Bicyclo[5,6] imidazole pyrimidone derivative and preparation method therefor and use thereof

Abstract

The present invention relates to the field of pharmaceutical chemistry, and in particular to a bicyclo[5,6] imidazole pyrimidone derivative and a preparation method therefor and a use thereof. In particular, the present invention relates to a compound represented by general formula (IA), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, a preparation method therefor, an intermediate thereof, a pharmaceutical composition containing the compound, and a use of the compound or the pharmaceutical composition thereof as an Lp-PLA2 inhibitor in preparation of a drug for preventing and / or treating related diseases mediated by Lp-PLA2.

Description

Bicyclo[5,6]imidazole pyrimidone derivatives, preparation method and application thereof

[0001] This application claims priority to Chinese Patent Application No. 2023108731979 filed on July 17, 2023, priority to Chinese Patent Application No. 2023110231425 filed on August 15, 2023, and priority to Chinese Patent Application No. 2023115453855 filed on November 20, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry and particularly relates to a bicyclo[5,6]imidazole pyrimidone derivative, a preparation method, and applications thereof. More specifically, the present invention relates to a bicyclo[5,6]imidazole pyrimidone derivative, a preparation method, intermediates, a pharmaceutical composition comprising the bicyclo[5,6]imidazole pyrimidone derivative, and the use of the bicyclo[5,6]imidazole pyrimidone derivative or its pharmaceutical composition as an Lp-PLA2 inhibitor in the preparation of a medicament for preventing and / or treating diseases mediated by Lp-PLA2. Background Art

[0003] Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase (PAF-AH), is involved in the hydrolysis of lipoprotein lipids or phospholipids. Lp-PLA2 travels with low-density lipoprotein (LDL) and hydrolyzes the sn-2 ester of oxidized phosphatidylcholine, producing lipid mediators: lysophosphatidylcholine (lysoPC) and oxidized non-esterified fatty acids (NEFAs). Studies have shown that lysoPC and NEFAs can cause inflammatory responses (Zalewski A, et al., Arterioscler. Thromb. Vase. Biol., 2005, 25, 923-31).

[0004] Products derived from the action of Lp-PLA2 (LysoPC and NEFAs) can promote atherosclerosis (Macphee CH, et al. Biochem J, 1999, 338, 479-87; Macphee CH et al. Current Opinion in Pharmacology, 2006, 6, 154-161; Zalewski A, et al. Arterioscler Thromb Vase Biol 2005, 25, 923-31). Studies have shown that LysoPC promotes the development of atherosclerotic plaques, ultimately leading to the formation of a necrotic core (Wilensky et al., Current Opinion in Lipidology, 2009, 20, 415-420). In addition, the products of Lp-PLA2 enzyme action are associated with plaque vulnerability and pathology (Kolodgie FD, et al. Arteriosclerosis Thrombosis and Vascular Biology, 2006, 26, 2523-9; Ferguson, JF, et al. Journal of the American College of Cardiology, 2012, 59, 764-772). The effect of Lp-PLA2 inhibitors on atherosclerotic plaque composition has also been demonstrated in diabetic and hypercholesterolemic pig models of accelerated coronary atherosclerosis (Wilensky et al, Nature Medicine, 2008, 10, 1015-1016). Clinical studies have also found that Lp-PLA2 inhibitors can stabilize atherosclerotic plaques in patients, preventing further plaque development and rupture (The STABILITY Investigators et al. N Engl J Med, 2014, 370, 1702-1711; O'Donoghue ML, et al. JAMA, 2014, 312, 1006-1015; Serruys PW, et al. Circulation, 2008, 118, 1172-1182; Mohler ER III, et al. Journal of the American College of Cardiology, 2008, 51, 1632-1641).

[0005] Other studies have shown that high levels of Lp-PLA2 are associated with a higher risk of dementia, including Alzheimer's disease (AD) (Van Oijen et al. Annals of Neurology, 2006, 59, 139). Higher levels of oxidized LDL have also been observed in AD patients (Kassner et al. Current Alzheimer Research, 2008, 5, 358-366; Sinem et al. Current Alzheimer Research, 2010, 7, 463-469). Furthermore, studies have shown neuroinflammation and upregulation of multiple cytotoxic inflammatory cytokines in AD patients (Colangelo et al. Journal of Neuroscience Research, 2002, 70, 462-473). Studies have also shown that LysoPC is a proinflammatory cytokine that can induce the release of multiple toxic inflammatory cytokines (Shi et al. Atherosclerosis, 2007, 191, 54-62). Therefore, these research evidences indicate that Lp-PLA2 inhibitors can reduce the production of LysoPC by inhibiting the activity of Lp-PLA2 and thus be used to treat AD.

[0006] In addition to its inflammatory effects, LysoPC is also associated with leukocyte activation, induction of apoptosis, and regulation of endothelial dysfunction (Wilensky et al. Current Opinion in Lipidology, 2009, 20, 415-420). Therefore, Lp-PLA2 inhibitors could be used to treat diabetes-related tissue damage by reducing LysoPC production. Given the inflammatory effects of Lp-PLA2 and the association between local inflammatory processes and diabetic retinopathy, it is hypothesized that Lp-PLA2 inhibitors could be used to treat diabetic eye diseases. Clinical studies have shown that Lp-PLA2 inhibitors can be used to treat diabetic macular edema (DME) (Staurenghi G et al. Ophthalmology, 2015, 122, 990).

[0007] Many Lp-PLA2 inhibitors and / or their uses have been previously described in the literature (including WO96 / 13484, WO96 / 19451, WO97 / 02242, WO97 / 12963, WO97 / 21675, WO97 / 21676, WO97 / 41098, WO97 / 41099, WO99 / 2442, WO00 / 10980, WO00 / 66566, WO00 / 66567, WO00 / 68208, WO01 / 60805, WO02 / 30904, WO02 / 309 11. WO03 / 015786, WO03 / 016287, WO03 / 041712, WO03 / 042179, WO03 / 042206, WO03 / 042218, WO03 / 086400, WO03 / 87088, WO0 8 / 04886, US2008 / 0103156, US2008 / 0090851, US2008 / 0090852, WO08 / 048866, WO05 / 003118, WO06 / 063811, WO06 / 063813, W O08 / 141176, CN103827118, CN103827116, WO11 / 146494, WO12 / 037782, WO12 / 075917, WO12 / 076435, CN104478812, WO13 / 0 13503, WO13 / 014185, WO14 / 114248, WO14 / 114249, CN104968665, WO14 / 114694, WO16 / 011930, WO16 / 011931, WO16 / 101927, JP200188847, US2008 / 0279846, US2010 / 0239565, US2008 / 0280829, WO16 / 012916, CN112778331, WO21 / 063145, WO21 / 228159, WO21 / 089032, CN113666930, WO22 / 001881, WO22 / 007810, WO22 / 233302, CN115925721, WO23 / 109471, CN116120329, etc.). However, there is still a strong demand in the art for new and differentiated Lp-PLA2 inhibitors.

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide an Lp-PLA2 inhibitor with a novel structure. Specifically, a bicyclic [5,6] imidazole pyrimidinone derivative, a preparation method thereof, an intermediate thereof, a pharmaceutical composition thereof and a use thereof are provided. The compound has good inhibitory activity against Lp-PLA2 and / or better metabolic stability, such as a lower clearance rate and / or a longer half-life.

[0010] The object of the present invention is to provide a compound represented by general formula (IA), its stereoisomers, its pharmaceutically acceptable salts or prodrugs thereof:

[0011] in:

[0012] L is -O(CH2) n1 -、-S(CH2) n1 -、-(CH2) n1 -or-NR aa (CH2) n1 -, of which -(CH2) n1 - end is connected to ring A;

[0013] R aa For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl, preferably hydrogen, deuterium, C 1-3 Alkyl or C 1-3 deuterated alkyl;

[0014] n1 is an integer from 1 to 4;

[0015] Y is H or

[0016] Ring A and Ring B are each independently C 6-14 aryl or a 5-14 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S; when Y is not H, ring A is at least a divalent group;

[0017] R 1 and R 2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C3-6 Cycloalkyl or -S(O)2-C 3-6 Cycloalkyl;

[0018] m and n are each independently an integer from 0 to 6;

[0019] R a For hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-6 Cycloalkyl, preferably hydrogen, deuterium, halogen, hydroxy, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 Alkylamino;

[0020] x is an integer from 0 to 5.

[0021] In a further preferred embodiment of the present invention, the general formula (IA) is further shown as the general formula (I):

[0022] in:

[0023] Y is H or

[0024] Ring A and Ring B are each independently C 6-14 Aryl or a 5-14 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S;

[0025] R 1 and R 2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino;

[0026] m and n are each independently 0, 1, 2, 3 or 4.

[0027] In a further preferred embodiment of the present invention, Ring A and Ring B are each independently C 6-12 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, preferably C6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, preferably phenyl, naphthyl, pyridyl, pyrimidinyl or pyrazolyl, more preferably It should be noted that, under the condition that the basic valence bond theory is satisfied, when Y is not H, the ring A drawn here is actually a divalent or higher valent group, which depends on the R 1 The number of substituents is the same below.

[0028] In a further preferred embodiment of the present invention, ring A is

[0029] In a further preferred embodiment of the present invention, when Y is H, ring A is

[0030] In a further preferred embodiment of the present invention, when Y is When ring A is

[0031] In a further preferred embodiment of the present invention, ring B is

[0032] In a further preferred embodiment of the present invention, R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl, preferably hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 The haloalkyl group is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl or trifluoromethyl.

[0033] In a further preferred embodiment of the present invention, R 1 is hydrogen, fluorine, chlorine, cyano, methyl or trifluoromethyl.

[0034] In a further preferred embodiment of the present invention, R 2 is hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl or trifluoromethyl.

[0035] In a further preferred embodiment of the present invention, m and n are each independently 0, 1, 2 or 3.

[0036] In a further preferred embodiment of the present invention, m is 0, 1, 2 or 3.

[0037] In a further preferred embodiment of the present invention, n is 0, 1 or 2.

[0038] In a further preferred embodiment of the present invention, the compound represented by general formula (I) is:

[0039] or a mixture thereof.

[0040] In a further preferred embodiment of the present invention, for

[0041] In a further preferred embodiment of the present invention, for

[0042] In a further preferred embodiment of the present invention, for Preferably

[0043] In a further preferred embodiment of the present invention, for

[0044] In a further preferred embodiment of the present invention, the general formula (I) is further represented by the general formula (II):

[0045] In a further preferred embodiment of the present invention, the general formula (II) is:

[0046] In a further preferred embodiment of the present invention, the general formula (I) is further represented by the general formula (III):

[0047] In a further preferred embodiment of the present invention, the general formula (III) is:

[0048] In a further preferred embodiment of the present invention, the general formula (I) is further represented by the following compound:

[0049] The present invention also provides a compound represented by (IA-1) or (IA-2), a stereoisomer thereof, or a salt thereof:

[0050] Among them, X 1 is halogen, R a and x as above.

[0051] Furthermore, the (IA-1) or (IA-2) is preferably represented by (I-1) or (I-2), respectively:

[0052] Preferably, said (I-1) is

[0053] Said (I-2) is

[0054] Among them, X 1 is halogen, preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.

[0055] Based on the common knowledge in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0056] The present invention further provides a method for preparing the compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof. The preparation method can be synthesized using commercially available raw materials by known methods.

[0057] In one embodiment, the preparation method preferably comprises the following steps:

[0058] In a solvent, the compound represented by the general formula (IA-1) reacts with the compound represented by the general formula (IA-3) to obtain the compound represented by the general formula (IA);

[0059] in:

[0060] X 1 is halogen, preferably fluorine, chlorine, bromine or iodine;

[0061] L, R a ,x,ring A,R 1 , Y, and m are as described above.

[0062] In one embodiment, the reaction conditions may be conventional conditions for such reactions in the art.

[0063] In a certain embodiment, the solvent can be a conventional solvent for such reactions in the art, for example, water or an organic solvent, preferably one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene.

[0064] The present invention further provides a method for preparing the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof. The preparation method can be synthesized using commercially available raw materials by known methods.

[0065] In one embodiment, the preparation method preferably comprises the following steps:

[0066] In a solvent, the compound represented by the general formula (I-1) reacts with the compound represented by the general formula (I-3) to obtain the compound represented by the general formula (I);

[0067] Alternatively, the compound represented by the general formula (I-2) reacts with the compound represented by the general formula (I-4) in a solvent to obtain the compound represented by the general formula (I);

[0068] in:

[0069] X 1 and X 2 are each independently halogen, preferably fluorine, chlorine, bromine or iodine;

[0070] Ring A, R 1 , Y, and m are as described above.

[0071] In one embodiment, the reaction conditions may be conventional conditions for such reactions in the art.

[0072] In a certain embodiment, the solvent can be a conventional solvent for such reactions in the art, for example, water or an organic solvent, preferably one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene.

[0073] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds shown, its stereoisomers, its pharmaceutically acceptable salts or prodrugs thereof and one or more pharmaceutically acceptable carriers.

[0074] In some embodiments of the present invention, the pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. These carriers are conventional carriers in the pharmaceutical field, for example: diluents such as water; binders such as cellulose derivatives, gelatin, and polyvinyl pyrrolidone; fillers such as starch; disintegrants such as calcium carbonate and sodium bicarbonate; and lubricants such as calcium stearate or magnesium stearate. Additionally, other adjuvants such as sweeteners, flavoring agents, or colorants may be added to the compositions.

[0075] In some embodiments of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or administration via an external implanted reservoir, wherein oral administration is preferred.

[0076] When administered orally, the compounds of the present application can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.

[0077] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs, wherein the drugs are Lp-PLA2 inhibitors.

[0078] The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for Lp-PLA2-mediated related diseases.

[0079] The present invention also relates to a method for preventing and / or treating Lp-PLA2-mediated diseases, comprising administering to the mammal a therapeutically effective dose of any one of the compounds shown, its stereoisomers, or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, or a pharmaceutical composition thereof.

[0080] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with Lp-PLA2 dysfunction.

[0081] In a further preferred embodiment of the present invention, the disease is one or more of neurodegenerative diseases, cardiovascular and cerebrovascular diseases, and diabetic complications.

[0082] In a further preferred embodiment of the present invention, the neurodegenerative disease is dementia, amyotrophic lateral sclerosis or Parkinson's disease.

[0083] In a further preferred embodiment of the present invention, the dementia is Alzheimer's disease, vascular dementia or multi-infarct dementia.

[0084] In a further preferred embodiment of the present invention, the cardiovascular and cerebrovascular diseases are coronary heart disease, stroke, and atherosclerosis.

[0085] In a further preferred embodiment of the present invention, the diabetic complication is diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathy pain or diabetic foot.

[0086] Detailed Description of the Invention

[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0088] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), further preferably an alkyl having 1 to 6 carbon atoms (ie, C1-6 Alkyl), most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3 Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof.

[0089] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 8 carbon atoms (i.e., C 1-8 Alkylene), further preferably an alkylene having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), most preferably an alkylene having 1 to 3 carbon atoms (i.e., C 1-3 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0090] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

[0091] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0092] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., C 3-5 Cycloalkyl), or a cycloalkyl group having 5 to 6 carbon atoms (i.e., C 3-5 Cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls. The cycloalkyls may be optionally substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, or alkylamino.

[0093] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclic group), wherein 1 to 4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., a 5-6-membered heterocyclic group), wherein 1 to 4, 1 to 3 or 1 to 2 heteroatoms are selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocyclic group include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl. Non-limiting examples of the polycyclic heterocyclic group include: spiroheterocyclic group, fused heterocyclic group and bridged heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, amino, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino.

[0094] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C 6-14 The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl group having 6 to 10 carbon atoms (i.e., C 6-10The aryl group is preferably a phenyl group or a naphthyl group, and most preferably a phenyl group. The monocyclic aryl group is, for example, a phenyl group. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl, etc. The aryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, or alkylamino.

[0095] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2), preferably a heteroatom selected from nitrogen, oxygen, or sulfur, but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, or S. The monocyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, non-limiting examples of which include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, and the like. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, and C 6-10 Aryl or C 6-10The 5- to 10-membered heteroaryl group is preferably an aryl group containing 1 to 4 heteroatoms selected from N, O or S, further preferably a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S and a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S and a phenyl group or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S, non-limiting examples of which include indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl and the like. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxy, amino, cyano, oxo, alkyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio or alkylamino.

[0096] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C 1-8 Alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (ie, C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (ie C 1-3 Alkoxy). Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0097] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably an alkylthio group having 1 to 6 carbon atoms (ie, C 1-6 alkylthio), more preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 Non-limiting examples include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0098] The term "alkylamino" refers to -NH-(alkyl or unsubstituted cycloalkyl), or -N(alkyl or unsubstituted cycloalkyl)-(alkyl or unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like.

[0099] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0100] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0101] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0102] The term "hydroxy" refers to -OH.

[0103] The term "amino" refers to -NH2.

[0104] The term "cyano" refers to -CN.

[0105] The term "oxo" or "oxo" refers to =0.

[0106] “n-BuOH” refers to n-butanol. “MeOH” refers to methanol. “PPh3” refers to triphenylphosphine. “DBAD” refers to di-tert-butyl azodicarboxylate. “ACN” refers to acetonitrile. “DMF” refers to N,N-dimethylformamide. “DMSO” refers to dimethyl sulfoxide. “DCM” refers to dichloromethane. “DIEA” refers to diisopropylethylamine. “EA” refers to ethyl acetate. “PE” refers to petroleum ether. “THF” refers to tetrahydrofuran. “TEA” refers to triethylamine. “toluene” refers to toluene.

[0107] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0108] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0109] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0110] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0111] The expression mn used herein refers to the range from m to n and the subranges and individual point values ​​therein. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 ” or “C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be encompassed, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6" covers a range of 1-6 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any subranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions herein should be understood in a similar manner.

[0112] As used herein, different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0113] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0114] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0115] If a substituent is described as being "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =0), this means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also mean that the corresponding group is "non-substituted" or "unsubstituted." Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0116] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0117] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

[0118] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All of these isomers and their mixtures are within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0119] The compounds of the present invention include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0120] All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the deuterium replacement may be partial or complete, wherein partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0121] In the compounds of the present invention, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0122] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0123] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0124] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components, such as a physiologically / pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0125] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0126] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0127] As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0128] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0129] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0130] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0131] The term "room temperature" refers to a temperature of 10-40°C. In some embodiments, "room temperature" refers to a temperature of 15-30°C; in other embodiments, "room temperature" refers to a temperature of 18-25°C.

[0132] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0133] In the context of the present invention, when or whether the words "about" or "approximately" are used, they mean within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0134] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses. Beneficial effects

[0135] The present invention relates to a class of novel structural compounds that act as inhibitors of Lp-PLA2 and have the potential to prevent and / or treat Lp-PLA2-mediated diseases. In some embodiments, the compounds of the present invention have good affinity for Lp-PLA2 and can effectively inhibit human plasma Lp-PLA2 activity. In some embodiments, the compounds of the present invention exhibit improved metabolic stability (e.g., lower clearance rate and / or longer half-life) in liver microsomes of SD rats, beagle dogs, cynomolgus monkeys, and humans. In some embodiments, the compounds of the present invention exhibit superior drug properties, such as improved pharmacokinetic properties (e.g., good plasma concentration and area under the concentration-time curve, improved bioavailability, suitable half-life and duration of action), improved in vivo pharmacodynamics, improved safety (lower toxicity and / or fewer side effects), good patient compliance, and / or reduced tolerance.

[0136] Specifically, the results of the present disclosure on human plasma Lp-PLA2 inhibitory activity demonstrate that the compounds of the present invention are effective Lp-PLA2 inhibitors with excellent inhibitory activity. In vitro liver microsomal stability experiments demonstrate that the compounds of the present invention have lower clearance rates and longer half-lives in liver microsomes of SD rats, beagle dogs, cynomolgus monkeys, and humans. Based on the pharmacodynamic activity and pharmacological mechanisms of this series of compounds, a slower metabolic rate facilitates the compounds' pharmacodynamic activity. Therefore, in terms of metabolic stability, the compounds of the present invention exhibit superior effects. DETAILED DESCRIPTION

[0137] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0138] Example

[0139] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0140] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0141] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer or a Varian Mercury Plus 400 MHz spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0142] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer or an Agilent LC / MSD 1200 Series quadrupole mass spectrometer.

[0143] HPLC determination was performed using a Shimadzu LC20A liquid chromatograph.

[0144] The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.

[0145] Intermediates used in the examples The following structure is preferred:

[0146] It can be synthesized according to the following scheme 1-2.

[0147] Alcohol used in the examples Preferably More preferably, the following structure:

[0148] They can be purchased, or synthesized according to the following scheme 3, or those skilled in the art can obtain them through conventional synthesis methods based on the synthesis methods of alcohol compounds and the product structure.

[0149] The compound represented by the general formula (I) of the present invention can be synthesized by the representative reactions of Schemes 1-5.

[0150] Option 1:

[0151] Option 2:

[0152] Option 3:

[0153] Option 4:

[0154] or,

[0155] Option 5:

[0156] or,

[0157] Intermediate 1

[0158] (R)-6,7,7a,8-Tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione

[0159] Synthesis route:

[0160] Step 1: Synthesis of (R)-1-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)azetidine-2-carboxylic acid butyl ester

[0161] To a solution of (R)-azetidine-2-carboxylic acid (50.0 g, 0.494 mol) in n-butanol (3 L) were added 6-chloro-1,3-dihydropyrimidine-2,4-dione (72.4 g, 0.494 mol) and triethylamine (75.0 g, 0.741 mol), and the mixture was stirred at 120°C for 12 hours. The reaction mixture was cooled to 0°C, and thionyl chloride (147.08 g, 1.236 mol) was added at 0°C, followed by stirring at room temperature for 2 hours. The reaction mixture was filtered, concentrated, and water (2 L) was added, followed by extraction with DCM (2 L x 3). The combined extracts were concentrated to give a crude product, which was isolated and purified by column chromatography (DCM:MeOH = 30:1) to obtain the desired product (80 g, 54% yield).

[0162] LC-MS[M+H] + :268.1.

[0163] Step 2: Synthesis of (R)-6-(2-(hydroxymethyl)azetidin-1-yl)pyrimidine-2,4(1H,3H)-dione

[0164] To a solution of (R)-butyl 1-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)azetidine-2-carboxylate (80.0 g, 0.299 mol) in THF / MeOH (2000 mL / 500 mL) at 0°C was added NaBH4 (33.9 g, 0.897 mol) and stirred at 25°C for 12 hours. MeOH (1 L) was added to the reaction solution, which was then filtered and concentrated. The mixture was added to water (1 L) and extracted with DCM (1 L x 3). The extract was freeze-dried to yield the desired product (150 g, crude product).

[0165] LC-MS[M+H] + :198.1.

[0166] Step 3: Synthesis of (R)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione

[0167] Under nitrogen, PPh3 (266.0 g, 1.014 mol) and DBAD (233.5 g, 1.014 mol) were added to a solution of (R)-6-(2-(hydroxymethyl)azetidin-1-yl)pyrimidine-2,4(1H,3H)-dione (80.0 g, 0.405 mol) in DMF (2000 mL) and stirred at 85°C for 12 hours. The reaction mixture was filtered, concentrated, and purified by column chromatography (DCM:MeOH = 10:1) to obtain the target product, Intermediate 1 (20 g, 24% yield).

[0168] LC-MS[M+H] + :180.1.

[0169] 1 H NMR (400MHz, DMSO-d6): δ10.71(s,1H),4.81(s,1H),4.79-4.72(m,1H),4.38-4.31 (m,1H),3.97-3.8(m,2H),3.62-3.56(m,1H),2.84-2.75(m,1H),2.52-2.44(m,1H).

[0170] Intermediate 2

[0171] 6,7,7a,8-Tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione

[0172] Synthesis route:

[0173] The preparation method of Intermediate 2 refers to the preparation method of Intermediate 1, except that (R)-azetidine-2-carboxylic acid in the first step is replaced by azetidine-2-carboxylic acid.

[0174] LC-MS[M+H] + :180.1.

[0175] 1 H NMR (400MHz, DMSO-d6): δ10.71(s,1H),4.81(s,1H),4.79-4.72(m,1H),4.38-4.31 (m,1H),3.97-3.8(m,2H),3.62-3.56(m,1H),2.84-2.75(m,1H),2.52-2.44(m,1H).

[0176] Intermediate 3

[0177] (S)-6,7,7a,8-Tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione

[0178] Synthesis route:

[0179] The preparation method of Intermediate 3 refers to the preparation method of Intermediate 1, except that (R)-azetidine-2-carboxylic acid in the first step is replaced by (S)-azetidine-2-carboxylic acid.

[0180] LC-MS[M+H] + :180.1.

[0181] Example 1

[0182] 3-((3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0183] Synthesis route:

[0184] Step 1: Synthesis of 5-(4-(bromomethyl)-2-fluorophenoxy)-2-(trifluoromethyl)pyridine

[0185] (3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (250 mg, 0.870 mmol) was stirred in a 48% HBr solution (5 mL) at 100° C. for 12 hours. The reaction mixture was cooled, saturated NaHCO (aqueous solution) (50 mL) was added, and the mixture was extracted with EA (50 mL×2). The combined organic phases were washed with brine, dried over Na SO , filtered, and concentrated to give a crude product (260 mg, 76% yield), which was used directly in the next step without purification.

[0186] LC-MS[M+H] + :350.0.

[0187] Step 2: Synthesis of 3-((3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0188] A solution of 6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (100 mg, 0.558 mmol) and AgCO (384.7 mg, 1.395 mmol) in toluene (10 mL) was stirred at 110°C for 1 hour. The reaction solution was cooled to 70°C. 5-(4-(bromomethyl)-2-fluorophenoxy)-2-(trifluoromethyl)pyridine (214.9 mg, 0.613 mmol) was added to the reaction solution. The reaction solution was cooled, filtered, concentrated, and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (100 mg). Purification by HPLC gave the desired product (24.1 mg, 9.6% yield).

[0189] LC-MS[M+H] + :449.1.

[0190] 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.7Hz,1H),7.90(d,J=8.7Hz,1H),7.55(dd ,J=7.8,5.2Hz,2H),7.43(t,J=8.2Hz,1H),7.36(d,J=8.5Hz,1H),5.47(s,1H), 5.38-5.29(m,2H),4.88-4.76(m,1H),4.39(dd,J=17.0,9.0Hz,1H),4.05-3.95 (m,2H),3.65(td,J=9.5,3.7Hz,1H),2.87-2.74(m,1H),2.47(d,J=7.2Hz,1H).

[0191] Example 2

[0192] 3-((3,4,5-trifluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0193] Synthesis route:

[0194] LC-MS[M+H] + :324.1.

[0195] Example 3

[0196] 3-((3-chloro-5-fluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0197] Synthesis route:

[0198] LC-MS[M+H] + :322.1.

[0199] Example 4

[0200] 3-((3,5-difluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0201] Synthesis route:

[0202] LC-MS[M+H] + :306.1.

[0203] Example 5

[0204] 3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0205] Synthesis route:

[0206] LC-MS[M+H] + :372.1.

[0207] Example 6

[0208] 3-((2,4-difluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0209] Synthesis route:

[0210] LC-MS[M+H] + :306.1.

[0211] Example 7

[0212] 3-((4-Fluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-acetyl[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0213] Synthesis route:

[0214] LC-MS[M+H] + :288.1.

[0215] 1 H NMR (400MHz, DMSO-d6) δ7.47(dd,J=8.6,5.6Hz,2H),7.26-7.16(m,2H),5.42(s,1H),5.27(q,J=12.3Hz,2H),4.82(qd,J=7.5,4.7Hz,1H),4 .37(dd,J=16.9,9.2Hz,1H),4.02-3.94(m,2H),3.63(td,J=9.5,3.7Hz,1H),2.79(dq,J=17.8,9.6Hz,1H),2.48-2.45(m,J=7.3,3.9Hz,1H).

[0216] Example 8

[0217] 3-((4-methylbenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0218] Synthesis route:

[0219] LC-MS[M+H] + :284.1.

[0220] 1 H NMR (400MHz, DMSO-d6) δ7.30(d,J=8.0Hz,2H),7.18(d,J=7.8Hz,2H),5.40(s,1H),5.24(q,J=12.2Hz,2H),4.82(qd,J=7.4,4.5Hz,1H),4. 37(dd,J=16.9,9.2Hz,1H),4.09-3.91(m,2H),3.63(td,J=9.5,3.9Hz,1H),2.79(dq,J=17.8,9.5Hz,1H),2.48-2.39(m,1H),2.30(s,3H).

[0221] Example 9

[0222] 3-((3,4-difluoro-5-methylbenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0223] Synthesis route:

[0224] LC-MS[M+H] + :320.1.

[0225] Example 10

[0226] 3-((3-cyano-5-fluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0227] Synthesis route:

[0228] LC-MS[M+H] + :313.1.

[0229] Example 11

[0230] 3-((3,4-difluoro-5-chlorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0231] Synthesis route:

[0232] LC-MS[M+H] + :340.1.

[0233] Example 12

[0234] 3-((4-phenoxybenzyl)oxy)-6,7,7a,8-tetrahydro-1H-acetyl[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0235] Synthesis route:

[0236] LC-MS[M+H] + :362.1.

[0237] 1H NMR (400MHz, DMSO-d6) δ7.49-7.35(m,4H),7.15(t,J=7.4Hz,1H),7.06-6.97(m,4H),5.41(s,1H),5.27(q,J=12.2Hz,2H),4.89- 4.76(m,1H),4.38(dd,J=17.0,9.2Hz,1H),4.07-3.92(m,2H),3.63(td,J=9.5,3.7Hz,1H),2.88-2.72(m,1H),2.47-2.41(m,1H).

[0238] Example 13

[0239] 3-((4-(pyridin-4-yloxy)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0240] Synthesis route:

[0241] LC-MS[M+H] + :363.1.

[0242] Example 14

[0243] 3-((4-(pyridin-2-yloxy)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0244] Synthesis route:

[0245] LC-MS[M+H] + :363.1.

[0246] Example 15

[0247] 3-((4-(pyrimidin-4-yloxy)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0248] Synthesis route:

[0249] LC-MS[M+H] + :364.1.

[0250] Example 16

[0251] 3-((6-phenoxypyridin-3-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0252] Synthesis route:

[0253] LC-MS[M+H] + :363.1.

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=2.2Hz,1H),7.92(dd,J=8.4,2.4Hz,1H),7.42(t,J= 7.9Hz,2H),7.22(t,J=7.4Hz,1H),7.13(d,J=8.2Hz,2H),7.04(d,J=8.4Hz,1H),5.41(s ,1H),5.27(q,J=12.3Hz,2H),4.82(qd,J=7.4,4.6Hz,1H),4.37(dd,J=16.9,9.1Hz,1H) ,4.07-3.93(m,2H),3.63(td,J=9.4,3.6Hz,1H),2.86-2.71(m,1H),2.47-2.43(m,1H).

[0255] Example 17

[0256] 3-((5-phenoxypyridin-2-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0257] Synthesis route:

[0258] LC-MS[M+H] + :363.1.

[0259] Example 18

[0260] 3-((5-phenoxypyridin-2-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0261] Synthesis route:

[0262] LC-MS[M+H] + :364.1.

[0263] Example 19

[0264] 3-((6-(pyrimidin-4-yloxy)pyridin-3-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0265] Synthesis route:

[0266] LC-MS[M+H] + :365.1.

[0267] Example 20

[0268] 5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin-1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

[0269] Synthesis route:

[0270] LC-MS[M+H] + :456.1.

[0271] Example 21

[0272] 5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin-1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile

[0273] Synthesis route:

[0274] Step 1: Synthesis of 5-(bromomethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile

[0275] To a solution of 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (200 mg, 0.679 mmol) in DCM (5 mL) was added CBr (225.4 mg, 0.679 mmol) and PPh (178.2 mg, 0.679 mmol). The reaction was stirred at 25°C for 12 hours, quenched with water (20 mL), and extracted with DCM (20 mL x 2). The combined organic phases were dried over NaSO, filtered, concentrated, and purified by column chromatography (PE:EA = 3:1) to obtain the desired product (230 mg, 95.04% yield).

[0276] LC-MS[M+H] + :357.

[0277] Step 2: Synthesis of 5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidine[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile

[0278] A solution of 6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (90 mg, 0.502 mmol) and AgCO (346.2 mg, 1.255 mmol) in toluene (10 mL) was stirred at 110°C for 1 hour. The reaction solution was cooled to 70°C. 5-(bromomethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (197.3 mg, 0.552 mmol) was added to the reaction solution. After stirring at 120°C for 12 hours, the reaction solution was cooled, filtered, concentrated, and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (100 mg). Purification by HPLC afforded the desired product (24.6 mg, 10.6% yield).

[0279] LC-MS[M+H] + :456.1.

[0280] 1H NMR (400MHz, DMSO-d6) δ8.49 (s, 1H), 8.10 (s, 1H), 7.94 (d, J = 8.4Hz, 1H), 7.85 (dd ,J=9.7,2.6Hz,1H),7.78(d,J=8.2Hz,1H),6.73(d,J=9.7Hz,1H),5.50(s,1H),5. 48-5.36(m,2H),4.89-4.77(m,1H),4.39(dd,J=16.9,9.1Hz,1H),4.05-3.95(m,2 H),3.66(td,J=9.5,3.7Hz,1H),2.81(dt,J=18.8,9.6Hz,1H),2.50-2.46(m,1H).

[0281] Example 22

[0282] 5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azepino[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile

[0283] Synthesis route:

[0284] LC-MS[M+H] + :455.1.

[0285] 1 H NMR(400MHz, DMSO-d6)δ8.00(d,J=2.0Hz,1H),7.81-7.67(m,2H),7.64(d,J=7.9H z,1H),7.58(s,1H),7.48(d,J=8.0Hz,1H),7.11(d,J=8.7Hz,1H),5.45(s,1H),5. 39-5.24(m,2H),4.90-4.74(m,1H),4.39(dd,J=16.9,9.1Hz,1H),4.07-3.92(m,2 H),3.64(td,J=9.5,3.7Hz,1H),2.80(dt,J=18.9,9.6Hz,1H),2.50-2.47(m,1H).

[0286] Example 23

[0287] 3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0288] Synthesis route:

[0289] LC-MS[M+H] + :449.1.

[0290] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=5.7Hz,1H),7.64-7.44(m,3H),7.40(d,J=8.4Hz,1H),7.20(dd,J=5.6,2.3Hz,1H),5.48(s,1H),5.41-5.29(m,2H ),4.93-4.75(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.07-3.94(m,2H),3.6 5(td,J=9.5,3.7Hz,1H),2.81(dt,J=19.0,9.5Hz,1H),2.48-2.44(m,1H).

[0291] Example 24

[0292] 3-((4-(3,4-difluorophenoxy)-3-fluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0293] Synthesis route:

[0294] LC-MS[M+H] + :416.1.

[0295] 1 H NMR (400MHz, DMSO-d6) δ7.46(ddd,J=21.8,13.0,5.4Hz,2H),7.24(ddd,J=13.5,11.8,5.8Hz,3H),6.87-6.78(m,1H),5.45(s,1H),5.38-5.19(m,2H ),4.83(tt,J=12.1,6.1Hz,1H),4.39(dd,J=16.9,9.1Hz,1H),4.07-3.94( m,2H),3.64(td,J=9.6,3.8Hz,1H),2.87-2.71(m,1H),2.48-2.43(m,1H).

[0296] Example 25

[0297] 2-(3,4-difluorophenoxy)-5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

[0298] Synthesis route:

[0299] LC-MS[M+H] + :423.1.

[0300] Example 26

[0301] 2-Chloro-4-(2-cyano-4-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)benzonitrile

[0302] Synthesis route:

[0303] LC-MS[M+H] + :446.1.

[0304] Example 27

[0305] 3-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6-,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0306] Synthesis route:

[0307] LC-MS[M+H] + :467.1.

[0308] Example 28

[0309] 3-((4-cyanobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0310] Synthesis route:

[0311] LC-MS[M+H] + :295.1.

[0312] 1H NMR (400MHz, DMSO-d6) δ7.86(d,J=8.2Hz,2H),7.59(d,J=8.2Hz,2H),5.48(s,1H),5.46-5.32(m,2H),4.83(qd,J=7.5,4.8H z,1H),4.39(dd,J=16.9,9.2Hz,1H),4.05-3.93(m,2H),3.65(td,J=9.5,3.8Hz,1H),2.88-2.72(m,1H),2.48-2.42(m,1H).

[0313] Example 29

[0314] 5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin-1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile

[0315] Synthesis route:

[0316] LC-MS[M+H] + :455.1.

[0317] Example 30

[0318] 2-(4-chloro-3-fluorophenoxy)-5-((1-oxo-6,7,7a,8-tetrahydro-1H-acetyl[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

[0319] Synthesis route:

[0320] LC-MS[M+H] + :439.1.

[0321] Example 31

[0322] 3-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0323] Synthesis route:

[0324] LC-MS[M+H] + :467.1.

[0325] Example 32

[0326] 3-((4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0327] Synthesis route:

[0328] LC-MS[M+H] + :433.1.

[0329] Example 33

[0330] 3-(2-Fluoro-4-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin-1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)-5-(trifluoromethyl)benzonitrile

[0331] Synthesis route:

[0332] LC-MS[M+H] + :473.1.

[0333] Example 34

[0334] 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0335] Synthesis route:

[0336] Step 1: Synthesis of 4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine

[0337] To a solution of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (11.3 g, 0.037 mol) in DCM (200 mL) was added CBr4 (12.2 g, 0.038 mol) and PPh3 (9.7 g, 0.033 mol). The reaction solution was stirred at 25°C for 12 hours, quenched with water (50 mL), and extracted with DCM (50 mL x 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA = 33:1) to give the desired product (6.5 g, 42% yield).

[0338] LC-MS[M+H] + :368.0.

[0339] Step 2: Synthesis of 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0340] 6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (2.7 g, 0.015 mol) and Ag2CO3 (10.41 g, 0.038 mol) were stirred in toluene (150 mL) at 110°C for 1 h. The reaction solution was then cooled to 70°C and 4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine (6.1 g, 0.016 mol) was added. The reaction solution was cooled to room temperature, filtered, concentrated, and separated and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (3 g). Purification by HPLC gave the desired product.

[0341] LC-MS[M+H] + :467.1.

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.6Hz,1H),7.67(d,J=2.3Hz,1H),7.48(d,J=8.9Hz,2H),7.32(dd,J=5.5,2.2Hz,1H),5.51(s,1H),5.44-5.28(m,2 H),4.91-4.76(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.09-3.94(m,2H),3. 66(td,J=9.4,3.6Hz,1H),2.81(dt,J=19.0,9.7Hz,1H),2.50-2.46(m,1H).

[0343] Example 34-R

[0344] (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0345] Synthesis route:

[0346] Step 1: Synthesis of 4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine

[0347] To a solution of (3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (11.3 g, 0.037 mol) in DCM (200 mL) was added CBr4 (12.2 g, 0.038 mol) and PPh3 (9.7 g, 0.033 mol). The reaction solution was stirred at 25°C for 12 hours, quenched with water (50 mL), and extracted with DCM (50 mL x 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA = 33:1) to give the desired product (6.5 g, 42% yield).

[0348] LC-MS[M+H] + :368.0.

[0349] Step 2: Synthesis of (R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0350] (R)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (2.7 g, 0.015 mol) and Ag2CO3 (10.41 g, 0.038 mol) were stirred in toluene (150 mL) at 110°C for 1 h. The reaction solution was then cooled to 70°C and 4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine (6.1 g, 0.016 mol) was added. The reaction solution was cooled to room temperature, filtered, concentrated, and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (3 g). Purification by HPLC gave the desired product (2.02 g, 28% yield).

[0351] LC-MS[M+H] + :467.1.

[0352] 1H NMR (400MHz, DMSO-d6) δ8.68(d,J=5.6Hz,1H),7.67(d,J=2.3Hz,1H),7.48(d,J=8.9Hz,2H),7.32(dd,J=5.5,2.2Hz,1H),5.51(s,1H),5.44-5.28(m,2 H),4.91-4.76(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.09-3.94(m,2H),3. 66(td,J=9.4,3.6Hz,1H),2.81(dt,J=19.0,9.7Hz,1H),2.50-2.46(m,1H).

[0353] Example 34-S

[0354] (S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0355] Synthesis route:

[0356] The synthetic route refers to Example 34-R, except that the (R)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione in the second step is replaced by (S)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione.

[0357] LC-MS[M+H] + :467.1.

[0358] 1 H NMR (400MHz, CDCl3): δ8.60(d,J=5.6Hz,1H),7.26(s,1H),7.15(d,J=5.2Hz,2H),6.98(dd,J=2Hz,5.6Hz,1H),5.49-5. 41(m,2H),5.37(s,1H),4.94-4.88(s,1H),4.58-4.50(m,1H),4.23-4.13(m,2H),3.73-3.67(m,1H),2.82-2.67(m,2H).

[0359] Example 35

[0360] 3-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0361] Synthesis route:

[0362] LC-MS[M+H] + :449.1.

[0363] Example 36

[0364] 3-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0365] Synthesis route:

[0366] Step 1: Synthesis of 5-(4-(bromomethyl)-2,6-difluorophenoxy)-2-methylpyridine

[0367] (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (10.0 g, 0.039 mol) was added to HBr (100 mL) solution and stirred at 100 ° C for 12 hours. The reaction solution was cooled to room temperature, saturated NaHCO3 aqueous solution (500 mL) was added, and extracted with EA (500 mL × 2). The extract was washed with saturated brine, dried over anhydrous Na2SO4, and then filtered and concentrated to give the target crude product (9.0 g, yield 64%), which was used directly in the next reaction without further purification.

[0368] LC-MS[M+H] + :314.0.

[0369] Step 2: Synthesis of 3-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0370] 6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (4.0 g, 0.022 mol) and Ag2CO3 (15.3 g, 0.055 mol) were added to a toluene (150 mL) solution and stirred at 110°C for 1 hour. The reaction solution was cooled to 70°C, and 5-(4-(bromomethyl)-2,6-difluorophenoxy)-2-methylpyridine (7.7 g, 0.024 mol) was added. The mixture was stirred at 120°C for 12 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and separated and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (2.5 g). Purification by HPLC gave the desired product.

[0371] LC-MS[M+H] + :413.1.

[0372] 1 H NMR(400MHz,DMSO-d6)δ8.26(d,J=2.9Hz,1H),7.40(d,J=8.9Hz,2H),7.29(dd ,J=8.6,2.9Hz,1H),7.23(d,J=8.6Hz,1H),5.49(s,1H),5.39-5.25(m,2H),4. 88-4.76(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.06-3.92(m,2H),3.65(td,J= 9.5,3.7Hz,1H),2.81(dt,J=19.0,9.5Hz,1H),2.50-2.47(m,1H),2.43(s,3H).

[0373] Example 36-R

[0374] (R)-3-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one)

[0375] Synthesis route:

[0376] Step 1: Synthesis of 5-(4-(bromomethyl)-2,6-difluorophenoxy)-2-methylpyridine

[0377] (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (10.0 g, 0.039 mol) was added to HBr (100 mL) solution and stirred at 100 ° C for 12 hours. The reaction solution was cooled to room temperature, saturated NaHCO3 aqueous solution (500 mL) was added, and extracted with EA (500 mL × 2). The extract was washed with saturated brine, dried over anhydrous Na2SO4, and then filtered and concentrated to give the target crude product (9.0 g, yield 64%), which was used directly in the next reaction without further purification.

[0378] LC-MS[M+H] + :314.0.

[0379] Step 2: Synthesis of (R)-3-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0380] (R)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione (4.0 g, 0.022 mol) and Ag2CO3 (15.3 g, 0.055 mol) were added to a toluene (150 mL) solution and stirred at 110°C for 1 hour. The reaction solution was cooled to 70°C, and 5-(4-(bromomethyl)-2,6-difluorophenoxy)-2-methylpyridine (7.7 g, 0.024 mol) was added. The mixture was stirred at 120°C for 12 hours. The reaction solution was cooled to room temperature, filtered, concentrated, and separated and purified by column chromatography (EA:MeOH = 10:1) to obtain a crude product (2.5 g). Purification by HPLC gave the desired product (1.56 g, 6.4% yield).

[0381] LC-MS[M+H] + :413.1.

[0382] 1H NMR (400MHz, DMSO-d6) δ8.26(d,J=2.9Hz,1H),7.40(d,J=8.9Hz,2H),7.29(dd,J=8.6,2.9Hz,1H),7.24(d,J=8.6Hz,1H),5.49(s,1H),5.38-5.26(m,2H ),4.90-4.75(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.07-3.95(m,2H),3.66 (td,J=9.5,3.7Hz,1H),2.88-2.72(m,1H),2.50-2.47(m,1H),2.44(s,3H).

[0383] Example 36-S

[0384] (S)-3-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one)

[0385] Synthesis route:

[0386] The synthetic route refers to Example 36-R, except that the (R)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione in the second step is replaced by (S)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidine-1,3(2H)-dione.

[0387] LC-MS[M+H] + :413.1.

[0388] 1 H NMR (400MHz, DMSO-d6): δ8.26(d,J=2.8Hz,1H),7.41-7.38(m,2H),7.30-7.23(m,2H),5.49(s,1H),5.34-5.33(m,2H),4 .86-4.83(m,1H),4.41-4.39(m,1H),4.03-4.01(m,2H),3.69-3.64(m,1H),2.83-2.79(m,1H),2.51(s,1H),2.44(s,3H).

[0389] Example 37

[0390] 3-((4-(3,4-difluorophenoxy)-3,5-difluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0391] Synthesis route:

[0392] LC-MS[M+H] + :434.1.

[0393] Example 38

[0394] 3-((6-(4-chloro-3-(trifluoromethyl)phenoxy)-5-fluoropyridin-3-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0395] Synthesis route:

[0396] LC-MS[M+H] + :483.1.

[0397] 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),8.03-7.97(m,1H),7.80(dd,J=5.7,2.8Hz,2H),7.61(dd,J=8.8,2.7Hz,1H),5.42(s,1H),5.36-5.24(m ,2H),4.87-4.75(m,1H),4.38(dd,J=16.9,9.1Hz,1H),4.05-3.92(m,2H),3.63(td,J=9.5,3.7Hz,1H),2.91-2.79(m,1H),2.50-2.46(m,1H).

[0398] Example 39

[0399] 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

[0400] Synthesis route:

[0401] LC-MS[M+H] + :489.1.

[0402] 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.81(d,J=8.7Hz,1H),7.75(d,J=9.7Hz,2H),7.51(d,J=8.4Hz,1H),7.17(d,J=8.7Hz,1H),5.45(s,1H),5.37 -5.24(m,2H),4.90-4.74(m,1H),4.39(q,J=8.9Hz,1H),4.01(dd,J=11.6 ,8.0Hz,2H),3.64(d,J=9.2Hz,1H),2.86-2.73(m,1H),2.49-2.44(m,1H).

[0403] Example 40

[0404] 3-((3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0405] Synthesis route:

[0406] LC-MS[M+H] + :466.1.

[0407] Example 41

[0408] 3-((6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0409] Synthesis route:

[0410] LC-MS[M+H] + :449.1.

[0411] 1H NMR(400MHz,DMSO-d6)δ8.22(d,J=2.1Hz,1H),7.97(dd,J=8.4,2.3Hz,1H),7.62 (d,J=5.1Hz,1H),7.59-7.55(m,2H),7.15(d,J=8.5Hz,1H),5.40(s,1H),5.28(q, J=12.3Hz,2H),4.87-4.75(m,1H),4.37(dd,J=16.9,9.1Hz,1H),4.05-3.93(m,2 H),3.63(td,J=9.5,3.8Hz,1H),2.79(dt,J=19.1,9.6Hz,1H),2.50-2.46(m,1H).

[0412] Example 42

[0413] 2-(3,5-difluorophenoxy)-5-(((1-oxo-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

[0414] Synthesis route:

[0415] LC-MS[M+H] + :423.1.

[0416] Example 43

[0417] 3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0418] Synthesis route:

[0419] LC-MS[M+H] + :468.1.

[0420] Example 44

[0421] 3-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0422] Synthesis route:

[0423] LC-MS[M+H] + :414.1.

[0424] 1 H NMR (400MHz, DMSO-d6) δ8.55(s,2H),7.42(d,J=9.0Hz,2H),5.49(s,1H),5.41-5.26(m,2H),4.91-4.77(m,1H),4.40(dd,J=16 .9,9.1Hz,1H),4.06-3.94(m,2H),3.66(td,J=9.5,3.8Hz,1H),2.81(dt,J=19.1,9.5Hz,1H),2.60(s,3H),2.49-2.44(m,1H).

[0425] Example 45

[0426] 3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0427] Synthesis route:

[0428] LC-MS[M+H] + :402.1.

[0429] 1 H NMR (400MHz, DMSO-d6) δ7.60(s,1H),7.32(d,J=8.9Hz,2H),7.27(s,1H),5.47(s,1H),5.36-5.22(m,2H),4.84(tt,J=12.3,6.0Hz,1 H),4.39(dd,J=16.9,9.1Hz,1H),4.08-3.94(m,2H),3.73(s,3H),3.65(td,J=9.5,3.7Hz,1H),2.86-2.74(m,1H),2.47-2.41(m,1H).

[0430] Example 46

[0431] 3-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0432] Synthesis route:

[0433] LC-MS[M+H] + :416.2.

[0434] Example 47

[0435] 3-((4-((1-isopropyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0436] Synthesis route:

[0437] LC-MS[M+H] + :430.2.

[0438] 1 H NMR (400MHz, DMSO-d6) δ7.68 (s, 1H), 7.32 (d, J = 8.8Hz, 2H), 7.26 (s, 1H), 5.47 (s, 1H), 5.36-5.21 (m, 2H), 4.90-4.75 (m, 1H), 4.46-4 .27(m,2H),4.08-3.92(m,2H),3.65(td,J=9.5,3.7Hz,1H),2.80(dt,J=19.0,9.5Hz,1H),2.50-2.47(m,1H),1.35(d,J=6.7Hz,6H).

[0439] Example 48

[0440] 3-((4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0441] Synthesis route:

[0442] LC-MS[M+H] + :456.1.

[0443] Example 49

[0444] 3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-aza[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0445] Synthesis route:

[0446] LC-MS[M+H] + :384.1.

[0447] Example 50

[0448] 3-((4-(4-chloro-3-(trifluoromethyl)phenoxy)benzyl)oxy)-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0449] Synthesis route:

[0450] LC-MS[M+H] + :464.1.

[0451] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.8Hz,1H),7.50(d,J=8.5Hz,2H),7.46(d,J=2 .8Hz,1H),7.29(dd,J=8.9,2.8Hz,1H),7.14(d,J=8.5Hz,2H),5.43(s,1H),5.30( q,J=12.4Hz,2H),4.83(tt,J=11.8,5.9Hz,1H),4.38(dd,J=17.0,9.1Hz,1H),4.0 9-3.93(m,2H),3.63(td,J=9.6,3.7Hz,1H),2.89-2.72(m,1H),2.46-2.37(m,1H).

[0452] Example 51

[0453] 3-((3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0454] Synthesis route:

[0455] LC-MS[M+H] + :450.1.

[0456] 1H NMR(400MHz, DMSO-d6)δ8.88(s,2H),7.56(dd,J=11.6,1.5Hz,1H),7.49(t,J=8.4Hz,1H),7.36(d,J=8.1Hz,1H),5.47(s,1H),5.40-5.28(m,2H), 4.89-4.78(m,1H),4.39(dd,J=16.9,9.1Hz,1H),4.07-3.93(m,2H),3.65 (td,J=9.6,3.8Hz,1H),2.80(dt,J=19.1,9.5Hz,1H),2.50-2.48(m,1H).

[0457] Example 52

[0458] 3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0459] Synthesis route:

[0460] LC-MS[M+H] + :467.1.

[0461] 1 H NMR (400MHz, DMSO-d6) δ8.68(d,J=2.8Hz,1H),7.91(d,J=8.8Hz,1H),7.63(dd,J=8.6,2.7Hz,1H),7.46(d,J=8.9Hz,2H),5.50(s,1H),5.40-5.2 7(m,2H),4.91-4.75(m,1H),4.40(dd,J=16.9,9.1Hz,1H),4.08-3.93(m ,2H),3.66(td,J=9.5,3.7Hz,1H),2.91-2.72(m,1H),2.48-2.36(m,1H).

[0462] Example 53

[0463] 2-Chloro-5-(2-fluoro-4-(((1-oxo-6,7,7a,8-tetrahydro-1H-acetyl[1',2':3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)benzonitrile

[0464] Synthesis route:

[0465] LC-MS[M+H] + :439.1.

[0466] 1 H NMR (400MHz, DMSO-d6) δ7.75-7.69(m,2H),7.51(d,J=12.2Hz,1H),7.38-7.27(m,3H),5.46(s,1H),5.38-5.25(m,2H),4.83(qd,J=7 .5,4.9Hz,1H),4.39(dd,J=16.9,9.1Hz,1H),4.06-3.93(m,2H),3.64(td,J=9.5,3.8Hz,1H),2.90-2.73(m,1H),2.48-2.42(m,1H).

[0467] Example 54

[0468] 3-((3,4-difluorobenzyl)oxy)-6,7,7a,8-tetrahydro-1H-azetidin[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one

[0469] Synthesis route:

[0470] LC-MS[M+H] + :306.1.

[0471] 1 H NMR (400MHz, DMSO-d6) δ7.55-7.40(m,2H),7.33-7.25(m,1H),5.45(s,1H),5.33-5.21(m,2H),4.83(qd,J=7.4,4.6Hz, 1H), 4.38 (dt, J=9.2, 7.7Hz, 1H), 4.06-3.94 (m, 2H), 3.64 (td, J=9.5, 3.8Hz, 1H), 2.87-2.72 (m, 1H), 2.48-2.41 (m, 1H).

[0472] The synthetic routes of the enantiomers of Examples 1-54 refer to the preparation of their racemates, as shown in the following table:

[0473] Biological test evaluation

[0474] The present invention is further described and explained below with reference to test examples, but these examples are not intended to limit the scope of the invention. The compounds of the present invention are Lp-PLA2 inhibitors and, therefore, can be used to treat diseases or conditions associated with Lp-PLA2 activity. The biological activity of the compounds of the present invention can be determined using any suitable assay, as well as tissue and in vivo models, including the assays described herein, to determine the activity of the compounds as Lp-PLA2 inhibitors. The biological activity data for each example compound tested is reported in either at least one experiment or in multiple experiments. The data presented here may reasonably vary depending on the specific conditions and procedures used by the experimenter.

[0475] The chemical structure of the following comparative example 1 of the present invention is shown below, and it was prepared according to the method of Example E67 of international patent application WO2016011931A1.

[0476] Test Example 1 Determination of the inhibitory activity of the compounds of the present invention on human plasma Lp-PLA2

[0477] Literature reports that 2-Thio-PAF, commercially available from Cayman Chemical, is a substrate for PAF hydrolase (PAF-AH). Upon cleavage by PAF-AH, the free thiol released at the sn-2 position can react with 7-diethylamino-3-(4'-maleimidophenyl)-4-methylcoumarin (CPM), resulting in increased fluorescence. Therefore, Lp-PLA2 inhibitors prevent this cleavage, and no increase in fluorescence is observed. The human plasma assay used in this experiment utilizes the same thioester analog of PAF as described in the recombinant human Lp-PLA2 assay.

[0478] 1.1 Experimental reagents, consumables and instruments:

[0479] 1.2 Test method:

[0480] (1) Thio-PAF assays were performed as quenched 75 μL assays. Compound source plates were first prepared by making 1:4 (volume) serial dilutions of the compounds in neat DMSO in a 96-well microtiter plate.

[0481] (2) Using a Rainin multichannel pipette, transfer 1 μL of the test compound from the compound source plate into a 96-well microplate containing 40 μL of pre-thawed human plasma. The thawed plasma was centrifuged at room temperature at 2000 rpm for 10 minutes. The plate was shaken on an ELISA plate shaker for 2 minutes to mix thoroughly.

[0482] (3) After a 30-minute preincubation at room temperature, 10 μL of substrate solution containing 2.5 mM 2-thio-PAF (from an ethanol stock solution), 32 μM CPM (from a DMSO stock solution), and 3.2 mM N-ethylmaleimide (prepared fresh in DMSO for each experiment) in an assay buffer consisting of 50 mM HEPES, 150 mM NaCl, 1 mM CHAPS, pH 7.4, was added to the 96-well microtiter plate using a Rainin multichannel pipette. The plate was immediately shaken for 2 minutes after addition. The total substrate reaction time was 4 minutes. After completion of the reaction, the reaction was quenched with 25 μL of 5% trifluoroacetic acid in water. The plate was centrifuged at 1000 rpm for 1 minute.

[0483] (4) The FLINT signal (FLINT380 / 480) is read using an enzyme-linked microplate reader.

[0484] (5) IC analysis using GraphPad Prism 8.0 and Excel 50 Data, curve and QC analysis.

[0485] 1.3 Experimental results:

[0486] The inhibitory activity IC of the compounds of the present invention on human plasma Lp-PLA2 was obtained through the above scheme. 50 The specific results are shown in Table 1.

[0487] Table 1 Inhibitory activity of the compounds of the present invention on human plasma Lp-PLA2

[0488] 1.4 Experimental Conclusions:

[0489] The results of in vitro experiments showed that the compounds of the present invention have an inhibitory activity against human plasma Lp-PLA2. 50 The values ​​are all less than 300 nM. Preferably, the inhibitory activity IC values ​​of Examples 1, 22, 23, 24, 34, 34-R, 36, 36-R, 39, 44, 50, 51, 62, 53 and 54 on human plasma Lp-PLA2 are 50 The values ​​were all less than 50 nM. More preferably, the inhibitory activity IC values ​​of human plasma Lp-PLA2 of Examples 1, 22, 23, 34, 34-R, 39 and 52 were 50 The values ​​were all less than 10 nM, indicating that the compounds of the present invention have good inhibitory activity against Lp-PLA2.

[0490] Test Example 2 Liver microsome stability test of the compound of the present invention

[0491] 2.1 Experimental Purpose

[0492] The first-phase metabolic stability of the compounds of the present invention was evaluated in liver microsomes of SD rats, beagle dogs, cynomolgus monkeys and humans.

[0493] 2.2 Experimental Materials

[0494] 2.2.1 Main reagents for the experiment

[0495] 2.2.2 Experimental instruments

[0496] 2.3 Experimental methods

[0497] (1) Preparation of buffer: Dissolve 73.21 g of potassium phosphate dibasic trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH of the solution to 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide, with a final concentration of 100 mM.

[0498] (2) Solution preparation and dilution: Prepare a 10 mM stock solution of the test compound in dimethyl sulfoxide (DMSO) and store at 4°C. Dilute to a 100 μM working solution with pure acetonitrile before use. Prepare a 10 mM stock solution of the control compound testosterone in DMSO and store at -20°C. Dilute to a 400 μM working solution with pure acetonitrile before use.

[0499] (3) Preparation of stop solution: The stop solution is an acetonitrile solution containing an internal standard (terfenadine). The prepared stop solution is stored in a refrigerator at 2-8°C.

[0500] (4) Preparation of liver microsome solution: Dilute liver microsomes from various species (SD rat, beagle dog, cynomolgus monkey, and human) to a 20× working solution using 100 mM potassium phosphate buffer. The final concentration of liver microsomes in the reaction system is 0.5 mg / mL.

[0501] (5) Preparation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system: Weigh appropriate amounts of nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl2), and glucose-6-phosphate dehydrogenase (G6PDH) to prepare stock solutions at concentrations of 65.33 mM, 330 mM, 300 mM, and 250 units / mL, respectively. Add the four stock solutions to an appropriate amount of buffer and gently mix by inverting. The final concentrations in the NADPH regeneration system are: 2.65 mM NADP, 10.2 mM G6P, 6.12 mM MgCl2, and 2.45 units / mL G6PDH.

[0502] (6) Incubation process: Incubation was performed in a 96-well plate. Several incubation plates were prepared and designated as T0, T5, T10, T20, T40, T60, and NCF60. The first six plates corresponded to reaction time points of 0, 5, 10, 20, 40, and 60 minutes, respectively. In the NCF60 plate, potassium phosphate buffer was used instead of the NADPH regeneration system solution for incubation for 60 minutes. All condition samples were run in triplicate.

[0503] Add 2 μL of test compound or control compound and 100 μL of microsomal working solution (containing 1 mg / mL liver microsomal protein) to T0, T5, T10, T20, T40, T60, and NCF60 plates, respectively. Add only microsomal working solution to the Blank 60 plate, and then pre-incubate the plates in a 37°C water bath for approximately 10 minutes.

[0504] After the preincubation, 98 μL of NADPH regeneration system working solution was added to each well except for the NCF60 and T0 plates to initiate the reaction. For the NCF60 plates, 98 μL of potassium phosphate buffer was added to each well. Therefore, for wells containing the test or control working solution, the final concentrations of TC and testosterone were 1 μM and 4 μM, respectively. The concentration of liver microsomes was 0.5 mg / mL. The final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0505] After incubation for an appropriate time (eg, 5, 10, 20, 40, and 60 minutes), 600 μL of stop solution (acetonitrile solution containing 100 ng / mL Tolbutamide) was added to each test compound sample and control compound sample well to terminate the reaction.

[0506] For the T0 plate, the stop solution was added first, followed by the NADPH regeneration system working solution. All samples were shaken and centrifuged at 4000 rpm for 20 minutes. Then, 50 μL of supernatant from each test compound and control compound well was diluted into 150 μL of pure water and shaken well before analysis by LC-MS / MS. Data were processed using Analyst 7.1 (Sciex, Framingham, Massachusetts, USA).

[0507] 2.4 Experimental results: The results of the in vitro liver microsome stability test of the compounds of the present invention are shown in Table 2.

[0508] Table 2 Results of in vitro liver microsome stability test

[0509] Note: The clearance classification standards are shown in the following table:

[0510] 2.5 Experimental Conclusion

[0511] According to the results in Table 2 above, the compounds of the present invention have lower clearance rates and longer half-lives in SD rats, beagle dogs, cynomolgus monkeys and human liver microsomes. Based on the pharmacodynamic activity and pharmacological mechanism of this series of compounds, a slower metabolic rate is conducive to the compounds exerting their pharmacodynamic activity. Therefore, in terms of metabolic stability, the compounds of the present invention show more excellent effects.

Claims

1. A compound represented by general formula (IA), its stereoisomer, its pharmaceutically acceptable salt or its prodrug: in: L is -O(CH2) n1 -、-S(CH2) n1 -、-(CH2) n1 -or-NR aa (CH2) n1 -; (CH2) n1 The end is connected to ring A; R aa For hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 3-6 Cycloalkyl; n1 is an integer from 1 to 4; Y is H or Ring A and Ring B are each independently C 6-14 aryl or a 5-14 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S; when Y is not H, ring A is at least a divalent group; R 1 and R 2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or -S(O)2-C 3-6 Cycloalkyl; m and n are each independently an integer from 0 to 6; R a is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino or C 3-6 Cycloalkyl; x is an integer from 0 to 5.

2. The compound represented by the general formula (IA) according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: The general formula (IA) is further shown as the general formula (I): in: Y is H or Ring A and Ring B are each independently C 6-14 Aryl or a 5-14-membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S; R 1 and R 2 are independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino; m and n are each independently 0, 1, 2, 3 or 4.

3. The compound represented by the general formula (IA) according to claim 1 or 2, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: It meets one or more of the following conditions: (1) Ring A and Ring B are each independently C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; (2) R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl; (3) m and n are each independently 0, 1, 2 or 3; (4) The compound represented by general formula (I) is: or a mixture thereof, wherein each group is as defined in claim 1 or 2.

4. The compound represented by the general formula (IA) according to any one of claims 1 to 3, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: It meets one or more of the following conditions: (1) Ring A and Ring B are each independently phenyl, naphthyl, pyridyl, pyrimidinyl or pyrazolyl; (2) R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl.

5. The compound represented by the general formula (IA) according to any one of claims 1 to 4, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: It meets one or more of the following conditions: (1) Ring A and Ring B are each independently (2) R1 and R2 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl or trifluoromethyl.

6. The compound represented by the general formula (IA) according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: It meets one or more of the following conditions: (1) for (2) for 7. The compound represented by the general formula (IA) according to any one of claims 1 to 6, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: for 8. The compound represented by the general formula (IA) according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: The general formula (IA) is further shown as the general formula (II): Among them, ring A, R 1 and m are as defined in claim 1.

9. The compound represented by the general formula (IA) according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or its prodrug, characterized in that: The general formula (IA) is further shown in the general formula (III): Among them, ring A, B, R 1 , R 2 , m and n are defined as in claim 1.

10. The compound represented by the general formula (IA) according to any one of claims 1 to 9, its pharmaceutically acceptable salt or its prodrug, characterized in that: Selected from the following compounds:

11. A compound represented by the general formula (IA-1) or (IA-2), a stereoisomer thereof, or a salt thereof: in, X 1 is halogen, R a and x as claimed in claim 1; Preferably, the general formula (IA-1) or (IA-2) further has a structure represented by the general formula (I-1) or (I-2): Among them, X 1 It is a halogen.

12. A method for preparing a compound represented by general formula (IA), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: In a solvent, the compound represented by the general formula (IA-1) reacts with the compound represented by the general formula (IA-3) to obtain the compound represented by the general formula (IA); in: X 1 is a halogen; L, R a , x, ring A, R 1 , Y, and m as described in any one of claims 1-10.

13. A method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: In a solvent, the compound represented by the general formula (I-1) reacts with the compound represented by the general formula (I-3) to obtain the compound represented by the general formula (I); Alternatively, in a solvent, the compound represented by the general formula (I-2) reacts with the compound represented by the general formula (I-4) to obtain the compound represented by the general formula (I); in: X 1 and X 2 are each independently a halogen; Ring A, R 1 , Y, and m as described in any one of claims 1-10.

14. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 10, its stereoisomer, its pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers.

15. Use of the compound according to any one of claims 1 to 10, its stereoisomer, its pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 14 in the preparation of Lp-PLA2 inhibitor drugs.

16. Use of the compound according to any one of claims 1 to 10, its stereoisomer, its pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating Lp-PLA2-mediated related diseases.

17. The use according to claim 16, characterized in that The disease is one or more of neurodegenerative diseases, cardiovascular and cerebrovascular diseases and diabetic complications, the neurodegenerative disease is dementia, amyotrophic lateral sclerosis or Parkinson's disease; the cardiovascular and cerebrovascular diseases are coronary heart disease, stroke or atherosclerosis; the diabetic complications are diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic peripheral neuropathy pain or diabetic foot; the dementia is Alzheimer's disease, vascular dementia or multi-infarct dementia.

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