0°C, and sodium borohydride (118.0 mg, 3.12 mmol) was slowly added. The reaction was stirred at this temperature for 0.5 h, and water (10 mL) was added dropwise to quench the reaction. The solvent was concentrated under reduced pressure, extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give an off-white solid compound 33c (700 mg, 73%).

[0345] LC-MS: [M+H] + :307.4.

[0346] Compounds 33 and 34: Synthesis of (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyloxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyloxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0347]

[0348] Compound 1h-1 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol 33c (63.4 mg, 0.21 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl)palladium (II) (19.6 mg, 0.02 mmol) was added. The atmosphere was replaced with nitrogen three times, heated to 100°C for 2 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain white solid compound 33 (27.6 mg, 26%).

[0349] LC-MS: [M+H] + :512.3.

[0350] 1 H NMR (400MHz, CDCl3) δ8.55(s,2H),7.17-7.11(m,2H),5.42(s,2H),4.98(s,1H),4.43-4.31(m,2H),4.06-3.98(m,2H),3.81- 3.73(m,2H),3.67-3.60(m,1H),3.60-3.53(m,1H),3.33(ddd,J=13.2,5.2,2.0Hz,1H),2.15-2.05(m,1H),2.03-1.95(m,1H).

[0351] Compound 1h-2 (50.0 mg, 0.21 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol 33c (63.4 mg, 0.21 mmol), and cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (19.6 mg, 0.02 mmol) was added. The atmosphere was replaced with nitrogen three times, heated to 100°C for 2 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain white solid compound 34 (26.9 mg, 25%).

[0352] LC-MS: [M+H] + :512.3.

[0353] 1 H NMR (400MHz, CDCl3) δ8.55(s,2H),7.17-7.11(m,2H),5.42(s,2H),4.98(s,1H),4.43-4.31(m,2H),4.06-3.98(m,2H),3.81- 3.73(m,2H),3.67-3.60(m,1H),3.60-3.53(m,1H),3.33(ddd,J=13.2,5.2,2.0Hz,1H),2.15-2.05(m,1H),2.03-1.95(m,1H).

[0354] Embodiment 11:

[0355] Compounds 37 and 38: (R)-3-((3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0356]

[0357] Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole 37b:

[0358]

[0359] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 37a (24.0 g, 123.69 mmol), 1,1,1-trifluoro-2-iodoethane (27.3 g, 129.87 mmol) and cesium carbonate (44.3 g, 136.05 mmol) were dissolved in N,N-dimethylformamide (200 mL), replaced with nitrogen three times, and slowly heated to 80°C for 18 h. The reaction solution was filtered, water (200 mL) was added, and ethyl acetate was used for washing (200 mL x 3). The organic phases were combined and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil 37b (5.0 g, 15%).

[0360] LC-MS: [M+H] + :277.4.

[0361] Synthesis of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ol 37c:

[0362]

[0363] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole 37b (5.0 g, 18.11 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0°C, and hydrogen peroxide (4.4 g, 110.72 mmol) and sodium hydroxide solution (3M, 12.9 mL, 38.88 mmol) were slowly added, and the mixture was returned to room temperature for 4 h. Saturated sodium sulfite solution (100 mL) was added to the reaction solution, and 1M HCl solution was added dropwise at 0°C to adjust the pH to 4-5, and the mixture was extracted three times with ethyl acetate (120 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column (petroleum ether: ethyl acetate = 6:1) to obtain a colorless oil 37c (2.6 g, 86%).

[0364] LC-MS: [M+H] + :167.0.

[0365] Synthesis of 3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde 37d:

[0366]

[0367] Compound 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-ol 37c (2.6 g, 15.65 mmol), 3,4,5-trifluorobenzaldehyde (2.5 g, 15.65 mmol) and potassium carbonate (3.2 g, 23.48 mmol) were dissolved in N,N-dimethylformamide (50 mL), replaced with nitrogen three times, and slowly heated to 90°C for 2 h. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 37d (2.9 g, 61%).

[0368] LC-MS: [M+H] + :307.3.

[0369] Synthesis of (3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol 37e:

[0370]

[0371] Compound 3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde 37d (2.8 g, 9.15 mmol) was dissolved in methanol (30 mL), cooled to 0°C, sodium borohydride (0.5 g, 13.72 mmol) was slowly added, and the temperature was slowly restored to room temperature for 3 h. Saturated aqueous ammonium chloride solution (30 mL) was added dropwise at 0°C, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 37e (1.5 g, 53%).

[0372] LC-MS: [M+H] + :309.4.

[0373] Compounds 37 and 38: Synthesis of (R)-3-((3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one:

[0374]

[0375] (3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol 37e (57.4 mg, 0.19 mmol), compound 1h-1 (45.0 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.7 mg, 0.02 mmol) and cesium carbonate (121.3 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 37 (27.6 mg, 29%).

[0376] LC-MS: [M+H]+: 514.2.

[0377] 1 H NMR (400MHz, CDCl3) δ7.39(s,1H),7.30(s,1H),7.03(d,J=8.4Hz,2H),5.36(s,2H),4.96(s,1H),4.58(q,J=8.4Hz,2H),4.41-4.31(m,2 H),4.05-3.98(m,2H),3.80-3.72(m,2H),3.67-3.52(m,2H),3.32(ddd,J=13.6,5.2,2.4Hz,1H),2.14-2.04(m,1H),2.03-1.94(m,1H).

[0378] (3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol 37e (57.4 mg, 0.19 mmol), compound 1h-2 (45.0 mg, 0.19 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (17.7 mg, 0.02 mmol) and cesium carbonate (121.3 mg, 0.37 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, and slowly heated to 100°C for 2 h. The reaction solution was filtered and concentrated under reduced pressure, and the residue was purified by column (dichloromethane: methanol = 10:1) to obtain white solid compound 38 (7.9 mg, 8%).

[0379] LC-MS: [M+H]+: 514.2.

[0380] 1H NMR (400MHz, CDCl3) δ7.39(s,1H),7.30(s,1H),7.03(d,J=8.4Hz,2H),5.36(s,2H),4.96(s,1H),4.58(q,J=8.4Hz,2H),4.41-4.31(m,2 H),4.05-3.98(m,2H),3.80-3.72(m,2H),3.67-3.52(m,2H),3.32(ddd,J=13.6,5.2,2.4Hz,1H),2.14-2.04(m,1H),2.03-1.94(m,1H).

[0381] Embodiment 12:

[0382] Compounds 41 and 42: (R)-3-((3,4,5-trifluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((3,4,5-trifluorobenzyl)oxy)-6,7,9,10,10a,11-hexahydro-1H-pyrimido[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0383]

[0384] (3,4,5-trifluorophenyl)methanol 41a (26.8 mg, 0.17 mmol), compound 1h-1 (40.0 mg, 0.17 mmol), cesium carbonate (107.9 mg, 0.33 mmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (15.7 mg, 0.02 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, heated to 100°C and reacted for 2 h. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase preparation (formic acid system) to obtain white solid compound 41 (14.6 mg, 24%).

[0385] LC-MS: [M+H] + :368.2.

[0386] 1H NMR (400MHz, CDCl3) δ7.06-6.98(m,2H),5.32(s,2H),4.95(s,1H),4.41-4.31(m,2H),4.05-3.97(m,2H),3.80-3.72(m ,2H),3.66-3.60(m,1H),3.58-3.52(m,1H),3.31(ddd,J=13.2,5.2,2.0Hz,1H),2.13-2.04(m,1H),2.02-1.96(m,1H).

[0387] (3,4,5-trifluorophenyl)methanol 41a (26.8 mg, 0.17 mmol), compound 1h-2 (40.0 mg, 0.17 mmol), cesium carbonate (107.9 mg, 0.33 mmol) and methanesulfonic acid (9,9-dimethyl-4,5-bis(diphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (15.7 mg, 0.02 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, heated to 100°C and reacted for 2 h. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase preparation (formic acid system) to obtain white solid compound 42 (18.9 mg, 31%).

[0388] LC-MS: [M+H] + :368.2.

[0389] 1 H NMR (400MHz, CDCl3) δ7.06-6.99(m,2H),5.32(s,2H),4.95(s,1H),4.41-4.31(m,2H),4.05-3.97(m,2H),3.80-3.72(m ,2H),3.67-3.60(m,1H),3.58-3.52(m,1H),3.31(ddd,J=13.2,5.2,2.0Hz,1H),2.14-2.04(m,1H),2.02-1.96(m,1H).

[0390] Embodiment 13:

[0391] Compounds 45 and 46: (R)-3-((2,3-difluorobenzyl)oxy)-6,7,9,10,11,11-hexahydro-1H-pyrimidinyl[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one and (S)-3-((2,3-difluorobenzyl)oxy)-6,7,9,10,11,11-hexahydro-1H-pyrimidinyl[6',1':2,3]imidazo[1,5-d][1,4]oxazepan-1-one

[0392]

[0393] Compound 1h-1 (50.0 mg, 0.21 mmol), (2,3-difluorophenyl)methanol 45a (29.8 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19.6 mg, 0.02 mmol), cesium carbonate (134.8 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100°C and stirred for 2 h. The reaction solution was cooled and filtered, and water (100 mL) and ethyl acetate (30 mL*2) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, prepared for separation (ammonium bicarbonate system), and concentrated and freeze-dried to obtain white solid compound 45 (17.1 mg, 24%).

[0394] LC-MS: [M+H] + :350.0.

[0395] 1 H NMR (400MHz, CDCl3) δ7.24-7.19(m,1H),7.15-7.01(m,2H),5.46(d,J=1.2Hz,2H),4.92(s,1H),4.36-4.29(m,2H), 4.01-3.95(m,2H),3.77-3.71(m,2H),3.66-3.58(m,1H),3.54-3.48(m,1H),3.30-3.25(m,1H),2.08-1.95(m,2H).

[0396] Compound 1h-2 (50.0 mg, 0.21 mmol), (2,3-difluorophenyl)methanol 45a (29.8 mg, 0.21 mmol), methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (19.6 mg, 0.02 mmol), cesium carbonate (134.9 mg, 0.41 mmol) were dissolved in dioxane (5 mL), heated to 100°C and stirred for 2 h. The reaction solution was cooled and filtered, and water (100 mL) and ethyl acetate (30 mL*2) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, prepared for separation (ammonium bicarbonate system), and freeze-dried to obtain white solid compound 46 (18.6 mg, 26%).

[0397] LC-MS: [M+H]+: 350.0.

[0398] 1H NMR (400MHz, CDCl3) δ7.26-7.21(m,1H),7.14-7.05(m,2H),5.47(d,J=1.2Hz,2H),4.93(s,1H),4.38-4.31(m,2H), 4.04-3.97(m,2H),3.79-3.73(m,2H),3.67-3.60(m,1H),3.56-3.50(m,1H),3.32-3.27(m,1H),2.10-1.97(m,2H).

[0399] Embodiment 14:

[0400] Compounds 17 and 18: (R)-2-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-4-one and (S)-2-((3,5-difluoro-4-((2-trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-4-one

[0401]

[0402] Synthesis of tert-butyl 3-formylmorpholine-4-carboxylate 17b:

[0403]

[0404] Compound 3-(Hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester 17a (5.0 g, 22.90 mmol) was dissolved in dichloromethane (75.0 mL), and Dess-Martin periodinane (14.57 g, 34.35 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium bicarbonate aqueous solution, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, and the obtained organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 10:1) to obtain white solid compound 17b (2.5 g, 51%). LC-MS: [M+H-56] + :160.1.

[0405] Synthesis of tert-butyl (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate 17c:

[0406]

[0407] Compound tert-butyl 3-formylmorpholine-4-carboxylate 17b (4.0 g, 18.50 mmol) was dissolved in dichloromethane (100.0 mL), ethyl 2-(triphenyl-5-phosphoramidite)acetate (6.44 g, 18.50 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 10:1) to obtain a colorless oil compound 17c (1.6 g, 30%).

[0408] LC-MS: [M+H-56] + :230.1.

[0409] Synthesis of tert-butyl 3-(3-ethoxy-3-oxypropyl)morpholine-4-carboxylate 17d:

[0410]

[0411] Compound (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylic acid tert-butyl ester 17c (1.8 g, 6.30 mmol) was dissolved in ethanol (100.0 mL), palladium carbon catalyst (0.21 g, 2.00 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain a colorless oil compound 17d (1.7 g, 94%).

[0412] LC-MS: [M+H-100] + :188.1.

[0413] Synthesis of tert-butyl 3-(3-hydroxypropyl)morpholine-4-carboxylate 17e:

[0414]

[0415] Compound 3-(3-ethoxy-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester 17d (1.7 g, 5.90 mmol) and calcium chloride (1.64 g, 14.75 mmol) were dissolved in ethanol (34.0 mL), sodium borohydride (0.56 mg, 14.75 mmol) was added to the mixture, and the mixture was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 4:1) to obtain yellow oil compound 17e (1.2 g, 83%).

[0416] LC-MS: [M+H-56] + :190.1.

[0417] Synthesis of tert-butyl 3-(3-(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)morpholine-4-carboxylate 17f:

[0418]

[0419] Compound 3-(3-hydroxypropyl)morpholine-4-carboxylic acid tert-butyl ester 17e (550.0 mg, 2.23 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (490.76 mg, 3.35 mmol), triphenylphosphine (878.46 mg, 3.35 mmol) were dissolved in tetrahydrofuran (22.0 mL), diisopropyl azodicarboxylate (677.24 mg, 3.35 mmol) was added to the mixture, and the mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 1:20) to obtain yellow oil compound 17f (160.0 mg, 19%).

[0420] LC-MS: [M+H-100] + :274.1.

[0421] Synthesis of 6-chloro-1-(3-(morpholin-3-yl)propyl)pyrimidine-2,4(1H,3H)-dione 17g:

[0422]

[0423] Compound 3-(3-(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl)morpholine-4-carboxylic acid tert-butyl ester 17f (150 mg, 0.40 mmol) was dissolved in 4M hydrochloric acid dioxane solution (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a colorless oil compound 17g (100.0 mg, 91%).

[0424] LC-MS: [M+H] + :274.1.

[0425] Synthesis of 7,8,8a,9,11,12-hexahydro-2H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepine-2,4(3H)-dione 17h:

[0426]

[0427] Compound 6-chloro-1-(3-(morpholin-3-yl)propyl)pyrimidine-2,4(1H,3H)-dione 17g (100.0 mg, 0.37 mmol) was dissolved in acetonitrile (5.0 mL), N,N-diisopropylethylamine (0.25 g, 6.72 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 1:20) to obtain yellow oil compound 17h (20.0 mg, 23%).

[0428] LC-MS: [M+H] + :238.1.

[0429] Synthesis of 4-oxo-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepine-2-yl 2,4,6-triisopropylbenzenesulfonate 17i:

[0430]

[0431] Compound 7,8,8a,9,11,12-hexahydro-2H,6H-[1,4]oxazine[4,3-c]pyrimido[1,6-a][1,3]diazepine-2,4(3H)-dione 17h (100.0 mg, 0.42 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (191.48 mg, 0.63 mmol) and triethylamine (127.95 mg, 1.26 mmol), 4-dimethylaminopyridine (5.2 mg, 0.042 mmol) were dissolved in dichloromethane solution (5.0 mL) and reacted at 25°C 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 = 30: 1) to give a white solid compound 17i (200.0 mg, 94%).

[0432] LC-MS: [M+H] + :504.1.

[0433] Synthesis of 2-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-4-one 17j:

[0434]

[0435] Compound 4-oxo-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-2-yl 2,4,6-triisopropylbenzenesulfonate 17i (200.0 mg, 0.40 mmol), compound Int-1 (181.8 mg, 0.60 mmol), cesium carbonate (258.8 mg, 0.79 mmol) and methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (37.7 mg, 0.040 mmol) were dissolved in toluene (6.0 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 isolated by preparative separation to give white solid compound 17j (50.0 mg, 24%).

[0436] LC-MS: [M+H] + :525.1.

[0437] Compounds 17 and 18: Synthesis of (R)-2-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-4-one and (S)-2-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepin-4-one:

[0438]

[0439] 2-((3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-7,8,8a,9,11,12-hexahydro-4H,6H-[1,4]oxazino[4,3-c]pyrimido[1,6-a][1,3]diazepine-4-one 17j (15.0 mg, 0.031 mmol) was chiral prepared (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% MeOH (NH4OH 0.2%): 60% CO2) to give white solid compound 17 (11.5 mg, 23%) and white solid compound 18 (16.5 mg, 33%).

[0440] Compound 17:

[0441] LC-MS: [M+H] + :525.2.

[0442] RT:2.84min.

[0443] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=5.6Hz,1H),7.26(s,1H),7.15(d,J=8.1Hz,2H),6.99(dd,J=5.6,2.2Hz,1H),5.44(d,J=5.8Hz,3H),4.28(s,2H),3.95 (d,J=11.3Hz,1H),3.77-3.67(m,2H),3.50(t,J=10.8Hz,1H),3.45-3.32( m,3H),1.91-1.85(m,2H),1.77-1.72(m,1H),1.63(dd,J=14.6,5.9Hz,1H).

[0444] Compound 18:

[0445] LC-MS: [M+H] + :525.1.

[0446] RT:3.03min.

[0447] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=5.6Hz,1H),7.26(s,1H),7.15(d,J=8.2Hz,2H),7.00(d,J=5.3Hz,1H),5.43(s,2H),5.40(s,1H),4.28(s,2H) ,3.94(d,J=10.9Hz,1H),3.76-3.67(m,2H),3.50(t,J=10.7Hz,1H),3. 42-3.31(m,3H),1.87(d,J=6.5Hz,2H),1.78(s,1H),1.66-1.60(m,1H).

[0448] Biological evaluation

[0449] 1. Recombinant human Lp-PLA2 inhibition assay (rhLp-PLA2)

[0450] 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.

[0451] 1. Prepare assay buffer: 50 mM MES (pH 6.5), 150 mM NaCl, 0.1% BSA

[0452] 2. Dissolve the compound powder in DMSO to a 10 mM stock solution and keep at room temperature for later use.

[0453] 3. The compound solution was diluted four-fold with DMSO.

[0454] 4. Use Echo to transfer serial dilutions of compounds to 384-well plate experiments.

[0455] 5. Prepare 2x PLA2G7 in assay buffer.

[0456] 6. Add 15 μl of prepared PLA2G7 to the 384-well plate and place it in a 25°C incubator for incubation.

[0457] 7. Prepare a 2x mixture of 2-Thio-PAF and DTNB in ​​assay buffer.

[0458] 8. Add 15 μl of the mixture of 2x 2-Thio-PAF and DTNB to the plate and incubate in a 25°C incubator.

[0459] 9. Data was read using Envision, ABS 405nm. The results are listed in Table 1.

[0460] Table 1

[0461]

[0462]

[0463] Experimental reagents:

[0464] PLA2G7 (Sino biological, 10848-H08H); 2-Thio-PAF (Cayman, 60945); DTNB (Sigma, D-8130);

[0465] II: Human plasma Lp-PLA2 inhibition assay

[0466] 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.

[0467] Determination method:

[0468] 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;

[0469] 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.

[0470] 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);

[0471] 4. Set the parameters of the microplate reader (Abs414, time interval 1min, recording for 40min).

[0472] 5. The exported data were processed and analyzed using GraphPad Prism7. The results are listed in Table 2.

[0473] Table 2

[0474]

[0475]

[0476] Experimental reagents:

[0477] Human plasma(PreceDo,20230203EDTA); DTNB(TCI,D0944); 2-thio-PAF(MCE,HY-101263)

[0478] 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 represented by formula (I) or a pharmaceutically acceptable salt thereof, in, n 1 、n 2 Each independently is 0, 1 or 2; R 1 , R 2 each is independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen; Cy is a 3-8 membered saturated heterocyclic ring or a non-aromatic unsaturated heterocyclic ring; X 1 , X 2 Each is independently: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: H, alkyl, deuterated alkyl, or cycloalkyl; Ar is an arylene or heteroarylene group; the arylene or heteroarylene group is optionally substituted by 0, 1 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 aryl or heteroaryl; the aryl or heteroaryl is optionally substituted with 0, 1 or more substituents, each of which is independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R" is alkyl or cycloalkyl; R"' is alkylene; Z is O or S; The halogen atoms in the "halogen", "haloalkyl" and "haloalkoxy" 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”, and “amino substituted with monoalkyl or dialkyl” are each independently C 1 -C 10 Straight or branched chain alkyl; optionally, C 1 -C 7 Straight or branched chain alkyl; optionally, C 1 -C 4 a linear or branched alkyl group; 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, 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 C 1 -C 10 A straight or branched alkylene group; optionally, C 1 -C 7 Straight or branched chain alkylene; optionally, C 1 -C 5 linear or branched alkylene; 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, isohexylene, 1,1-dimethylbutylene, 2, 2-dimethylbutylene, 3,3-dimethylbutylene, 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 C 3 -C 10 Monocyclic or bicyclic cycloalkyl, optionally, C 3 -C 7 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 "Cy" is a 3-8 membered saturated heterocyclic ring or a non-aromatic unsaturated heterocyclic ring containing 0-2 heteroatoms selected from N, O, and S in addition to the common N atom on the ring; alternatively, the Cy is a 3-8 membered saturated heterocyclic ring containing 0 or 1 O atom in addition to the common N atom on the ring; alternatively, the Cy is an oxaziridine ring, an oxaziridine ring, an oxaziridine ring, an aziridine ring, an azetidine ring, an azopentane ring, an azohexane ring, an azoheptane ring, an azooctane 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, pyrazol-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-4-yl, pyridin-5-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, benzimidazolyl, benzothiazolyl, benzoxapinyl, 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[1,5-a]pyridinyl, pyrimidinyl, pyrido[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, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-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.

2. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in, n 1 is 0 or 2, optionally, n 2 is 1 or 2; Cy is a 3-8 membered saturated heterocyclic ring; optionally, it is an oxazepine ring, an oxazepine ring, an oxazepine ring, an aziridine ring, an azetidine ring, an azocyclopentane ring, an azohexane ring, an azocycloheptane ring, an azocyclooctane ring; R 1 , R 2 Each independently selected from: -H, or C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 A straight chain or branched chain alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); optionally, R 1 -H, or -CH 3 ; Optionally, R 2 -H, or -CH 3 ; Optionally, R 1 is -H; optionally, R 2 is -H; X 1 , X 2 Each independently is: C 1 -C 7 Alkylene (optionally, -CH 2 -, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; optionally, X 1 -CH 2 -, or -O-; optionally, X 1 is -O-; optionally, X 2 is -O-; wherein R' is selected from -H, C 1 -C 7 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, -CD 3 , -C 2 D 5 , or -C 3 D 7 ), or C 3 -C 6 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); Ar is phenylene or pyridyl, and the phenylene or pyridyl is optionally substituted by 0, 1, 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -I, -CN, -Me, -CF 3 , -C 2 H 5 , -C 3 H 7 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD 3 ,-OCD 3 , -OMe, or -OCF 3 ; Optionally, Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN; Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD 3 ,-OCD 3 , -CF 3 , -CHF 2 、-CH 2 F, -CH 2 CF 3 、-OCF 3 、-OCHF 2 、-OCH 2 F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH 3 、-OC 2 H 5 、-OC 3 H 7 , or -OAr'; optionally, Y is -H, -F, -Cl, -Br, -I, or -OAr'; optionally, Y is -F, or -OAr'; wherein Ar' is selected from phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl, which are optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -CN, C 1 -C 7 Alkyl (which may be 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), -CD 3 ,-OCD 3 , C 1 -C 6 Haloalkyl, -OCH 3 、-OC 2 H 7 、-OC 3 H 7 , C 1 -C 6 Haloalkoxy, hydroxy, hydroxyalkyl, cyano, or C 3 -C 6 Cycloalkyl (optionally, cyclopropane, cyclobutane, cyclopentane, or cyclohexane); Optionally, Ar' is selected from phenyl, pyridyl, pyrimidinyl, or pyrazolyl, optionally substituted with 1 or 2 substituents; Optionally, Ar' is selected from phenyl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5-yl or pyrazol-4-yl, optionally substituted with 1 or 2 substituents, the substituents being selected from -F, -Cl, -CH 3 , -CF 3 、-CH 2 CF 3 , or -OCF 3 ; Z is O.

3. A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, in, n 1 is 0 or 2, n 2 is 1; R 1 , R 2 each independently -H; Cy is an oxaziridine ring, an oxaziridine ring, an oxazirocidine ring, an aziridine ring, an azetidine ring, an azopentane ring, an azohexane ring, an azepane ring, an azooctane ring; X 1 -O-, or -CH 2 -, X 2 for -O-; Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN; Y is -F, or -OAr'; wherein Ar' is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl or pyrazol-4-yl optionally substituted by 1 or 2 substituents selected from -Cl, -CH 3 , -CF 3 、-OCF 3 or -CH 2 CF 3 ; Z is O.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of formula (I) is selected from the following compounds:

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, in, 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.

6. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, comprising the following synthetic route 1 or route 2: Route 1: Route 2: In each structural formula, n 1 、n 2 , R 1 , R 2 , Cy, X 1 , X 2 , Z, Ar and Y are as defined in any one of claims 1-5.

7. 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 5 and optionally a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition comprises 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 5, or the pharmaceutical composition according to claim 7 or 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 5, or the pharmaceutical composition according to claim 7 or 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 includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

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