Bridged ring pyrimidone compound, and preparation method, pharmaceutical composition and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a bridged pyrimidone compound, a preparation method thereof, a pharmaceutical composition thereof, and its use in medicine. In particular, the present invention relates to a bridged pyrimidone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as an Lp-PLA2 inhibitor for treating neurodegenerative diseases such as Alzheimer's disease, glaucoma, age-related macular degeneration (AMD), cardiovascular diseases such as atherosclerosis, diabetic macular edema, or prostate 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 disorders, 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 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 cause of AD has not yet 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 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-stage clinical trials have so far failed to demonstrate clinical efficacy. These disappointing results suggest 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 113666930 A discloses a bridged cyclic 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 atherosclerosis, diabetic macular edema.

[0011] Summary of the invention

[0012] The present invention provides a novel Lp-PLA2 inhibitor, which can be used to treat neurodegenerative diseases, such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), cardiovascular diseases including atherosclerosis, diabetic macular edema (DME), or prostate diseases.

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

[0014]

[0015] in,

[0016] in,

[0017] n1, n2, n5 are each independently 0, 1 or 2;

[0018] n3 and n4 are each independently 1 or 2;

[0019] R1 and R4 are each independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen;

[0020] R2 and R3 are each independently -H, =O, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen;

[0021] m, o are each independently 0, 1 or 2; wherein when m or o is 2, two R2 or R3 optionally together with the C atoms connecting them form a 3-6 membered saturated carbon ring;

[0022] X1 and X2 are each independently selected from: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: H, alkyl, deuterated alkyl, or cycloalkyl;

[0023] 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;

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

[0025] Z is O or S;

[0026] The halogen atoms in the "halogen", "haloalkyl" and "haloalkoxy" are each independently selected from F, Cl, Br or I;

[0027] 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;

[0028] 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;

[0029] The "cycloalkyl" is C3-C 10 Monocyclic or bicyclic cycloalkyl, optionally, C3-C7 monocyclic cycloalkyl; optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

[0030] 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;

[0031] The "aryl" is a 6-10 membered aryl; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl;

[0032] The "arylene group" is a 6-10 membered arylene group; optionally, it is a phenylene group or a naphthylene group;

[0033] 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;

[0034] 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.

[0035] Optionally, in the bridged pyrimidone compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0036] n1, n2, n5 are each independently 0, 1 or 2; optionally, n1 is 0, 1 or 2; optionally, n2 is 0, 1 or 2; optionally, n5 is 0 or 1;

[0037] n3 and n4 are each independently 1 or 2; optionally, n3 is 1 or 2; optionally, n4 is 1 or 2;

[0038] R1 and R4 are each independently selected from: -H, C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 Straight or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); Optionally, R1 is -H or -CH3; Optionally, R4 is -H or -CH3;

[0039] R2 and R3 are each independently selected from: -H, =O, C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 Straight or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); optionally, R2 is -H, or -CH3; optionally, R3 is -H, =O, or -CH3;

[0040] m, o are each independently 0, 1 or 2; alternatively, m is 0, or 1; alternatively, o is 0, 1 or 2; wherein when m or o is 2, two R2 or two R3 optionally together with the C atom connecting them form a 3-6 membered saturated carbon ring, alternatively, two R2 or two R3 optionally together with the C atom connecting them form a cyclopropane ring;

[0041] X1 and X2 are each independently selected from: C1-C7 alkylene (optionally, -CH2-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; optionally, X1 is -CH2-, or -O-; optionally, X1 is -O-; optionally, X2 is -O-; wherein R′ is selected from -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl , 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), or C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane);

[0042] 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, -OMe, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN;

[0043] 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, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), hydroxyl, hydroxyalkyl, cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5;

[0044] Z is O.

[0045] Optionally, in the bridged ring pyrimidone compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof,

[0046] n1 is 0, 1 or 2; n2 is 0, 1 or 2; n5 is 1;

[0047] n3 is 1 or 2; n4 is 1 or 2;

[0048] R1 is -H or -CH3; R4 is -H;

[0049] R2 is -H; R3 is -H, =O or -CH3;

[0050] m is 0; o is 0, 1, or 2, wherein when o is 2, two R3 optionally together with the C atom to which they are connected form a cyclopropane ring;

[0051] X1 is -O- or -CH2-, and X2 is -O-;

[0052] Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN;

[0053] 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 by 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5;

[0054] Z is O.

[0055] Optionally, in the bridged cyclic pyrimidone compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, the compound of formula (I) is selected from the following compounds:

[0056]

[0057]

[0058] Optionally, in the bridged ring pyrimidone compound represented by formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, the pharmaceutically acceptable salt includes an anionic salt of the compound of formula (I);

[0059] Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound of formula (I); optionally, the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium;

[0060] Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an organic base; Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, or N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine;

[0061] Optionally, the pharmaceutically acceptable salt includes a salt formed by a compound of formula (I) and an acid; optionally, the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

[0062] 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.

[0063] Optionally, the dosage form of the pharmaceutical composition includes an oral preparation, a rectal preparation, or a parenteral preparation;

[0064] 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;

[0065] Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

[0066] 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.

[0067] 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.

[0068] 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;

[0069] Optionally, the neurodegeneration-related disease includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

[0070] 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.

[0071] 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:

[0072]

[0073] In each structural formula, n1, n2, n3, n4, n5, R1, R2, R3, R4, m, o, X1, X2, Z, Ar and Y are as defined above, and W is a halogen or a sulfonate group.

[0074] Compound 1A and compound 1B are reacted by substitution reaction (for example, in the presence of a base such as K2CO3) to generate compound 1C; compound 1C is reacted by intramolecular cyclization (for example, by Mitsunobu reaction using an appropriate nucleophilic reagent such as diisopropyl azodicarboxylate and an appropriate reagent such as triphenylphosphine); compound 1D is reacted by chlorination (for example, reaction with POCl3) or by esterification (for example, reaction with sulfonyl chloride) to generate compound 1E (Z=O); compound 1E is reacted by sulfidation (for example, reaction with Lawesson reagent) to generate compound 1F (Z=S); compound 1E / 1F is reacted by CX coupling (for example, using a catalyst such as methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethyloxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) and an alkaline reagent cesium carbonate) or aromatic nucleophilic substitution (for example, in the presence of a base such as NaH or Cs2CO3) to obtain compound 1G.

[0075] 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).

[0076] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention is a bridged cyclic pyrimidone compound, which is a new Lp-PLA2 inhibitor, and can be used to treat neurodegenerative diseases such as Alzheimer's disease (AD), glaucoma and age-related macular degeneration (AMD), including cardiovascular diseases such as atherosclerosis, diabetic macular edema (DME), or prostate diseases. DETAILED DESCRIPTION

[0077] 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.

[0078] Example

[0079] 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.

[0080] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0081] In the examples, unless otherwise specified, the reaction temperature is room temperature, for example, 20-30°C.

[0082] Embodiment 1:

[0083] Compounds 1 and 2: (10S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoc-1(5H)-one and (10R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoc-1(5H)-one

[0084]

[0085] Synthesis of 6-((3-hydroxypiperidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 1b:

[0086]

[0087] A solution of 6-chloromethylpyrimidine-2,4(1H,3H)-dione 1a (5.0 g, 0.031 mol), 3-hydroxypiperidine (3.7 g, 0.037 mol) and potassium carbonate (6.4 g, 0.046 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane: methanol = 5: 1 (50 mL), the insoluble potassium carbonate was filtered off, the filter cake was washed with methanol, the filtrate was collected and dried, and the obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a white solid compound 1b (5.0 g, 71%).

[0088] LC-MS: [M+H] + :225.9.

[0089] Synthesis of 7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoline-1,3(2H,5H)-dione 1c:

[0090]

[0091] Compound 6-((3-hydroxypiperidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 1b (5.0 g, 0.022 mol) and triphenylphosphine (11.6 g, 0.044 mol) were dissolved in tetrahydrofuran (100 mL), the mixture was cooled to 0°C, diisopropyl azodicarboxylate (8.9 g, 0.044 mol) was slowly added dropwise, and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was dried, the residue was diluted with saline, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid compound 1c (1.3 g, 28%). LC-MS: [M+H] + :208.2.

[0092] Synthesis of 1-oxo-1,5,7,8,9,10-hexahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoctan-3-yl 2,4,6-triisopropylbenzenesulfonate 1d:

[0093]

[0094] Compound 7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazocine-1,3(2H,5H)-dione 1c (1.2 g, 5.80 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (3.5 g, 0.012 mol), triethylamine (1.7 g, 0.017 mol) and 4-dimethylaminopyridine (0.07 g, 0.58 mmol) were dissolved in dichloromethane solution (20.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to give a white solid compound 1d (2.0 g, 73%).

[0095] LC-MS: [M+H] + :474.3.

[0096] Synthesis of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1e:

[0097]

[0098] Compound 3,4,5-trifluorobenzaldehyde 1e-1 (23.0 g, 143.67 mmol), 2-(trifluoromethyl)pyridin-4-ol (25.8 g, 158.04 mmol), potassium carbonate (19.9 g, 143.67 mmol) were dissolved in DMF (200 mL) and reacted at 90°C for 1 h. After cooling to room temperature, the reaction solution was poured into ice water (2 L), extracted with ethyl acetate (500 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:5) to obtain white solid compound 1e-2 (22.0 g, 51%).

[0099] LC-MS: [M+H] + :304.0.

[0100] Compound 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 1e-2 (20.0 g, 65.97 mmol) was dissolved in ethanol (200 mL), cooled to 0°C, sodium borohydride (2.5 g, 65.97 mmol) was added, and the temperature was slowly raised to room temperature and stirred for 1 h. The reaction solution was spin-dried, added to water (500 mL), extracted with ethyl acetate (300 mL*3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by chromatography column (ethyl acetate: petroleum ether = 1:1) to obtain white solid compound 1e (20.0 g, 99%).

[0101] LC-MS: [M+H] + :306.1.

[0102] Synthesis of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazocin-1(5H)-one 1f:

[0103]

[0104] Compound 1-oxo-1,5,7,8,9,10-hexahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoctan-3-yl-2,4,6-triisopropylbenzenesulfonate 1d (500.0 mg, 1.05 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1e (484.9 mg, 1.58 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (100.2 mg, 0.10 mmol) and cesium carbonate (687.9 mg, 2.11 mmol) were dissolved in anhydrous toluene (5 mL), and the mixture was stirred at 100° C. for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to obtain a white solid compound 1f (40.0 mg, 8%). LC-MS: [M+H] + :495.2.

[0105] Compounds 1 and 2: (10S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoc-1(5H)-one and (10R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazoc-1(5H)-one

[0106]

[0107] 3-((3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7,8,9,10-tetrahydro-6,10-methylenepyrimido[1,6-a][1,4]diazocin-1(5H)-one 1f (40.0 mg, 0.08 mmol) was chiral prepared (CHIRALPAK AD-H, 250 mm*20 mm, 5 μm, 40% EtOH and 60% CO2) to give white solid compound 1 (5.2 mg, 13%) and white solid compound 2 (8.8 mg, 22%).

[0108] Compound 1:

[0109] RT:2.18min.

[0110] LC-MS: [M+H] + :495.2.

[0111] 1 H NMR (400MHz, DMSO-d6) δ = 8.68 (d, J = 5.7, 1H), 7.68 ( d, J = 2.4, 1H), 7.50 ( d, J = 8.9, 2H), 7.33 ( d, J = 2.2, 1H), 5.96 ( s, 1H), 5.37 ( d, J = 7.0, 2H), 4 .28(s,1H),4.16(d,J=19.3,1H),3.86(s,1H),3.16(s,1H),3.09(s,1H ),2.91(d,J=5.5,2H),1.80(dd,J=18.5,11.4,2H),1.34-1.27(m,2H).

[0112] Compound 2:

[0113] RT:3.28min.

[0114] LC-MS: [M+H] + :495.2.

[0115] 1H NMR (400MHz, DMSO-d6) δ = 8.68 (d, J = 5.7, 1H), 7.68 (d, J = 2.4, 1H), 7.50 (d, J = 8. 9,2H),7.32(dd,J=5.6,2.2,1H),5.96(s,1H),5.37(q,J=13.3,2H),4.28(s,1H) ,4.16(d,J=19.6,1H),3.84(d,J=18.9,1H),3.18(d,J=13.8,1H),3.07(d,J=13. 9, 1H), 2.92 (t, J = 7.0, 2H), 1.82 (dt, J = 9.8, 8.0, 2H), 1.32 (d, J = 3.3, 2H). Example 2:

[0116] Compounds 3 and 4: (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0117]

[0118] Synthesis of 6-((3-hydroxypyrrolidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 3b:

[0119]

[0120] A solution of 6-chloromethylpyrimidine-2,4(1H,3H)-dione 1a (5.0 g, 0.031 mol), 3-hydroxypyrrolidine (3.2 g, 0.037 mol) and potassium carbonate (6.4 g, 0.046 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane: methanol = 5:1, the insoluble potassium carbonate was filtered off, the filter cake was eluted with methanol, and the filtrate was dried by spin drying. The obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 10:1) to obtain a white solid compound 3b (3.0 g, 46%). LC-MS: [M+H] + :212.2.

[0121] Synthesis of 4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 3c:

[0122]

[0123] Compound 6-((3-hydroxypyrrolidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 3b (3.0 g, 0.014 mol) and triphenylphosphine (7.3 g, 0.028 mol) were dissolved in tetrahydrofuran (60 mL), the mixture was cooled to 0°C, diisopropyl azodicarboxylate (5.6 g, 0.028 mol) was slowly added dropwise, and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was extracted three times with ethyl acetate and washed twice with brine, the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20:1) to obtain white solid compound 3c (1.8 g, 67%).

[0124] LC-MS: [M+H] + :194.1.

[0125] Synthesis of 7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-9-yl 2,4,6-triisopropylbenzenesulfonate 3d:

[0126]

[0127] Compound 4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 3c (1.8 g, 9.32 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (4.2 g, 13.87 mmol) and triethylamine (2.7 g, 0.027 mol), 4-dimethylaminopyridine (0.11 g, 0.90 mmol) were dissolved in dichloromethane (30.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid compound 3d (1.3 g, 30%). LC-MS: [M+H] + :460.3.

[0128] Synthesis of 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-7(1H)-one 3e:

[0129]

[0130] Compound 7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-9-yl 2,4,6-triisopropylbenzenesulfonate 3d (700.0 mg, 1.52 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1e (695.0 mg, 2.28 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (143.0 mg, 0.15 mmol) and cesium carbonate (991.0 mg, 3.04 mmol) were dissolved in anhydrous toluene (10 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and the crude product was purified by silica gel chromatography (dichloromethane:methanol=10:1) to obtain white solid compound 3e (70.0 mg, 10%).

[0131] LC-MS: [M+H] + :481.0.

[0132] Compounds 3 and 4: (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0133]

[0134] 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylenepyrimido[1,6-a][1,4]diazepine-7(1H)-one 3e (70.0 mg, 0.15 mmol) was chiral prepared (CHIRALPAK AD-H 250 mm*20 mm, 5 μm; mobile phase: 40% EtOH (0.2% NH4OH): 60% CO2) to give pale yellow solid compound 3 (27.5 mg, 39%) and pale yellow solid compound 4 (27.3 mg, 39%).

[0135] Compound 3:

[0136] RT:2.18min.

[0137] LC-MS: [M+H] + :481.1.

[0138] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.7Hz,1H),7.68(d,J=2.5Hz,1H),7.48(d,J=8.8Hz,2H),7 .32(dd,J=5.7,2.4Hz,1H),5.90(s,1H),5.35(s,2H),4.98(d,J=2.4Hz,1H),4.20(d,J=18.7Hz ,1H),3.77(d,J=18.7Hz,1H),3.14(d,J=12.1Hz,1H),3.05(s,1H),2.91(dd,J=15.6,9.9Hz,1 H), 2.79 (d, J = 11.9Hz, 1H), 2.08 (ddd, J = 12.6, 10.5, 5.3Hz, 1H), 1.86 (dd, J = 12.1, 6.1Hz, 1H).

[0139] Compound 4:

[0140] RT:3.28min.

[0141] LC-MS: [M+H] + :481.1.

[0142] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.6Hz,1H),7.68(d,J=2.5Hz,1H),7.48(d,J=8.8Hz,2H),7.3 2(dd,J=5.6,2.4Hz,1H),5.88(s,1H),5.35(s,2H),4.96(dd,J=4.8,2.4Hz,1H),4.17(d,J=18.9H z,1H),3.73(d,J=18.7Hz,1H),3.10(d,J=12.2Hz,1H),2.99(dd,J=10.9,4.5Hz,1H),2.87(dd,J= 12.6, 6.5Hz, 1H), 2.73 (d, J=12.1Hz, 1H), 2.06 (ddd, J=10.5, 6.2, 3.4Hz, 1H), 1.87-1.80 (m, 1H).

[0143] Embodiment 3:

[0144] Compound 6: 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-ethylidenepyrimidin[1,6-a][1,4]diazepine-7(1H)-one

[0145]

[0146] Synthesis of 6-((4-hydroxypiperidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 6b:

[0147]

[0148] Compound 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione 1a (3.0 g, 18.70 mmol) and piperidine-4-ol (2.27 g, 22.47 mmol) were dissolved in N,N-dimethylformamide (30.0 mL), potassium carbonate (3.88 g, 28.12 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 6b (2.6 g, 62%).

[0149] LC-MS: [M+H] + :226.1.

[0150] Synthesis of 4,5-dihydro-3H-2,5-ethylenepyrimidine[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 6c:

[0151]

[0152] Compound 6-((4-hydroxypiperidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 6b (2.6 g, 11.50 mmol) and triphenylphosphine (6.03 g, 23.00 mmol) were dissolved in dioxane (20 mL), diisopropyl azodicarboxylate (4.65 g, 23.00 mmol) was added dropwise to the mixture at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain a light yellow solid compound 6c (150.0 mg, 6%).

[0153] LC-MS: [M+H] + :208.1.

[0154] Synthesis of 7-oxo-1,4,5,7-tetrahydro-3H-2,5-ethylidenepyrimido[1,6-a][1,4]diazepine-9-yl-2,4,6-triisopropylbenzenesulfonate 6d:

[0155]

[0156] Compound 4,5-dihydro-3H-2,5-ethylidenepyrimidine [1,6-a] [1,4] diazepine-7,9 (1H, 8H) -dione 6c (150.0 mg, 0.72 mmol) and 4-dimethylaminopyridine (8.8 mg, 0.072 mmol) were dissolved in dichloromethane (10 mL), triethylamine (219.7 mg, 2.17 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (328.8 mg, 1.09 mmol) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 6d (150.0 mg, 44%).

[0157] LC-MS: [M+H] + :474.2.

[0158] Compound 6: 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-ethylidenepyrimidin[1,6-a][1,4]diazepine-7(1H)-one:

[0159]

[0160] Compound 7-oxo-1,4,5,7-tetrahydro-3H-2,5-ethylidenepyrimido[1,6-a][1,4]diazepine-9-yl-2,4,6-triisopropylbenzenesulfonate 6d (80.0 mg, 0.17 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 1e (77.6 mg, 0.25 mmol), cesium carbonate (110.1 mg, 0.34 mmol), and methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (16.0 mg, 0.017 mmol) were dissolved in toluene (4.0 mL), and the mixture was stirred at 100° C. for 1 hour under argon protection. The mixture was extracted with ethyl acetate, washed with saturated brine, concentrated in vacuo and dried. The crude product was separated by preparative separation to obtain white solid compound 6 (2.6 mg, 3%). LC-MS: [M+H] + :495.1.

[0161] 1H NMR: (400MHz, DMSO-d6) δ8.63(d,J=5.7Hz,1H),7.46(d,J=2.5Hz,1H),7.39(t,J=6.9Hz,2H),7.19(dd,J=5.7,2.4Hz,1H),6.17(s,1H),5 .82-5.77(m,1H),5.72-5.66(m,1H),5.47(s,2H),4.93(s,1H),3.51(s,2H),3.07-3.04(m,2H),2.65(t,J=5.7Hz,2H),2.25-2.21(m,2H).

[0162] Embodiment 4:

[0163] Compounds 15 and 16: (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0164]

[0165] Synthesis of 6-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 15b:

[0166]

[0167] Compound 3-methylpyrrolidin-3-ol (5.0 g, 49.50 mmol) and 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione 15a (9.5 g, 59.40 mmol) were dissolved in N,N-dimethylformamide (70.0 mL), potassium carbonate (13.7 g, 99.00 mmol) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain white solid compound 15b (2.5 g, 35%).

[0168] LC-MS: [M+H] + :226.2.

[0169] Synthesis of 5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 15c:

[0170]

[0171] Compound 6-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)pyrimidine-2,4(1H,3H)-dione 15b (300.0 mg, 1.33 mmol) and triphenylphosphine (524.0 mg, 2.00 mmol) were dissolved in tetrahydrofuran (6.0 mL), diisopropyl azodicarboxylate (404.0 mg, 2.00 mmol) was slowly added at zero degrees, and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 15c (150.0 mg, 55%).

[0172] LC-MS: [M+H] + :208.1.

[0173] Synthesis of 5-methyl-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-9-yl-2,4,6-triisopropylbenzenesulfonate 15d:

[0174]

[0175] Compound 5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7,9(1H,8H)-dione 15c (110.0 mg, 0.23 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (84.0 mg, 0.28 mmol) and triethylamine (46.0 mg, 0.46 mmol), 4-dimethylaminopyridine (3.0 mg, 0.02 mmol) were dissolved in dichloromethane solution (3.0 mL) and reacted at room temperature for 3 hours. After the reaction was completed, it was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 15d (60.0 mg, 24%).

[0176] LC-MS: [M+H] + :474.3.

[0177] Synthesis of 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 15e:

[0178]

[0179] Compound 5-methyl-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-9-yl-2,4,6-triisopropylbenzenesulfonate 15d (60.0 mg, 0.13 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)phenyl)methanol 1e (48.0 mg, 0.16 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) (9.0 mg, 0.01 mmol) and cesium carbonate (84.0 mg, 0.26 mmol) were dissolved in anhydrous toluene (3.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo and the crude product was purified by silica gel chromatography (dichloromethane:methanol=20:1) to obtain white solid compound 15e (12.0 mg, 38%).

[0180] LC-MS: [M+H] + :495.1.

[0181] Compounds 15 and 16: Synthesis of (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0182]

[0183] Compound 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-5-methyl-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 15e (12.0 mg, 0.02 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 15 (3.4 mg, 28%) and white solid compound 16 (3.7 mg, 31%).

[0184] Compound 15:

[0185] LC-MS: [M+H] + :495.1.

[0186] RT:2.51min.

[0187] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.3Hz,1H),7.67(s,1H),7.50(d,J=8.9Hz,2H),7.32(d,J=2.5Hz,1H),6.07(s,1H),5.38(d,J=5.6Hz,2H) ,4.80(s,1H),4.08(d,J=3.4Hz,2H),3.10(d,J=7.0Hz,1H),2.48-2.41(m,2H),1.94(s,1H),1.44-1.39(m,1H),1.27(dd,J=6.8,2.8Hz,3H).

[0188] Compound 16:

[0189] LC-MS: [M+H] + :495.2.

[0190] RT:3.12min.

[0191] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=5.7Hz,1H),7.68(d,J=2.4Hz,1H),7.50(d,J=8.8Hz,2H),7.32(dd,J=5.6,2.3Hz,1H),6.07(s,1H),5.38(d,J=5.9Hz, 2H),4.81(d,J=3.1Hz,1H),4.08(d,J=4.1Hz,2H),3.09(t,J=7.0Hz,1H),2.4 8-2.43(m,2H),1.99-1.93(m,1H),1.45-1.38(m,1H),1.28(d,J=6.9Hz,3H).

[0192] Embodiment 5:

[0193] Compounds 25 and 26: (5S)-9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0194]

[0195] Synthesis of 3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 25b:

[0196]

[0197] 3,4-difluorobenzaldehyde 25a (10.0 g, 70.37 mmol), 2-(trifluoromethyl)pyridin-4-ol (11.5 g, 70.37 mmol) and cesium carbonate (45.9 g, 140.75 mmol) were dissolved in N,N-dimethylformamide (100 mL), heated to 80°C, and stirred for 3 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was added with water (100 mL), extracted with ethyl acetate (100 mL x 2), and the organic phases were combined and washed with water (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain yellow oil compound 25b (5.3 g, 26%).

[0198] LC-MS: [M+H] + :286.0

[0199] Synthesis of (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 25c:

[0200]

[0201] 3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde 25b (1.0 g, 3.51 mmol) was dissolved in methanol (10 mL), cooled to 0°C under nitrogen protection, sodium borohydride (199.0 mg, 5.26 mmol) was added in batches, and the reaction was stirred at room temperature for 3 h. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the methanol was spin-dried. The solution was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The white solid compound 25c (600.0 mg, 60%) was purified by column chromatography (petroleum ether: ethyl acetate = 1:1).

[0202] LC-MS: [M+H] + :288.4.

[0203] Synthesis of 9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 25d:

[0204]

[0205] Compound 3d (450.0 mg, 0.98 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol 25c (337.5 mg, 1.17 mmol), cesium carbonate (638.0 mg, 1.96 mmol) and methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (692.95 mg, 0.098 mmol) were dissolved in toluene (15.0 mL), and the mixture was stirred at 100° C. for 2 hours under argon protection. The reaction solution was concentrated in vacuo, and the crude product was separated by preparative separation to obtain white solid compound 25d (10.0 mg, 2%).

[0206] LC-MS: [M+H] + :463.1.

[0207] Compounds 25 and 26: Synthesis of (5S)-9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0208]

[0209] Compound 9-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 25d (10.0 mg, 0.022 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 25 (3.6 mg, 36%) and white solid compound 26 (3.9 mg, 39%).

[0210] Compound 25:

[0211] LC-MS: [M+H] + :463.1.

[0212] RT:2.21min.

[0213] 1H NMR (400MHz, CDCl3) δ8.58 (d, J = 5.6Hz, 1H), 7.34-7.26 (m, 2H), 7.23-7.18 (m,2H),6.96(d,J=5.4Hz,1H),5.73(s,1H),5.43(s,2H),5.32(s,1H),4.33 (d,J=18.5Hz,1H),3.77(d,J=18.6Hz,1H),3.39-3.30(m,1H),3.17(d,J=12 .6Hz,1H),3.04-2.92(m,2H),2.15(d,J=7.1Hz,1H),2.00(d,J=5.9Hz,1H).

[0214] Compound 26:

[0215] LC-MS: [M+H] + :463.1.

[0216] RT:2.82min.

[0217] 1 H NMR(400MHz, CDCl3)δ8.58(d,J=5.6Hz,1H),7.33-7.26(m,2H),7.20(dd,J=13.8,5.4 Hz,2H),6.96(dd,J=5.6,2.2Hz,1H),5.71(s,1H),5.43(s,2H),5.28(dd,J=4.5,2.4H z,1H),4.28(d,J=18.6Hz,1H),3.72(d,J=18.6Hz,1H),3.32-3.24(m,1H),3.13(d,J= 12.5Hz,1H),2.93(dd,J=17.8,9.6Hz,2H),2.14-2.08(m,1H),2.00(d,J=6.0Hz,1H).

[0218] Embodiment 6:

[0219] Compounds 27 and 28: 5-(((5S)-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile and 5-(((5R)-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile

[0220]

[0221] Synthesis of 5-formyl-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27b:

[0222]

[0223] 2-Fluoro-5-formylbenzonitrile 27a (10.0 g, 67.06 mmol), 2-(trifluoromethyl)pyridin-4-ol (10.9 g, 67.06 mmol), cesium carbonate (32.8 g, 100.60 mmol) were dissolved in N,N-dimethylformamide (100 mL), stirred at 90°C for 2 h. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 27b (10.0 g, 51%).

[0224] LC-MS: [M+H] + :293.0

[0225] Synthesis of 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27c:

[0226]

[0227] 5-Formyl-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27b (1.0 g, 3.42 mmol) was dissolved in methanol (20 mL), cooled to 0°C, and sodium borohydride (194.1 mg, 5.13 mmol) was slowly added. The reaction was stirred at room temperature for 2 h, and water (10 mL) was added to quench the reaction. The solvent was concentrated under reduced pressure and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 27c (1.0 g, 99%) as a white solid.

[0228] LC-MS: [M+H] + :295.0.

[0229] Synthesis of 5-(((7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27d:

[0230]

[0231] Compound 3d (300.0 mg, 0.65 mmol), 5-(hydroxymethyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27c (192.0 mg, 0.65 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (56.0 mg, 0.06 mmol) and cesium carbonate (332.0 mg, 1.30 mmol) were dissolved in anhydrous toluene (9.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain white solid compound 27d (8.0 mg, 3%).

[0232] LC-MS: [M+H] + :470.0.

[0233] Compounds 27 and 28: Synthesis of 5-(((5S)-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile and 5-(((5R)-7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile:

[0234]

[0235] Compound 5-(((7-oxo-1,4,5,7-tetrahydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-9-yl)oxy)methyl)-2-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzonitrile 27d (8.0 mg, 0.02 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 27 (2.1 mg, 26%) and white solid compound 28 (2.3 mg, 28%).

[0236] Compound 27:

[0237] LC-MS: [M+H] + :470.2.

[0238] RT:2.47min

[0239] 11H NMR (400 MHz, CD3OD) δ 8.64 (d, J = 5.7 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 8.6, 2.1 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 5.7, 2.4 Hz, 1H), 5.95 (s, 1H), 5.44 (s, 2H), 5.14 (dd, J = 4.9, 2.7 Hz, 1H), 4.30 (d, J = 18.8 Hz, 1H), 3.86 (d, J = 18.7 Hz, 1H), 3.23 (d, J = 12.4 Hz, 1H), 3.18 (dd, J = 11.4, 4.9 Hz, 1H), 3.04 - 2.98 (m, 1H), 2.94 (d, J = 12.4 Hz, 1H), 2.20 (d, J = 6.9 Hz, 1H), 2.03 (s, 1H).

[0240] Compound 28:

[0241] LC-MS: [M+H] + : 470.2.

[0242] RT: 2.92 min

[0243] 1 1H NMR (400 MHz, CD3OD) δ 8.64 (d, J = 5.7 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.6, 2.2 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 5.7, 2.4 Hz, 1H), 5.95 (s, 1H), 5.44 (s, 2H), 5.16 - 5.13 (m, 1H), 4.30 (d, J = 18.7 Hz, 1H), 3.86 (d, J = 18.7 Hz, 1H), 3.23 (d, J = 12.4 Hz, 1H), 3.18 (dd, J = 10.8, 4.3 Hz, 1H), 3.01 (d, J = 6.0 Hz, 1H), 2.94 (d, J = 12.2 Hz, 1H), 2.21 - 2.17 (m, 1H), 2.03 (d, J = 5.4 Hz, 1H).

[0244] Example 7:

[0245] Compounds 29 and 30: (5S)-9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0246] Synthesis of 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde 29b:

[0247]

[0248] 2-Methylpyridin-4-ol (25.0 g, 229.06 mmol), 3,4,5-trifluorobenzaldehyde 29a (40.3 g, 251.99 mmol) and potassium carbonate (47.5 g, 343.63 mmol) were dissolved in N,N-dimethylformamide (300 mL), replaced with nitrogen three times, slowly heated to 90°C, and stirred for 3 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow oily product compound 29b (19.0 g, 33%).

[0249] LC-MS: [M+H] + :250.4.

[0250] Synthesis of (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol 29c:

[0251]

[0252] 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde 29b (18.0 g, 72.23 mmol) was dissolved in methanol (200 mL), cooled to 0°C, sodium borohydride (4.1 g, 108.34 mmol) was slowly added, and the temperature was slowly restored to room temperature for 2 h. Saturated ammonium chloride solution (200 mL) was added dropwise at 0°C to quench the reaction, the solvent was concentrated under reduced pressure, extracted with ethyl acetate (200 mL x 2), the organic phases were combined, and dried over anhydrous sodium sulfate, and the residue was purified by column (petroleum ether: ethyl acetate = 7:1) to obtain white solid compound 29c (14.0 g, 77%).

[0253] Synthesis of 9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 29d:

[0254]

[0255] Compound 3d (200.0 mg, 0.44 mmol), (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol 29c (166.0 mg, 0.66 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (41.0 mg, 0.04 mmol) and cesium carbonate (287.0 mg, 0.88 mmol) were dissolved in anhydrous toluene (6.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain white solid compound 29d (40.0 mg, 22%).

[0256] LC-MS: [M+H] + :427.1.

[0257] Compounds 29 and 30: Synthesis of (5S)-9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0258]

[0259] Compound 9-(3,5-difluoro-4-(2-methylpyridin-4-yl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 29d (40.0 mg, 0.09 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAKAD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 29 (3.5 mg, 9%) and white solid compound 30 (3.7 mg, 9%).

[0260] Compound 29:

[0261] LC-MS: [M+H]+ : 427.1.

[0262] RT: 3.52 min

[0263] 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H), 6.82 (dd, J = 5.6, 2.0 Hz, 1H), 5.87 (s, 1H), 5.34 (s, 2H), 4.96 (d, J = 2.2 Hz, 1H), 4.16 (d, J = 18.8 Hz, 1H), 3.72 (d, J = 18.8 Hz, 1H), 3.10 (d, J = 12.2 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.87 (dd, J = 12.4, 6.2 Hz, 1H), 2.73 (d, J = 12.0 Hz, 1H), 2.43 (s, 3H), 2.09 - 2.01 (m, 1H), 1.84 (d, J = 6.8 Hz, 1H). Compound 30:

[0264] LC-MS: [M + H] + : 427.1.

[0265] RT: 3.92 min

[0266] 1 ¹H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 8.9 Hz, 2H), 6.88 (s, 1H), 6.82 (dd, J = 5.6, 2.0 Hz, 1H), 5.87 (s, 1H), 5.34 (s, 2H), 4.96 (d, J = 2.2 Hz, 1H), 4.16 (d, J = 18.8 Hz, 1H), 3.72 (d, J = 18.8 Hz, 1H), 3.10 (d, J = 12.2 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.87 (dd, J = 12.4, 6.2 Hz, 1H), 2.73 (d, J = 12.0 Hz, 1H), 2.43 (s, 3H), 2.09 - 2.01 (m, 1H), 1.84 (d, J = 6.8 Hz, 1H). Example 8:

[0267] Compounds 31 and 32: (5S)-9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazoc-7(1H)-one and (5R)-9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazoc-7(1H)-one

[0268]

[0269] Synthesis of 3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzaldehyde 31b:

[0270]

[0271] Compound 2-(trifluoromethoxy)pyridin-4-ol (260.0 mg, 1.45 mmol), 3,4,5-trifluorobenzaldehyde 31a (232.4 mg, 1.45 mmol) and potassium carbonate (300.9 mg, 2.18 mmol) were dissolved in N,N-dimethylformamide (8 mL), replaced with nitrogen three times, and slowly heated to 90°C for 4 hours. The reaction solution was filtered and concentrated under reduced pressure to remove N,N-dimethylformamide, and the residue was purified by column (petroleum ether: ethyl acetate = 5:1) to obtain a colorless oil compound 31b (300.0 mg, 65%).

[0272] LC-MS: [M+H] + :320.0.

[0273] Synthesis of (3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 31c:

[0274]

[0275] Compound 3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)benzaldehyde 31b (300.0 mg, 0.94 mmol) was dissolved in methanol (10 mL), cooled to 0°C, sodium borohydride (53.3 mg, 1.41 mmol) was slowly added, and the temperature was slowly restored to room temperature for 2 hours. Saturated aqueous ammonium chloride solution (30 mL) was added dropwise at 0°C, the reaction solution was concentrated under reduced pressure, extracted three times with ethyl acetate (30 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column (petroleum ether: ethyl acetate = 5:1) to obtain compound 31c (160 mg, 53%) as a white solid.

[0276] LC-MS: [M+H] + :322.0.

[0277] Synthesis of 9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazocin-7(1H)-one 31d:

[0278]

[0279] Compound 3d (500.0 mg, 1.09 mmol), (3,5-difluoro-4-((2-(trifluoromethoxy)pyridin-4-yl)oxy)phenyl)methanol 31c (419.3 mg, 1.31 mmol), cesium carbonate (708.9 mg, 2.18 mmol) and methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (103.3 mg, 0.11 mmol) were dissolved in toluene (15.0 mL), and the mixture was stirred at 100° C. for 2 hours under argon protection. The reaction solution was concentrated in vacuo, and the crude product was separated by preparative separation to obtain white solid compound 31d (20.0 mg, 4%).

[0280] LC-MS: [M+H] + :497.1.

[0281] Compounds 31 and 32: Synthesis of (5S)-9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazoc-7(1H)-one and (5R)-9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazoc-7(1H)-one:

[0282]

[0283] Compound 9-(3,5-difluoro-4-(2-(trifluoromethoxy)pyridin-4-yl)oxy)benzyl)oxy-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazocin-7(1H)-one 31d (10.0 mg, 0.022 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 31 (8.3 mg, 42%) and white solid compound 32 (3.9 mg, 27%).

[0284] Compound 31:

[0285] LC-MS: [M+H] + :497.1.

[0286] RT:1.89min

[0287] 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=5.8Hz, 1H), 7.13-7.08 (m, 2H), 6.82 (dd, J=5.8 ,2.2Hz,1H),6.48(d,J=2.1Hz,1H),5.71(s,1H),5.41(s,2H),5.28(dd,J=4.7,2 .5Hz,1H),4.28(d,J=18.7Hz,1H),3.72(d,J=18.7Hz,1H),3.32-3.23(m,1H),3 .13(d,J=12.5Hz,1H),2.97-2.87(m,2H),2.25-2.17(m,1H),2.14-2.07(m,1H).

[0288] Compound 32:

[0289] LC-MS: [M+H] + :497.1.

[0290] RT:2.34min

[0291] 1H NMR (400MHz, CDCl3) δ8.21 (d, J=5.8Hz, 1H), 7.14-7.08 (m, 2H), 6.82 (dd, J=5.8, 2. 2Hz,1H),6.48(d,J=2.2Hz,1H),5.74(s,1H),5.41(s,2H),5.32(d,J=1.5Hz,1H),4. 34(d,J=18.7Hz,1H),3.78(d,J=18.6Hz,1H),3.36(t,J=9.1Hz,1H),3.18(d,J=12.2 Hz,1H),3.06-2.92(m,2H),2.25(ddd,J=15.6,10.4,5.1Hz,1H),2.18-2.10(m,1H).

[0292] Embodiment 9:

[0293] Compounds 33 and 34: (5S)-9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0294]

[0295] Synthesis of 3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde 33b:

[0296]

[0297] Compound 6-(trifluoromethyl)pyridin-3-ol 33a (5.0 g, 30.66 mmol), 3,4,5-trifluorobenzaldehyde 33a (4.9 g, 30.66 mmol), potassium carbonate (6.4 g, 45.98 mmol) were dissolved in N,N-dimethylformamide (100 mL) and stirred at 90°C for 2 h. Water (50 mL) was added, and the reaction solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a colorless oil compound 33b (5.0 g, 54%).

[0298] LC-MS: [M+H] + :304.0.

[0299] Synthesis of (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol 33c:

[0300]

[0301] Compound 3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde 33b (5.0 g, 16.49 mmol) was dissolved in methanol (100 mL), sodium borohydride (935.73 mg, 24.74 mmol) was added to the mixture at 0°C and stirred at room temperature for 2 h. The reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound 33c (4.0 g, 79%) as a colorless oil.

[0302] LC-MS: [M+H] + :306.0.

[0303] Synthesis of 9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 33d:

[0304]

[0305] Compound 3d (400.0 mg, 0.87 mmol), (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol 33c (318.0 mg, 1.04 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (85.0 mg, 0.09 mmol) and cesium carbonate (567.0 mg, 1.74 mmol) were dissolved in anhydrous toluene (12.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 33d (30.0 mg, 7%).

[0306] LC-MS: [M+H] + :481.0.

[0307] Compounds 33 and 34: Synthesis of (5S)-9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0308]

[0309] Compound 9-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 33d (30.0 mg, 0.06 mmol) was chirally prepared (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm; mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 33 (7.3 mg, 24%) and white solid compound 34 (8.7 mg, 29%).

[0310] Compound 33:

[0311] LC-MS: [M+H] + :481.1.

[0312] RT:5.63min

[0313] 1 H NMR (400MHz, DMSO-d6) δ8.69(d,J=2.8Hz,1H),7.91(d,J=8.8Hz,1H),7.64(dd,J=8.7,2.7H z,1H),7.46(d,J=8.8Hz,2H),5.87(s,1H),5.34(s,2H),4.96(dd,J=4.8,2.3Hz,1H),4.17(d , J = 18.9 Hz, 1H), 3.75 (s, 1H), 3.10 (d, J = 12.2 Hz, 1H), 2.99 (dd, J = 10.8, 4.5 Hz, 1H), 2.87 (dd, J = 12.2, 6.2 Hz, 1H), 2.74 (d, J = 12.0 Hz, 1H), 2.07-1.99 (m, 1H), 1.88-1.81 (m, 1H). Compound 34:

[0314] LC-MS: [M+H] + :481.1.

[0315] RT:6.42min

[0316] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),7.91(dd,J=8.6,5.3Hz,1H),7.65(d,J=3.2H z,1H),7.47(dd,J=8.8,4.9Hz,2H),5.88(d,J=4.4Hz,1H),5.35(d,J=4.3Hz,2H), 4.96(s,1H),4.17(dd,J=18.6,3.8Hz,1H),3.75(s,1H),3.11(d,J=11.6Hz,1H),3 .01(s,1H),2.88(s,1H),2.74(d,J=11.9Hz,1H),2.09-2.03(m,1H),1.85(s,1H).

[0317] Embodiment 10:

[0318] Compounds 35 and 36: (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0319]

[0320] Synthesis of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde 35b:

[0321]

[0322] 2-(Trifluoromethyl)pyrimidin-5-ol (1.0 g, 6.09 mmol), 3,4,5-trifluorobenzaldehyde 35a (1.2 g, 7.31 mmol), potassium carbonate (1.1 g, 7.92 mmol) were dissolved in N,N-dimethylformamide (15 mL) and stirred at 90°C for 2 h. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain yellow solid compound 35b (1.1 g, 59%).

[0323] LC-MS: [M+H] + :305.0.

[0324] Synthesis of (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol 35c:

[0325]

[0326] 3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde 35b (950.0 mg, 3.12 mmol) was dissolved in methanol (10 mL), cooled to 0°C, and sodium borohydride (118.0 mg, 3.12 mmol) was slowly added. The reaction was stirred at this temperature for 0.5 h, and water (10 mL) was added dropwise to quench the reaction. The solvent was concentrated under reduced pressure, extracted with ethyl acetate (10 mL x 2), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give an off-white solid compound 35c (700 mg, 73%).

[0327] LC-MS: [M+H] + :307.4.

[0328] Synthesis of 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 35d:

[0329]

[0330] Compound 3d (500.0 mg, 1.09 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol 35c (366.41 mg, 1.20 mmol), cesium carbonate (708.9 mg, 2.18 mmol) and methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (103.3 mg, 0.11 mmol) were dissolved in toluene (15.0 mL), and the mixture was stirred at 100° C. for 2 hours under argon protection. The reaction solution was concentrated in vacuo, and the crude product was separated by preparative separation to obtain white solid compound 35d (5.0 mg, 1%).

[0331] LC-MS: [M+H] + :482.1.

[0332] Compounds 35 and 36: Synthesis of (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0333]

[0334] Compound 9-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 35d (5.0 mg, 0.01 mmol) was chiral prepared (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% MeOH (NH4OH 0.2%): 60% CO2) to give white solid compound 35 (1.8 mg, 36%) and white solid compound 36 (1.6 mg, 32%).

[0335] Compound 35:

[0336] LC-MS: [M+H] + :482.1.

[0337] RT:3.06min

[0338] 1 H NMR (400MHz, CDCl3) δ8.55(s,2H),7.14(d,J=8.2Hz,2H),5.74(s,1H),5.42(s,2H),5.31(s,1H),4.35(d,J=18.7H z,1H),3.79(d,J=18.2Hz,1H),3.36(s,1H),3.18(d,J=12.6Hz,1H),3.06-2.94(m,2H),2.22(s,1H),2.02(s,1H).

[0339] Compound 36:

[0340] LC-MS: [M+H] + :482.1.

[0341] RT:7.30min

[0342] 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 2H), 7.15 (d, J = 9.7 Hz, 2H), 5.73 (s, 1H), 5.42 (s, 2H), 5.30 (s, 1H), 4.34 (d, J = 19.2 Hz, 1H), 3.77 (d, J = 19.0 Hz, 1H), 3.35 (s, 1H), 3.17 (d, J = 11.4 Hz, 1H), 2.99 (s, 2H), 2.22 (s, 1H), 2.02 (s, 1H). Example 11:

[0343] Compounds 37 and 38: (5S)-9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0344]

[0345] Synthesis of 3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)formaldehyde 37b:

[0346]

[0347] 3-(Trifluoromethoxy)phenol (25.0 g, 140.36 mmol), 3,4,5-trifluorobenzene-1-carbaldehyde 37a (22.5 g, 140.36 mmol), potassium carbonate (29.1 g, 210.54 mmol) were dissolved in N,N-dimethylformamide (400 mL) and stirred at 90°C for 2 h. Water (200 mL) was added, and the reaction solution was extracted with ethyl acetate (200 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 37b (25.0 g, 56%) as a colorless oil.

[0348] Synthesis of (3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)phenyl)methanol 37c:

[0349]

[0350] 3,5-Difluoro-4-(3-(trifluoromethoxy)phenoxy)formaldehyde 37b (25.0 g, 78.57 mmol) was dissolved in methanol (400 mL), sodium borohydride (4.5 g, 117.85 mmol) was added to the mixture at 0°C and stirred at room temperature for 2 h. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give a colorless oil 37c (20.0 g, 79%).

[0351] Synthesis of 9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 37d:

[0352]

[0353] Compound 3d (200.0 mg, 0.44 mmol), (3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)phenyl)methanol 37c (211.0 mg, 0.66 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (41.0 mg, 0.04 mmol) and cesium carbonate (287.0 mg, 0.88 mmol) were dissolved in anhydrous toluene (6.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to obtain white solid compound 37d (20.0 mg, 10%).

[0354] LC-MS: [M+H] + :496.0.

[0355] Compounds 37 and 38: Synthesis of (5S)-9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0356]

[0357] Compound 9-(3,5-difluoro-4-(3-(trifluoromethoxy)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 37d (20.0 mg, 0.04 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 37 (3.9 mg, 19%) and white solid compound 38 (4.0 mg, 20%).

[0358] Compound 37:

[0359] LC-MS: [M+H] + :496.0.

[0360] RT:3.20min

[0361] 1 H NMR (400MHz, DMSO-d6) δ7.49(t,J=8.3Hz,1H),7.42(d,J=8.9Hz,2H),7.14(d,J=8.2Hz,1H),7. 08(s,1H),6.99(dd,J=8.4,2.4Hz,1H),5.87(s,1H),5.33(s,2H),4.95(dd,J=4.9,2.4Hz,1H),4 .16(d,J=18.9Hz,1H),3.72(d,J=18.7Hz,1H),3.10(d,J=12.2Hz,1H),2.98(dd,J=11.1,4.8Hz, 1H),2.91-2.82(m,1H),2.73(d,J=11.8Hz,1H),2.06-2.00(m,1H),1.84(dd,J=5.1,2.3Hz,1H).

[0362] Compound 38:

[0363] LC-MS: [M+H] + :496.0.

[0364] RT:4.19min

[0365] 1H NMR(400MHz, DMSO-d6)δ7.50(t,J=8.3Hz,1H),7.43(t,J=6.0Hz,2H),7.17-7.12(m,1H),7. 08(s,1H),6.99(dd,J=8.4,2.4Hz,1H),5.87(s,1H),5.33(s,2H),4.95(dd,J=4.9,2.5Hz,1 H), 4.16 (d, J = 18.9 Hz, 1H), 3.72 (d, J = 18.7 Hz, 1H), 3.10 (d, J = 12.2 Hz, 1H), 3.04-2.95 (m, 1H), 2.92-2.81 (m, 1H), 2.73 (d, J = 11.7 Hz, 1H), 2.07-2.00 (m, 1H), 1.88-1.80 (m, 1H). Example 12:

[0366] Compounds 39 and 40: (5S)-9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0367]

[0368] Synthesis of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzaldehyde 39b:

[0369]

[0370] Compound 4-chloro-3-(trifluoromethyl)phenol (25.0 g, 127.19 mmol), 3,4,5-trifluorobenzaldehyde 39a (20.4 g, 127.19 mmol) and potassium carbonate (26.4 g, 190.79 mmol) were dissolved in N,N-dimethylformamide (200 mL), replaced with nitrogen three times, and slowly heated to 90°C for 4 hours. The reaction solution was filtered and concentrated under reduced pressure to remove N,N-dimethylformamide, and the residue was purified by column (petroleum ether: ethyl acetate = 8:1) to obtain yellow solid compound 39b (28.5 g, 67%).

[0371] Synthesis of (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol 39c:

[0372]

[0373] Compound 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzaldehyde 39b (1.0 g, 2.97 mmol) was dissolved in methanol (15 mL), cooled to 0°C, sodium borohydride (0.17 g, 4.46 mmol) was slowly added, and the temperature was slowly restored to room temperature for 3 h. Saturated ammonium chloride solution was added dropwise at 0°C, and the methanol was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column (petroleum ether: ethyl acetate = 8:1) to obtain white solid compound 39c (710.0 mg, 71%).

[0374] Synthesis of 9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 39d:

[0375]

[0376] Compound 3d (300.0 mg, 0.65 mmol), (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorophenyl)methanol 39c (331.6 mg, 0.98 mmol), cesium carbonate (425.3 mg, 1.31 mmol), and methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (61.9 mg, 0.065 mmol) were dissolved in toluene (9.0 mL), and the mixture was stirred at 100° C. for 1 hour under argon protection. The reaction solution was concentrated in vacuo, and the crude product obtained was separated by preparative separation to give white solid compound 39d (20.0 mg, 6%).

[0377] LC-MS: [M+H] + :495.1.

[0378] Compounds 39 and 40: Synthesis of (5S)-9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0379]

[0380] Compound 9-((4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 39d (20.0 mg, 0.039 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK IG 300mm*30mm, 10 μm, mobile phase: 40% MeOH (NH4OH 0.2%): 60% CO2) to give white solid compound 39 (5.7 mg, 29%) and white solid compound 40 (6.8 mg, 34%).

[0381] Compound 39:

[0382] LC-MS: [M+H] + :514.1.

[0383] RT:3.9min

[0384] 1 H NMR (400MHz, CDCl3) δ7.42(d,J=8.8Hz,1H),7.29(d,J=3.0Hz,1H),7.09(d,J=8.1Hz,2H),7.02(dd,J=8.8,3.0Hz,1H),5.75(s,1H),5.40(s,2H),5.35 (s,1H),4.37(d,J=18.8Hz,1H),3.82(d,J=18.8Hz,1H),3.42(s,1H),3.21 (d,J=12.3Hz,1H),3.04(d,J=41.0Hz,2H),2.32-2.24(m,1H),2.17(s,1H).

[0385] Compound 40:

[0386] LC-MS: [M+H] + :514.1.

[0387] RT:4.8min

[0388] 1H NMR (400MHz, CDCl3) δ7.42(d,J=8.8Hz,1H),7.29(d,J=2.9Hz,1H),7.08(d, J=8.1Hz,2H),7.01(dd,J=8.9,3.0Hz,1H),5.74(s,1H),5.40(s,2H),5.33(s ,1H),4.35(d,J=18.6Hz,1H),3.79(d,J=18.3Hz,1H),3.38(s,1H),3.19(d, J=11.9Hz,1H),3.07-2.93(m,2H),2.30-2.22(m,1H),2.16(d,J=6.4Hz,1H).

[0389] Embodiment 13:

[0390] Compounds 41 and 42: (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0391]

[0392] Synthesis of 3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzaldehyde 41b:

[0393]

[0394] Compound 2-(trifluoromethyl)quinolin-7-ol (1.0 g, 4.69 mmol), 3,4,5-trifluorobenzaldehyde 41a (900.0 mg, 5.63 mmol) and potassium carbonate (1.3 g, 9.38 mmol) were dissolved in N,N-dimethylformamide (15.0 mL), and the mixture was stirred at 90°C for 9 hours. After the reaction was completed, the reaction solution was diluted with water, extracted twice with ethyl acetate, the combined organic phases were washed with saturated brine, the obtained organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, and the obtained crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 41b (1.2 g, 75%).

[0395] LC-MS: [M+H] + :354.0.

[0396] Synthesis of (3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)phenyl)methanol 41c:

[0397]

[0398] Compound 3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzaldehyde 41b (1.2 g, 3.39 mmol) was dissolved in ethanol (20.0 mL), cooled to 0°C, sodium borohydride (190.0 mg, 4.07 mmol) was added, and the mixture was stirred at 25°C for 3 hours. After the reaction was completed, aqueous ammonium chloride solution was added to quench, and the mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to give white solid compound 41c (0.8 g, 67%).

[0399] LC-MS: [M+H] + :356.0.

[0400] Synthesis of 9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 41d:

[0401]

[0402] Compound 3d (300.0 mg, 0.65 mmol), (3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)phenyl)methanol 41c (277.0 mg, 0.78 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino-9,9-dimethylxanthene)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (56.0 mg, 0.06 mmol) and cesium carbonate (423.0 mg, 1.30 mmol) were dissolved in anhydrous toluene (9.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane:methanol=20:1) to obtain white solid compound 41d (20.0 mg, 6%).

[0403] LC-MS: [M+H] + :531.0.

[0404] Compounds 41 and 42: Synthesis of (5S)-9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0405]

[0406] Compound 9-((3,5-difluoro-4-((2-(trifluoromethyl)quinolin-7-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 41d (20.0 mg, 0.04 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 41 (5.6 mg, 28%) and white solid compound 42 (7.4 mg, 37%).

[0407] Compound 41:

[0408] LC-MS: [M+H] + :531.1.

[0409] RT:7.48min

[0410] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=8.5Hz,1H),8.26(d,J=9.1Hz,1H),7.92(d,J=8.5Hz,1H),7.74 (dd,J=9.1,2.6Hz,1H),7.48(d,J=8.8Hz,2H),7.30(d,J=1.9Hz,1H),5.89(s,1H),5.37(s,2H),4 .96(d,J=2.3Hz,1H),4.17(d,J=18.8Hz,1H),3.73(d,J=18.8Hz,1H),3.11(d,J=12.3Hz,1H),3.0 4-2.96(m,1H),2.91-2.82(m,1H),2.74(d,J=12.4Hz,1H),2.09-2.01(m,1H),1.90-1.80(m,1H).

[0411] Compound 42:

[0412] LC-MS: [M+H] + :531.1.

[0413] RT:8.33min

[0414] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=8.5Hz,1H),8.26(d,J=9.1Hz,1H),7.92(d,J=8.5Hz,1H),7.74( dd,J=9.1,2.6Hz,1H),7.48(d,J=8.8Hz,2H),7.30(d,J=2.2Hz,1H),5.89(s,1H),5.37(s,2H),4.96 (d,J=2.4Hz,1H),4.17(d,J=18.7Hz,1H),3.73(d,J=18.8Hz,1H),3.11(d,J=12.1Hz,1H),2.99(d, J=6.6Hz,1H),2.91-2.84(m,1H),2.74(d,J=12.1Hz,1H),2.07-2.01(m,1H),1.86(d,J=7.0Hz,1H).

[0415] Embodiment 14:

[0416] Compounds 43 and 44: (5S)-9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0417]

[0418] Synthesis of 3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde 42b:

[0419]

[0420] Compound 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-ol (2.6 g, 15.65 mmol), 3,4,5-trifluorobenzaldehyde 43a (2.5 g, 15.65 mmol) and potassium carbonate (3.2 g, 23.48 mmol) were dissolved in N,N-dimethylformamide (50 mL), replaced with nitrogen three times, and slowly heated to 90°C for 2 h. The reaction solution was concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 43b (2.9 g, 61%) as a white solid.

[0421] LC-MS: [M+H] + :307.3.

[0422] Synthesis of (3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol 43c:

[0423]

[0424] Compound 3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde 43b (2.8 g, 9.15 mmol) was dissolved in methanol (30 mL), cooled to 0°C, sodium borohydride (0.5 g, 13.72 mmol) was slowly added, and the temperature was slowly restored to room temperature for 3 h. Saturated aqueous ammonium chloride solution (30 mL) was added dropwise at 0°C, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid compound 43c (1.5 g, 53%).

[0425] LC-MS: [M+H] + :309.4.

[0426] Synthesis of 9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 43d:

[0427]

[0428] Compound 3d (300.0 mg, 0.65 mmol), (3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol 43c (301.7 mg, 0.98 mmol), cesium carbonate (425.3 mg, 1.31 mmol) and methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (61.9 mg, 0.065 mmol) were dissolved in toluene (9.0 mL), and the mixture was stirred at 100° C. for 2 hours under argon protection. The reaction solution was concentrated in vacuo, and the crude product was separated by preparative separation to give white solid compound 43d (15.0 mg, 5%).

[0429] LC-MS: [M+H] + :495.1.

[0430] Compounds 43 and 44: Synthesis of (5S)-9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one:

[0431]

[0432] Compound 9-(3,5-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 43d (15.0 mg, 0.031 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 43 (3.9 mg, 26%) and white solid compound 44 (4.1 mg, 27%).

[0433] Compound 43:

[0434] LC-MS: [M+H] + :484.1.

[0435] RT:2.56min.

[0436] 1H NMR (400MHz, CDCl3) δ7.39(s,1H),7.31(s,1H),7.05-7.00(m,2H),5.71(s,1H),5.35(s,2H),5.30(s,1H),4.59(d,J=8.4Hz,2H),4.31(d, J=18.5Hz,1H),3.76(d,J=18.6Hz,1H),3.34(s,1H),3.16(d,J=12.5Hz,1H),3.03-2.92(m,2H),2.26-2.20(m,1H),2.14(d,J=6.3Hz,1H).

[0437] Compound 44:

[0438] LC-MS: [M+H] + :484.1.

[0439] RT:4.68min

[0440] 1 H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.32 (s, 1H), 7.05-7.00 (m, 2H), 5.72 (s, 1H), 5.35 (s, 2H), 5.32 (s, 1H), 4.58 (t, J = 8.4 Hz, 2H), 4.33 (d, J = 18.4 Hz, 1H), 3.78 (d, J = 18.4 Hz, 1H), 3.37 (s, 1H), 3.18 (d, J = 12.5 Hz, 1H), 3.06-2.94 (m, 2H), 2.25 (dd, J = 12.1, 7.0 Hz, 1H), 2.15 (d, J = 6.2 Hz, 1H). Example 15:

[0441] Compounds 45 and 46: (5S)-9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0442]

[0443] Synthesis of 9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 45b:

[0444]

[0445] Compound 3d (300.0 mg, 0.65 mmol), (3,4,5-trifluorophenyl)methanol 45a (126.0 mg, 0.78 mmol), methanesulfonic acid (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (56.0 mg, 0.06 mmol) and cesium carbonate (423.0 mg, 1.30 mmol) were dissolved in anhydrous toluene (9.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 45b (10.0 mg, 5%).

[0446] LC-MS: [M+H] + :338.0.

[0447] Compounds 45 and 46: Synthesis of (5S)-9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0448]

[0449] Compound 9-((3,4,5-trifluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 45b (10.0 mg, 0.03 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 45 (2.3 mg, 23%) and white solid compound 46 (2.5 mg, 25%).

[0450] Compound 45:

[0451] LC-MS: [M+H] + :338.1.

[0452] RT:2.38min.

[0453] 1H NMR (400MHz, DMSO-d6) δ7.40(dd,J=8.6,7.0Hz,2H),5.84(s,1H),5.26(s,2H),4.94(dd,J=4.8,2.4Hz,1H),4.15(d,J=18.8Hz,1H),3.71(d, J=18.5Hz,1H),3.09(d,J=12.2Hz,1H),3.03-2.95(m,1H),2.89-2.81(m,1H),2.72(d,J=12.0Hz,1H),2.08-2.00(m,1H),1.86-1.78(m,1H).

[0454] Compound 46:

[0455] LC-MS: [M+H] + :338.1.

[0456] RT:4.49min.

[0457] 1 H NMR (400MHz, DMSO-d6) δ7.40(dd,J=8.6,7.0Hz,2H),5.84(s,1H),5.26(s,2H),4.94(dd,J=4.8,2.4Hz,1H),4.15(d,J=18.8Hz,1H),3.71(d,J=18.3H z,1H),3.09(d,J=12.2Hz,1H),3.03-2.94(m,1H),2.89-2.81(m,1H),2.72 (d,J=12.1Hz,1H),2.04(ddd,J=10.6,6.5,2.7Hz,1H),1.87-1.78(m,1H).

[0458] Embodiment 16:

[0459] Compounds 47 and 48: (5S)-9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0460]

[0461] Synthesis of 9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 47b:

[0462]

[0463] Compound 3d (300.0 mg, 0.65 mmol), (2,3-difluorophenyl)methanol 47a (112.0 mg, 0.78 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (56.0 mg, 0.06 mmol) and cesium carbonate (423.0 mg, 1.30 mmol) were dissolved in anhydrous toluene (9.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 20: 1) to obtain white solid compound 47b (15.0 mg, 7%).

[0464] LC-MS: [M+H] + :320.0.

[0465] Compounds 47 and 48: Synthesis of (5S)-9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0466]

[0467] Compound 9-((2,3-difluorobenzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 47b (15.0 mg, 0.05 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 47 (5.9 mg, 39%) and white solid compound 48 (2.5 mg, 16%).

[0468] Compound 47:

[0469] LC-MS: [M+H] + :320.1.

[0470] RT:5.30min.

[0471] 1H NMR(400MHz,CD3OD)δ7.33-7.22(m,2H),7.19-7.13(m,1H),5.90(s,1H),5.44(s,2 H),5.14(dd,J=4.9,2.6Hz,1H),4.29(d,J=18.8Hz,1H),3.84(d,J=18.7Hz,1H),3. 23(d,J=12.3Hz,1H),3.17(dd,J=11.3,4.8Hz,1H),3.00(ddd,J=12.8,8.4,4.0Hz, 1H), 2.94 (t, J=8.9Hz, 1H), 2.22 (ddd, J=10.6, 8.3, 5.3Hz, 1H), 2.08-2.01 (m, 1H).

[0472] Compound 48:

[0473] LC-MS: [M+H] + :320.1.

[0474] RT:6.21min.

[0475] 1 H NMR (400MHz, CD3OD) δ7.33-7.22(m,2H),7.19-7.13(m,1H),5.90(s,1H),5.44(s, 2H),5.14(dd,J=4.9,2.6Hz,1H),4.29(d,J=18.8Hz,1H),3.85(d,J=18.6Hz,1H), 3.24(d,J=12.3Hz,1H), 3.17(dd,J=11.3,4.8Hz,1H), 3.00(dd,J=12.8,6.4Hz,1H ),2.93(d,J=12.4Hz,1H),2.22(ddd,J=10.4,8.2,5.2Hz,1H),2.08-2.02(m,1H).

[0476] Embodiment 17:

[0477] Compounds 49 and 50: (5S)-9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one and (5R)-9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepin-7(1H)-one

[0478]

[0479] Synthesis of 3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzaldehyde 49b:

[0480]

[0481] Compound 3-(pentafluorosulfanyl)phenol (1.80 g, 8.20 mmol) and 3,4,5-trifluorobenzaldehyde 49a (1.97 g, 12.30 mmol) were dissolved in N,N-dimethylformamide (54 mL), potassium carbonate (3.40 mg, 24.60 mmol) was added to the mixture, and the mixture was stirred at 90°C for 1 hour. After the reaction was completed, the mixture was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed twice with saturated brine and dried over anhydrous sodium sulfate. The organic phases were concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 10:1) to obtain yellow oil compound 49b (2.0 g, 68%). LC-MS: [M+Na] + :383.3.

[0482] Synthesis of (3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)phenyl)methanol 49c:

[0483]

[0484] Compound 3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzaldehyde 49b (2.0 g, 5.60 mmol) was dissolved in ethanol (40.0 mL), sodium borohydride (0.25 g, 6.72 mmol) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether = 1:1) to obtain yellow oil compound 49c (1.4 g, 70%).

[0485] LC-MS: [M+Na] + :385.3.

[0486] Synthesis of 9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 49d:

[0487]

[0488] Compound 3d (300.0 mg, 0.65 mmol), (3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)phenyl)methanol 49c (200.0 mg, 0.55 mmol), methanesulfonic acid (4,5-bisdiphenylphosphino-9,9-dimethylxanthene) (2-amino-1,1'-biphenyl-2-yl)palladium (II) (47.0 mg, 0.05 mmol) and cesium carbonate (357.0 mg, 1.10 mmol) were dissolved in toluene (6.0 mL), and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) to give white solid compound 49d (30.0 mg, 10%).

[0489] Compounds 49 and 50: Synthesis of (5S)-9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one and (5R)-9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one:

[0490]

[0491] Compound 9-(3,5-difluoro-4-(3-(pentafluorosulfanyl)phenoxy)benzyl)oxy)-4,5-dihydro-3H-2,5-methylpyrimido[1,6-a][1,4]diazepine-7(1H)-one 49d (30.0 mg, 0.05 mmol) was subjected to chiral preparation (chromatographic column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 40% EtOH (NH4OH 0.2%): 60% CO2) to give white solid compound 49 (12.3 mg, 41%) and white solid compound 50 (12.2 mg, 41%).

[0492] Compound 49:

[0493] LC-MS: [M+H] + :538.1.

[0494] RT:5.75min

[0495] 1H NMR(400MHz, DMSO-d6)δ7.70(dd,J=8.2,1.6Hz,1H),7.64-7.59(m,2H),7.44(d,J=8.9H z,2H),7.26(d,J=8.1Hz,1H),5.91(s,1H),5.34(s,2H),5.00(d,J=2.2Hz,1H),4.25(d, J=18.4Hz,1H),3.83(d,J=18.6Hz,1H),3.19(d,J=12.0Hz,1H),3.10(s,1H),2.96(d,J= 6.1Hz, 1H), 2.86 (d, J = 11.8Hz, 1H), 2.11 (dd, J = 13.3, 5.5Hz, 1H), 1.89 (d, J = 5.6Hz, 1H).

[0496] Compound 50:

[0497] LC-MS: [M+H] + :538.1.

[0498] RT:6.20min

[0499] 1 H NMR(400MHz, DMSO-d6)δ7.70(d,J=8.3Hz,1H),7.64-7.59(m,2H),7.44(d,J=8.9Hz, 2H),7.26(d,J=8.2Hz,1H),5.90(s,1H),5.34(s,2H),4.99(s,1H),4.22(d,J=18.7H z,1H),3.80(d,J=18.7Hz,1H),3.16(d,J=12.0Hz,1H),3.07(s,1H),2.93(d,J=5.8H z,1H),2.82(d,J=11.8Hz,1H),2.10(dd,J=12.6,4.8Hz,1H),1.88(d,J=5.6Hz,1H).

[0500] Biological evaluation

[0501] 1. Recombinant human Lp-PLA2 inhibition assay (rhLp-PLA2)

[0502] 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.

[0503] 1. Prepare assay buffer: 50 mM MES (pH 6.5), 150 mM NaCl, 0.1% BSA

[0504] 2. Dissolve the compound powder in DMSO to a 10 mM stock solution and keep at room temperature for later use.

[0505] 3. The compound solution was diluted four-fold with DMSO.

[0506] 4. Use Echo to transfer serial dilutions of compounds to 384-well plate experiments.

[0507] 5. Prepare 2x PLA2G7 in assay buffer.

[0508] 6. Add 15 μl of prepared PLA2G7 to the 384-well plate and place it in a 25°C incubator for incubation.

[0509] 7. Prepare a 2x mixture of 2-Thio-PAF and DTNB in ​​assay buffer.

[0510] 8. Add 15 μl of the mixture of 2x 2-Thio-PAF and DTNB to the plate and incubate in a 25°C incubator.

[0511] 9. Data was read using Envision, ABS 405nm. The results are listed in Table 1.

[0512] Table 1

[0513]

[0514]

[0515] Experimental reagents:

[0516] PLA2G7 (Sino biological, 10848-H08H); 2-Thio-PAF (Cayman, 60945); DTNB (Sigma, D-8130);

[0517] II: Human plasma Lp-PLA2 inhibition assay

[0518] 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.

[0519] Determination method:

[0520] 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;

[0521] 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.

[0522] 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);

[0523] 4. Set the parameters of the microplate reader (Abs414, time interval 1min, recording for 40min).

[0524] 5. The exported data were processed and analyzed using GraphPad Prism7. The results are listed in Table 2.

[0525] Table 2

[0526]

[0527]

[0528] Experimental reagents:

[0529] Human plasma (PreceDo, 20230203EDTA); DTNB (TCI, D0944); 2-thio-PAF (MCE, HY-101263)

[0530] 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, n1, n2, n5 are each independently 0, 1 or 2; n3 and n4 are each independently 1 or 2; R1 and R4 are each independently -H, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen; R2 and R3 are each independently -H, =O, cyano, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, or halogen; m, o are each independently 0, 1 or 2; wherein when m or o is 2, two R2 or R3 optionally together with the C atoms connecting them form a 3-6 membered saturated carbon ring; X1 and X2 are each independently selected from: alkylene, -O-, -S-, or -NR'-; wherein R' is selected from: H, alkyl, deuterated alkyl, or cycloalkyl; Ar is an arylene or heteroarylene group; the arylene or heteroarylene group is optionally substituted by 0, 1 or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, monoalkyl or dialkyl substituted amino, nitro, carboxyl, aldehyde, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Y is -H, halogen, alkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, -OAr', -SAr', -NH-Ar', -N(alkyl)-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 or cycloalkyl; R"' is alkylene; Z is O or S; The halogen atoms in the "halogen", "haloalkyl" and "haloalkoxy" are each independently selected from F, Cl, Br or I; The alkyl groups in the aforementioned “alkyl”, “deuterated alkyl”, “deuterated alkoxy”, “hydroxyalkyl”, “haloalkyl”, “haloalkoxy”, “alkoxy”, and “amino substituted with monoalkyl or dialkyl” are each independently 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: n1, n2, n5 are each independently 0, 1 or 2; optionally, n1 is 0, 1 or 2; optionally, n2 is 0, 1 or 2; optionally, n5 is 0 or 1; n3 and n4 are each independently 1 or 2; optionally, n3 is 1 or 2; optionally, n4 is 1 or 2; R1 and R4 are each independently selected from: -H, C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 Straight or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); Optionally, R1 is -H or -CH3; Optionally, R4 is -H or -CH3; R2 and R3 are each independently selected from: -H, =O, C 1-7 Straight or branched alkyl; optionally, -H, or C 1-4 Straight or branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl); optionally, R2 is -H, or -CH3; optionally, R3 is -H, =O, or -CH3; m, o are each independently 0, 1 or 2; alternatively, m is 0, or 1; alternatively, o is 0, 1 or 2; wherein when m or o is 2, two R2 or two R3 optionally together with the C atom connecting them form a 3-6 membered saturated carbon ring, alternatively, two R2 or two R3 optionally together with the C atom connecting them form a cyclopropane ring; X1 and X2 are each independently selected from: C1-C7 alkylene (optionally, -CH2-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, -S-, or -NR′-; optionally, X1 is -CH2-, or -O-; optionally, X1 is -O-; optionally, X2 is -O-; wherein R′ is selected from -H, C1-C7 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl , 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2D5, or -C3D7), or C3-C6 cycloalkyl (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane); 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, -OMe, or -OCF3; alternatively, Ar is phenylene, the phenylene is optionally substituted by 1 or 2 substituents, the substituents are -F, or -CN; Y is -H, halogen, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCD3, -CF3, -CHF2, -CH2F, -CH2CF3, -OCF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2H5, -OC3H7, or -OAr'; Alternatively, Y is -H, -F, -Cl, -Br, -I, or -OAr'; Alternatively, Y is -H, -F, or -OAr'; wherein Ar' is selected from 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, halosulfanyl (optionally, fluorosulfanyl or chlorosulfanyl), hydroxyl, hydroxyalkyl, cyano, or C3-C6 cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazol-4-yl or quinolin-7-yl, optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5; Z is O.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: n1 is 0, 1 or 2; n2 is 0, 1 or 2; n5 is 1; n3 is 1 or 2; n4 is 1 or 2; R1 is -H or -CH3; R4 is -H; R2 is -H; R3 is -H, =O or -CH3; m is 0; o is 0, 1, or 2, wherein when o is 2, two R3 optionally together with the C atom to which they are connected form a cyclopropane ring; X1 is -O- or -CH2-, and X2 is -O-; Ar is a phenylene group, and the phenylene group is optionally substituted by 1 or 2 substituents, and the substituents are -F or -CN; Y is -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 by 1 or 2 substituents selected from -F, -Cl, -CH3, -CF3, -CH2CF3, -OCF3 or -SF5; Z is O.

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

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

6. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, comprising the following synthetic route: In each structural formula, n1, n2, n3, n4, n5, R1, R2, R3, R4, m, o, X1, X2, Z, Ar and Y are defined as described in any one of claims 1 to 5; W is a halogen or a sulfonate group.

7. A pharmaceutical composition comprising one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5 and optionally a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition comprises an oral preparation, a rectal preparation, or a parenteral preparation; Optionally, the oral preparation includes a solid preparation or a liquid preparation; Optionally, the solid preparation includes a tablet, a powder, a granule, or a capsule; Optionally, the liquid preparation includes an aqueous or oil suspension, or a syrup; Optionally, the preparation for parenteral administration includes a solution for injection, or an aqueous or oily suspension.

9. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7 or 8 in the preparation of an Lp-PLA2 inhibitor.

10. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 7 or 8, in the preparation of a medicament for treating neurodegenerative diseases, cardiovascular diseases, diabetic macular edema (DME) or prostate diseases; Optionally, the neurodegeneration-related disease includes Alzheimer's disease (AD), glaucoma, or age-related macular degeneration (AMD); and the cardiovascular disease includes atherosclerosis.

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