CN113666930B

CN113666930B - Bridged pyrimidone compounds, preparation method, composition and application thereof

Info

Publication number: CN113666930B
Application number: CN202010700049.3A
Authority: CN
Inventors: 顾正华; 王冬琴
Original assignee: Shanghai Newsk Biotechnology Co ltd
Current assignee: Shanghai Newsk Biotechnology Co ltd
Priority date: 2020-05-13
Filing date: 2020-07-20
Publication date: 2022-10-25
Anticipated expiration: 2040-07-20
Also published as: CN113666930A

Abstract

A bridged pyrimidinone compound shown in formula (I) or pharmaceutically acceptable salt thereof has a structure shown in formula (I), is a brand-new Lp-PLA2 inhibitor, and can be used for treating neurodegenerative related diseases, such as Alzheimer Disease (AD), glaucoma, age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis and the like.

Description

Bridged pyrimidone compounds, preparation method, composition and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a bridged pyrimidone compound or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a preparation method thereof, a composition thereof and application thereof in medicines. In particular, the disclosure relates to bridged pyrimidinone derivatives represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and uses of the derivatives as LpPLA2 inhibitors in treating neurodegenerative diseases such as alzheimer's disease, glaucoma, age-related macular degeneration (AMD), atherosclerosis, and diabetic macular edema.

Background

Lipoprotein-associated phospholipase A2 (Lp-PLA 2) 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 secreted mainly by monocytes, macrophages, T lymphocytes and primary 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 I.J Biol chem.1997,272, 19708-19713). Phosphatidylcholine sn-2 esters are produced during oxidation of Low Density Lipoproteins (LDL), and Lp-PLA2 is responsible for the hydrolysis of oxidatively modified phosphatidylcholine sn-2 esters, followed by the production of oxidized fatty acids and lysophosphatidylcholine (LysopC) (Caslake MJ, packard CJ, suckling KE, holmes SD, chamberlin P, macpheee CH. Atheroscleosis.2000, 150,413-419 MacPhe CH, moores KE, boyd HF, dhanak D, ife RJ, leach CA, leake DS, milliner KJ, patterson RA, suckling KE, tew DG, hickey DM. Biome J.1999,338, 479-487). Both oxidized fatty acids and LysoPC 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 U S a.1988,85, 2805-2809). LysoPC has been reported to induce the release of a variety of cytotoxic inflammatory cytokines (Shi, et al, atherosclosis, 2007,191,54-62). In addition, lysoPC is involved in leukocyte activation, induction of apoptosis and mediation of endothelial dysfunction (Wilensky et al, current Opinion in lipopology, 2009,20,415-420).

Plasma Lp-PLA2 levels have been reported to be associated with cardiovascular disease (Fitzpatrick AL, irizarry MC, cushman M, jenny NS, chi GC, koro c. Atherosclososis.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.122, 990-996), prostate Cancer (Bertilsson H, tessem MB, flutbergg a, viset T, gridbest I, angelen a, halgusst J. Clin Cancer resn 2012,18, 3261-3269).

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-protective ability (Hardy J, et al, science2002,297, 353-356). Alzheimer's disease usually begins slowly and gradually worsens over time, which is responsible for 60 to 70% of dementia cases and affects about 6% of the population over the age of 65. AD patients will gradually exit the home and society, become more and more dependent on help, and eventually progress to death. AD is one of the most costly diseases in developed countries and also at high costs in other countries. These costs will increase dramatically, especially as aging becomes an important social issue. Needless to say, AD is a complex disease involving multiple factors. Although the etiology of AD has not been fully elucidated, it is clear that several factors are involved in the development and progression of disease, including aggregated tau and Α β peptides, oxidative stress and neuroinflammation (Echeverria V, yarkov a, aliev g. Prog neurobiol.2016,144, 142-157). Current AD drug development is mainly focused on the targets of a β 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 the strong preclinical data, the results of late-stage clinical trials have not proven clinically effective to date. These disappointing results suggest that other neuropathological mechanisms, such as oxidative stress and neuroinflammation, may have to be explored for AD treatment.

Elevated plasma levels of Lp-PLA2 increase the risk of Dementia, including AD (Van Oijen, et al, annals of Neurology,2006,59,139), vascular and mixed dementias, as well as high oxidized LDL levels (human-Edwards G, de ' Ath J, barnet C, lavrov A, lockhart A, alzheimer's & Dementia: translational Research & Clinical Interventions.2015,1,131-140, kassner al. Current Alzheimer Research,2008,5,358-366, dildar, et al, alzheimer's Disasonic Disordd, 24, april-June (2010, health, current Research, 3763, current 469). Neuroinflammation and upregulation of a variety of inflammatory cytokines have also been found in AD patients (Colangelo, et al, journal of Neuroscience Research,2002,70,462-473 Wys-Coray, nature Medicine,2006,12, sept..

Based on all these findings, lp-PLA2 is a potential target for treating AD, and the Clinical results of the Lp-PLA2 inhibitor, rilapadib, in AD patients further confirmed this (Maher-Edwards G, de 'Ath J, barnet C, lavrov A, lockhart A, alzheimer's & Dementia: comparative Research & Clinical interventions.2015,1, 131-140).

Glaucoma and age-related macular degeneration (AMD) belong to retinal neurodegenerative diseases. Buschini et al report that inflammation, including TNF- α signaling, may play a significant 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, ISSN0079-6123, chapter 28). In addition, shi et al demonstrate that Lp-PLA2 inhibitors can block the release of inflammatory cytokines (Shi, et al, atherosclerosis,2007,191,54-62). Inhibition of Lp-PLA2 is a potential treatment for glaucoma and AMD.

A number of 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.Lett.2005, 15,1525-1527, jeong HJ, park YD, park HY, jeong IY, jeong TS, lee WS. Bioorg Med.Lett.2006, 16, 5576-5579), amides of xanthureic acid (Lin EC, hu Y, amantea CM, LM, cajica J, okeerg E, brownHE, fraser A, kohn Y, ishiyama J, kozarrich JW, shreder KR.Bioorg Med Chem 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, kozarrich JW, shreder KR.Bioorg Med Chem Lett.2013,23, 1553-1556.), and carbamates (Nagano JM, hsu, whitby LR, niphakis MJ, speers AE, brown SJ, spicer T, fernandez-Vega V, ferguson J, hodder P, srinivasan P, gonz TD, ronzaleson H, bahnave J, bhattan J, batt J, bhattan J, BF 843-849, BF 3-849).

The Lp-PLA2 inhibitor Darapidib is reported to be a potential treatment against atherosclerosis and DME (Magrioti V, kokotos G. Expert Optin Ther Pat.2013; 23.

Disclosure of Invention

The present inventors have found that Lp-PLA2 inhibitors play an important role in the treatment of neurodegenerative related diseases such as Alzheimer's Disease (AD), glaucoma and age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis and the like. Therefore, the inventor aims to develop a brand-new Lp-PLA2 inhibitor, namely, bridged pyrimidinone compounds.

The bridged pyrimidinone compound is a compound with a structure shown in formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

n ₁ 、n ₂ 、n ₃ each independently is 0,1 or 2;

R ₁ 、R ₂ each independently selected from: -H, hydroxy, cyano, halogen, alkyl, deuterated alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, arylene or heteroarylene;

X ₁ 、X ₂ each independently selected from: alkylene, -O-) -S-or-NR' -,

r' is selected from: -H, alkyl, deuterated alkyl or cycloalkyl;

ar is arylene or heteroarylene; the hydrogen atoms in the arylene or heteroarylene group are optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, mono-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, arylene, heteroarylene, -OAr ', -SAr ', -NR "-Ar ', -N R" R ", or-R '" -Ar ';

ar' is selected from aryl or heteroaryl; the hydrogen atoms in the aryl or heteroaryl groups are optionally substituted with one or more substituents each independently selected from: halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, cyano, amino, nitro, carboxy, aldehyde, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

r' is H, alkyl or cycloalkyl;

r' "is alkylene;

z is O or S.

Alternatively, the halogen atoms present in the "halogen", "haloalkyl", "haloalkoxy" are each independently selected from F, cl, br or I;

alternatively, each alkyl group of the "alkyl", "deuterated alkoxy", "hydroxyalkyl", "haloalkyl", "haloalkoxy", "alkoxy", "monoalkyl-or dialkyl-substituted amino" is independently C ₁ -C ₁₀ A linear or branched alkyl group; alternatively, is C ₁ -C ₇ A linear or branched alkyl group; alternatively, is C ₁ -C ₄ A linear or branched alkyl group; alternatively, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3856 zxft 56-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 5329-trimethylbutyl 5329-trimethylzft 5329;

optionally, each of said "alkylene" is independently C ₁ -C ₁₀ Linear or branched alkylene of (a); alternatively, is C ₁ -C ₇ A linear or branched alkylene group; alternatively, is C ₁ -C ₅ A linear or branched alkylene group; alternatively, a monomer selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, t-butylene, sec-butylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, isohexylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 3579-dimethylbutylene, 2-ethylbutylene, n-heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3735 zxft 3835-dimethylpentylene, 56-zxft 5256-dimethylpentylene, 5283, 5-dimethylpentylene, 5383, or trimethylpentylene-5329;

alternatively, said "cycloalkyl" is C ₃ -C ₁₀ Monocyclic or bicyclic cycloalkyl, optionally C ₃ -C ₇ A monocyclic cycloalkyl group, alternatively, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;

optionally, the "heterocyclyl" is a 3-10 membered non-aromatic heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, O, S in the ring, optionally, the heterocyclic ring is a 3-10 membered non-aromatic ring containing 1 or 2 heteroatoms selected from N, O in the ring; optionally, the heterocycle is a 3-6 membered non-aromatic ring containing 1 or 2 heteroatoms in the ring selected from N, O; optionally, the heterocycle is a 3-10 membered non-aromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S; optionally, the heterocyclic ring is a 3-6 membered non-aromatic ring containing 1 or 2 heteroatoms selected from N, S in the ring;

alternatively, the "aryl" is a 6-10 membered aryl; optionally phenyl or naphthyl, optionally phenyl, 1-naphthyl, or 2-naphthyl;

alternatively, the "arylene" is a 6-to 10-membered arylene; optionally phenylene or naphthylene;

alternatively, the "heteroaryl" is a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms in the ring selected from N, O and S; alternatively, a 5-10 membered heteroaromatic ring containing 1-2 heteroatoms selected from N, O and S in the ring; optionally, the heteroaromatic ring is selected from a pyridine ring, a pyrrole ring, a pyrazole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring; alternatively, the heteroaryl group is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, thieno [ 3584-b ] furyl, furo [3,2-b ] -pyranyl, pyrido [2,3-d ] oxazinyl, pyrazolo [ 23 zxft 5623-d ] oxazolyl, imidazo [4,5-d ] thiazolyl, pyrazino [2,3-d ] pyridazinyl, imidazo [ 3456 zxft 56-b ] thiazolyl, imidazo [ 3838 b-3838 b ],38, 2,4] triazinyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzoxazpinyl, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo [2,3-b ] pyridyl, pyrrolo [3,2-c ] pyridyl, pyrrolo [3,2-b ] pyridyl, imidazo [4,5-b ] pyridyl, imidazo [4,5-c ] pyridyl, pyrazolo [4,3-d ] pyridyl, pyrazolo [4,3-c ] pyridyl, pyrazolo [3,4-c ] pyridyl, pyrazolo [3,4-d ] pyridyl, pyrazolo [3,4-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [ 3925-a ] zxft 3928-a ] pyridyl, pyrazolo [ 3925-b ] zxft 3925-d ] pyridyl, 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, or pyrimidin-5-yl;

alternatively, the "heteroarylene" is a 5-10 membered heteroarylene ring containing 1-3 heteroatoms in the ring selected from N, O and S; alternatively, a 5-10 membered heteroarylene ring containing 1-2 heteroatoms selected from N, O and S in the ring; alternatively, the heteroarylene ring is selected from a pyridylene ring, a pyrrole ring, a pyrazole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, or a furan ring.

Alternatively, the compound of formula (I) is in the form of a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture of such isomers.

Alternatively, n ₁ 、n ₂ 、n ₃ Each independently 0,1 or 2.

Alternatively, n ₁ Is 1.

Alternatively, n ₂ Is 1.

Alternatively, n ₃ Is 1.

Alternatively, R ₁ 、R ₂ Each independently selected from: -H, fluoro, chloro, bromo, iodo, hydroxy, hydroxyalkyl, cyano, C ₁ -C ₇ Alkyl (such as 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, 3856 zxft 56-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl or 5329-trimethylbutyl), C29-trimethylbutyl, C29-methyl-, 3-pentyl, 3-methyl-, 3-pentyl, and mixtures thereof ₁ -C ₃ Deuterated alkyl (e.g., -CD) ₃ 、-C ₂ D ₅ or-C ₃ D ₇ )、C ₁ -C ₃ Deuterated alkoxy (e.g., -OCD) ₃ 、-OC ₂ D ₅ or-OC ₃ D ₇ )、C ₁ -C ₃ Haloalkyl (e.g., -CF) ₃ 、-CHF ₂ 、-CH ₂ F、-C ₂ F ₅ 、-C ₃ F ₇ )、C ₁ -C ₇ Haloalkoxy, C ₁ -C ₇ Alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; alternatively, R ₁ is-H; alternatively, R ₂ is-H;

alternatively, X ₁ 、X ₂ Each independently selected from: c ₁ -C ₇ Alkylene, -O-, -S-or-NR' -; alternatively, X ₁ Is C ₁ -C ₇ Alkylene (optionally, -CH) ₂ -, ethylene, n-propylene, isopropylene, n-butylene or isobutylene), -O-, or-S-; alternatively, X ₁ Is C ₁ -C ₇ Alkylene or-O-; alternatively, X ₁ is-CH ₂ -or-O-; alternatively, X ₂ is-O-or-S-; alternatively, X ₂ is-O-;

alternatively, R' is selected from-H, C ₁ -C ₇ Alkyl (such as 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, 3432 zxft 32-dimethylpentyl, 3-ethylpentyl or 2,2,3-trimethylbutyl), optionally substituted alkyl (2,4-dimethylpentyl, 3-CD) ₃ 、-C ₂ D ₅ or-C ₃ D ₇ ) Or C ₃ -C ₆ Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl);

alternatively, ar is phenylene or pyridinyl, the hydrogen atom in which is optionally substituted with 1,2 or 3 substituents each independently selected from: F. cl, br, I, -CN, -Me, -CF ₃ 、-CHF ₂ 、-C ₂ H ₅ 、-C ₃ H ₇ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD ₃ 、-OCD ₃ 、-OMe、-OCF ₃ or-OCHF ₂ ；

Alternatively, ar is arylene; alternatively, ar is phenylene, a hydrogen atom in the phenylene optionally substituted with 1 or 2 substituents which are halo; alternatively, the substituent is F;

alternatively, Y is-H, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, isopropyl, -CD ₃ 、-OCD ₃ 、-CF ₃ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-OCF ₃ 、-OCHF ₂ 、-OCH ₂ F. Cyclopropyl, -cyclobutyl, -cyclopentyl, cyclohexyl, -OCH ₃ 、-OC ₂ H ₅ 、-OC ₃ H ₇ or-OAr';

alternatively, Y is H, halogen, or-OAr'; alternatively, Y is H, -F, or-OAr';

optionally, ar' is selected from phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl, each independently, a hydrogen atom in the phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl ring optionally substituted with 1,2, or 3 substituents, each independently selected from: F. cl, br, -CN, C ₁ -C ₇ Alkyl (optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl 2,2,3-trimethylbutyl), -CD ₃ 、-OCD ₃ 、C ₁ -C ₆ Haloalkyl, -OCH ₃ 、-OC ₂ H ₇ 、-OC ₃ H ₇ 、C ₁ -C ₆ Haloalkoxy, hydroxy, hydroxyalkyl, cyano, or C ₃ -C ₆ Cycloalkyl (optionally cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);

optionally, ar' is selected from phenyl, pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl, optionally substituted with 1 or 2 substituents, said substituentsSelected from halogen, alkyl, haloalkyl or haloalkoxy; alternatively, the substituents are selected from F, cl, -CH ₃ 、-CF ₃ or-OCF ₃ ；

Optionally, Z is O or S; optionally, Z is O.

Alternatively, in the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound of formula (I) is selected from the following compounds:

alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises an anionic salt or a cationic salt of the compound of formula (I);

alternatively, the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound of formula I; optionally, the alkali metal comprises sodium, potassium, lithium, or cesium, and the alkaline earth metal comprises magnesium, calcium, or strontium;

alternatively, the pharmaceutically acceptable salts include salts of the compounds of formula I with organic bases;

alternatively, the organic base comprises trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5, 1,8-diazabicyclo [5.4.0] undecene-7, 1,4-diazabicyclo [2.2.2] octane; alternatively, the trialkylamine comprises trimethylamine, triethylamine, or N-ethyldiisopropylamine; alternatively, the N-alkyl morpholine comprises N-methyl morpholine;

alternatively, the pharmaceutically acceptable salt comprises a salt of a compound of formula I with an acid;

optionally, the acid comprises an inorganic acid, or an organic acid; optionally, the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid comprises formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

In another aspect, there is provided a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising: the step of reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (I):

alternatively, the preparation method comprises the step of reacting the compound of formula (IV) with phosphorus oxychloride to produce a compound of formula (II):

alternatively, the preparation method comprises the step of subjecting the compound of formula (V) to a cyclization reaction to produce a compound of formula (IV):

alternatively, the preparation method comprises the steps of reacting a compound of formula (VII) with a compound of formula (VIII) to produce a compound of formula (VI), and further deprotecting the compound of formula (VI) to produce a compound of formula (V):

alternatively, the preparation method comprises the following reaction scheme:

in each of the above preparation processes, n ₁ 、n ₂ 、n ₃ 、R ₁ 、R ₂ 、X ₁ 、X ₂ Z, ar and Y are as defined above.

The specific reaction conditions for each reaction are not particularly limited, and conventional reaction conditions or steps can be employed.

In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of formula (I) above, or a pharmaceutically acceptable salt thereof, and optionally pharmaceutically acceptable excipients.

Optionally, the dosage form of the pharmaceutical composition comprises an oral formulation, a rectal formulation, or a parenteral formulation;

optionally, the oral formulation comprises a solid formulation, or a liquid formulation;

optionally, the solid formulation comprises a tablet, a powder, a granule, or a capsule;

optionally, the liquid formulation comprises water or an oil suspending agent, or a syrup;

alternatively, the parenteral formulation comprises a solution for injection, or an aqueous or oily suspension.

In another aspect, there is provided the use of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of an Lp-PLA2 inhibitor.

In another aspect, there is provided the use of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a neurodegenerative related disease;

optionally, the neurodegenerative-related disease comprises Alzheimer's Disease (AD), glaucoma, age-related macular degeneration (AMD).

In another aspect, there is provided the use of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of cardiovascular disease, diabetic Macular Edema (DME), or prostate disease;

optionally, the cardiovascular disease comprises atherosclerosis.

Has the advantages that:

the compound of the formula (I) or the pharmaceutically acceptable salt thereof is a bridged pyrimidinone compound and is a brand new Lp-PLA2 inhibitor. Can be used for treating neurodegenerative related diseases such as Alzheimer Disease (AD), glaucoma and age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis, diabetic Macular Edema (DME) or prostate disease.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that the examples herein are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The starting materials of the present invention can be synthesized by or according to methods known in the art and are also commercially available from companies such as ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shaoyuan ChemBiotech (Accela ChemBio Inc), darril Chemicals, and the like.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, without particular limitation, room temperature, for example, 20 ℃ to 30 ℃.

EXAMPLE 1 preparation of Compound 1

The first step is as follows: preparation of Compound 1c

6-chlorouracil 1b (8.5g, 58.0 mmol), 3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester 1a (15g, 69.6 mmol) and triphenylphosphine (22.8g, 86.9mmol) were dissolved in a mixed solvent of 250mL of anhydrous tetrahydrofuran and 25mL of anhydrous N, N-dimethylformamide under nitrogen protection and at 0 ℃ while dropping diisopropyl azodicarboxylate (23mL, 115.8mmol), and after stirring at 0 ℃ for 2 hours, the reaction mixture was warmed to room temperature overnight, filtered, extracted with ethyl acetate (50 mL. Times.3), the organic phase was combined, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain a colorless oily product 1c (8.34 g, yield: 41.8%).

The second and third steps: preparation of Compound 1e

The compound tert-butyl 3- (((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) piperidine-1-carboxylate 1c (8.34g, 24.3mmol) was dissolved in 80mL dichloromethane at room temperature, 20mL trifluoroacetic acid was added at 0 ℃, the reaction was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the next reaction was carried out directly, the crude product of the previous step was dissolved in 100mL acetonitrile, diisopropylethylamine (9.3g, 72.9mmol) was added at room temperature, the reaction was stirred for 4 hours, concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the product 1e as a white solid (4.7g, 93.3%).

¹ H NMR(400MHz,DMSO)δ11.01(s,1H),5.09(s,1H),3.84(m,1H),3.51(m,1H),3.30(m,1H),3.16(m,1H),3.04(m,1H),2.94(m,1H),2.25(m,1H),1.89–1.68(m,2H),1.61–1.46(m,1H),1.36(m,1H).

The fourth step: preparation of Compound 1f

Compound 1e (2.0g, 9.7mmol) and dimethylaniline (2.34g, 19.3mmol) were dissolved in toluene at room temperature, phosphorus oxychloride (1.48g, 9.7mmol) was added dropwise, after heating and refluxing for 4 hours, the reaction was quenched with ice water, concentrated under reduced pressure, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove a drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain product 1f (0.89g, 40.7%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.06(s,1H),4.06(m,1H),3.77(m,1H),3.52(m,1H),3.29(m,1H),3.22–3.15(m,1H),3.02(m,1H),2.52(m,1H),2.01–1.85(m,2H),1.62–1.44(m,2H).

The fifth step: preparation of Compound 1

(3-fluorophenyl) methanol 1g (30mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃ and after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added and after stirring for 1 hour, the reaction was quenched by adding a small amount of water and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 1 as a white solid (8mg, 11.5%).

¹ H NMR(400MHz,CDCl ₃ )δ7.32(m,1H),7.15(m,2H),7.04–6.97(m,1H),5.60(s,1H),5.40(s,2H),4.06(m,1H),3.80(m,1H),3.44(m,1H),3.29–3.19(m,1H),3.13(m,1H),3.03(m,1H),2.41(m,1H),2.00–1.82(m,2H),1.58–1.45(m,2H).

EXAMPLE 2 preparation of Compound 2

(2,4-difluorophenyl) methanol (35mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 2 (10mg, 13.6%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.49(m,1H),6.94–6.80(m,2H),5.58(s,1H),5.44(s,2H),4.09(m,1H),3.82(m,1H),3.45(m,1H),3.29–3.20(m,1H),3.16(m,1H),3.05(mm,1H),2.44(m,1H),2.02–1.83(m,2H),1.57–1.47(m,2H).

EXAMPLE 3 preparation of Compound 3

(2,4,5-trifluorophenyl) methanol (39mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain product 3 (12mg, 15.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.32(m,1H),6.93(m,1H),5.57(s,1H),5.40(s,2H),4.06(m,1H),3.79(m,1H),3.43(m,1H),3.28–3.21(m,1H),3.13(m,1H),3.02(m,1H),2.42(m,1H),1.93(m,2H),1.50(m,2H).MS(ESI):m/z 352.1[M+H] ⁺ 。

EXAMPLE 4 preparation of Compound 4

(3,5-difluorophenyl) methanol (35mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 4 (6 mg, 8.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.99–6.93(m,2H),6.81–6.72(m,1H),5.63(s,1H),5.41(s,2H),4.09(m,1H),3.82(m,1H),3.53–3.43(m,1H),3.33–3.20(m,1H),3.17(m,1H),3.06(m,1H),2.45(m,1H),1.96(m,2H),1.54(m,2H).

EXAMPLE 5 preparation of Compound 5

The first step is as follows: preparation of Compound 5c

2- (trifluoromethyl) pyridin-4-ol 5b (0.85g, 5.2 mmol), 3,4,5-trifluorobenzaldehyde 5a (1 g,6.2 mmol) and potassium carbonate (0.93g, 6.76mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 1 hour, cooled to room temperature and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 5/1) to give 5c (1.47 g, yield: 93.2%) as a yellow solid product.

¹ H NMR(400MHz,CDCl ₃ )δ9.97(s,1H),8.65(m,1H),7.63(m,2H),7.27(m,1H),7.01(m,1H)。

The second step: preparation of Compound 5d

3,5-difluoro-4- ((2- (trifluoromethyl) pyridin-4-yl) oxy) benzaldehyde 5c (1.47g, 4.85mmol) was dissolved in 50mL ethanol at room temperature and NaBH was added at 0 deg.C ₄ (184mg, 4.85mmol), the reaction stirred at room temperature for 0.5 hours, concentrated under reduced pressure, added water, extracted with ethyl acetate (100 mL × 2), the organic phases combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate concentrated under reduced pressure, purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 2/1) to give the product 5d as a white solid (1.04 g, yield: 70.3%).

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,1H),7.24(m,1H),7.11(m,2H),6.99(m,1H),4.75(m,2H),2.19(m,1H)。

The third step: preparation of Compound 5

(3,5-difluoro-4- ((2- (trifluoromethylpyridin-4-yl) oxy) phenyl) methanol 5d (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 5 (13mg, 12%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.60(m,1H),7.26(s,1H),7.15(m,2H),6.99(m,1H),5.64(s,1H),5.43(s,2H),4.08(m,1H),3.80(m,1H),3.47(m,1H),3.27(m,1H),3.16(m,1H),3.04(m,1H),2.44(m,1H),1.91(m,2H),1.53(m,2H).MS(ESI):m/z 494.9[M+H] ⁺ 。

EXAMPLE 6 preparation of Compound 6

The first step is as follows: preparation of Compound 6b

2-methylpyridin-4-ol 6a (0.5 g,4.6 mmol), 3,4,5-trifluorobenzaldehyde 5a (0.88g, 5.5 mmol) and potassium carbonate (0.823g, 5.95mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled to room temperature and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the combined organic phases were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 6b (0.4 g, yield: 34.9%).

¹ H NMR(400MHz,CDCl ₃ )δ9.94(s,1H),8.39(m,1H),7.62–7.56(m,2H),6.70–6.66(m,2H),2.52(s,3H)。

The second step: preparation of Compound 6c

3,5-difluoro-4- ((2-methylpyridin-4-yl) oxy) benzaldehyde 6b (0.4g, 1.6 mmol) was dissolved in 50mL of methanol at room temperature and NaBH was added at 0 deg.C ₄ (71mg, 1.86mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, added with water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 6c as a colorless oil (0.40 g, yield: 99%).

¹ H NMR(400MHz,CDCl ₃ )δ8.29(m,1H),7.07(m,2H),6.70–6.64(m,2H),4.73(s,2H),3.20(m,1H),2.50(s,3H)。

The third step: preparation of Compound 6

(3,5-difluoro-4- ((2-methyl) pyridin-4-yl) oxy) phenyl) methanol 6c (55mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring the reaction at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the target product 6 (8mg, 8.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.36(m,1H),7.10(m,2H),6.70–6.66(m,2H),5.63(s,1H),5.42(s,2H),4.08(m,1H),3.81(m,1H),3.47(m,1H),3.30–3.22(m,1H),3.16(m,1H),3.05(m,1H),2.51(s,3H),2.44(m,1H),1.91(m,2H),1.53(m,2H).MS(ESI):m/z 441.0[M+H] ⁺ 。

EXAMPLE 7 preparation of Compound 7

The first step is as follows: preparation of Compound 7b

6-methylpyridin-3-ol 7a (0.57g, 5.2 mmol), 3,4,5-trifluorobenzaldehyde 5a (1g, 6.2 mmol) and potassium carbonate (0.93g, 6.76mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, the reaction was stirred at 90 ℃ for 1 hour, cooled to room temperature and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give 7b (0.91 g, yield: 69.2%) as a yellow solid.

¹ H NMR(400MHz,CDCl ₃ )δ9.92(s,1H),8.28(s,1H),7.62–7.49(m,2H),7.18–7.10(m,2H),2.54(s,3H)。

The second step is that: preparation of Compound 7c

3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) benzaldehyde 7b (0.91g, 3.6 mmol) was dissolved in 50mL methanol at room temperature and NaBH was added at 0 deg.C ₄ (161mg, 4.3 mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, added with water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 7c as a colorless oil (0.89 g, yield: 98.4%).

¹ H NMR(400MHz,CDCl ₃ )δ8.20(m,1H),7.16–6.98(m,4H),4.69(m,2H),2.88(m,1H),2.50(s,3H)。

The third step: preparation of Compound 7

(3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) phenyl) methanol 7c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 7 (17mg, 17.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.27(m,1H),7.10(m,4H),5.62(s,1H),5.39(s,2H),4.07(m,7.3Hz,1H),3.80(m,1H),3.46(m,1H),3.29–3.21(m,1H),3.15(m,1H),3.04(m,1H),2.50(s,3H),2.43(m,1H),1.97–1.86(m,2H),1.51(m,2H).MS(ESI):m/z441.0[M+H] ⁺ 。

EXAMPLE 8 preparation of Compound 8

The first step is as follows: preparation of Compound 8b

2-methylpyrimidin-5-ol 8a (0.25g, 2.3mmol), 3,4,5-trifluorobenzaldehyde 5a (0.44g, 2.8mmol) and potassium carbonate (0.41g, 2.9mmol) were dissolved in 30mL N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down, poured into 100mL ice water, extracted with ethyl acetate (50 mL. Times.3), the combined organic phases washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give product 8b as a yellow solid (0.24 g, yield: 41.7%).

¹ H NMR(400MHz,CDCl ₃ )δ9.93(s,1H),8.39(s,2H),7.64–7.54(m,2H),2.72(s,3H)。

The second step is that: preparation of Compound 8c

3,5-difluoro-4- ((2-methylpyrimidin-5-yl) oxy) benzaldehyde 8b (0.24g, 0.96mmol) was dissolved in 50mL of methanol at room temperature and NaBH was added at 0 deg.C ₄ (30mg, 0.79mmol), the reaction was stirred at room temperature for 0.5 hours, concentrated under reduced pressure, added with water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 8c (0.17 g, yield: 70.2%) as a colorless oily product.

¹ H NMR(400MHz,CDCl ₃ )δ8.33(s,2H),7.04(m,2H),4.71(m,2H),2.70(s,3H)。

The third step: preparation of Compound 8

(3,5-difluoro-4- ((2-methylpyrimidin-5-yl) oxy) phenyl) methanol 8c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring the reaction at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 8 (10mg, 10.3%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.35(s,2H),7.11(m,2H),5.62(s,1H),5.40(s,2H),4.06(s,1H),3.80(m,1H),3.47(m,1H),3.25(s,1H),3.15(m,1H),3.04(m,1H),2.71(s,3H),2.44(m,1H),1.91(m,2H),1.52(m,2H).MS(ESI):m/z 442.0[M+H] ⁺ 。

EXAMPLE 9 preparation of Compound 9

The first step is as follows: preparation of Compound 9b

2- (trifluoromethyl) pyrimidin-5-ol 9a (0.25g, 1.52mmol), 3,4,5-trifluorobenzaldehyde 5a (0.29g, 1.81mmol) and potassium carbonate (0.27g, 1.98mmol) were dissolved in 20mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give product 9b (0.24 g, yield: 51.9%) as a yellow solid.

¹ H NMR(400MHz,CDCl ₃ )δ9.97(s,1H),8.59(s,2H),7.69–7.54(m,2H)。

The second step: preparation of Compound 9c

3,5-difluoro-4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) benzaldehyde 9b (0.24g, 0.79mmol) was dissolved in 50mL methanol at room temperature and Na was added at 0 deg.CBH ₄ (30mg, 0.79mmol), the reaction stirred at room temperature for 0.5h, concentrated under reduced pressure, added water, extracted with ethyl acetate (100 mL × 2), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate concentrated under reduced pressure, purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 9c as a colorless oil (0.12 g, yield: 49.6%).

¹ H NMR(400MHz,CDCl ₃ )δ8.54(s,2H),7.12(m,2H),4.74(m,2H),2.23(m,1H)。

The third step: preparation of Compound 9

(3,5-difluoro-4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) phenyl) methanol 9c (73mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 9 (8mg, 7.3%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.58(s,2H),7.19(m,2H),5.66(s,1H),5.45(s,2H),4.10(m,7.4Hz,1H),3.82(m,1H),3.49(m,1H),3.34–3.23(m,1H),3.18(m,1H),3.07(m,1H),2.47(m,1H),1.97(m,2H),1.60–1.50(m,2H).MS(ESI):m/z 496.1[M+H] ⁺ 。

EXAMPLE 10 preparation of Compound 10

The first step is as follows: preparation of Compound 10b

3- (trifluoromethyl) phenol 10a (1g, 6.2mmol), 3,4,5-trifluorobenzaldehyde 4a (1.09g, 6.8mmol) and potassium carbonate (1.1g, 8.02mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for reaction for 2 hours, cooled down, poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 10b (1.7 g, yield: 90.7%).

¹ H NMR(400MHz,CDCl ₃ )δ9.94(s,1H),7.63–7.55(m,2H),7.46(m,1H),7.39(m,1H),7.21(s,1H),7.13(m,1H)。

The second step is that: preparation of Compound 10c

3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) benzaldehyde 10b (1.7g, 5.6 mmol) was dissolved in 50mL of methanol at room temperature and NaBH was added at 0 deg.C ₄ (213mg, 5.6 mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, added with water, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give a colorless oily product 10c (1.27 g, yield: 74.5%).

The third step: preparation of Compound 10

(3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol 10c (73mg, 0.24mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 10 (6mg, 5.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.42(m,1H),7.33(m,1H),7.20(s,1H),7.10(m,3H),5.63(s,1H),5.41(s,2H),4.11–4.02(m,1H),3.80(m,1H),3.47(m,1H),3.26(m,1H),3.15(m,1H),3.04(m,1H),2.43(m,1H),2.00–1.85(m,2H),1.55–1.48(m,2H).MS(ESI):m/z494.0[M+H] ⁺ 。

EXAMPLE 11 preparation of Compound 11

The first step is as follows: preparation of Compound 11b

4-chloro-3-methylphenol 11a (1g, 7.0 mmol), 3,4,5-trifluorobenzaldehyde 5a (1.2g, 7.5 mmol) and potassium carbonate (1.3g, 9.1 mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down, poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 11b (1.2 g, yield: 60.6%).

¹ H NMR(400MHz,CDCl ₃ )δ9.92(s,1H),7.61–7.51(m,2H),7.30–7.23(m,1H),6.85(m,1H),6.73(m,1H),2.34(s,3H)。

The second step is that: preparation of Compound 11c

4- (4-chloro-3-methylphenoxy) -3,5-difluorobenzaldehyde 11b (1.2g, 4.2mmol) was dissolved in 50mL of methanol at room temperature, and NaBH was added at 0 deg.C ₄ (161mg, 4.2mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, water was added, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 11c as a colorless oil (0.89 g, yield: 74.4%).

The third step: preparation of Compound 11

4- (4-chloro-3-methylphenoxy) -3,5-difluorobenzyl alcohol 11c (77mg, 0.27mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.42mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 11 (9mg, 8.6%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.27(m,1H),7.12(m,2H),6.86(m,1H),6.74(m,1H),5.66(s,1H),5.43(s,2H),4.11(m,1H),3.84(m,1H),3.50(m,1H),3.34–3.25(m,1H),3.19(m,1H),3.08(m,1H),2.47(m,1H),2.36(s,3H),1.98(m,2H),1.61–1.51(m,2H).

EXAMPLE 12 preparation of Compound 12

The first step is as follows: preparation of Compound 12b

3- (trifluoromethoxy) phenol 12a (0.50g, 2.8mmol), 3,4,5-trifluorobenzaldehyde 5a (0.5g, 3.1mmol) and potassium carbonate (0.5g, 3.64mmol) were dissolved in 30mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down, poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 12b (0.73 g, yield: 91.8%).

¹ H NMR(400MHz,CDCl ₃ )δ9.94(s,1H),7.64–7.54(m,2H),7.34(m,1H),7.00(m,1H),6.87(m,2H)。

The second step is that: preparation of Compound 12c

4- (3- (trifluoromethoxy) phenoxy) -3,5-difluorobenzaldehyde 12b (0.73g, 2.3mmol) was dissolved in 50mL of methanol at room temperature and NaBH was added at 0 deg.C ₄ (86mg, 2.28mmol), the reaction stirred at room temperature for 0.5 hours, concentrated under reduced pressure, added water, extracted with ethyl acetate (100 mL × 2), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate concentrated under reduced pressure, purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give the product 12c as a colorless oil (0.57 g, yield: 77.4%).

¹ H NMR(400MHz,CDCl ₃ )δ7.30(m,1H),7.06(m,2H),6.94(m,1H),6.85(m,1H),6.81(s,1H),4.72(m,2H),1.94(m,1H)。

The third step: preparation of Compound 12

4- (3- (trifluoromethoxy) phenoxy) -3,5-difluorophenyl) methanol 12c (70mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 12 (6 mg, 5.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.29(m,1H),7.08(m,2H),6.93(m,1H),6.88–6.77(m,2H),5.62(s,1H),5.39(s,2H),4.06(m,1H),3.81(m,1H),3.46(m,1H),3.31–3.20(m,1H),3.13(m,1H),3.04(m,1H),2.43(m,1H),1.89(m,2H),1.51(m,2H).MS(ESI):m/z 510.0[M+H] ⁺ 。

EXAMPLE 13 preparation of Compound 13

The first step is as follows: preparation of Compound 13b

4- (trifluoromethyl) phenol 13a (0.84g, 5.2 mmol), 3,4,5-trifluorobenzaldehyde 5a (1g, 6.2 mmol) and potassium carbonate (0.93g, 6.76mmol) were dissolved in 30mL N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 1 hour, cooled to room temperature, poured into 100mL ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 5/1) to give the product 13b as a yellow solid (1.33 g, yield: 84.6%).

¹ H NMR(400MHz,CDCl ₃ )δ9.94(m,1H),7.59(m,4H),7.04(m,2H)。

The second step is that: preparation of Compound 13c

3,5-difluoro-4- (4- (trifluoromethyl) phenoxy) benzaldehyde 13b (1.33g, 4.4 mmol) was dissolved in 50mL of methyl ethanol at room temperature and NaBH was added at 0 deg.C ₄ (166mg, 4.4 mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, added with water, extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined and washed with saturated aqueous sodium chloride solutionDried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 2/1) to give 13c (0.85 g, yield: 63.5%) as a colorless oily product.

¹ H NMR(400MHz,CDCl ₃ )δ7.57(m,2H),7.09–7.00(m,4H),4.72(m,2H),2.03(m,1H)。

The third step: preparation of Compound 13

3,5-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) methanol 13c (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 13 (111mg, 10.1%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.57(m,2H),7.10(m,2H),7.01(m,2H),5.63(s,1H),5.41(s,2H),4.11–4.04(m,1H),3.80(m,1H),3.47(m,1H),3.30–3.21(m,1H),3.16(m,1H),3.04(m,1H),2.44(m,1H),1.99–1.85(m,2H),1.57–1.48(m,2H).MS(ESI):m/z494.0[M+H] ⁺ 。

EXAMPLE 14 preparation of Compound 14

The first step is as follows: preparation of Compound 14b

4-chloro-3- (trifluoromethyl) phenol 14a (0.5g, 2.5mmol), 3,4,5-trifluorobenzaldehyde 5a (0.45g, 2.8mmol) and potassium carbonate (0.46g, 3.3mmol) were dissolved in 30mL N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down, poured into 100mL ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 14b (0.6 g, yield: 71.3%).

¹ H NMR(400MHz,CDCl ₃ )δ9.94(s,1H),7.64–7.55(m,2H),7.45(m,1H),7.31(m,1H),7.05(m,1H)。

The second step is that: preparation of Compound 14c

4- (4-chloro-3- (trifluoromethyl) phenoxy) -3,5-difluorobenzaldehyde 14b (0.6g, 1.78mmol) was dissolved in 50mL of methanol at room temperature and NaBH was added at 0 deg.C ₄ (67mg, 1.78mmol), the reaction stirred at room temperature for 0.5 hour, concentrated under reduced pressure, added water, extracted with ethyl acetate (100 mL × 2), the organic phases combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate concentrated under reduced pressure, purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 14c as a white solid (0.28 g, yield: 46.4%).

¹ H NMR(400MHz,CDCl ₃ )δ7.41(m,1H),7.28(m,1H),7.08–7.00(m,3H),4.73(m,2H),1.94(m,1H)。

The third step: preparation of Compound 14

(4- (4-chloro-3- (trifluoromethyl) phenoxy) -3,5-difluorophenyl) methanol 14c (74 mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 14 (22mg, 18.9%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.41(m,1H),7.30(m,1H),7.11(m,2H),7.01(m,1H),5.63(s,1H),5.41(s,2H),4.07(m,1H),3.80(m,1H),3.47(m,1H),3.30–3.21(m,1H),3.15(m,1H),3.04(m,1H),2.44(m,1H),1.95(m,2H),1.57–1.47(m,2H).

EXAMPLE 15 preparation of Compound 15

The first step is as follows: preparation of Compound 15b

3-chloro-4- (trifluoromethoxy) phenol 15a (0.50g, 2.4 mmol), 3,4,5-trifluorobenzaldehyde 5a (0.41g, 2.6 mmol) and potassium carbonate (0.42g, 3.04mmol) were dissolved in 20mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give product 15b (0.62 g, yield: 73.2%) as a yellow solid.

¹ H NMR(400MHz,CDCl ₃ )δ9.94(s,1H),7.63–7.54(m,2H),7.29(m,1H),7.07(m,1H),6.90(m,1H)。

The second step is that: preparation of Compound 15c

4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3,5-difluorobenzaldehyde 15b (0.62g, 1.8mmol) was dissolved in 50mL of methanol at room temperature, and NaBH was added at 0 deg.C ₄ (62mg, 1.94mmol), the reaction was stirred at room temperature for 0.5 hour, concentrated under reduced pressure, water was added, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give 15c (0.53 g, yield: 83.0%) as a colorless oily product.

¹ H NMR(400MHz,CDCl ₃ )δ7.25(m,1H),7.06(m,2H),7.01(m,1H),6.87(m,1H),4.72(s,2H),2.04(m,1H)。

The third step: preparation of Compound 15

(4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3,5-difluorophenyl) methanol 15c (79mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 15 (7mg, 5.8%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.24(m,1H),7.10(m,2H),7.03(m,1H),6.87(m,1H),5.63(s,1H),5.41(s,2H),4.10–4.03(m,1H),3.80(m,1H),3.47(m,1H),3.30–3.21(m,1H),3.16(m,1H),3.04(m,1H),2.44(m,1H),1.95(m,2H),1.56–1.49(m,2H).

EXAMPLE 16 preparation of Compound 16

The first step is as follows: preparation of Compound 16b

3-chloro-4- (trifluoromethyl) phenol 16a (0.25g, 1.23mmol), 3,4,5-trifluorobenzaldehyde 5a (0.22g, 1.4 mmol) and potassium carbonate (0.23g, 1.65mmol) were dissolved in 20mL of N, N-dimethylformamide at room temperature, stirred at 90 ℃ for 2 hours, cooled down and poured into 100mL of ice water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 10/1) to give a yellow solid product 16b (0.32 g, yield: 77.3%).

¹ H NMR(400MHz,CDCl ₃ )δ9.95(s,1H),7.69–7.56(m,3H),7.10(m,1H),6.92(m,1H)。

The second step is that: preparation of Compound 16c

4- (3-chloro-4- (trifluoromethyl) phenoxy) -3,5-difluorobenzaldehyde 16b (0.32g, 0.95mmol) was dissolved in 50mL methanol at room temperature and NaBH was added at 0 deg.C ₄ (36mg, 0.94mmol), stirred at room temperature for 0.5 hours, concentrated under reduced pressure, added water, extracted with ethyl acetate (100 mL. Times.2), combined organic phases, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated the filtrate under reduced pressure, purified by silica gel column chromatography with an eluent system (petroleum ether/ethyl acetate = 4/1) to give product 16c as a white solid (0.15 g, yield: 46.6%))。

¹ H NMR(400MHz,CDCl ₃ )δ7.62(m,1H),7.13–7.00(m,3H),6.90(m,1H),4.74(m,2H),1.88(m,1H)。

The third step: preparation of Compound 16

(4- (3-chloro-4- (trifluoromethyl) phenoxy) -3,5-difluorophenyl) methanol (74.5mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.44mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 1f (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 16 (13mg, 11.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.62(m,1H),7.12(m,2H),7.07(m,1H),6.90(m,1H),5.63(s,1H),5.42(s,2H),4.12–4.03(m,1H),3.81(m,1H),3.45(m,1H),3.32–3.21(m,1H),3.16(m,1H),3.05(m,1H),2.44(m,1H),1.91(m,2H),1.56–1.49(m,2H).

EXAMPLE 17 preparation of Compound 17

The first step is as follows: preparation of Compound 17b

6-Chlorouracil (8.2 g, 55.9mmol), (S) -3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester 17a (12g, 55.7mmol) and triphenylphosphine (20g, 76.2mmol) were dissolved in a mixed solvent of 250mL of anhydrous tetrahydrofuran and 50mL of anhydrous N, N-dimethylformamide under nitrogen protection at 0 ℃ and diisopropyl azodicarboxylate (20mL, 111.6mmol) was added dropwise, and after stirring at 0 ℃ for 2 hours, the reaction mixture was warmed to room temperature overnight, the reaction mixture was filtered, extracted with ethyl acetate (50 mL. Times.3), the organic phase was combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain colorless oily product 17b (7.8 g, yield: 40.6%).

The second step and the third step: preparation of Compound 17d

The compound (S) -3- (((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) piperidine-1-carboxylic acid tert-butyl ester 17b (7.8g, 22.7mmol) was dissolved in 80mL of dichloromethane at room temperature, 10mL of trifluoroacetic acid was added at 0 ℃, the reaction was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the next reaction was carried out directly.

¹ H NMR(400MHz,CDCl ₃ )δ9.51(s,1H),5.35(s,1H),4.03(m,1H),3.78–3.64(m,1H),3.43(m,1H),3.24(m,1H),3.18–2.96(m,2H),2.37(m,1H),2.00–1.83(m,2H),1.72–1.49(m,2H).

The fourth step: preparation of Compound 17e

Compound 17d (0.51g, 2.46mmol) and dimethylaniline (0.3g, 2.47mmol) were dissolved in toluene at room temperature, phosphorus oxychloride (0.76g, 4.96mmol) was added dropwise, after heating under reflux for 4 hours, the reaction was quenched with ice water, concentrated under reduced pressure, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 17e (0.24g, 43.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.05(s,1H),4.04(m,1H),3.74(m,1H),3.51(m,1H),3.28(m,1H),3.20–3.14(m,1H),3.01(m,1H),2.51(m,1H),1.92(m,2H),1.59–1.41(m,2H).

The fifth step: preparation of Compound 17

(3,5-difluoro-4- ((2- (trifluoromethylpyridin-4-yl) oxy) phenyl) methanol 5d (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 18mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 17e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 17 (28mg, 25.7%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,1H),7.25(s,1H),7.15(m,2H),6.98(m,1H),5.63(s,1H),5.42(s,2H),4.07(m,1H),3.80(m,1H),3.46(m,1H),3.27(m,1H),3.16(m,1H),3.03(m,1H),2.44(m,1H),1.90(m,2H),1.52(m,2H).MS(ESI):m/z 495.1[M+H] ⁺ 。

EXAMPLE 18 preparation of Compound 18

(3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) phenyl) methanol 7c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring for 5 minutes at room temperature, compound 17e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 18 (22mg, 22.7%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.27(m,1H),7.10(m,4H),5.62(s,1H),5.39(s,2H),4.07(m,1H),3.80(m,1H),3.46(m,1H),3.29–3.21(m,1H),3.15(m,1H),3.04(m,1H),2.51(s,3H),2.44(m,1H),1.99–1.84(m,2H),1.51(m,2H).MS(ESI):m/z 441.2[M+H] ⁺ 。

EXAMPLE 19 preparation of Compound 19

(3,5-difluoro-4- ((2-methyl) pyridin-4-yl) oxy) phenyl) methanol 6c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 17e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the objective product 19 (58mg, 59.8%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.35(m,1H),7.10(m,2H),6.67(m,2H),5.62(s,1H),5.41(s,2H),4.07(m,1H),3.79(m,1H),3.46(m,1H),3.30–3.18(m,1H),3.15(m,1H),3.04(m,1H),2.50(s,3H),2.43(m,1H),1.91(m,2H),1.55–1.46(m,2H).MS(ESI):m/z 441.2[M+H] ⁺ 。

EXAMPLE 20 preparation of Compound 20

(3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol 10c (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring the reaction at room temperature for 5 minutes, compound 17e (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 20 (46mg, 42.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.41(m,1H),7.32(m,1H),7.19(s,1H),7.09(m,3H),5.62(s,1H),5.40(s,2H),4.06(m,1H),3.79(m,1H),3.46(m,1H),3.30–3.19(m,1H),3.14(m,1H),3.03(m,1H),2.43(m,1H),1.98–1.84(m,2H),1.57–1.46(m,2H).MS(ESI):m/z494.1[M+H] ⁺ 。

EXAMPLE 21 preparation of Compound 21

3,5-difluorobenzyl alcohol (32mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 17e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 21 as a white solid (17mg, 23.2%).

¹ H NMR(400MHz,CDCl ₃ )δ6.96–6.87(m,2H),6.74(m,1H),5.60(s,1H),5.37(s,2H),4.06(m,1H),3.79(m,1H),3.45(m,1H),3.23(m,1H),3.14(m,1H),3.03(m,1H),2.42(m,1H),1.99–1.83(m,2H),1.57–1.46(m,2H).MS(ESI):m/z 334.1[M+H] ⁺ 。

EXAMPLE 22 preparation of Compound 22

2,4,5-trifluorobenzyl alcohol (36mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 17e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 22 as a white solid (36mg, 46.6%).

¹ H NMR(400MHz,CDCl ₃ )δ7.32(m,1H),6.94(m,1H),5.57(s,1H),5.40(s,2H),4.06(m,1H),3.79(m,1H),3.44(m,1H),3.29–3.17(m,1H),3.14(m,1H),3.03(m,1H),2.42(m,1H),1.99–1.83(m,2H),1.55–1.45(m,2H).MS(ESI):m/z 352.1[M+H] ⁺ 。

EXAMPLE 23 preparation of Compound 23

The first step is as follows: preparation of Compound 23b

6-Chlorouracil (6.1 g,41.6 mmol), (R) -3- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester 23a (9 g,41.8 mmol) and triphenylphosphine (16.3 g,62.1 mmol) were dissolved in a mixture of 250mL of anhydrous tetrahydrofuran and 50mL of anhydrous N, N-dimethylformamide at room temperature under nitrogen protection and 0 ℃ with dropwise addition of diisopropyl azodicarboxylate (1695 mL, 83mmol), and after stirring at 0 ℃ for 2 hours, the reaction mixture was warmed to room temperature for overnight reaction, filtered, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 23b as a colorless oil (8.3 g, yield: 58.0%).

The second and third steps: preparation of Compound 23d

The compound (R) -3- (((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) piperidine-1-carboxylic acid tert-butyl ester 23b (8.3 g,24.1 mmol) was dissolved in 80mL of dichloromethane at room temperature, 10mL of trifluoroacetic acid was added at 0 deg.C, the reaction was stirred at room temperature for 2 hours, the reaction was concentrated under reduced pressure, and the next reaction was directly carried out.A crude product of the previous step was dissolved in 80mL of acetonitrile, potassium carbonate (7.0 g,50.9 mmol) was added at room temperature, the reaction was heated under reflux overnight, filtered, the filter cake was washed with acetonitrile and methanol, respectively, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give a white solid product 23d (1.5 g, 29.9%).

¹ H NMR(400MHz,CDCl ₃ )δ8.85(s,1H),5.33(s,1H),4.01(m,1H),3.70(m,1H),3.42(m,1H),3.23(m,1H),3.11(m,1H),3.03(m,1H),2.35(m,1H),1.99–1.82(m,2H),1.67–1.47(m,2H).

The fourth step: preparation of Compound 23e

Compound 23d (0.5g, 2.4 mmol) and dimethylaniline (0.29g, 2.4 mmol) were dissolved in toluene at room temperature, phosphorus oxychloride (0.74g, 4.8 mmol) was added dropwise, after heating under reflux for 4 hours, the reaction was quenched with ice water, concentrated under reduced pressure, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 23e (0.31g, 57.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.05(s,1H),4.05(m,1H),3.76(m,1H),3.51(m,1H),3.28(m,1H),3.22–3.13(m,1H),3.02(m,1H),2.52(m,1H),2.01–1.82(m,2H),1.61–1.39(m,2H).

The fifth step: preparation of Compound 23

(3,5-difluoro-4- ((2- (trifluoromethylpyridin-4-yl) oxy) phenyl) methanol 5d (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 23e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 23 (25mg, 23.0%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,1H),7.25(s,1H),7.14(m,2H),6.98(m,1H),5.63(s,1H),5.42(s,2H),4.07(m,1H),3.79(m,1H),3.46(m,1H),3.26(m,1H),3.15(m,1H),3.04(m,1H),2.44(m,1H),2.00–1.84(m,2H),1.56–1.46(m,2H).MS(ESI):m/z 495.1[M+H] ⁺ 。

EXAMPLE 24 preparation of Compound 24

(3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) phenyl) methanol 7c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring the reaction for 5 minutes at room temperature, compound 23e (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 24 as a white solid (52mg, 53.7%).

¹ H NMR(400MHz,CDCl ₃ )δ8.27(m,1H),7.09(m,4H),5.61(s,1H),5.38(s,2H),4.06(m,1H),3.80(m,1H),3.46(m,1H),3.28–3.20(m,1H),3.15(m,1H),3.04(m,1H),2.51(s,3H),2.43(m,1H),1.92(m,2H),1.57–1.45(m,2H).MS(ESI):m/z 441.2[M+H] ⁺ 。

EXAMPLE 25 preparation of Compound 25

(3,5-difluoro-4- ((2-methyl) pyridin-4-yl) oxy) phenyl) methanol 6c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 23e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 25 (38mg, 39.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.36(m,1H),7.11(m,2H),6.67(m,2H),5.63(s,1H),5.41(s,2H),4.07(m,1H),3.80(m,1H),3.47(m,1H),3.32–3.21(m,1H),3.15(m,1H),3.04(m,1H),2.51(s,3H),2.44(m,1H),2.00–1.83(m,2H),1.59–1.46(m,2H).MS(ESI):m/z441.2[M+H] ⁺ 。

EXAMPLE 26 preparation of Compound 26

(3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol 10c (67mg, 0.22mmol) was dissolved in 5mL dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring the reaction for 5 minutes at room temperature, compound 23e (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 26 (58mg, 53.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.42(m,1H),7.33(m,1H),7.20(s,1H),7.11(m,3H),5.63(s,1H),5.41(s,2H),4.07(m,1H),3.80(m,1H),3.47(m,1H),3.30–3.20(m,1H),3.15(m,1H),3.04(m,1H),2.43(m,1H),1.98–1.84(m,2H),1.56–1.48(m,2H).MS(ESI):m/z494.1[M+H] ⁺ 。

EXAMPLE 27 preparation of Compound 27

3,5-difluorobenzyl alcohol (32mg, 0.22mmol) was dissolved in 5mL dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring reaction at room temperature for 5 minutes, compound 23e (50mg, 0.22mmol) was added, after stirring reaction for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the target product 27 as a white solid (19mg, 25.9%).

¹ H NMR(400MHz,CDCl ₃ )δ6.96–6.87(m,2H),6.73(m,1H),5.58(s,1H),5.37(s,2H),4.05(m,1H),3.79(m,1H),3.45(m,1H),3.29–3.19(m,1H),3.14(m,1H),3.03(m,1H),2.41(m,1H),1.98–1.82(m,2H),1.55–1.46(m,2H).MS(ESI):m/z334.1[M+H] ⁺ 。

EXAMPLE 28 preparation of Compound 28

2,4,5-trifluorobenzyl alcohol (36mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 23e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 28 (18mg, 23.3%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.32(m,1H),6.95(m,1H),5.58(s,1H),5.40(s,2H),4.06(m,1H),3.79(m,1H),3.44(m,1H),3.29–3.19(m,1H),3.14(m,1H),3.03(m,1H),2.43(m,1H),1.93(m,2H),1.55–1.46(m,2H).MS(ESI):m/z 352.1[M+H] ⁺ 。

EXAMPLE 29 preparation of Compound 29

The first step is as follows: preparation of Compound 29b

6-Chlorouracil (10g, 69mmol), (S) -2- (hydroxymethyl) morpholine-4-carboxylic acid tert-butyl ester 29a (15g, 69mmol) and triphenylphosphine (27g, 102.9mmol) were dissolved in 250mL of anhydrous tetrahydrofuran and 50mL of an anhydrous N, N-dimethylformamide mixed solvent at room temperature, diisopropyl azodicarboxylate (27ml, 138mmol) was added dropwise under nitrogen protection at 0 ℃, the reaction mixture was stirred at 0 ℃ for 2 hours, then warmed to room temperature for overnight reaction, the reaction mixture was filtered, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, 100mL of PE/EA =3/1 was added, a large amount of white solid was precipitated, filtered, the reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain a colorless oily product 29b (11.5 g, yield: 48.2%).

The second step and the third step: preparation of Compound 29d

The compound (S) -tert-butyl 2- (((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) morpholine-4-carboxylate 29b (11.5g, 33.2 mmol) was dissolved in 80mL of dichloromethane at room temperature, 10mL of trifluoroacetic acid was added at 0 ℃ and the reaction was stirred at room temperature for 2 hours, the reaction was concentrated under reduced pressure and the next step was carried out directly the crude product of the previous step was dissolved in 80mL of acetonitrile, potassium carbonate (9.2 g, 67mmol) was added at room temperature, the reaction was heated under reflux overnight, the filter cake was washed with acetonitrile and methanol, respectively, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the product 29d as a white solid (1.9g, 27.4%).

¹ H NMR(400MHz,CDCl ₃ )δ9.39(s,1H),5.41(s,1H),4.36–4.28(m,1H),4.05(m,1H),3.95(m,1H),3.78(m,1H),3.69–3.55(m,2H),3.44–3.37(m,1H),3.24(m,1H),2.96(m,1H).

The fourth step: preparation of Compound 29e

Compound 29d (0.5g, 2.4 mmol) and dimethylaniline (0.29g, 2.4 mmol) were dissolved in toluene at room temperature, phosphorus oxychloride (0.73g, 4.8mmol) was added dropwise, after heating under reflux for 4 hours, the reaction was quenched with ice water, concentrated under reduced pressure, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 29e (0.3g, 54.9%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.12(s,1H),4.49(m,1H),4.08(m,1H),3.99(m,1H),3.72–3.61(m,3H),3.48(m,1H),3.37(m,1H),2.96(m,1H).

The fifth step: preparation of Compound 29

(3,5-difluoro-4- ((2- (trifluoromethylpyridin-4-yl) oxy) phenyl) methanol 5d (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 29 (31mg, 28.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.59(m,1H),7.25(s,1H),7.14(m,2H),6.98(m,1H),5.69(s,1H),5.43(s,2H),4.40(m,1H),4.12(m,1H),4.03(m,1H),3.70–3.57(m,3H),3.44(m,1H),3.27(m,1H),2.95(m,1H).MS(ESI):m/z 497.1[M+H] ⁺ 。

EXAMPLE 30 preparation of Compound 30

(3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) phenyl) methanol (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 30 (49mg, 50.3%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.26(m,1H),7.16–7.05(m,4H),5.69(s,1H),5.40(s,2H),4.40(m,1H),4.13(m,1H),4.04(m,1H),3.70–3.58(m,3H),3.45(m,1H),3.27(m,1H),2.96(m,1H),2.52(s,3H).MS(ESI):m/z443.1[M+H] ⁺ 。

EXAMPLE 31 preparation of Compound 31

(3,5-difluoro-4- ((2-methyl) pyridin-4-yl) oxy) phenyl) methanol 6c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the objective product 31 (38mg, 39.0%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.35(m,1H),7.11(m,2H),6.72–6.63(m,2H),5.70(s,1H),5.42(s,2H),4.39(m,1H),4.17–4.08(m,1H),4.03(m,1H),3.71–3.57(m,3H),3.50–3.40(m,1H),3.27(m,1H),2.95(m,1H),2.50(s,3H).MS(ESI):m/z 443.1[M+H] ⁺ 。

EXAMPLE 32 preparation of Compound 32

(3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol 10c (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring the reaction at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched with a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 32 (31mg, 28.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.42(m,1H),7.34(m,1H),7.19(s,1H),7.10(m,3H),5.70(s,1H),5.42(s,2H),4.40(m,1H),4.17–4.00(m,2H),3.71–3.57(m,3H),3.45(m,1H),3.28(m,1H),2.96(m,1H).MS(ESI):m/z 496.1[M+H] ⁺ 。

EXAMPLE 33 preparation of Compound 33

3,5-difluorobenzyl alcohol (32mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the target product 33 (21mg, 28.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.98–6.91(m,2H),6.77(m,1H),5.70(s,1H),5.40(s,2H),4.41(m,1H),4.14(m,1H),4.04(m,1H),3.72–3.58(m,3H),3.46(m,1H),3.28(m,1H),2.97(m,1H).MS(ESI):m/z 336.1[M+H] ⁺ 。

EXAMPLE 34 preparation of Compound 34

2,4,5-trifluorobenzyl alcohol (36mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 29e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 34 as a white solid (29mg, 37.3%).

¹ H NMR(400MHz,CDCl ₃ )δ7.36–7.27(m,1H),6.95(m,1H),5.64(s,1H),5.40(s,2H),4.42–4.35(m,1H),4.12(m,1H),4.02(m,1H),3.73–3.55(m,3H),3.43(m,1H),3.24(m,1H),2.95(m,1H).MS(ESI):m/z 354.1[M+H] ⁺ 。

EXAMPLE 35 preparation of Compound 35

The first step is as follows: preparation of Compound 35b

6-Chlorouracil (10g, 68.2mmol), (R) -2- (hydroxymethyl) morpholine-4-carboxylic acid tert-butyl ester 35a (15g, 69mmol) and triphenylphosphine (27g, 102.9mmol) were dissolved in a mixed solvent of 250mL of anhydrous tetrahydrofuran and 50mL of anhydrous N, N-dimethylformamide at room temperature, diisopropyl azodicarboxylate (27ml, 138mmol) was added dropwise under nitrogen protection at 0 ℃, after stirring at 0 ℃ for reaction for 2 hours, the reaction mixture was allowed to warm to room temperature for overnight reaction, the reaction mixture was filtered, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated under reduced pressure, 100mL of PE/EA =3/1 was added, a large amount of white solid was precipitated, filtered, the filtrate was concentrated under reduced pressure, and purified with a silica gel column chromatography using an eluent system (dichloromethane/methanol = 20/1) to obtain a colorless oily product 35b (7.2 g, yield: 30.5%).

The second step and the third step: preparation of Compound 35d

The compound (R) -tert-butyl 2- (((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) morpholine-4-carboxylate 35b (7.2g, 20.8mmol) was dissolved in 80mL dichloromethane at room temperature, 10mL trifluoroacetic acid was added at 0 ℃, the reaction was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the next reaction was carried out directly, the crude product of the previous step was dissolved in 80mL acetonitrile, diisopropylethylamine (8.1g, 62.7 mmol) was added at room temperature, the reaction was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, and purified by a silica gel column chromatography system (dichloromethane/methanol = 20/1) to give 35d (2.5g, 57.4%) as a white solid product.

¹ H NMR(400MHz,CDCl ₃ )δ9.32(s,1H),5.42(s,1H),4.35–4.29(m,1H),4.07(m,1H),3.96(m,1H),3.78(m,1H),3.70–3.55(m,2H),3.45–3.36(m,1H),3.24(m,1H),2.96(m,1H).

The fourth step: preparation of Compound 35e

Compound 35d (0.1g, 0.48mmol) and dimethylaniline (0.058g, 0.48mmol) were dissolved in toluene at room temperature, phosphorus oxychloride (0.73g, 4.8mmol) was added dropwise, after heating under reflux for 4 hours, the reaction was quenched with ice water, concentrated under reduced pressure, extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove a drying agent, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to obtain product 35e (0.04g, 36.4%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.12(s,1H),4.48(m,1H),4.06(m,1H),3.99(m,1H),3.73–3.61(m,3H),3.47(m,1H),3.42–3.32(m,1H),2.96(m,1H).

The fifth step: preparation of Compound 35

(3,5-difluoro-4- ((2- (trifluoromethylpyridin-4-yl) oxy) phenyl) methanol 5d (67mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 35e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 35 (41mg, 37.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.60(m,1H),7.25(s,1H),7.15(m,2H),6.99(m,1H),5.70(s,1H),5.44(s,2H),4.40(m,1H),4.13(m,1H),4.04(m,1H),3.70–3.58(m,3H),3.44(m,1H),3.28(m,1H),2.96(m,1H).MS(ESI):m/z 497.1[M+H] ⁺ 。

EXAMPLE 36 preparation of Compound 36

(3,5-difluoro-4- ((6-methylpyridin-3-yl) oxy) phenyl) methanol 7c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 35e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 36 (42mg, 43.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.21(m,1H),7.06(m,4H),5.65(s,1H),5.37(s,2H),4.36(m,1H),4.13–4.03(m,1H),3.98(m,1H),3.66–3.53(m,3H),3.40(m,1H),3.23(m,1H),2.93(m,1H),2.47(s,3H).MS(ESI):m/z 443.1[M+H] ⁺ 。

EXAMPLE 37 preparation of Compound 37

(3,5-difluoro-4- ((2-methyl) pyridin-4-yl) oxy) phenyl) methanol 6c (56mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% content in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 35e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the target product 37 (18mg, 18.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ8.36(m,1H),7.09(m,2H),6.70–6.65(m,2H),5.70(s,1H),5.43(s,2H),4.41(m,1H),4.13(m,1H),4.04(m,1H),3.72–3.58(m,3H),3.46(m,1H),3.28(m,1H),2.96(m,1H),2.51(s,3H).MS(ESI):m/z 443.1[M+H] ⁺ 。

EXAMPLE 38 preparation of Compound 38

(3,5-difluoro-4- (3- (trifluoromethyl) phenoxy) phenyl) methanol 10c (67mg, 0.22mmol) was dissolved in 5mL dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring the reaction for 5 minutes at room temperature, compound 35e (50mg, 0.22mmol) was added, after stirring the reaction for 1 hour, the reaction was quenched by the addition of a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give product 38 (55mg, 50.5%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.41(m,1H),7.33(m,1H),7.18(s,1H),7.10(m,3H),5.70(s,1H),5.41(s,2H),4.40(m,1H),4.15–4.07(m,1H),4.03(m,1H),3.70–3.55(m,3H),3.45(m,1H),3.27(m,1H),2.96(m,1H).MS(ESI):m/z 496.1[M+H] ⁺ 。

EXAMPLE 39 preparation of Compound 39

3,5-difluorobenzyl alcohol (32mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 35e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the desired product 39 (37mg, 50.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ6.96–6.89(m,2H),6.75(m,1H),5.68(s,1H),5.39(s,2H),4.40(m,1H),4.12(m,1H),4.03(m,1H),3.70–3.55(m,3H),3.44(m,1H),3.26(m,1H),2.95(m,1H).MS(ESI):m/z 336.1[M+H] ⁺ 。

EXAMPLE 40 preparation of Compound 40

2,4,5-trifluorobenzyl alcohol (36mg, 0.22mmol) was dissolved in 5mL of dry N, N-dimethylformamide, sodium hydride (60% in mineral oil, 11mg, 0.26mmol) was added at 0 ℃, after stirring at room temperature for 5 minutes, compound 35e (50mg, 0.22mmol) was added, after stirring for 1 hour, the reaction was quenched by adding a small amount of water, and purified by silica gel column chromatography with an eluent system (dichloromethane/methanol = 20/1) to give the target product 40 (39mg, 50.2%) as a white solid.

¹ H NMR(400MHz,CDCl ₃ )δ7.36–7.28(m,1H),6.95(m,1H),5.65(s,1H),5.41(s,2H),4.42–4.35(m,1H),4.17–4.08(m,1H),4.03(m,1H),3.71–3.55(m,3H),3.44(m,1H),3.25(m,1H),2.95(m,1H).MS(ESI):m/z 354.1[M+H] ⁺ 。

Biological evaluation

The biological activity of a compound can be determined by using any suitable assay and tissue and in vivo models for determining the activity of a compound as an LpPLA2 inhibitor.

(1) Recombinant human Lp-PLA2 assay (rhLp-PLA 2), also known as the assay for PED6

PED6 is a fluorescently labeled phospholipid that is directly available from Invitrogene or Molecular Probes. The Sn3 position of the fluorescent material has a fluorescence quenching p-nitrophenyl group, the Sn2 position of the fluorescent material has a Bodipy Fluorescein (FL) group, and the FL group is released once the fluorescent material is broken by Lp-PLA2 enzyme, so that the fluorescence is enhanced. However, lp-PLA2 inhibitors can prevent the generation of such cleavage, so that no fluorescence enhancement is observed.

The determination method comprises the following steps: the test compounds (as shown in table 1) were mixed with DMSO solutions at a volume ratio of 1:3 and diluted to prepare a source plate of 384-well microplate. Then 0.01. Mu.l of the compound was transferred from the source plate to a 384 well Greiner784076 plate using an ECHO liquid dispenser, and 5. Mu.l of a buffer consisting of 50mM HEPES, pH7.4,150mM NaCl,1mM CHAPS containing recombinant human Lp-PLA2 enzyme at a concentration of 4nM or 110pM was added to each well on the plate. After centrifugation of the plate at 500rpm for 10 seconds and 30 minutes of preincubation, 5 microliters of the above buffer was added to 384 well Greiner784076 plates, and after centrifugation of the plates at 500rpm for 10 seconds, incubation at room temperature in the dark for 20 minutes, fluorescence intensity was read at ex 480/em 540 using a ViewLux microplate imager, curve and QC analysis were performed using an XL fit model for Excel, and pIC50 was calculated, and the results are listed in table 1.

TABLE 1

(2) Human plasma Lp-PLA2 assay (also called Thio-PAF assay)

Human plasma assays utilize thiol analogs of PAF (phosphatidylcholine) which hydrolyze to produce free thiol-containing phospholipids, which are combined with CPM Michael to produce fluorescence-enhancing maleimides, and the thiol can be continuously quantitated by measuring the intensity of fluorescence. The method can detect the inhibitory activity of the Lp-PLA2 inhibitor on the Lp-PLA2 enzyme in human plasma.

The determination method comprises the following steps: the test compounds (shown in table 2) were diluted with DMSO solutions at a volume ratio (1:3) to make a source plate of 384-well microtiter plates. Transfer 0.01 microliters of compound from source plate to 384 well Greiner784076 low volume plate with ECHO liquid dispenser, then add pre-aliquoted and frozen 8 microliters of pooled human plasma. After the plates were centrifuged at 500rpm for 10 seconds and preincubated for 30 minutes, 2. Mu.l of substrate solution, 2-thioPAF (ethanol solution) containing 2.5mM, 32. Mu.M CPM (DMSO solution) and 3.2mM N-ethylmaleimide (NEM) buffer (50mM HEPES, pH7.4,150mM NaCl,1mM CHAPS buffer) were added to 384-well Greiner784076 low volume plates using a BRAVO liquid handling station, after 2 minutes the reaction was quenched with 5. Mu.l of 5% trifluoroacetic acid, after incubation for 40 minutes at ambient temperature protected from light, the fluorescence intensity was read at ex 380/em 485 using an Envision microplate reader, curve and QC fitting analyses were performed using Excel's XL model, and the pIC50 was calculated, the results are listed in Table 2.

TABLE 2

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

n ₁ 、n ₂ 、n ₃ each independently is 0,1 or 2;

R ₁ 、R ₂ each independently selected from: -H, alkyl, deuterated alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy;

X ₁ is alkylene, -O-, or-S-;

X ₂ is-O-, or-S-;

ar is arylene; the hydrogen atoms in the arylene group are optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, cyano, cycloalkyl;

y is-H, halogen, alkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, deuterated alkyl, deuterated alkoxy, hydroxy, hydroxyalkyl, cyano, -OAr ', -SAr';

ar' is selected from aryl or heteroaryl; the hydrogen atoms in the aryl or heteroaryl groups are optionally substituted with one or more substituents each independently selected from: halogen, alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, or deuterated alkoxy;

z is O or S;

the halogen atoms in the "halogen", "haloalkyl", "haloalkoxy" are each independently selected from F, cl, br or I;

the alkyl group of the "alkyl group", "deuterated alkoxy group", "hydroxyalkyl group", "haloalkyl group", "haloalkoxy group" or "alkoxy group" is independently C ₁ -C ₁₀ A linear or branched alkyl group;

the "aryl" is 6-10 membered aryl;

the "arylene" is a 6-to 10-membered arylene;

the "heteroaryl" is a 5-10 membered heteroaromatic ring containing 1-3 heteroatoms selected from N, O and S in the ring.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the alkyl group of "alkyl", "deuterated alkoxy", "hydroxyalkyl", "haloalkyl", "haloalkoxy", "alkoxy" is independently C ₁ -C ₇ Straight or branched chain alkyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the alkyl group of "alkyl", "deuterated alkoxy", "hydroxyalkyl", "haloalkyl", "haloalkoxy", "alkoxy" is independently C ₁ -C ₄ Straight or branched chain alkyl.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the alkyl groups present in the "alkyl", "deuterated alkoxy", "hydroxyalkyl", "halogenated alkyl", "halogenated alkoxy", "alkoxy" are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 5364 zxft 8655364-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 3525-dimethylpentyl, 3,3, pentyl-dimethylpentyl, 5229-pentyl, 4283, and 5229-dimethylpentyl.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein "aryl" is phenyl or naphthyl.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein "aryl" is phenyl, 1-naphthyl, or 2-naphthyl.

7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the "arylene" is phenylene or naphthylene.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein the "heteroaryl" group is a 5-10 membered heteroaromatic ring containing 1-2 heteroatoms in the ring selected from N, O and S.

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the heteroaromatic ring is selected from the group consisting of a pyridine ring, a pyrrole ring, a pyrazole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring.

10. <xnotran> 1 (I) , , -2- , -3- , -4- , -3- , -4- , -2- , -4- , -5- , -2- , -3- , , , , , , , , , , , , , , [ 4984 zxft 4984-b ] , [ 5272 zxft 5272-b ] - , [ 7945 zxft 7945-d ] , [ 3272 zxft 3272-d ] , [ 3424 zxft 3424-d ] , [ 3535 zxft 3535-d ] , [ 3584 zxft 3584-b ] , [ 4284 zxft 4284-b ] [ l, 5325 zxft 5325 ] , , , , , , , , , [ 5623 zxft 5623-b ] , [ 6262 zxft 6262-c ] , [ 3256 zxft 3256-b ] , [ 3456 zxft 3456-b ] , [ 3838 zxft 3838-c ] , [ 5749 zxft 5749-d ] , [ 6595 zxft 6595-c ] , [ 6898 zxft 6898-c ] , [ 3428 zxft 3428-d ] , [ 3476 zxft 3476-b ] , </xnotran> 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.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the heteroaryl group is selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1,

X ₁ selected from: c ₁ -C ₇ Alkylene, -O-, or-S-.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is ₁ is-CH ₂ -, ethylene, n-propylene, isopropylene, n-butylene or isobutylene, -O-, or-S-.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is ₁ is-CH ₂ -or-O-.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1,

X ₂ is-O-.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that,

ar is phenylene in which the hydrogen atoms are optionally substituted with 1,2 or 3 substituents each independently selected from: F. cl, br, I.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar is phenylene in which the hydrogen atom is optionally substituted with 1 or 2 substituents, said substituents being F.

18. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Y is-H, -F, -Cl, -Br, -I, or-OAr;

ar' is selected from the group consisting of a phenyl, pyridyl, or pyrimidyl ring, each independently optionally substituted with 1,2, or 3 substituents each independently selected from the group consisting of: F. cl, br, C ₁ -C ₇ Alkyl, -CD ₃ 、-OCD ₃ 、C ₁ -C ₆ Haloalkyl, -OCH ₃ 、-OC ₂ H ₇ 、-OC ₃ H ₇ 、C ₁ -C ₆ Alkyl halidesAn oxy group.

19. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 18, wherein C is ₁ -C ₇ Alkyl is 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.

20. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 18, wherein Ar 'is selected from phenyl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5-yl, said Ar' is substituted with 1 or 2 substituents selected from F, cl, -CH ₃ 、-CF ₃ or-OCF ₃ 。

21. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein Z is O.

22. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is in the form of its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of such isomers.

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

24. the compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-23, wherein the pharmaceutically acceptable salt comprises an anionic salt or a cationic salt of the compound of formula (I).

25. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-23, wherein the pharmaceutically acceptable salt comprises an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound of formula (I); the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium.

26. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-23, wherein the pharmaceutically acceptable salt comprises a salt of the compound of formula (I) with an organic base.

27. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 26 wherein the organic base comprises trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo [4.3.0] nonene-5, 1,8-diazabicyclo [5.4.0] undecene-7, 1,4-diazabicyclo [2.2.2] octane; the trialkylamine comprises trimethylamine, triethylamine, or N-ethyldiisopropylamine; the N-alkyl morpholine includes N-methyl morpholine.

28. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-23, wherein the pharmaceutically acceptable salt comprises a salt of the compound of formula (I) with an acid;

the acid comprises an inorganic acid, or an organic acid; the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; the organic acid comprises formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

29. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-28, which comprises: the step of reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (I):

in the formulae (ii), n ₁ 、n ₂ 、n ₃ 、R ₁ 、R ₂ 、X ₁ 、X ₂ Z, ar and Y are as defined in any of claims 1-28.

30. The process of claim 29, comprising the step of reacting a compound of formula (VI) with phosphorus oxychloride to form a compound of formula (II):

in each formula, n ₁ 、n ₂ 、R ₁ 、R ₂ 、X ₁ Z is as defined in claim 29.

31. A process according to claim 30, comprising the step of subjecting the compound of formula (V) to a cyclisation reaction to produce a compound of formula (IV):

in the formulae (ii), n ₁ 、n ₂ 、R ₁ 、R ₂ 、X ₁ Z is as defined in claim 30.

32. The method of claim 31, comprising the steps of reacting a compound of formula (VII) with a compound of formula (VIII) to produce a compound of formula (VI), and deprotecting the compound of formula (VI) to produce a compound of formula (V):

in the formulae (ii), n ₁ 、n ₂ 、R ₁ 、R ₂ 、X ₁ Z is as defined in claim 31.

33. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-28,

the preparation method is characterized by comprising the following synthetic route:

34. A pharmaceutical composition comprising one or more compounds of formula (I) as described in any one of claims 1-28 or a pharmaceutically acceptable salt thereof and optionally pharmaceutically acceptable excipients.

35. The pharmaceutical composition of claim 34, in a dosage form comprising an oral, rectal, or parenteral formulation;

the oral preparation comprises a solid preparation or a liquid preparation,

the solid preparation comprises a tablet, a powder, a granule or a capsule;

the liquid preparation comprises water or oil suspending agent, or syrup;

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

36. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-28, or a pharmaceutical composition as claimed in claim 34 or 35, in the manufacture of an Lp-PLA2 inhibitor.

37. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-28, or a pharmaceutical composition as claimed in claim 34 or 35, in the manufacture of a medicament for the treatment of a neurodegenerative-related disease.

38. The use of claim 37, wherein the neurodegenerative-related disease comprises Alzheimer's Disease (AD), glaucoma, age-related macular degeneration (AMD).

39. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-28, or a pharmaceutical composition as claimed in claim 34 or 35, in the manufacture of a medicament for the treatment of cardiovascular disease, diabetic Macular Edema (DME), or prostate disease;

the cardiovascular disease includes atherosclerosis.