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

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a cyclopropane Lp-PLA2 inhibitor, a preparation method thereof, a pharmaceutical composition thereof, and a use thereof in medicine. The use includes the use of the Lp-PLA2 inhibitor in the treatment of 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 112574221A discloses a tetracyclic pyrimidone compound shown in the following formula, a preparation method thereof, a composition thereof and uses thereof. The compound or its composition is used to treat neurodegenerative diseases such as Alzheimer's disease, glaucoma, age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis.

[0011]

[0012] Chinese patent application CN 113861220A discloses a tricyclic pyrimidone compound shown in the following formula, a preparation method thereof, a composition thereof and uses thereof. The compound or its composition can be used to treat neurodegenerative diseases, such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis.

[0013] Summary of the invention

[0014] The present invention provides a new 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.

[0015] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0016]

[0017] in,

[0018] The Cy ring is a 5-7 membered saturated heterocyclic ring, a non-aromatic unsaturated heterocyclic ring, or an aromatic heterocyclic ring, which contains 0-2 heteroatoms selected from N, O, and S in addition to the common N atom on the ring; alternatively, the Cy ring is a 5-7 membered saturated heterocyclic ring, or an aromatic heterocyclic ring, which contains 0-1 N atoms in addition to the common N atom on the ring; alternatively, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, a diazacycloheptane ring, an azacyclohexane, an azacyclohexane, an azacyclohexane, an imidazole ring, a pyridine ring, or a pyrimidine ring; m, n, and o are each independently 0, 1, or 2;

[0019] X is =CH-, -CH=, -CH2-, -O-, -S-, =N-, -N=, or -NR3-; wherein R3 is selected from: -H, alkyl, deuterated alkyl, hydroxyalkyl, or cycloalkyl;

[0020] V is -CHR4-, -CR4=, =CR4-, or a single bond; wherein R4 is selected from: -H or alkyl;

[0021] W is -H, -CH2-R5, -O-R5, -S-R5, -N(R5)2; wherein R5 is selected from: -H, alkyl, deuterated alkyl, haloalkyl, hydroxyl, hydroxyalkyl, or cycloalkyl;

[0022] R1 is each independently cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen;

[0023] R2 are each independently alkyl, deuterated alkyl, haloalkyl, cyano, or halogen;

[0024] Optionally, when m is 2, two R1s are connected by a single bond or -O-, and together with the Cy ring form a non-aromatic spiro ring;

[0025] Optionally, when m is 1 or 2, one of R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring, fused ring, spirocyclic ring or bridged ring containing 1-3 heteroatoms selected from N, O, or S, which is fused to the Cy ring, or a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which together with the Cy ring forms a bridged ring;

[0026] Optionally, when V is -CHR4-, V forms a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring with X through a single bond, -O-, or -CH2-; or, V is connected to W or the carbon atom where W is located through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring and the pyrimidine ring represented by Cx;

[0027] Optionally, when V is a single bond, X is connected to W or the carbon atom where W is located through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which is fused together with the Cy ring and the pyrimidine ring represented by Cx;

[0028] 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;

[0029] Y is -H, halogen, alkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, -OAr', -SAr', -NH-Ar', -N(R')-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, halosulfanyl, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R' is alkyl; R" is alkyl or cycloalkyl; R"' is alkylene;

[0030] Z is O or S;

[0031] The halogen atoms in the “halogen”, “haloalkyl”, “haloalkoxy” and “halosulfanyl” are each independently selected from F, Cl, Br or I;

[0032] 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;

[0033] 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;

[0034] The "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

[0035] 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;

[0036] The "aryl" is a 6-10 membered aryl; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl;

[0037] The "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group;

[0038] 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-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl , pyrimidin-4-yl, pyrimidin-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]oxazinyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl, benzothiophenyl, benzo[ oxazolyl, benzimidazolyl, benzothiazolyl, benzoxaphene, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[ [1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazolo[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl; optionally, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl;

[0039] 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.

[0040] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0041] The Cy ring is a 5-6 membered aromatic heterocyclic ring; optionally, the Cy ring is an imidazole ring, a pyridine ring, or a pyrimidine ring;

[0042] V is a single bond;

[0043] m and n are each independently 0, 1 or 2; optionally; n is 0 or 1; optionally, m is 0 and n is 0;

[0044] Optionally, X is =CH-, =N-, or -NR3-, wherein R3 is selected from: -H, alkyl, deuterated alkyl, or hydroxyalkyl; Optionally, X is =CH-, =N-, or -N(CH3)-;

[0045] Optionally, W is -H, -CH2-R4, or -O-R4; wherein R4 is selected from: -H, alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, or -CH3; Optionally, W is -H;

[0046] Optionally, R1 is each independently alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, or hydroxyalkyl; Optionally, R1 is each independently alkyl, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3; Optionally, R1 is each independently -CH3.

[0047] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0048] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring;

[0049] m and n are each independently 0, 1 or 2; V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3;

[0050] Optionally; n is 0 or 1;

[0051] Optionally, X is -CH2-, -O-, or -NR3-, wherein R3 is -H, alkyl, deuterated alkyl, or hydroxyalkyl; Optionally, X is -O-, -N(CH3)-, or -N(CH2CH3)-;

[0052] Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, deuterated alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, -CH3, -CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H;

[0053] Optionally, R1 is each independently alkyl, alkoxy, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3; Optionally, R1 is each independently -CH3, or -CH2CH3;

[0054] Optionally, when m is 2, two R1s form a non-aromatic spiro ring together with the Cy ring through a single bond or -O-; optionally, the non-aromatic spiro ring is:

[0055]

[0056] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0057] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring;

[0058] m and n are each independently 0, 1 or 2; V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3;

[0059] Optionally, n is 0;

[0060] Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -N(CH3)-, or -N(CH2CH3)-;

[0061] Optionally, W is -CH2-R4, or -O-R4; wherein R4 is selected from: -H, alkyl, deuterated alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, or -CH3; Optionally, W is -H;

[0062] Optionally, R1 is each independently alkyl;

[0063] Optionally, V forms a 5-8 membered non-aromatic monocyclic ring fused with the Cy ring and containing 1-3 heteroatoms selected from N, O, or S through a single bond, -O-, or -CH2- with X; Optionally, the structure after the non-aromatic monocyclic ring is fused with Cy is:

[0064]

[0065] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0066] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring;

[0067] m and n are each independently 0, 1 or 2;

[0068] V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3;

[0069] Optionally, m is 0; Optionally, n is 0 or 1;

[0070] Optionally, X is -NR3-, wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, or -N(CH3)-; Optionally, X is -N(CH3)-;

[0071] Optionally, W is -H, -CH2-R4, or -O-R4, wherein R4 is selected from: -H, or alkyl; Optionally, W is -H, -CH3, -CH2CH3, -O-CH3, or -O-CH2CH3; Optionally, W is -H, -CH3, -O-CH3, or -O-CH2CH3; Optionally, W is -O-CH3;

[0072] Optionally, R1 is each independently alkyl, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3;

[0073] Optionally, V forms a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S with W through a single bond or -CH2-, which is fused with the Cy ring and the pyrimidine ring represented by Cx; Optionally, the structure after the non-aromatic monocyclic ring is fused with the Cy ring and Cx is:

[0074]

[0075] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0076] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring;

[0077] m is 0, 1 or 2;

[0078] V is -CHR4- or a single bond, wherein R4 is selected from: -H, -CH3, or -CH2CH3;

[0079] Optionally, n is 0;

[0080] Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -N(CH3)-;

[0081] Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, or alkyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H;

[0082] Optionally, R1 is independently -H, alkyl, or alkoxy; Optionally, R1 is independently -CH3, -CH2CH3, -OCH3, or -OCH2CH3;

[0083] Optionally, when m is 1, R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic, fused, spirocyclic or bridged ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring; optionally, the structure after the non-aromatic monocyclic ring is fused to the Cy ring is:

[0084]

[0085] Optionally, the structure after the non-aromatic fused ring, spiro ring or bridged ring is fused with the Cy ring is:

[0086]

[0087] Alternatively, when m is 2 and V is a single bond, one R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring; alternatively, the structure formed by the non-aromatic monocyclic ring and another R1 and Cy ring is:

[0088]

[0089] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0090] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is a diazacyclopentane ring or a diazacyclohexane ring;

[0091] m is 0, 1 or 2;

[0092] V is -CHR4- or a single bond, wherein R4 is selected from: -H, -CH3, or -CH2CH3;

[0093] Optionally, m is 0 or 1; Optionally, n is 0; Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, -N(CH3)-, or -N(CH2CH3)-;

[0094] Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, or hydroxyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H;

[0095] Optionally, R1 is independently -H, alkyl, or alkoxy; Optionally, R1 is independently -H, -CH3, -CH2CH3, -OCH3, or -OCH2CH3;

[0096] Optionally, R1 is connected to X through a single bond or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which together with the Cy ring constitutes a non-aromatic bridge ring; optionally, the structure of the non-aromatic bridge ring is:

[0097]

[0098] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0099] The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is a diazacyclopentane ring or a diazacyclohexane ring;

[0100] m and n are each independently 0, 1 or 2; V is a single bond;

[0101] Optionally, m is 0; Optionally, n is 0 or 1;

[0102] Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, -N(CH3)-, or -N(CH2CH3)-;

[0103] Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, or hydroxyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -CH3, -CH2CH3, -CH2OH, or -O-CH3;

[0104] Optionally, X is connected to W through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which is fused together with the Cy ring and the pyrimidine ring represented by Cx; Optionally, the structure after the non-aromatic monocyclic ring is fused together with the Cy ring and the pyrimidine ring represented by Cx is:

[0105]

[0106] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0107] o is 0 or 2;

[0108] R2 is each independently alkyl, cyano, or halogen, optionally, R2 is each independently -CH3, -CN, -Cl, or -F;

[0109] Ar is phenylene or pyridinylene, the phenylene or pyridinylene 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, -OCH3, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN;

[0110] Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCD3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2H5, -OC3H7, or -OAr'; Alternatively, Y is -H, -F, -Cl, -Br, -I, or -OAr'; Alternatively, Y is -H, -F, or -OAr'; wherein Ar' is selected from 1, phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl substituted with 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -CN, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, -OCD3, C1-C6 haloalkyl, -OCH3, -OC2H7, -OC3H7, C1- C6 haloalkoxy, hydroxy, hydroxyalkyl, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5;

[0111] Z is O.

[0112] Optionally, in the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0113] o is 0 or 2;

[0114] R2 is each independently -CH3, -Cl, or -F;

[0115] Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN;

[0116] Y is -H, -F, or -OAr'; wherein Ar' is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl, or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5;

[0117] Z is O.

[0118] Optionally, in the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention, the compound of formula (I) is selected from the following compounds:

[0119]

[0120] Optionally, in the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention,

[0121] 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.

[0122] 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.

[0123] Optionally, the dosage form of the pharmaceutical composition includes an oral preparation, a rectal preparation, or a parenteral preparation;

[0124] 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;

[0125] Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

[0126] Optionally, the pharmaceutical composition is used to prevent or treat Lp-PLA2-mediated diseases; optionally, the pharmaceutical composition is used to prevent or treat neurodegeneration-related diseases, cardiovascular diseases, diabetic macular edema (DME) or prostate diseases; optionally, the neurodegeneration-related diseases include Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); the cardiovascular diseases include atherosclerosis.

[0127] 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.

[0128] 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;

[0129] Optionally, the neurodegeneration-related disease includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

[0130] On the other hand, the present invention provides a method for preventing or treating a disease mediated by Lp-PLA2, comprising administering to a subject in need (e.g., a human or an animal) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in an effective amount for preventing or treating the disease. Alternatively, a method for preventing or treating a disease is provided, comprising administering to a subject in need (e.g., a human or an animal) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in an effective amount for preventing or treating the disease, wherein the disease comprises: a neurodegenerative disease, a cardiovascular disease, diabetic macular edema (DME), or a prostate disease; optionally, the neurodegenerative disease comprises Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); the cardiovascular disease comprises atherosclerosis.

[0131] 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:

[0132] Route 1:

[0133]

[0134] In each structural formula, Cy ring, m, n, o, R1, R2, V, W, X, Z, Ar and Y are as defined above; A is a halogen or a sulfonate group.

[0135] Compound 1A is subjected to a carburization reaction (for example, reacting with dimethyl 1-diazo-2-oxopropylphosphonate in the presence of a base such as K2CO3) to generate compound 1B; compound 1B is subjected to hydroboration (for example, reacting with pinacol borane in the presence of dinonyl iron) to generate compound 1C; compound 1C is subjected to cyclopropanation (for example, Simmons-Smith reaction, i.e., reacting with CH2I2 and diethylzinc) to generate compound 1D; compounds 1D and 1E are subjected to a coupling reaction (for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex as a catalyst, using Cs2CO3 or the like as a base) to obtain (I).

[0136] Route 2:

[0137]

[0138] In each structural formula, Cy ring, m, n, o, R1, R2, V, W, X, Z, Ar and Y are as defined above; A is a halogen or a sulfonate group.

[0139] Compound 2A is subjected to a carbon addition reaction (for example, reacting with dimethyl 1-diazo-2-oxopropylphosphonate in the presence of a base such as K2CO3) to generate compound 2B; compound 2B is subjected to hydroboration (for example, reacting with pinacol borane in the presence of dinonyl iron carbonyl) to generate compound 2C; compounds 2C and 2D are subjected to a coupling reaction (for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex as a catalyst, using Cs2CO3 or the like as a base) to obtain 2E; compound 2E is subjected to cyclopropanation (for example, reacting with trimethyl sulfoxide iodide) to obtain (I).

[0140] 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).

[0141] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention is a cyclopropane Lp-PLA2 inhibitor, 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 including atherosclerosis, diabetic macular edema (DME), or prostate diseases. DETAILED DESCRIPTION

[0142] 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.

[0143] Example

[0144] 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.

[0145] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0146] In the examples, unless otherwise specified, the reaction temperature is room temperature, for example, 20-30°C.

[0147] Embodiment 1:

[0148] Compound 1: Synthesis of 9-(2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxyphenyl)cyclopropyl)-2,3,5,6-tetrahydro-4H,7H-1-oxa-3a,6a,8-triazaphenanthran-7-one:

[0149]

[0150] Synthesis of 2-((2,6-dichloro-5-methoxypyrimidin-4-yl)amino)ethane-1-ol 1b:

[0151]

[0152] 2,4,6-Trichloro-5-methoxypyrimidine 1a (10.0 g, 46.85 mmol), 2-aminoethan-1-ol (4.3 g, 70.27 mmol) and N,N-diisopropylethylamine (9.1 g, 70.27 mmol) were dissolved in acetonitrile (100 mL) and stirred at room temperature for 2 h. After concentration, the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain white solid compound 1b (8.0 g, 72%).

[0153] LC-MS: [M+H] + :238.3.

[0154] Synthesis of 2,4-dichloro-6-((2-hydroxyethyl)amino)pyrimidin-5-ol 1c:

[0155]

[0156] Dissolve 2-((2,6-dichloro-5-methoxypyrimidin-4-yl)amino)ethane-1-ol 1b (8.0 g, 33.60 mmol) in dichloromethane (200 mL), replace with nitrogen three times, cool to 0°C, slowly add boron tribromide (25.3 g, 100.81 mmol), and stir at 0°C for 2 h. Add methanol (10 mL) dropwise at 0°C to quench, concentrate, and purify the residue by column chromatography (dichloromethane / methanol = 20 / 1) to obtain white solid compound 1c (6.3 g, 84%). LC-MS: [M+H] + :224.2.

[0157] Synthesis of 2,4-dichloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine 1d:

[0158]

[0159] Dissolve triphenylphosphine (10.5 g, 40.17 mmol) in tetrahydrofuran (100 mL), replace with nitrogen 3 times, cool to 0°C, slowly add diisopropyl azodicarboxylate (8.1 g, 40.17 mmol) to the mixture, stir at 0°C for 15 min, add a mixed solution of 2,4-dichloro-6-((2-hydroxyethyl)amino)pyrimidin-5-ol 1c (3.0 g, 13.39 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (40 mL), and stir at 0°C for 4 h. Add water (100 mL) to quench the reaction, extract the aqueous phase with ethyl acetate (30 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is purified by column chromatography (dichloromethane / methanol=40 / 1) to obtain white solid compound 1d (6.1 g, crude product), which is directly used in the next step.

[0160] LC-MS: [M+H] + :206.0.

[0161] Synthesis of 3-(2,4-dichloro-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)propan-1-ol 1e:

[0162]

[0163] 2,4-Dichloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine 1d (6.1 g, crude), 3-iodopropan-1-ol (6.6 g, 35.53 mmol) and potassium carbonate (8.2 g, 59.21 mmol) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 80°C for 2 h. The mixture was cooled to room temperature and filtered, and the filtrate was diluted with ethyl acetate (100 mL), washed with saturated brine (100 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 4) to obtain yellow oily compound 1e (2.1 g, 59%, 2 steps).

[0164] LC-MS: [M+H] + :264.0.

[0165] Synthesis of 3-(2,4-dichloro-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)methanesulfonic acid propyl ester 1f:

[0166]

[0167] 3-(2,4-dichloro-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)propan-1-ol 1e (2.1 g, 7.95 mmol) and triethylamine (2.4 g, 23.85 mmol) were dissolved in dichloromethane (30 mL), cooled to 0°C, and methanesulfonyl chloride (1.4 g, 11.93 mmol) was added dropwise to the mixture, and stirring was continued for 0.5 h. The mixture was concentrated to obtain a yellow oil compound 1f (2.7 g, crude product), which was used directly in the next step.

[0168] LC-MS: [M+H] + :342.3.

[0169] Synthesis of 1 g of 9-chloro-2,3,5,6-tetrahydro-1-oxa-3a,6a,8-triazaphenanthran-7(4H)-one:

[0170]

[0171] 3-(2,4-dichloro-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-8-yl)methanesulfonic acid propyl ester 1f (2.7 g, 7.89 mmol) and potassium carbonate (3.3 g, 23.67 mmol) were dissolved in 1,4-dioxane (20 mL) and water (20 mL) and stirred at 90°C for 2 h. The mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 mL) and washed with saturated brine (30 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 8 / 1) to obtain a white solid compound 1g (300.0 mg, 17%, 2 steps).

[0172] LC-MS: [M+H] + :228.2.

[0173] Synthesis of 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 1i:

[0174]

[0175] Compound 3,4,5-trifluorobenzaldehyde 1h (23.0 g, 143.67 mmol), 2-(trifluoromethyl)pyridin-4-ol (25.8 g, 158.04 mmol), potassium carbonate (19.9 g, 143.67 mmol) were dissolved in DMF (200 mL) and reacted at 90°C for 1 h. After cooling to room temperature, the reaction solution was poured into ice water (2 L), extracted with ethyl acetate (500 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:5) to obtain white solid compound 1i (22.0 g, 51%).

[0176] LC-MS: [M+H] + :304.0.

[0177] Synthesis of 4-(4-ethynyl-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine 1j:

[0178]

[0179] 3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 1i (10.0 g, 32.98 mmol) and potassium carbonate (9.1 g, 65.97 mmol) were dissolved in methanol (200 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (9.5 g, 49.47 mmol) was slowly added. The mixture was stirred at room temperature for 4 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain yellow oily compound 1j (6.0 g, 61%).

[0180] LC-MS: [M+H] + :300.2.

[0181] Synthesis of 4-(2,6-difluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenoxy)-2-(trifluoromethyl)pyridine 1k:

[0182]

[0183] 4-(4-ethynyl-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine 1j (6.0 g, 20.05 mmol), dinonylcarbonyl iron (3.7 g, 10.03 mmol), pinacol borane (3.1 g, 24.06 mmol) were dissolved in toluene (70 mL), replaced with nitrogen three times, heated to 100 ° C and stirred for 3 h. Filtered, the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a yellow solid product compound 1k (3.0 g, 35%).

[0184] LC-MS: [M+H] + :428.4.

[0185] Synthesis of 4-(2,6-difluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)phenoxy)-2-(trifluoromethyl)pyridine 11:

[0186]

[0187] 1M diethylzinc hexane solution (23.4 mL, 23.41 mmol) was dissolved in dichloromethane (15 mL), cooled to 0°C, and then trifluoroacetic acid (1.6 g, 14.05 mmol) was added dropwise. The mixture was stirred for 0.5 h, and diiodomethane (3.8 g, 14.05 mmol) was added dropwise. After stirring for another 0.5 h, 4-(2,6-difluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenoxy)-2-(trifluoromethyl)pyridine 1k (1.0 g, 2.34 mmol) was added. The mixture was stirred at room temperature for 3 h. The reaction solution was quenched with saturated sodium bicarbonate (30 mL) at 0°C and extracted with dichloromethane (70 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the residue was purified by reverse phase preparation (formic acid system) to give a white solid product, compound 11 (40.0 mg, 4%).

[0188] LC-MS: [M+H] + :442.0

[0189] Compound 1: Synthesis of 9-(2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxyphenyl)cyclopropyl)-2,3,5,6-tetrahydro-4H,7H-1-oxa-3a,6a,8-triazaphenanthran-7-one:

[0190]

[0191] 4-(2,6-difluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)phenoxy)-2-(trifluoromethyl)pyridine 1l (40.0 mg, 0.09 mmol), 9-chloro-2,3,5,6-tetrahydro-4H,7H-1-oxa-3a,6a,8-triazaphenanthran-7-one 1g (21 mg, 0.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.0 mg, 0.01 mmol), and cesium carbonate (59 mg, 0.18 mmol) were dissolved in 1,4-dioxane (2 mL) and water (4 mL), replaced with nitrogen three times, and the temperature was raised to 100°C and stirred for 3 h. The crude product was separated by reverse phase preparative separation (formic acid system) and freeze-dried to obtain a white solid product, compound 1 (8.5 mg, 19%).

[0192] LC-MS: [M+H] + :507.2.

[0193] 1 H NMR (400 MHz, CDCl3) δ8.59 (d, J = 5.6 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 6.98 (dd, J = 5.6, 2.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.26-4.22 (m, 2H), 4.09-4.03 (m, 2H), 3.65-3.59 (m, 2H), 3.53-3.48 (m, 2H), 2.93-2.88 (m, 1H), 2.54-2.50 (m, 1H), 2.24-2.19 (m, 2H), 2.08-2.00 (m, 1H), 1.42-1.37 (m, 1H). Example 2:

[0194] Compound 2 and Compound 3:

[0195] Synthesis of 9-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one and 9-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one:

[0196]

[0197] Synthesis of (2,4,6-trichloropyrimidin-5-yl)methanol 2b

[0198]

[0199] Compound 2,4,6-trichloropyrimidine-5-carboxaldehyde 2a (25.0 g, 118.24 mmol) was dissolved in tetrahydrofuran (250 mL), cooled to 0°C, sodium borohydride (6.7 g, 177.36 mmol) was added, and the mixture was slowly heated to room temperature and stirred for 1 h. Water (100 mL) was added dropwise to quench, and the mixture was extracted with ethyl acetate (300 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain white solid compound 2b (15.0 g, 59%).

[0200] LC-MS: [M+H] + :213.0.

[0201] Synthesis of (4-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)-2,6-dichloropyrimidin-5-yl)methanol 2d:

[0202]

[0203] Compound (2,4,6-trichloropyrimidin-5-yl)methanol 2b (10.0 g, 46.85 mmol), 3-((tert-butyldiphenylsilyl)oxy)propan-1-amine 2c (13.2 g, 42.17 mmol), N,N-diisopropylethylamine (9.1 g, 70.28 mmol) were dissolved in acetonitrile (200 mL) and stirred at room temperature for 2 h. The reaction solution was dried and purified by column chromatography (ethyl acetate: petroleum ether = 1:10) to obtain white solid compound 2d (15.0 g, 65%).

[0204] LC-MS: [M+H] + :490.4.

[0205] Synthesis of 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5,7-dichloro-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine 2e:

[0206]

[0207] Compound (4-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)-2,6-dichloropyrimidin-5-yl)methanol 2d (2.0 g, 4.08 mmol) and p-toluenesulfonic acid (1.4 g, 8.15 mmol) were dissolved in toluene (30 mL), and formaldehyde (37% in H2O, 661.6 mg, 8.16 mmol) was added, and the temperature was raised to 100°C and stirred for 16 h. Saturated sodium carbonate (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:20) to obtain white solid compound 2e (1.2 g, 59%).

[0208] LC-MS: [M+H] + :502.0.

[0209] Synthesis of 3-(5,7-dichloro-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)yl)propan-1-ol 2f:

[0210]

[0211] Compound 1-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5,7-dichloro-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine 2e (1.2 g, 2.39 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, tetrabutylammonium fluoride (1M in THF, 4.8 mL, 4.80 mmol) was slowly added, and the temperature was slowly raised to room temperature and stirred for 2 h. Water (20 mL) was slowly added to quench, and the mixture was extracted with ethyl acetate (40 mL*2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain white solid compound 2f (500.0 mg, 79%).

[0212] LC-MS: [M+H] + :264.0.

[0213] Synthesis of 2g of 3-(5,7-dichloro-2H-pyrimido[4,5-d][1,3]oxazine-1(4H)-yl)propyl methanesulfonate:

[0214]

[0215] Compound 3-(5,7-dichloro-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)yl)propan-1-ol 2f (500.0 mg, 1.89 mmol) and triethylamine (287.4 mg, 2.84 mmol) were dissolved in dichloromethane (10 mL), cooled to 0°C, methylsulfonyl chloride (260.2 mg, 2.27 mmol) was added, and the mixture was heated to room temperature and stirred for 1 h. The reaction solution was spin-dried to obtain 2 g (800.0 mg crude) of crude product.

[0216] LC-MS: [M+H] + :342.0.

[0217] Synthesis of 9-chloro-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one 2h:

[0218]

[0219] Dissolve 2g (800.0mg, crude) of the compound 3-(5,7-dichloro-2H-pyrimido[4,5-d][1,3]oxazin-1(4H)-yl)propyl methanesulfonate and potassium carbonate (783.7mg, 5.67mmol) in dioxane (10mL) and water (10mL), and heat to 90℃ and stir for 2h. Cool down and filter, spin dry the reaction solution, add methanol (10mL) and dichloromethane (100mL) and stir for 0.5h, then filter, spin dry the filtrate to obtain 2h (90.0mg, 17%). LC-MS: [M+H] + :228.0.

[0220] Synthesis of (E)-9-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one 2i:

[0221]

[0222] 4-(2,6-difluoro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenoxy)-2-(trifluoromethyl)pyridine 1k (440.0 mg, 1.03 mmol), 9-chloro-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one 2h (350.9 mg, 1.54 mmol), potassium carbonate (284.1 mg, 2.06 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (150.4 mg, 0.21 mmol) were dissolved in 1,4-dioxane (13.0 mL) and water (13.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 80°C for 16 hours. After the reaction was completed, water (30.0 mL) was added to the obtained mixture for dilution, and then extracted twice with ethyl acetate (30.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid compound 2i (260.0 mg, 51%).

[0223] LC-MS: [M+H] + :493.1.

[0224] Compound 2 and Compound 3:

[0225] Synthesis of 9-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one and 9-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one:

[0226]

[0227] The solution of trimethylsulfoxide iodide (557.6 mg, 2.53 mmol) in dimethylsulfoxide (27.0 mL) was cooled to 0°C, and then sodium hydride (101.3 mg, 2.53 mmol) was added to the mixture at 0°C. The reaction system was gradually warmed to room temperature and stirred for 30 minutes. At room temperature, (E)-9-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-5,6-dihydro-1H,3H,4H,7H-2-oxa-3a,6a,8-triazaphenanthran-7-one 2i (250.0 mg, 0.51 mmol) was added to the above mixture. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate. Water (50.0 mL) was added to the obtained crude product for dilution, and then extracted twice with ethyl acetate (50.0 mL). The obtained crude product was purified by silica gel chromatography (dichloromethane:methanol=12:1) to obtain compound 2j.

[0228] Compound 2j was prepared by chiral chromatography (chromatographic column: Chiralpak-AS, mobile phase: CO2-MeOH(DEA)) to give white solid compound 2 (100.9 mg, 39%) and white solid compound 3 (105.0 mg, 41%).

[0229] Compound 2:

[0230] RT = 2.37 min.

[0231] LC-MS: [M+H] + :507.1.

[0232] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=5.6Hz,1H),7.64(d,J=2.2Hz,1H),7.30(s,1H),7.28(s,2H),4.87-4.72(m,4H),3.81-3.71(m,2H ),3.28(t,J=5.7Hz,2H),2.62-2.55(m,1H),2.10(dd,J=10.8,6.8Hz,1H),2.03-1.94(m,2H),1.70-1.63(m,1H),1.42-1.35(m,1H).

[0233] Compound 3:

[0234] RT = 2.90 min.

[0235] LC-MS: [M+H] + :507.1.

[0236] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=5.6Hz,1H),7.64(d,J=2.2Hz,1H),7.30(s,1H),7.28(s,2H),4.88-4.72(m,4H),3.82-3.70 (m,2H),3.29(t,J=5.6Hz,2H),2.61-2.57(m,1H),2.14-2.07(m,1H),2.05-1.94(m,2H),1.71-1.61(m,1H),1.44-1.34(m,1H).

[0237] Embodiment 3:

[0238] Compound 4: (8R)-3-(2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8,8a,9-tetrahydro-1H,6Hpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0239] Synthesis of (R)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol 4b:

[0240]

[0241] 2,4,6-Trichloropyrimidine (10.9 g, 59.32 mmol) and triethylamine (10.0 g, 98.86 mmol) were dissolved in acetonitrile (90 mL), cooled to 0°C, and a solution of (R)-pyrrolidin-2-ylmethanol 4a (5.0 g, 49.43 mmol) in acetonitrile (10 mL) was added dropwise. The mixture was reacted at 0°C for 2 h, filtered, and the filtrate was dried and purified by column chromatography (PE:EA=2:1) ​​to obtain an off-white solid compound 4b (7.8 g, 63%).

[0242] LC-MS: [M+H] + :248.2.

[0243] Synthesis of (R)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methyl methanesulfonate 4c:

[0244]

[0245] (R)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol 4b (7.8 g, 31.36 mmol) and triethylamine (9.5 g, 94.07 mmol) were dissolved in tetrahydrofuran (100 mL), cooled to 0°C, and a solution of methylsulfonyl chloride (5.4 g, 47.04 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction flask. The mixture was reacted at 0°C for 10 min. The reaction solution was dried to obtain a yellow solid compound 4c (10.2 g, 100%).

[0246] LC-MS: [M+H] + :326.0.

[0247] Synthesis of (R)-3-chloro-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 4d:

[0248]

[0249] (R)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methyl methanesulfonate 4c (18.7 g, 57.23 mmol) was dissolved in acetonitrile (240 mL), potassium carbonate (23.7 g, 171.70 mmol) was added, and the mixture was reacted at 90 °C for 4 h. The mixture was cooled to room temperature and filtered. The filtrate was dried and passed through a column (DCM:MeOH=20:1) to obtain an off-white solid compound 4d (8.4 g, 69%).

[0250] LC-MS: [M+H] + :212.2.

[0251] Synthesis of (R,E)-3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 4e:

[0252]

[0253] (R)-3-chloro-7,8,8a,9-tetrahydro-1H,6H-pyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 4d, compound 1k (119.0 mg, 0.28 mmol), potassium carbonate (66.0 mg, 0.48 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (14.0 mg, 0.02 mmol) were dissolved in 1,4-dioxane (2.0 mL) and water (2.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 80°C for 16 hours. After the reaction was completed, water (10.0 mL) was added to the obtained mixture for dilution, and then extracted twice with ethyl acetate (10.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The obtained crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give white solid compound 4e (50.0 mg, 45%).

[0254] LC-MS: [M+H] + :477.2.

[0255] Compound 4: Synthesis of (8R)-3-(2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8,8a,9-tetrahydro-1H,6Hpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one:

[0256]

[0257] A solution of trimethylsulfoxide iodide (121 mg, 0.55 mmol) in dimethylsulfoxide (3.0 mL) was cooled to 0 °C. Then, sodium hydride (22.0 mg, 0.55 mmol) was added to the above mixture at 0°C, and the reaction system was gradually warmed to room temperature and stirred for 30 minutes. At room temperature, (R,E)-3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-7,8,8a,9-tetrahydro-1H,6Hpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 4e (50.0 mg, 0.11 mmol) was added to the above mixture. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate. Water (3.0 mL) was added to the obtained crude product for dilution, and then extracted twice with ethyl acetate (5.0 mL). The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 15:1) to obtain white solid compound 4 (15.0 mg, 29%).

[0258] LC-MS: [M+H] +:491.1.

[0259] 1 H NMR(400MHz, DMSO-d6)δ8.68(d,J=5.7Hz,1H),7.63(t,J=2.3Hz,1H),7.32-7.2 6(m,3H),5.96(d,J=3.4Hz,1H),4.15-4.06(m,2H),3.91(d,J=7.5Hz,1H),2.58 (ddd,J=18.2,8.4,5.2Hz,2H),2.27-2.22(m,1H),2.00(ddd,J=23.6,13.6,7.6 Hz,3H),1.79-1.70(m,1H),1.62-1.56(m,1H),1.52-1.45(m,1H),1.24(s,1H).

[0260] Embodiment 4:

[0261] Compound 5 and Compound 6: 9-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-4H,7H-1-oxa-3a,6a,8-triazaphenanthran-7-one and 9-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-4H,7H-1-oxa-3a,6a,8-triazaphenanthran-7-one

[0262]

[0263] Compound 1 (18.0 mg, 0.04 mmol) was chiral prepared (Chiralpak-AS, mobile phase: CO2-MeOH(DEA)) to give white solid compound 5 (7.6 mg, 42%) and white solid compound 6 (7.8 mg, 43%).

[0264] Compound 5:

[0265] LC-MS: [M+H] + :507.2.

[0266] RT:1.90min.

[0267] 1H NMR (400MHz, DMSO-d6) δ8.66(d,J=5.3Hz,1H),7.65(s,1H),7.28(d,J=9.6Hz,3H),4.11-4.04(m,2H),3.76 (s,2H),3.51(s,3H),2.44(d,J=3.9Hz,2H),2.01(s,2H),1.66(d,J=3.6Hz,1H),1.51(s,1H),1.24(s,1H).

[0268] Compound 6:

[0269] LC-MS: [M+H] + :507.2.

[0270] RT:2.53min.

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 5.4 Hz, 1H), 7.65 (s, 1H), 7.28 (d, J = 10.1 Hz, 3H), 4.07 (d, J = 4.0 Hz, 2H), 3.76 (s, 2H), 3.50 (s, 3H), 2.44 (d, J = 3.8 Hz, 2H), 2.00 (s, 2H), 1.65 (d, J = 3.0 Hz, 1H), 1.50 (s, 1H), 1.25 (s, 1H). Example 5:

[0272] Compound 7 and Compound 8: (R)-2-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one and (R)-2-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one

[0273] Synthesis of (R)-2-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)ethanol 7b:

[0274]

[0275] Dissolve 2,4,6-trichloropyrimidine (2.4 g, 12.87 mmol) and triethylamine (3.0 g, 29.70 mmol) in acetonitrile (20 mL), cool to 0°C, add dropwise a solution of (R)-2-(morpholin-3-yl)ethane-1-ol 7a (1.3 g, 9.90 mmol) in acetonitrile (5 mL), and react at 0°C for 2 hours. After the reaction is complete, filter, and the filtrate is dried and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid compound 7b (1.0 g, 32%). LC-MS: [M+H] + :278.1.

[0276] Synthesis of (R)-2-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)ethyl methanesulfonate 7c:

[0277]

[0278] Take (R)-2-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)ethanol 7b (1.0 g, 3.60 mmol) and triethylamine (1.1 g, 10.80 mmol) and dissolve them in tetrahydrofuran (10 mL). Cool to 0 °C, add a solution of methylsulfonyl chloride (0.65 g, 5.65 mmol) in tetrahydrofuran (20 mL) dropwise into the reaction flask, react at 0 °C for 1 hour, spin dry the reaction solution to obtain a yellow solid compound 7c which is directly used in the next step.

[0279] LC-MS: [M+H] + :356.1.

[0280] Synthesis of (R)-2-chloro-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one 7d:

[0281]

[0282] (R)-2-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)ethyl methanesulfonate 7c (1.2 g, 3.40 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (0.7 g, 5.10 mmol) was added, and the mixture was reacted at 90 °C for 4 hours. The mixture was cooled to room temperature and filtered. The filtrate was dried and purified by column chromatography (dichloromethane:methanol=20:1) to obtain white solid compound 7d (1.4 g, 85%).

[0283] LC-MS: [M+H] + :242.1.

[0284] Synthesis of (R,E)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one 7e:

[0285]

[0286] Compound 1k (620.1 mg, 1.45 mmol), (R)-2-chloro-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one 7d (500.0 mg, 2.07 mmol), potassium carbonate (571.9 mg, 4.14 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (151.4 mg, 0.21 mmol) were dissolved in 1,4-dioxane (10.0 mL) and water (1.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 80°C for 16 hours. After the reaction was completed, water (30.0 mL) was added to the resulting mixture for dilution, and then extracted twice with ethyl acetate (30.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to obtain a white solid compound 7e (300.0 mg, 24%).

[0287] LC-MS: [M+H] + :507.1.

[0288] Compounds 7 and 8: Synthesis of (R)-2-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one and (R)-2-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one:

[0289]

[0290] The solution of trimethylsulfoxide iodide (216.9 mg, 0.99 mmol) in dimethylsulfoxide (5.0 mL) was cooled to 0°C, and then sodium hydride (39.4 mg, 0.96 mmol) was added to the above solution. The reaction system was gradually warmed to room temperature and stirred for 30 minutes. At room temperature, (R,E)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-6,7,7a,8,10,11-hexahydro-4H-pyrimido[6',1':2,3]pyrimido[6,1-c][1,4]oxazin-4-one 7e (100.0 mg, 0.20 mmol) was added to the above mixture. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate. Water (10.0 mL) was added to the obtained crude product for dilution, and then extracted twice with ethyl acetate (20.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a mixture product. The mixture product was chiral prepared (CHIRALPAK OJ-H 250mm*20mm, 5μm, Modifier: 40% IPA (NH4OH 0.2%): 60% CO2) to obtain white solid compound 7 (12.1 mg, 12%) and white solid compound 8 (16.2 mg, 16%).

[0291] Compound 7:

[0292] LC-MS: [M+H] + :521.1.

[0293] RT:3.89min.

[0294] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=5.7Hz,1H),7.62(d,J=2.4Hz,1H),7.32-7.24(m,3H),6.07(s,1H),4.17(dt,J=13.7,4.3Hz,1H),3.88(dd d,J=13.9,8.7,5.6Hz,3H),3.46(ddd,J=24.0,15.6,8.0Hz,4H),3.20-3.11(m,2H),2.17-2.06(m,2H),1.74-1.67(m,1H),1.58-1.45(m,2H).

[0295] Compound 8:

[0296] LC-MS: [M+H] +:521.1.

[0297] RT:5.19min.

[0298] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=5.7Hz,1H),7.64(d,J=2.2Hz,1H),7.27(d,J=9.5 Hz,3H),6.06(d,J=7.0Hz,1H),4.16(dt,J=13.6,4.2Hz,1H),3.87(dt,J=19.8,12.3 Hz,3H),3.44(ddd,J=25.6,13.2,6.8Hz,4H),3.14(ddd,J=15.6,15.0,7.2Hz,2H),2 .17-2.04(m,2H),1.68(dt,J=9.1,4.5Hz,1H),1.52(ddd,J=15.1,12.4,7.5Hz,2H).

[0299] Embodiment 6:

[0300] Compound 9 and Compound 10: 3-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one and 3-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0301] Synthesis of (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]heptane-1-yl)methanol 9b:

[0302]

[0303] Compound (7-azabicyclo[2.2.1]hept-1-yl)methanol 9a (500.0 mg, 3.94 mmol) and 2,4,6-trichloropyrimidine (860.0 mg, 4.72 mmol) were dissolved in acetonitrile (10.0 mL), triethylamine (795.0 mg, 7.88 mmol) was added at 0°C, and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain white solid compound 9b (600.0 mg, 56%).

[0304] LC-MS: [M+H] + :274.0.

[0305] Synthesis of (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]heptane-1-yl)methyl methanesulfonate 9c:

[0306]

[0307] Take (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]heptane-1-yl)methanol 9b (600.0 mg, 2.19 mmol) and triethylamine (663.0 mg, 6.57 mmol) and dissolve them in tetrahydrofuran (8.0 mL), cool to 0°C, add methylsulfonic anhydride (571.0 mg, 3.28 mmol) to the reaction bottle, and react the mixture at 0°C for 1 hour. After the reaction is completed, the reaction solution is dried to obtain a yellow solid, which is directly used in the next step (600.0 mg). LC-MS: [M+H] + :352.1.

[0308] Synthesis of 3-chloro-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 9d:

[0309]

[0310] Take (7-(2,6-dichloropyrimidin-4-yl)-7-azabicyclo[2.2.1]heptane-1-yl)methyl methanesulfonate 9c (600.0 mg, 1.71 mmol) and dissolve it in acetonitrile (10 mL). Add potassium carbonate (471.0 mg, 3.42 mmol) and react at 25 ° C for 16 hours. After the reaction is completed, filter, and the filtrate is dried and purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid compound 9d (40.0 mg, 16%).

[0311] LC-MS: [M+H] + :238.1.

[0312] Synthesis of (E)-3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 9e:

[0313]

[0314] Compound 1k (162.1 mg, 0.39 mmol), 3-chloro-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 9d (60.0 mg, 0.25 mmol), potassium carbonate (69.8 mg, 0.50 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (18.5 mg, 0.025 mmol) were dissolved in 1,4-dioxane (10.0 mL) and water (1.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 80°C for 16 hours. After the reaction was completed, water (30.0 mL) was added to the obtained mixture for dilution, and then extracted twice with ethyl acetate (30.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The obtained crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give white solid compound 9e (80.0 mg, 53%).

[0315] LC-MS: [M+H] + :503.1.

[0316] Compound 9 and Compound 10: Synthesis of 3-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one and 3-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one:

[0317]

[0318] A solution of trimethylsulfoxide iodide (109.3 mg, 0.50 mmol) in dimethylsulfoxide (5.0 mL) was cooled to 0°C, sodium hydride (19.49 mg, 0.50 mmol) was added to the mixture, and the reaction system was gradually warmed to room temperature and stirred for 30 minutes. At room temperature, (E)-3-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-7,8-dihydro-1H,6H,9H-6,8-ethylpyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one 9e (50.0 mg, 0.10 mmol) was added to the above mixture. The mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate. Water (10.0 mL) was added to the obtained crude product for dilution, and then extracted twice with ethyl acetate (20.0 mL). The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a mixture product. The mixture product was chiral prepared (CHIRALPAK OJ-H 250mm*20mm, 5μm, Modifier: 40% IPA (NH4OH 0.2%): 60% CO2) to obtain white solid compound 9 (7.9 mg, 15%) and white solid compound 10 (6.9 mg, 13%).

[0319] Compound 9:

[0320] LC-MS: [M+H] + :517.1.

[0321] RT:2.75min.

[0322] 1 H NMR (400MHz, CD3OD) δ8.60(d,J=5.7Hz,1H),7.40(d,J=2.4Hz,1H),7.15(dd,J=5 .7,2.4Hz,1H),7.11-7.04(m,2H),6.03(s,1H),4.36(t,J=4.5Hz,1H),4.03(s,2 H),2.70-2.63(m,1H),2.23-2.18(m,1H),2.11-2.02(m,2H),1.86(ddd,J=16.9, 7.9, 3.9Hz, 5H), 1.78 (dd, J=14.9, 2.9Hz, 2H), 1.54 (ddd, J=8.6, 6.2, 4.7Hz, 1H).

[0323] Compound 10:

[0324] LC-MS: [M+H] + :517.1.

[0325] RT:3.38min.

[0326] 1 H NMR (400MHz, CD3OD) δ8.60(d,J=5.7Hz,1H),7.40(d,J=2.4Hz,1H),7.15(dd,J=5 .7,2.3Hz,1H),7.10-7.04(m,2H),6.03(s,1H),4.36(t,J=4.5Hz,1H),4.03(s,2 H),2.70-2.62(m,1H),2.21(ddd,J=9.6,5.5,4.2Hz,1H),2.11-2.02(m,2H),1.9 1-1.81(m,5H),1.77(dd,J=14.8,2.9Hz,2H),1.54(ddd,J=8.6,6.2,4.7Hz,1H).

[0327] Embodiment 7:

[0328] Compound 11 and Compound 12: (5R)-10-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazin-8-one and (5R)-10-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazin-8-one

[0329] Synthesis of (R)-tert-butyl 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)morpholine-4-carboxylate 11b:

[0330]

[0331] At room temperature, (R)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester 11a (10.0 g, 46.03 mmol), 6-chloropyrimidine-2,4(1H,3H)-dione (6.7 g, 46.03 mmol) and triphenylphosphine (16.9 g, 64.44 mmol) were dissolved in tetrahydrofuran (200 mL) and N,N-dimethylformamide (40 mL), and diisopropyl azodicarboxylate (18.6 g, 92.06 mmol) was added dropwise at 0°C. Stir at 0°C for 2 h, and then react at room temperature for 16 h. Water (100 mL) was added to dilute the reaction solution, and ethyl acetate (100 mL*3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain a colorless oil compound 11b (4.87 g, 31%).

[0332] LC-MS: [M+Na] + :368.0.

[0333] Synthesis of (R)-6-chloro-1-(morpholin-2-ylmethyl)pyrimidine-2,4(1H,3H)-dione 11c:

[0334]

[0335] (R)-tert-butyl 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)morpholine-4-carboxylate 11b (4.9 g, 14.08 mmol) was dissolved in dichloromethane (40 mL), and trifluoroacetic acid (32.1 g, 281.68 mmol) was added dropwise at 0° C. The mixture was reacted at room temperature for 2 h, and concentrated under reduced pressure to obtain compound 11c (4.9 g, 100%) as a yellow oil.

[0336] LC-MS: [M+H] + :246.0.

[0337] Synthesis of (5R)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimidin[1,6-d][1,4,6]oxadiazolidine-8,10(9H)-dione 11d:

[0338]

[0339] (R)-6-Chloro-1-(morpholin-2-ylmethyl)pyrimidine-2,4(1H,3H)-dione 11c (4.9 g, 19.82 mmol) was dissolved in acetonitrile (30 mL), and N,N-diisopropylethylamine (7.7 g, 59.47 mmol) was added. The mixture was reacted at room temperature for 4 h, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH=20:1) to obtain a light pink solid compound 11d (590.0 mg, 14%).

[0340] LC-MS: [M+H] + :210.0.

[0341] Synthesis of (5R)-8-oxo-2,3,5,6-tetrahydro-8H-1,5-methylenepyrimidinyl[1,6-d][1,4,6]oxadiazol-10-yl 2,4,6-triisopropylbenzenesulfonate 11e:

[0342]

[0343] Compound (5R)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimidine [1,6-d] [1,4,6] oxadiazolidine-8,10 (9H) -dione 11d (35 mg, 0.17 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (101.3 mg, 0.33 mmol) and triethylamine (50.7 mg, 0.50 mmol), 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were dissolved in dichloromethane solution (2.0 mL) and reacted at room temperature for 3 h. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid compound 11e (70.0 mg, 87%).

[0344] LC-MS: [M+H] + :476.2.

[0345] Synthesis of (5R)-10-((E)-3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazin-8-one 11f:

[0346]

[0347] Compound 1k (291.7 mg, 0.39 mmol), (5R)-8-oxo-2,3,5,6-tetrahydro-8H-1,5-methylenepyrimidinyl[1,6-d][1,4,6]oxadiazol-10-yl 2,4,6-triisopropylbenzenesulfonate 11e (270.0 mg, 0.57 mmol), potassium phosphate (241.0 mg, 1.14 mmol) and tetrakistriphenylphosphine palladium (131.2 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (10.0 mL), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 50°C for 16 hours. After the reaction was completed, water (30.0 mL) was added to the obtained mixture for dilution, and then extracted twice with ethyl acetate (30.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The obtained crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to obtain white solid compound 11f (100.0 mg, 28%).

[0348] LC-MS: [M+H] + :493.1.

[0349] Compound 11 and Compound 12: Synthesis of (5R)-10-((1R,2R)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazin-8-one and (5R)-10-((1S,2S)-2-(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)cyclopropyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazin-8-one:

[0350]

[0351] The solution of trimethylsulfoxide iodide (44.6 mg, 0.20 mmol) in dimethylsulfoxide (5.0 mL) was cooled to 0°C, sodium hydride (8.1 mg, 0.20 mmol) was added to the above solution, and the reaction system was gradually heated to room temperature and stirred for 30 minutes. At room temperature, (5R)-10-((E)-3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenylvinyl)-2,3,5,6-tetrahydro-8H-1,5-methylpyrimido[1,6-d][1,4,6]oxadiazine-8-one 11f (20.0 mg, 0.041 mmol) was added to the above mixture, and the mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate. Water (10.0 mL) was added to the obtained crude product for dilution, and then extracted twice with ethyl acetate (20.0 mL), the organic phases were combined and washed with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude oil. The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a mixture product. The mixture product was chiral prepared (CHIRALPAK OJ-H250mm*20mm, 5μm, Modifier: 40% IPA (NH4OH 0.2%): 60% CO2) to obtain white solid compound 11 (4.1 mg, 20%) and white solid compound 12 (3.1 mg, 15%).

[0352] Compound 11:

[0353] LC-MS: [M+H] + :507.1.

[0354] RT:4.06min.

[0355] 1 H NMR (400MHz, CD3OD) δ8.60(d,J=5.7Hz,1H),7.39(d,J=2.4Hz,1H),7.15(dd,J=5.7,2.4Hz,1 H),7.13-7.06(m,2H),6.38(s,1H),4.49-4.44(m,1H),4.06(dd,J=16.0,5.1Hz,1H),3.91(d, J=16.0Hz,1H),3.71-3.60(m,3H),3.54-3.43(m,2H),3.04(d,J=13.6Hz,1H),2.77-2.69(m, 1H), 2.28 (ddd, J=9.5, 5.5, 4.2Hz, 1H), 1.90-1.83 (m, 1H), 1.61 (ddd, J=8.6, 6.3, 4.7Hz, 1H).

[0356] Compound 12:

[0357] LC-MS: [M+H] + :507.1.

[0358] RT:4.98min.

[0359] 1 H NMR (400MHz, CD3OD) δ8.60(d,J=5.7Hz,1H),7.41(d,J=2.4Hz,1H),7.16(dd,J=5.7,2.4Hz,1H ),7.13-7.06(m,2H),6.37(s,1H),4.49-4.43(m,1H),4.07(dd,J=16.0,5.1Hz,1H),3.94-3.88 (m,1H),3.71-3.62(m,3H),3.54-3.45(m,2H),3.04(d,J=13.6Hz,1H),2.73-2.66(m,1H),2.2 8(ddd,J=9.4,5.5,4.2Hz,1H), 1.89(dt,J=9.1,4.9Hz,1H), 1.59(ddd,J=8.6,6.3,4.7Hz,1H).

[0360] Biological evaluation

[0361] 1. Recombinant human Lp-PLA2 inhibition assay (rhLp-PLA2)

[0362] 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.

[0363] 1. Prepare assay buffer: 50 mM MES (pH 6.5), 150 mM NaCl, 0.1% BSA

[0364] 2. Dissolve the compound powder in DMSO to a 10 mM stock solution and keep at room temperature for later use.

[0365] 3. The compound solution was diluted four-fold with DMSO.

[0366] 4. Use Echo to transfer serial dilutions of compounds to 384-well plate experiments.

[0367] 5. Prepare 2x PLA2G7 in assay buffer.

[0368] 6. Add 15 μl of prepared PLA2G7 to the 384-well plate and place it in a 25°C incubator for incubation.

[0369] 7. Prepare a 2x mixture of 2-Thio-PAF and DTNB in ​​assay buffer.

[0370] 8. Add 15 μl of the mixture of 2x 2-Thio-PAF and DTNB to the plate and incubate in a 25°C incubator.

[0371] 9. Data was read using Envision, ABS 405nm. The results are listed in Table 1.

[0372] Table 1

[0373]

[0374]

[0375] Experimental reagents:

[0376] PLA2G7 (Sino biological, 10848-H08H); 2-Thio-PAF (Cayman, 60945); DTNB (Sigma, D-8130);

[0377] II: Human plasma Lp-PLA2 inhibition assay

[0378] 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.

[0379] Determination method:

[0380] 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;

[0381] 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.

[0382] 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);

[0383] 4. Set the parameters of the microplate reader (Abs414, time interval 1min, recording for 40min).

[0384] 5. The exported data were processed and analyzed using GraphPad Prism7. The results are listed in Table 2.

[0385] Table 2

[0386] Compound No. <![CDATA[H plasma Lp-PLA2(IC 50 ,nM)]]> Compound 1 (Example 1) 4.1 Compound 3 (Example 2) 6.9 Compound 4 (Example 3) 27.7 Compound 6 (Example 4) 6.1 Compound 7 (Example 5) 12.8 Compound 9 (Example 6) 13.4 Compound 11 (Example 7) 3.7 Darapladib 8.0

[0387] Experimental reagents:

[0388] Human plasma(PreceDo,20230203EDTA); DTNB(TCI,D0944); 2-thio-PAF(MCE,HY-101263)

[0389] 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, The Cy ring is a 5-7 membered saturated heterocyclic ring, a non-aromatic unsaturated heterocyclic ring, or an aromatic heterocyclic ring, which contains 0-2 heteroatoms selected from N, O, and S in addition to the common N atom on the ring; alternatively, the Cy ring is a 5-7 membered saturated heterocyclic ring, or an aromatic heterocyclic ring, which contains 0-1 N atoms in addition to the common N atom on the ring; alternatively, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, a diazacycloheptane ring, an azacyclohexane, an azacycloheptanane, an azacyclohexane, an azacycloheptanane, an imidazole ring, a pyridine ring, or a pyrimidine ring; m, n, and o are each independently 0, 1, or 2; X is =CH-, -CH=, -CH2-, -O-, -S-, =N-, -N=, or -NR3-; wherein, R3 is selected from: -H, alkyl, deuterated alkyl, hydroxyalkyl, or cycloalkyl; V is -CHR4-, -CR4=, =CR4-, or a single bond; wherein R4 is selected from: -H or alkyl; W is -H, -CH2-R5, -O-R5, -S-R5, -N(R5)2; wherein R5 is selected from: -H, alkyl, deuterated alkyl, haloalkyl, hydroxyl, hydroxyalkyl, or cycloalkyl; R1 is each independently cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen; R2 are each independently alkyl, deuterated alkyl, haloalkyl, cyano, or halogen; Optionally, when m is 2, two R1s are connected by a single bond or -O-, and together with the Cy ring form a non-aromatic spiro ring; Optionally, when m is 1 or 2, one of R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring, fused ring, spirocyclic ring or bridged ring containing 1-3 heteroatoms selected from N, O, or S, which is fused to the Cy ring, or a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which together with the Cy ring forms a bridged ring; Optionally, when V is -CHR4-, V forms a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring with X through a single bond, -O-, or -CH2-; or, V is connected to W or the carbon atom where W is located through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring and the pyrimidine ring represented by Cx; Optionally, when V is a single bond, X is connected to W or the carbon atom where W is located through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which is fused together with the Cy ring and the pyrimidine ring represented by Cx; 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', -N(R')-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, halosulfanyl, cyano, amino, nitro, aldehyde, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R' is alkyl; R" is alkyl or cycloalkyl; R"' is alkylene; Z is O or S; The halogen atoms in the "halogen", "haloalkyl", "haloalkoxy" and "halosulfanyl" are each independently selected from F, Cl, Br or I; The alkyl groups in the aforementioned “alkyl”, “deuterated alkyl”, “deuterated alkoxy”, “hydroxyalkyl”, “haloalkyl”, “haloalkoxy”, “alkoxy”, 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; The "alkylene" is each independently C1-C 10 A straight or branched alkylene group; optionally, a C1-C7 straight or branched alkylene group; optionally, a C1-C5 straight or branched alkylene group; optionally, selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, tert-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene 1,2-dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n-heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3-dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, or 2,2,3-trimethylbutylene; The "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; The "heterocyclic group" is a 3-10-membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; alternatively, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocyclic group is a 3-10-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring; alternatively, the heterocyclic group is a 3-6-membered non-aromatic heterocyclic group containing 1 or 2 heteroatoms selected from N and S on the ring; The "aryl" is a 6-10 membered aryl; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl; The "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group; The "heteroaryl" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; alternatively, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; alternatively, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group; alternatively, the heteroaromatic group is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl , pyrimidin-4-yl, pyrimidin-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]oxazinyl, imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl, benzothiophenyl, benzo[ oxazolyl, benzimidazolyl, benzothiazolyl, benzoxaphene, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[ [1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazolo[2,3-b]pyrazinyl, or pyrimido[4,5-d]pyrimidinyl; optionally, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl; The "heteroarylene" is a 5-10 membered heteroaromatic ring group containing 1-3 heteroatoms selected from N, O and S on the ring; alternatively, it is a 5-10 membered heteroaromatic ring group containing 1-2 heteroatoms selected from N, O and S on the ring; alternatively, the heteroaromatic ring group is selected from a pyridine ring group, a pyrrole ring group, a pyrazole ring group, a pyrimidine ring group, a pyrazine ring group, a pyridazine ring group, a thiophene ring group, or a furan ring group.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The Cy ring is a 5-6 membered aromatic heterocyclic ring; optionally, the Cy ring is an imidazole ring, a pyridine ring, or a pyrimidine ring; V is a single bond; m and n are each independently 0, 1 or 2; optionally; n is 0 or 1; optionally, m is 0 and n is 0; Optionally, X is =CH-, =N-, or -NR3-, wherein R3 is selected from: -H, alkyl, deuterated alkyl, or hydroxyalkyl; Optionally, X is =CH-, =N-, or -N(CH3)-; Optionally, W is -H, -CH2-R4, or -O-R4; wherein R4 is selected from: -H, alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, or -CH3; Optionally, W is -H; Optionally, R1 is each independently alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, or hydroxyalkyl; Optionally, R1 is each independently alkyl, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3; Optionally, R1 is each independently -CH3.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring; m and n are each independently 0, 1 or 2; V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3; Optionally; n is 0 or 1; Optionally, X is -CH2-, -O-, or -NR3-, wherein R3 is -H, alkyl, deuterated alkyl, or hydroxyalkyl; Optionally, X is -O-, -N(CH3)-, or -N(CH2CH3)-; Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, deuterated alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, -CH3, -CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H; Optionally, R1 is each independently alkyl, alkoxy, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3; Optionally, R1 is each independently -CH3, or -CH2CH3; Optionally, when m is 2, two R1s form a non-aromatic spiro ring together with the Cy ring through a single bond or -O-; optionally, the non-aromatic spiro ring is:

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring; m and n are each independently 0, 1 or 2; V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3; Optionally, n is 0; Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -N(CH3)-, or -N(CH2CH3)-; Optionally, W is -CH2-R4, or -O-R4; wherein R4 is selected from: -H, alkyl, deuterated alkyl, hydroxyl, or hydroxyalkyl; Optionally, W is -H, or -CH3; Optionally, W is -H; Optionally, R1 is each independently alkyl; Optionally, V forms a 5-8 membered non-aromatic monocyclic ring fused with the Cy ring and containing 1-3 heteroatoms selected from N, O, or S through a single bond, -O-, or -CH2- with X; Optionally, the structure after the non-aromatic monocyclic ring is fused with Cy is:

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring; m and n are each independently 0, 1 or 2; V is -CHR4-, wherein R4 is selected from: -H, -CH3, or -CH2CH3; Optionally, m is 0; Optionally, n is 0 or 1; Optionally, X is -NR3-, wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, or -N(CH3)-; Optionally, X is -N(CH3)-; Optionally, W is -H, -CH2-R4, or -O-R4, wherein R4 is selected from: -H, or alkyl; Optionally, W is -H, -CH3, -CH2CH3, -O-CH3, or -O-CH2CH3; Optionally, W is -H, -CH3, -O-CH3, or -O-CH2CH3; Optionally, W is -O-CH3; Optionally, R1 is each independently alkyl, alkoxy, or hydroxyalkyl; Optionally, R1 is each independently -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -OCH3, or -OCH2CH3; Optionally, V forms a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S with W through a single bond or -CH2-, which is fused with the Cy ring and the pyrimidine ring represented by Cx; Optionally, the structure after the non-aromatic monocyclic ring is fused with the Cy ring and Cx is:

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is an azacyclohexane ring, a diazacyclopentane ring, a diazacyclohexane ring, an azaoxane ring, or an azaoxepane ring; optionally, the Cy ring is a diazacyclopentane ring, a diazacyclohexane ring, or an azaoxepane ring; m is 0, 1 or 2; V is -CHR4- or a single bond, wherein R4 is selected from: -H, -CH3, or -CH2CH3; Optionally, n is 0; Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -N(CH3)-; Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, or alkyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H; Optionally, R1 is independently -H, alkyl, or alkoxy; Optionally, R1 is independently -CH3, -CH2CH3, -OCH3, or -OCH2CH3; Optionally, when m is 1, R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic, fused, spirocyclic or bridged ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring; optionally, the structure after the non-aromatic monocyclic ring is fused to the Cy ring is: Optionally, the structure after the non-aromatic fused ring, spiro ring or bridged ring is fused with the Cy ring is: Alternatively, when m is 2 and V is a single bond, one R1 is connected to X through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S and fused to the Cy ring; alternatively, the structure formed by the non-aromatic monocyclic ring and another R1 and Cy ring is:

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is a diazacyclopentane ring or a diazacyclohexane ring; m is 0, 1 or 2; V is -CHR4- or a single bond, wherein R4 is selected from: -H, -CH3, or -CH2CH3; Optionally, m is 0 or 1; Optionally, n is 0; Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, -N(CH3)-, or -N(CH2CH3)-; Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, or hydroxyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -H; Optionally, R1 is independently -H, alkyl, or alkoxy; Optionally, R1 is independently -H, -CH3, -CH2CH3, -OCH3, or -OCH2CH3; Optionally, R1 is connected to X through a single bond or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which together with the Cy ring constitutes a non-aromatic bridge ring; optionally, the structure of the non-aromatic bridge ring is:

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein The Cy ring is a 5-7 membered saturated heterocyclic ring; optionally, the Cy ring is a diazacyclopentane ring or a diazacyclohexane ring; m and n are each independently 0, 1 or 2; V is a single bond; Optionally, m is 0; Optionally, n is 0 or 1; Optionally, X is -NR3-; wherein R3 is selected from: -H, or alkyl; Optionally, X is -NH-, -N(CH3)-, or -N(CH2CH3)-; Optionally, W is -H, -CH2-R5, or -O-R5; wherein R5 is selected from: -H, alkyl, or hydroxyl; Optionally, W is -H, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -O-CH3, or -O-CH2CH3; Optionally, W is -CH3, -CH2CH3, -CH2OH, or -O-CH3; Optionally, X is connected to W through a single bond, -O-, or -CH2- to form a 5-8 membered non-aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, or S, which is fused together with the Cy ring and the pyrimidine ring represented by Cx; Optionally, the structure after the non-aromatic monocyclic ring is fused together with the Cy ring and the pyrimidine ring represented by Cx is:

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: o is 0 or 2; R2 is each independently alkyl, cyano, or halogen, optionally, R2 is each independently -CH3, -CN, -Cl, or -F; Ar is phenylene or pyridinylene, the phenylene or pyridinylene 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, -OCH3, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN; Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCD3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2H5, -OC3H7, or -OAr'; Alternatively, Y is -H, -F, -Cl, -Br, -I, or -OAr'; Alternatively, Y is -H, -F, or -OAr'; wherein Ar' is selected from 1, phenyl, pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrazolyl, or quinolyl substituted with 2 or 3 substituents, each of which is independently selected from: -F, -Cl, -Br, -CN, C1-C7 alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, -OCD3, C1-C6 haloalkyl, -OCH3, -OC2H7, -OC3H7, C1- C6 haloalkoxy, hydroxy, hydroxyalkyl, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5; Z is O.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein o is 0 or 2; R2 is each independently -CH3, -Cl, or -F; 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, -F, or -OAr'; wherein, Ar′ is phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl, or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3, or -SF5; Z is O.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the compound of formula (I) is selected from the following compounds:

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: 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.

13. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, comprising the following synthetic route: Route 1: In each structural formula, the definitions of Cy ring, m, n, o, R1, R2, V, W, X, Z, Ar and Y are as described in any one of claims 1 to 12; A is a halogen or a sulfonate group. Route 2: In each structural formula, the definitions of Cy ring, m, n, o, R1, R2, V, W, X, Z, Ar and Y are as described in any one of claims 1 to 12; A is a halogen or a sulfonate group.

14. 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 12 and optionally a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, 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.

16. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 14 or 15 in the preparation of an Lp-PLA2 inhibitor.

17. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 14 or 15, 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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