Bridged cyclic pyrimidinone compound, preparation method therefor, composition containing same and use thereof

Abstract

Disclosed is a bridged cyclic pyrimidinone compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has the structure as represented by formula (I), is a completely new Lp-PLA2 inhibitor, and can be used for treating neurodegenerative-related diseases, such as Alzheimer's disease (AD), glaucoma, age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis, etc.

Description

ENDOCYCLIC PYRIMIDINONE COMPOUNDS, AND PREPARATION METHODS, COMPOSITIONS AND USE THEREOF TECHNICAL FIELD The present disclosure relates to an endocyclic pyrimidinone compound, or a tautomer, meso isomer, racemate, enantiomer, diastereomer or mixture thereof, and to a preparation method, composition and medicinal use thereof. In particular, the present disclosure relates to an endocyclic pyrimidinone of Formula (I), a method of preparing it, and a pharmaceutical composition containing it, and to use of it as an LpPLA2 inhibitor in the treatment of neurodegenerative diseases such as Alzheimer’s disease, glaucoma, and age-related macular degeneration (AMD), or the treatment of atherosclerosis and diabetic macular edema. BACKGROUND Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 superfamily (Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Chem Rev. 2011, 111, 6130-6185). It is mainly secreted by monocytes, macrophages, T lymphocytes and chief cells (Stafforini DM, Elstad MR, McIntyre TM, Zimmerman GA, Prescott SM. J Biol Chem. 1990, 265: 9682-9687; Nakajima K, Murakami M, Yanoshita R, Samejima Y, Karasawa K, Setaka M, Nojima S Kudo I. J Biol Chem. 1997, 272, 19708-19713). Phosphatidylcholine sn-2 ester is produced during the oxidation of low density lipoprotein (LDL); Lp-PLA2 is responsible for the hydrolysis of oxidized phosphatidylcholine sn-2 ester, which then produces oxidized fatty acids and lysophosphatidylcholine (LysoPC) (Caslake MJ, Packard CJ, Suckling KE, Holmes SD, Chamberlain P, Macphee CH. Atherosclerosis. 2000, 150, 413-419; MacPhee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, Leake DS, Milliner KJ, Patterson RA, Suckling KE, Tew DG, Hickey DM. Biochem J. 1999, 338, 479-487). Both oxidized fatty acids and LysoPC play roles in activating macrophages, increasing oxidative stress, affecting the function of T lymphocytes, and inducing inflammatory responses (Quinn MT, Parthasarathy S, Steinberg D. Proc Natl Acad Sci U S A. 1988, 85, 2805-2809). LysoPCs have been reported to induce the release of multiple cytotoxic inflammatory cytokines (Shi, et al, Atherosclerosis, 2007, 191, 54-62). In addition, LysoPCs have also been involved in the activation of leukocytes, the induction of apoptosis, and the mediation of endothelial dysfunction (Wilensky et al, Current Opinion in Lipidology, 2009, 20, 415-420). It has been reported that plasma level of Lp-PLA2 is associated with cardiovascular diseases (Fitzpatrick AL, Irizarry MC, Cushman M, Jenny NS, Chi GC, Koro C. Atherosclerosis. 2014, 235, 384-391), diabetic macular edema (DME) (Staurenghi G, Ye L, Magee MH, Danis RP, Wurzelmann J, Adamson P, McLaughlin MM, Darapladib DMES G. Ophthalmology. 2015, 122, 990-996), and prostate cancer (Bertilsson H, Tessem MB, Flatberg A, Viset T, Gribbestad I, Angelsen A, Halgunset J. Clin Cancer Res. 2012, 18, 3261-3269). Alzheimer's disease (AD) is a chronic neurodegenerative disease that results in decreasd cognitive abilities, mood swings, irreversible memory loss, disorientation, speech impairment, and loss of self-protection (Hardy J, et al. Science 2002, 297, 353- 356). Alzheimer's disease usually begins slowly and progressively worsens over time, which is the cause of 60 % to 70 % of dementia cases and affects about 6 % of the population over 65 years old. AD patients gradually go away from family and society, rely increasingly on help, and eventually progress to death. AD is one of the most costly diseases in developed countries and also incurs high costs in other countries. Especially as aging becomes an important social problem, these costs will grow dramatically. 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 the disease, including aggregated tau protein and AP peptides, oxidative stress and neuroinflammation (Echeverria V, Yarkov A, Aliev G. Prog Neurobiol. 2016, 144, 142-157). The current research and development of AD medicaments is focused primarily on targets of AB 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 later clinical trials have not demonstrated clinical efficacy to date. These disappointing results predict that other neuropathological mechanisms such as oxidative stress and neuroinflammation may have to be explored for AD treatment. Elevated levels of Lp-PLA2 in plasma increase the risk of dementia, including AD (Van Oijen, er al. Annals of Neurology, 2006, 59,139). In addition to vascular dementia and mixed dementia, high oxidized LDL levels have been found in AD patients (Maher- Edwards G, De’Ath J, Barnett C, Lavrov A, Lockhart A, Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2015, 1, 131-140; Kassner et al. Current Alzheimer Research, 2008, 5, 358-366; Dildar, et al., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem, et al. Current Alzheimer Research, 2010, 7, 463- 469). Neuroinflammation and upregulation of multiple inflammatory cytokines have also been found in AD patients (Colangelo, et al., Journal of Neuroscience Research, 2002, 70, 462-473; Wyss-Coray, Nature Medicine, 2006, 12, Sept.). Based on all these findings, Lp-PLA?2 is a potential target for the treatment of AD, and this is further confirmed by the clinical results of the Lp-PLA2 inhibitor Rilapladib for AD patients (Maher-Edwards G, De’Ath J, Barnett C, Lavrov A, Lockhart A, Alzheimers & Dementia: Translational Research & Clinical Interventions. 2015, 1, 131-140). Glaucoma and age-related macular degeneration (AMD) are among retinal neurodegenerative diseases. Buschini et al reported that inflammation, including TNF- a signaling, may play an important role in the pathogenesis of glaucoma and AMD (Buschini et al, Progress in Neurobiology, 2011, 95, 14-25; Tezel, Progress in Brain Research, vol. 173, ISSN0079-6123, Chapter 28). Additionally, Shi et al demonstrated that Lp-PLA2 inhibitors can block the release of inflammatory cytokines (Shi, et al, Atherosclerosis, 2007, 191, 54-62). Inhibition of Lp-PLA2 is potential therapy for glaucoma and AMD. A number of Lp-PLA2 inhibitors have been reported, including B-lactams (Tew DG, Boyd HF, Ashman S, Theobald C, Leach CA. Biochemistry. 1998, 37, 10087- 10093), oximes (Jeong TS, Kim MJ, Yu H, Kim HS, Choi JK, Kim SS, Lee WS. Bioorg Med Chem Lett. 2005, 15, 1525-1527; Jeong HJ, Park YD, Park HY, Jeong IY, Jeong TS, Lee WS. Bioorg Med Chem Lett. 2006, 16, 5576-5579), amides of xanthuric acid (Lin EC, Hu Y, Amantea CM, Pham LM, Cajica J, Okerberg E, Brown HE, Fraser A, Du L, Kohno Y, Ishiyama J, Kozarich 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, Kozarich JW, Shreder KR. Bioorg Med Chem Lett. 2013, 23, 1553-1556), and carbamates (Nagano JM, Hsu KL, Whitby LR, Niphakis MJ, Speers AE, Brown SJ, Spicer T, Fernandez-Vega V, Ferguson J, Hodder P, Srinivasan P, Gonzalez TD, Rosen H, Bahnson BJ, Cravatt BF. Bioorg Med Chem Lett. 2013, 23, 839-843). The Lp-PLA2 inhibitor Darapladib has been reported to be potential therapy for atherosclerosis and DME (Magrioti V, Kokotos G. Expert Opin Ther Pat. 2013; 23: 333-344). SUMMARY The present inventors have found that Lp-PLA2 inhibitors play an important role in the treatment of neurodegeneration-related diseases such as Alzheimer's disease (AD), glaucoma and age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis and the like. Thus, the present inventors have endeavored to develop an entirely new Lp-PLA2 inhibitor: an endocyclic pyrimidinone compound. The endocyclic pyrimidinone compound is a compound having a structure represented by Formula (I) or a pharmaceutically acceptable salt thereof, z f A bg . TT, Sy N X; LS wo Su R, : ’ wherein ny, n2, and n3 are each independently 0, 1, or 2; R; and R; are each independently selected from -H, hydroxyl, cyano, halogen, alkyl, deuterated alkyl, deuterated alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, arylene, or heteroarylene; X) and X; are each independently selected from alkylene, -O-, -S-, or -NR'-, R'is selected from -H, alkyl, deuterated alkyl, or cycloalkyl; Ar is arylene or heteroarylene, wherein hydrogen atoms in the arylene or heteroarylene are optionally substituted with one or more substituents, and the substituents are each independently selected from halogen, alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteroalkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, monoalkyl- or dialkyl-substituted amino, nitro, carboxy, formyl, 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, NR"R", or -R"-Ar'"; Ar 'is selected from aryl or heteroaryl, wherein hydrogen atoms in the aryl or heteroaryl are optionally substituted with one or more substituents, the substituents are each independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, cyano, amino, nitro, carboxy, formyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R" is H-, alkyl, or cycloalkyl; R'" is alkylene; ZisOorS. Optionally, halogens in the "halogen" "haloalkyl" and "haloalkoxy" are each independently selected from F, Cl, Br, or I; optionally, alkyls in the "alkyl" "deuterated alkyl" "deuterated alkoxy" "hydroxyalkyl" "haloalkyl", "haloalkoxy" "alkoxy" and "mono- or di-alkyl substituted amino" are each independently Ci-Cio linear or branched alkyl; optionally each independently Ci-C7 linear or branched alkyl; optionally each independently C;i-Cs linear or branched alkyl; and optionally selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, l-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; optionally, "alkylenes" are each independently Ci-Cio linear or branched alkylene; optionally each Ci-C7 linear or branched alkylene; optionally each Ci-Cs linear or branched alkylene; and optionally each selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, tert-butylene, sec-butylene, n-pentylene, 1- methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, isohexylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2- dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n- heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3- dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, or 2,2,3-trimethylbutylene; optionally, "cycloalkyl" is C3-C1o monocyclic or bicyclic cycloalkyl, optionally C3-C7 monocyclic cycloalkyl, and optionally cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; optionally, "heterocyclyl" is 3- to 10-membered non-aromatic heterocyclehaving in the ring 1, 2, or 3 heteroatoms selected from N, O, and S; optionally 3- to 10- membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and O; optionally 3- to 6-membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and O; optionally 3- to 10-membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and S; and optionally 3- to 6-membered non- aromatic ring having in the ring 1 or 2 heteroatoms selected from N and S; optionally, "aryl" is 6- to 10-membered aryl; optionally phenyl or naphthy, and optionally phenyl, 1-naphthyl, or 2-naphthyl; optionally, "arylene" is 6- to 10-membered arylene; and optionally phenylene or naphthylene; optionally, "heteroaryl" is 5- to 10-membered heteroaryl ring having in the ring 1- 3 heteroatoms selected from N, O, and S; optionally 5- to 10-membered heteroaryl ring having in the ring 1-2 heteroatoms selected from N, O, and S; optionally the heteroaryl ring is selected from pyridine ring, pyrrole ring, pyrazole ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiophene ring, and furan ring; optionally 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[2,3-b] furanyl, furo[3,2-b]-pyranyl, pyrido[2,3-dJoxazinyl, pyrazolo[4,3-dJoxazolyl, imidazo[4,5- dJthiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[l,2- b][1,2,4]triazinyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzoxepinyl, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5- clpyridyl, pyrazolo[4,3-d]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridyl, pyrazolo[3,4-b] pyridinyl, imidazo[l,2-aJpyridinyl, pyrazolo[1,5-aJpyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[l,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; and is optionally selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; optionally, "heteroarylene" is 5- to 10-membered heteroarylene ring having in the ring 1-3 heteroatoms selected from N, O, and S; optionally 5- to 10-membered heteroaromatic ring having in the ring 1-2 heteroatoms selected from N, O, and S; and optionally the heteroarylene ring is selected from pyridinylene ring, pyrrolylene ring, pyrazolylene ring, pyrimidinylene ring, pyrazine ring, pyridazine ring, thiophene ring, or furanylene ring. Optionally, the compound of Formula (I) is in the form of a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof. Optionally, nj, nz, and n3 are each independently 0, 1, or 2. Optionally, ni is 1. Optionally, nz is 1. Optionally, n3is 1. Optionally, R; and R are each independently selected from -H, fluorine, chlorine, bromine, iodine, hydroxyl, hydroxyalkyl, cyano, C1-C7 alkyl (such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,l-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), Ci-Cs deuteroalkyl (such as -CDs, -C2Ds, or - C3Dy), C1-Cs deuteroalkoxy (such as -OCD3, -OC;Ds, or -OC3D5), C1-Cs haloalkyl (such as -CF3, -CHF,, -CHzF, -CoFs, or -C3F7), Ci-C7 haloalkoxy, Ci-C7 alkoxy, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl; optionally, Ri is -H; and optionally, Rj is-H; optionally, X: and X: are each independently selected from Ci-Cy alkylene, -O-, - S-, or -NR’-; optionally, X is C1-C7 alkylene (optionally, -CHa-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, or -S-; optionally, X; is C1-C7 alkylene or -O-; optionally, Xi is -CHa- or -O-; optionally, X» is -O- or -S-; and optionally, X> is -0-; optionally, R'is selected from -H, C,-C5 alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, I-methylbutyl, 2- methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2- dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3- ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2Ds, or - C3Dy), or C3-Cs cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar is phenylene or pyridyl, wherein hydrogen atoms in the phenylene or pyridyl are optionally substituted with 1, 2, or 3 substituents, the substituents are each independently selected from F, Cl, Br, I, -CN, -Me, -CF3, -CHF3, -C2Hs, -C3Hy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CDs, -OCD3, -Ome, -OCFs, or- OCHF3; optionally, Ar is arylene; and optionally, Ar is phenylene, wherein hydrogens in the phenylene are optionally substituted with one or two substituents, the substituents are halogen, and optionally F; optionally, Y is -H, -F, -CI, -Br, -1, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCDs, -CF3, -CHF,, -CHyF, -CH,CF3, -OCF3, -OCHF», -OCHF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCH3, -OC2Hs, -OCsH7, or -OAr'; optionally, Y is H, halogen, or -OAr'; and optionally, Y is H, -F, or -OAr’; optionally, Ar' is selected from phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl, wherein hydrogen atoms in the phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl ring are each independently optionally substituted with 1, 2, or 3 substituents, the substituents are each independently selected from F, Cl, Br, -CN, Ci-C7 alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2- methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3- dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, - OCD3, Ci-Ce haloalkyl, -OCH3, -OC:Hs, -OC3H7, Ci-Cs haloalkoxy, hydroxyl, hydroxyalkyl, cyano, or C3-Cs cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar' is selected from phenyl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5- yl, and is optionally substituted with 1 or 2 substituents, the substituents are selected from halogen, alkyl, haloalkyl, or haloalkoxy, and optionally selected from F, Cl, -CHs, -CF3, or-OCF3; optionally, Z is O or S; and optionally, Z is O. Optionally, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is selected from the following compounds: 2 : nL , Cy x £2 CMe, < “CL, Qo 0 o WA Nw on AK 2 AX g ] cr, Cpr oy Cryer Chr F 8 F sf 12 A ’ ly Soe, Shoocar Soto, 3, CLOT Conn 5 % Fa : 15 F ! oi wl wd Eat Weg, Porgy AY snl, ory 22 u [o Se F SA £ 22 F ma 4 9 \ Wo GN F ot, So . 23 % ° o a GA - . 27 GLa hy Cry a. 26 £ oO 31 5 0 Por? tb wo wo 1 CXL L LL, FAN OC, Fz ’ 2 QL 2 TEAL, > © TEL H 1 h 9 H 1 TI ont my C0 PO ar © a TEL CER. SY H o A TR u F i 1 o A ° wold NTN EF H A NS he nr EX nr 34 F 4 Any uy HL Prey Bogeg Phy ig) A E Optionally, of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt includes an anionic salt or cationic salt of the compound of Formula (I); optionally, the pharmaceutically acceptable salt includes alkali metal salt, alkaline earth metal salt, or ammonium salt of the compound of Formula (I); optionally, the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium; optionally, the pharmaceutically acceptable salt includes salt formed by the compound of Formula (I) and an organic base; optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5- diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0Jundecene-7, 1,4- diazabicyclo[2.2.2] octane; optionally, the trialkylamine includes trimethylamine, triethylamine, or N-ethyldiisopropylamine; and optionally, the N-alkyl morpholine includes N-methylmorpholine; optionally, the pharmaceutically acceptable salt includes a salt formed by the compound of Formula (I) and an acid; optionally, the acid includes inorganic acid, or organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid. In another aspect, there is provided a preparation method 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 the compound of Formula (I): 7 Y ptt ar? z Ro. A ) NN CO, How Zz Votes nN ’ Xe Na N St L optionally, the preparation method comprises the step of reacting a compound of Formula (IV) with phosphorus oxychloride to produce the compound of Formula (II): Z =. Zz POCI3 Ry < hy 1 Gv ye nM RR, Ra Sm Rz R4 z hay xX JS hy Ry v Il optionally, the preparation method comprises the step of subjecting a compound of Formula (V) to cyclization reaction to produce the compound of Formula (IV): “Pe k 1 N™ "NH ow oe 1% Ry z hp X1 Car Ny R, Vv wv optionally, the preparation method comprises the step of reacting a compound of Formula (VII) with a compound of Formula (VIII) to produce a compound of Formula (VI), and further removing the protective group from the compound of Formula (VI) to produce the compound of Formula (V): Zz i. 7 nn ao R, x 1 SE i i NH Wo) ro R, Zz Ry Sh 3 hy ao Boc Ry Rs 1 TFA DCM PPh, DAD xml JU me J moo x Ja {Fo { Ty NA 5 J aR hw oo Boc Ry Re RZ Rr, z A _POCHNN-Dimetyiniive NN _rosiNDimsheve | 4 CIA Fe RK Sa % Sy Ry R; iz A a LL a, In each of the formulas in the preparation method described above, ni, nz, n3, Ri, Ro, Xi, Xa, Z, Ar, and Y are defined as above. No particular limitation is necessary for conditions under which each of the reactions described above is carried out, and they can be carried out under conventional conditions or by following conventional steps. In another aspect, there is provided a pharmaceutical composition, comprising a therapeutically effective amount of one or more of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and optionally, a pharmaceutically acceptable excipient(s). Optionally, the dosage form of the pharmaceutical composition includes oral, rectal, or parenteral formulation; optionally, the oral formulation includes solid or liquid formulation; optionally, the solid formulation includes tablet, powder, granule, or capsule; optionally, the liquid formulation includes aqueous or oily suspension, or syrup; optionally, the parenteral formulation includes solution for injection, or aqueous or oily suspension. In another aspect, there is provided use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of an Lp-PLA2 inhibitor. In another aspect, there is provided use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for treatment of neurodegeneration-related diseases; optionally, the neurodegeneration-related diseases include Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). In another aspect, there is provided use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the preparation of a medicament for the treatment of cardiovascular diseases, diabetic macular edema (DME), or prostate diseases; optionally, the cardiovascular diseases include atherosclerosis. Beneficial effects of the present disclosure are as follows: The compound of Formula (I) or a pharmaceutically acceptable salt thereof is an endocyclic pyrimidinone compound as well as an entirely novel Lp-PLA2 inhibitor. It is useful in treating neurodegeneration-related diseases such as Alzheimer's disease (AD), glaucoma and age-related macular degeneration (AMD), or cardiovascular diseases including atherosclerosis and the like, diabetic macular edema (DME), or prostate diseases and the like. DETAILED DESCRIPTION The present disclosure is further illustrated by means of examples that will be described later. It should be appreciated that the examples are for illustrative purposes only and not intended to limit the scope of the present invention in any way. The starting materials of the present invention can be synthesized by a method known in the art, or be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Darry Chemicals, among other companies. Unless otherwise specified, the solution in the examples refers to an aqueous solution. Unless otherwise specified, the temperature in the examples at which the reaction is carried out is room temperature, e.g., 20 °C to 30 °C. Example 1 Preparation of Compound 1 1 aod 1 Stepile 9 NONE Ay 1c 1d 10 StepiVe in = _ StepVe LAD o wo GR, og Copy 11 19 Step I: Preparation of compound 1¢ yon 1 fours + aN“SNi _PPhaDIAD Oy vo AAT UALR Boc 1a 1b 1c To a solution of 6-chlorouracil 1b (8.5 g, 58.0 mmol), tert-butyl 3- (hydroxymethyl)piperidine-1-carboxylate 1a (15 g, 69.6 mmol) and triphenylphosphine (22.8 g, 86.9 mmol) dissolved in a mixed solvent of anhydrous tetrahydrofuran (250 mL) and N,N-dimethylformamide (25 mL) at room temperature, was added dropwise diisopropyl azodicarboxylate (23 ml, 115.8 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH>Cly / CH3;OH (20 / 1) afforded the title compound 1c (8.34 g, yield: 41.8 %) as a colorless oil. Steps II and III: Preparation of compound le 1) TFA, DCM 2) DIPEA o ° oOCy Sy aA Boc 1c 1e To a solution of tert-butyl 3-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)methyl)piperidine-1-catboxylate 1c (8.34 g, 24.3 mmol) dissolved in dichloromethane (80 mL) at room temperature, was added trifluoroacetic acid (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure. The afforded residue was used directly in the next step, and was dissolved in acetonitrile (100 mL), then diisopropylethylamine (9.3 g, 72.9 mmol) was added at room temperature. The reaction mixture was stirred for 4 h, and concentrated under reduced pressure, followed by purification on a silica gel column CH:2Cl / CH3OH (20 / 1) to afford the title compound 1e (4.7 g, 93.3 %) as a white solid. 'H NMR (400 MHz, DMSO) § 11.01 (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). Step IV: Preparation of compound 1f 0 0 re POCly Wu SA SA 1e 1f To a solution of compound 1e (2.0 g, 9.7 mmol) and dimethylaniline (2.34 g, 19.3 mmol) in toluene, was added phosphorous oxychloride (1.48 g, 9.7 mmol) dropwise at room temperature. The reaction mixture was heated to reflux for 4 h, quenched with ice water, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH,Cl / CH3;OH (20 / 1) afforded the title compound 1f (0.89 g, 40.7 %) as a white solid. 'H NMR (400 MHz, CDCl3) & 6.06 (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). Step V: Preparation of compound 1 oT NaH. DMF o A NTN CCL, 2 J 1 1g To a solution of (3-fluorophenyl)methanol 1g (30 mg, 0.24 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred at room temperature for 5 min. Then compound 1f (50 mg, 0.22 mmol) was added, and stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with CH2Cl / CH3OH (20 / 1) afforded the title compound 1 (8 mg, 11.5 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.32 (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 0 CX F A 3 F 3 To a solution of (2,4-Difluorophenyl)methanol (35 mg, 0.24 mmol) in dry N,N- dimethylformamide (5 mL), was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred at room temperature for 5 min. Then compound 1f (50 mg, 0.22 mmol) was added, and stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with CH,Cl / CH3;OH (20 / 1) afforded the title compound 2 (10 mg, 13.6 %) as a white solid. 'H NMR (400 MHz, CDCl3) 8 7.49 (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 0 oe F So 5 F & To a solution of (2,4,5-Trifluorophenyl)methanol (39 mg, 0.24 mmol) in dry N,N- dimethylformamide (5 mL), was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred at room temperature for 5 min. Then compound 1f (50 mg, 0.22 mmol) was added, and stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with CH,CL / CH3;OH (20 / 1) afforded the title compound 3 (12 mg, 15.5 %) as a white solid. 'H NMR (400 MHz, CDCl) § 7.32 (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 o ” Cg F To a solution of (3,5-Difluorophenyl)methanol (35 mg, 0.24 mmol) in dry N,N- dimethylformamide (5 mL), was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred at room temperature for 5 min. Then compound 1f (50 mg, 0.22 mmol) was added, and stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with CH2Cl / CH3OH (20 / 1) afforded the title compound 4 (6 mg, 8.2 %) as a white solid. 'H NMR (400 MHz, CDCl) § 6.99 — 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 0 GC fry SNe, 5 F 0 N Hn Ag F Stepie stepdle r” Foy ” F 3, " F fi} ¥ Fa Fa Stepdllv = 0 Cs XL, 5 Step I: Preparation of compound 5¢ 3,4,5-trifluorobenzaldehyde 5a (1 g, 6.2 mmol), 2-(trifluoromethyl)pyridin-4-ol 5b (1 g, 6.2 mmol) and potassium carbonate (0.93 g, 6.76 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After cooled to room temperature ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated. Purification on a silica gel column with PE / EtOAc (5 / 1) afforded the title compound 5¢ (1.47 g, 93.2 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) 3 9.97 (s, 1H), 8.65 (m, 1H), 7.63 (m, 2H), 7.27 (m, 1H), 7.01 (m, 1H). Step II: Preparation of compound 5d To a solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)benzaldehyde 5c (1.47 g, 4.85 mmol) dissolved in ethanol (50 mL) at room temperature, was added NaBH4 (184 mg, 4.85 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure. Water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (2 / 1) afforded the title compound 5d (1.04 g, yield: 70.3 %) as a white solid. 'H NMR (400 MHz, CDCl3) 5 8.59 (m, 1H), 7.24 (m, 1H), 7.11 (m, 2H), 6.99 (m, 1H), 4.75 (m, 2H), 2.19 (m, 1H). Step III: Preparation of compound 5 To a solution of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4- yl)oxy)phenyl)methanol 5d (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 5 (13 mg, 12 %) as a white solid. 'H NMR (400 MHz, CDCl3) & 8.60 (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 (ESD): m / z 494.9 [M+H]". Example 6 Preparation of Compound 6 & “TCL 6 F GLO CX Step I: Preparation of compound 6b 3,4,5-trifluorobenzaldehyde 5a (0.88 g, 5.5 mmol), 2-methylpyridin-4-ol 6a (0.5 8, 4.6 mmol), and potassium carbonate (0.93 g, 6.76 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled to room temperature ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 6b (0.4 g, 34.9 %) as a yellow solid. 'H NMR (400 MHz, CDCls) § 9.94 (s, 1H), 8.39 (m, 1H), 7.62 — 7.56 (m, 2H), 6.70 — 6.66 (m, 2H), 2.52 (s, 3H). Step II: Preparation of compound 6¢ To a solution of 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde 6b (0.4 8, 1.6 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH4 (71 mg, 1.86 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure. Water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 6¢ (0.4 g, yield: 99 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) 5 8.29 (m, 1H), 7.07 (m, 2H), 6.70 — 6.64 (m, 2H), 4.73 (s, 2H), 3.20 (m, 1H), 2.50 (s, 3H). Step III: Preparation of compound 6 To a solution of (3,5-Difluoro-4-((2-methyl)pyridin-4-yl)oxy)phenyl)methanol 6¢ (55 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 6 (8 mg, 8.2 %) as a white solid. 'H NMR (400 MHz, CDCls) § 8.36 (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 1 X Ck CLL TT gedeg Stepdlle GLY Step I: Preparation of compound 7b 3,4,5-trifluorobenzaldehyde 5a (1 g, 6.2 mmol), 6-methylpyridin-3-ol 7a (0.57 g, 5.2 mmol) and potassium carbonate (0.93 g, 6.76 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After cooled to room temperature ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 7b (0.91 g, 69.2 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) 9.92 (s, 1H), 8.28 (s, 1H), 7.62 — 7.49 (m, 2H), 7.18 ~ 7.10 (m, 2H), 2.54 (s, 3H). Step II: Preparation of compound 7¢ To a solution of 3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde 7b (0.91 g, 3.6 mmol) in methanol (50 mL) was added NaBH, (161 mg, 4.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 7c (0.89 g, yield: 98.4 %) as a colorless oil. 'H NMR (400 MHz, CDCls) § 8.20 (m, 1H), 7.16 — 6.98 (m, 4H), 4.69 (m, 2H), 2.88 (m, 1H), 2.50 (s, 3H). Step III: Preparation of compound 7 To a solution of (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol 7¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 7 (17 mg, 17.5 %) as a white solid. 'H NMR (400 MHz, CDCl3) 5 8.27 (m, 1H), 7.10 (m, 4H), 5.62 (s, 1H), 5.39 (s, 2H), 4.07 (m, 7.3 Hz, 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 / z 441.0 [M+H]". Example 8 Preparation of Compound 8 TH Ye GUO “CL = geess Stepille "GL ir Step I: Preparation of compound 8b 3,4,5-trifluorobenzaldehyde 5a (0.44 g, 2.8 mmol), 2-methylpyrimidin-5-ol 8a (0.25 g, 2.3 mmol), and potassium carbonate (0.41 g, 2.9 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2h. After cooled downice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 8b (0.24 g, 41.7 %) as a yellow solid. "HNMR (400 MHz, CDCl) 8 9.93 (s, 1H), 8.39 (s, 2H), 7.64 — 7.54 (m, 2H), 2.72 (s, 3H). Step II: Preparation of compound 8¢ To a solution of 3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzaldehyde 8b (0.24 g, 0.96 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH; (30 mg, 0.79 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with sodium chloride solution and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 8c (0.17 g, yield: 70.2 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) 5 8.33 (s, 2H), 7.04 (m, 2H), 4.71 (m, 2H), 2.70 (s, 3H). Step III: Preparation of compound 8 To a solution of (3,5-Difluoro-4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol 8¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 8 (10 mg, 10.3%) as a white solid. 'H NMR (400 MHz, CDCls) § 8.35 (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 Co Ng F _N_CFs CRE 9 F “CT, CT ik Stepile gedsglices CL 5a 9a ab 8c i" Stepille - or Step I: Preparation of compound 9b 3,4,5-trifluorobenzaldehyde 5a 0.29 8, 1.81 mmol), 2- (trifluoromethyl)pyrimidin-5-ol 9a (0.25 g, 1.52 mmol), and potassium carbonate (0.27 g, 1.98 mmol) were dissolved in N,N-dimethylformamide (DMF) (20 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 9b (0.24 g, 51.9 %) as a yellow solid. 'H NMR (400 MHz, CDCls) § 9.97 (s, 1H), 8.59 (s, 2H), 7.69 — 7.54 (m, 2H). Step II: Preparation of compound 9¢ To a solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5- yl)oxy)benzaldehyde 9b (0.24 g, 0.79 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH4 (30 mg, 0.79 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 9¢ (0.12 g, yield: 49.6 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) § 8.54 (s, 2H), 7.12 (m, 2H), 4.74 (m, 2H), 2.23 (m, 1H). Step III: Preparation of compound 9 To a solution of (3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5- yloxy)phenyl)methanol 9¢ (73 mg, 0.24 mmol) in dry N, N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 9 (8 mg, 7.3%) as a white solid. 'H NMR (400 MHz, CDCl) 8 8.58 (s, 2H), 7.19 (m, 2H), 5.66 (s, 1H), 5.45 (s, 2H), 4.10 (m, 7.4 Hz, 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 x Ca Sega, Stepdle - Stepdl r y ssp , - ; v LL J, 5a 108 10b 10¢ 1 Stepille 0b. ol, “GAL, Step I: Preparation of compound 10b 3,4,5-trifluorobenzaldehyde 5a (1.09 g, 6.8 mmol), 3-(trifluoromethyl)phenol 10a (1 g, 6.2 mmol), and potassium carbonate (1.1 g, 8.02 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 10b (1.7 g, 90.7 %) as a yellow solid. 'H NMR (400 MHz, CDCls) § 9.94 (s, 1H), 7.63 — 7.55 (m, 2H), 7.46 (m, 1H), 7.39 (m, 1H), 7.21 (s, 1H), 7.13 (m, 1H). Step II: Preparation of compound 10¢ To a solution of 3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzaldehyde 10b (1.7 g, 5.6 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH. (213 mg, 5.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 10¢ (1.27 g, yield: 74.5 %) as a colorless oil. Step III: Preparation of compound 10 To a solution of (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol 10c (73 mg, 0.24 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 10 (6 mg, 5.5%) as a white solid. 'H NMR (400 MHz, CDCl3) 8 7.42 (m, 1H), 7.33 (m, 1H), 7.20 (s, 1H), 7.10 (m, 3H), 5.63 (s, 1H), S41 (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 / z 494.0 [M+H]". Example 11 Preparation of Compound 11 © SX : ge des Stepdlle oh, “GX Step I: Preparation of compound 11b 3,4,5-trifluorobenzaldehyde 5a (1.2 g, 7.5 mmol), 4-chloro-3-methylphenol 11a (1 g, 7.0 mmol) and potassium carbonate (1.1 g, 8.02 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 11b (1.2 g, 60.6 %) as a yellow solid. 'H NMR (400 MHz, CDCl) § 9.92 (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). Step II: Preparation of compound 11¢ To a solution of 4-(4-chloro-3-methylphenoxy)-3,5-difluorobenzaldehyde 11b (1.2 g, 4.2 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBHs (161 mg, 4.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 11¢ (0.89 g, yield: 74.4 %) as a colorless oil. Step III: Preparation of compound 11 To a solution of 4-(4-Chloro-3-methylphenoxy)-3,5-difluorobenzyl alcohol 11c (77 mg, 0.27 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 11 (9 mg, 8.6%) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.27 (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 2X J N NF #0 eT OCF, Stepde Stepdle He, re “GL “CLL, AL ©, Stepdlly “GUA. Step I: Preparation of compound 12b 3,4,5-trifluorobenzaldehyde 5a (0.5 g, 2.8 mmol), 3-(trifluoromethoxy)phenol 12a (0.5 g, 2.8 mmol), and potassium carbonate (0.5 g, 3.6 mmol) were dissolved in N,N- dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 12b (0.73 g, 91.8 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) § 9.94 (s, 1H), 7.64 — 7.54 (m, 2H), 7.34 (m, 1H), 7.00 (m, 1H), 6.87 (m, 2H). Step II: Preparation of compound 12¢ To a solution of 4-(3-(trifluoromethoxy)phenoxy)-3,5-difluorobenzaldehyde 12b (0.73 g, 2.3 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH; (86 mg, 2.28 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 12¢ (0.57 g, yield: 77.4 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) § 7.30 (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). Step III: Preparation of compound 12 To a solution of (4-(3-(Trifluoromethoxy)phenoxy)-3,5-difluorophenyl)methanol 12¢ (70 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 12 (6 mg, 5.4%) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.29 (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 <0 F CF, x 3 iy CLAY 12 F + Stepte , , Ste 7 * 1 “CX “QL aad “LL or oe go or CL Stepdlls go” Step I: Preparation of compound 13b 3,4,5-trifluorobenzaldehyde 5a (1 g, 6.2 mmol), 4-(trifluoromethyl)phenol 13a (0.84 g, 5.2 mmol), and potassium carbonate (0.93 g, 6.76 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After cooled to room temperature ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (5 / 1) afforded the title compound 13b (1.33 g, 84.6 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) § 9.94 (m, 1H), 7.59 (m, 4H), 7.04 (m, 2H). Step II: Preparation of compound 13¢ To a solution of 3,5-difluoro-4-(4-(trifluoromethyl)phenoxy)benzaldehyde 13b (1.33 g, 4.4 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH; (166 mg, 4.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (2 / 1) afforded the title compound 13¢ (0.85 g, yield: 63.5 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) § 7.57 (m, 2H), 7.09 — 7.00 (m, 4H), 4.72 (m, 2H), 2.03 (m, 1H). Step III: Preparation of compound 13 To a solution of 3,5-Difluoro-4-(4-(trifluoromethyl)phenoxy)phenyl)methanol 13¢ (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 13 (11 mg, 10.1%) as a white solid. 'H NMR (400 MHz, CDCl3) 3 7.57 (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 / z 494.0 [M+H]". Example 14 Preparation of Compound 14 0 NN GX, F oc “OF 4 > . “ sept ; y Septe ; o A . N LX, LL Ane Step I: Preparation of compound 14b 3,4,5-trifluorobenzaldehyde 5a (045 g 2.8 mmol), 4-chloro-3- (trifluoromethyl)phenol 14a (0.5 g, 2.5 mmol), and potassium carbonate (0.46 g, 3.3 mmol) were dissolved in N,N-dimethylformamide (DMF) (30 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 14b (0.6 g, 71.3 %) as a yellow solid. 'H NMR (400 MHz, CDCls) § 9.94 (s, 1H), 7.64 — 7.55 (m, 2H), 7.45 (m, 1H), 7.31 (m, 1H), 7.05 (m, 1H). Step II: Preparation of compound 14¢ To a solution of 4-(4-chloro-3-(trifluoromethyl)phenoxy)-3,5- difluorobenzaldehyde 14b (0.6 g, 1.78 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH4 (67 mg, 1.78 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduce pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 14¢ (0.28 g, yield: 46.4 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.41 (m, 1H), 7.28 (m, 1H), 7.08 — 7.00 (m, 3H), 4.73 (m, 2H), 1.94 (m, 1H). Step III: Preparation of compound 14 To a solution of (4-(4-Chloro-3-(trifluoromethyl)phenoxy)-3,5- difluorophenyl)methanol 14¢ (74 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 14 (22 mg, 18.9%) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.41 (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 3, NN F OCF, CR 5 wo, © Step - ocr, Stepile - Fs GLC, OCC CLC “CL OC, CRE Stepdlle Ae Step I: Preparation of compound 15b 3,4,5-trifluorobenzaldehyde 5a (041 g 2.6 mmol), 3-chloro-4- (trifluoromethoxy)phenol 15a (0.5 g, 2.4 mmol), and potassium carbonate (0.42 g, 3.04 mmol) were dissolved in N,N-dimethylformamide (DMF) (20 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduce pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 15b (0.62 g, 73.2 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) 8 9.94 (s, 1H), 7.63 — 7.54 (m, 2H), 7.29 (m, 1H), 7.07 (m, 1H), 6.90 (m, 1H). Step II: Preparation of compound 15¢ To a solution of 4-(3-chloro-4-(trifluoromethoxy)phenoxy)-3,5- difluorobenzaldehyde 15b (0.62 g, 1.8 mmol) dissolved in methanol (50 mL), was added NaBH4 (62 mg, 1.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 15¢ (0.53 g, yield: 83.0 %) as a colorless oil. 'H NMR (400 MHz, CDCl3) § 7.25 (m, 1H), 7.06 (m, 2H), 7.01 (m, 1H), 6.87 (m, 1H), 4.72 (s, 2H), 2.04 (m, 1H). Step III: Preparation of compound 15 To a solution of (4-(3-Chloro-4-(trifluoromethoxy)phenoxy)-3,5- difluorophenyl)methanol 15¢ (79 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 15 (7 mg, 5.8%) as a white solid. 'H NMR (400 MHz, CDCl3) 3 7.24 (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 0 os NAN F oe CL cl [Cl a Fw a Step ’ or, Step ’ ” ’ A, + CL. le LX AA Stepdlle Tea Step I: Preparation of compound 16b 3,4,5-trifluorobenzaldehyde Sa (022 g 14 mmol), 3-chloro-4- (trifluoromethyl)phenol 16a (0.25 g, 1.23 mmol) and potassium carbonate (0.23 g, 1.65 mmol) were dissolved in N,N-dimethylformamide (DMF) (20 mL) at room temperature. The reaction mixture was stirred at 90 °C for 2 h. After cooled down ice water (100 mL) was added thereto. The reaction mixture was extracted with ethyl acetate (50 mLx 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (10 / 1) afforded the title compound 16b (0.32 g, 77.3 %) as a yellow solid. 'H NMR (400 MHz, CDCl3) 8 9.95 (s, 1H), 7.69 — 7.56 (m, 3H), 7.10 (m, 1H), 6.92 (m, 1H). Step II: Preparation of compound 16¢ To a solution of 4-(3-chloro-4-(trifluoromethyl)phenoxy)-3,5- difluorobenzaldehyde 16b (0.32 g, 0.95 mmol) dissolved in methanol (50 mL) at room temperature, was added NaBH4 (36 mg, 0.94 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h, concentrated under reduced pressure, water was added thereto and extracted with ethyl acetate (100 mLx 2). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with PE / EtOAc (4 / 1) afforded the title compound 16¢ (0.15 g, yield: 46.6 %) as a while solid. 'H NMR (400 MHz, CDCl3) 3 7.62 (m, 1H), 7.13 — 7.00 (m, 3H), 6.90 (m, 1H), 4.74 (m, 2H), 1.88 (m, 1H). Step III: Preparation of compound 16 To a solution of (4-(3-Chloro-4-(trifluoromethyl)phenoxy)-3,5- difluorophenyl)methanol 16¢ (74.5 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 18 mg, 0.44 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 1f (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 16 (13 mg, 11.2%) as a white solid. 'H NMR (400 MHz, CDCl3) 7.62 (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 Stepdlle @ He Zales u A Step u 1. StepiVe Me mii | pecan a StepVe ° o Stepive aA | 17e 5d 1” Fs Step I: Preparation of compound 17b o 0 Ao . © o no PPhy. DIAD Jy AKT URL Cu Boc Boc To a solution of 6-chlorouracil 1b (8.2 g, 55.9 mmol), tert-butyl (S)-3- (hydroxymethyl)piperidine-1-carboxylate 17a (12 g, 557 mmol) and triphenylphosphine (20 g, 76.2 mmol) dissolved in a mixed solvent of anhydrous tetrahydrofuran (250 mL) and N,N-dimethylformamide (50 mL) at room temperature, was added dropwise diisopropyl azodicarboxylate (20 ml, 111.6 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reducded pressure. Purification on a silica gel column with CH>CL / CH;OH (20 / 1) afforded the title compound 17b (7.8 g, yield: 40.6 %) as a colorless oil. Steps II and III: Preparation of compound 17d fe) - iN 1) TFA.DCM dd 2) DIPEA CF aN H o ory LSA, iy Boe 17b 17d To a solution of tert-butyl (S)-3-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- ylmethyl)piperidine-1-carboxylate) 17b (7.8 g, 22.7 mmol) dissolved in dichloromethane (80 mL) at room temperature, was added trifluoroacetic acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure. The afforded residue was used directly in the next step, and dissolved in acetonitrile (80 mL), then diisopropylethylamine (8.8 g, 68.1 mmol) was added at room temperature. The reaction mixture was stirred for 4 h, and concentrated under reduced pressure, followed by purification on a silica gel column CH>Cl / CH;OH (20 / 1) to afford the title compound 17d (1.5 g, 31.9 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 9.51 (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). Step IV: Preparation of compound 17e N.N-dimethylaniline 0 0 H H Ory POCl3 Ory ia.." ~ ~ ASA, N.N-dimethylaniline GSA 17d 17e To a solution of compound 17d (0.51 g, 2.46 mmol) and dimethylaniline (0.3 g, 2.47 mmol) in toluene, was added phosphorous oxychloride (0.76 g, 4.96 mmol) dropwise at room temperature. The reaction mixture was heated to reflux for 4 h, quenched with ice water, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH2Cl / CH3;OH (20 / 1) afforded the title compound 17e (0.24 g, 43.2 %) as a white solid. 'H NMR (400 MHz, CDCl3) 3 6.05 (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). Step V: Preparation of compound 17 o . o H StepVe ° o wn Foo stepve MA Ho N J — | Jud, CL SG GSS r or 0” cE, 17e sd 17 _ CL J To a solution of (3,5-Difluoro-4-((2-(trifluoromethylpyridin-4- yl)oxy)phenyl)methanol 5d (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water,. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 17 (28 mg, 25.7%) as a white solid. 'H NMR (400 MHz, CDCl;) 8.59 (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 0 0 H H Cory — (OU AA 0 NAN al, E or + NN 17e Te 18 i To a solution of (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol 7¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 18 (22 mg, 22.7%) as a white solid. 'H NMR (400 MHz, CDCl3) 8 8.27 (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 07 E 17e 6c 19 X H CQO SACL x i 19 To a solution of (3,5-Difluoro-4-((2-methyl)pyridin-4-yl)oxy)phenyl)methanol 6c (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 19 (58 mg, 59.8%) as a white solid. 'H NMR (400 MHz, CDCl) § 8.35 (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 F “CL QL "0 'CFa f 17e 10c 20 1 o oy “CLO 0 CFy 20 i To a solution of (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol 10c (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 20 (46 mg, 42.4%) as a white solid. 'H NMR (400 MHz, CDCl3) 3 7.41 (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 / z 494.1 [M+H]". Example 21 Preparation of Compound 21 Q H N Tg 21 To a solution of 3,5-Difluorobenzyl alcohol (32 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 21 (17 mg, 23.2%) as a white solid. 'H NMR (400 MHz, CDCl3) 3 6.96 — 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 RE wo X NON F CLL QL, 22 F To a solution of 2,4,5-Trifluorobenzyl alcohol (36 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 17e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 22 (36 mg, 46.6%) as a white solid. 'H NMR (400 MHz, CDCls) & 7.32 (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 Stepdve Pa, A a, reg A A A Step V ° Mody GI, "CLAY. 23 54 23 dy i £ ry Coy a. 2 I Step I: Preparation of compound 23b Oo oo 0 H 4 Non H Av) oH ono Ske ? A NN “TY TNTONH NI N aA “sw aA Boo dhs Sur 23a 1b 230 To a solution of 6-chlorouracil 1b (6.1 g 41.6 mmol), tert-butyl (R)-3- (hydroxymethyl)piperidine-1-carboxylate 23a (9 g 41.8 mmol) and triphenylphosphine (16.3 g, 62.1 mmol) dissolved in a mixed solvent of anhydrous tetrahydrofuran (250 mL) and N,N-dimethylformamide (50 mL) at room temperature, was added dropwise diisopropyl azodicarboxylate (16 ml, 83 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH>Cl / CH30H (20 / 1) afforded the title compound 23b (8.3 g, yield: 58 %) as a colorless oil. Steps II and III: Preparation of compound 23d H H I 1) TFA.DCM Z 2) K,COa H o Ce AA - ory (FAK, Boc 23b 23d To a solution of tert-butyl (R)-3-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yhmethyl)piperidine-1-carboxylate) 23b (8.3 g, 24.1 mmol) dissolved in dichloromethane (80 mL) at room temperature, was added trifluoroacetic acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure. The afforded residue was used directly in the next step, and dissolved in acetonitrile (80 mL), then potassium carbonate (7.0 g, 50.9 mmol) was added at room temperature. The reaction mixture was heated to reflux overnight, and filtrated, and the filter cake was washed with acetonitrile and methanol, respectively. The filtrate was concentrated under reduced pressure, followed by purification on a silica gel column CH,ClyCH;0H (20 / 1) to afford the title compound 23d (1.5 g, 29.9 %) as a white solid. 'H NMR (400 MHz, CDCl) § 8.85 (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). Step IV: Preparation of compound 23e POCI / N.N-Dimethylaniline PhMe H 0 H ° 4 A POCI, / N.N-Dimethylaniline LY J AC VOW ae C or 'e Gants Ce 23d 23e To a solution of compound 23d (0.5 g, 2.4 mmol) and dimethylaniline (0.29 g, 2.4 mmol) in toluene, was added phosphorous oxychloride (0.74 g, 4.8 mmol) dropwise at room temperature. The reaction mixture was heated to reflux for 4 h, quenched with ice water, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH2ClL / CH3OH (20 / 1) afforded the title compound 23e (0.31 g, 57.2 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 6.05 (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). Step V: Preparation of compound 23 oO Stepve Bnd CXR, 07 gy I 23e 5d 23 Ho J ONTON GRE, oy “CLL, 23 1 To a solution of (3,5-Difluoro-4-((2-(trifluoromethylpyridin-4- yloxy)phenyl)methanol 5d (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 23 (25 mg, 23.0%) as a white solid. 'H NMR (400 MHz, CDCl3) 8.59 (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 a ! 23e 7c 24 F no J . NN “OLE 24 F To a solution of (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol 7¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 24 (52 mg, 53.7%) as a white solid. 'H NMR (400 MHz, CDCl3) 8 8.27 (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 oO NT Ng) 0 a H aby £m, AA | ] . | EL RS F oS 23e 6c 25 F To a solution of (3,5-Difluoro-4-((2-methyl)pyridin-4-yl)oxy)phenyl)methanol 6¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 25 (38 mg, 39.2%) as a white solid. 'H NMR (400 MHz, CDCls) 5 8.36 (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 / z 441.2 [M+H]". Example 26 Preparation of Compound 26 0 NTN) oO CFa F 23e 10¢c 26 o sy GRA, ‘A » I 0’ CFs To a solution of (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol 10c (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 26 (58 mg, 53.4%) as a white solid. 'H NMR (400 MHz, CDCls) 3 7.42 (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 / z 494.1 [M+H]"*. Example 27 Preparation of Compound 27 7 0 1 wo SY 27 E To a solution of 3,5-Difluorobenzyl alcohol (32 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 27 (19 mg, 25.9%) as a white solid. 'H NMR (400 MHz, CDCl3) § 6.96 — 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 / z 334.1 [M+H]". Example 28 Preparation of Compound 28 yw 0 gael 2 2 1 To a solution of 2,4,5-Trifluorobenzyl alcohol (36 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 23e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 28 (18 mg, 23.3%) as a white solid. 'H NMR (400 MHz, CDCls) § 7.32 (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 Stepllle Step MH || Stepil o ” fo aA, mero LICL, old 2 Stepte on 1 wow ar a Gx, Naa: — CI, StepdVe M ah eS Lo \ StepVe doy ° o Stepive faye * ur Stepver fA = TRL TR, T= Sep gy 29e 5d 3 "5 Step I: Preparation of compound 29b H don PPh, DIAD, SW o HNPNH Boc uw 0 Oy A NH Sw a IA Boo 2%a 1b 29b To a solution of 6-chlorouracil 1b (10 g, 69 mmol), tert-butyl (S)-2- (hydroxymethyl)morpholine-4-carboxylate 29a (15 g 69 mmol) and triphenylphosphine (27 g, 102.9 mmol) dissolved in a mixed solvent of anhydrous tetrahydrofuran (250 mL) and N,N-dimethylformamide (50 mL) at room temperature, was added dropwise diisopropyl azodicarboxylate (27 ml, 138 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. Then the mixed solvent PE / EA = 3 / 1 (100 ml) was added to the residue, and a large amout of a white solid precipitated. Filtered, and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH,Cly / CH30H (20 / 1) afforded the title compound 29b (11.5 g, yield: 48.2 %) as a colorless oil. Steps II and III: Preparation of compound 29d 1) TFA 2) K;COs 'e L o LAK foe © N JL, Boc 28b 29d To a solution of Tert-butyl (S)-2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- ylmethyl)morpholine4-carboxylate 29b (11.5 g, 33.2 mmol) dissolved in dichloromethane (80 mL) at room temperature, was added trifluoroacetic acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure. The afforded residue was used directly in the next step, and dissolved in acetonitrile (80 mL), then potassium carbonate (9.2 g, 67 mmol) was added at room temperature. The reaction mixture was heated to reflux overnight, and filtrated, the filter cake was washed with acetonitrile and methanol, respectively. The filtrate was concentrated under reduced pressure, followed by purification on a silica gel column CH,Cl / CH30H (20 / 1) to afford the title compound 29d (1.9 g, 27.4 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 9.39 (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). Step IV: Preparation of compound 29e 0 9 H H E- reggae rd nomen OL LK, 26d 2% To a solution of compound 29d (0.5 g, 2.4 mmol) and dimethylaniline (0.29 g, 2.4 mmol) in toluene, was added phosphorous oxychloride (0.73 g, 4.8 mmol) dropwise at room temperature. The reaction mixture was heated to reflux for 4 h, quenched with ice water, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH>Cl / CH3;OH (20 / 1) afforded the title compound 29e (0.3 g, 54.9 %) as a white solid. 'H NMR (400 MHz, CDCl3) 3 6.12 (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). Step V: Preparation of compound 29 o o H me StepVe H XL o mn & WA ; —_— * i TL, ohm — re A oP Sry on 0 3 i Sey 2% 5d 29 F To a solution of (3,5-Difluoro-4-((2-(trifluoromethylpyridin-4- yl)oxy)phenyl)methanol 5d (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 29 (31 mg, 28.4%) as a white solid. 'H NMR (400 MHz, CDCl) § 8.59 (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 or LOK, a 7 ord o CAS © 0 ~-N : 29e 7c 30 Eo To a solution of (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol 7¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 30 (49 mg, 50.3%) as a white solid. "HNMR (400 MHz, CDCl3) § 8.26 (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 / z 443.1 [M+H]". Example 31 Preparation of Compound 31 Ho 07 F o Ho Ld nr ONS il N ] CL or 20e 6c 31 Fo To a solution of (3,5-Difluoro-4-((2-methyl) pyridin-4-yl)oxy)phenyl)methanol 6c (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 31 (38 mg, 39.0%) as a white solid. 'H NMR (400 MHz, CDCl3) 3 8.35 (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 u o X o N LIL, “Cr 2, 0 CFs 7 28e 10¢c 32 H A Choy QQ... To a solution of (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol 10c¢ (67 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 32 (31 mg, 28.4%) as a white solid. 'H NMR (400 MHz, CDCl) § 7.42 (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 Egy To a solution of 3,5-Difluorobenzyl alcohol (32 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 33 (21 mg, 28.5%) as a white solid. 'H NMR (400 MHz, CDCl3) § 6.98 — 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 Hore 2) F F To a solution of 2,4,5-Trifluorobenzyl alcohol (36 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 29e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 34 (29 mg, 37.3%) as a white solid. 'H NMR (400 MHz, CDCl3) § 7.36 — 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 o aq Stepiv ol. 1 stepile SH step Q Hon rN 0 LE bmg Sw ot Gas TT Ge 16a 1b 5b ae 54 Stepive 3 StepVe p- Nay A nm pi pV md LIL, Fy 168 5d a5 . o Stepve OLY HOE One, Step I: Preparation of compound 35b ok ON 0H PPh;. DIAD 0 nA NS ny Boc H o rp Sy aro Boe To a solution of 6-chlorouracil 1b (10 g, 69 mmol), tert-butyl (R)-2- (hydroxymethyl)morpholine-4-carboxylate 35a (15 g 69 mmol) and triphenylphosphine (27 g, 102.9 mmol) dissolved in a mixed solvent of anhydrous tetrahydrofuran (250 mL) and N,N-dimethylformamide (50 mL) at room temperature, was added dropwise diisopropyl azodicarboxylate (27 ml, 138 mmol) under nitrogen at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then the mixed solvent PE / EA = 3 / 1 (100 ml) was added to the residue, and a large amout of a white solid precipitated. Filtered and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH:Cl / CH30H (20 / 1) afforded the title compound 35b (7.2 g, yield: 30.5 %) as a colorless oil. Steps II and III: Preparation of compound 35d 1) TFA 2) DIPEA Luts 3 ONTONH CL H Hd Sy aA Boe 35b asd To a solution of Tert-butyl (R)-2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- ylmethyl)morpholine-4-carboxylate 35b (7.2 g, 20.8 mmol) dissolved in dichloromethane (80 mL) at room temperature, was added trifluoroacetic acid (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, and concentrated under reduced pressure. The afforded residue was used directly in the next step, and dissolved in acetonitrile (80 mL), then diisopropylethylamine (8.1 g, 62.7 mmol) was added at room temperature. The reaction mixture was stired at room temperature for 4 h, and concentrated under reduced pressure, followed by purification on a silica gel column CH2Cl / CH3;0H (20 / 1) to afford the title compound 35d (2.5 g, 57.4 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 9.32 (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). Step IV: Preparation of compound 35e 0 Q Soy PoouNNEnagaingl ~yy o — | LAs Ao vA 35d 35e To a solution of compound 35d (0.1 g, 0.48 mmol) and dimethylaniline (0.06 g, 0.48 mmol) in toluene, was added phosphorous oxychloride (0.73 g, 4.8 mmol) dropwise at room temperature. The reaction mixture was heated to reflux for 4 h, quenched with ice water, and concentrated under reduced pressure. The residue was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the desiccant was filtered out and the filtrate was concentrated under reduced pressure. Purification on a silica gel column with CH2Cl / CH;OH (20 / 1) afforded the title compound 35e (0.04 g, 36.4 %) as a white solid. 'H NMR (400 MHz, CDCl3) § 6.12 (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). Step V: Preparation of compound 35 o I. 0 H 1 id, A cape oF ns Stepie om N”°N LRA, Sr, 25e 5d 35 u a oe oY LR, F 5 ; Ll. To a solution of (3,5-Difluoro-4-((2-(trifluoromethylpyridin-4- yl)oxy)phenyl)methanol 5d (67 mg, 0.22 mmol) in dry N, N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 35 (41 mg, 37.5%) as a white solid. 'H NMR (400 MHz, CDCl) § 8.60 (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 H 1 TCC, cl 2 F 358 7c 36 ody, rer To a solution of (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol 7¢ (56 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 36 (42 mg, 43.2%) as a white solid. 'H NMR (400 MHz, CDCl3) § 8.21 (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 o Lp N N CC, 0 x I 35e 6c ar sey ey 37 w > r To a solution of (3,5-Difluoro-4-((2-methyl)pyridin-4-yl)oxy)phenyl)methanol 6¢ (56 mg, 0.22 mmol) in dry N, N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 37 (18 mg, 18.5%) as a white solid. 'H NMR (400 MHz, CDCls) & 8.36 (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 IM+H]". Example 38 Preparation of Compound 38 Bg} ee CRN, 0 CF 7 35e 10¢c 38 " o Sor vibe "OL 0 CFa Pr Pa To a solution of (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol 10¢ (67 mg, 0.22 mmol) in dry N, N-dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 38 (55 mg, 50.5%) as a white solid. 'H NMR (400 MHz, CDCl) § 7.41 (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 0 A Chey 39 i To a solution of 3,5-Difluorobenzyl alcohol (32 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 39 (37 mg, 50.2%) as a white solid. 'H NMR (400 MHz, CDCls) 3 6.96 — 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 H A F To a solution of 2,4,5-Trifluorobenzyl alcohol (36 mg, 0.22 mmol) in dry N,N- dimethylformamide (5 mL) was added sodium hydride (60 % in mineral oil, 11 mg, 0.26 mmol) at 0 °C, and stirred for 5 min at room temperature, followed by addition of compound 35e (50 mg, 0.22 mmol). The reaction mixture was stirred for 1 h, quenched with a small amount of water. Purification on a silica gel column with dichloromethane / methanol (20 / 1) afforded the title compound 40 (39 mg, 50.2%) as a white solid. 'H NMR (400 MHz, CDCls) § 7.36 — 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 bioactivity of a compound could be determined using any suitable assay as well as tissue and in vivo model for determining the activity of a compound as an LpPLA2 inhibitor. (1) Recombinant human Lp-PLA2 (rhLp-PLA2) assay (also known as PED6 assay) PEDS6 is a fluorescently labeled phospholipid, which could be purchased directly from Invitogene or Molecular Probes. PED6 has a fluorescence quenching p- nitrophenyl group at the Sn3 position and a Bodipy fluorescein (FL) group at the sn2 position. Once cleaved by an Lp-PLA2 enzyme, it will release the FL group, resulting in enhanced fluorescence. An Lp-PLA?2 inhibitor can prevent such cleavage so that no fluorescence enhancement is observed. Assay Method: The compound to be tested (as shown in Table 1) was mixed with a DMSO solution in a volume ratio of 1:3, and diluted to prepare a source plate of a 384-well microplate. Then 0.01 pl of the compound was transferred via an ECHO liquid dispenser from the source plate to a 384-well Greiner 784076 plate, and 5 pl of a buffer consisting of 50 mM HEPES, pH7.4, 150 mM NaCl, and 1 mM CHAPS (the buffer solution containing a recombinant human Lp-PLA2 enzyme at a concentration of 4 nM or 110 pM) was added to each well of the plate. The plate was centrifuged at 500 rpm for 10 seconds. After a 30-min pre-incubation, 5 pl of the above-mentioned buffer was added to a 384-well Greiner 784076 plate, the plate was centrifuged at 500 rpm for 10 seconds. After the plate was incubated at room temperature for 20 min in a dark place, the fluorescence intensity was read at ex 480 / em 540 with a ViewLux microplate imager, and the XL fitting model in Excel was used to perform the curve analysis and QC analysis to calculate pIC50. The results were listed in Table 1. Compound No. | rhLp-PLA2 (pICso) R.7 2 R6 3 75 4 85 5 10.5 6 10.2 oy 10.1 8 95 9 10.0 10 99 11 10.1 12 95 13 10.2 14 10.4 15 97 16 10.1 18 10.1 20 10.5 21 8.5 22 7.5 24 10.0 26 10.4 3 RSs 28 74 30 98 133 84 34 713 36 99 39 84 40 7.3 Positive Compound 8.9 Rilapladib (2) Human plasma Lp-PLA2 assay (also known as Thio-PAF assay) The human plasma assay was conducted using the sulphatide analog of PAF (phosphatidylcholine). After hydrolysis, it would generate phospholipids containing free sulfhydryl groups, which would be subjected to Michael addition with CPM to generate fluorescence-enhancing maleimide. Continuous quantitative analysis of thiol could be conducted by detecting the fluorescence intensity. This assay can be used to detect the inhibitory activity of the Lp-PLA2 inhibitor on the Lp-PLA2 enzyme in human plasma. Assay Method: The compound to be tested (as shown in Table 2) was mixed with a DMSO solution in a volume ratio of (1:3), and diluted to prepare a source plate of a 384-well microplate. Then 0.01 pl of the compound was transferred via an ECHO liquid dispenser from the source plate to a 384-well Greiner 784076 low-volume plate, and 8 pl of pre-aliquoted and frozen mixed human plasma was then added. The plate was centrifuged at 500 rpm for 10 seconds. After a 30-min pre-incubation, 2 pl of a substrate solution, and a buffer containing 2.5 mM 2-thio-PAF (a solution in ethanol), 32 uM CPM (a solution in DMSO) and 3.2 mM N-ethylmaleimide (NEM) (a buffer solution consisting of 50 mM HEPES, pH7.4, 150 mM NaCl, 1 mM CHAPS) was added by a BRAVO liquid handling station to a 384-well Greiner 784076 low-volume plate. Two minutes later, the reaction was quenched with 5 pl of 5% trifluoroacetic acid. After the plate was incubated at room temperature for 40 min in a dark place, the fluorescence intensity was read at ex 380 / em 485 with an Envision microplate reader, and the XL fitting model in Excel was used to perform the curve analysis and QC analysis to calculate pIC50. The results are shown in Table 2. Compound No. Thio-PAF (pICso) 75 2 7.5 3 6.5 4 74 5 8.5 6 82 7 21 8 7.8 9 8.0 10 8.0 11 8.1 12 7.8 13 8.1 14 82 15 79 16 8.1 18 8.1 20 8.5 21 7.4 392 6.5 24 8.1 26 84 27 713 28 6.5 30 80 13 7.1 34 6.3 36 7.9 39 7.0 40 6.3 Positive compound 7.8 sitive compound | 7.8 Rilapladib

Claims

What is claimed is:

1. A compound of Formula (1) or a pharmaceutically acceptable salt thereof, z " J ry . ! ASN EN Sw XN x e {I wherein ny, nz, and n;3 are each independently 0, 1, or 2; Ri and R: are each independently selected from -H, hydroxyl, cyano, halogen, alkyl, deuterated alkyl, deuterated alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, alkoxy, arylene, or heteroarylene; X, and X; are each independently selected from alkylene, -O-,’-S-,’or -NR'-, R'is selected from -H, alkyl, deuterated alkyl, or cycloalkyl; Ar is arylene or heteroarylene, wherein hydrogens in the arylene or heteroarylene are each optionally substituted with one or more substituents, and the substituents are each independently selected from halogen, alkyl, deuteroalkyl, haloalkyl, alkoxy, deuteroalkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, monoalkyl- or dialkyl-substituted amino, nitro, carboxy, formyl, 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', -NR'R", or -R"-Ar": Aris selected from aryl or heteroaryl, wherein hydrogens in the aryl or heteroaryl are optionally substituted with one or more substituents, the substituents are each independently selected from halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, cyano, amino, nitro, carboxy, formyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R" is H-, alkyl, or cycloalkyl; R" is alkylene; ZisOorS.

2. The compound or a salt thereof according to claim 1, wherein halogens in the "halogen" "haloalkyl" and "haloalkoxy " are each independently selected from F, Cl, Br, or I; optionally, alkyls in the "alkyl" "deuterated alkyl" "deuterated alkoxy" "hydroxyalkyl" "haloalkyl", "haloalkoxy" "alkoxy" and "mono- or di-alkyl substituted amino" are each independently Ci-Cio linear or branched alkyl; optionally each independently Ci-C linear or branched alkyl; optionally each independently C-Cs linear or branched alkyl; and optionally selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, isopentyl, 1-cthylpropyl, neopentyl, n-hexyl, l-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; optionally, "alkylenes" are each independently C1-Cyo linear or branched alkylene; optionally each Ci-C7 linear or branched alkylene; optionally each Ci-Cs linear or branched alkylene; and optionally each selected from methylene, ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene, tert-butylene, sec-butylene, n-pentylene, 1- methylbutylene, 2-methylbutylene, 3-methylbutylene, isopentylene, 1-ethylpropylene, neopentylene, n-hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, isohexylene, 1,1-dimethylbutylene, 2,2-dimethylbutylene, 3,3-dimethylbutylene, 1,2- dimethylbutylene, 1,3-dimethylbutylene, 2,3-dimethylbutylene, 2-ethylbutylene, n- heptylene, 2-methylhexylene, 3-methylhexylene, 2,2-dimethylpentylene, 3,3- dimethylpentylene, 2,3-dimethylpentylene, 2,4-dimethylpentylene, 3-ethylpentylene, or 2,2,3-trimethylbutylene; optionally, "cycloalkyl" is C3-Cio monocyclic or bicyclic cycloalkyl, optionally C3-C7 monocyclic cycloalkyl, and optionally cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; optionally, "heterocyclyl" is 3- to 10-membered non-aromatic heterocycle having in the ring 1, 2, or 3 heteroatoms selected from N, O, and S; optionally 3- to 10- membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and O; optionally 3- to 6-membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and O; optionally 3- to 10-membered non-aromatic ring having in the ring 1 or 2 heteroatoms selected from N and S; and optionally 3- to 6-membered non- aromatic ring having in the ring 1 or 2 heteroatoms selected from N and S; optionally, "aryl" is 6- to 10-membered aryl; optionally phenyl or naphthy, and optionally phenyl, 1-naphthyl, or 2-naphthyl; optionally, "arylene" is 6- to 10-membered arylene; and optionally phenylene or naphthylene; optionally, "heteroaryl" is 5- to 10-membered heteroaryl ring having in the ring 1- 3 heteroatoms selected from N, O, and S; optionally 5- to 10-membered heteroaryl ring having in the ring 1-2 heteroatoms selected from N, O, and S; optionally the heteroaryl ring is selected from pyridine ring, pyrrole ring, pyrazole ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiophene ring, and furan ring; optionally 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[2,3-b] furanyl, furo[3,2-b]-pyranyl, pyrido[2,3-dJoxazinyl, pyrazolo[4,3-dJoxazolyl, imidazo[4,5- dthiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2- bl[l,2,4]triazinyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzoxepinyl, benzoxazinyl, benzofuranyl, benzotriazolyl, pyrrolo[2,3-blpyridyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5- clpyridyl, pyrazolo[4,3-d]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-d]pyridyl, pyrazolo[3,4-b] pyridinyl, imidazo[l,2-a]pyridinyl, pyrazolo[1,5-aJpyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[l,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; and is optionally selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl; optionally, "heteroarylene" is 5- to 10-membered heteroarylene ring having in the ring 1-3 heteroatoms selected from N, O, and S; optionally 5- to 10-membered heteroaromatic ring having in the ring 1-2 heteroatoms selected from N, O, and S; and optionally the heteroarylene ring is selected from pyridinylene ring, pyrrolylene ring, pyrazolylene ring, pyrimidinylene ring, pyrazine ring, pyridazine ring, thiophene ring, or furanylene ring; optionally, the compound of Formula (I) is in the form of a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof.

3. The compound or a salt thereof according to claim 1 or 2, wherein ni, m2, and n3 are each independently 0, 1, or 2; optionally, ni is 1; optionally, nz is 1; optionally, n3 is 1; optionally, R1 and Ry are each independently selected from -H, fluorine, chlorine, bromine, iodine, hydroxyl, hydroxyalkyl, cyano, C1-C7 alkyl (such as methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,l1-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), C;-Cs deuteroalkyl (such as -CDs, -C2Ds, or - CsDy), Ci-Cs deuteroalkoxy (such as -OCDs, -OC.Ds, or -OC3Ds), Ci-C; haloalkyl (such as -CF3, -CHFa, -CHyF, -CoFs, or -CsF7), C1-C; haloalkoxy, Ci-C; alkoxy, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl; optionally, R; is -H; and optionally, R; is-H; optionally, X; and X> are each independently selected from C;-C- alkylene, -O-, - S-, or -NR'-; optionally, Xi is Ci-C7 alkylene (optionally, -CH>-, ethylene, n-propylene, isopropylene, n-butylene, or isobutylene), -O-, or -S-; optionally, Xi is C1-C7 alkylene or -O-; optionally, Xi is -CH>- or -O-; optionally, X: is -O- or -S-; and optionally, X is -0-; optionally, R'is selected from -H, C;-C7 alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, I-methylbutyl, 2- methylbutyl, 3-methylbutyl, isopentyl, l-ethylpropyl, neopentyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,l1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, 2-ethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,2- dimethylpentyl, 3,3-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3- ethylpentyl, or 2,2,3-trimethylbutyl), deuterated alkyl (optionally, -CD3, -C2Ds, or - C3Dy), or C3-Cs cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar is phenylene or pyridyl, wherein hydrogen atoms in the phenylene or pyridyl are optionally substituted with 1, 2, or 3 substituents, the substituents are each independently selected from F, Cl, Br, I, -CN, -Me, -CF3, -CHF, -C;Hs, -C3Hy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CD3, -OCDs, -OMe, -OCF3, or- OCHF2; optionally, Ar is arylene; and optionally, Ar is phenylene, wherein hydrogen atoms in the phenylene are optionally substituted with one or two substituents, the substituents are halogen, and optionally F; optionally, Y is -H, -F, -Cl, -Br, -1, methyl, ethyl, n-propyl, isopropyl, -CD3, -OCDs3, -CF3, -CHF,, -CHF, -CH,CF3, -OCF3, -OCHF;, -OCH_F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OCHs3, -OC2Hs, -OC3Hj7, or -OAr'; optionally, Y is H, halogen, or -OAr'; and optionally, Y is H, -F, or -OAr’; optionally, Ar' is selected from phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl, wherein hydrogen atoms in the phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, or quinolinyl ring are each independently optionally substituted with 1, 2, or 3 substituents, the substituents are each independently selected from F, Cl, Br, C1-C; alkyl (optionally, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropyl, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 2- methylhexyl, 3-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2,3- dimethylpentyl, 2,4-dimethylpentyl, 3-ethylpentyl, or 2,2,3-trimethylbutyl), -CD3, - OCD3, Ci-Cs haloalkyl, -OCH3, -OC;H7, -OC3H7, C1-Ce haloalkoxy, hydroxyl, hydroxyalkyl, cyano, or C3-Cs cycloalkyl (optionally, cyclopropanyl, cyclobutanyl, cyclopentanyl, or cyclohexanyl); optionally, Ar' is selected from phenyl, pyridin-3-yl, pyridin-4-yl, or pyrimidin-5- yl, and is optionally substituted with 1 or 2 substituents, the substituents is selected from halogen, alkyl, haloalkyl, or haloalkoxy, and optionally selected from F, Cl, -CH3, -CF3, or-OCF3; optionally, Z is O or S; and optionally, Z is O.

4. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the compound of Formula (I) is selected from the following compounds: BE 0 0 K A GCL - CRA N Cr N oe i 3 FF 3 et F CRA ° F Ao oy ergy, Sire o wy Coney F 0 a o i A, A GL, Fz GR, Fr GL, FN or oor SMa Sere F 8 F 2 F F 8 F $F 2, 2 1 N N N’ N N N GX ’ CX e ma (GN y N’ 0° N ke) N’ 'Q’ “LO, “LK CQ, w 1 aX a ¥ 0 OF B "oF 127 OF XL hy 2 NN NON NOON GLX F CF3 GLX F cl & J F N o N ASN Fa Go” eer, Cero woF 1 [CI 2 AL od od Frege Egg Py H A, ” 4 ’ ” 8 LY SCL STO, Engr 21 F 22 0 NTN ges 22 Tex LP 4 SOE oer, 0 wa Shy ¥ a 53, Ga Ml o sy Meera 2% 0° CF ” q fon Ay # H A H A Cy Thy; 1 Spy or EJ rr 2 Te Cok » T q fh oS Hom A OL . 20 Kee vs c AA . oA . 24 ig Ko F o o WX 4 . ogo, Tope Wo 3 WoL PY Or) x F FCI F CC F SMa Ta, Se sak i) 5. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the pharmaceutically acceptable salt includes an anionic salt or cationic salt of the compound of Formula (I); optionally, the pharmaceutically acceptable salt includes alkali metal salt, alkaline earth metal salt, or ammonium salt of the compound of Formula (I); optionally, the alkali metal includes sodium, potassium, lithium, or cesium, and the alkaline earth metal includes magnesium, calcium, or strontium; optionally, the pharmaceutically acceptable salt includes salt formed by the compound of Formula (I) and an organic base; optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5- diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0Jundecene-7, 14- diazabicyclo[2.2.2] octane; optionally, the trialkylamine includes trimethylamine, triethylamine, or N-ethyldiisopropylamine; and optionally, the N-alkyl morpholine includes N-methylmorpholine; optionally, the pharmaceutically acceptable salt includes salt formed by the compound of Formula (I) and an acid; optionally, the acid includes inorganic acid, or organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, or pamoic acid.

6. A preparation method of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, comprising the step of reacting a compound of Formula (II) with a compound of Formula (III) to produce the compound of Formula (I): 7 y WE z Ra A , ) — nN CO, How N So r Z Wr. By ! X: Se o Gary mL optionally, the preparation method comprises the step of reacting a compound of Formula (IV) with phosphorus oxychloride to produce the compound of Formula (II): Z Wo - POCIs < Ry NES. 1 NT Mo Ra Sr R2 Ry z XL oh NH 1 x Lon mL v Il optionally, the preparation method comprises the step of subjecting a compound of Formula (V) to cyclization reaction to produce the compound of Formula (IV): z R z Ry 1 Fob _ PES J AA 1 nN” cl 0 NT Ng Vv wv optionally, the preparation method comprises the step of reacting a compound of Formula (VII) with a compound of Formula (VIII) to produce a compound of Formula (VI), and further removing the protective group from the compound of Formula (VI) to produce the compound of Formula (V): z o z nS ao R; Re £ — tay hy a’ R, z Ry [Tht hi oo Boc 2 vil vii Vv optionally, the preparation method includes the following reaction scheme: THF z R R y Pad TFADCM Face DIPEA S Bn” a No oN ate Boe 2 POCIy / NN-Dimethylaniline ~~ \ #4. A “HW. _¥y NaH ¥ xh Bnd i __POCHNN-Dinetryaniine Sh x, [) Fine Goro Ag wT Ry i R i Ry 1 POCIYN.N-Dimetnytaniline AY NeH ANN QC wy COD Cy Nx a oh ! x We ey = Saye wherein in each of the formulas, ni, nz, n3, Ri, R2, Xi, Xz, Z, Ar, and Y are defined as in any one of claims 1-5.

7. A pharmaceutical composition, comprising a therapeutically effective amount of one or more of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, and optionally, pharmaceutically acceptable excipient(s).

8. The pharmaceutical composition according to claim 7, wherein the dosage form of the pharmaceutical composition includes oral, rectal, or parenteral formulation; optionally, the oral formulation includes solid or liquid formulation; optionally, the solid formulation includes tablet, powder, granule, or capsule; optionally, the liquid formulation includes aqueous or oily suspension, or syrup; optionally, the parenteral formulation includes solution for injection, or aqueous or oily suspension.

9. Use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 7 or 8, in the preparation of an Lp-PLA?2 inhibitor.

10. Use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 7 or 8, in the preparation of a medicament for treatment of neurodegeneration-related diseases; optionally, the neurodegeneration-related diseases include Alzheimer's disease (AD), glaucoma, and age-related macular degeneration (AMD).

11. Use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 7 or 8, in the preparation of a medicament for the treatment of cardiovascular diseases, diabetic macular edema (DME), or prostate diseases; optionally, the cardiovascular diseases include atherosclerosis.