WO2013000108A1

WO2013000108A1 - Azole heterocylic compounds, preparation methods, pharmaceutical compositions and uses thereof

Info

Publication number: WO2013000108A1
Application number: PCT/CN2011/076402
Authority: WO
Inventors: 沈建华; 王逸平; 王凯
Original assignee: 中国科学院上海药物研究所
Priority date: 2011-06-27
Filing date: 2011-06-27
Publication date: 2013-01-03

Abstract

Provided are azole heterocylic compounds of formula (I) or formula (II), their preparation methods, their pharmaceutical compositions and their use in the preparation of medicaments for treating diseases associated with the enzyme Lp-PLA₂, wherein the definitions for each substituent are same as described in the description.

Description

Azole heterocyclic compound, preparation method thereof, pharmaceutical composition and use thereof

The present invention relates to the field of medicinal chemistry, and in particular to novel azole heterocyclic compounds and preparation methods thereof, pharmaceutical compositions containing the compounds as active ingredients, and their use in the preparation of a medicament for treating diseases associated with Lp-PLA ₂ enzyme activity Applications. Background of the invention

Atherosclerosis is the pathophysiological basis of cardiovascular and cerebrovascular diseases. The formation of thrombus after rupture of atheromatous plaques and vascular occlusion is the main cause of cardiovascular events. Therefore, prevention and treatment of atherosclerosis is an important issue that needs to be solved urgently in the medical field. The current standard drug regimen is: statins modulate blood lipids, antihypertensive drugs to control blood pressure, and take drugs that resist platelet aggregation. However, even patients who adhere to long-term use of the treatment regimen, especially critically ill patients, still have a high risk of recurrence.

Studies have shown that atherosclerosis is not only associated with abnormal blood lipid levels, but also an inflammation-related disease. Inflammatory factors that inhibit atherosclerosis are new ways to treat the disease. Oxidized low-density lipoprotein (ox-LDL) is a risk factor present in the blood paddle that promotes inflammation and causes atherosclerosis.

Zalewski A reported (Arterioscler Thromb Vase Biol, 2005, 25 (5): 923-931) lipoprotein-associated phospholipase ₂ eight (eight ₂ ^ 1) during the formation of pro-inflammatory effects and the ox-LDL induced atherosclerosis It plays an important role in mediating the above biological effects of ox-LDL.

1 ^1^ ₂ is a member of the PLA ₂ superfamily and belongs to Vn type PLA ₂ . Lp-PLA _{2 is} also called plasma platelet activating factor (PAF acetylhydrolase, which contains 441 amino acids with a relative molecular mass of 45 kD. 70% of 1 ^1^ ₂ in human blood paddles binds to LDL, 30% Lp-PLA ₂ binds to high-density lipoprotein (HDL), which means that it is easily transported along with LDL to the site of damage in the vessel wall. Lp-PLA ₂ can hydrolyze PAF, PAF-like phospholipids and oxidatively modified Phosphatidylcholine, etc. Its enzymatic activity does not require the presence of divalent cations such as calcium ions, which is different from many other PLA _2. Lp-PLA ₂ has strong specificity for the short strand residues of the sn-2 position of phospholipids. When the residue at position sn-2 is acetyl, it has the maximum hydrolytic activity, and the phospholipid substrate with the long-chain fatty acid at the sn-2 position has no enzymatic activity. Site-directed mutagenesis identifies Ser-273, Asp in Lp-PLA ₂ -296 and His-351 constitute the center of its enzyme activity.

Maphee et al. (Macphee CH, Moores KE, Boyd HF, et al. Biochem J 1999; 338: 479-87) first proposed the mechanism by which Lp-PLA ₂ causes atherosclerosis. The long strand of the sn-2 position of the component lecithin of LDL is shortened by oxidative modification, and enters the arterial intima to become a substrate for Lp-PLA ₂ . Lp-PLA ₂ hydrolyzes it to hydrolyze it, producing lysophosphatidylcholine (Lyso-PC) and oxidized free fat Acid ( _0X -NEFA), both have a strong pro-inflammatory effect. These two biological mediators cause anterior atherosclerotic effects by initiating inflammatory/immune responses to a variety of cells including endothelial cells, smooth muscle cells, monocytes/macrophages, T cells, neutrophils, such as Upregulation of adhesion molecules levels allows mononuclear/macrophage to aggregate into atherosclerotic plaques, induces expression of cytokines such as interferon, activates leukocytes, induces oxidative stress, induces cell membrane permeability, and induces apoptosis. These effects further lead to the growth and instability of atherosclerotic plaque, the core of plaque necrosis continues to expand, the fibrous cap becomes thinner, ruptures and forms a thrombus, and eventually develops into clinically seen myocardial infarction, coronary heart disease, ischemic stroke And other diseases.

Therefore, the application of Lp-PLA ₂ inhibitor may reduce the occurrence of the aforementioned inflammatory response, and is a new, non-lipid-lowering strategy for the treatment of atherosclerosis. Selective inhibitors of Lp-PLA ₂ were observed in humans to significantly reduce ox-NEFA production and ox-LDL-induced apoptosis in macrophages (Rosenson RS, Vracar-Grabar M, Helenowski I. Cardiovasc Drags Ther 2008) 22:55-8). Experiments performed on animal models also support the role of Lp-PLA ₂ inhibitors, and Wilensky et al. (Wilensky RL, Shi Y, Mohler ER, et al. Nat Med 2008; 14: 1059-66) studied Lp-PLA in detail. ₂ Inhibitor Darapladib affects the volume, composition and gene expression of atherosclerotic plaque in diabetic/high cholesterol pigs and is found to be effective in inhibiting the continued growth of atherosclerotic plaque.

A large number of clinical studies have demonstrated that the incidence of cardiovascular events is positively correlated with Lp-PLA ₂ levels. Caslake et al. (Packard CJ, O'Reilly DS, Caslake MJ, et al. West of Scotland Coronary Prevention Group. N Engl J Med 2000; 343: 1148-55) had a myocardial infarction, ischemic reperfusion, or 580 Coronary heart disease-related deaths and 1,168 controls underwent a nested case-control study called West of Scotland Coronary Prevention Study (WOSCOPS), which demonstrated the first level of Lp-PLA ₂ and coronary heart disease events (CHD). Relationship, pointing out that Lp-PLA ₂ is an independent risk factor for predicting coronary heart disease. Except for positive correlation with LDL performance, it has little correlation with fibrinogen, and almost no C-reactive protein, white blood cell count and other risk factors. Relevance, its level is also unaffected by smoking. For every one standard deviation of Lp-PLA ₂ levels, the incidence of coronary heart disease events will increase by 22%.

Studies of seemingly healthy patients have shown that Lp-PLA ₂ can be used as a quantitative diagnostic indicator to alert patients with low LDL levels but with potential cardiovascular risk. In the Atherosclerosis Risk in Comnmnities (ARIC) study, Balkntyne surveyed 12,000 middle-aged male and female patients. When LDL levels were <130 mg dl, the incidence of cardiovascular events increased with Lp-PLA ₂ levels. On the other hand, the risk index of the highest level of Lp-PLA ₂ is 1.78 times that of the lowest level of 1/3. However, this result was not verified in populations with LDL levels >130 mg dl. However, the study of 7983 people over 55 years of age without a history of coronary heart disease made "Rotterdam Study" shows that, regardless of the level of cholesterol levels, warning factor 1 ^ ₂ are eight coronary events, but also of ischemic stroke Early warning factor. In people with a history of cardiovascular disease (such as secondary prevention patients), Lp-PLA ₂ is a risk factor for predicting disease recurrence. A study using coronary angiography indicated that for every one standard deviation of Lp-PLA ₂ levels, the incidence of coronary heart disease increased by 30% in four years. This effect of Lp-PLA ₂ is independent of traditional risk factors and C-reactive protein (CRP). Another study of patients undergoing rehabilitation therapy found that one-third of people with higher Lp-PLA ₂ levels had twice the risk of recurrent cardiovascular disease than the lower one-third.

An increase in the level of lysophosphatidylcholine (Lyso-PC), a hydrolysate of ox-LDL, is thought to be associated with endothelial dysfunction in patients with atherosclerosis, and the 1 octa ₂ inhibitor may improve the condition. Lp-PLA ₂ inhibitors may be used for other diseases that exhibit endothelial dysfunction such as diabetes, hypertension, angina, and reperfusion in ischemic areas.

Lp-PLA ₂ is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus Lp-PLA ₂ inhibitors can be used in the treatment of conditions associated with inflammatory cells, Such as psoriasis and a variety of airway inflammatory diseases including asthma, chronic bronchitis.

Furthermore, Lp-PLA ₂ inhibitors may be universally applicable to any process involving the hydrolysis of lipids into the two inflammatory traits with the participation of Lp-PLA ₂ . This includes the aforementioned atherosclerosis, diabetes, hypertension, angina pectoris, rheumatoid arthritis, stroke, myocardial infarction, reperfusion, acute and chronic inflammatory diseases.

Patent applications W096/13484, W096/19451, WO97/02242, W097/21765, W097/21766, WO97/41098 and WO97/41099 (Smit Kline Beecham pic) disclose a series of monocyclic [3 lactam derivatives which are An irreversible, acetylation inhibitor of Lp-PLA ₂ CTew et al, Biochemistry, 37, 10087, 1998).

Smit line Beecham pic has developed a class of potent reversible inhibitors of Lp-PLA ₂ (WO 99/24420, WO 01/60805, WO 02/30911, WO 03/016287, WO 03/042179, WO 03/042206, WO 08/048867, etc., characterized by a pyrimidinone or pyridone group in the structure. Among them, the Lp-PLA ₂ inhibitor Darapladib (SB480848) is in the clinical stage of the flood season.

Researchers in Korea have developed (US7642291) a novel class of 0-acetylated oxindole derivatives with micromolar activity.

We have discovered novel azole heterocyclic compounds which have been shown to be potent inhibitors of Lp-PLA ₂ by pharmacological experiments. Summary of the invention

An object of the present invention is to provide a pharmaceutically acceptable azole heterocyclic compound represented by the formula (I) or (Π), a cis-trans isomer, an enantiomer thereof and a diastereomer thereof. , a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a process for the preparation of the compound of the formula (I).

Another object of the present invention is to provide a use of the compound of the formula (I) or (II) as an Lp-PLA ₂ inhibitor, thereby preparing a disease for preventing, treating or ameliorating the activity associated with Lp-PLA ₂ enzyme activity. Use of the drug, such as atherosclerosis, stroke, myocardial infarction, angina pectoris, myocardial ischemia, reperfusion injury, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases .

Another object of the present invention is to provide a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I) or (A) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt Accepted accessories.

Another object of the present invention is to provide a method for preventing, treating or ameliorating a disease associated with Lp-PLA ₂ enzyme activity, comprising the azole heterocyclic compound of the present invention, a cis-trans isomer thereof, and an enantiomeric A conformation, diastereomer, racemate, solvate, hydrate, or a pharmaceutically acceptable salt thereof, or a composition according to the invention. In a first aspect of the invention, there is provided an azole heterocyclic compound represented by the formula (I) or (Π), a cis-trans isomer, an enantiomer, a diastereomer thereof, a racemic Body, hydrate, solvate, or pharmaceutically acceptable

among them

T is a four to six dollar fat ring, or a benzene ring;

R is a sulfhydryl group;

X is CH or N;

Y is a phenyl ring and is optionally substituted with one or more substituents selected from the group consisting of:

c _s embankment group, d_ _s embankment group, a halogen atom-substituted alkyl with d_ _s;

W is selected from the following six structures of af:

(f)

R ^{1 is} selected from H,

, C ₃ _.12 1⁄2 alkenyl, d. ₁₂ 1⁄2 fluorenyl, -NR ⁴ R ⁵ substituted C ₂ _ ₄ fluorenyl, ⁴

R ^{2 is} selected from H'

, -COR ⁴ , -COOR ⁴ ,

-CONR ⁴ R ⁵ , -CH=NNR ⁴ R ⁵ , -C(=CH ₂ )-OC(=0)R ⁴ , the base of C _1-12 , the cyclic fluorenyl group of C _3-7 , phenyl, The fluorenyl, cyclodecyl and phenyl are optionally halogen, -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , -S0 ₂ R ⁴ ,

H alo~

X. R ⁷

-NHCOR ⁴ , -NHS0 ₂ R ⁴ , -NHCSNHR ⁴ , ^rS , -N ₃ , substituted by phenyl;

R ³ may be in the ortho, meta or para position, is selected from H, halogen atom, alkyl with the d_ _s, partially or fully halogenated alkyl with d_ _s;

R ⁴ , R ⁵ are each independently selected from g H, C ₃ _-7 cyclodecyl, C _s linear or branched fluorenyl, optionally substituted by -COOR ⁹ , -NR ⁹ R ¹⁰ '-OR ⁹ '-COR ⁹ , substituted by a benzene ring, a benzyl group, an aromatic and a non-aromatic heterocyclic ring, optionally a halogen atom Replaced by the sulfhydryl group of C _s ; or

R ⁴ , R ⁵ and its attached N together form a 5-8 membered non-aromatic heterocyclic ring which may comprise another hetero atom selected from N, 0, S, and optionally a halogen atom, a group, -NR"R ¹² , -OR ¹¹ , substituted by oxo, benzyl; the thiol group of the _ _s is optionally substituted by -COOR ⁴ ;

R ^s , R ⁷ , R ^s are each independently selected from the group consisting of a fluorenyl group, a hydroxy-substituted C _M fluorenyl group, a benzyl group, which is optionally substituted with a fluorenyl group of a halogen atom;

R ⁹ , R ^1Q are each independently selected as g H, C _s thiol; or

R ⁹ , R ^{1Q together} with the N to which it is bonded constitutes a 5-8 membered non-aromatic heterocyclic ring, and the heterocyclic ring may comprise another hetero atom selected from N, 0, S; R ¹¹ ' R ¹² are each independently selected as g H, d. _s fluorenyl.

Halo represents a halogen atom. In another preferred embodiment, in the formula (I): T is a five-membered aliphatic ring, or a benzene ring; X is CH or in another preferred embodiment, in the formula (I): when T is five When the aliphatic ring is a member, X is N; when T is a benzene ring, X is CH. In a preferred embodiment, (IA)-(IG):

Wherein, the definitions of Y, R ¹ and R ² are as defined above. In another preferred embodiment, in the general formulae (I) and (Π) and (IA)-(IG): Y is a fluorine atom-substituted benzene

In another preferred embodiment, in the formulae (I) and (II) and (IA)-(IG): Y is "4-fluorophenyl", "2,3-difluorophenyl". In another preferred embodiment, in the general formulae (I) and (II): w is selected from the five structures _a - _e ,

Wherein R ¹ and R ^{2 are} as described above. In another preferred embodiment, in the formulae (I) and (Π) and (IA)-(IG): R ¹ is a fluorenyl group of ₄ substituted by ^^^^ ^r3 or -NR ⁴ R ⁵ . In another preferred embodiment, in the formulae (I) and (II) and (IA)-(IG): R ¹ is "(4-trifluoromethylbiphenyl-4-yl)methyl". In another preferred embodiment, in the general formulae (I) and (Π) and (IA)-(IG):

R ² is -COR ⁴ , an indenyl group of -CONR ⁴ R ⁵ , a cycloalkyl group of C^ ₅ , optionally substituted by -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , -S0 ₂ R ⁴ , =NNR ⁴ R ⁵ , -NHCOR ⁴ , -NHS0 ₂ R ⁴ ,

-NHCSNHR ⁴ ,

Replaced. In another preferred embodiment, in the general formulae (I) and (Π) and (IA)-(IG):

R ² is -C0R ⁴ , -CONR ⁴ R ⁵ , cyclopropyl, sulfhydryl group of C ₅ , and the fluorenyl group is -NR ⁴ R ⁵ , -OR ⁴ ,

-SR ⁴ , -S0 ₂ R ⁴ , =NNR ⁴ R ⁵ , -NHC0R ⁴ , -NHS0 ₂ R ⁴ , -NHCSNHR ⁴

R ² is -CONR ⁴ R ⁵ , cyclopropyl, and is -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , =NNR ⁴ R ⁵ , or

Substituted C ₅ thiol group. In another preferred embodiment, in the general formulae (I) and (Π) and (IA)-(IG):

R ^{2 is} selected from "NN-dimethylamino", "N-(2-diethylamino)ethylamino", methyl-N-(2-diethylamino)ethylamino", "dimethyl Aminomethyl", "diethylaminomethyl", "(tetrahydropyrrole small)methyl", "(N-methyl-p-fluorobenzamide)methyl", "isopropyl", "cyclopropyl"","(3-diethylamino)propyl","(4-diethylamino)butyl","hydroxymethyl","(1-hydroxy)ethyl","(p-fluorobenzylthio))methyl","(N-methylisopropylamino)methyl","[(1-ethylpyrrole-2-yl)methylamino]methyl","(N-ethylpiperazine-1-yl)methyl",methyl-(2-dimethylamino)ethylamino]methyl","[N-methyl-(2-diethylamino)ethylamino]methyl","[N-B-(2-dimethylamino)ethane]methyl","[N-methyl-(3-dimethylamino)propylamino]methyl","[N-methyl-(pyridin-2-yl))methylamino]methyl","(4-dimethylaminopiperidin-1-yl)methyl","(NN-dimethylsulfonium)methyl","(2-hydroxyethoxy)methyl"","(2-Diethylaminoethoxy)methyl","[1-(2-dimethylamino)ethylamino]ethyl","[1-(methyl)(2-dimethylaminoethyl)Ammonia]ethyl","[1-(2-diethylamino)ethylamino]ethyl","[1-(methyl)(2-diethylamino) Ethyl], "[1-(methyl)(3-dimethylaminopropyl) oxy]ethyl",

In another preferred embodiment, the compound is selected from the group consisting of:

1-(5-n-heptyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H- Cyclopenta-4-(5H> ketone;

1-(5-n-decyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H- Cyclopenta-4-(5H> ketone;

1-(5-n-heptyl-4,5-dihydro-l,2,4-tloxadiazol-3-yl)methyl-2-(4-fluorobenzylthio)-4(1H)- Quinoxalinone L-[5-(p-Trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxadiazol-3-yl]methyl-2-p-fluorobenzylsulfide base

-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

(£)-1-[5-n-heptyl-4-(1-n-octene)-4,5-dihydro-l,2,4-tloxadiazol-3-yl]methyl-2- P-fluorobenzylthio

-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxazolidine-3- Methyl-2-(2,3-difluorobenzylthio)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-4 (5H> ketone;

4-{3-[2-(2,3-difluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl-5- (p-trifluoro Ethyl methylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxadiazol-4-yl}piperidine-1-carboxylate;

4-{3-[2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl-5- (p-trifluoromethyl linkage) Ethyl phenyl-4-yl)-4,5-dihydro-1,2,4-Hoxadiazol-4-yl}piperidine-1-carboxylate;

1-{4-[2-(piperidin-1-yl)-ethyl]-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4- Tloxadiazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(2-diethylaminoethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4-H oxadiazole-3 -yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5Η)-one;

1-{4-[2-(piperidin-1-yl)-ethyl]-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4- Tloxadiazol-3-yl}methyl-2-(2,3-difluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-(5-phenyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine

-4(5H)-one;

1-(1H-tetrazol-5-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone; 1-[ 1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclo Pentyl [pyrimidine-4(5H)-one;

1-(1-n-dodecyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H ) ketone;

1-(1-n-butyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4(5H)_ Ketone

1-[1-(p-chlorobiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclo Pyrimidin-4 (5H> ketone;

1-[1-(biphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[ Pyrimidine-4(5H)-one;

1-(1-n-butyl-5-p-chlorophenyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopentapyridine -4 (5H> ketone;

1-(1-n-butyl-5-p-chlorophenyl-1H-imidazol-2-yl)methyl-2-pronitrobenzylthio-6,7-dihydro-1H-cyclopentapyridine- 4 (5H> ketone;

1-(1-Diethylaminoethyl-5-n-decyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H- Cyclopenta-4-(5H>ketone;

1-[1-Diethylaminoethyl-5-(p-trifluoromethylbiphenyl-4-yl)-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6 , 7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-(1-Benzyl-5-diethylaminomethyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopentyl Pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6, 7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio) -6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(tetrahydropyrrole-1-yl)methyl-1H-imidazol-2-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzylamino)methyl-1H-imidazol-2-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(4-phenylmethylpiperazin-1-yl)methyl-1H-imidazol-2-yl]methyl- 2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio) -6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

Dimethyl-N-(4-fluorobenzyl)-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidine-1 (5H)-yl]methyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-yl}methylammonium bromide; 1-[1-(p-trifluoro) Methylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H - cyclopenta [pyrimidine-4 (5H> ketone;

N-(4-fluorobenzyl)-N-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidine]

-1(5H)-yl]methyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazole-5-yl}methyltetrahydropyrrole ammonium bromide;

{2-[2-(4-Fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta-pyrimidine-1(5H>yl]methyl-1-(trifluoromethyl) Ethyl phenyl-4-yl)methyl-1H-imidazol-5-yl}carboxylate;

{2-[2-(4-Fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta-pyrimidine-1(5H>yl]methyl-1-(trifluoromethyl) Benzyl-4-yl)methyl-1H-imidazol-5-yl}carboxylic acid;

NN-dimethyl-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H>yl]methyl-1 - (p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-yl}carboxamide;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-benzoimidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-di Hydrogen-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylsulfide -6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone; 1-[4-Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-l,2,4-triazol-3-yl]methyl-2-p-methoxybenzoate Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-2-(2,3-di Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-ethyl-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7 -dihydrogen

-1H-cyclopenta [pyrimidine-4(5H)-one;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluoro Benzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)- 6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

Methyl, N-{3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidin-1(5H>yl]methyl-4- Methyl (p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl}methylaminoacetate;

N-methyl-{3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4Η-cyclopenta[pyrimidin-1(5H>yl]methyl-4- (p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl}methylaminoacetic acid;

1-[5-Methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluoro Benzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[5-n-propyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[5-isopropyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[5-cyclopropyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-benzylsulfonemethyl-4H-1,2,4-triazol-3-yl]methyl-2- (4-fluorobenzylthio)-6,7-dihydro-1 Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(3-diethylamino)propyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1 Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(4-diethylamino)butyl- 4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-hydroxymethyl-4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H- 1 ,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)- 6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H-pyrimidine-1 -yl]methyl-4H-1,2,4-triazol-3-yl-carbaldehyde; L-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

Dimethyl-N-(4-fluorobenzyl)-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidine-1 (5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl}methylammonium bromide;

N,N-trimethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentadienyl-1(5H)-yl]methyl -4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl}methylammonium iodide;

N,NN-trimethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentadienyl-1(5H)-yl]methyl -4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl}methylammonium bromide;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl-2-( 4-fluorobenzylthio)-6,7-dihydro-1 Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzamide)methyl-4H-1,2,4-triazole

-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-isopropylamino)methyl-4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

(±)-1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(N-ethylpyrrole-2-yl)methylamino]methyl

-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1- {4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2S,6J?)-2,6-dimethylmorpholine-4-yl]methyl

-4H-1,2,4-triazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one ;

2-methyl-2-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4- Oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}aminopropionic acid methyl ester;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-ethylpiperazin-1-yl)methyl-4H-1,2,4-triazole-3 -yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-methoxy)ethylamino]methyl-4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

₂ _Methyl_ ₂ _{ΛΚ4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4- Oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methylpiperazin-1-yl}propionic acid methyl ester;

₂ _Methyl_ ₂ _{ΛΚ4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4- Oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methylpiperazin-1-yl}propionic acid;

1-[ ⁴ - (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(methyl)( ² -dimethylaminoethyl)amino]methyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4(5H>ketone-tartrate

1-[ ⁴ - (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(methyl)( ³ -dimethylaminopropyl)amino]methyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-morpholine)ethylamino]methyl-4H-1,2,4-triazol-3-yl Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

(J?)-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(3-dimethylamino)pyrrole-1 -yl]methyl

(-1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(3-dimethylamino)pyrrole-1-yl]methyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(piperidin-1-yl)ethylamine]methyl-4H-1,2,4-triazole-3 -yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-pyrrole-1-yl)ethylamino]methyl-4H-1,2,4-triazole

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-diisopropylamino)ethylamino]methyl-4H-1,2,4-triazole

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-diethylamino)ethylamino]methyl-4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(methylpiperazin-1-yl)methyl- /-1,2,4-triazol-3-yl Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[N-methyl-(pyridin-2-yl)methylamino]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-cyclopropylamino)methyl-4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(4-dimethylaminopiperidin-1-yl)methyl-4H-1,2,4-triazole- 3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(3,3-difluoropyrrole-1-yl)methyl-4H-1,2,4-triazole 3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-dimethylamino)ethylamino]methyl-4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

(-1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(N-ethylpyrrole-2-yl)methylamino]methyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(2-oxoisidazolin-1-yl)ethylamine]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-azidomethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4 - Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-aminomethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

N-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H- Pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methylethanesulfonamide;

N-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H- Pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methyl-2-imidazolidinone;

3-methyl-1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4- Oxo-4H-pyrimidin-1-yl 1 methyl-4H-1,2,4-triazol-3-yl}methylthiourea;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-chloromethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(p-fluorobenzylthio)methyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(NN-dimethylindenyl)methyl-4H-1,2,4-triazole

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-tert-butylfluorenylene)methyl-4H-1,2,4-triazol-3-yl Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(piperidin-1-yl)imino]methyl-4H-1,2,4-triazole

1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H- Pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}vinyl acetate;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(1-hydroxy)ethyl-4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-acetyl-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluoro Benzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

N,N-Dimethyl-N-hydroxyethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta-pyrimidine-1 ( 5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl}methylammonium chloride;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(2-hydroxyethoxy)methyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(2-diethylaminoethoxy)methyl-4H-1,2,4-triazol-3-yl] Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(n-butyloxy)methyl- 4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[1-(2-dimethylamino)ethylamino]ethyl-4H-1,2,4-triazole -3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4 (5H>ketone;

1- -(p-trifluoromethylbiphenyl 4-yl)methyl- ^5- [1-(methyl)( ² -dimethylaminoethyl)amino]ethyl

1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[1-(2-diethylamino)ethylamino]ethyl -4H-1,2,4-triazole

-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1--(p-trifluoromethylbiphenyl 4-yl)methyl- ^5- [1-(methyl)( ² -diethylaminoethyl)amino]ethyl

-4H-1,2,4-triazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone- Tartrate;

1--(p-trifluoromethylbiphenyl 4-yl)methyl- ^5- [1-(methyl)( ³ -dimethylaminopropyl)amino]ethyl

-4H-1,2,4-triazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one ; 1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[N-ethyl-(2-dimethylamino)ethane]methyl-4H-1,2,4 - triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

N-(2-diethylamino)ethyl-N- {3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta-pyrimidine-1 ( 5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl}methylaminoacetate;

N-(2-diethylamino)ethyl-N-{3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4Η-cyclopenta[d]pyrimidine -1(5Η)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4Η-1,2,4-triazol-5-yl}methylaminoacetic acid;

N-(2-Diethylamino)ethyl-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta-pyrimidine-1 (5H) Methyl]p-(trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-yl}carboxamide;

Methyl-N-(2-diethylamino)ethyl-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[pyrimidine-1 (5H)-yl]methyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-yl}carboxamide;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-1H-imidazol-2-yl] Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4 (5H> ketone. In a second aspect of the invention, a pharmaceutical composition is provided, An azole heterocyclic compound, cis-trans isomer, enantiomer, diastereomer, racemate, solvate thereof, of the present invention comprising one or more effective therapeutic doses a hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. In a preferred embodiment, the composition further comprises one or more drugs selected from the group consisting of: a hypolipidemic agent, an anti-arterial Atherosclerosis, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs, antihypertensive drugs or lipid-lowering proteins Drugs. In a third aspect of the invention, there is provided an azole heterocyclic compound, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate thereof, hydrated according to the invention. Use of a substance, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an Lp-PLA ₂ inhibitor. In a fourth aspect of the invention, there is provided an azole heterocyclic compound, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate thereof, hydrated according to the invention. on the object, or a pharmaceutically acceptable salt thereof in the manufacture of preventing, treating or ameliorating drug eight 1 ^ ₂ related diseases in enzymatic activity. In a preferred embodiment, the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases. In a fourth aspect of the invention, a method for preventing, treating or ameliorating a disease associated with Lp-PLA ₂ enzymatic activity, comprising administering an azole heterocyclic compound, a cis-trans isomer thereof, a pair of the invention The enantiomers, diastereomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts thereof, or compositions of the invention. In a preferred embodiment, the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases.

In a fifth aspect of the invention, there is further provided an azole heterocyclic compound represented by the formula (I), a cis-trans isomer thereof, an enantiomer, a diastereomer, a racemate, a solvent A process for the preparation of a compound, a hydrate, or a pharmaceutically acceptable salt thereof, characterized in that one of the following Reaction Scheme 1 - Reaction Scheme 4 is employed:

5 Reaction route 1

When W in the compound of the formula (I) is a structure and ! ¹ is an alkenyl group, the compound of the formula (I) (i.e., compound 6) can be produced by the method shown in Reaction Scheme 1: wherein R ¹³ is C ₁ . The thiol group, the definition of TXYR ² is as described above;

Amidation of compound 1 to compound 2; compound 2 produces compound 3 under the action of a dehydrating reagent; compound 3 is reacted with hydroxylamine hydrochloride under the action of a base to prepare compound 4; compound 4 is catalyzed by boron trifluoride diethyl ether with R ² CHO reaction produces compound 5, the reaction is carried out in an aprotic solvent; compound 5 is reacted with R ¹³ CH ₂ CHO under the catalysis of boron trifluoride etherate to obtain compound 6;

Or,

Reaction route 2

When T in the compound of the formula (I) is a 4-6 membered aliphatic ring, Χ=Ν and R ^{1 is} not an alkenyl group, the compound of the formula (I) (ie, compound 10) can be prepared by the method shown in Scheme 2. Wherein R ¹⁴ is methyl or ethyl, and Halo, TW, Y are as defined above;

0 In a polar solvent, compound 7 is condensed with a cyclic fluorenone carboxylate ^R14 °3⁄4 ^ in the presence of a dehydrating agent to form compound 8; compound 8 forms a compound 9 under the action of Me ₃ SiNCS; Compound 9 is reacted with Y^Halo in a polar solvent to form compound 10;

13

Reaction Scheme 3 When W in the above compound 10 is the structure 0 and! ^{When 2} is a hydroxymethyl group, the compound (that is, a compound)

14) can be prepared by two methods shown in Reaction Scheme 3: wherein Halo, T, Y, R ¹ are as defined above;

In the method 1, the compound 11 and the aqueous formaldehyde solution are co-heated to form the compound 12; under the action of a base, the compound 12 and Y ^ Halo in a polar solvent to form a compound 14;

In the method 2, the compound 11 is first reacted with Y^Halo to form a compound 13, and then co-heated with an aqueous formaldehyde solution to form a compound 14;

Or,

1S

twenty two

Reaction route 4

The compound of the formula (I) can be converted by a functional group to form another compound of the formula (I), and such a functional group is converted as shown in Reaction Scheme 4:

When the formula (I) wherein R ² is a hydroxy-substituted alkyl with α-, compounds of formula (I) is the compound 15, wherein R ¹⁵ ¾ H, d_ _s a group embankment, R ¹⁶ is alkyl with the d_ _s And the fluorenyl group is optionally substituted by NR ⁴ R ⁵ or a phenyl group, which is optionally substituted by a halogen atom, R ¹³ is a fluorenyl group, L is NR ⁴ , 0 or S, Z is CH, N or 0, T, X, Y, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^s are as defined above;

Compound 15 is formed under the action of a chlorinating reagent to form compound 16; compound 16 is reacted with R ¹⁶ LH under the action of a base to obtain compound 17;

Compound 15 is oxidized to compound 18; compound 18 is reacted with HNR ⁴ R ⁵ under the action of a reducing agent to form compound 19;

Compound 16 is condensed with R ^S NR ⁷ R ^S to give compound 20;

Condensation of compound 19 with R ^s -Halo also gives compound 20; Compound 18 is condensed with H ₂ NNR ⁴ R ⁵ to form compound 21;

Compound 18 reacts with R ^ls BrMg to yield compound 22.

detailed description

"Substituted" as used in the present invention means replaced by one or more groups. When a plurality of groups are selected from the same series of candidate substituents, they may be the same or different.

The phrase "independently" as used in the present invention means that a plurality of defined groups can be selected from the same series of candidate groups, which do not affect each other, and may be the same or different.

The "fat ring" described in the present invention represents a cyclic hydrocarbon group having 3 to 12 carbon atoms, and may contain an unsaturation, preferably a 4-6 membered aliphatic ring such as cyclopentanyl or cyclopentene.

The terms "mercapto" and the like "decyloxy" as used in the present invention include all branched and straight chain isomers of a specific number of carbon atoms, preferably C ₁₂ fluorenyl, more preferably d _s fluorenyl. More preferably, it is a C ₁₄ fluorenyl group, and a fluorenyl group is further preferable. Representative examples are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.

The "alkenyl group" as used in the present invention represents all branched and straight-chain aliphatic hydrocarbon chains having one to five double bonds at a specific number of carbon atoms. For example, C ₃ _-12 alkenyl, C ₃ _{s s} alkenyl. Representative examples are but not limited to: vinyl, propylene.

The "cycloalkyl" as used in the present invention represents a non-aromatic, saturated, cyclic aliphatic hydrocarbon group at a specific number of carbon atoms. Representative examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The "non-aromatic heterocyclic ring" as used in the present invention, unless specifically defined, represents a saturated monocyclic ring system having 2 to 10 carbon atoms and having one to four hetero atoms selected from g, 0, and S. Representative examples are, but are not limited to, aziridine, thiazine, azetidinium, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine and the like.

The "aromatic heterocyclic ring" as used in the present invention represents a monocyclic ring system having 4 to 10 ring-forming atoms, containing one to four hetero atoms (selected from N, 0, S) and obeying the Hiickel rule. Representative examples are, but are not limited to, pyridine, pyrimidine, pyrazole, furan, thiophene, thiazole, pyrazine.

The "halogen" as used in the present invention includes fluorine, chlorine, bromine and iodine unless specifically defined.

Substitutions on a fluorenyl, alkenyl or cyclodecyl group in the present invention, if not indicated to occur on a particular carbon atom, indicate that a carbon atom of any number of substituents has not yet reached saturation.

The substitution on the benzene ring or the heterocyclic ring in the present invention, if not indicated to occur on a specific atom, means that it can occur at any position which is not substituted by hydrogen and other atoms.

The "effective therapeutic dose" as used in the present invention means that the disease, disorder, side effect, and the like of the subject receiving the dose are cured, improved, effectively prevented, or the incidence thereof is significantly lowered as compared with the subject not receiving the dose. In addition, it also includes an effective dose that enhances normal physiological function. The partial compound represented by the formula (I) or (II) of the present invention itself is in the form of a salt, such as when R ² is a fluorenyl Halo _r5

-I ^3⁄4 -N | \R. ⁶

And replaced by R ⁴ . In addition to this, other compounds may also be present in the form of a pharmaceutically acceptable salt, which is a particularly important part of the scope of the invention.

"Pharmaceutically acceptable salt" means that the compound of formula 0) retains the desired biological activity and has minimal toxic side effects. The pharmaceutically acceptable salt can be obtained directly during the preparation and purification of the compound, or it can be obtained indirectly by reacting the free acid or free base of the compound with another suitable base or acid.

In particular, some of the compounds of the present invention contain a basic functional group such as, but not limited to, when R ² is a fluorenyl group and is substituted with -NR ⁴ R ^{5 to} form a pharmaceutically acceptable salt with a suitable acid. The suitable acid may be a mineral acid or an organic acid. Representative examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, methanesulfonate, nitric acid, phosphate, acetate, oxalate, succinate, Tartrate, maleate, arginine, etc.

Some of the compounds of the present invention contain acidic functional groups such as, but not limited to, when R ² is a thiol group and is substituted with -COOH, a pharmaceutically acceptable salt can be formed with a suitable base. The suitable base may be an inorganic base or an organic base. Representative examples of pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic ions, such as sodium salts, potassium salts, lithium salts, calcium salts, aluminum salts, zinc salts, ammonium salts, and the like; Salts such as methylamine salt, ethylamine salt, triethylamine salt, meglumine salt, tromethamine salt and the like.

A part of the compound of the present invention or a pharmaceutically acceptable salt thereof is crystallized or recrystallized from water or an organic solvent, and the solvent may be used in the crystal. In addition, different crystallization conditions may result in different crystal forms of the compound. Therefore, a crystallization solvent containing a different chemical amount and a compound represented by the formula ω or (II) or a pharmaceutically acceptable salt thereof in all crystal forms are within the scope of the present invention.

Some of the compounds of the present invention have one or more chiral centers, such as, but not limited to, when w is a structure, and thus may exist as a racemate, a racemic mixture, an enantiomer, a diastereomer, Various forms such as diastereomeric mixtures. All such isomeric forms of the compounds of the formula (I) or (II) are within the scope of the invention. A part of the compound represented by the formula ω or (II) may exist in the form of a cis-trans isomer, such as but not limited to when R ¹ is an alkenyl group, and thus one isomer and two cis-trans isomers Mixtures are all within the scope of the invention. The compound represented by Formula 1 or (II) may have a rotamer due to the restriction of free rotation of a certain group, and thus a certain form of rotamer and a mixture of a plurality of rotamers are also Within the scope of the invention of this patent.

The term 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term 'hydrate' is used when the solvent is water. Preferred embodiment

Within the definition of the substituent of the compound of the formula (I) or (II), a more detailed definition of the group as follows is a preferred embodiment of the invention:

T is preferably a five-membered aliphatic ring, or a benzene ring;

X is CH or N;

More preferably, when T is a five-membered aliphatic ring, X is N; when T is a benzene ring, X is CH; Y is preferably a halogen atom-substituted benzene ring, more preferably a fluorine atom-substituted benzene ring, most Preferred is "4-fluorophenyl", "2,3-difluorophenyl";

R ^{1 is} most preferably "(4-trifluoromethylbiphenyl-4-yl)methyl";

R ² is preferably -COR ⁴ , an indenyl group of -CONR ⁴ R ⁵ , a cycloalkyl group of C^ ₅ , optionally substituted by -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , -S0 ₂ R ⁴ , =NNR ⁴ R ⁵ , -NHCOR ⁴ , -NHS0 ₂ R ⁴ ,

Halo _r3

-NHCSNHR ⁴ ,

Replaced

More preferably, R ² is -COR ⁴ , -CONR ⁴ R ⁵ , cyclopropyl, C _1-5 fluorenyl, and the fluorenyl group is -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , -S0 ₂ R ⁴ , =NNR ⁴ R ⁵ , -NHCOR ⁴ , -NHS0 ₂ R ⁴ , -NHCSNHR ⁴ or

Replaced by ^RS ;

R ^{2 is} most preferably -CONR ⁴ R ⁵ , cyclopropyl, and -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , =NNR ⁴ R ⁵ ,

Substituted C ₅ fluorenyl; specifically, R ² includes but is not limited to: "NN-dimethyl N-(2-diethylamino)ethylamino", methyl-N-(2-diethylammonium) Ethylamino", "dimethylaminomethyl", "diethylaminomethyl", "(tetrahydropyrrole-1-yl)methyl", "(N-methyl-p-fluorobenzamide) A ",""isopropyl","cyclopropyl","(3-diethylamino)propyl","(4-diethylamino)butyl","hydroxymethyl","(1-hydroxyl)Ethyl","(p-fluorobenzylthio)methyl","(N-methylisopropyl)methyl","[(1-ethylpyrrole-2-yl)methyl] methyl ",ethylpiperazin-1-yl)methyl", "[N-methyl-(2-dimethylamino)ethylamino]methyl", "[N-methyl-(2-diethylamino)"Ethylamino]methyl","[N-ethyl-(2-dimethylamino)ethylamino]methyl",methyl-(3-dimethylamino)propylamino]methyl","[N-A-(pyridin-2-yl)methylammonium]methyl","(4-dimethylaminopiperidin-1-yl)methyl","(NN-dimethylfluorene)methyl","(2-Diethylaminoethoxy)methyl","[1-(2-dimethylamino)ethylamino]ethyl","[1-(methyl)(2-dimethylaminoethyl)]]","[1-(2-diethylamino)ethylamino]ethyl","[1-(methyl)(2-diethylammonium) Ethyl) gas] ethyl "," [1- (methyl) (3-dimethylaminopropyl) amino] ethyl group ",

a compound of the formula (I):

L-(5-n-heptyl-4,5-dihydro-1,2,4-Hoxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H -cyclopentadienyl-4 (5H> ketone;

1-(5-n-decyl-4,5-dihydro-1,2,4-Hoxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H -cyclopentadienyl-4 (5H> ketone;

1-(5-n-heptyl-4,5-dihydro-l,2,4-tloxadiazol-3-yl)methyl-2-(4-fluorobenzylthio)-4(1H)- Quinoxalinone

1-[5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxadiazol-3-yl]methyl-2-p-fluorobenzyl sulfide base

-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

1-[4-(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxazolidine-3- Methyl-2-(2,3-difluorobenzylthio)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-4 (5H>ketone; 4-{3-[2-(2,3-difluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl-5- (p-trifluoro Ethyl methylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxadiazol-4-yl}piperidine-1-carboxylate;

-4(5H)-one;

1-(1-diethylaminoethyl-5-n-decyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopentyl Pyrimidine-4 (5H> ketone;

1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylsulfide -6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylsulfide -6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-l,2,4-triazol-3-yl]methyl-2-p-methoxybenzoate Thio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

-1H-cyclopenta[pyrimidin-4(5H)-one; 1-[4-Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluoro Benzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(4-diethylamino)butyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1 Η-cyclopenta[pyrimidine-4 (5H> ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H-pyrimidine-1 -yl]methyl-4H-1,2,4-triazol-3-yl-carbaldehyde;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl- 4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

N,N-trimethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopentadienyl-1(5H)-yl] Methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl}methylammonium iodide;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl- 4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone-tartrate;

(J?)-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(3-dimethylamino)pyrrolidin-1-yl]methyl -4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-azidomethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4 - fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

N-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H-

2S Pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methyl-2-imidazolidinone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[1-(2-dimethylamino)ethylamino]ethyl -4H-1,2,4-triazole

1--(p-trifluoromethylbiphenyl 4-yl)methyl- ^5- [1-(methyl)( ² -diethylaminoethyl)amino]ethyl -4H-1,2,4-triazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one ;

N-(2-diethylamino)ethyl-N- {3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4Η-cyclopenta[d]pyrimidine- 1 ⁽⁵ Η) - yl] methyl ^--4-- (p-trifluoromethyl biphenyl ^--4-- yl) methyl ^{^{- 4 Η-1, 2,}} 4 - triazole ^--5-- yl} methyl amino acid;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-1H-imidazol-2-yl] Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

It is a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.

The structural formula of the above most preferred compound is shown in the following Preparation Examples.

The compounds of the present invention are potent inhibitors of lipoprotein-associated phospholipase A ₂ and are potentially useful for clinical treatment, particularly for the treatment and prevention of acute and chronic coronary heart disease, such as peripheral vascular and cerebrovascular atherosclerosis. This type of event is caused; that is, the present invention provides a compound of the formula (I) or (Π) which can be used for clinical treatment.

The compound represented by the formula (I) or (II) of the present invention can inhibit the formation of lysophosphatidylcholine (Lyso-PC), and thus can be generally applied to diseases associated with endothelial dysfunction, such as atherosclerosis, diabetes. , high blood pressure, angina pectoris and ischemic reperfusion. Furthermore, the compounds of the formula (I) or (II) can be generally applied to any condition involving the hydrolysis of oxidized lipids with the participation of Lp-PLA ₂ , in addition to atherosclerosis, diabetes, These conditions also include ischemia, rheumatoid arthritis, stroke, brain inflammatory diseases (such as Alzheimer's disease), myocardial infarction, reperfusion injury, sepsis, acute and chronic inflammatory diseases. Lp-PLA ₂ is expressed in activated inflammatory cells (macrophages, lymphocytes, neutrophils, eosinophils, etc.), and thus the compounds of the formula (I) or (II) of the present invention can be treated Applications in conditions associated with inflammatory cell activation, such as psoriasis and a variety of airway inflammatory diseases including asthma and chronic bronchitis.

That is, the present invention provides formula (I) or (II) use of a compound represented by further treated by inhibition of Lp-PLA ₂ enzyme activity of Lp-PLA ₂ activation and associated diseases. These diseases may be associated with the following events: activation of inflammatory cells; formation of lysophosphatidylcholine and oxidized free fatty acids; Lp-PLA ₂ catalyzed lipid oxidation; endothelial cell dysfunction.

The compound of the formula (I) or (II) of the present invention can also be used in combination with the following drugs in the treatment of the above diseases: hypolipidemic drugs, antiatherogenic drugs, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs Medicine, antihypertensive drugs or lipid-lowering proteins & drugs. For example, statins that inhibit cholesterol synthesis, antioxidants, probucol, insulin sensitizers, calcium channel antagonists, or non-steroidal anti-inflammatory drugs.

The compound of the formula (I) or (II) of the present invention can be used in combination with a cholesterol lowering drug such as a statin. Statins are HMG-CoA reductase inhibitors such as atorvastatin, swastatin, pravastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and the like. Both drugs can be taken at the same time or separately as recommended by your doctor.

Up to 30% of patients with high cholesterol do not respond to statin therapy. Further use of the compounds of the formula (I) or (II) according to the invention may be suitable for this part of the patient.

Since the cardiovascular event is the main cause of death of a diabetic person, the compound of the formula (I) or (II) of the present invention can be used in combination with a hypoglycemic agent or an insulin sensitizer. The combined insulin sensitizer is preferably a PPAR-gamma agonist such as rosiglitazone or pioglitazone.

When used in therapy, the compounds of the invention are typically administered in the form of a standard pharmaceutical composition. That is, the present invention provides a pharmaceutical composition comprising one or more effective therapeutic doses of a compound of the formula (I) or (II), and a pharmaceutically acceptable adjuvant. The pharmaceutically acceptable excipient is a pharmaceutically acceptable carrier, a sputum or a sustained release agent, and the like.

The compounds and pharmaceutical compositions provided herein may be in various forms, such as tablets, capsules, powders, troches, solutions, suspensions, aerosols, and the like, and may be presented in a suitable solid or liquid carrier. Or in the diluent. The pharmaceutical compositions of the invention may also be stored in a suitable injectable or drip sterilizing device. Odorants, flavoring agents and the like may also be included in the pharmaceutical composition.

In the present invention, the pharmaceutical composition contains a safe or effective amount (e.g., 0.1 to 99.9% by weight, preferably 1 to 90 parts by weight) of the compound of the formula (I) or (II) or a pharmaceutically acceptable compound thereof. a salt; and a balance of a pharmaceutically acceptable excipient wherein the total weight of the composition is 100 parts by weight. Alternatively, the pharmaceutical compositions of the present invention comprise from 0.1 to 99.9% by weight based on the total weight. /. a compound of the formula (I) or (II) or a pharmaceutically acceptable salt thereof, preferably from 1 to 90% by weight, based on the total weight; and the balance of a pharmaceutically acceptable excipient, wherein the group The total weight of the compound was 100% by weight.

A preferred ratio of the compound of the formula (I) or (II) to a pharmaceutically acceptable carrier, a scorpion or a sustained release agent is that the formula (I) as an active ingredient accounts for more than 60% by weight of the total weight, and the remainder is 0-% by weight. 40%, the amount of the remaining portion is preferably from 1 to 20%, most preferably from 1 to 10%.

The compound of the formula (I) or (Π) or the pharmaceutical composition comprising the compound of the formula (I) or (II) may be used clinically in mammals, including humans and animals, and the route of administration may include oral, nasal inhalation. , transdermal absorption, pulmonary administration or gastrointestinal tract. A preferred route of administration is oral. It is preferably in a unit dosage form, and each dose contains the active ingredient of 0.01 mg to 200 mg, preferably 0.5 mg to 100 mg, once or in divided doses. Regardless of the method of administration, the optimal dosage for the individual should be based on the specific treatment. Usually starting with a small dose, gradually increase the dose until the most appropriate dose is found.

The pharmaceutical composition of the present invention can be administered orally and intravenously, intramuscularly or subcutaneously. From the standpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, especially tablets and solid filled or liquid filled capsules. Oral administration of the pharmaceutical composition is preferred.

The solid carrier includes: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and the liquid carrier includes: sterile water, polyethylene glycol, nonionic surfactant and edible oil (such as corn oil). , peanut oil and sesame oil, etc., as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required. Adjuvants which are usually used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, coloring agents, preservatives and antioxidants such as vitamin E, vitamin C, BHT and hydrazine.

Injectable formulations include, but are not limited to, sterile, injectable, aqueous, oily solutions, suspensions, emulsions and the like. These formulations may also be formulated with parenteral diluents, dispersing agents, wetting agents, suspending agents, and the like. Such injectable formulations can be sterilized by filtration in a filter that traps bacteria. These formulations may also be formulated with a bactericide which is dissolved or dispersed in an injectable medium or by other methods known in the art. Preparation

Abbreviation

DBU—— 1,8-diazaheterocycle [5,4,0]Η ^-ene-7

DCE - Dichloroacetamidine

DCM - Dichloromethane

DIPEA - diisopropylethylamine

DMAP—— 4-dimethylaminopyridine

DME - ethylene glycol dimethyl ether

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide DPPA ^diphenylphosphoryl azide

EA - ethyl acetate

EDCI - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Et ₂ 0 ether

EtOH - ethanol

HOBt - 1-hydroxybenzotriazole

HOBu-t - tert-butanol

i-PrOH - isopropanol

KOBu-t - potassium tert-butoxide

LDA ^diisopropylamide lithium

m-CPBA - m-chloroperoxybenzoic acid

MeOH - methanol

NaH - sodium hydride

NaHMDS - sodium bis(trimethylsilyl)amide

n-BuLi-n-butyllithium

NCS - N-chlorosuccinimide

PE - petroleum ether

s-BuLi-isobutyllithium

TFFA - trifluoroacetic anhydride

THF - tetrahydrofuran

synthetic route

The compound of the present invention can be produced by the method shown in Reaction Scheme 1, 2, 3 or 4. Unless special

Reaction route 1

When W in the compound of the formula (I) is a structure and ! ¹ is an alkenyl group, the compound of the formula (I) (i.e., compound 6) can be produced by the method shown in Reaction Scheme 1: wherein R ¹³ is C ₁ . The definition of thiol, T, X, Y, R ² is the same as above;

Compound 1 can be purchased or prepared by methods known in the literature (e.g., WO03016287, WO03042206, the entire disclosure of which is incorporated herein by reference).

Amidation of compound 1 to form compound 2; one method of this process is that compound 1 firstly forms an acid chloride and then undergoes amination, the acylating reagent is thionyl chloride or oxalyl chloride, and the ammoniating reagent is a large excess of concentrated ammonia or ammonia. Gas methanol solution; reaction solvent includes aprotic solvent such as DCM, DCE, acetonitrile, THF; reaction temperature is between -15'C and O'C; and another method is direct reaction with inorganic ammonium salt in the presence of condensing agent For the reaction, the condensing agent used includes dicyclohexylcarbodiimide (DCC), diethyl azodicarboxylate/triphenylphosphine, carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride/1-hydroxy-benzo-triazole (EDCI/HOBt), 0-(lH-benzotriazol-1-yl)-NNN', N'-tetramethyl Isourea boron tetrafluoride (TBTU) or the like; the inorganic ammonium salt such as ammonium chloride, ammonium carbonate, ammonium hydrogencarbonate or the like; the reaction is carried out in the presence of an organic base such as triethylamine, DIPEA, DBU, etc.; Including non-alcoholic solvents such as DCM, DCE, acetonitrile, THF, toluene, DMF, most commonly DCM, acetonitrile, DMF; reaction temperature between O'C and room temperature.

The compound 2 is dehydrated to form the compound 3; the dehydrating agent is preferably trifluoroacetic anhydride or phosphorus oxychloride; optionally, an organic base such as pyridine or triethylamine is added to the reaction; and the reaction solvent includes an aprotic solvent such as DCM, DCE or THF. Most preferred are DCM, THF, and the reaction temperature is between -40 ° C and room temperature.

Compound 3 is reacted with hydroxylamine hydrochloride under the action of excess alkali to prepare compound 4; the base used is an organic base or an inorganic base such as triethylamine, potassium carbonate, sodium hydroxide, etc.; the reaction is carried out in a polar solvent such as methanol or ethanol. , DMF, water, etc. or a mixed solvent thereof; the reaction temperature is from O'C to 60'C, preferably room temperature.

Under the catalysis of boron trifluoride diethyl ether, compound 4 is reacted with one equivalent of R ² CHO to form compound 5; boron trifluoride ether is used in an amount of more than 1 equivalent, usually 2 equivalents; and the reaction solvent is most usually diethyl ether or THF. The temperature is between O'C and 40 'C, preferably room temperature.

The compound 5 is reacted with R ¹³ CH ₂ CHO to obtain the compound 6 under the catalysis of boron trifluoride diethyl ether; the boron trifluoride ether is used in an amount of more than 1 equivalent, usually 2 equivalents; the reaction solvent is most usually diethyl ether or THF;

°C to 40 ° C, the best room temperature.

8 9 10

Reaction route 2 When T in the compound of the formula (I) is a 4-6 membered aliphatic ring, Χ=Ν and R ^{1 is} not an alkenyl group, the compound of the formula (I) (ie, compound 10) can be prepared by the method shown in Scheme 2. : wherein R ¹⁴ is methyl or ethyl, and Halo, T, W, Y have the same definitions as above;

8; When using the hydrochloride salt of compound 7, it is necessary to add at least one equivalent of an organic base such as triethylamine or

DIPEA; the reaction is carried out in the presence of a dehydrating agent, including a molecular sieve, toluene azeotrope, Si(OEt) _4, etc.; the reaction solvent includes methanol, ethanol, toluene, acetic acid, etc.; the reaction temperature is between O'C and 140 'C, preferably the reflux temperature of the solvent used.

Compound 8 is condensed with isocyanate to form compound 9; the isocyanate includes Me ₃ SiNCS, 0 0

^Et0 ^ ^NCS , Ph CS , etc., most preferably Me ₃ SiNCS, the amount is usually 3.5 equivalents of compound 8; the reaction is carried out without solvent or in DMF; the reaction temperature is between 100 ° C and 160 ° C, preferably 140 ' C.

Compound 9 is reacted with Y^Halo to form compound _10; more than one equivalent of an organic base or an inorganic base such as triethylamine, DBU, DIPEA, potassium carbonate, sodium carbonate or the like is added to the reaction; optionally, a catalyst such as potassium iodide or tetra is added. The reaction solvent includes acetonitrile, acetone, DME, DCM, DCE, EA, ethanol, methanol, THF, etc.; the reaction temperature is from O'C to 80 'C, preferably the reflux temperature of the solvent used.

13

Reaction route 3 When W in the above compound 10 is the structure 0 and! ^{When 2} is a hydroxymethyl group, the compound (i.e., compound 14) can be produced by the two methods shown in Scheme 3: wherein Halo, T, Y, and R ¹ have the same definitions as described above;

Compound 11 is prepared by the method described in Compound 9;

In the method 1, the compound 11 is co-heated with a large excess of aqueous formaldehyde solution to form the compound 12; the reaction is carried out in a pressure-tight container or a reflux condenser; the reaction is carried out without a solvent or in a dioxane; the reaction temperature is between 100' C to 160 ° C _; compound 12 is reacted with Y^Halo to form compound _14; reaction conditions are described with reference to the preparation of compound 10 from compound 9;

In Method 2, compound 11 is first reacted with Y^Halo to form compound ₁₃ , and the reaction conditions are described with reference to the preparation of compound 10 from compound 9; compound 13 is further formed by co-heating with a large excess of aqueous formaldehyde solution.

Reaction route 4 In some cases, the compound of the formula (I) can be converted by a functional group to form another compound of the formula (I), and some examples of such functional group conversion are shown in Reaction Scheme 4. It is to be noted that these examples are only a part, but not all, of the conversion of the functional groups in the present invention, and thus do not limit the preparation method of the compound of the present invention in any way. Further examples of functional group transformations will be given in the preparation of the specific example compounds.

The preparation method of the functional group conversion shown in Reaction Scheme 4 is as follows:

When R ² is a-hydroxy substituted indenyl, the compound of formula (I) is compound 15, wherein 1 ¹⁵ is H, an indenyl group, R ¹⁶ is an indenyl group, and the fluorenyl group is optionally NR ⁴ R ⁵ or phenyl substituted, the phenyl group is optionally substituted by a halogen atom, R ¹³ is a fluorenyl group, L is NR ⁴ , 0 or 3, Z is CH, N or 0, T, X, Y, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^s have the same definitions as above;

Compound 15 is chlorinated to give compound 16; the chlorinating reagent is 30 1 ₂ or PC1 _{3 ; the} reaction is carried out in a non-polar solvent such as DCM, DCE, CC, Et ₂ 0; the reaction temperature is between O'C and room temperature;

Compound 16 is reacted with R ^1S LH under the action of a base to obtain compound 17; the base used includes an inorganic base such as NaH, n-BuLi, KOBu-t, K ₂ CO ₃ or an organic base such as triethylamine, DIPEA, DBU or DMAP; The reaction solvent is selected from THF, CH ₃ CN, DME, DMF, EtOH, MeOH or HOBu-t depending on the base used; the reaction temperature is between -80 ° C and 80 ° C _;

Compound 15 is oxidized to compound 18; the reaction conditions are extensively described in the reference book, such as Comprehensive Org. Syn., Vol. 7, pp 251-327; in the present invention, the preferred oxidizing agent is activated manganese dioxide in an amount of at least a compound. 5 equivalents of 15; the reaction solvent is dioxane or chloroform; the temperature is between room temperature and 80'C, preferably 50-70 'C;

Compound 18 is reductively aminated with HNR ⁴ R ⁵ to form compound 19; the reaction conditions are extensively described in the reference book, such as Comprehensive Org. Trans., 2 ^nd ed., Wiley-VCH, NY, 1999, pp. 835 Preferably, the reducing agent in the present invention is a borohydride such as NaBH ₄ , NaBH ₃ CN/TXOPr-i) ₄ or NaBH(OAc) _{3 ; the} reaction solvent includes DCM, DCE, THF, EtOH, MeOH, etc.; From 0 to 80'C, preferably at room temperature;

Compound 16 is condensed with R ^S NR ⁷ R ^S to give compound 20; and when R ⁴ = R ^S and R ⁵ = R ⁷ , compound 19 is condensed with R ^s -Halo in a suitable solvent to obtain compound 20; , chloroform, tetrahydrofuran, DMF or acetonitrile; reaction temperature between -20 ° C and room temperature;

Compound 18 is condensed with H ₂ NNR ⁴ R ⁵ in a suitable solvent to form compound 21; the reaction solvent is DCM, DCE, THF, EtOH or MeOH; optionally, a water absorbing agent such as molecular sieve or anhydrous magnesium sulfate is added; 0 ° C to room temperature;

Compound 18 is reacted with R ^ls BrMg to form compound 22; the reaction solvent is dry THF, Et ₂ 0 or DME; and the reaction temperature is between -20 ° C and room temperature. Wherein the above intermediate compound 7 can be obtained by the two methods shown in Reaction Scheme 5 and Reaction Scheme 6.

Reaction route 5

When W in the intermediate compound 7 is the structure a, the compound (i.e., compound 28) can be produced by the method shown in Reaction Scheme 5; R ¹ , R ² are as defined above;

Compound 23 can be purchased or prepared by methods known in the literature. CTetrahedron Letters 2001, ¥2, 315-317); Compound 23 is condensed with hydroxylamine hydrochloride under the action of a base to form compound 24; the base used includes an organic base or an inorganic base. Such as triethylamine, potassium carbonate, sodium hydroxide, etc.; the reaction is carried out in a polar solvent, such as methanol, ethanol, DMF, water, etc. or a mixed solvent thereof; the reaction temperature is between O'C and 40'C _;

Compound 24 is chlorinated to the compound 25 by an equivalent amount of NCS; the reaction solvent includes THF, DMF, etc.; the reaction temperature is between O'C and 60 'C;

Compound 25 is dehydrochlorinated under the action of a base to form a dipolar ionic intermediate 26, and then

^R1 . ^N "^ ^R2 addition to give compound 27; the base used is an organic base such as triethylamine, DIPEA or DBU; the reaction solvent includes THF, DMF, etc.; the reaction temperature is between -40 ° C and room temperature;

Compound 27 is decomposed by hydrazine hydrate to give compound 28; the reaction is carried out in a polar solvent such as THF, methanol or ethanol; the reaction temperature is from O'C to 80'C, preferably 50-60'C _;

3S

Reaction route 6

In the case of the intermediate compound 7, where W is the structure a, the remaining compound can be produced by the method shown in the reaction scheme 6; wherein R ¹ and R ² are as defined above;

Compound 29 reacts with DPPA under the action of a base to form compound 30; the base used is an organic base such as triethylamine, DIPEA, DBU or DMAP, most preferably DBU and DMAP; and the reaction solvent includes THF, CH ₃ CN, DME, etc. a non-protic solvent, most preferably THF; the reaction temperature is between O'C and 100 'C, preferably the reflux temperature of the solvent used;

Compound 30 is subjected to hydrogenation reduction or Staudinger reaction (Gololobov, YG Sixty years of Staudinger reaction. Tetrahedron 1981, 37: 437) to obtain compound 7; the hydrogenation reduction catalyst is palladium on carbon, and the reaction is carried out in methanol, ethanol, EA or THF. The temperature is between O'C and 80 'C, preferably room temperature; the reagent used for the Staudinger reaction is an excess of Ph ₃ P, and the reaction is carried out in THF-H ₂ 0 at a temperature between 0 ° C and 50 ° C.

Wherein the above intermediate compound 29 can be produced by one of the following various methods: Compound 31 is directly reacted with a large excess of aqueous formaldehyde solution to form compound 29, and the reaction conditions are as described with reference to the preparation of compound 14 from compound 12;

Compound 31 is condensed with a formic acid derivative under the action of a strong base to form compound 32, and then reduced by NaBH ₄ to obtain compound 29; the strong base includes n-BuLi, s-BuLi, LDA, NaHMDS, etc., preferably n-BuLi _; derivative of the acid such as DMF, methyl or ethyl; and the reaction solvent is THF; reaction temperature between -80 ° C to room temperature;

Compound 33 is co-heated with a large excess of aqueous formaldehyde to directly form compound 29, and the reaction conditions are referred to Compound 12 describes the preparation of compound 14;

The compound 34 is co-heated with a large excess of aqueous formaldehyde to directly form the compound 29, and the reaction conditions are as described with reference to the preparation of the compound 14 from the compound 12;

Compound 35 is condensed with a formic acid derivative under the action of a strong base to form compound 36, and then reduced by NaBH ₄ to obtain compound 29; the strong base includes n-BuLi, s-BuLi, LDA, NaHMDS, etc., and most preferably n-BuLi _; the carboxylic acid derivatives such as DMF, ethyl or by methyl; and the reaction solvent is THF; reaction temperature between -80 ° C to room temperature.

37 38

Reaction route 7

When W in the intermediate compound 29 is structure 0 and ! ² = 11, the compound (i.e., compound 38) can also be produced by the method shown in Scheme 7; wherein R ¹ is as defined above;

0

Under the action of a base, R ¹ - NCS is condensed with '' -V and MHMH 2 to form compound _37; the base used is an inorganic base such as potassium carbonate, sodium carbonate or sodium hydroxide; the solvent is a strong polar protic solvent such as water or ethanol or The mixed solvent; the reaction temperature is the reflux temperature of the solvent used.

Oxidative desulfurization of compound 37 to produce compound 38; oxidant such as hydrogen peroxide, nitric acid / sodium nitrite or (III) valence iron salt, preferably 30% hydrogen peroxide solution; acetic acid can be added as a catalyst in the reaction; reaction solvent is water / DCM mixture or water/AcOH mixture. 2

31

TosMIC = H ₃ C— ^ ^>— SO^CHaNC Reaction Route 8

Wherein, the above intermediate compound 31 can be produced by the method shown in Reaction Scheme 8; wherein R ¹ and R ² are as defined above;

Under the action of a base, ^R is condensed with TosMIC to form compound 31; the base used includes NaH,

An inorganic base such as KOBu-t, K ₂ C0 ₃ or Cs ₂ C0 ₃ or an organic base such as pyridine, triethylamine, DIPEA or DBU, or Used directly as a base; the reaction solvent includes THF, CH ₃ CN, DME, DMF, EtOH, MeOH, HOBu-t or a mixed solvent thereof; the reaction temperature is between 0 and 80 ° C _;

0

R^NH HCl and KSCN are first co-heated to form compound 39, and then oxidative desulfurization is used to prepare compound 31; the condensation reaction is carried out in acetonitrile or HOBu-t, and acetic acid or propionic acid is added, and the reaction temperature is between 50 and 100'. C; Oxidative Desulfurization Reaction Conditions The description of Compound 38 prepared from Compound 37 is referred to.

R ²

Reaction route 9

Wherein the above intermediate compound 33 can be produced by the method shown in Reaction Scheme 9; wherein R ¹ ,

The definition of R ^{2 is} the same as above;

0

^{R2 NHNHa} , and N,N-dimethylformylaminodiacetal co-heat condensation directly to form compound 33; the reaction is carried out in a CH ₃ CN / AcOH mixture; the reaction temperature is between 60 and 120 ° C _; or

NCS is first condensed under the action of a base to form compound 40, followed by oxidative desulfurization to give compound 33; condensation reaction conditions are described with reference to the preparation of compound 37; oxidative desulfurization reaction conditions are described with reference to the preparation of compound 38 from compound 37.

43

Reaction route 10

Wherein, when R in the above intermediate compound 31 or compound 33 ^:

When, the The compound (i.e., compound 44) can be prepared by the two methods shown in Scheme 10: wherein R ¹⁷ is a chemical bond or a linear or branched fluorenylene group of _Cl _ ₄ , and U represents 11 or ^, R ¹ , R ² , R ⁴ , R ⁵ have the same definitions as above;

In Method A, Compound 41 is first oxidized to Compound 42 and the oxidizing conditions are preferably active manganese dioxide or Swern oxidation (AJ Mancuso, SL. Huang, D. Swern. J. Org. Chem., 1978, 43, 2480); The use of manganese dioxide is described with reference to the preparation of compound 18 from compound 15; the preferred reagent for Swern oxidation in the present invention is oxalyl chloride/DMSO/NEt ₃ combination; compound 42 and HNR ⁴ R ⁵ are reacted by reductive amination to give compound 44, reaction Conditions are described with reference to the preparation of compound 19 from compound 18.

In the method B, the compound 41 is first chlorinated to the compound 43, and the reaction conditions are as described with reference to the preparation of the compound 16 from the compound 15; the compound 43 is condensed with HNR ⁴ R ⁵ under the action of a base to give a compound 44, the base used is triethylamine, DIPEA, DBU or potassium carbonate may be added with KI as a catalyst, a reaction solvent such as acetonitrile, DCM, DCE, THF or acetone, and the reaction temperature is from room temperature to 90 ° C, preferably the reflux temperature of the solvent used.

The intermediate compounds in the present invention are prepared in addition to the procedures shown in Scheme 5 to Scheme 10, and other novel intermediates or starting materials can be synthesized by methods analogous to the literature, and will be described in detail in the preparation of the compounds of the examples. . Known intermediates or starting materials can be purchased or synthesized by methods known in the literature. Specific embodiment

The invention will be further illustrated by the following examples. It is to be understood that the examples are only illustrative of the invention and are not intended to limit the invention in any way. All parameters and remaining descriptions in the examples are based on quality unless otherwise stated. The filler used for column chromatography separation is silica gel unless otherwise stated. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the present invention. The preferred embodiments and materials described herein are for illustrative purposes only. Preparation example

The numbering of the synthetic intermediates in the present invention begins with the English letters "M, A, B, C, D, E", such as the intermediates "ΜΓ", "Α8"; and the final embodiment number begins with the word "example". Such as "Example 18".

Ml——(p-trifluoromethylbiphenyl-4

4-trifluoromethylbenzeneboronic acid (3.80 g, 1 equivalent), p-bromobenzaldehyde (3.7 g, 1 equivalent), palladium acetate (0.225 g, 0.05 equivalent) and a 2 mol/L Na ₂ CO ₃ solution (20 ml, 2 equivalents) in 40 ml of DME were purged with nitrogen and refluxed for 3 h. The reaction was completed by TLC. The insoluble material was removed by hot filtration, washed with EA, transferred to a sep. funnel, and the organic phase was separated. The aqueous phase was extracted twice with EA. The organic phase was combined, washed twice with brine and dried over magnesium sulfate. The precipitate is separated or recrystallized from diethyl ether-petroleum ether.

M2——4-trifluoromethanesulfonyloxybenzene

Trifluoromethanesulfonic anhydride (4.3 ml, 26 mmol, 1.3 eq.) was dissolved in 100 ml of dichloromethane, protected with nitrogen and placed in a -40 ° C low temperature reactor. Pyridine (2.5 ml, 30 mmol, 1.5 eq.) was added dropwise with a syringe. A precipitate appeared and stirred vigorously. Methyl p-hydroxyphenylacetate (3.32 g, 20 mmol, 1 equivalent) was dissolved in 40 ml of dichloromethane and added to the reaction flask using a syringe, and the addition was completed in 5 min. Stop the cooling, stir 30min, was quenched with saturated ammonium chloride, the organic phase was separated, successively with dilute hydrochloric acid, brine, NaHC0 ₃ saturated solution, washed with brine, dried over magnesium sulfate, and the solvent was distilled off to give 3.15g of oil, placed It turns into crystallization. ^{_{! H-NMR (CDC1 3,}} 300MHz) δ 3.65 (s, 2Η), 3.71 (s, 3H), 7.24 (d, 2H, J = 8.7), 7.37 (d, 2H, J = 9.0).

M3——2-(p-trifluoromethyl-4-yl)acetic acid methyl ester

Prepared by the method of Ml, except that M2 is substituted for "p-bromobenzaldehyde". ^{_{! H-NMR (CDC1 3,}} 300MHz) δ 3.69 (s, 2Η), 3.72 (s, 3H), 7.39 (d, 2H, J = 8.1), 7.56 (m, 2H, J = 7.8), 7.68 (m , 4H)

Benz-4-yl)formaldehyde

Prepared by the method of Ml, except that "phenyl boronic acid" was substituted for "4-trifluoromethylphenylboronic acid". ^-NMR (CDC1 ₃ , 400MHz) δ 7.42 (m, 1Η), 7.49 (m, 2Η), 7.64 (m, 2H), 7.76 (d, 2H, J=8.4), 7.96 (d, 2H, J= 8.4), 10.06 (s, 1H).

M5——(p-methylbiphenyl-4-yl)

Prepared by the method of Ml, except that "p-methylphenylboronic acid" was substituted for "4-trifluoromethylphenylboronic acid". ^{_{! H-NMR (CDC1 3,}} 400MHz) δ 2.42 (s, 3Η), 7.29 (d, 2H, J = 8.0), 7.54 (d, 2H, ^ 8.4): 7.79 (d, 2H, J = 8.0), 7.94 (d, 2H, J=8.0), 10.04 (s, 1H). M6 ^ (p-chlorobiphenyl-4-yl)carboxaldehyde

Prepared by the method of Ml, except that p-chlorophenylboronic acid was substituted for 4-trifluoromethylbenzeneboronic acid.

H-NMR (CDC1 ₃ , 300MHz) δ 7.46 (d, 2Η, J=8.4), 7.58 (d, 2H, J=8.4), 7.73 (d, 2H _: J=8.1), 7.94 (d, 2H, J=8.1), 10.07 (s, 1H).

Mil - (p-trifluoromethylbiphenyl-4-yl)methyl bromide

2.5 g of intermediate M1 (1 eq.) in 20 ml of absolute ethanol, 190 mg of sodium borohydride was added portionwise in an ice bath, and then reacted at room temperature for 1 h to stop. Ethanol was distilled off under reduced pressure, and the residue was diluted with water, and concentrated hydrochloric acid was added dropwise to the ice bath with stirring until no more bubbles appeared, and then quenched with sodium bicarbonate solution. Dichloromethane was extracted three times, and the combined organic phases were washed twice with brine, dried over anhydrous magnesium sulfate and evaporated H-NMR (CDC1 ₃ , 300ΜΗζ) δ 4.77(s, 2Η), 7.48 (d, 2H, J=8.4), 7.61 (d, 2H, J=8.1), 7.70 (s, 4H).

2.02 g of intermediate M10 (1 eq.) in 20 ml of anhydrous diethyl ether, placed in an ice bath, and a CaCl ₂ drying tube was used to isolate water vapor. Phosphorus tribromide (0.38 ml, 0.5 eq.) was added, and the mixture was reacted at room temperature for 1.5 h to obtain a clear liquid. The reaction was completed by TLC. It was quenched with saturated sodium bicarbonate solution, and insoluble matter was formed and removed by filtration. The filtrate was extracted twice with 40 ml of dichloromethane, dried over magnesium sulfate and evaporated to dryness.

Ml 5 - (E)-3-(l-methyl-IH-pyrazol-4-yl)acrylic acid

4.1 g of methylpyrrolidine (50 mmol, 1 equivalent) and 11.6 ml (3 equivalents) of dry DMF were placed in a 100 ml two-necked flask equipped with a spherical condenser (with a CaCl ₂ drying tube) and a constant pressure dropping funnel. Warm 90'C oil bath. About 5.6 ml (1.2 equivalents) of phosphorus oxychloride was added dropwise over 1 hour, and the mixture was stirred for 2 hours, stopped, and cooled. Pour the reaction solution into a large amount of ice water, adjust the pH to 4~5 with 10% NaOH aqueous solution, then extract several times with dichloromethane to the aqueous phase. The organic phase is combined, and then a small amount of brine is added. It was washed twice, dried over anhydrous magnesium sulfate, and evaporated to dryness to give the crude product of 1-methyl-1H-pyrazole-4-carbaldehyde, which was used in the next step without isolation.

The product obtained above and malonic acid (4.68 g, 45 mmol), pyridine (4 ml, 50 mmol), piperidine (0.09 ml, 1 mmol) were placed in a 250 ml flask, reacted at 110 ° C for 6 h under nitrogen, quenched and cooled. 100 ml of water was added thereto, and concentrated aqueous ammonia was added dropwise to the ice bath to dissolve the solid. The pH was adjusted to about 1 with concentrated hydrochloric acid, and the precipitate was collected by filtration, washed several times, and dried to yield 2.9 g. ^-NMR (d ₆ -DMSO, 300 MHz) 53.83 (s, 3H), 6.17 (d, 1H, J = 16.2), 7.45 (d, 1H, J = 15.9), 7.83 (s, 1H), 8.07 ( s, 1H), 12.07 (s, 1H).

Ml 6 - (E)-3-(l-methyl-IH-pyrazol-4-yl)acrylate

Intermediate M15 (2.9 g, 19. lmmol) was suspended in 30 ml of methanol, and 1.9 ml of concentrated sulfuric acid was added dropwise with stirring. There is an exotherm, then reflux for 2.5h, stop. Most of the solvent was evaporated under reduced pressure, and ice water was added to the residue, which was then adjusted to neutral with a 10% aqueous NaOH solution, and the mixture was extracted three times, dried over magnesium sulfate and evaporated to dryness. H-NMR (CDC1 ₃ , 300 MHz) 53.75 (s, 3H), 3.89 (s, 3H), 6.14 (d, 1H, J=15.9), 7.53 (s, 1H), 7.54 (d, 1H, J =16.2), 7.67 (s, 1H).

Ml 7 ~~ 3-(l-national methyl-1H-pyrazole-4-

Intermediate M16 (3.08 g, 18.55 mmol) was added to 300 ml of 10% palladium on carbon hydrogenation catalyst in 20 ml of anhydrous methanol. The hydrogenation reaction was carried out at 50 ° C for 3.5 h at atmospheric pressure. The TLC was monitored. The palladium on carbon catalyst was removed by filtration, and the filtrate was evaporated to dryness. iH-NMR (CDC1 ₃ , 300 MHz) 52.54 (t, 2H, J=7.2), 2.77 (t, 2H, J=7.2), 3.65 (s, 3H), 3.83 (s, 3H), 7.16 (s, 1H), 7.30 (s, 1 H).

M18 ~~ 3-hydroxy-2-(l-methyl-1H-acid methyl ester

Intermediate M17 (2.53 g, 15.06 mmol, 1 eq.) was dissolved in 20 mL of dry DME eluted with EtOAc EtOAc (EtOAc: EtOAc Then, 2.74 ml (3 equivalents) of formic acid formate was added and stirred at room temperature for 15 h. After adding 100 ml of anhydrous diethyl ether and stirring for 15 min, the precipitate was collected by filtration and washed with diethyl ether. The filter cake is poured into a saturated solution of ammonium chloride, and concentrated hydrochloric acid is added dropwise to an ice bath to pH=4~5, extracted three times with dichloromethane, the organic phase is combined, washed twice with brine, dried over magnesium sulfate, evaporated to dryness 0.51 g of a solid was obtained which was used directly for the next reaction.

M19 ^ N-(l-methoxy-2-methyl--1-carboxylic acid tert-butyl ester

3.72 g (2 equivalents) of piperazine-1-carboxylic acid tert-butyl ester, 2.58 ml (2 equivalents) of 2-methyl-2-bromo-substituted methyl propionate, 5.52 g (4 equivalents) of anhydrous potassium carbonate and 166 mg ( 0.1 equivalent of potassium iodide was refluxed in 40 ml of acetonitrile for 8 h, and then 1.29 ml (1 eq.) of 2-methyl-2-bromo-substituted methyl propionate was refluxed for 12 h to stop the reaction. After cooling, the inorganic substance was removed by filtration, and the filtrate was separated by silica gel column chromatography, eluting with PE/EA = 2:1 to obtain 2.82 g of oil. ¹ H-NMR (CDC1 ₃ , 400 MHz) 51.31 (s, 6H), 1.44 (s, 9H), 2.52 (vbrs, 4H), 3.42 (vbrs, 4H), 3.69 (s, 3H).

M20 ~~ 2-methyl-2-(ylazine-1-yl)

Intermediate M19 (2.82 g, 1 eq.) was taken in EtOAc EtOAc EtOAc. A portion of methanol was evaporated under reduced pressure, and a white solid was precipitated, and then 20 ml of diethyl ether was added. After stirring for a few minutes, the precipitate was collected by filtration and dried to give 2.33 g. ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 51.49 (s, 6H), 3.33 (vbrs, 8H), 3.73 (s, 3H), 9.52 (s, 1H).

Al——5,6-trimethylene-2-thiouracil

Reference [J. Amer. Chem. Soc, 81, 3108 (1959).]

A2—— 2-(4-fluorobenzylthio)-5,6-trimethylene-1H-pyrimidin-4-one

Intermediate Al (4.06 g, 1 eq.), p-fluorobenzyl bromide (3.2 ml, 1.05 eq.), anhydrous K ₂ C0 ₃ (5 g, 1.5 eq.), potassium iodide (0.4 g, 0.1 eq.). The reaction is completed. Most of the solvent was distilled off under reduced pressure, and the residue was poured into water, neutralized with concentrated hydrochloric acid, and collected by filtration, washed with water several times, and drained as much as possible. The solid was transferred to a flask, and refluxed with 30 ml of methanol for half an hour. After cooling, the solid was collected by filtration and dried to give 4.62 g.

A3——12-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl acetate

Intermediate A2 (2.67 g, 10 mmol), 2-bromoacetic acid methyl ester (1 ml, 1 1 mmol), DIPEA (1.82 ml, l lmmol) It was poured into a saturated solution of NH ₄ C1, extracted twice with EA, washed twice with water, dried over MgSO ₄ and separated by column chromatography eluting with DCM / MeOH = 30:1. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 52.10 (m, 2H), 2.81 (m, 4H), 2.98 (t 2H, J=7.5), 3.78 (s, 3H), 4.49 (s, 2H), 4.57 (s, 2H), 6.97 (t, 2H, J=8.4), 7.35 (dd, 2H, J=7.8, 6.0 ).

A4 ~ I2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]acetic acid

Intermediate A3 (6.9 g, 1 eq.) was dissolved in EtOAc (2 g, EtOAc) Place in an ice bath, add concentrated hydrochloric acid to a pH of less than 3, collect the precipitate by filtration, wash it several times with water, and drain the water as much as possible. The solid was transferred to a 100 ml flask, refluxed with 30 ml of acetone for 0.5 h, stopped, and placed in a refrigerator for several hours to be completely crystallized, collected by filtration, washed with acetone and dried to give a white solid. ^-NMR (d ₆ -DMSO, 300 MHz) 51.96 (m, 2 Η), 2.58 (t, 2 Η, J = 7.2), 2.82 (t, 2H, J = 7.5), 4.42 (s, 2H), 4.69 ( s, 2H), 7.13 (t, 2H, J=9.0), 7.47 (dd, 2H, J=8.9, 5.6), 13.5 (vbrs, 1H)- MS (ESI): 333 (MH) . A5 ^ I2- (4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]acetamide

Intermediate A4 (2.0 g, 1 eq.) was suspended in 151 ^ _{2 2} , the drying tube was sealed to moisture, placed in an ice bath, and 0.47 ml (1.1 eq.) of thionyl chloride and two drops of DMF were added as a catalyst. A brown clear liquid was obtained. It was dropped into a flask containing 20 ml of concentrated aqueous ammonia in an ice bath while vigorously stirring, and dripping was completed for 10 minutes. The precipitated solid was collected by filtration, washed with water several times and then washed with EtOAc (EtOAc)EtOAc. MS (ESI): 334 (M+H).

A6 ^ I2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidine-1-yl]acetonitrile

The intermediate A5 (10 mmol) was suspended in 20 ml of dry THF, and then evaporated, evaporated, and evaporated. Reaction was continued to room temperature, quenched with saturated aqueous NaHC0 _3. The EA was extracted twice, and the organic phase was combined, washed twice with brine, dried and purified by column chromatography. ^-NMR (CDC1 ₃ , 300 MHz) 52.16 (m, 2H), 2.82 (t, 2H, ^7.2), 2.98 (t, 2H, J=7.5), 4.53 (s, 2H), 4.76 (s, 2H ), 5.67 (t, 1H, J = 4.8), 7.00 (t, 2H, J = 8.7), 7.39 (dd, 2H, J = 8.3, 5.3); MS (ESI): 316 (M+H).

A7 ^ I2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]acetamide

The intermediate A6 (10 mmol) was added to 20 ml of absolute ethanol, and then hydroxylamine hydrochloride (Bmmol) and K ₂ CO ₃ (15 mmol) were reacted at room temperature for 12 h, and the reaction was monitored by TLC. Most of the ethanol was distilled off under reduced pressure, and the residue was added 10 ml of water and 10 ml of EA, and the mixture was stirred for 1 hour, and the precipitate was collected by filtration, washed with water, washed with EA, and dried to give the desired product. H-NMR (d ₆ -DMSO, 300 MHz) 51.96 (m, 2 Η), 2.59 (t, 2H, J = 7.3), 2.90 (t, 2H, J = 7.3), 4.43 (s, 2H), 4.55 (s, 2H), 5.72 (s, 2H), 7.17 (t, 2H, J=8.8), 7.49 (dd, 2H, J=8.8, 5.6), 9.44 (s, 1H); MS (ESI): 349 (M+H).

Example 1 - 1-(5-n-heptyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-di Hydrogen-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Intermediate A7 (1 mmol), octanal (1.1 mmol) in 5 mL of dry THF.

4S A solution of boron trifluoride diethyl ether (2 mmol) was added, and the mixture was reacted at room temperature, and the reaction was monitored by TLC. After completion of the reaction, it was poured into a saturated solution of NaHC0 ₃ and extracted with EA, dried over anhydrous magnesium H-NMR (CDC1 ₃ , 300 MHz) δθ.84 (t, 3Η, J=6.9), 1.22-1.32 (m, 10H), 1.70 (m, 2H), 2.13 (m, 2H), 2.69 (t , 2H, J=7.5), 3.00 (m, 2H), 4.52 (s, 2H), 4.76 (2x d, 2H, J=16.5), 5.67 (t, 1H, X8), 6.93 (t, 2H, J = 9.0), 7.10 (s, 1H), 7.48 (dd, 2H, J = 8.7, 5.1); MS (ESI): 459 (M+H).

Example 2 - 1-(5-n-decyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-di Hydrogen-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared according to the method of Example 1. In addition to "positive H ^ - aldehyde" instead of "octanal" as raw material. ^-NMR (CD ₃ OD, 400 MHz) 50.89 (t, 3 Η, J=6.6), 1.27 (m, 16H), 1.60 (m, 2H), 2.12 (m, 2H), 2.75 (t, 2H, J =7.2), 3.00 (t, 2H, J=7.6), 4.52 (s, 2H), 4.86 (s, 2H), 5.56 (t, 1H, 4.8),

A13 A14

5-(p-fluorobenzylthio)(phenylamino)methylene-2,2-dimethyl-1,3-dioxane-4,6-dione The isopropylidene malonate (1.5 g, 1 eq.) was dissolved in 10 ml of DMF, and triethylamine (2.7 ml, 2 eq. Further, phenyl isocyanate (1.2 ml, 1 eq.) was added, and the mixture was reacted at 40 to 45 ° C for 5 h. Then, bromo bromide (1.25 ml, 1 eq.) was added dropwise in an ice bath and stirred at room temperature overnight. The reaction solution was poured into water, extracted with EA three times, and the organic phase was combined, washed several times with brine, dried, and concentrated to give a large solid, which was collected by filtration and dried to yield 2.2 g. ^-NMR (d ₆ -DMSO, 300 MHz) 51.63 (s, 6H), 4.09 (s, 2H), 7.14 (t, 2H, J = 8.7), 7.29 (dd, 2H, J = 8.9, 5.6), 7.44 (m, 5H) _: 12.13 (s, 1H)- MS (ESI): 388 (M+H).

A9 ~~ 2-[N-(2,2-Dimethyl-4,6-dioxo-1,3-dioxane-5-methylene) (p-fluorobenzylthio)methylaniline Methyl acetate

Intermediate A8 (13.55 g, 1 eq.) was dissolved in 40 mL dry EtOAc EtOAc. Methyl 2-bromoacetate (6.7 ml, 2 eq.) was added, and the mixture was reacted at room temperature for 2 h and then reacted at 60 C overnight. The reaction was monitored by TLC. Into a saturated solution of NH ₄ C1, extracted three times with 200 ml of EA, the organic phase was combined and washed five times with brine, dried with MgSO ₄ , separated by column chromatography, eluted with PE/EA = 2:1 to obtain a gel. g. ^-NMR (CDC1 ₃ , 400 MHz) 51.56 (s, 6H), 3.72 (s, 3H), 4.31 (s, 2H), 4.82 (s, 2H), 6.98 (t, 2H, J=8.6), 7.21 (m, 2H), 7.39 (m _: 5H).

Intermediate _A10 _ I2-(4-fluorobenzylthio)-4-oxoquinoxaline-1(H)-yl]methyl acetate

Intermediate A9 (8.2 g, 17.86 mmol) was stirred in 15 mL EtOAc EtOAc. The excess of trifluoroacetic anhydride was distilled off under reduced pressure, and then 20 ml of saturated sodium hydrogencarbonate solution was added to the residue, and extracted three times with 301 ^ 11 ₂ 1 ₂ , and the organic phases were combined, dried over magnesium sulfate and separated by column chromatography. PE/EA = 1:3 eluted 5.5 g. ^-NMR (CDC1 ₃ , 400 MHz) 53.79 (s, 3H), 4.23 (s, 2H), 5.09 (s, 2H), 6.44 (s, 1H), 7.02 (t, 2H, J=8.6), 7.18 (d, 1H, J=8.7), 7.33 (dd, 2H, J=8.8, 5.2), 7.39 (t, 1H, J=7.4), 7.63 (ddd, 1H, J=8.8, 7.2, 1.6), 8.41 (dd, 1H, 8.2, 1.4).

Intermediate _A11 -p-(4-fluorobenzylthio)-4-oxoquinoxaline_1(4H)-yl]acetic acid

The intermediate A10 was used as a raw material and prepared according to the method of A4. ^-NMR (d ₆ -DMSO, 300 MHz)

54.45 (s, 2H), 5.18 (s, 2H), 6.25 (s, 1H), 7.19 (t, 2H, J=8.7), 7.37 (t, 1H, J=7.2), 7.50 (dd, 2H, J =8.7, 5.4), 7.60 (d, 1H, J=8.7), 7.69 (ddd, 1H, J=8.7, 7.2, 1.7), 8.13 (dd, 1H, J=8.0, 1.8).

Intermediate _A12- [2-(4-fluorobenzylthio)-4-oxoquinoxaline-1(4H)-yl]acetamide

The intermediate All (1.37 g, 1 eq.) was suspended in 6 mL of dry DMF, and then evaporated. Was added EDCI (1.15g, 1.5 equiv.) And HOBt (0.81g, 1.5 eq.), The reaction 0.5h to give a yellow clear liquid was added DIPEA (2.64ml, 4 equiv) and NH ₄ Cl (0.43g, 2 eq.), Room temperature The reaction was overnight. 20 ml of water and EA were added to the reaction mixture, and the mixture was stirred for 1 hour, and the solid was collected by filtration, washed with water and EA, and then evaporated. The mother liquor was separated from the aqueous layer and acidified with concentrated hydrochloric acid to recover the material All H-NMR (d ₆ -DMSO, 300 MHz) 54.42 (s, 2H), 5.04 (s, 2H), 6.23 (s, 1H), 7.19 (t, 2H, J=8.9), 7.36 (t, 1H, J=7.4), 7.49 (m, 4H), 7.68 (t, 1H, J=7.4), 7.79 (s, 2H), 8.13 (d, 1H, J=7.8); MS (ESI) fo dish d (M+H) = 343.

Intermediate _A13 -p-(4-fluorobenzylthio)-4-oxoquinoxaline-1(H)-yl]acetonitrile

The intermediate A12 was used as a raw material and prepared according to the method of A6. ^-NMR (CDC1 ₃ , 300 MHz) 54.27 (s, 2H), 5.22 (s, 2H), 6.43 (s, 1H), 7.03 (t, 2H, J=8.6), 7.33 (dd, 2H, J= 8.7, 5.1), 7.41 (d, 1H, J=8.7), 7.45 (dd, 1H, J=7.5, 7.5), 7.75 (ddd, 1H, J=8.7, 7.2, 1.5), 8.41 (dd _: 1H, J=8.0, 1.7).

Intermediate _{A14_2-} (4-Fluorobenzylthio)-4-oxoquinoxaline-1(4H)-yl]acetamidoxime

The intermediate A13 was used as a raw material, and it was prepared by the method of A7. ^-NMR (d ₆ -DMSO, 300 MHz) 54.42 (s, 2H), 5.04 (s, 2H), 5.68 (s, 2H), 6.21 (s, 1H), 7.19 (t, 2H, J=8.7) , 7.33 (t, 1H, J=7.4), 7.47-7.55 (m, 3H), 7.68 (m, IH), 8.09 (dd, 1H, J=7.8, 1.5).

Example 3 - 1-(5-n-heptyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-(4-fluorobenzylthio)-4 ( 1^)-quinoline

The intermediate A14 and octanal were used as raw materials, and the preparation was carried out in the same manner as in Example 1. ^-NMR (CDC1 ₃ , 400 MHz) 50.83 (t, 3Η, J=7.0), 1.18-1.30 (m, 10H), 1.70 (m, 2H), 4.08 (s, 2H), 5.21 (s, 2H) , 5.59 (t, 1H, J=5.2), 5.71 (s, 1H), 6.04 (s, 1 H), 7.03 (t, 2H, J=8.6), 7.33 (m, 3H), 7.67 (m, 2H) ), 8.25 (d, 1H, J=7.6).

Example 4——1-(5-n-butyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-di Hydrogen-1H-cyclopenta[pyrimidine-4(5H)-

Prepared according to the method of Example 1, except that "n-valeric acid" was used instead of "octanoic acid". ^-NMI^CDC 400 MHz) δ 0.85 (t, 3H, J=7.2), -1.30 (m, 4H), 1.68 (m, 2H), 2.13 (m, 2H), 2.70 (t _: 2H, J= 7.2), 3.00 (t, 2H), 4.45 (s, 2H), 4.75 (2x d, 2H, J=16.4), 5.66 (t, 1H, J=4.8): 6.94 (t, 2H, J=8.4), 7.29 (dd, 2H, J=8.4, 4.8).

Example 5 - 1-(5-n-decyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl-2-(4-fluorobenzylthio)-4 ( 1^)-quinoxalinone

Prepared by the method of Example 1 using Intermediate A14 and n-H^-aldehyde as starting materials. ^-NMR (CDC1 ₃ , 400 MHz) δθ.86 (t, 3Η), 1.20 (m, 16Η), 1.71 (m, 2Η), 4.11 (s, 2H), 5.21 (s, 2H), 5.58 (t , (1,1H) Preparation of the method of Example 1:

Example 8——(E)-l-[5-n-heptyl-4-(l-n-octene)-4,5-dihydro-1,2,4-oxadiazol-3-yl]methyl -2-p-fluorobenzylthio-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The compound of Example 1 (1 eq.) and octanal (2 eq.) were placed in dry THF. Under a nitrogen atmosphere, a solution of boron trifluoride diethyl ether (3 eq.) was added, and the reaction was carried out at room temperature for 2 h, about half of the starting material was converted, and the reaction time was not increased. There is a clear conversion. Into saturated NaHC0 ₃ solution, extracted with EA, dried over anhydrous magnesium sulfate, and separated by column chromatography to give the desired product. ^-NMR (d ₆ -DMSO, 400 MHz) δ θ.84 (m, 6 Η), 1.19-1.32 (m, 18H), 1.68 (m, 2H), 1.96 (m, 4H), 2.57 (t, 2H, J=7.2), 2.88 (M, 2H), 4.42 (2x d, 2H, J=13.4), 4.75 (dt, 1H, J=13.6, 6.8), 5.07 (s, 2H), 5.87 (m, 1H) , 7.13 (t, 2H, 8.8), 7.47 (dd, 2H, J=8.4, 5.6); MS (ESI): 569 (M+H).

Bl—— 2-(2,2-dimethoxyethyl)-isoindole-1,3-dione

Reference [ wr. J. Org. Chem., 2008, 895-913.]

B2—— 2-(l,3-dioxoisoindol-2-yl)acetaldehyde

The intermediate Bl (4.18 g) was suspended in 20 ml of water, and 4 ml of concentrated hydrochloric acid was added and refluxed for 1 hour, and the reaction was completed by TLC. It was extracted three times with dichloromethane, and the organic phase was combined, washed twice with brine, once with NaHC0 ₃ saturated solution, and dried with MgSO ₄ and deactivated with activated carbon. Separation by column chromatography eluted with PE/EA = 2:1. H-NMR (CDC1 ₃ , 300 MHz) 54.55 (s, 2H), 7.75 (m, 2H), 7.88 (m, 2H), 9.65 (s, 1H)

B3—— 2-(l,3-dioxoisoindol-2-yl)acetaldehyde oxime Intermediate B2 (1.46g, 1 eq.), Hydroxylamine hydrochloride (0.64g, 1.2 eq), anhydrous K ₂ C0 ₃ (1.6g, 1.5 equiv.) In 10ml of anhydrous methanol was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was diluted with water, CH _₂ C1 ₂ and extracted three times, the combined organic phases were washed with salt until colorless, dried, and the solvent was distilled off to give a white solid 0.75g. ^{_{! H-NMR (d 6 -DMSO}} , 400 MHz, ca 1: 1 cis and trans isomers) 54.30 / 4.37 (2x d, 2H, J = 4.0), 6.81 / 7.35 (2x t, 1H, X0), 7.81 -7.88 (m, 4H), 10.86/11.34 (2x s, 1H); MS (EI) m/z: 204 (M.

4 ~~ 2-(l,3-dioxoisoindol-2-yl)-N-hydroxyiminoacetyl chloride

Intermediate B3 (0.43 g, 1 eq.) and NCS (0.28 g, 1 eq.) were taken in 5 ml of DMF and heated at 60 ° C for 2 h. After cooling, the reaction solution was diluted with 20 ml of EA, washed with brine and washed three times with DMF, then dried and evaporated to give a white powder. ^-NMR (d _s -DMSO, 300 MHz) δ 4.60 (s, 2H), 7.89-7.97 (m, 4H), 12.02 (s, 1 H)

Intermediate B5——2-[4-(2-Diethylaminoethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4- two! ¾_ ₃ _] methyl isobutyl group D |? _1 noise, ₃ _ dione

Intermediate Ml (10 mmol), 2-diethylaminoethylamine (10 mmol) in 10 ml of dichloromethane, 3 g of 4A molecular sieves, CaCl ₂ drying tube to prevent water vapor reflux for 2 h to obtain a solution of the intermediate imine, stop heating , cooled for standby.

Intermediate B4 (10 mmol) was taken in 15 mL dry THF EtOAc. Triethylamine (Bmmol) was added dropwise to precipitate a white precipitate, which was stirred vigorously, and then the mixture was stirred for 5 minutes, and the reaction was further continued for 15 minutes. Then, the above imine solution of methylene chloride was quickly added, and then reacted at room temperature for 2 h to stop. The reaction solution was poured into a saturated aqueous solution of NH ₄ C1, and then extracted twice with CH ₂ C1 ₂ , and the organic phase was combined, washed twice with brine, dried and purified by column chromatography. ^{_{! H-NMR (CDC1 3,}} 400 MHz) δΐ .02 (t, 6H, J = 7.2), 2.44-2.53 (m, 6H), 3.14 (m, 1H), 3.25 (m, 1H), 4.75 (2x d, 2H, J=16.0) _: 6.38 (s, 1H), 7.63 (2x d, 4H, J=8.4), 7.71 (s, 4H), 7.77 (m, 2H), 7.93 (m, 2H)- MS (ESI): 551 (M+H).

Intermediate B6——2-μ-(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazole -3-yl]methyliso B?|哚-1,3-dione

Prepared by the method of B5 except that "2-diethylaminoethylamine" was replaced by "2-morpholineethylamine". H-NMR (CDC1 ₃ , 300MHz) δ 2.40 (m, 6Η), 3.18 (dt, 1H, J=15.0, 6.0), 3.29 (dt, 1H _: J=15.0, 6.3), 3.68 (t, 4H, J-4.7), 4.72 (2x d, 2H, J=15.9), 6.35 (s, 1H), 7.56 (d, 2H, J=8.4), 7.62 (d, 2H, J=8.4), 7.68 (m, 4H), 7.75 (m, 2H), 7.90 (m, 2H).

Intermediate BIO——2-[4-(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4- um Azole-3-yl]methylamine cyclopent-1-enecarboxylate

Intermediate B6 2.57 g (1 equivalent) in 15 ml of THF, 0.78 ml equivalent of 85% hydrazine hydrate was added, and reacted at 50 ° C for 5 h, and the reaction was completed by TLC. After cooling, the white insoluble material was filtered off, the filtrate was evaporated to dryness under reduced pressure, and then toluene was taken to remove a trace amount of water, and twice, to obtain an intermediate B9 1.82 g of oil.

Under nitrogen, the intermediate B9 1.82g (l eq.), Cyclopentanone-2-carboxylate 0.65ml (1.05 _{eq.), Si (OEt) 4 1.86ml} (2 equivalents) in absolute ethanol was refluxed for 4h, The reaction is completed. Move directly into the right amount of silica gel,

5S After spin-drying, silica gel column chromatography gave 1.37 g of mp.H-NMR CCDCl </ </ RTI></RTI></RTI></RTI> δ 1.26 (t, 3H, J = 7.2), 1.87 (m, 2H), 2.34 (m, 6H), 2.54 ( t, 2H, J= 7.2), 2.72 (t, 2H, J= 7.2), 3.20 (m, 2H), 3.63 (t, 4H, J= 4.5), 4.13 (q, 2H, J= 7.2), 4.18 (d, 2H, J= 6.6), 6.37 (s, 1H), 7.54 (d, 2H, J= 8.4), 7.63 (d, 2H, J= 8.4), 7.70 (m, 5H).

Intermediate Bll——1_[4-(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazole -3-yl]methyl-5,6-trimethylene-2-thiouracil

Under the protection of nitrogen, intermediate BIO 1.36 g (1 equivalent), trimethylsilyl isocyanate 1.33 ml (4 equivalents), dried DMF 2 ml was heated at 140 ° C for 4 h, and the reaction was completed by TLC. The flask was placed in an ice bath, diluted with saturated sodium bicarbonate solution, and then added with 20 ml of EA - stirring for 0.5 h, then transferred to a separating funnel, the organic layer was separated, washed twice with brine, and dried with MgS04 The activated carbon was decolorized, and the solution was concentrated and mixed with at least silica gel, and separated by column chromatography. The desired product fraction was collected and recrystallized from PE-EA to give a white solid. ^-NMR (d ₆ -DMSO, 400 ΜΗζ) δ 2.05 (m, 2 Η), 2.32 (m, 6H), 2.62 (t, 2H, J = 7.6), 3.04 (m, 3H), 3.35 (m, 1H) , 3.56 (m, 4H), 5.38 (s, 2H), 6.44 (s, 1 H), 7.64 (d, 2H, J= 8.4), 7.83 (d, 2H, J= 8.4), 7.93 (d, 2H , J= 8.4), 12.65 (s, IH); MS (ESI): 586 (M+H).

Example 19 - 1_μ_(2-morpholineethyl)-5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-oxadiazol-3-yl Lmethyl-2-(2,3-difluorobenzylthio)-6,7-dihydro-lH-cyclopentyl 〖d]pyrimidin-4(5H)-one

30 mg of intermediate B10 (1 equivalent), 2,3-difluorobenzyl bromide 7.2 μl (1.1 eq.), anhydrous potassium carbonate (1 mM) (1.5 eq.). The inorganic salt was filtered off, and the filtrate was purified eluting with CH ₂ Cl ₂ /MeOH = 15:1. ¹ H-NMR (CDC1 ₃ , 300MHz) δ 2.13 (m, 2Η), 2.38 (m, 6H), 2.83 (t, 2H, J=7.2), 3.07 (m, 4H), 3.64 (m, 4H), 4.65 (2x d, 2H, J=12.9), 4.84 (s, 2H), 6.37 (s, 1H), 7.05 (m, 2H), 7.38 (m, 1H), 7.52 (d, 2H, J=6.9) , 7.63 (d, 2H, J=7.5), 7.70 (4H, m)- MS (ESI): 712 (M+H).

Example 20—— 1-ί4-ρ-(octyl-1-yl)-ethyl b-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4 - oxadiazol-3-yl}methyl-2-(4-fluorobenzyl-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 19 from B6, except that B8 was used instead of B6, and "4-fluorobenzyl bromide" was substituted for "2,3-difluorobenzyl bromide". H-NMR (CDC1 ₃ , 300MHz) δ 1.45 (m, 2Η), 1.62 (m, 4H), 2.12 (m, 2H), 2.47 (m, 6H), 2.83 (t, 2H, J=6.9), 3.03 (t, 2H, J=7.2), 3.30 (m, 2H), 4.55 (2x d, 2H, J=12.9), 5.00 (2x d, 2H, ^18.0), 6.31 (s, 1H), 6.99 ( d, 2H, 8.7), 7.40 (dd, 2H, J=7.2, 5.7), 7.52 (d, 2H, J=8.1), 7.59 (d, 2H, J=8.1), 7.66 (d, 2H, ^8.4 ), 7.72 (d, 2H, J=8.4)- MS (ESI): 692 (M+H).

Example 21—— 4-ί3-[2-(2,3-difluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl-5- ( Ethyl p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazol-4-ylindazin-1-carboxylate

The synthesis was carried out by the method of Preparation Example 19 from B6, except that B6 was used instead of B6, and "4-fluorobenzyl bromide" was substituted for "2,3-difluorobenzyl bromide". H-NMR (CDC1 ₃ , 300MHz) δ 1.16 (m, 2Η), 1.23 (t, 3H, J=6.9), 1.57 (m, 1H), 1.84 (m, 1H), 2.09 (m, 2H), 2.53 (t, 1H, J=13.5), 2.70 (t, 1H, J=12.6), 2.80 (t, 2H _: J=6.9), 2.96 (m, 2H), 3.41 (t, 1H, J=12.3) , 4.10 (m, 3H), 4.30 (m, 1H), 4.65 (2x d, 2H, J=13.8), 4.80 (2x d, 2H J=17.4), 6.39 (s, 1H), 7.05 (m, 2H) ), 7.38 (t, 1H, J=6.3), 7.47 (d, 2H, J=8.1), 7.59 (d, 2H, J=8.1), 7.69 (4H, m); MS (ESI): 754 (M +H)+

Example 22——4-{3-[2-(4-fluorobenzylthio)-5,6-trimethylene-4-oxo-4H-pyrimidin-1-yl]methyl 5-(p-trifluoro Ethyl methylbiphenyl-4-yl)-4,5-dihydro-1,2,4-oxadiazol-4-yl}-pyridin-1-carboxylate

The synthesis was carried out by referring to the method of Preparation Example 19 from B6, except that B6 was used instead of B6. ^{_{! H-NMR (CDC1 3,}} 300MHz) δ 1.26 (m, 5H), 1.54 (m, 1H), 1.82 (m, 1H), 2.10 (m, 2H), 2.50 (t, 1H, J = 12.0), 2.66 (t, 1H, J=13.2), 2.83 (t, 2H, J=7.2), 2.97 (m, 2H), 3.39 (t, 1H, J=12.3), 4.11 (m, 3H), 4.30 (m , 1H), 4.52 (d, 1H, J=13.5), 4.65 (d, 1H, J=13.5), 4.80 (2x d, 2H J=17.4), 6.40 (s, 1H), 7.00 (t, 2H, J=8.4), 7.40 (dd, 2H, J=8.4, 5.1), 7.47 (d, 2H, J=8.9), 7.57 (d, 2H, J=8.4), 7.67 (d, 2H, ^8.4), 7.71 (d, 2H, J=8.7); MS (ESI): 736 (M+H) ⁺ .

Example 23——1-{4-12-(cyclopropyl-1-yl)-ethyl 5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-1,2,4 - umoxazol-3-yl}methyl-2-(2,3-di-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 19 from B6, except that B8 was used instead of B6, and "4-fluorobenzyl bromide" was substituted for "2,3-difluorobenzyl bromide". H-NMR (CDC1 ₃ , 300MHz) δ 1.46 (m, 2Η), 1.61 (m, 4H), 2.13 (m, 2H), 2.46 (m, 6H), 2.84 (t, 2H), 3.01 (t, 2H), 3.25 (m, 2H), 4.63 (2x d, 2H), 4.94 (2x d, 2H), 6.32 (s, 1H), 7.04 (m, 2H), 7.38 (m, 1H), 7.55 (d , 2H), 7.63 (d, 2H), 7.71 (4H, m); MS (ESI): 710(M+H)+ The following compounds were also synthesized by reference to the method of Preparation Example 19 from B6.

CI——2-oxo-2-phenylethyl-[4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidin-1(5H)-yl]acetate

Intermediate A4 (1.67 g, 1 eq.), 2-bromoacetophenone (1 g, 1 eq.), anhydrous K ₂ C0 ₃ (1.38 g, 2 eq.) in 20 ml of acetone, stirred at room temperature for 6 h. . The solvent was evaporated under reduced pressure and the residue was diluted with water. The precipitate was collected by filtration, and washed with water and EA to yield 1. The organic layer was separated from the filtrate, and 0.75 g was precipitated after concentration. 1H-NMR (d ₆ -DMSO, 300 MHz) 51.99 (m, 2H), 2.60 (t, 2H, J=7.3), 2.95 (t, 2H, J=7.5), 4.45 (s, 2H), 5.02 (s, 2H), 5.66 (s, 2H), 7.15 (t, 2H, J=8.8), 7.49 (dd, 2H, J=8.8, 5.6), 7.56 (t, 2H, J=7.3), 7.69 (t, 1H, J=7.2), 7.95 (d, 1H, J=6.6); MS (ESI): 453 (M+H).

Example 26 - 1-(5-phenyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidine- 4(5H)-ketone

Under a nitrogen atmosphere, the intermediate D29 (665 mg, 1.47 mmol) and ammonium acetate (560 mg, 5 eq.) were refluxed in toluene and dehydrated for 1.5 h. The toluene was evaporated, the residue was dissolved in EtOAc (methanol), EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 52.00 (m, 2H), 2.61 (t, 2H, J = 7.5), 3.02 (t, 2H, ^ 6.9), 4.41 (s, 2H), 5.17 ( s, 2H), 7.11 (t, 2H, J=9.0), 7.34 (m, 3H) _: 7.45 (dd, 2H, J=8.6, 5.6), 7.68 (d, 2H, J=6.0); MS (ESI ): 433 (M+H).

Example 27 ^ 1-(1H-Tetrazolium-5-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidine-4 (5H) Ketone

Intermediate A6 (95 mg, 1 eq.), sodium azide (21 mg, 1.06 eq.), ammonium chloride (18 mg, 1.1 eq.) in 2 ml of DMF. Dilute with water, adjust the pH to 3-4 with concentrated hydrochloric acid, extract EA three times, combine the organic phase, wash with brine to neutral, dry over magnesium sulfate, dilute solvent and recrystallize from MeOH-EA system to give solid llmg H-NMR (d ₆ -DMSO, 300 MHz) 51.97 (m, 2Η), 2.58 (t, 2H, J=7.4), 2.91 (t, 2H, J=7.6), 4.36 (s, 2H), 5.46 (s, 2H), 7.10 (t, 2H, J=9.0), 7.40 (dd, 2H, J=8.8, 5.6); MS (ESI): 359 (M+H).

C2——1H-imidazole-2-formaldehyde

Reference [J Het. Chem., 32, 611 (1995).]

C3——II-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]formaldehyde

1.26 g of intermediate Ml l (1 eq.), 396 mg of Intermediate C2 (1 eq.), 830 mg of anhydrous K ₂ C0 ₃ (1.5 eq.). The insoluble material was removed by filtration, and washed with EA. The filtrate was concentrated and chromatographed. ^-NMR (CDC1 ₃ , 300 MHz) 55.67 (s, 2H), 7.20 (s, IH), 7.30 (d, 2H, J=8.4), 7.33 (s, IH), 7.57 (d, 2H, J= 8.4), 7.67 (q, 4H), 9.86 (s, IH); MS (ESI): 331 (M+H).

The following intermediates were prepared according to the method of C3:

C9 ^ II- (p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazole-2-yl]methanol

Prepared by the method of M10 using C3 as a raw material. H-NMR (CDC1 ₃ , 300 MHz) 54.68 (s, 2H) _: 5.29 (s, 2H), 6.88 (s, 1H), 6.97 (s, 1H), 7.25 (d, 2H, J=8.1), 7.57 (d, 2H, J=8.1), 7.65 (d, 2H, J = 9.0), 7.69 (d, 2H, J = 9.0) - MS (ESI): 333 (M+H).

CIO——2-azidomethyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-IH-imidazole

C9 1.05 g (1 eq.), DPPA 0.89 ml (1.3 eq.) and DBU 0.66 ml (1.4 eq.) were refluxed in 10 ml of THF for 3 h. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with EA, washed twice with brine, dried and then purified by column chromatography. 1H-NMR (CDC1 ₃ , 300 MHz) 54.41 (s, 2H), 5.23 (s, 2H), 6.97 (d, 1H, J=1.5), 7.08 (d, 1H, J=0.9), 7.20 (d, 2H, J=8.4), 7.59 (d, 2H, J=8.4), -7.68 (m, 4H).

Cll——[I-(p-trifluoromethylbiphenyl-4-yl)methyl-IH-imidazole-2-yl]methylamine

0.50 g of C10 (1 equivalent) was dissolved in THF-H ₂ O (5-0.5 mm), and 550 mg of Ph ₃ P (1.5 eq.) was added to react at room temperature for 4 h. Stir in the silica gel, evaporate to a short silica gel column, first wash off the low polarity triphenylphosphine and triphenylphosphine oxide with EA, then elute with methanol to collect the target product part, and evaporate the methanol, residue It was dissolved in a mixture of CH ₂ Cl ₂ /MeOH = 15:1, and the insoluble silica gel was filtered out, and evaporated to dryness to give 0.45 g of pale yellow solid.

C12——2-[1-(p-trifluoromethylbiphenyl-4-yl)methylene-lH-imidazol-2-yl]methylamine cyclopent-1-enecarboxylate

0.45 g of C11 (1 equivalent) was dissolved in 5 ml of absolute ethanol, 210 μl (1.05 equivalents) of cyclopentanone-2-carboxylate and 610 μl (2 equivalents) of tetraethyl silicate were added, refluxed under nitrogen, TLC monitoring The progress of the reaction was completed in 3 hours. The mixture was directly stirred into silica gel, evaporated to dryness, and then purified by column chromatography. H-NMR (CDC1 ₃ , 300 MHz) 51.22 (t, 3Η, J=7.1) 1.77 (m, 2H), 2.48 (m, 4H), 4.08 (q, 2H, J=7.2), 4.37 (d, 2H, J=5.7), 5.21 (s, 2H), 6.93 (d, 1H, J=1.2), 7.03 (d, 1H, ^0.9), 7.15 (d, 2H, J=8.4), 7.55 (d, 2H, J=8.1), 7.67 (m, 5H)- MS (ESI) fo dish d (M+H) = 470. C13—— 1-[1-(p-trifluoromethylbiphenyl-4-yl) methyl-IH-imidazol-2-yl]methyl-5,6-trimethylene-2-thiouracil

Under nitrogen, C12 0.55 g (1 equivalent), trimethylsilyl isothiocyanate 620 μl (3.5 equivalents) and 1 ml of dry DMF were heated at 140 ° C, and the reaction was stopped at 4 h. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise. Then, 15 ml of EA and 10 ml of water were added and stirred for 10 min. The EA phase was separated, and the aqueous phase was extracted once with 10 ml of EA, and the organic phases were combined. Wash twice with brine and dry over 3⁄430 ₄ while decolorizing the activated carbon. After lh, the insoluble material was removed by filtration, and the filtrate was concentrated to about 3 ml. The mixture was cooled to stand overnight, usually white solid was precipitated, filtered, and dried to give 100 mg; if solid was not precipitated, it was separated by silica gel column chromatography. ¹ H-NMR (d ₆ -DMSO, 300 MHz) 51.93 (m, 2H), 2.52 (t, 2H), 2.88 (t, 2H, J = 7.6), 5.43 (s, 2H), 5.52 (s, 2H) ), 6.90 (d, 1H, J=0.6), 7.27 (d, 3H), 7.71 (d, 2H, J=8.4), 7.81 (d, 2H, J=8.4), 7.87 (d, 2H, J= 8.1), 12.50 (s, IH)- MS (ESI) found (M+H) = 483.

Example 28 ^ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7- Dihydro-1H-cyclopenta[pyrimidin-4(5H)-one

30 mg of intermediate C13 (1 eq.), 4-fluorobenzyl bromide (9 eq.) (1.1 eq.), anhydrous potassium carbonate (13 mg (1.5 eq.)). The inorganic salt was filtered off, and the filtrate was subjected to silica gel column chromatography or purified to afford TLC, eluting with CH ₂ Cl ₂ /MeOH = 20:1. H-NMR (CDC1 ₃ , 300 MHz) 51.97 (m, 2Η), 2.68 (m, 4H), 4.47 (s, 2H), 5.01 (s, 2H), 5.19 (s, 2H), 6.90-7.03 ( m, 5H), 7.10 (s, 1H), 7.33 (t, 2H), 7.48 (d, 2H, ^7.8),

C —— 3-[l-(p-trifluoromethylbiphenyl-4-yl)methylene-1H-imidazol-2-yl]methylammon-2-(1-methyl-1H-pyrazole-4 -yl)methyl methacrylate

0.23 g of Cl l (1 equivalent) was dissolved in 3 ml of anhydrous methanol, and 200 mg (1.43 equivalents) of intermediate M18 and 445 μl (2 equivalents) of tetraethyl silicate were added, refluxed under nitrogen atmosphere, and the reaction was monitored by TLC. The mixture was directly stirred into silica gel, evaporated to dryness, and then purified by column chromatography eluting with CH ₂ Cl ₂ /MeOH = 30: H-NMR (CDC1 ₃ , 300 MHz, ca 2.3: 1 cis and trans isomer) 53.18/3.24 (2x s, 2H), 3.62/3.64 (2x s, 3H), 3.80/3.77 (2x s, 3H) , 4.33/4.34 (2x d, 2H, J=5.4), 5.17/5.13 (2x s, 2H), 6.56/7.32 (2x d, 1H, ^12.9), 6.95/6.97 (2x d, 1H, J=1.2 ), 7.06-7.13 (m, 4H), 7.22/7.23 (2x s, 1H), 7.55/7.57 (2x d, 2H, J=8.1), 7.64 (m, 4H), 7.84 (m, 1H).

C15——1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-5-(l-methyl-1H-pyrazole-4- Methyl-2-thiouracil

Under nitrogen, 0.34 g (1 equivalent) of intermediate C14, trimethylsilyl isothiocyanate 340 μl (3.5 eq.) and 0.6 ml of dry DMF were heated at 140 ° C and completed at 3 h. After cooling, the flask was placed in an ice bath, diluted with saturated sodium bicarbonate solution, and stirred with 5 ml of EA and 5 ml of water for 20 min to dissolve the product (if a small amount of methanol could be dissolved), then placed in the refrigerator. overnight. The precipitated solid was collected by filtration and dried to give 130 mg. H-NMR (d ₆ -DMSO, 300 MHz) 53.29 (s, 2H), 3.74 (s, 3H), 5.39 (s, 2H), 5.45 (s, 2H), 6.94 (d, 1H, J=0.9 ), 7.20 (s, 1H), 7.22 (d, 2H, J=8.7), 7.33 (d, 1H, J=0.9), 7.43 (s, 1H), 7.47 (s, 1H), 7.66 (d, 2H, J=8.4), 7.81 (d, 2H, J=8.7), 7.85 (d, 2H, J=8.4), 12.60 (s, 1H); MS (ESI): 537 (M+H).

Example 29 ^ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-5-(1 -methyl-1H-pyrazol-4-yl)methyl-pyrimidine-4(1H)-one

Prepared by the method of Example 28, except that the intermediate C15 was used instead of C13. ^-NMR (CDC1 ₃ , 300 MHz) 53.38 (s, 2H), 3.79 (s, 3H), 4.44 (s, 2H), 4.92 (s, 2H), 5.11 (s, 2H), 6.90-6.98 (m , 5H), 7.05 (s, 1H), 7.12 (s, 1H), 7.19 (s, 1H), 7.22 (s, 1H), -7.37 (m, 4H), 7.62 (d, 2H, J=8.4) , 7.70 (d, 2H, J=8.1); MS (ESI): 645 (M+H).

Example 30 _ n-Dodecyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)- Ketone

The synthesis was carried out by the method of Preparation Example C from C3, except that C4 was used instead of C3. ^-NMR (CDC1 ₃ , 300 MHz) δ 0.85 (t, 3Η), 1.23 (m, 18Η), 1.69 (m, 2Η), 2.08 (m, 2H), 2.86 (m, 4H), 3.86 (t, 2H), 4.48 (s, 2H), 5.05 (s, 2H), 6.88 (s, 1H), 6.96 (t, 2H), 6.99 (s, 1H), 7.30 (dd, 2H)- MS (ESI): 525 (M+H).

Example 31 - 1-(1-n-butyl-1H-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidine -4(5H)-ketone

The synthesis was carried out by the method of Preparation Example C from C3, using C5 instead of C3 as a starting material. ^-NMR (CDC1 _3: 300 MHz) 50.89 (t, 3Η, J=7.5), 1.28 (m, 2H), 1.66 (m, 2H), 2.08 (m, 2H), 2.82 (t, 2H, J= 7.5), 2.89 (t, 2H, J=7.8), 3.87 (t, 2H, J=7.5), 4.48 (s, 2H), 5.05 (s, 2H), 6.88 (s, 1H), 6.95 (t, 2H, J=9.0), 6.98 (s, 1H), 7.32 (dd, 2H, J=8.7, 5.8); MS (ESI): 413 (M+H). Example 32 - 1-11- Biphenyl-4-yl)methyl-1H-imidazol-2-yl-1methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4(5H) -ketone

6S

The synthesis was carried out by referring to the method from Preparation C3 of C3, except that C8 was used instead of C3. ^-NMR (CDC1 ₃ , 300 MHz) 51.96 (m, 2Η), 2.68 (m, 4H), 4.46 (s, 2H), 5.00 (s, 2H), 5.17 (s, 2H), 6.91-7.03 (m , 5H), 7.09 (s, 1H), 7.32 (dd, 2H, J=8.1, 5.4), 7.43 (m, 6H); MS (ESI): 557 (M+H).

Example 33——1-[1-(Biphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H - cyclopenta [pyrimidine-4(5H)-one

The synthesis was carried out by the method of Preparation Example C from C3, except that C6 was used instead of C3. ^-NMR (CDC1 ₃ , 300 MHz) 51.98 (m, 2Η), 2.71 (m, 4H), 4.46 (s, 2H), 4.98 (s, 2H), 5.17 (s, 2H), 6.92 (t, 2H , J=8.4), 7.02 (d, 2H, ^8.1), 7.04 (s, 1H), 7.09 (s, 1H), 7.30 (dd, 2H, J=8.4, 5.4), 7.39 (m, 1H), 7.50 (m, 6H); MS (ESI): 523 (M+H).

Example ₃₄ - 1-[1-(p-methylbiphenyl-4-yl)methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-5-(l- Methyl-1H-pyrazol-4-yl)methyl-pyrimidine-4(1H)-one

The synthesis was carried out by referring to the method of Preparation Example 29 from C3, except that C3 was used instead of C3. ^-NMR (CDC1, 300 MHz) 52.40 (s, 3H), 3.43 (s, 2H), 3.80 (s, 3H), 4.46 (s, 2H), 4.90 (s, 2H), 5.08 (s _: 2H) , 6.90-6.93 (m, 5H), 7.04 (s, 1H), 7.11 (s, 1H), 7.22~7.30 (m, 4H), -7.34 (m, 2H) _: 7.43 (m, - MS (ESI) : 591 (M+H).

CI 6 - 1-n-butyl -5-p-chlorophenyl -1H-imidazole

2.2 ml (2.2 eq.) of n-butylamine, 1.4 g (l equivalent) of p-chlorobenzaldehyde in 10 ml of anhydrous methanol, a CaCl ₂ drying tube was insulated from water vapor, and 5 g of 4A molecular sieve was added thereto for 3 hours, and occasionally oscillated. Subsequently, 10 ml of DME and 2.34 g of p-toluenesulfonylmethyl isocyanide (1.2 equivalent) were added, and the mixture was heated at 50 to 60 ° C for 12 hours to stop the reaction. After cooling, the molecular sieve was removed by filtration, and the filtrate was stirred into silica gel, and evaporated to dryness. ^-NMR (CDC1 ₃ , 300 MHz) 50.83 (t, 3Η, J=7.4), 1.22 (m, 2H), 1.59 (m, 2H), 3.93 (t, 2H, J=7.4), 7.04 (d, 1H, ^1.2), 7.29 (d, 2H, J=9.0), 7.40 (d, 2H, J=8.7), 7.55 (d, 1H, J=0.9)- MS (EI) m/z: 234 (M .

CI 7 ^ (1-n-butyl-5-p-chlorophenyl-1H-imidazol-2-yl)carboxaldehyde

0.97 g (1 equivalent) of intermediate C16 dissolved in 5 ml of dry THF, replaced with nitrogen, placed at -80 'C low Temperature reactor. 1.72 ml (1.2 equivalents) of n-butyllithium solution (1.6 M solution in hexane) was added dropwise with a syringe, and the mixture was stirred for 5 minutes, and stirring was continued for further 1 hour. Dry 0.64 ml of DMF (2 equivalents) was added dropwise to the syringe, and after cooling, the cooling was stopped, and the reaction was allowed to reach room temperature, followed by stirring for several hours. It was quenched with a saturated aqueous solution of ammonium chloride, extracted twice with EA, and then washed twice with brine and dried over magnesium sulfate. 'H-NMR (CDC1 ₃ , 300 MHz) 50.82 (t, 3Η, J=7.4), 1.21 (m, 2H), 1.62 (m, 2H), 4.34 (t, 2H, J=7.6), 7.29 (s , 1H), 7.33 (d, 2H, J=8.4), 7.48 (d, 2H, J=8.7), 9.85 (s, 1H)- MS (EI) m/z: 262 (M^). C18 ^ [ L-(2-diethylaminoethyl)-5-orthoaldehyde

Prepared according to the method of C17 except starting from furfural and "2-diethylaminoethylamine". H-NMR (CDC1 ₃ , 300 MHz) δ 0.87 (t, 3Η), 1.03 (t, 6Η), 1.26 (m, 14Η), 1.69 (m, 2Η) _: 2.66 (m, 8Η), 4.40 (t , 2Η), 7.08 (s, 1H), 9.70 (s, IH)

C19 ^ [l-(2-Diethylaminoethyl)--(p-trifluoromethylbiphenyl-4-yl)-IH-imidazole-2-yl]formaldehyde

Prepared according to the method of C17 except that Ml and "2-diethylaminoethylamine" were used as starting materials. H-NMR (CDC1 ₃ , 300 MHz) δθ.84 (t, 6Η, J=7.2), 2.42 (q, 4H, J=7.2), 2.65 (t, 2H, J=6.9), 4.51 (t, 2H, J=6.9), 7.36 (s, 1H), 7.58 (d, 2H, J=8.4), 7.72 (d, 2H, J=8.1), 7.73 (s, 4H), 9.85 (s, IH)- MS (ESI): 416 (M+H).

Example 35 _ 1-(1-n-Butyl-5-p-chlorophenyl-IH-mipropen-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H -cyclopenta[pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation from C3, except that Intermediate C17 was used instead of C3. ^{_{! H-NMR (CDC1 3,}} 300 MHz) δθ.77 (t, 3Η, J = 7.2), 1.14 (m, 2H), 1.48 (m, 2H), 2.12 (m, 2H), 2.85 (t, 2H , J=7.5), 2.95 (t, 2H, J=7.5), 3.89 (t, 2H, J=7.6), 4.50 (s, 2H), 5.10 (s, 2H), 6.95 (t, 2H, J= 8.7), 6.97 (s, 1H), 7.24 (d, 2H, J=8.7), 7.33 (dd, 2H, J=8.7, 5.3): 7.41 (d, 2H, J=8.1)- MS (ESI): 523 (M+H).

Example 36 - 1-(1-n-butyl-5-p-chlorophenyl-IH-imidazol-2-yl)methyl-2-pronitrobenzylthio-6,7-dihydro-1H- Cyclopenta[pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation of C3, except that Intermediate C17 was used instead of C3, and "N-nitrobenzyl chloride" was used instead of "4-fluorobenzyl bromide". ^-NMR (CDC1 ₃ , 300 MHz) δθ.81 (t, 3H, J=7.2), 1.16 (m, 2H), 1.50 (m, 2H), 2.12 (m, 2H), 2.86 (t, 2H, J=7.4), 2.97 (t, 2H, J=7.2), 3.92 (t, 2H, J=7.6), 4.89 (s, 2H), 5.05 (s, 2H), 6.92 (s, 1H), 7.27 ( d, 2H, ^8.1), 7.42 (m, 3H), 7.56 (t, 1H, J=7.6), 7.99 (m, 2H)- MS (ESI): 550 (M+H).

Example 37 ^ 1-(1-Diethylaminoethyl-5-n-decyl-IH-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H -cyclopenta[pyrimidin-4(5H)-one

The product was synthesized by reference to the method of Preparation from C3, except that the intermediate C18 was used instead of C3. H-NMR (CDC1 ₃ , 400 MHz) 50.90 (m, 9Η), 1.26 (m, 14Η), 1.63 (m, 2Η), 2.14 (m, 2H), 2.46 (m, 6H), 2.56 (t, 2H, J=7.6), 2.84 (t, 2H, J=7.4), 2.91 (t, 2H, J=7.5), 3.84 (t, 2H, J=7.5), 4.47 (s, 2H), 5.10 (s , 2H), 6.72 (s, 1H), 6.95 (t, 2H, J=8.6), 7.32 (dd, 2H, J=8.6, 5.6); MS (ESI): 596 (M+H).

Example 38 ^ 1-[1-Diethylaminoethyl-5-(p-trifluoromethylbiphenyl-4-yl)-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio) )-6,7-dihydro-1H-cyclo[rf]pyrimidin-4(5H)-one

The synthesis was carried out by referring to the method of Preparation from C3, except that the intermediate C19 was used instead of C3. 1H-NMR (CDC1 ₃ , 300 MHz) 50.83 (t, 6Η, J=6.9), 2.13 (m, 2H), 2.43 (m, 6H), 2.88 (t, 2H, J=6.9), 3.00 (t, 2H, J=7.2), 4.05 (t, 2H, J=5.7), 4.51 (s, 2H), 5.22 (s, 2H), 6.96 (t, 2H, J=8.6), 7.06 (s, 1H), 7.35 (dd, 2H, ^8.1, 5.7), 7.45 (d, 2H, 8.1), 7.71 (m, 6H); MS (ESI): 676 (M+H).

■(1-Benzyl-2-mercapto-1H-imidazol-5-yl)methanol To a solution of benzylamine (3.3 ml, 30 mmol) in 30 ml of EtOAc (EtOAc)EtOAc. Then, 2.5 ml of propionic acid, 1,3-dihydroxyacetone (4.5 g, 25 mmol) and potassium thiocyanate (2.9 g, 30 mmol) were added, and the mixture was heated at 70 ° C for 2 h, quenched and cooled. To the reaction liquid, 100 ml of water was added and stirred for 20 minutes, and the precipitate was collected by filtration, washed with water, washed with cold industrial ethanol to white, and dried to yield 4.72 g. ^-NMR (d ₆ -DMSO, 300 MHz) 54.13 (s, 2H), 5.26 (s, 1H, -OH), 5.32 (s, 2H), 6.85 (s, 1H), 7.27 (m, 5H), 12.17 (s, 1H).

C21——(1-Benzyl-IH-imidazole-5-yl)methanol

Intermediate C20 (4.72g, 21.45mmol, 1 eq) was suspended in 30ml CH _₂ C1 ₂ was added 2.5ml of acetic acid. First, add 0.5ml of 30% by mass aqueous hydrogen peroxide solution, slightly heat to initiate the reaction, and then add 5.5ml of aqueous hydrogen peroxide solution (total >2.5 equivalents) at a rate to maintain the microbial boiling of the reaction solution. After stirring at room temperature for 0.5 h. Then, the reaction flask was placed in an ice bath, and a 10% aqueous sodium hydroxide solution was added dropwise thereto to a pH of more than 10, and it was allowed to stand for several hours, and the precipitated solid was collected by filtration, and washed with water and CH ₂ C1 ₂ . The organic phase was separated from the filtrate, and solid was precipitated after concentration and collected by filtration to give a total of 3.25 g. ¹ H-NMR (CDC1 ₃ , 300 MHz) 54.49 (s, 2H), 5.22 (s, 2H), 6.92 (s, 1H), 7.12 (m, 2H), 7.32 (m, 3H), 7.44 (s, 1H)- MS (EI) m/z: 188 (M.

C22——(1-p-bromobenzyl-IH-imidazole-5-

Prepared by the method of C21 except that "4-bromobenzylamine" was substituted for "benzylamine". ^-NMR (d ₆ -DMSO _: 300 MHz) 54.30 (d, 2H, J = 4.8), 5.13 (t, 1H, ^5.1, -OH), 5.21 (s, 2H), 6.83 (s, 1H) _: 7.11 (d, 2H, J=8.1), 7.55 (d, 2H, J=8.4), 7.69 (s, IH); MS (ESI): 267/269 (M+H). C23—— 5-methyl -1-p-bromobenzyl-IH-

Prepared according to the method of C21 except that 2-hydroxyacetone was used instead of 1,3-dihydroxyacetone. ^-NMR (CDC1 ₃ , 300 MHz) 52.06 (s, 3H), 5.01 (s, 2H), 6.83 (s, 1H), 6.90 (d, 2H, J=8.4), 7.45 (d, 2H, J= 8.1), 7.50 (s, IH); MS (ESI): 251/253 (M+H). N

n-BuLi, DMF

C24——(1-Benzyl-IH-imidazole-5-yl)formaldehyde

11.5 g of intermediate C21 (1 eq.) was added to 60 ml of dioxane, and active 32 g of Mn0 ₂ (6 eq.) was added and heated at 60 ° C for 3 h. The Mn0 _{2 was} removed by filtration and washed with EtOAc. H-NMR (CDC1 ₃ , 300 MHz) 55.52 (s, 2H), 7.20 (m, 2H), 7.33 (m, 3H), 7.71 (s, 1H), 7.83 (s, 1H), 9.76 (s, 1H); MS (EI) m/z: 186 (M^).

C25—— 1-Benzyl-5-diethylaminomethyl-IH-imidazole

1.5 g of intermediate C24 (1 eq.), 0.875 ml of diethylamine (1.05 eq.), 3.1 ml of tetraisopropyl titanate (1.3 eq.) in 8 ml of dichloromethane. Then, 8 ml of absolute ethanol was added, and 507 mg of sodium cyanoborohydride (1 equivalent) was added thereto, and the mixture was reacted at room temperature for 16 hours. Quenched with 20 mL of water to give a white solid, which was filtered and washed with 20 EtOAc. The filtrate was transferred to a separatory funnel, and the EA layer was separated. The aqueous phase was extracted once again with 20 ml of EA. The organic phase was combined and washed twice with saturated brine, dried over magnesium sulfate and chromatographed with EA/EtOH = 4:1 Elected 1.32 g of oil. ¹ H-NMR (CDC1 ₃ , 300 MHz) δθ.94 (t, 6H, J=6.9), 2.46 (q, 4H, ^7.2), 3.39 (s, 2H), 5.30 (s, 2H), 6.95 ( s, IH), 7.08 (m, 2H), 7.29 (m, 3H), 7.53 (s, IH); MS (ESI): 244 (M+H).

C26——(1-Benzylmethyl-5-diethylaminomethyl-IH-imidazole-2-yl)formaldehyde

Prepared according to the method of C17 except that C16 was replaced by C25. ^-NMR (CDC1 ₃ , 300 MHz) 50.96 (t, 6H, J=7.1), 2.49 (q, 4H, J=7.2), 3.46 (s, 2H), 5.88 (s, 2H), 6.97 (m, 2H), 7.27 (m, 4H), 9.80 (s, IH).

Example 39 - 1-(1-Benzyl-5-diethylaminomethyl-IH-imidazol-2-yl)methyl-2-(4-fluorobenzylthio)-6,7-dihydro- 1H-cyclopenta [pyrimidine-4(5H)-

The synthesis was carried out by the method of Preparation Example C from C3, except that Intermediate C26 was used instead of C3. 1H-NMR (CDC1 ₃ , 300 MHz) 50.93 (t, 6Η, J=7.2), 2.00 (m, 2H), 2.48 (m, 4H), 2.72 (q, 4H, J=7.4), 3.47 (s, 2H), 4.42 (s, 2H), 4.85 (s, 2H), 5.39 (s, 2H), 6.87 (m, 2H), 6.96 (m, 3H), 7.23-7.33 (m, 5H); MS (ESI ): 532 (M+H).

C27 ^ 5-methyl-1-(p-trifluoromethylbiphenyl--IH-imidazole

Nitrogen protection, intermediate C23 (1.07 g, 4.26 mmol, 1 eq.), p-trifluoromethylbenzeneboronic acid (0.85 g, 1.05 eq.), bismuth carbonate (2.8 g, 2 eq.) and tetratriphenylphosphoryl palladium ( 246 mg, 0.05 eq.) was refluxed for 6 h in 10 ml of dioxane. The inorganic salt was removed by filtration. The filtrate was stirred in silica gel, evaporated to dryness and then purified by column chromatography eluting with CH ₂ Cl ₂ /MeOH = 15 : 1 l .l lg solid. ^-NMR (CDC1 ₃ , 300 MHz) 52.13 (s, 3H), 5.13 (s, 2H), 6.87 (s, 1H), 7.15 (d, 2H, J=7.8), 7.57 (d, 2H, J= 7.8), 7.58 (s, 1H), 7.65 (d, 2H, J=9.0), 7.70 (d, 2H, J=9.3)- MS (ESI): 317 (M+H).

C28—— 15-methyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-IH-imidazole-2-yl]methanol

Intermediate 27 (1.53 & 4.841 ^1) dissolved in 31 ^ dioxane and 101 ^ 37% aqueous formaldehyde solution were placed in a pressure-resistant tube, swirled purple plug, heated and stirred at 140 ~ 150 ° C for 36 h, stop cooling , TLC monitoring reaction is completed. The reaction solution was poured into 20 ml of a saturated aqueous solution of sodium chloride and extracted three times with 60 ml of dichloromethane. The organic phase was combined and washed three times with brine, dried over magnesium sulfate H-NMR (CDC1 ₃ , 300 MHz) 52.10 (s, 3H), 4.62 (s, 2H), 5.29 (s, 2H), 6.73 (s, 1H), 7.10 (d, 2H, J=8.4), 7.54 (d, 2H, J=8.4), 7.67 (m, 4H)- MS (ESI): 347 (M+H). Example 0--[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-methyl-1H-imidazol-2-yl]methyl-2-(4-fluorothio)-6 ,7-dihydro-1H-cyclopenta[rf]

The synthesis was carried out by the method of Preparation Example 28, except that C28 was used instead of C9. ^-NMR (CDC1 ₃ , 300 MHz) 51.93 (m, 2Η), 2.22 (s, 3H), 2.60 (t, 2H, J=7.2), 2.69 (t, 2H, J=7.5), 4.46 (s, 2H), 5.01 (s, 2H), 5.14 (s, 2H), 6.84 (d, 2H, J=8.1), 6.88 (s, 1H), 6.95 (t, 2H, J=8.4), 7.34 (dd, 2H, J=5.4, 8.4), 7.44 (d, 2H, J=8.4), 7.63 (d, 2H, J=8.4), 7.70 (d, 2H, J=8.1)- MS (ESI): 605 (M +H).

Example 41——1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio) -5-(1-Methyl-1H-pyrazol-4-yl)methyl-pyrimidin-4(1H)-one

The synthesis was carried out by referring to the method from Preparation C29 of C9, except that C28 was used instead of C9. ^-NMR (CDC1 ₃ , 300 MHz) 52.20 (s, 3H), 3.39 (s, 2H), 3.80 (s, 3H), 4.40 (s, 2H), 4.89 (s, 2H), 5.09 (s, 2H) ), 6.74 (d, 2H, J=8.1), -6.96 (m, 4H), 7.23 (s, 1H), -7.33 (m, 5H), 7.62 (d, 2H, J=8.1), 7.70 (d , 2H, J=8.7); MS (ESI): 659 (M+H).

C29 C30 C31 C32

C29——II-(p-trifluoromethylbiphenyl-4-yl)methyl-IH-imidazole-5-yl]methanol

Nitrogen replacement, intermediate C22 (10 mol, 1 eq.), p-trifluoromethylbenzeneboronic acid (1.1 eq.), cesium carbonate (2 eq.) and tetratriphenylphosphoryl palladium (0.05 eq.) in 30 mL of dioxane After refluxing for 15 h, the inorganic salt was removed by filtration and washed with dioxane. The filtrate was evaporated under reduced pressure to give a brown oil or a solid, which was then dissolved in 20 ml of ethyl acetate. The solid was precipitated for a period of time, collected by filtration, dried, and the above liquid was repeated. ^-NMR (d ₆ -DMSO, 300 MHz) 54.35 (s, 2H), 5.30 (s, 2H), 6.85 (s, 1H), 7.29 (d, 2H, J = 8.1), 7.73 (d, 2H, J=7.8), 7.74 (s, 1H), 7.80 (d, 2H, J=8.1), 7.88 (d, 2H, J=8.4). C30——II- (p-trifluoromethylbiphenyl-4- Methyl-IH-imidazole-5-yl]formaldehyde

Prepared according to the method of C24. ^-NMR (CDC1 ₃ , 300 MHz) 55.58 (s, 2H), 7.30 (d, 2H,

J=8.1), 7.57 (d, 2H, J=8.1), 7.67 (m, 4H), 7.78 (s, 1H), 7.84 (s, 1H), 9.78 (s, 1 H). C31—— 1- (p-trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-IH-imidazole

Prepared according to the method of C25. ^-NMR (CDC1 ₃ , 300 MHz) 50.99 (t, 6Η, J=7.2), 2.53 (q, 4H, J=6.9), 3.47 (s, 2H), 5.39 (s, 2H), 7.00 (s, 1H), 7.17 (d, 2H, J=7.8), 7.55 (d, 2H, J=8.1), 7.63 (s, IH), 7.67 (m, 4H); MS (ESI): 388 (M+H) .

C32——[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-IH-imidazole-2-yl]methanol

Prepared according to the method of C28. ^-NMR (CDC1 ₃ , 300 MHz) 50.93 (t, 6Η, J=7.2), 2.46 (q, 4H, J=7.2), 3.37 (s, 2H), 4.62 (s, 2H), 5.53 (s, 2H), 6.87 (s, IH), 7.10 (d, 2H, J=8.4), 7.53 (d, 2H, J=8.4), 7.67 (m, 4H).

C33——1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(tetrahydropyrrole-1-yl)methyl-IH-imidazole-2-yl J-methyl alcohol

7S

The synthesis was carried out by referring to the method for preparing C32 from C30, and "diethylamine" was replaced by "pyrrole". ^{_{! H-NMR (CDC1 3,}} 300 MHz) 51.72 (m, 4Η), 2.42 (m, 4Η), 3.41 (s, 2Η), 4.62 (s, 2H), 5.49 (s, 2H), 6.83

C34 ~ 1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-chloromethyl-1H-imidazole hydrochloride

In a 100 ml flask, 5 mmol of intermediate C29 and 20 ml of methylene chloride were placed, and 2 drops of DMF was added as a catalyst, and placed in an ice bath. 0.42 ml (about 6 mmol) of thionyl chloride dissolved in 5 ml of dichloromethane was added dropwise with a constant pressure dropping funnel, and the mixture was dropwise added for 10 minutes, and then reacted at room temperature. The progress of the reaction was monitored by TLC and the reaction was completed in about 2 hours. The precipitate was collected using a Buchner funnel and washed twice with dichloromethane. 80'C was dried to a white or light yellow powder. H-NMR (d ₆ -DMSO, 300 MHz) 54.96 (s, 2H), 5.61 (s, 2H), 7.52 (d, 2H, J = 8.4), 7.82 (m, 3H), 7.89 (m, 4H) ), 9.39 (s, 1 H).

C35^1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzoylamino)methyl-1H-imidazole intermediate C34 (1.38 g, 3.57 mmol, 1 Equivalent), N-methyl-p-fluorobenzylamine (0.5g, 1 eq.) and diisopropylethylamine (1.47ml, 2.5 eq.) in 10ml acetonitrile, heated at 70-80 ° C overnight, TLC detection reaction completed . The acetonitrile was distilled off, and the residue was added to 40 ml of an ammonium chloride solution, and the mixture was extracted twice. The organic phase was combined and washed twice with brine. ¹ H-NMR (CDC1 ₃ , 400 MHz) 52.16 (s, 3H), 3.38 (s, 2H), 3.46 (s, 2H), 5.31 (s, 2H), 6.97 (t, 2H, J=8.4), 7.03 (s, 1H), 7.08 (d, 2H, J=8.4), 7.21 (dd, 2H, J=8.4, 5.6), 7.54 (d, 2H, 8.0), 7.60 (s, 1H), 7.68 (d , 2H, J=8.8), 7.72 (d, 2H, J=8.0).

C36 ^ [1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzylamino)methyl-1H-imidazol-2-yl]methanol Prepared according to the method of C28, except that C35 was used instead of C27. ^-NMR (CDC1 ₃ , 300 MHz) 52.07 (s, 3H), 3.26 (s, 2H), 3.37 (s, 2H), 4.60 (s, 2H), 5.45 (s, 2H), 6.83 (s, 1H) ), 6.92 (t, 2H, J=8.4), 7.01 (d, 2H, J=8.4), 7.12 (dd, 2H, J=8.4, 5.4), 7.49 (d, 2H, J=8.1), 7.64

C37 ^ II- (p-trifluoromethylbiphenyl-4-yl)methyl -2-hydroxymethyl -1H-imidazole -5-yl]formaldehyde

Prepared according to the method of C28, except that C30 was used instead of C27. ^-NMR (CDC1 ₃ , 300 MHz) 54.75 (s, 2H), 5.74 (s, 2H), 7.22 (d, 2H, J=8.1), 7.54 (d, 2H, J=7.8), 7.63 (d, 2H, J=8.7), 7.69 (d, 2H, J=8.7), 7.77 (s, 1H), 9.46 (s, 1H).

C38——[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(benzylidazine-1-yl)methyl-1H-imidazole-2-yl 1 Methanol

0.56 g (1 eq.) of intermediate C37, 300 μl of N-benzylpiperazine (1.1 eq.), 495 mg of NaBH (OAc) ₃ (1.5 eq.) and EtOAc (2 eq. The reaction was completed by TLC. The reaction solution was washed twice with brine, then twice with a saturated aqueous sodium hydrogen carbonate solution, and dried over sodium sulfate and then evaporated. ^-NMR (CDC1 ₃ , 400 MHz) 52.43 (m, 8H), 3.45 (s, 2H), 3.52 (s, 2H), 4.75 (s, 2H), 5.50 (s, 2H), 7.26 (m, 8H) ), 7.55 (d, 2H, J=8.4), 7.65 (d, 2H, J=8.4), 7.69 (d, 2H, J=8.4).

C39 ^ [1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methanol

Synthesis by the method of C37 for the preparation of C38, except for "dimethylamine hydrochloride" and "2 equivalents of DIPEA" Instead of "N-benzyl piperazine" as a raw material. Ή-NMR (CDC1 ₃ , 300 MHz) 52.15 (s, 6H), 3.19 (s, 2H), 4.62 (s, 2H), 4.63 (vbrs, 1H), 5.49 (s, 2H), 6.83 (s, 1H ), 7.14 (d, 2H, J=8.1), 7.54 (d, 2H, J=8.1), 7.67 (m, 4H)- MS (ESI): 390 (M+H).

Example ₄ 2-I1-[1-(p-trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-IH-imidazol-2-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta [rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 28, except that C32 was used instead of C9. ^-NMR

(CDC1 ₃ , 300 MHz) 50.93 (t, 6Η, J=6.9), 1.97 (m, 2H), 2.47 (q, 4H, J=6.9), 2.70 (m,

4H), 3.48 (s, 2H), 4.45 (s, 2H), 4.92 (s, 2H), 5.44 (s, 2H), 6.95 (m, 5H), 7.31 (m, 2H),

7.45 (d, 2H, J=7.8), 7.62 (d, 2H, J=7.8), 7.70 (d, 2H, J=8.1); MS (ESI): 676 (M+H). Example ₄₃ (for Trifluoromethylbiphenyl-4-yl)methyl-5-(tetrahydropyrrol-1-yl)methyl-IH-imidazol-2-yl J-methyl-2-(4-fluorobenzylthio) - 6,7-Dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 28, except that C33 was used instead of C9. ^-NMR (CDC1 ₃ , 300 MHz) 51.79 (m, 4Η), 1.96 (m, 4Η), 2.53 (m, 2Η), 2.68 (m, 4H), 3.61 (s, 2H), 4.44 (s, 2H ), 4.95 (s, 2H), 5.45 (s, 2H), 6.93 (m, 4H), 6.99 (s, 1H), 7.30 (dd, 2H, J=7.8, 5.4), 7.43 (d, 2H, J=7.8), 7.60 (d, 2H, ^7.8), 7.70 (d, 2H, J=7.8).

Example 44 ~ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzylamino)methyl-IH-imidazol-2-yl] A 2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 28, except that C36 was used instead of C9. ^-NMR (CDC1 ₃ , 400 MHz) 51.98 (m, 2Η), 2.18 (s, 3H), 2.70 (m, 4H), 3.43 (s, 2H), 3.45 (s, 2H), 4.45 (s, 2H) ), 4.94 (s, 2H), 5.29 (s, 2H), 6.84-6.96 (m, 6H), 7.02 (s, 1H), 7.11 (m, 2H), 7.31 (dd, 2H, ^8.4, 6.4) , 7.44 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.4), 7.73 (d, 2H, J=8.0)- MS (ESI): 742 (M+H).

Example 45—— 1-11-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(4-benzylidazine--1-yl)methyl-IH-imidazole

-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta [rf]pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example 28, except that C38 was used instead of C9. ^-NMR (CDC1 ₃ , 400 MHz) 51.99 (m, 2Η), 2.40 (m, 4H), 2.53 (m, 4H), 2.66 (t, 2H), 2.78 (t, 2H), 3.50 (s, 2H ), 3.74 (s, 2H), 4.47 (s, 2H), 5.05 (s, 2H), 5.45 (s, 2H), 6.96 (m, 4H), 7.31 (m, 8H), 7.48 (d, 2H) , 7.65 (d, 2H), 7.74 (d, 2H). Example 46 ^ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzyl) Thio)-6,7-dihydro-1H

The synthesis was carried out by the method of Preparation Example 28, except that C39 was used instead of C9. ^-NMR (CDC1 ₃ , 300 MHz) 51.96 (m, 2Η), 2.19 (s, 6H), 2.68 (m, 4H), 3.33 (s, 2H), 4.45 (s, 2H), 4.93 (s, 2H ), 5.39 (s, 2H), 6.93 (m, 5H), 7.31 (m, 2H), 7.45 (d, 2H, J=7.8), 7.62 (d, 2H, J=7.8), 7.70 (d, 2H) , J = 7.5); MS (ESI): 648 (M+H).

Example ₄₇ N,N-Dimethyl-N-(4-fluorobenzyl)-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H- Cyclopentadienyl-1(5H)-yl]methyl-1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidyl-5-yl}methylammonium bromide

25 mg of Example 46, fluorobenzyl bromide 6 μl was refluxed for 1.5 h in 1.5 ml of acetone, and most of the reaction was monitored by TLC. The reaction was stopped, and the solid was precipitated after standing in the refrigerator for a while, collected by filtration, and dried to obtain 10 mg of a white powder. ^-NMR (CDC1 ₃ , 300 MHz) 52.06 (m, 2H), 2.71 (t, 2H, J=6.6), 2.85 (t, 2H, J=6.6), 2.98 (s, 6H), 4.36 (s, 2H), 4.62 (s, 2H), 4.80 (s, 2H), 5.25 (s, 2H), 5.57 (s, 2H), 6.86 (t, 2H, J=8.7), 7.07 (d, 2H, J= 7.8), 7.27 (m, 4H), 7.74 (s, 1H), 7.59 (m, 4H), 7.71

S3 (d, 2H, J = 8.1), 7.75 (d, 2H, J = 8.4) - MS (ESI): 756 (M-Br).

Example 48 _ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzyl) Thio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one-hydrochloride

Example 46 100 mg (1 equivalent) was dissolved in 1.5 ml of isopropanol, placed in an ice bath, 15 μl (about 1.1 equivalents) of concentrated hydrochloric acid was added, stirred for 20 min, 5 ml of diethyl ether was added, and the mixture was placed in a refrigerator to precipitate a white solid. , dried to 80mg.

Example ₄ 9 - N-(4-fluorobenzyl)-N-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[ Rf]pyrimidine-1(5H)-yl]methyl-1-(p-trifluoromethylbiphenyl-yl)methyl-1H-imidazol-5-yl}methyltetrahydropyrrole ammonium bromide

The preparation was carried out in the same manner as in Example 47 except that "Example 43" was used instead of "Example 46".

C39 ~~ 2-p-bromobenzylaminoacetate

p-Bromobenzylamine (20 mmol), triethylamine (20 mmol), 30 mL DMF in a 100 mL flask and placed in a 40-50 C oil bath. Ethyl chloroacetate (20 mmol) was dissolved in 10 ml of DMF, and the mixture was dropped into a flask with a constant pressure dropping funnel, and the mixture was stirred for 1.5 h and stopped for 1.5 h. The reaction solution was diluted with 150 ml of EA, washed with brine twice, and then dried over 30~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ H-NMR (CDC1 ₃ , 300 MHz) 51.28 (t, 3Η, J=7.2), 2.17 (s, 1H), 3.39 (s, 2H), 3.77 (s, 2H), 4.19 (q, 2H, J =7.2), 7.21 (d, 2H, J=8.4), 7.44 (d, 2H, J=8.4).

C40 ~~ 2-(N-p-bromobenzoylamino)ethyl acetate

Intermediate C39 (3.4 g, 13.6 mmol, 1 equivalent of formic acid (1.5 ml, 2.5 eq.) was refluxed in toluene. Water was collected in a water separator until no water was formed, toluene was distilled off, and the residue was stirred in silica gel and evaporated to dryness. Column chromatography separation eluted with PE EA = 2: 1 yielded 2.87 g of oil. ^-NMR (CDC1 ₃ , 400 MHz, ca 2:1 rotamer) 51.27 (t, 3H, J = 7.2), 3.96 /3.85 (2x s, 2H), 4.19 (m, 2H), 4.51/4.59 (2x s, 2H), 7.12/7.14 (2x d, 2H, J=8.0), 7.52/7.47 (2x d, 2H, 8.0 ), 8.36/8.19 (2x s, 1H).

C41——(1-p-Bromobenzyl-2-indolyl-1H-imidazole-5-yl)carboxylic acid ethyl ester

Intermediate C40 (6.21 g, 20.7 mmol, 1 eq.) was dissolved in 50 ml of DME, ice-bath, nitrogen-protected, l.Og NaH (dispersed in oil at a ratio of 55-65%), reacted for 20 min, added 5 ml of ethyl formate was reacted at room temperature for 4 h. The solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals crystalssssssssssssssssssssssss The mixture was placed in an ice bath, and the pH was adjusted to 6-7 with a 10% sodium hydroxide solution. The precipitate was precipitated, collected by filtration, and dried to give 3.11 g. ^{_{! H-NMR (d 6 -DMSO}} , 400 MHz) δΐ .17 (t, 3H, J = 7.2), 4.15 (q, 2H, J = 7.2), 5.51 (s, 2H): 7.14 (d, 2H, J=8.4), 7.50 (d, 2H, J=8.4), 7.88 (s, 1H), 13.10 (s, 1H).

C42——(1-p-Bromobenzyl- 1H-imidazole-5-yl)carboxylic acid ethyl ester

Intermediate C41 (3.10g, 9.09mmol, 1 eq) was suspended in 20ml CH _₂ C1 ₂ was added 1ml of acetic acid.

S5 First, add 0.2ml of 30% by mass aqueous hydrogen peroxide solution, slightly heat to initiate the reaction, and then add 2.5ml of aqueous hydrogen peroxide solution (total >2.5 equivalents) at a rate to maintain the microbial boiling of the reaction solution. After stirring at room temperature for 0.5 h. The reaction flask was then placed in an ice bath, 10% aqueous sodium hydroxide solution was added dropwise to pH = 6-7, and then poured into 15 ml of a saturated sodium hydrogen carbonate solution. 1 ₂ layers were separated, and the aqueous phase was extracted once again with 11 ₂ 1 ₂ , and the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate and evaporated H-NMR (CDC1 ₃ , 400 MHz) 51.31 (t, 3Η, J=7.2), 4.25 (q, 2H, J=7.2), 5.48 (s, 2H), 7.02 (d, 2H, J=8.4) , 7.44 (d, 2H, J=8.8), 7.63 (s, 1H), 7.76 (s, 1H).

C43——II-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazole-5-yl]carboxylate

The preparation was carried out in the same manner as the intermediate C27 except that C42 was used instead of C23. ^-NMR (CDC1 ₃ , 400 MHz) 51.33 (t, 3H, J=7.2), 4.29 (q, 2H, J=6.8), 5.58 (s, 2H), 7.26 (d, 2H, J=8.4), 7.57 (d, 2H _: J=8.4), 7.68 (m, 5H), 7.79 (s, 1H).

C44 ~ II- (p-trifluoromethylbiphenyl-4-yl-2-hydroxymethyl-1H-imidazole-5-yl) ethyl formate

The preparation was carried out in the same manner as the intermediate C28 except that C43 was used instead of 0X1. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 51.30 (t, 3Η, J = 7.2), 4.27 (q, 2H, J = 7.2), 4.70 (s, 2H), 5.76 (s, 2H), 7.16 (d , 2H, J=7.8), 7.53 (d, 2H, J=8.4), 7.66 (m, 5H).

Example 50 - {2-[2-(4-Fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidin-1(5H)-yl]methyl- Ethyl 1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-yl}carboxylate

S6

The synthesis was carried out by the method of Preparation Example 28, except that C44 was used instead of C9. ^-NMR (CDC1 ₃ , 300 MHz) 51.35 (t, 3Η, J=6.9), 2.02 (m, 2H), 2.71 (m, 4H), 4.32 (q, 2H, J=7.2), 4.41 (s, 2H), 5.03 (s, 2H), 5.74 (s, 2H), 6.89 (t, 2H, J=8.4), 7.05 (d, 2H, J=7.8): 7.27 (dd, 2H, J=8.1, 5.4 ), 7.46 (d, 2H, J=7.8), 7.59 (d, 2H, J=8.1), 7.69 (d, 2H, J=8.1), 7.75 (s, 1H).

Example 51 - {2-[2-(4-Fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidin-1(5H)-yl]methyl- 1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-imidazol-5-ylindolecarboxylic acid

The compound of Example 50 was dissolved in 3 ml of ethanol in an ice bath, and 0.5 ml of a 10% aqueous NaOH solution was added thereto, followed by a reaction at room temperature for 2 hours, and the TLC detection was completed. 15 ml of ice water was added to the flask, and the H value was adjusted to 5-6 with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to yield 60 mg. ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 51.91 (m, 2H), 2.56 (t, 2H, J = 7.2), 2.73 (t, 2H, J = 7.2), 4.29 (s, 2H), 5.21 (s, 2H), 5.72 (s, 2H), 7.01 (t, 2H, J=8.7), 7.14 (d, 2H, J=8.1), 7.31 (dd, 2H, J=8.4, 5.7), 7.62 ( d, 2H, J=7.8), 7.83 (m, 5H), 12.98 (s, 1H).

Example 52——N,N-Dimethyl-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro- ff-cyclopenta[rf]pyrimidine -1(5H)-yl]methyl-1-(p-trifluoro-5-ylindolecarboxamide

Example 51 Compound 40mg, EDCI 18mg, HOBt 13mg, dimethylamine hydrochloride 8mg, DIPEA 17μ1 was reacted in 5ml DCM for 4h at room temperature, washed twice with ammonium chloride saturated solution, dried anhydrous NaS0 ₄ to prepare TLC, 20mg White solid. ¹ H-NMR (CDC1 ₃ , 300 MHz) 52.01 (m, 2H), 2.75 (m, 4H), 3.07 (s, 3H), 3.09 (s, 3H), 4.44 (s, 2H), 4.96 (s, 2H), 5.49 (s, 2H), 6.89 (t, 2H, J=8.4), 7.11 (d, 2H, J=7.8), 7.27 (m, 3H), 7.46 (d, 2H, J=7.8), 7.59 (d, 2H, ^8.1),

=8.7).

C45—— 1-(p-trifluoromethylbiphenyl-4-yl)methyl-1H-benzimidazole

Nitrogen-protected, benzimidazole (519 mg, 4.4 mmol, ll eq.), Intermediate Mll (1.26 g, 4 mmol, 1 eq.), DIPEA (730 ml, 1.1 eq.). The insoluble material was removed by filtration, and the filtrate was stirred to silica gel, evaporated to dryness, and then purified by column chromatography to afford 590 mg of white solid. H-NMR (CDC1 ₃ , 300 MHz) 55.43 (s, 2H), -7.29 (m, 5H), 7.57 (d, 2H, J=8.1), 7.67 (m, 4H), 7.86 (m, 1H) , 8.00 (s, 1H); MS (ESI): 353 (M+H).

C46 ^ [1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-benzimidazole-2-yl]formaldehyde

The preparation method is the same as C17 except that C45 is used instead of C16 as raw material H-NMR (CDC1 ₃ , 300 MHz). 55.92 (s, 2H), 7.27 (d, 2H, J=8.1), 7.42-7.53 (m, 5H), 7.62 (d, 2H, J=8.7), 7.67 (d, 2H, J=8.4), 7.98 (m, 1H), 10.17 (s, 1H).

Example _53-1- [1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-benzoimidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6, 7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one

The synthesis was carried out by the method of Preparation Example C from C3, and C3 was replaced with Intermediate C46. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 51.95 (m, 2H), 2.68 (m, 4H), 4.46 (s, 2H), 5.22 (s, 2H), 5.44 (s, 2H), 6.90 (t 2H , J=8.7), 7.00 (d, 2H, J=7.8), 7.26-7.37 (m, 5H), 7.43 (d, 2H, J=7.8), 7.60 (d, 2H, J=8.4), 7.69 ( d, 2H, J=8.4), 7.82 (m, 2H)-MS (ESI) found (M+H) = 641.

Example ₅₄ _ 1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-benzoimidazol-2-yl]methyl-2-(4-fluorobenzylthio)-5- (1-methyl-1H-pyrazole-4

The synthesis was carried out by the method of Preparation Example 29 from C3, and C3 was replaced with Intermediate C46. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 53.40 (s, 2H), 3.74 (s, 3H), 4.45 (s, 2H), 5.11 (s, 2H), 5.40 (s, 2H), 6.91-6.99 ( m, 5H), 7.19 (s, 1H), 7.22 (s, 1H), -7.35 (m, 7H), 7.60 (d, 2H, J=7.5), 7.70 (d, 2H, J=7.5), 7.84 (m, 1H)- MS (ESI): 695 (M+H).

Dl——(p-trifluoromethylbiphenyl-4-yl)formylhydrazide

10.5 g of intermediate M7 In 30 ml of methanol, 20 ml of a water and hydrazine solution having a mass fraction of 85% was added, and refluxed for 4 hours, and the reaction was monitored by TLC. The solvent was evaporated to dryness under reduced pressure, and then the residue was taken toluene to give a white solid. ^-NMR (CDC1 ₃ , 300 MHz) δ 4.15 (s, 2Η), 7.53 (s, 1 H), 7.67 (d, 2H, J=8.1), 7.71 (s, 4H), 7.85 (d, 2H, J=8.1); MS (EI) m/z: 280 (M^).

D2——-ethyl-2-mercapto-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazole

5.6 g of intermediate D1 (1 eq.), 1.76 ml of ethyl isothiocyanate (1 eq.) was refluxed in 30 ml of anhydrous ethanol for 2.5 h. Most of the ethanol was distilled off under reduced pressure, and 3.26 g (1. 1 eq.) of K ₂ C0 ₃ and 30 ml of water were added and refluxed for 2 hr. The flask was placed in an ice bath, concentrated hydrochloric acid was added dropwise to neutral, and a large white solid was precipitated, collected by filtration, washed with water and dried to yield 6.3 g. 1H-NMR (d ₆ -DMSO, 300 MHz) δ ΐ .90 (t, 3 Η, J = 7.2), 4.09 (q, 2H, ^ 7.2), 7.82 (d, 2H, J = 8.4), 7.85 (d, 2H, J=9.3), 7.94 (d, 2H, J=8.4), 7.98 (d, 2H, J=8.1), 13.99 (s, 1H); MS (EI) m/z: 349 (M^). D3—— 4-ethyl-5-(p-trifluoromethylbiphenyl-yl)-4H-1,2,4-triazole

6.3 g of intermediate D2 (1 eq.) was suspended in 30 ml of CH ₂ C1 ₂ , 1.5 ml of AcOH was added and placed in a 35 'C oil bath. 5.1 ml of aqueous hydrogen peroxide solution (total > 2.5 equivalents) was slowly added dropwise, and the mixture was dropped over 0.5 h, and stirred at room temperature for 0.5 h. Then, the reaction flask was placed in an ice bath, 10% aqueous sodium hydroxide solution was added dropwise to a pH value of more than 10, CH ₂ C1 _{2 was} extracted twice, and the organic phase was combined with brine to wash twice, and dried magnesium sulfate, column layer The precipitate was isolated to give 4.5 g of a solid. ¹ H-NMR (CDC1 ₃ , 300 MHz) 51.47 (t, 3H, J = 7.4), 4.15 (q, 2H, J = 7.2), 7.73 (d, 8H), 8.30 (s, 1H); MS (EI m/z: 317 (M.

Ό4——〖4-Ethyl-5-(p-trifluoromethylbiphenyl-4-yl) ~ ff-l,2,4-triazol-3-yl]methanol

4.5g of intermediate D3 was refluxed in 20ml of 37% formaldehyde aqueous solution for 12h to obtain a clear liquid. After cooling, 20ml of saturated brine was added, then extracted with 100ml of dichloromethane, and the organic phase was combined and washed with saturated brine. Four times, the magnesium sulfate was dried, and the solution was evaporated to at least an amount of product, which was collected by filtration and dried to obtain 2.0 g. The mother liquor column was chromatographed to give 2.3 g of a white solid. ^{_{! H-NMR (CD 3 OD}} , 300 MHz) 51.33 (t, 3Η, J = 7.2), 4.28 (q, 2H, J = 7.2), 4.85 (s, 2H), 7.78 (d, 4H, J = 8.1 ), 7.90 (d, 4H _: J = 7.8) - MS (EI) m/z: 347 (M.

D5—— 3-azidomethyl-4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazole

Under nitrogen, 1.04 g (1 eq.) of D4, 0.77 ml (1.2 eq.) of DPPA and 0.67 ml (1.5 eq.) of DBU were refluxed in 10 ml of THF for 3 h. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with EA, and washed twice with brine, dried and then purified by column chromatography eluting with CH ₂ Cl ₂ /MeOH = 20:1. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 51.38 (t, 3Η, J = 7.4), 4.15 (q, 2H, J = 7.4), 4.64 (s, 2H), 7.74 (d, 8H) - MS (EI m/z: 372 (M^).

D6——〖4-Ethyl-5-(p-trifluoromethylbiphenyl-4-yl) ~ ff-l,2,4-triazol-3-yl]methylamine

0.94 g of intermediate D5 (1 eq.) was dissolved in THF-H ₂ O (8-0.5 mm), and 990 mg of Ph ₃ P (1.5 eq. Stir in the silica gel, and evaporate to dry a short silica gel column. Wash the low-polarity triphenylphosphine and triphenylphosphine oxide with EA, then collect the target product with methanol. Evaporate the methanol and leave the residue. The mixture was dissolved in a mixture of CH ₂ Cl ₂ /MeOH = 15:1, and the insoluble silica gel was filtered out and evaporated to dryness. H-NMR (CDC1 ₃ , 300 MHz) 51.35 (t, 3Η, J=7.5), 1.75 (s, 2H), 4.13 (s, 2H), 4.15 (q, 2H, J=7.4), 7.72 (s) , 8H); MS (EI) m/z: 346 (M.

D7 ~~ 2-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-l,2,4-triazol-3-yl]methylamine-cyclopentan-1- Ethyl carboxylic acid

0.67 g of intermediate D6 (1 equivalent) was dissolved in 10 ml of absolute ethanol, and 320 μl (1.1 equivalent) of cyclopentanone was added.

Ethyl-2-carboxylate and 860 μl (2 equivalents) of tetraethyl silicate were refluxed under nitrogen. The reaction was monitored by TLC and was completed in 5 h. Stirred directly into a silica gel, evaporated to dryness and after column _{_{chromatography, CH 2 Cl 2 / MeOH =}} 30: 1 as eluent afforded 0.88g of solid. H-NMR (CDC1 ₃ , 300 MHz) 51.25 (t, 3Η, J=7.2), 1.34 (t, 3H, J=7.2), 1.86 (m, 2H), 2.52 (t, 2H, J=7.2) , 2.74 (t, 2H, J=7.6), 4.13 (q, 2H, J=7.2), 4.65 (d, 2H, ^6.6), 7.73 (m, 9H)- MS (EI) m/z: 484 (M.

D8——1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-5,6-triam Methyl-2-thiouracil

Under nitrogen, 0.80 g (1 equivalent) of intermediate D7, 0.9 ml (4 equivalents) of trimethylsilyl isothiocyanate and 2 ml of dry DMF were heated at 140 ° C, and the reaction was completed in 8 h. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise, and 15 ml of EA and 10 ml of water were added and stirred. After 2 hours, the precipitated solid was collected and dried to give 0.53 g. ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 51.35 (t, 3H, J = 7.2), 2.06 (m, 2H), 2.67 (t, 2H, J = 7.5), 3.07 (t, 2H, J = 7.2), 4.20 (q, 2H, J=7.2), 5.68 (s, 2H) _: 7.79 (d, 2H, J=8.4), 7.86 (d, 2H, ^8.7), 7.94 (d, 2H, J= 8.4), 7.99 (d, 2H, J=8.1); MS (EI) m/z: 497 (M^).

Example 55 - Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)- ff-l,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio) -6,7-Dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

100 mg of intermediate D8 (1 equivalent), 4-fluorobenzyl bromide 28 μl (1.1 eq.), anhydrous potassium carbonate 40 mg (1.5 eq.), refluxed for 3 h in 3 ml of acetone, and the reaction was completed. The inorganic salt was filtered off, and the filtrate was applied to silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH = 10: ^-NMR (CDC1 ₃ , 300 MHz) 51.30 (t, 3Η, J=7.2), 2.13 (m, 2H), 2.86 (t, 2H, J=7.4), 3.05 (t, 2H, J=7.6), 4.10 (q, 2H, J=7.2), 4.53 (s, 2H), 5.24 (s, 2H), 6.97 (t, 2H, J=8.7), 7.35 (dd, 2H, J=8.7, 5.3), 7.67 -7.76 (m, 8H); MS (ESI): 606 (M+H).

Example 56 - Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-2-p-methoxybenzoic acid -6,7-dihydro-1H-[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 55 except that "p-methoxybenzyl bromide" was used instead of "4-fluorobenzyl bromide". H-NMR (CDC1 ₃ , 300 MHz) 51.28 (t, 3Η, J=7.2), 2.12 (m, 2H), 2.85 (t, 2H, J=7.4) _: 3.05 (t, 2H, J=7.6) , 3.76 (s, 3H), 4.10 (q, 2H, J=7.2), 4.51 (s, 2H), 5.24 (s, 2H), 6.81 (d, 2H, J=8.4), 7.29 (d, 2H, J=8.7), 7.73 (m, 8H)-MS (ESI): 618 (M+H). Example 57——1-[4-Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-1,2,4-triazol-3-yl]methyl-2-(2 , 3-: fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4 (5 ketone

Prepared according to the method of Example 55, except that "2-, 2-difluorobenzyl bromide" was used instead of "4-fluorobenzyl bromide".

H-NMR (CDC1 ₃ , 300 MHz) δ 1.31 (t, 3Η), 2.13 (m, 2Η), 2.86 (t, 2H), 3.06 (t, 2H),

4.13 (q, 2H), 4.61 (s, 2H), 5.23 (s, 2H), 7.04 (m, 2H), 7.35 (t, 1H), 7.74 (m, 8H).

Example 58 - Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)- ff-l,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio) ) 5-(1-methyl-1H-pyrazol-4-yl)methyl-pyrimidine-4(1H)-one

The synthesis was carried out by the method of Preparation from C3, except that D6 was used instead of C3.

300MHz) δ 1.16 (t, 3H, J=7.2), 3.56 (s, 2H), 3.83 (s, 3H), 4.02 (q, 2H, J=7.2), 4.55 (s, 2H), 5.16 (s, 2H), 6.99 (t, 2H, J=8.4), 7.21 (s, 1H), 7.30 (s, 1H), 7.32 (s, 1H), 7.40 (m, 2H), 7.72 (m, 8H); MS (ESI): 660 (M+H).

D9——4-Benzylbutyrate

5-phenylbutyric acid (3.28 g, 20 mmol) was dissolved in 20 ml of anhydrous methanol, and 2 ml of concentrated sulfuric acid was added dropwise with stirring. There is an exotherm, then reflux for 4h, stop. Most of the solvent was distilled off under reduced pressure, and 30 ml of ice water was added to the residue, and neutralized with a 10% sodium hydroxide solution. 60 m of dichloromethane was extracted three times, and the organic phases were combined, dried over magnesium sulfate, and evaporated to dryness. ^-NMR (CDC1 ₃ , 300MHz) δ 1.96 (m _: 2Η), 2.33 (t, 2H, J=7.5), 2.65 (t, 2H, J=7.5), 3.66 (s, 3H), -7.25 (m , 5H).

D10 ^ 4-Phenylbutyrohydrazide

Prepared according to the method of D1 except that D9 was used instead of M7. H-NMR (CD ₃ OD, 300 MHz) 51.97 (m, 2H), 2.14 (t, 2H, J = 7.2), 2.64 (t, 2H, ^7.2), 3.89 (vbrs, 2H), 6.80 (vbrs, 1H), 7.17 (m, 3H), 7.27 (m, 2H).

Dll—— 2- (p-trifluoromethyl)

Prepared according to the method of D1, using M3 instead of M7 as a raw material. ^-NMR (d ₆ -DMSO, 300 MHz) δ 3.41 (s, 2 Η), 4.26 (s, 2H, -NH ₂ ), 7.39 (d, 2H), 7.67 (d, 2H), 7.80 (d, 2H ), 7.87 (d, 2H), 9.26 (s, 1H)

Example 59——1_[4-ethyl-5-(3-phenylpropyl)- ff-l,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)- 6,7-Dihydro-1H-cyclopenta[rf]pyrimidine-4 (

The synthesis was carried out by referring to the method of Preparation Example 55 from D1, except that D1 was used instead of D1. ¹ H-NMR (CDC1 ₃ , 300MHz) δ 1.13 (t, 3Η), 2.13 (m, 4Η), 2.66 (t, 2Η), 2.78 (m, 4H), 2.95 (t, 2H), 3.79 (q, 2H), 4.49 (s, 2H), 5.12 (s, 2H), 6.95 (t, 2H), 7.18 (m, 3H), 7.28 (m, 2H), 7.33 (dd, 2H)- MS (ESI): 504 (M+H).

Example 60 - Ethyl-5-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-3-yl-1methyl-2-(4-fluorobenzyl Thio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidine-4 (5 ketone

The synthesis was carried out by referring to the method of Preparation Example 55 from D1, except that D1 was used instead of D1. ^-NMR (CDC1 ₃ , 300 MHz) 51.02 (t, 3Η, J=7.2), 2.11 (m, 2H), 2.83 (t, 2H, J=7.5), 2.98 (t, 2H, J=7.5), 3.82 (q, 2H, J=7.2), 4.23 (s, 2H), 4.49 (s, 2H), 5.11 (s, 2H), 6.95 (t, 2H, J=8.7): 7.31 (m, 4H), 7.53 (d, 2H, J=8.1), 7.64 (d, 2H, ^8.4), 7.69 (d, 2H, ^8.7); MS (ESI): 620 (M+H).

D12—— 1-(p-trifluoromethylbiphenyl-4-yl)oxazole

1.25 g (p-trifluoromethylbiphenyl-4-yl)bromoformin, 0.4 g of 1,2,4-triazole and 0.9 ml of DIPEA were refluxed in 15 ml of acetonitrile for 3 h, filtered to remove insolubles, and the filtrate was stirred. The silica gel was subjected to spin-drying and then purified by column chromatography to yield 0.54 g. 1H-NMR (CD ₃ OD, 300 MHz) 55.49 (s, 2H), 7.42 (d, 2H, J = 8.1), 7.68 (d, 2H, J = 8.1), 7.72 (d, 2H, J = 8.4) , 7.79 (d, 2H, J=8.4), 8.02 (s, 1H), 8.60 (s, 1H). D13——II- (p-trifluoromethylbiphenyl-4-triazol-3-yl) Methanol

Prepared by the method of D4. ^-NMR (CDC1 ₃ , 300 MHz) 53.91 (s, 1H), 4.79 (s, 2H) _: 5.48 (s, 2H), 7.37 (d, 2H, J=8.4), 7.58 (d, 2H, J= 8.4), 7.64 (d, 2H, J=8.7), 7.69 (d, 2H. J=8.7), 7.84 (s, 1H).

Example 61——1-[1-(p-Trifluoromethylbiphenyl-4-yl)methyl-1H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzyl) Thio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4(5H)-one

The synthesis was carried out by the method of Preparation Example 55 of D4, and D13 was used instead of D4. ^-NMR (CDC1 ₃ , 300 MHz) 51.99 (m, 2Η), 2.71 (m, 4H), 4.45 (s, 2H), 5.10 (s, 2H), 5.46 (s, 2H), 6.92 (t 2H, J=7.8), 7.18 (d, 2H, J=8.1), 7.29 (m, 2H), 7.50 (d, 2H, J=7.8), 7.62 (d, 2H, J=7.8): 7.70 (d, 2H) , J = 7.8), 7.92 (s, 1H).

D14 p-bromobenzyl isothiocyanate

The drying tube was sealed with water vapor, and a flask containing 100 ml of THF was charged with 22.8 g (0.1 mol, 1 equivalent) of p-bromobenzylamine and 17.5 ml (3.3 equivalent) of triethylamine, and placed in an ice bath. Dissolved in 25ml THF is added dropwise 6ml (l eq.) CS _2, ₃ 0 minutes dropwise to give a white emulsion, then at room temperature for 1 hour. Then, 20.9 g (ll equivalent) of p-toluenesulfonyl chloride was added in portions in an ice bath. After the reaction was continued for 1 hour, ice water was added thereto, and the pH was adjusted to about 5 with concentrated hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and evaporated. The solvent was obtained as a yellow oil which was used in the next step without purification. D15 ~~ 2-hydroxyacetyl hydrazine

9 g (0.1 mol, 1 equivalent) of methyl hydroxyacetate and 9.6 ml (1.5 equivalents) of 85% hydrazine hydrate were refluxed in 100 ml of methanol for 8 hours, and the reaction was completed. Methanol and excess hydrazine hydrate were distilled off under reduced pressure, and toluene was added to remove residual water to obtain a white solid which was directly used for the next reaction.

D16——(4-p-bromobenzyl-3-indolyl-4H-1,2,4-triazole-5-yl)methanol

The D14 and D15 synthesized above were refluxed in 200 ml of ethanol for 2 h, and a large amount of white precipitate appeared. Most of the ethanol was distilled off under reduced pressure, and 200 ml of water and 20.7 g (1.5 eq.) of potassium carbonate were added to the residue, followed by reflux for 1 h. After cooling, put it in an ice bath, adjust the pH value of hydrochloric acid to 8-9, and precipitate a large amount of white solid. If there is a yellow solid, add a small amount of methylene chloride and stir it. Collect it by filtration, wash it several times, and wash off the dichloromethane. The color, after drying, gave 25 g of a white solid. ^-NMR (d ₆ -DMSO, 300 MHz) 54.37 (s, 2H), 5.24 (s, 2H), 5.73 (s, 1H, -OH), 7.25 (d, 2H, J=8.4), 7.54 (d , 2H, J=8.7), 13.80 (s, 1H).

D17——(4-p-bromobenzyl-ff-l,2,4-triazole-5-yl)methanol

25 g of intermediate D16 (1 eq.) was suspended in 100 ml of CH ₂ C1 ₂ , 6 ml of AcOH was added and placed in a 35 'C oil bath. 24 ml of aqueous hydrogen peroxide solution (>2.5 eq.) was slowly added dropwise, and the mixture was stirred for about 1 hour, and then stirred at room temperature for 0.5 h. Then, the reaction flask was placed in an ice bath, and a 10% aqueous sodium hydroxide solution was added dropwise thereto to a pH of more than 10, and it was allowed to stand for 0.5 hour. The precipitated solid was collected by filtration and washed with water and CH ₂ C1 ₂ . The filtrate was separated into an organic phase. After concentration, solids were precipitated, collected by filtration, and dried to give a white powder (20.4 g). ^-NMR (d _s -DMSO, 300 MHz) 54.55 (s, 2H), 5.27 (s, 2H), 5.64 (s, 1H, -OH), 7.22 (d, 2H, J=8.4), 7.57 (d , 2H, J=8.4), 8.53 (s, 1H).

Dl 8 - 14-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazole-5-yl]methanol

Nitrogen replacement, intermediate D17 13.4 g (50 mol, 1 equivalent), p-trifluoromethylbenzeneboronic acid 10.4 g (1.1 eq.), cesium carbonate 32.6 g (2 eq.) and tetratriphenylphosphine palladium 2.9 g ( 0.05 equivalent) was refluxed in 100 ml of dioxane for 18 h and stopped. The inorganic salt was removed by filtration and washed with dioxane. The filtrate was evaporated to dryness and then recrystallized from CH ₂ C1 ₂ /MeOH to yield about 13 g of pale yellow powder. iH-NMR (d ₆ -DMSO, 300 MHz) 54.59 (d, 2H, J = 5.4), 5.37 (s, 2H), 5.69 (t, 1 H, J = 5.4), 7.40 (d, 2H, J = 8.1), 7.75 (d, 2H, J=8.4), 7.81 (d, 2H, J=8.4), 7.89 (d, 2H, J=8.4), 8.59 (s, 1H); MS (ESI): 334 ( M+H).

D19——5-Chloromethyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazole hydrochloride

In a 100 ml flask, 5 mmol of intermediate D18 and 20 ml of methylene chloride were placed, and 2 drops of DMF was added as a catalyst, and placed in an ice bath. 0.42 ml (about 6 mmol) of thionyl chloride dissolved in 5 ml of dichloromethane was added dropwise with a constant pressure dropping funnel, and the mixture was dropwise added for 10 minutes, and then reacted at room temperature. The progress of the reaction was monitored by TLC and the reaction was completed in about 2 hours. (Treatment 1) The precipitate was collected using a Buchner funnel and washed twice with dichloromethane. 80'C was dried to a white or light yellow powder. (Process 2) The filtrate is evaporated to dryness to give a yellow solid which can be directly used for the next reaction. ^-NMR (d ₆ -DMSO, 300 MHz) 55.06 (s, 2H), 5.46 (s, 2H), 7.47 (d, 2H, J = 8.0), 7.77 (d, 2H, J = 8.4), 7.80 ( d, 2H, J=8.8), 7.89 (d, 2H, ^8.0), 9.12 (s, 1H).

9S D20——N-methyl-N-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl]methylaminoacetate

2.0 g (1 equivalent) of intermediate D19, sarcosine methyl ester hydrochloride 0.86 g (1.2 equivalents) and diisopropylethylamine 3 ml (about 3 equivalents) in 20 ml of acetonitrile, heated at 70-80 ° C, TLC monitors the progress of the reaction. After completion of the reaction, acetonitrile was distilled off, and the residue was added to 40 ml of an ammonium chloride solution, and the mixture was extracted twice. The organic phase was combined and washed twice with brine. ^-NMR (CDC1 ₃ , 300 MHz) 52.38 (s, 3H), 3.32 (s, 2H), 3.70 (s, 3H), 3.86 (s, 2H), 5.51 (s, 2H), 7.31 (d, 2H , J=8.4), 7.60 (d, 2H, J=8.1), 7.68 (m, 4H), 8.16 (s, 1H).

D21——N-Methyl-N-[3-hydroxymethyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-5-yl] Methyl methylaminoacetate

Intermediate D20 1.13 g was refluxed in 15 ml of 37% aqueous formaldehyde for 5 h, and the reaction was monitored by TLC. The reaction mixture was poured into 40 ml of a saturated aqueous solution of sodium chloride, and the organic phase was combined, and the organic phase was washed three times with brine. ¹ H-NMR (CDC1 ₃ , 400 MHz) 52.33 (s, 3H), 3.26 (s, 2H), 3.66 (s, 3H), 3.75 (s, 2H), 4.74 (s, 2H), 5.62 (s, 2H), 7.26 (d, 2H, J=8.0), 7.56 (d, 2H, J=8.0), 7.65 (d, 2H, J=8.8), 7.69 (d, 2H, ^8.8). D22——N -methyl-N-[3-azidomethyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,triazol-5-yl 1methylaminoacetate ester

Intermediate D21 1.0 g (1 eq.), DPPA 0.58 ml (1.2 eq.) and DBU 0.44 ml (1.3 eq.) were refluxed in 10 ml of THF for 3 h under nitrogen atmosphere. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with EA, and washed twice with brine. H-NMR (CDC1 ₃ , 400 MHz) 52.44 (s, 3H), 3.36 (s, 2H), 3.70 (s, 3H), 3.88 (s, 2H), 4.47 (s, 2H), 5.63 (s, 2H), 7.22 (d, 2H, J=8.0), 7.61 (d, 2H, J=8.0), 7.69 (d, 2H, J=8.4), 7.72 (d, 2H, J=8.8).

D23——AL methyl_AL[3-aminomethyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-5-yl] methyl Methyl aminoacetate

0.97 g of Intermediate D22 (1 eq.) was dissolved in THF-H ₂ O (8-0.5 ml), and 806 mg of Ph ₃ P (1.5 eq. Stir in the silica gel, evaporate to a short silica gel column, first wash off the low polarity triphenylphosphine and triphenylphosphine oxide with EA, then elute with methanol to collect the target product part, and evaporate the methanol, residue The solution was dissolved in a mixture of CH ₂ Cl ₂ / MeOH = 15:1. ^{_{! H-NMR (CDC1 3,}} 400 MHz) 52.37 (s, 2H + 3H), 3.30 (s, 2H), 3.69 (s, 3H), 3.81 (s, 2H), 4.01 (s, 2H), 5.62 ( s, 2H), 7.23 (d, 2H, J=8.4), 7.59 (d, 2H, J=8.0), 7.69 (m, 4H).

D24 ~~ 2-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(methyl)(2-methoxy-2-oxoethyl)aminomethyl-4H- 1,2,4-triazol-3-yl]methylamine-cyclopent-1-enecarboxylate 0.8 g of intermediate D23 (1 equivalent) was dissolved in 10 ml of absolute ethanol, and 260 μl (1 equivalent) of ethyl cyclopentanone-2-carboxylate and 800 μl (2 equivalents) of tetraethyl silicate were added and refluxed under nitrogen. The progress of the reaction was monitored by TLC and completed in 3 hours. The mixture was directly stirred into silica gel, evaporated to dryness, and then purified by column chromatography eluting with CH ₂ Cl ₂ /MeOH = 40:1. H-NMR (CDC1 ₃ , 400 MHz) 51.21 (t, 3Η, J=7.2), 1.75 (m, 2H), 2.36 (s, 3H), 2.50 (m, 4H), 3.29 (s, 2H), 3.65 (s, 3H), 3.82 (s, 2H), 4.06 (q, 2H, J=7.5), 4.36 (d, 2H, J=6.0), 5.56 (s, 2H), 7.15 (d, 2H, J = 8.1), 7.56 (m, 3H), 7.68 (m, 4H); MS (ESI): 586 (M+H).

D25——N-methyl, V_{5-[4-oxo-2-thioxo, 4,6,7-tetrahydro-2H-cyclopentadienyl-1(5H)-yl] methyl-4 - (p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-ylindolemethylaminoacetate

Under nitrogen, 0.89 g (1 eq.) of intermediate D24, 0.77 ml (4 eq.) of trimethylsilyl isothiocyanate and 1 ml of dry DMF were heated at 140 ° C, and the reaction was completed in 6 h. After cooling, the flask was placed in an ice bath, and the mixture was stirred with a saturated aqueous solution of sodium hydrogencarbonate, and then added with 10 ml of EA and 10 ml of water, and the precipitated solid was collected after 2 h, and dried to give O. g H-NMR (d ₆ - DMSO, 300 MHz) 51.94 (m, 2Η), 2.24 (s, 3H), 2.50 (t, 2H), 2.83 (t, 2H, J=6.9), 3.35 (s, 2H), 3.57 (s, 3H) , 3.81 (s, 2H), 5.50 (s, 2H), 5.61 (s, 2H), 7.26 (d, 2H, J=8.1), 7.71 (d, 2H, ^8.1), 7.81 (d, 2H, 8.4 ), 7.87 (d, 2H, J=9.0), 12.55 (s, 1H).

Example 62 - N-methyl, N-{3-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidin-1 (5H )-yl 1 methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-ylindole methylaminoacetate 120 mg intermediate D25 (1 equivalent), 4-fluorobenzyl bromide 28 μl (1.1 eq.), anhydrous potassium carbonate 55 mg (2 eq.) was refluxed in 3 ml of acetone for 1 h, and the reaction was completed. The inorganic salt was filtered off and the filtrate was quickly separated to give 65 mg of solid. H-NMR (CDC1 ₃ , 400 MHz) 51.98 (m, 2Η), 2.43 (s, 3H), 2.67 (t, 2H, J=7.2), 2.76 (t, 2H, 3.38 (s, 2H), 3.66 (s, 3H), 3.95 (s, 2H), 4.43 (s, 2H), 5.03 (s, 2H),

5.64 (s, 2H), 6.92 (t, 2H, J=8.0), 7.00 (d, 2H, J=7.6), 7.30 (m, 2H), 7.46 (d, 2H, J=7.6), 7.61 (d , 2H, J=8.0), 7.71 (d, 2H, ^8.0).

Example 63 - N-methyl-ί3- [2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta]pyrimidin-1(5H)-yl 1 methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-yl}methylaminoacetic acid

40 mg of the compound 62 in a mixed solution of i-PrOH-CH ₂ Cl ₂ -H ₂ O (1 ml - 0.5 ml - 3 ml), ice-cooled, and added 0.1 ml of a 10% aqueous NaOH solution, and the reaction was completed for lh. 5 ml of water was added, washed once with 3 ml of CH ₂ C1 ₂ , separated into an aqueous phase, neutralized with a dilute acetic acid solution, and a solid was precipitated, collected by filtration, washed twice with 50% aqueous acetone, and dried to give 12 mg of white solid. ¹ H-NMR (CD ₃ OD, 300 MHz) 52.06 (m, 2H), 2.41 (s, 3H), 2.70 (t, 2H, J = 7.2), 2.84 (t, 2H, J = 6.9), 3.38 ( s, 2H), 4.00 (s, 2H), 4.35 (s, 2H) _: 5.26 (s, 2H), 5.67 (s, 2H), 6.86 (t, 2H, ^8.7), 7.23-7.31 (m, 4H) ), 7.56 (d, 2H, 7.8), 7.73 (m, 4H)- MS (ESI): 691 (MH).

D26—— 5-methyl-4-p-bromobenzyl-ff-l,-triazole

2.6 ml of N,N-dimethylformylaminodiacetal and 2 g of acetohydrazide in 3 ml of acetonitrile, heated at 60 ° C for 0.5 h, then added 3.72 g of p-bromobenzylamine and 4.5 ml of acetic acid, 120 ° C reaction for 3 h . After cooling, it was poured into water, and the mixture was extracted twice with EA. ¹ H-NMR (CDC1 ₃ , 300 MHz) 52.36 (s, 3H), 5.04 (s, 2H), 6.97 (d, 2H, J=8.4), 7.50 (d, 2H, J=8.4), 8.08 (s _: 1H).

D27—— 5-methyl-4-(p-trifluoromethylbiphenyl-Φ-yl)methyl-4H-1,2,4-triazole

Nitrogen replacement, intermediate D26 2.0 g (1 equivalent), p-trifluoromethylbenzeneboronic acid 1.6 g (1.05 equivalent), cesium carbonate 5.2 g (2 equivalents) and tetratriphenylphosphine palladium 0.5 g (0.05 equivalents) 15 ml of dioxane was refluxed for 12 h and stopped. The inorganic salt was removed by filtration and washed with dioxane. The filtrate was evaporated to a minimum amount, and the solid was precipitated, collected by filtration, and dried to yield 1.65 g. ^{_{! H-NMR (CDC1 3,}} 300 MHz) 52.42 (s, 3H), 5.15 (s, 2H), 7.21 (d, 2H, J = 8.4), 7.61 (d, 2H, J = 8.1), 7.66 (d , 2H, J=8.7), 7.70 (d, 2H, J=9.0), 8.13 (s, 1H). D28——II-(p-trifluoromethylbiphenyl-4-yl)methyl-5- ke-Iff-imidazol-2-yl]methanol

Prepared according to the method of D21 except that D27 was replaced by D27. ^-NMR (CDC1 ₃ , 300 MHz) 52.34 (s, 3H), 4.75 (s, 2H), 5.32 (s, 2H), 7.17 (d, 2H), 7.57 (d, 2H), 7.66 (d, 2H ), 7.69 (d, 2H).

D29 ^butyrylhydrazide

The preparation method is the same as that of D15 except that "methyl butyrate" is used instead of "methyl hydroxyacetate".

D30——5-n-propyl-4-t-bromobenzyl -3-mercapto-4H-1,2,4-triazole

Prepared according to the method of D16 except D15 which was replaced by D29. H-NMR (d ₆ -DMSO, 300 MHz) 50.83 (t, 3 Η, J = 7.2), 1.49 (m, 2H), 2.48 (t, 2H, ^7.2), 5.21 (s, 2H), 7.22 (d , 2H, J=8.7), 7.56 (d, 2H, J=8.7), 13.69 (s, 1H).

D31—— 5-n-propyl-4--4-bromobenzyl- 4H-1,2,4-triazole

1.2 g of intermediate D2 (1 equivalent) was suspended in 30 ml of CH ₂ C1 ₂ , added with 0.3 ml of AcOH, and placed in a 35 ° C oil bath. 1.1 ml of aqueous hydrogen peroxide solution (total > 2.5 equivalents) was slowly added dropwise, and the mixture was dropped at about 10 minutes, and stirred at room temperature for 0.5 h. Then, the reaction flask was placed in an ice bath, 10% aqueous sodium hydroxide solution was added dropwise to a pH value of more than 10, CH ₂ C1 _{2 was} extracted twice, and the organic phase was combined with brine to wash twice, and dried magnesium sulfate, column layer The 630 m g gel was separated. H-NMR (CDC1 ₃ , 300 MHz) 50.98 (t, 3H, J = 7.2), 1.77 (m, 2H), 2.62 (t, 2H, J = 7.2), 5.04 (s, 2H), 6.97 (d, 2H, J=8.7), 7.51 (d, 2H, J=8.7), 8.06 (s, 1H).

D32—— 5-n-propyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazole

Nitrogen replacement, intermediate D31 0.62 g (1 equivalent), p-trifluoromethylbenzeneboronic acid 0.466 g (ll equivalent), cesium carbonate 1.45 g (2 equivalents) and tetratriphenylphosphino palladium 0.13 g (0.05 equivalents) 8 ml of dioxane was refluxed for 12 h and stopped. The inorganic salt was removed by filtration and washed with dioxane. The filtrate was evaporated to at least an amount of silica gel and then subjected to column chromatography to give 0.62 g of solid. H-NMR (CDC1 ₃ , 300 MHz) δ 1.00 (t, 3H), 1.81 (m, 2H), 2.68 (t, 2H), 5.15 (s, 2H), 7.20 (d, 2H), 7.61 (d, 2H), 7.69 (m, 4H), 8.13 (s, 1H).

D33——II-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-n-propyl-1H-imidazole-2-yl]methanol

Prepared according to the method of D21 except that D32 was replaced by D32. H-NMR (CDC1 ₃ , 400 MHz) δθ.97 (t, 3Η), 1.76 (m, 2Η), 2.62 (t, 2H), 4.66 (s, 1H), 4.76 (s, 2H), 5.35 (s , 2H), 7.18 (d, 2H), 7.60 (d, 2H), 7.68 (d, 2H), 7.72 (d, 2H).

D34——II-(p-trifluoromethylbiphenyl-4-yl)methyl-5-isopropyl-1H-imidazole-2-yl]methanol

Prepared according to the method of D33 except that "2-methylpropionate" was used instead of "methyl butyrate" as a starting material. H-NMR (CDC1 ₃ , 400 MHz) 51.30 (d, 6H), 2.30 (s, 1H), 2.92 (m, 1H), 4.67 (s, 2H), 5.34 (s, 2H), 7.13 (d, 2H) ), 7.59 (d, 2H), 7.68 (m, 4H).

D35——II-(p-trifluoromethylbiphenyl-4-yl)methyl-5-cyclopropyl-1H-imidazol-2-yl]methanol

Prepared according to the method of D33, except that "methyl cyanocarboxylate" was used instead of "methyl butyrate" as a starting material.

Example 64 - I-methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-ring

The synthesis was carried out by referring to the method of Preparation Example 62 from D21, except that D28 was used instead of D21. ^-NMR (CDC1 ₃ , 300 MHz) 51.92 (m, 2Η), 2.50 (s, 3H), 2.56 (t, 2H, J=7.2), 2.73 (t, 2H, J=7.2), 4.46 (s, 2H), 5.11 (s, 2H), 5.18 (s, 2H), 6.82 (d, 2H, J=7.8), 6.95 (t, 2H, J=8.7): 7.34 (dd, 2H, J=5.4, 8.7 ), 7.44 (d, 2H, J = 8.1), 7.62 (d, 2H, J = 8.1), 7.70 (d, 2H, J = 8.7) - MS (ESI): 606 (M+H).

Example 65——I-Methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio) - 5-(1-methyl-1H-pyrazol-4-yl)methyl-pyrimidin-4(1H)-one

The synthesis was carried out by referring to the method of Preparation Example 29 from C3, except that D28 was used instead of C3. ^-NMR (CDC1 ₃ , 300 MHz) 52.46 (s, 3H), 3.37 (s, 2H), 3.78 (s, 3H), 4.39 (s, 2H), 5.01 (s, 2H), 5.13 (s, 2H) ), 6.77 (d, 2H, J=8.1), 6.97 (m, 3H), 7.34 (m, 6H), 7.65 (m, 4H); MS (ESI): 660 (M+H).

Example 66 - 1-[5-n-propyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-

The synthesis was carried out by referring to the method of Preparation Example 62 from D21, except that D33 was used instead of D21. ^-NMR (CDC1 ₃ , 300 MHz) δΐ .04 (t, 3Η, ^7.5), 1.82-2.00 (m, 4Η), 2.56 (t, 2Η, J=7.2), 2.75 (m, 4H), 4.42 (s, 2H), 5.16 (s, 2H), 5.25 (s, 2H), 6.86 (d, 2H, J=8.1), 6.93 (t, 2H, J=8.7), 7.32 (dd, 2H, J= 5.7, 8.4), 7.45 (d, 2H, J=7.8), 7.61 (d, 2H, J=8.1), 7.71 (d, 2H, J=8.4).

Example 67——1-[5-Isopropyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one

The synthesis was carried out by referring to the method of Preparation Example 62 from D21, except that D. ^-NMR (CDC1 ₃ , 300 MHz) 51.42 (d, 6Η, J=6.9), 1.93 (m, 2H), 2.57 (t, 2H, J=7.5), 2.76 (t, 2H _: J=7.5), 2.99 (m, 1H), 4.43 (s, 2H), 5.10 (s, 2H), 5.25 (s, 2H), 6.82 (d, 2H, J=8.1), 6.94 (t, 2H, J=8.7), 7.33 (dd, 2H, J=8.4, 5.4), 7.44 (d, 2H, J=7.8), 7.61 (d, 2H, J=8.4), 7.70 (d, 2H, J=8.7).

Example 68——1-[5-Cyclopropyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-ff-l,2,4-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1

The synthesis was carried out by referring to the method of Preparation Example 62 from D21, except that D35 was used instead of D21. ^-NMR (CDC1 ₃ , 300 MHz) δΐ .07 (m, 2Η), 1.23 (m, 2H), 1.71 (m, 2H), 1.90 (m, 2H), 2.54 (t, 2H), 2.70 (t , 2H), 2.99 (m, 1 H), 4.47 (s, 2H), 5.10 (s, 2H), 5.31 (s, 2H), 6.87 (d, 2H), 6.96 (t, 2H), 7.35 (dd , 2H), 7.45 (d, 2H), 7.63 (d, 2H), 7.71 (d, 2H).

D36—— 4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-benzylthiomethyl- 4H-1,2,4-triazole

Intermediate D19 610 mg, benzyl mercaptan 0.18 ml, DIPEA 0.65 ml in 10 ml of acetonitrile, heated at 60 ° C for 3 h. The acetonitrile was evaporated, and the residue was dissolved in EtOAc. ^-NMR (CDC1 ₃ , 300 MHz) 53.70 (s, 2H), 3.71 (s, 2H), 5.22 (s, 2H), 7.21 (d, 2H, J=8.4), 7.33 (m, 5H), 7.65 (d, 2H, J=8.4), 7.70 (d, 2H, J=8.4), 8.16 (s, 1H).

D37 ^ II- (p-Trifluoromethylbiphenyl-4-yl)methyl-5-phenylmethylthiomethyl-1H-imidazol-2-yl]methanol

Prepared according to the method of D21 except that D20 was replaced by D36. ^-NMR (d ₆ -DMSO, 300 MHz) 53.65 (s, 2H), 3.70 (s, 2H), 4.52 (d, 2H, J = 5.7), 5.36 (s, 2H), 5.64 (t, 1H, 5.7), 7.21 (d, 2H, J=8.1), 7.29 (m, 5H), 7.70 (d, 2H, ^8.4), 7.80 (d, 2H, ^8.4), 7.87 (d, 2H, J=8.7 ).

D38——II-(p-trifluoromethylbiphenyl-4-yl)methyl-5-phenylsulfonemethyl-1H-imidazole-2-yl]methanol

Intermediate D37 0.7 g (1 eq.) was suspended in 15 ml of DCM, and 1.07 g of m-CPBA (70-75% pure, 3 eq.) was added to the ice bath and then reacted at room temperature for 2 h. It is quenched with saturated NaHC0 ₃ solution, stirred until no more bubbles are formed, the organic phase is separated, and the aqueous phase is extracted once with DCM. The organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate and then evaporated. solid. 1H-NMR (CDC1 ₃ , 300 MHz) 52.90 (s, 1H), 4.18 (s, 2H), 4.37 (s, 2H), 4.87 (s, 2H), 5.54 (s, 2H), 7.19 (d, 2H , J=7.8), 7.36 (m, 3H), 7.53 (d, 2H, J=8.1), 7.58 (m, 4H), 7.67 (d, 2H, J=8.7).

Example 69——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-phenylmethylsulfonemethyl-ff-l,2,4-triazol-3-yl] A 2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out by referring to the method of Preparation Example 62 from D21, except that D38 was used instead of D21. ^-NMR (CDC1 ₃ , 400 MHz) 52.04 (m, 2H), 2.71 (t, 2H, J=7.2), 2.83 (t, 2H, ^7.2), 4.28 (s, 2H), 4.40 (s, 2H ), 4.44 (s, 2H), 5.08 (s, 2H), 5.42 (s, 2H), 6.91 (t, 2H, J=8.4), 6.96 (d, 2H, J=8.0), 7.29 (dd, 2H) , J=8.4, 5.6), 7.43 (m, 5H), 7.58 (d, 2H, J=8.4), 7.66 (m, 2H):

=8.0).

D39 ^ 4-hydroxybutyrylhydrazide

The preparation method is the same as that of D15 except that "γ-butyrolactone" is used instead of "methyl hydroxyacetate". ^-NMR (d ₆ -DMSO, 300 MHz) δ 1.61 (m, 2 Η), 2.03 (t, 2H), 3.45 (m, 2H), 4.13 (s, 2H), 4.44 (t, 1H, -OH) , 8.90 (s, 1H).

D40—— 4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(3-hydroxy)propyl-4H-1,2,4-triazole

Prepared according to the method of D32, except that D39 was used instead of D29. H-NMR (CDC1 ₃ , 300

10S MHz) δ 2.06 (m, 2H), 2.85 (t, 2H), 3.74 (t, 2H), 5.18 (s, 2H), 7.23 (d, 2H), 7.62 (d,

2H), 7.68 (m, 4H), 8.14 (s, 1H), 9.86 (s, 1 H).

D41—— 4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-propanal -4H-1,2,4-triazole

205 μl (1.5 eq.) of oxalyl chloride in 5 ml of DCM was protected with nitrogen and placed in a -60 C cold trap. 305 μl (3 equivalents) of DMSO dissolved in 5 ml of DCM was added in a constant pressure dropping funnel over 5 min, and 0.52 g (l equivalent) of intermediate D40 dissolved in 5 ml of DCM and 150 μl (3 equivalents) of DMSO was added over 5 min. , stir for 10 min. Then, 800 μl (4 equivalents) of NEt ₃ dissolved in 5 ml of DCM was added over 5 min, stirred for 10 min, and the reaction was quenched with a saturated aqueous solution of ammonium chloride. The DCM layer was separated and washed twice with saturated brine and dried over anhydrous sodium sulfate. , the quick column separates 360mg of glue. H-NMR (CDC1 ₃ , 300 MHz) δ 2.93 (t, 2H), 3.19 (t, 2H), 5.24 (s, 2H), 7.21 (d, 2H), 7.61 (d, 2H), 7.68 (m, 4H), 8.13 (s, 1H).

D42—— 4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(3-dimethylamino)propyl-4H-1,2,4-triazole

360 mg of intermediate D41 (1 eq.), 115 μl (1.1 eq.) of diethylamine was dissolved in 5 ml of DCM, placed in an ice bath, and 318 mg (1.5 eq.) of NaBH(OAc)3 was added for 1 h. The reaction was quenched with a saturated solution of NaHC.sub.3, and the DCM layer was separated and dried over anhydrous sodium sulfate. H-NMR (CDC1 ₃ , 300 MHz) δ 1.12 (t, 6H), 2.13 (m, 2H), 2.78 (m, 8H), 5.19 (s, 2H), 7.22 (d, 2H), 7.60 (d, 2H), 7.68 (m, 4H), 8.14 (s, 1H).

Example 70——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(3-diethylamino)propane S~ ff-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The synthesis was carried out in accordance with the method of Example 62 except that D42 was used instead of D20. 1H-NMR (CDC1 ₃ , 300 MHz) δ 1.35 (t, 6H), 2.00 (m, 2H), 2.41 (m, 2H), 2.69 (t, 2H), 2.83 (t, 2H), 3.02 (t, 2H), 3.10 (q, 4H), 3.22 (t, 2H), 4.42 (s, 2H), 5.07 (s, 2H), 5.33 (s, 2H), 6.91 (t, 2H), 6.97 (d, 2H ), 7.29 (dd, 2H), 7.44 (d, 2H), 7.59 (d, 2H), 7.70 (d, 2H)- MS (ESI):

705 (M+H).

Example 71——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(4-diethylammonium)butane S~4H-1,2,4-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-di-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 70, except that "δ-valerolactone" was used instead of "γ-butyrolactone". ^-NMR (CDC1 ₃ , 300 MHz) δ 1.23 (t, 6Η), 1.89 (m, 6Η), 2.63 (t, 2Η), 2.79 (m, 6H), 2.89 (q, 4H), 4.42 (s, 2H), 5.08 (s, 2H), 5.24 (s, 2H), 6.88 (d, 2H), 6.91 (t, 2H), 7.30 (dd, 2H), 7.44 (d, 2H), 7.59 (d, 2H ), 7.70 (d, 2H)-MS (ESI): 719 (M+H) ⁺ .

El—— 3-azidomethyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl--ff-l,2,4-triazole

Intermediate D18 9.6 g (1 equivalent), DPPA 7.5 ml (1.2 eq.) and DBU 5.6 ml (1.3 eq.) were refluxed for 3 h in 100 ml of THF under nitrogen atmosphere. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride, extracted with EA, and washed twice with brine, and then dried and then purified by column chromatography. H-NMR (CDC1 ₃ , 300 MHz) δ 4.54 (s, 2Η), 5.31 (s, 2H), 7.28 (d, 2H), 7.62 (d, 2H), 7.66 (d, 2H), 7.70 (d , 2H), 8.40 (s, 1H).

E2—— 14-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazole-3-yl]methylamine

(Method 1) 10.6 g of the intermediate El (1 eq.) was dissolved in THF-H ₂ O (100-10 ml), and 11.6 g of Ph ₃ P (1.5 eq.) was added and stirred at room temperature overnight, and the reaction was completed. Stir in the silica gel, evaporate to a short silica gel column, first wash off the low polarity triphenylphosphine and triphenylphosphine oxide with EA, then elute with methanol to collect the target product part, and evaporate the methanol, residue Dissolve in a mixture of CH ₂ Cl ₂ /MeOH = 15:1, filter out insoluble silica gel, and evaporate The solvent gave 8.3 g of a solid.

(Method 2;) 8.7 g of the intermediate El was dissolved in 100 ml of absolute ethanol, and 1.3 g of a palladium carbon hydrogenation catalyst having a content of 10% was added thereto at a pressure of 1 atm. and hydrogenation reaction was carried out at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was evaporated to dryness.

E3——2-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methylamine cyclopent-1-encarboxylic acid Ester

(Method 1;) 2.8 g (1 equivalent) of intermediate E2, dissolved in 20 ml of absolute ethanol, and added 1.36 ml (ll equivalent) of ethyl cyclopentanone-2-carboxylate and 3.7 ml (2 equivalents) of silicic acid Ethyl acetate, reflux under nitrogen protection, TLC was used to monitor the progress of the reaction, and was completed in 5 hours. Stirred directly into a silica gel, evaporated to dryness and after column _{_{chromatography, CH 2 Cl 2 / MeOH =}} 25: 1 as eluent afforded 3.9g of solid.

(Method 2) 2.63 g (1 equivalent) of intermediate E2, dissolved in 20 ml of absolute ethanol, adding 1.2 ml (1.0 equivalent) of ethyl cyclopentanone-2-carboxylate and 10 g of dried 4A molecular sieve, nitrogen protection The reflux is completed for 10 hours. The molecular sieve was removed by filtration, and the filtrate was concentrated to at least an amount and precipitated in a refrigerator for a while to precipitate, collected by filtration, and dried to give 3.4 g of a solid. ^-NMR (CDC1 ₃ , 300 MHz) 51.23 (t, 3H, J = 7.2), 1.76 (m, 2H), 2.47 (m, 4H), 4.09 (q, 2H, J = 7.2), 4.44 (d, 2H, J=6.3), 5.26 (s, 2H), 7.22 (d, 2H, J=8.1), 7.60 (d, 2H, J=8.1), 7.68 (m, 5H), 8.17 (s, 1H).

E4——1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-5,6-trimethylene- 2-thiouracil

Under the protection of nitrogen, intermediate E3 2.0 g (1 equivalent), trimethylsilyl isothiocyanate 2.1 ml (3.5 equivalents) and 3 ml of dry DMF were heated at 140 ° C, and the reaction was completed in 4 h. After cooling, the flask was placed in an ice bath, and saturated with sodium bicarbonate solution was added dropwise, and 30 ml of EA and 20 ml of water were added and stirred for 10 min. The organic phase was separated, and the aqueous phase was extracted once again with 30 ml of EA, and the organic phases were combined. Concentrated to about 20 ml, the solid was precipitated in the refrigerator for a period of time, collected by filtration, and dried to obtain 1.6 g. ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 51.94 (m, 2H), 2.52 (t, 2H), 2.85 (t, 2H, J = 7.5), 5.48 (s, 2H), 5.60 (s, 2H ), 7.33 (d, 2H, J=8.1), 7.73 (d, 2H, J=8.4), 7.81 (d, 2H, J=8.4), 7.88 (d, 2H, J=8.7), 8.68 (s, 1H), 12.56 (s, 1H).

E5——1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5.hydroxymethyl-4H-1,2,4-triazol-3-yl]methyl-5, 6-trimethylene-2-thiouracil

1.6 g of the intermediate E4 was refluxed in 15 ml of 37% aqueous formaldehyde solution for 8 h, and the reaction was completed by TLC. After cooling, the precipitate was precipitated, collected by filtration, washed with water several times, and dried to yield 1.2 g. ^{_{! H-NMR (d 6 -DMSO}} , 300 MHz) 51.94 (m, 2H), 2.50 (t, 2H), 2.82 (t, 2H), 4.65 (d, 2H), 4.79 (t, 1H, -OH) , 5.50 (s, 2H), 5.55 (s, 2H), 7.26 (d, 2H), 7.72 (d, 2H), 7.81 (d, 2H), 7.88 (d, 2H), 12.56 (s, 1H)- MS (ESI): 512 (MH).

Example 72 - 1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-hydroxymethyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

(Method 1) 1.2 g (1 equivalent) of intermediate E5, 0.32 ml (ll equivalent) of fluorobenzyl bromide, 0.52 ml (1.5 equivalents) of DBU and 20 mg (0.05 equivalents) of potassium iodide in 10 ml of acetonitrile, stirred at room temperature overnight, TLC detection The reaction is completed. The acetonitrile was evaporated under reduced pressure, and 10 ml of water and 10 ml of EA was added to the residue, and the mixture was stirred for 0.5 hour. The solid was collected by filtration, washed with water, EA and dried to give 1.16 g.

(Method 2) 1.08 g (1 equivalent) of intermediate E5, 0.29 ml (ll equivalent) of fluorobenzyl bromide, 0.44 g (1.5 eq.) of anhydrous potassium carbonate in 10 ml of acetone was refluxed for 1 hour, and the reaction was confirmed by TLC. The acetone was evaporated under reduced pressure, and 10 ml of water and 10 ml of EA were added to the residue, and the mixture was stirred for 0.5 hr. The solid was collected by filtration, washed with water, EA, and dried. 1H-NMR (d ₆ -DMSO, 400 MHz) 51.90 (m, 2 Η), 2.54 (t, 2H), 2.67 (t, 2H), 4.27 (s, 2H), 4.64 (s, 2H), 5.14 (s , 2H), 5.44 (s, 2H), 5.80 (vbrs, 1H), 6.99 (t, 2H, J=8.4), 7.28 (d, 2H), 7.31 (dd, 2H), 7.64 (d, 2H), 7.80 (m, 4H).

Example 73 - 1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzyl) Thio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one

Prepared by the method of Example 72 except that the intermediate E4 was used instead of E5. 1H-NMR

(d ₆ -DMSO, 400 MHz) 51.90 (m, 2H), 2.54 (t, 2H, J = 7.2), 2.69 (t, 2H, J = 7.2), 4.29 (s, 2H), 5.24 (s, 2H ), 5.39 (s, 2H), 7.02 (t, 2H, 8.4), 7.32 (m, 4H), 7.67 (d, 2H, ^8.8), 7.82 (m, 4H), 8.74 (s, 1H).

Example ₇₄ _ 4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H- Pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl-formaldehyde

700 mg (1 equivalent) of Example 72 in 10 ml of dioxane, 0.6 g (6 equivalents) of active manganese dioxide was added, and 70-80 'C was heated for 3 hours to complete the reaction. The manganese dioxide was filtered off, and the filtrate was subjected to column chromatography, eluting with DCM / MeOH = 20:1 to afford 540 mg of solid. ^-NMR (CDC1 ₃ , 300 MHz) 51.99 (m, 2Η), 2.71 (m, 4H), 4.42 (s, 2H), 5.13 (s, 2H), 5.73 (s, 2H), 6.90 (m, 2H) ), 7.03 (d, 2H), 7.28 (dd, 2H), 7.47 (d, 2H), 7.59 (d, 2H), 7.70 (d, 2H).

Example 75——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-di

400 mg (1 eq. M. 74 compound 105 mg (2 eq.) dimethylamine hydrochloride, 215 </ RTI> (2 eq. of IPEA and 205 mg (1.5 eq.) of NaHB (OAc ₃ was stirred at room temperature in 8 ml of dichloromethane, and the reaction was monitored by TLC. After the completion of the reaction, the mixture was transferred to a sep. funnel, washed with brine, and dried, and then filtered, and then purified by column chromatography eluting with DCM/MeOH = 10:1 to yield 280 mg of solid. H-NMR (CDC1 ₃ , 300 MHz) 51.96 (m, 2 Η) , 2.32 (s, 6H), 2.63 (t, 2H, J=7.2), 2.75 (t, 2H, ^7.2), 3.70 (s, 2H), 4.44 (s, 2H), 5.03 (s, 2H), 5.49 (s, 2H), 6.93 (m, 4H), 7.31 (dd, 2H, J=8.4, 5.4), 7.45 (d, 2H, J=8.4), 7.61 (d, 2H, J=8.1), 7.70 (d, 2H, J = 8.1); MS (ESI): 649 (M+H). Example 76 - N,N-Dimethyl-N-(4-fluorobenzyl)-i5-P-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H- Cyclopentyl [rf]pyrimidin-1(5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-yl} Ammonium methyl bromide

Prepared by the method of Example 47 except that Example 75 was used instead of Example 46. ^-NMR (d ₆ -DMSO, 300 MHz) 51.92 (m, 2 Η), 2.55 (t, 2H, J = 6.6), 2.75 (t, 2H, J = 6.6), 3.08 (s, 6H), 4.29 ( s, 2H), 4.48 (s, 2H), 4.89 (s, 2H), 5.20 (s, 2H), 5.64 (s, 2H), 6.99 (t, 2H, J=8.4), 7.21 (d, 2H, J=7.8), 7.30 (t, 2H, J=7.8), 7.38 (t, 2H, J=8.7), 7.65 (d, 2H, J=8.4), 7.73 (t, 2H, J=7.8) _: 7.81 (m, 4H)- MS (ESI): 757 (M-Br).

Example 77——N,N,N-Trimethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidine- 1(5H)-yl]methyl-4-(p-triazol-3-ylindolemethylammonium iodide

65 mg (1 equivalent) of the compound of Example 75 in 3 ml of DCM, 19 μl (3 eq.) of iodomethyl hydrazide, stoppered, and stirred at room temperature overnight. The solvent was evaporated to dryness <RTI ID=0.0> ¹ H-NMR (d ₆ -DMSO, 300 MHz) 51.91 (m, 2H), 2.54 (t, 2H), 2.71 (t, 2H, ^6.9), 3.21 (s, 9H), 4.28 (s, 2H) , 4.93 (s, 2H), 5.14 (s, 2H), 5.56 (s, 2H), 6.99 (t, 2H, 8.7), 7.19 (d, 2H, J=7.8), 7.30 (dd, 2H, J=8.1, 5.7), 7.66 (d, 2H, J=8.1), 7.81 (m, 4H).

Example 78——N,A^V-trimethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[rf]pyrimidine

-1(5H)-yl]methyl-4-(p-tritriazol-3-yl}methylammonium bromide

90 mg of the 75 compound was dissolved in 2 ml of acetone, and the flask was sealed with a rubber stopper and placed in a -5 ° C cold trap. 0.5 ml of bromoformamidine was added by a syringe, and the reaction was completed overnight with stirring. The precipitate was collected by filtration, washed with acetone and dried in vacuo.

Example 79——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-di

200 mg (1 equivalent) of the compound of Example 74, 40 μl (1.2 eq.) of diethylamine and 103 mg (1.5 eq.) of NaHB(OA _C ) ₃ were stirred in 5 ml of dichloromethane, and the reaction was monitored by TLC. After completion of the reaction, the mixture was transferred to a sep. funnel, washed three times with brine, dried and then purified by column chromatography. iH-NMR (CDC1 ₃ , 300 MHz) 50.99 (t, 6Η, J=7.2), 1.97 (m, 2H), 2.57-2.65 (m, 6H), 2.77 (t, 2H, J=7.2), 3.82 ( s, 2H), 4.44 (s, 2H), 5.02 (s, 2H), 5.53 (s, 2H), 6.93 (m, 4H), 7.30 (m, 2H), 7.45 (d, 2H, J=8.1) , 7.63 (d, 2H, J=8.4), 7.70 (d, 2H, J=8.1)- MS (ESI): 677 (M+H).

Example 80——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-diethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dicarboxylate

105 mg (1 equivalent) of the compound of Example 79 was dissolved in 2 ml of isopropanol, 14 μl (about 1 equivalent) of concentrated hydrochloric acid was added to the ice bath, stirred for 0.5 h, and the solvent was evaporated to dryness under reduced pressure. It was chopped, collected by filtration, and dried in vacuo to give a white solid. 1H-NMR (d ₆ -DMSO, 300 MHz) δ ΐ.23 (m, 6H), 1.89 (m, 2H), 2.55 (t, 2H, J = 7.2), 2.72 (t, 2H, J = 7.2), 3.26 (m, 4H), 4.31 (s, 2H), 4.56 (s, 2H), 5.23 (s, 2H), 5.59 (s, 2H), 7.02 (t, 2H, J=8.7), 7.22 (d, 2H, J=8.1), 7.33 (dd, 2H, J=8.7, 5.4), 7.67 (d, 2H, J=8.1), 7.82 (m, 4H), 11.06 (s, 1H).

Example 81——1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-p-fluorobenzamide)methyl-H-1,2,4- Three! 3⁄4_3-yl]methyl-2-(4-H)-one

Prepared by the method of Example 79, except that methyl fluoroacetamide was substituted for "diethylamine". ^-NMR (CDC1 ₃ , 300 MHz) 51.95 (m, 2 Η), 2.34 (s, 3H), 2.62 (t , 2H, J=7.2), 2.73 (t, 2H, J=7.2), 3.61 (s, 2H), 3.75 (s, 2H), 4.44 (s, 2H), 5.01 (s, 2H), 5.31 (s , 2H), 6.80 (d, 2H, J=7.8), 6.93 (m, 4H), 7.18 (m, 2H), 7.30 (dd, 2H, J=8.1, 5.7), 7.41 (d, 2H, J=7.8), 7.62 (d, 2H, J = 8.1), 7.73 (d, 2H, J = 8.4); MS (ESI): 743 (M+H).

Example ⁸² a l- ^[4 - (p-trifluoromethyl biphenyl ^--4-- yl) methyl - ⁵ - (AL methyl - isopropyl amino) methyl _4H-1, ^2, ⁴ - triazole - 3-yl]methyl-2-(4-fluorobenzylsulfur-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79, except that "diethylamine" was replaced by isopropylmethylamine. ^-NMR (CDC1 ₃ , 400 MHz) δ 1.01 (d, 6H, J = 6.8), 1.96 (m, 2H) , 2.17 (s, 3H), 2.63 (t, 2H), 2.75 (t, 2H), 2.87 (m, 1H), 3.79 (s, 2H), 4.44 (s, 2H), 5.02 (s, 2H), 5.48 (s, 2H), 6.93 (m, 4H), 7.30 (dd, 2H), 7.45 (d, 2H), 7.61 (d, 2H, J=8.0), 7.70 (d, 2H, J=8.4).

Example 83——(±)-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(N-ethylpyrrolidin-2-yl)methylamine]methyl- &-1,2,4-triazol-3-yl]methyl [(/1 pyrimidine-4(5^)-one)

Prepared by the method of Example 79, except that "(±)-1-ethyl-2-aminomethylpyrrole" was substituted for "diethylamine". H-NMR (CDC1 ₃ , 400 MHz) δ 1.30 (t, 3Η, J=7.2), 1.86 (m, 1H), 2.00 (m, 3H), 2.10 (m, 2H), 2.69 (t, 2H, J=7.2), 2.83 (m, 4H), 3.13 (q, 2H), 3.37 (m, 2H), 3.77 (m, 1H), 4.09 (s, 2H), 4.40 (s, 2H), 5.02/5.08 (2x d, 2H, J=17.6), 5.44/5.66 (2x d, 2H J=16.8), 6.89 (t, 2H, J=8.8), 7.02 (d, 2H, J=8.0), 7.28 (m, 2H), 7.43 (d, 2H, J=7.6), 7.57 (d, 2H _: J=8.0), 7.69 (d, 2H, J=8.0).

Example 84—— 1-ί4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-1(25 6 -2, 6-dimethylmorphinolin-4-yl 1 methyl-ff- l,2,4-Triazol-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "(2S,6J?)-2,6-dimethylmorpholine" was substituted for "diethylamine". H-NMR (CDC1 ₃ , 400 MHz) δ 1.11 (d, 6H, J=6.0), 1.94 (m, 4H), 2.62 (m, 4H), 2.75 (t 2H, J=7.2), 3.48 (m) , 2H), 3.70 (s, 2H), 4.45 (s, 2H), 5.05 (s, 2H), 5.42 (s, 2H), 6.92 (m, 4H), 7.32 (dd, 2H, J=8.8, 5.6 ), 7.45 (d, 2H, J=8.0), 7.62 (d, 2H, J=8.0), 7.71 (d, 2H, J=8.0).

Example 85 - 2-Methyl-2-ί4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-I2-(4-fluorobenzylthio)-5,6-trimethyl- 4-oxo-4H-pyrimidin-1-yl] ester

Prepared by the method of Example 75, except that "dimethylamine hydrochloride was replaced with "2-methyl-2-aminopropionate hydrochloride". ^{_{! H-NMR (CDC1 3,}} 400 MHz) 51.33 (s, 6Η), 1.94 (m, 2Η), 2.62 (t, 2H), 2.71 (t, 2H), 3.68 (s, 3H), 3.94 (s, 2H), 4.45 (s, 2H), 5.03 (s, 2H), 5.45 (s, 2H), 6.94 (m, 4H), 7.32 (dd, 2H), 7.45 (d, 2H), 7.62 (d, 2H ), 7.71 (d, 2H).

Example 86 - (p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-ethyloxazin-1-yl)methyl -4H-1,2,4-tri

11S Zyrid-3-yl]methyl-2-(4-fluorobenzyl-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "N-ethylpiperazine" was substituted for "diethylamine". ^{_{! H-NMR (CDC1 3,}} 300 MHz) δ 1.07 (t, 3Η, J = 7.2), 1.96 (m, 4H), 2.39 (m, 4H), 2.54 (m, 4H), 2.64 (t, 2H, J=7.2), 2.76 (t, 2H, J=7.2), 3.72 (s, 2H), 4.45 (s, 2H), 5.04 (s, 2H), 5.42 (s, 2H), 6.94 (m, 4H) , 7.31 (dd, 2H), 7.46 (d, 2H, J=8.1), 7.62 (d, 2H), 7.71 (d, 2H).

Example 87 ^ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-methoxy)ethylamino]methyl-4H-1,2,4-triazole -3-yl]methyl-2-(4-fluorobenzyl-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "2-methoxyethylamine" was substituted for "diethylamine". H-NMR

(CDC1 ₃ , 300 MHz) 51.95 (m, 2H), 2.50 (vbrs, 1H), 2.62 (t, 2H), 2.74 (t, 2H), 2.91 (t, 2H), 3.31 (s, 3H), 3.51 (t, 2H), 4.09 (s, 2H), 4.43 (s, 2H), 5.06 (s, 2H), 5.45 (s, 2H), 6.93 (m, 4H), 7.31 (dd, 2H), 7.44 ( d, 2H), 7.60 (d, 2H), 7.70 (d, 2H).

Example 88 - 2 countries methyl-2-iN-i4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-P-(4-fluorobenzylthio)-5,6-trimethyl Methyl 4-oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-trisani-3-ylindolemethylpyrazine-1-ylpropionate

Prepared by the method of Example 75 except that "M20" was substituted for "dimethylamine hydrochloride". ^-NMR (CDC1 ₃ , 400 MHz) 51.29 (s, 6Η), 1.96 (m, 2Η), 2.53 (m, 8H), 2.63 (t, 2H), 2.75 (t, 2H), 3.64 (s _: 3H ), 3.71 (s, 2H), 4.44 (s, 2H), 5.03 (s, 2H), 5.42 (s, 2H), 6.94 (m, 4H), 7.31 (dd, 2H), 7.45 (d, 2H) , 7.62 (d, 2H), 7.70 (d, 2H).

Example 89 - 2 countries methyl-2-iN-i4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-P-(4-fluorobenzylthio)-5,6-trimethyl _4-oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-tri! 3⁄4-3-yl}methylpyrazine-1-ylpropanoic acid

Prepared by the method of Example 63 except that "Example 88" was substituted for "Example 62". MS (ESI): 774 (MH). </RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI> 1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-dimethylaminoethyl) Ammonia]methyl-&-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1cyclopenta[(/1 pyrimidine- 4(5^)-ketone

Prepared by the method of Example 79, except that "diethylamine" was replaced by trimethylethylenediamine.] H-NMR (CDC1 ₃ , 300 MHz) 51.93 (m, 2 Η), 2.07 (s, 6H), 2.24 ( s, 3H), 2.33 (t, 2H), 2.53 (t, 2H), 2.59 (t, 2H), 2.70 (t, 2H), 3.78 (s, 2H), 4.45 (s, 2H), 5.02 (s , 2H), 5.57 (s, 2H), 6.87 (d, 2H), 6.94 (t, 2H), 7.32 (dd, 2H), 7.43 (d, 2H), 7.62 (d, 2H), 7.70 (d, 2H). Example ⁹ _la -l-[ ^4- (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(methyl)( ² -diethylaminoethyl)amino]methyl- & -1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1cyclopenta[(/1pyrimidin-4(5^)-one)

Prepared by the method of Example 79, except that "methyl-N,N-diethylethylenediamine" was substituted for "diethylamine". H-NMR (CDC1 ₃ , 300 MHz) δ 1.28 (t, 6Η), 2.03 (m, 2Η), 2.41 (s, 3H), 2.74 (t, 2H), 2.95 (t, 2H), 3.05 (m) , 8H), 3.90 (s, 2H), 4.37 (s, 2H), 5.15 (s, 2H), 5.62 (s, 2H), 6.84 ( 2H), 7.06 (d, 2H), 7.23 (dd, 2H) , 7.40 (d, 2H), 7.55 (d, 2H), 7.70 (d, 2H).

Example Mb _ l-[ ⁴ - (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(methyl)( ² -diethylaminoethyl)amino]methyl-4H-1,2 ,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one-tartrate

76 mg of the compound of Example 91a was dissolved in 2 ml of anhydrous methanol, and 15 mg of tartaric acid (1 eq.) was added and the mixture was stirred at room temperature for 5 min. 1H-NMR (d ₆ -DMSO, 300 MHz) δ 1.09 (t, 6H, J = 7.2), 1.91 (m, 2H), 2.23 (s, 3H), 2.54 (t, 2H, J = 6.9), 2.70 (t, 2H _: J=6.9), 2.75 (t, 2H, ^5.7), 2.99 (q, 4H, ^7.2), 3.06 (t, 2H, ^6.0), 3.77 (s, 2H), 4.26 (s , 2H), 4.30 (s, 2H), 5.17 (s, 2H), 5.45 (s, 2H), 7.02 (t, 2H, J=8.7), 7.19 (d, 2H, J=8.1), 7.23 (dd , 2H, J=8.4, 6.0), 7.65 (d, 2H, ^8.4), 7.81 (m, 4H).

Example 92-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(3-dimethylaminopropyl)amino]methyl- &-1,2 , 4-triazol-3-yl] [(/1 pyrimidine-4(5^)-one)

Prepared by the method of Example 79, except that trimethyl-1,3-propanediamine was substituted for "diethylamine". H-NMR (CDC1 ₃ , 300 MHz) 51.89 (m, 2 Η), 2.00 (m, 2H), 2.39 (s, 3H), 2.64 (s, 6H), 2.70 (m, 4H), 2.89 (m, 4H), 3.86 (s, 2H), 4.39 (s, 2H), 5.17 (s, 2H) ), 5.58 (s, 2H), 6.87 (t, 2H), 7.04 (d, 2H), 7.27 (m, 2H), 7.42 (d, 2H), 7.58 (d, 2H), 7.70 (d, 2H) .

Example _93——1- [4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-morpholine)ethylamine]A S~4H-1,2,4-triazole -3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "morpholine ethylamine" was substituted for "diethylamine". ^-NMR (CDC1 ₃ , 300 MHz) δ 1.94 (m, 2Η), 2.50 (m, 6H), 2.61 (t, 2H), 2.72 (t, 2H), 2.79 (t, 2H), 3.70 (t 4H ), 4.03 (s, 2H), 4.46 (s, 2H), 5.04 (s, 2H), 5.45 (s, 2H), 6.92 (m, 4H), 7.33 (m, 2H), 7.44 (d, 2H) , 7.61 (d, 2H), 7.71 (d, 2H).

Example 94 ~ (R)-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(3-dimethylamino)pyrrolidin-1-yl]methyl- &- 1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1cyclopenta[(/1pyrimidin-4(5^)-one)

Prepared by the method of Example 79, except that "(J?)-3-dimethylaminopyrrole" was substituted for "diethylamine". H-NMR (CDC1 ₃ , 400 MHz) δ 1.72 (m, 1Η), 1.95 (m, 3Η), 2.17 (s, 6Η), 2.50 (m, 1Η), 2.61 (m, 4Η), 2.74 (m) , 4Η), 3.83 (s, 2Η), 4.46 (s, 2H), 5.05 (s, 2H), 5.43 (2x d, 2H), 6.88 (d, 2H), 6.95 (t, 2H), 7.33 (dd , (H, 2H) 5-[(3-dimethylamino)pyrrolidin-1-yl]methyl- &-1,2,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio) -6,7-dihydro-1cyclopenta[(/1 pyrimidine-4(5^)-one)

Prepared by the method of Example 79, except that S 3-dimethylaminopyrrole was substituted for "diethylamine". H-NMR (CDC1 ₃ , 400 MHz) δ 1.70 (m, 1 Η), 1.94 (m, 3 Η) , 2.17 (s, 6Η), 2.49 (m, 1Η), 2.61 (m, 4Η), 2.73 (m, 4Η), 3.83 (s, 2Η), 4.46 (s, 2H), 5.04 (s, 2H), 5.43 (2x d, 2H), 6.88 (d, 2H), 6.95 (t, 2H), 7.33 (dd, 2H), 7.44 (d, 2H), 7.62 (d, 2H), 7.71 (d, 2H). Example 96 ^ l-[ ⁴ - (p-Trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(oxadin-1-yl)ethylamine]methyl- ⁴ H-1, ² , ⁴ - Triazol-3-yl]methyl-2-(4-fluoro-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "[2-(piperidin-1-yl)]ethylamine" was substituted for "diethylamine". ^-NMR (CDC1 ₃ , 300 MHz) δΐ.40 (m, 2Η), 1.51 (m, 4H), 1.93 (m, 2H), 2.03 (t, 2H), 2.31 (t, 2H), 2.38 (t , 2H), 2.59 (t, 2H), 2.71 (t, 4H), 4.02 (s, 2H), 4.46 (s, 2H), 5.04 (s, 2H), 5.46 (s, 2H), 6.90 (d, 2H), 6.95 (t, 2H), 7.33 (dd, 2H), 7.43 (d, 2H), 7.62 (d, 2H), 7.71 (d, 2H).

Example 97 ^ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-pyrrolidin-1-yl)ethylamine]methyl-ff-l,2,4 -triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79, except that "2-(pyrrole-1-yl)ethylamine" was substituted for "diethylamine" H-NMR (CDC1 ₃ , 300 MHz) 51.73 (m, 4 Η), 1.94 (m, 2Η), 2.47 (m, 4H), 2.58 (m, 4H), 2.73 (m, 4H), 4.02 (s, 2H), 4.46 (s, 2H), 5.04 (s, 2H), 5.46 (s, 2H ), 6.90 (d, 2H), 6.94 (t, 2H), 7.33 (dd, 2H), 7.43 (d, 2H), 7.62 (d, 2H), 7.71 (d, 2H).

Example 98 ^ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-diisopropylamino)ethylamine]methyl-4H-1,2,4-tri ! 3⁄4_3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79 except that "NN-diisopropylethylenediamine" was substituted for "diethylamine". ^-NMR (CDC1 ₃ , 300 MHz) δ 1.11 (d, 12H), 1.96 (m, 2H), 2.64 (t, 2H), 2.75 (m, 6H), 3.17 (m, 2H), 4.01 (s, 2H), 4.43 (s, 2H), 5.04 (s, 2H), 5.47 (s, 2H), 6.94 (m, 4H), 7.31 (dd, 2H), 7.43 (d, 2H), 7.60 (d, 2H ), 7.70 (d, 2H).

Example 99 ^ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-diethylamino)ethylamine]methyl-4H-1,2,4-triazole -3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79, except that "NN-diethylethylenediamine" was substituted for "diethylamine". ^-NMR (CDC1 ₃ , 300 MHz) δ 0.96 (t, 6Η), 1.94 (m, 2Η), 2.49 (m, 6H), 2.66 (m, 6H), 4.01 (s, 2H), 4.46 (s, 2H), 5.03 (s, 2H), 5.46 (s, 2H), 6.94 (m, 4H), 7.32 (dd, 2H), 7.44 (d, 2H), 7.61 (d, 2H), 7.71 (d, 2H ).

Example ₁₀₀ _ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[N-methyl-(pyridin-2-yl)methylamino]methyl- &-1,2 , 4-triazol-3-yl]methylpenta[(/1 pyrimidine-4(5^)-one

Prepared by the method of Example 79, except that "N-methyl-(pyridin-2-yl)methylamine" was substituted for "diethylamine". ^{! H-NMR (MeOD, 300} MHz) δ 2.04 (m, 2Η), 2.26 (s, 3H), 2.67 (t, 2H), 2.82 (t, 2H), 3.73 (s, 2H), 3.84 (s, 2H), 4.36 (s, 2H), 5.25 (s, 2H), 5.49 (s, 2H), 6.87 (t, 2H), 7.04 (d, 2H), 7.20 (m, 1H), 7.29 (m, 3H) ), 7.51 (d, 2H), 7.57 (d, 1H), 7.62 (m, 1H), 7.72 (d, 2H), 7.75 (d, 2H), 8.36 (d, 1H).

Example 101 - 1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(N-methyl-cyclopropylamino)methyl-AH-^-triazole-3- Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 79, except that "diethylamine" was replaced by methylcyclopropylamine. ^-NMR (CDC1 ₃ , 400 MHz) δ 0.19 (m, 2 Η), 0.45 (m, 2H), 1.80 ( m, 1H), 1.95 (m, 2H), 2.30 (s, 3H), 2.62 (t, 2H, J=7.2), 2.74 (t, 2H, J=7.2), 3.90 (s, 2H), 4.40 ( s, 2H), 5.01 (s, 2H), 5.33 (s, 2H), 6.88 (d, 2H, J=8.0), 6.94 (t, 2H, J=8.8), 7.31 (dd, 2H, J=8.8 , 5.2), 7.45 (d _: 2H, J=8.4), 7.62 (d, 2H, J=8.0), 7.70 (d, 2H, J=8.4).

Example 102-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(2-oxoisidazolin-1-yl)ethylamine]methyl- &-1,2 ,4-triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1cyclopenta[(/1pyrimidin-4(5^)-one

Prepared by the method of Example 79, except that "1-(gasethyl)imidazolin-2-one" was substituted for "diethylamine".

H-NMR (CDC1 ₃ , 300 MHz) 51.94 (m, 2Η), 2.64 (t, 2H), 2.69 (t, 2H), 3.40 (t, 2H), 3.45 (t, 2H), 4.43 (s, 2H), 4.61 (s, 2H), 5.03 (s, 2H), 5.54 (s, 2H), 6.33 (s, 1H), 6.85 (t, 2H), 7.05 (d, 2H), 7.22 (dd, 2H) ), 7.33 (s, 1H), 7.46 (d, 2H), 7.58 (d, 2H), 7.69 (d, 2H). The following compounds were also prepared by the method of Example 79:

12S

Example 108——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-azidomethyl-4H-1,2,4-triazol-3-yl]methyl- 2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Intermediate E1 except that "Example 18" was substituted for "D18". ^{_{! H-NMR (CDC1 3,}} 400 MHz) 51.99 (m, 2H), 2.66 (t, 2H), 2.80 (t, 2H), 4.42 (s, 2H), 4.60 (s, 2H), 5.11 (s, 2H) _: 5.33 (s, 2H), 6.91 (t, 2H), 6.91 (d, 2H), 7.29 (dd, 2H), 7.47 (d, 2H), 7.60 (d, 2H), 7.71 (d, 2H ). Example 109——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-aminomethyl-4H-1,2,4-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared according to Method 1 of Intermediate E2 except that "Example 108" was substituted for "El". ^{_{! H-NMR (CDC1 3,}} 400 MHz) 51.95 (m, 2H), 2.60 (t, 2H), 2.72 (t, 2H), 4.09 (s, 2H), 4.43 (s, 2H), 5.03 (s, 2H), 5.40 (s, 2H), 6.92 (m, 4H), 7.30 (dd, 2H), 7.44 (d, 2H), 7.60 (d, 2H), 7.70 (d, 2H).

Example ₁₁₀ (p-Trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H-pyrimidine-1 -yl]methyl-4H-1,2,4-triazol-3-yl}methylacetamide

20 mg (1 equivalent) of the compound of Example 109 in 2 ml of DCM, a calcium chloride drying tube was isolated from water vapor, and ΙΟμΙ (2 equivalents) of triethylamine and 5 μl (2 equivalents) of acetyl chloride were added, and the reaction was completed at room temperature for 1 hour. It was transferred to a separatory funnel, washed three times with brine, and dried to give TLC. 1H-NMR (CDC1 ₃ , 400 MHz) 52.00 (m, 2H), 2.29 (s, 3H), 2.67 (t, 2H), 2.79 (t, 2H), 4.39 (s, 2H), 4.66 (s, 2H) ) _: 5.09 (s, 2H), 5.48 (s, 2H), 6.90 (t, 2H), 6.99 (d, 2H), 7.07 (vbrs, 1H), 7.28 (dd, 2H), 7.46 (d, 2H) , 7.58 (d, 2H), 7.70 (d, 2H).

Example 111 ^ N-i4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-I2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H -pyrimidin-1-yl]methyl-4H-

The preparation method was the same as in Example 110 except that "acetyl chloride" was substituted for "acetyl chloride". ^-NMR (CDC1 ₃ , 400 MHz) δ 1.37 (t, 3Η), 2.00 (m, 2Η), 2.69 (t, 2H), 2.77 (t, 2H), 3.10 (q, 2H), 4.40 (s, 2H), 4.47 (s, 2H), 5.03 (s, 2H), 5.41 (s, 2H), 6.11 (vbrs, 1H), 6.90 (t, 2H), 7.02 (d, 2H) _: 7.27 (m, 2H) ), 7.46 (d, 2H), 7.58 (d, 2H), 7.70 (d, 2H).

Example ₁₁₂ _ N-i4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-I2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo-4H -pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methyl-2-imidazolidinone

25 mg of the compound of Example 109 was added to 2 ml of absolute ethanol, and 12 μl of triethylamine and 6 μl of 2-chloroethyl isocyanate were added, and the reaction was completed overnight at room temperature. Ethanol was evaporated under reduced pressure, and the residue was evaporated and evaporated. 1H-NMR (CDC1 ₃ , 400 MHz) δ 1.94 (m, 2H), 2.66 (m, 4H), 3.40 (t, 2H), 3.45 (t, 2H), 4.34 (s, 2H), 4.61 (s, 2H), 5.03 (s, 2H), 5.54 (s, 2H), 6.33 (vbrs, IH), 6.85 (t, 2H), 7.05 (d, 2H), 7.22 (dd, 2H), 7.32 (vbrs, 1H ), 7.46 (d, 2H), 7.58 (d, 2H), 7.69 (d, 2H).

Example ₁₁₃ a 3-methyl -1-ί4- (p-trifluoromethyl biphenyl-4-yl) methyl -5-I2- (4- fluoro-benzylthio) -5,6-trimethyl • 4 -oxo-4H-pyrimidin-1-yl]methyl-4H-1,2,4-triazol-3-yl}methylthiourea

20 mg of the compound of Example 109 was added to 5 ml of methyl isothiocyanate in 2 ml of DCM and refluxed for 2 h. Direct preparation of TLC gave 12 mg of solid. ^-NMR (CDC1 ₃ , 400 MHz) δ 1.98 (m, 2Η), 2.69 (m, 4H), 2.91 (s, 3H), 4.35 (s, 2H), 5.00 (s, 2H), 5.09 (s, 2H), 5.71 (s, 2H), 6.83 (t, 2H), 7.13 (d, 2H), 7.20 (dd, 2H), 7.50 (m, 3H), 7.59 (d, 2H), 7.70 (d, 2H ), 9.07 (vbrs, IH).

Example ₁₁₄ - 1-[4-(p-Trifluoromethylbiphenyl-yl)methyl-5-chloromethyl-4H-1,2,4-triazol-3-yl]methyl-2-( 4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

200 mg (1 equivalent) of the compound of Example 72 in 5 ml of dry DCM, 1 ml of DMF was added, and a calcium chloride drying tube was used to isolate the water vapor and placed in an ice bath, and then 30 μl (1.2 equivalent) of thionyl chloride was added, and the reaction was completed for 0.5 h. It was quenched with a saturated solution of sodium bicarbonate, and then the organic phase was separated and washed with brine, dried over sodium sulfate, and evaporated to give a solvent.

Example ₁₁₅ _ 1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(p-fluorobenzylthio)methyl-4H-1,2,4-triazol-3-yl Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Referring to the first method of Intermediate D36, except "Example 114" was substituted for "D19", "4-fluorobenzyl mercaptan" was substituted for "Benzylthiol". ^{_{! H-NMR (CDC1 3,}} 300 MHz) 51.98 (m, 2Η), 2.63 (t, 2H), 2.76 (t, 2H), 2.91 (t, 2H), 3.69 (s, 4H), 4.46 (s, 2H), 5.04 (s, 2H), 5.26 (s, 2H), 6.95 (m, 6H), 7.34 (m, 4H), 7.43 (d, 2H), 7.60 (d, 2H), 7.71 (d, 2H ).

Example 116 - (p-Trifluoromethylbiphenyl-4-yl)methyl-5-(WN-dimethylindenyl)methyl-W-^-triazol-3-yl]methyl-2 -(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

30 mg (1 equivalent) of the compound of Example 74, 16 μl (2 equivalents) of DIPEA, 1,1-dimethylhydrazine monohydrochloride 7 mg (1.5 eq.) and 0.5 g of molecular sieves were placed in 3 ml of DCM, occasionally shaken for two hours. Finished. The molecular sieve was filtered off, and the filtrate was washed three times with brine. H-NMR (CDC1 ₃ , 300 MHz) 51.90 (m, 2Η), 2.57 (t, 2H), 2.65 (t, 2H), 2.97 (s, 6H), 4.45 (s, 2H), 5.08 (s, 2H), 5.71 (s, 2H), 6.93 (t, 2H), 7.96 (d, 2H), 7.32 (dd, 2H), 7.35 (s, 1H), 7.42 (d, 2H), 7.62 (d, 2H ), 7.69 (d, 2H)-MS (ESI): 662 (M+H).

Example ₁₁₇ _ l-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(oxadin-1-yl)imino]methyl-H-1,2,4-tri ! 3⁄4_3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

Prepared by the method of Example 114 except that "1-aminopiperidine" was used instead of "1,1-dimethylindole monohydrochloride". H-NMR (CDC1 ₃ , 300 MHz) 51.53 (m, 2Η), 1.67 (m, 4H), 1.91 (m, 2H), 2.58 (t, 2H), 2.65 (t, 2H), 3.11 (t, 4H), 4.45 (s, 2H), 5.08 (s, 2H), 5.74 (s, 2H), 6.93 (t, 2H), 7.97 (d, 2H), 7.31 (dd, 2H), 7.42 (d, 2H ), 7.62 (d, 2H), 7.68 (s, 1H), 7.69 (d, 2H). The following compounds were also prepared by the method of Example 116:

Example ₁₁₉ _ 1-ί4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[2-(4-fluorobenzylthio)-5,6-trimethyl-4-oxo- 4H-pyrimidin-1-yl]methyl-4H-1,2 4-triazol-3-yl}vinyl acetate

920 mg (1 eq.) of the compound of Example 73 and 0.65 ml of triethylamine (3 eq.) in 10 ml of DCM, which was then applied to the ice bath, and placed in an ice bath, slowly adding 0.28 ml (2.5 eq.) of acetyl chloride, and the reaction was continued for 2 h. Transfer to a separatory funnel, wash the saline three times, and dry to separate the column to give a 0.78 gummy solid. ¹ H-NMR (CDC1 ₃ , 400 MHz) δ 1.99 (m, 2Η), 2.07 (s, 3H), 2.66 (t, 2H), 2.77 (t, 2H), 4.42 (s, 2H), 5.03 (s , 2H), 5.42 (s, 2H), 5.43 (d, 1H, J=2.4), 5.49 (d, 1H, J=2.8), 6.95 (m, 4H), 7.31 (dd, 2H, J=8.8, 5.6), 7.47 (d, 2H, J=8.0), 7.61 (d, 2H), 7.71 (d, 2H).

Example 120 - 1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-(l-hydroxy)ethyl-ff-l,2,4-triazol-3-yl] Methyl-2-(4-fluorobenzylthio)-6,7-di-1H-cyclopenta[rf]pyrimidin-4(5H)-one

(Method 1) 200 mg (1 equivalent) of the sufficiently dried compound of Example 74 was dissolved in 3 ml of dry THF, replaced with nitrogen, placed in an ice bath, and added to a solution of 0.36 ml of methylmagnesium bromide (1 mol/L in THF, 1.1 eq.) , The reaction was quenched for 2 h, EtOAc (EtOAc)EtOAc.

(Method 2) 760 mg of the 119 compound and 85 mg of NaBH ₄ were reacted in ethanol in a 5 ml ice bath for 1 h to complete. Ethanol was distilled off under reduced pressure, and the residue was diluted with water, and concentrated hydrochloric acid was added dropwise to the ice bath with stirring until no more bubbles appeared, and then quenched with sodium bicarbonate solution. The chloroform was extracted three times, and the organic phases were combined and dried over anhydrous sodium sulfate. ^-NMR (d ₆ -DMSO, 300 MHz) δ 1.53 (d, 3 Η), 1.90 (m, 2 Η), 2.54 (t, 2H), 2.67 (t, 2H), 4.27 (s, 2H), 4.91 ( m, 1H), 5.10 (2x d, 2H), 5.48 (s, 2H), 6.99 (t, 2H), 7.24 (d, 2H), 7.31 (t, 2H), 7.63 (d, 2H), 7.80 ( m, 4H).

Example 121——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-acetyl-4H-1,2,4-triazol-3-yl]methyl-2- (4-fluorobenzylthio)-6,7-dihydrogen

(Method 1) 0.5 g of the compound of 119 was dissolved in 10 ml of isopropanol, and 1 ml of 6N hydrochloric acid was added thereto, and the mixture was stirred at room temperature overnight. Isopropyl alcohol was distilled off under reduced pressure, and the residue was dissolved in 10 ml of DCM and washed three times with brine.

(Method 2) 90 mg (1 equivalent) of the compound of Example 120 was added to 5 ml of dioxane, 123 mg (10 equivalents) of activated manganese dioxide was added, and the reaction was completed by heating at 70 ° C for 2 hours. Manganese dioxide was filtered off, and the filtrate was separated by column chromatography to give 50 mg of solid. H-NMR (CDC1 ₃ , 400 MHz) δ 1.99 (m, 2Η), 2.69 (m, 4H), 2.83 (s, 3H), 4.43 (s, 2H), 5.08 (s, 2H), 5.73 (s , 2H), 6.91 (t, 2H), 7.00 (d, 2H), 7.27 (dd, 2H), 7.46 (d, 2H), 7.59 (d, 2H), 7.70 (d, 2H).

Example ₁₂ 2 ^ N,N-Dimethyl-N-hydroxyethyl-{5-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro-4H-cyclopenta[ Rf] pyrimidine-1(5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-3-ylindole methyl chloride Ammonium

50 mg of the compound of Example 114, 50 mg of cesium carbonate and ΙΟμΙ 2-(dimethylamino)ethanol were refluxed in 2 ml of acetonitrile for 2 h, and the reaction was completed. The inorganic substance was filtered off, acetonitrile was evaporated under reduced pressure, and the residue was crystallized from acetone to give a white solid. H-NMR (CD ₃ OD, 400 MHz) δ 2.08 (m, 2Η), 2.71 (t, 2H), 2.91 (t, 2H), 3.39 (s, 6H), 3.77 (t, 2H), 4.08 ( t, 2H), 4.36 (s, 2H), 5.09 (s, 2H), 5.36 (s, 2H), 5.62 (s, 2H), 6.87 (t, 2H), 7.20 (d, 2H), 7.29 (dd , 2H), 7.59 (d, 2H), 7.71 (d, 2H), 7.75 (d, 2H).

Example ₁₂ 3——(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(2-hydroxyethoxy)methyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)

24 mg of NaH (1.5 eq., suspended in oil at 55-65%) in 2 ml of dry DMF, protected with nitrogen and placed in an ice bath. Add 42 μl (2 eq.) of ethylene glycol for 0.5 h, then add dropwise 250 mg (1 eq.) of the compound of Example 114 in 0.5 ml of DMF was applied dropwise over 2 min and stirring was continued for 15 min. It was quenched with a saturated aqueous solution of ammonium chloride, and extracted twice with DCM. The organic phase was washed twice with brine and dried over anhydrous sodium sulfate. ^-NMR (CDC1 ₃ , 300 MHz) 51.96 (m, 2Η), 2.63 (t, 2H), 2.73 (t, 2H), 3.67 (m, 4H), 4.42 (s, 2H), 4.78 (s, 2H) ), 5.03 (s, 2H), 5.36 (s, 2H), 6.91 (t, 2H), 6.98 (d, 2H), 7.29 (dd, 2H), 7.45 (d, 2H), 7.60 (d, 2H) , 7.70 (d, 2H). Example - ³ -[ ² -( ⁴ -fluorobenzylthio) - ⁴ -oxo- ⁶ , ⁷ -dihydro - ⁴ H-cyclopenta [ rf ] pyrimidine - i ( ⁵ H - methyl ) methyl

-4- (p-trifluoromethylbiphenyl-4-acetaldehyde)

The preparation method is the same as "D41" except that "Example 123" is used instead of "D40".

Example 125 ^ 1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(2-diethylaminoethoxy)methyl-H-1,2,4-triazole-3 -yl]methyl-2-(4-fluoro)-one

20 mg of the compound of Example 124 and 5 μl of diethylamine were added to 2 ml of DCM, and 10 mg of NaBH(OAc) _{3 was} added to react at room temperature for 0.5 h. It was washed twice with a saturated aqueous solution of sodium bicarbonate and dried over sodium sulfate. ^-NMR (CDC1 ₃ , 300 MHz) δ 1.02 (t, 6Η), 1.96 (m, 2Η), 2.59-2.78 (m, 10H), 3.68 (t, 2H), 4.42 (s, 2H), 4.75 ( s, 2H), 5.04 (s, 2H), 5.42 (s, 2H), 6.91 (t, 2H), 6.97 (d, 2H), 7.29 (dd, 2H), 7.43 (d, 2H), 7.59 (d , 2H), 7.70 (d, 2H)- MS (ESI): 721 (M+H).

Example ₁₂ 6 ^ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(n-butyloxy)methyl-4H-1,2,4-triazol-3-yl Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The preparation method was the same as "Example 123" except that "n-butanol" was used instead of "ethylene glycol". ^-NMR (CDC1 ₃ , 400 MHz) δ 0.86 (t, 3Η), 1.29 (m, 2Η), 1.41 (m, 2H), 2.06 (m, 2H), 2.63 (t, 2H), 3.11 (t, 2H), 3.60 (s, 2H), 3.69 (s, 2H), 5.10 (s, 2H), 5.53 (s, 2H), 6.89 (d, 2H), 6.98 (t, 2H), 7.35 (dd, 2H) ), 7.46 (d, 2H), 7.60 (d, 2H), 7.69 (d, 2H).

Example 127——1-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-(l-chloroethyl)- ff-l,2,4-triazol-3-yl] Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one

The preparation method was the same as in "Example 114" except that "Example 120" was used instead of "Example 72".

Example ₁₂₈ ^ 1-ί4-(p-trifluoromethylbiphenyl-yl)methyl-5-[1-(2-dimethylamino)ethylamine]ethyl- &-1,2,4-triazole- 3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1cyclopenta[(/1pyrimidin-4(5^)-one)

13S

50 mg (1 equivalent) of the compound of Example 127, 18 μl (2.1 eq.) of N,N-dimethylethylenediamine and 1 mg of potassium iodide were refluxed in 2 ml of acetonitrile, and the reaction was monitored by TLC. After completion of the reaction, acetonitrile was evaporated under reduced pressure. EtOAc was evaporated. 1H-NMR (CDC1 ₃ , 400 MHz) 51.53 (d, 3H), 1.98 (m, 2H), 2.24 (s, 6H), 2.37 (m, 2H), 2.55-2.78 (m, 6H), 4.11 (q , 1H), 4.43 (s, 2H), 4.98 (s, 2H), 5.53 (2x d, 2H), 6.92 (m, 4H), 7.29 (dd, 2H), 7.45 (d, 2H), 7.60 (d , 2H), 7.70 (d, 2H). Example ₁₂₉ ^ 1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[l-(methyl)(2-dimethylamino) Ethyl)ammonium]ethyl- &1,2,4-triazol-3-yl}methylpenta[(/1 pyrimidine-4(5^)-one

The method of preparing the same in "Example 128", in addition to trimethylethylenediamine "instead of" N, N- dimethylethylenediamine "as raw ^{_{material.! H-NMR (CDC1 3}} , 400 MHz) 51.48 (d, 3Η ), 2.01 (m, 2Η), 2.35 (s, 3H), 2.45 (s, 6H), 2.59-3.00 (m, 8H), 4.01 (q, 1H), 4.40 (2x d, 2H), 5.00 (d , 1H), 5.26 (d, 1H), 5.56 (d, 1H), 5.74 (d, 1H), 6.87 (t, 2H), 6.99 (d, 2H), 7.26 (m, 2H), 7.40 (d, 2H), 7.56 (d, 2H), 7.69 (d, 2H).

Example ₁₃₀ _ 1-{4-(p-trifluoromethylbiphenyl-yl)methyl-5-[1-(2-diethylamino)ethylamine]ethyl -&-1,2,4-triazol-3-yl}methyl[(/1 pyrimidine-4(5^)-one

The preparation method was the same as in "Example 128" except that "N,N-diethylethylenediamine" was used instead of "N,N-dimethylethylenediamine". H-NMR (CDC1 ₃ , 300 MHz) δΐ .10 (t, 6Η), 1.53 (d, 3Η), 1.99 (m, 2Η), 2.60-2.85 (m, 12H), 4.21 (q, 1H), 4.43 (s, 2H), 4.98 (s, 2H), 5.57 (2x d, 2H), 6.93 (m, 4H), 7.30 (dd, 2H), 7.45 (d, 2H), 7.60 (d, 2H), 7.70 (d, 2H).

Example i _{31 a} -1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[l-(methyl)(2-diethylaminoethyl)amino]ethyl-4H -1,2,4-triazol-3-ylpentyl [rf]pyrimidin-4(5H)-one

The preparation method was the same as in "Example 128" except that methyl-N^N-ethylethylenediamine was used instead of "dimethylethylenediamine". ^-NMR (CDC1 ₃ , 300 MHz) 51.25 (m, 6Η), 1.48 (d, 3Η), 2.02 (m, 2H), 2.35 (s, 3H), 2.74 (t, 2H), 2.85-3.03 (m, 10H), 4.10 (q, 1H), 4.38 (2x d, 2H), 5.03 (d, 1H), 5.21 (d, 1H), 5.65 (2x d, 2H), 6.85 (t, 2H), 7.02 (d, 2H), 7.25 (dd, 2H), 7.39 ( d, 2H), 7.55 (d, 2H), 7.69 (d, 2H).

Example i _{31 b} _ 1-{4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[l-(methyl)(2-diethylaminoethyl)amine]ethyl-4H -1,2,4-triazol-3-yl}methyl-2-(fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[rf]pyrimidin-4(5H)-one- Tartrate;

The preparation method was the same as "Example 91b" except that "Example 131 &" was substituted for "Example 91^". ^-NMR (d _s -DMSO, 300 MHz) δ ΐ.06 (t, 6 Η, J = 6.9), 1.35 (d , 3H, J=6.0), 1.91 (m, 2H), 2.17 (s, 3H), 2.54 ( 2H, J=7.2), 2.7 l(m, 4H), 2.9 l(m, 6H), 4.14 (q , 1H, J=6.0), 4.23 (s, 2H), 4.31 (s, 2H), 5.09/5.21 (2x d, 2H, J=12.9), 5.44/5.52 (2x d, 2H, J=16.5), 7.03 (t, 2H, ^8.4), 7.15 (d _: 2H, J=7.8), 7.34 (dd, 2H, J=8.4, 6.0), 7.65 (d, 2H, J=7.8), 7.81 (m, 4H ).

Example _132-1- {4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[l-(methyl)(3-dimethylaminopropyl)amino]ethyl- &-1 , 2,4-triazol-3-yl} [(/1 pyrimidine-4(5^)-one

The preparation method was the same as in "Example 128" except that "N-dimethylethylenediamine" was replaced by trimethyl-1,3-propanediamine. H-NMR (CDC1 ₃ , 300 MHz) 51.48 (d, 3Η), 1.75 (m, 2Η), 2.01 (m, 2H), 2.30 (s, 3H), 2.59 (m, 9H), 2.70 (t, 2H), 2.85 (m, 3H), 4.05 (q, 1H), 4.36 (2x d, 2H), 5.00 (d, 1H), 5.38 (d, 1H), 5.50 (d, 1H), 5.67 (d, 1H), 6.84 (t, 2H), 7.03 (d, 2H), 7.23 (m, 2H), 7.40 (d, 2H), 7.55 (d, 2H), 7.69 (d, 2H). Example 1 1-[ ^4- (p-Trifluoromethylbiphenyl- ⁴ -yl)methyl- ^5- [W-ethyl-( ² -dimethylamino)ethylamino]methyl-4H-1,2, 4-triazol-3-yl]methyl [pyrimidine-4 (5H>ketone;

Prepared by the method of Example 79, except that "ethyl-N,N-dimethylethylenediamine" was substituted for "diethylamine". H-NMR (CDC1 ₃ , 300 MHz) δΐ.11 (t, 3Η), 2.03 (m, 2Η), 2.61 (s, 6H), 2.69 (q, 2H), 2.75 (t, 2H), 2.97 ( m, 6H), 3.77 (s, 2H), 4.39 (s, 2H), 5.18 (s, 2H), 5.58 (s, 2H), 6.86 (t 2H), 7.03 (d, 2H), 7.25 (m, 2H), 7.40 (d, 2H), 7.56 (d, 2H), 7.70 (d, 2H).

Example 134——N-(2-Diethylamino)ethyl-N-{3-[2-(4-fluorobenzylthio)-oxo-6,7-dihydro-4H-cyclopenta[rf] Pyrimidine-1(5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-ylindole methylaminoacetic acid Ester

Prepared by the method of Example 79, except that "[2-(2-diethylamino)ethylamine]ethyl acetate" was substituted for "diethylamine,". H-NMR (CDC1 ₃ , 300 MHz) 51.22 (m, 3Η), 1.30 (m, 6Η), 2.02 (m, 2Η), 2.73 (t, 2H), 2.95 (t, 2H), 3.09 (m, 6H), 3.25 (t, 2H), 3.56 (s, 2H) ), 4.12 (q, 2H), 4.19 (s, 2H), 4.35 (s, 2H), 5.20 (s, 2H), 5.63 (s, 2H), 6.84 (t, 2H), 7.09 (d, 2H) , 7.22 (dd, 2H), 7.41 (d, 2H), 7.55 (d, 2H), 7.70 (d, 2H). Example 135——N-(2-Diethylamino)ethyl-N-{3-[2-(4-fluorobenzylthio)-oxo-6,7-dihydro-4H-cyclopenta[rf] Pyrimidine-1(5H)-yl]methyl-4-(p-trifluoromethylbiphenyl-4-yl)methyl-4H-1,2,4-triazol-5-ylindole methylaminoacetic acid

The preparation method was the same as "Example 63" except that "Example 134" was used instead of "Example 62". ^-NMR (d ₆ -DMSO, 300 MHz) 50.98 (t, 6 Η), 1.91 (m, 2 Η), 2.54 (t, 2H), 2.65-2.75 (m, 10H), 3.13 (s, 2H), 3.93 (s, 2H), 4.30 (s, 2H), 5.16 (s, 2H), 5.48 (s, 2H), 7.03 (t, 2H), 7.19 (d, 2H), 7.33 (dd, 2H), 7.63 ( d, 2H), 7.90 (m, 4H).

Example ₁₃₆ _ l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-pyrrolidinyl)amino]methyl- &-1,2, 4-triazol-3-yl]methyl [(/1 pyrimidine-4(5^)-one)

Prepared by the method of Example 79, except that methyl-[2-(pyrrole-1-yl)]ethylamine was substituted for "diethylamine,". H-NMR (CDC1 ₃ , 300 MHz) 52.00 (m, 6H), 2.37 (s, 3H), 2.73 (t, 2H), 2.91 (t, 2H), 3.07 (t, 2H), 3.77 (s, 2H), 4.39 (s, 2H), 5.14 (s, 2H), 5.59 (s, 2H), 6.86 (t, 2H), 7.02 (d, 2H), 7.26 (dd, 2H), 7.40 (d, 2H ), 7.56 (d, 2H), 7.70 (d, 2H).

Example 137——N-(2-Diethylamino)ethyl-{2-[2-(4-fluorobenzylthio)-4-oxo-6,7-dihydro- ff-cyclopenta[rf] Pyrimidine -1(5H)-yl]methyl-1-(p-carbamide)

Prepared by the method of Example 51 except that "NN-diethylethylenediamine" was substituted for "dimethylamine hydrochloride". H-NMR (CDC1 ₃ , 300 MHz) δ 1.38 (t, 6Η), 1.96 (m, 2Η), 2.66 (t, 4H), 3.17 (m, 6H), 3.78 (m, 2H), 4.42 (s , 2H), 4.96 (s, 2H), 5.74 (s, 2H), 6.90 (t, 2H), 7.01 (d, 2H), 7.29 (dd, 2H), 7.43 (d, 2H), 7.58 (d, 2H), 7.68 (d, 2H), 8.03 (s, 1H), 8.95 (t, 1H, -CONH-). Example ₁₃₈ AL methyl_Λ_(2-diethylamino)ethyl-{2-[2 - (4-fluorobenzyl) -4-oxo-6,7-dihydro-cyclopentyl -4H- [RF] pyrimidine -1 ⁽⁵ H) - yl] methyl - imidazole ^--5-- yl} carboxamide

Prepared by the method of Example 51 except that "methyl-NN-ethylethylenediamine" was substituted for "dimethylamine hydrochloride". Ή-NMR (CDC1 ₃ , 300 MHz) δ 1.20 (t, 6H), 1.99 (m, 2H), 2.69 (m, 6H), 2.89 (m, 4H), 3.22 (s, 3H), 3.70 (t, 3H), 4.36 (s, 2H), 4.92 (s, 2H), 5.43 (s, 2H), 6.84 (t, 2H), 7.08 (d, 2H), 7.22 (dd, 2H), 7.26 (s, 1H ), 7.43 (d, 2H), 7.55 (d, 2H), 7.65 (d, 2H). Example ₁₃₉ _ l-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5- [ (methyl) (2-diethylaminoethyl) ammonia] methyl-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclo Penta [rf]pyrimidine-4(5H)-one

Prepared by the method of Example 45 except that "methyl-diethylethylenediamine" was substituted for "benzylpiperazine". H-NMR (CDC1 ₃ , 300 MHz) δ 1.08 (t, 6Η), 1.98 (m, 2Η), 2.21 (s, 3H), 2.67-2.85 (m, 12H), 3.47 (s, 2H), 4.42 (s, 2H), 4.95 (s, 2H), 5.46 (s, 2H), 6.89 (t, 2H), 6.95 (d, 2H), 6.96 (s, 1H), 7.27 (dd, 2H), 7.42 ( d, 2H), 7.58 (d, 2H), 7.69 (d, 2H). Pharmacological examples

1. Determination of Lp-PLA ₂ inhibitory activity of compound on rabbit serum as enzyme source (in vitro)

1.1, experimental methods

Substrates were detected using tritiated platelet activating factor ([ ³ H] PAF, Perkinelmer, Lot NET910). The reaction was carried out in a 200 μl system (50 mmol/L hydroxyethylpiperazineethanesulfonic acid (HEPES) and 150 mmol/L sodium chloride (NaCl), pH 7.4). First, ΙΟμΙ rabbit serum and ΙΟμΙ test compound dissolved in dimethyl sulfoxide (see Table 2 below) were pre-incubated for 10 minutes at 37 °C. Then start the reaction by adding 20 nM [ ³ H] PAF (see Table 1 for the reaction system). The reaction was carried out at 37 ° C for 10 minutes, followed by the addition of 600 μl of CHCl ₃ /MeOH (2:1) to stop the reaction. After standing for a while, it was centrifuged at 12,000 x g for 15 minutes, and the supernatant of the aqueous layer was transferred to a new tube, and 200 μl of chloroform was added thereto, and the mixture was allowed to stand or centrifuged for 2 minutes. The supernatant of the ΙΟΟμΙ aqueous layer was taken for determination of radioactivity.

Table 1: List of reaction systems

Blank tube

Reaction buffer 180 170 170 Test compound 10 Dimethyl sulfoxide (solvent) 10 10

Substrate ([ ³ H] PAF) 10 10 10

Enzyme source (rabbit serum) 10 10 Inhibition rate calculation formula:

Inhibition rate =1- (test tube DPM value - blank tube DPM value) / (control tube DPM value - blank tube DPM value)

(Note: DPM is the unit of radioactivity.)

1.2, the experimental results are shown in Table 2 below.

Table 2: Inhibitory activity of some compounds on Lp-PLA ₂ enzymatically derived from rabbit serum at various concentrations

Inhibition rate, 1⁄4

Compound number

Example 1 62.6 10.0 NT Example 2 82.7 26.6 NT Example 3 12.5 NT NT Example 6 74.0 16.2 NT Example 7 60.3 25.0 NT Example 18 41.9 7.4 NT Example 19 76.8 29 NT Example 20 86.6 31 NT Example 21 51.2 ― NT Example 22 63.0 ― NT Example 23 82.4 33 NT Example 24 78.5 16.3 NT Example 25 74.3 23 NT Example 26 7.4 NT NT Example 28 96.5 79.6 16.9 Example 29 NT 64.9 12.6 Example 30 87.5 42.3

Example 32 NT 50.0 2 1 Example 34 NT 14.6 NT Example 38 20.4 16.0 NT Example 40 NT 90.7 53.1 Example 41 NT 64.9 12.6 Example 42 NT 97.7 88.3 Example 43 NT NT 78.6 06 1M 1Μ 18"

££1 1M 1Μ 6i"

£6 1M 1Μ LL

016 1M 1Μ L

£■88 1M 1Μ

U 1M 1Μ

96 1M 1Μ oi

68 1M 1Μ 69

I8 1Μ 89"

16 1M 1Μ L9"

88 1M 1Μ 99

009 IK IK £9

6'8i 1M 1Μ

8'£i 1M 1Μ 19"

618 1M 1M 19"

019 1M 19"

1M ― OOfr 09

1M ― £6 6£"

1M 8 6 8£"

1M VZL

1M \ζ 9££

6££ 888 1M ”

TO 106 1M

06 1Μ 1M

1Μ 1M oe"

996 1Μ 1M

696 986 1M LP"

Li8 .L6 1M

I8 1Μ 1M ”

Γ68 1Μ 1M

801000/εΐΟί ΟΛ\ Example 82 NT NT 85 Example 83 NT NT 93 Example 84 NT NT 76 Example 85 NT NT 77 Example 86 NT NT 90 Example 87 NT NT 75 Example 88 NT NT 67 Example 89 NT NT 13.4 Example 90 NT NT 96 Example 91a NT NT 98 Example 91 NT NT 98 Example 93 NT NT 98 Example 94 NT NT 98 Example 95 NT NT 99 Example 96 NT NT 97 Example 97 NT NT 98 Example 98 NT NT 97 Example 99 NT NT 97 Example 100 NT NT 91 Example 101 NT NT 86 Example 102 NT NT 97 Example 103 NT NT 82 Example 104 NT NT 67 Example 105 NT NT 98 Example 106 NT NT 96 Example 107 NT NT 68 Example 110 NT NT 67 Example 111 NT NT 75 Example 112 NT NT 63 Example 113 NT NT 64 Example 115 NT NT 78 Example 116 NT NT 94 Example 117 NT NT 80 Example 118 NT NT 68 Example 119 NT NT 93 Example 120 NT NT 90 Example NT NT 95 Example 123 NT NT 88 Example 125 NT NT 92 Example 128 NT NT 94 Example 129 NT NT 96 Example 130 NT NT 94 Example 131a NT NT 96 Example 132 NT NT 96 Example 133 NT NT 97 Example 135 NT NT 83

"One" means no inhibitory activity; "NT" means not tested.

2. Determination of Lp-PLA ₂ inhibitory activity of the compound on rabbit serum (in vitro)

2.1, experimental method

Substrates were detected using tritiated platelet activating factor ([ ³ H] PAF, Perkinelmer, Lot NET910). The reaction was carried out in a 200 μl system (50 mmol/L HEPES and 150 mmol/L NaCl, pH 7.4). First, ΙΟμΙ human blood paddles and 待μΙ test compounds dissolved in dimethyl sulfoxide (see Table 3 below) were pre-incubated for 10 minutes at 37 °C. Then start the reaction by adding 20 nM [ ³ H] PAF (see Table 1 for the reaction system). The reaction was carried out at 37 ° C for 10 minutes, followed by the addition of 600 μl of CHCl ₃ /MeOH (2:1) to stop the reaction. After standing for a while, it was centrifuged at 12,000 x g for 15 minutes, and the aqueous layer was transferred to a new tube, and 200 μl of chloroform was added thereto, and the mixture was allowed to stand or centrifuged for 2 minutes. The supernatant of the ΙΟΟμΙ aqueous layer was taken for determination of radioactivity.

2.2, the experimental results are shown in Table 3 below.

Table 3: Inhibitory activity of some compounds on human serum as Lp-PLA ₂ at various concentrations

Inhibition rate, 1⁄4

Compound number

ΙΟΟηΜ 10nM 0^1

9L IS

ZS 96 98"

6£16 £8

69 16

18 £6 £8

LL 86

£6 86 18"

89 £6 61

16 86 LL

001 001 91

£8 16 ""

£9 16 ZL

16 16 01

IS 16 69

£6 16 89

Z6 86 19

88 86 99

ZS 96 £9

U £6 9

91 6 19

£8 96 19

6£ 16 19

16 66 ζς"

16 86

£6 66

06

69 £6

19 S6

Z6

Z0l79 .0/ll0ZN3/X3d 801000/C10Z OAV Z6 IN

68 86 oz\

6 86 6Π

8£88 8Π"

19 16 il l"

LL IN en"

9£16 επ"

9£ i8 zu"

89 16 Π ΐ "

19 £8 on

OL 16 iOl

08 IN 901

ZL IN £01"

££ 98 frOl

86 £01"

LL 1M 201"

LL 96 101 3⁄4

16 86 001"

18 IN 66

S8 1M 86"

18 1M L6

8i 1M 96"

98 1M £6"

68 IN

£8 IN £6"

£6 1M 16"

Fr6 1M

£6 001 06

6£ 16 88 rot'^o/iiozNa/xad 801000/εΐΟί ΟΛ\ Example 123 NT 76 Example 125 NT 76 Example 128 NT 90 Example 129 NT 94 Example 130 NT 92 Example 131a NT 92 Example 132 NT 93 Example 133 NT 92 Example 135 NT 66

"NT" means not tested.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the invention as defined in the appended claims.

Claims

Claim

1. An azole heterocyclic compound represented by the formula (I) or (II), a cis-trans isomer, an enantiomer thereof, a diastereomer, a racemate, a hydrate, and a solution

among them

T is a four to six dollar fat ring, or a benzene ring;

R is a sulfhydryl group;

X is CH or N;

γ is a benzene ring, and optionally one or more selected from the group of substituents: a halogen atom, d_ _s embankment group, d_ _s embankment group, a halogen atom-substituted alkyl with d_ _s;

(f)

R ^{1 is} selected from H'

, ₁₂ alkenyl, ₁₂ fluorenyl, -NR ⁴ R ⁵ substituted ₄ fluorenyl, ⁴ substituted piperidine

R ^{2 is} selected from H,

-CONR ⁴ R ⁵ , C=NNR ⁴ R ⁵ , -C(=CH ₂ )-OC(=0)R ⁴ , a C _1-12 fluorenyl group, a C _3-7 cyclodecyl group, a phenyl group, the fluorenyl group, a cyclodecyl group and a phenyl group are optionally halogen, -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ ,

-NHCOR ⁴ , -NHS0 ₂ R ⁴ , -NHCSNHR ⁴ , ^RS , N ₃ , substituted by phenyl;

R ³ may be in the ortho, meta or para position, is selected from H, halogen atom, d_ _s the embankment group, partially or wholly halogenated group of embankment;

R ⁴ and R ⁵ each independently select a linear or branched fluorenyl group of g H, C cyclyl, which is optionally -COOR ⁹ , -NR ⁹ R ¹⁰ ' -OR ⁹ ' -COR ⁹ , substituted by a benzene ring, a benzyl group, an aromatic and a non-aromatic heterocyclic ring, optionally a halogen atom, a fluorenyl group Replaced; or

R ⁴ , R ⁵ and its attached N together form a 5-8 membered non-aromatic heterocyclic ring which may comprise another hetero atom selected from N, 0, S, and optionally a halogen atom, ^{^{group, -NR "R 12, -OR 11}} , oxo, substituted benzyl group; said d_ _s is optionally substituted alkyl with -COOR ^4;

R ⁹ , R ^1Q are each independently selected as g H, fluorenyl; or

R ⁹ , R ^{1Q together} with the N to which it is bonded constitutes a 5-8 membered non-aromatic heterocyclic ring, and the heterocyclic ring may comprise another hetero atom selected from N, 0, S;

R ¹¹ ' R ¹² are each independently selected as g H, d_ _s fluorenyl.

Halo represents a halogen atom.

2. The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, or a pharmaceutically thereof thereof An acceptable salt, characterized in that, in the formula (I):

T is a five-membered fat ring, or a benzene ring;

X is 11 or ^^.

The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof An acceptable salt, characterized in that, in the formula (I):

When T is a five-membered aliphatic ring, X is N; when T is a benzene ring, X is CH.

The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof An acceptable salt, characterized in that, in the formulae (I) and (II):

Y is a benzene ring substituted with a fluorine atom.

5. The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer thereof, a non- An enantiomer, a racemate, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein, in the formulae (I) and (II):

Y is "4-fluorophenyl", "2,3-difluorophenyl".

6. The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof An acceptable salt, characterized by the general formula (I) and Ml:

1

Wherein R ¹ and R ^{2 are} as defined in claim 1.

The azole heterocyclic compound according to claim 6, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof. An acceptable salt, characterized by

R ¹ is

Or -NR ⁴ R ⁵ substituted C ₂ _ ₄ fluorenyl.

The azole heterocyclic compound according to claim 6, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof. An acceptable salt, characterized by, in the formulae (I) and (II):

R ¹ is "(4-trifluoromethylbiphenyl-4-yl)methyl".

The azole heterocyclic compound according to claim 6, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof An acceptable salt, characterized by, in the formulae (I) and (II):

R ² is -COR ⁴ , an indenyl group of -CONR ⁴ R ⁵ , a cyclodecyl group of c ₃ _ ₅ , optionally substituted by -NR ⁴ R ⁵ , -OR ⁴ , -SR ⁴ , -S0 ₂ R% =NNR ⁴ R -NHCOR% -NHS0 ₂ R%

Halo

-NHCSNHR ⁴ , replaced by ^RG .

The azole heterocyclic compound according to claim 6, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof. An acceptable salt, characterized by, in the formulae (I) and (II): R ² is -COR ⁴ , -CONR ⁴ R ⁵ , a cyclopropyl group, and the fluorenyl group is -NR ⁴ R ⁵ , -OR ⁴ ,

-SR ⁴ , -S0 ₂ R ⁴ , =NNR ⁴ R ⁵ , -NHCOR ⁴ , -NHS0 ₂ R ⁴ , -NHCSNHR ⁴ or ^RG .

The sulfhydryl group of C ₅ substituted by ^RG .

R ^{2 is} selected from "NN-dimethylamino", "N-(2-diethylamino)ethylamino", methyl-N-(2-diethylamino)ethylamino", "dimethyl Aminomethyl", "diethylaminomethyl", "(tetrahydropyrrole small)methyl", "(N-methyl-p-fluorobenzamide)methyl", "isopropyl", "cyclopropyl"","(3-diethylamino)propyl","(4-diethylamino)butyl","hydroxymethyl","(1-hydroxy)ethyl","(p-fluorobenzylthio))methyl","(N-methylisopropylamino)methyl","[(1-ethylpyrrole-2-yl)methylamino]methyl","(N-ethylpiperazine-1-yl)methyl",methyl-(2-dimethylamino)ethylamino]methyl","[N-methyl-(2-diethylamino)ethylamino]methyl","[N-B-(2-dimethylamino)ethane]methyl","[N-methyl-(3-dimethylamino)propylamino]methyl","[N-methyl-(pyridin-2-yl))methylamino]methyl","(4-dimethylaminopiperidin-1-yl)methyl","(NN-dimethylsulfonium)methyl","(2-hydroxyethoxy)methyl"","(2-Diethylaminoethoxy)methyl","[1-(2-dimethylamino)ethylamino]ethyl","[1-(methyl)(2-dimethylaminoethyl)Ammonia]ethyl","[1-(2-diethylamino)ethylamino]ethyl","[1-(methyl)(2-diethylamino) Ethyl], "1-(methyl)(3-dimethylaminopropyl) gas]ethyl",

The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof Acceptable salt,

Wherein, Y, R ¹ , R ² are as defined in claim 1.

The azole heterocyclic compound according to claim 1, a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a hydrate, a solvate thereof, or a pharmaceutically thereof thereof An acceptable salt, characterized in that the compound is selected from the group consisting of:

1-(5-n-heptyl-4,5-dihydro-1,2,4-Hoxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H - cyclopurine M pyrimidine-4(5H)-one;

1-(5-n-decyl-4,5-dihydro-1,2,4-Hoxadiazol-3-yl)methyl-2-p-fluorobenzylthio-6,7-dihydro-1H - cyclopurine M pyrimidine-4(5H)-one;

1-[5-(p-trifluoromethylbiphenyl-4-yl)-4,5-dihydro-l,2,4-tloxadiazol-3-yl]methyl-2-p-fluorobenzyl sulfide base -6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

(£)-l-[5-n-heptyl-4-(l-n-octene)-4,5-dihydro-l,2,4-tloxadiazol-3-yl]methyl-2- P-fluorobenzylthio

-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

-4(5H)-one;

15S 1-[1-Diethylaminoethyl-5-(p-trifluoromethylbiphenyl-4-yl)-1H-imidazol-2-yl]methyl-2-(4-fluorobenzylthio)-6 , 7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-ethyl-5-(p-trifluoromethylbiphenyl-4-yl)-4H-l,2,4-triazol-3-yl]methyl-2-p-methoxybenzene Methylthio-6,7-dihydro-1H-cyclopenta[pyrimidin-4(5H)-one;

-1H-cyclopenta [pyrimidine-4(5H)-one;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-benzylsulfonemethyl- 4H-1,2,4-triazol-3-yl]methyl

-2-(4-fluorobenzylthio)-6,7-dihydro-1 Η-cyclopenta [pyrimidine-4 (5H> ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-dimethylaminomethyl-4H-1,2,4-triazol-3-yl]methyl -2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1Η-cyclopenta[pyrimidine-4 (5H> ketone;

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-4H-1,2,4- Triazol-3-yl]methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone-tartrate; L-[ ⁴ - (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ⁵ -[(methyl)( ³ -dimethylaminopropyl)amino]methyl

(J?)-l-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-[(3-dimethylamino)pyrrole-1-yl]methyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-azidomethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4 - fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone; L-[4-(p-Trifluoromethylbiphenyl-4-yl)methyl-5-aminomethyl-4H-1,2,4-triazol-3-yl]methyl-2-(4- Fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H>ketone;

-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone;

-3-yl}methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidin-4 (5H>ketone; L-{ ⁴ - (p-trifluoromethylbiphenyl- ⁴ -yl)methyl- ^5- [l-(methyl)( ² -dimethylaminoethyl)amino]ethyl

1-[4-(p-trifluoromethylbiphenyl-4-yl)methyl-5-[(methyl)(2-diethylaminoethyl)amino]methyl-1H-imidazol-2-yl] Methyl-2-(4-fluorobenzylthio)-6,7-dihydro-1H-cyclopenta[pyrimidine-4 (5H> ketone.

A pharmaceutical composition comprising one or more effective therapeutic doses of the azole heterocyclic compound according to any one of claims 1 to 14, a cis-trans isomer thereof, an enantiomer thereof, Diastereomers, racemates, solvates, hydrates, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

16. The pharmaceutical composition according to claim 15, further comprising one or more drugs selected from the group consisting of hypolipidemic agents, antiatherogenic agents, hypoglycemic agents, anti-angina drugs, anti-inflammatory drugs Medicine, antihypertensive drug or drug that lowers lipoprotein a.

The azole heterocyclic compound according to any one of claims 1 to 14, which is a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, or a hydrated compound. Or its pharmaceutically acceptable Use of a salt in the manufacture of a medicament for an Lp-PLA ₂ inhibitor.

The azole heterocyclic compound according to any one of claims 1 to 14, which is a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, or a hydrated compound. on the object, or a pharmaceutically acceptable salt thereof in the manufacture of preventing, treating or ameliorating drug eight 1 ^ ₂ related diseases in enzymatic activity.

The use according to claim 18, wherein the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases.

A method for preventing, treating or ameliorating a disease associated with Lp-PLA ₂ enzyme activity, comprising administering the azole heterocyclic compound according to any one of claims 1 to 14, a cis-trans isomer thereof, a pair A composition, a diastereomer, a racemate, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 15-16.

21. The method of claim 20, wherein the disease comprises atherosclerosis, stroke, coronary heart disease, diabetes, asthma, psoriasis, rheumatoid arthritis, acute and chronic inflammatory diseases.

An azole heterocyclic compound represented by the formula (I), a cis-trans isomer, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate thereof, or A method of preparing a pharmaceutically acceptable salt, one of which is specifically one of Reaction Scheme 4:

Reaction route 1

When W in the compound of the formula (I) is a structure and ! ¹ is an alkenyl group, the compound of the formula (I) (i.e., compound 6) can be produced by the method shown in Reaction Scheme 1: wherein R ¹³ is C ₁ . The thiol group, T, X, Y, R ² is as defined in claim 1;

Amidation of compound 1 to compound 2; compound 2 produces compound 3 under the action of a dehydrating reagent; compound 3 is reacted with hydroxylamine hydrochloride under the action of a base to prepare compound 4; compound 4 in boron trifluoride etherate Catalytic reaction with R ² CHO to form compound 5, the reaction is carried out in an aprotic solvent; compound 5 is reacted with R ¹³ CH ₂ CHO under the catalysis of boron trifluoride diethyl ether to obtain compound 6;

w

7 8 9 10

Reaction route 2

When T in the compound of the formula (I) is a 4-6 membered aliphatic ring, Χ=Ν and R ^{1 is} not an alkenyl group, the compound of the formula (I) (ie, compound 10) can be prepared by the method shown in Scheme 2. Wherein R ¹⁴ is methyl or ethyl, and Halo, T, W, Y are as defined in claim 1;

0 In a polar solvent, compound 7 is condensed with the cyclic fluorenone carboxylate ^σ in the presence of a dehydrating agent to form compound 8; compound 8 produces a compound 9 under the action of Me ₃ SiNCS; under the action of a base, compound 9 Y^Halo reacts in a polar solvent to form compound 10;

13

Reaction route 3 When W in the above compound 10 is the structure 0 and! ^{When 2} is a hydroxymethyl group, the compound (ie, compound 14) can be prepared by two methods shown in Scheme 3: wherein Halo, T, Y, R ¹ are as defined in claim 1;

Or,

twenty two

Reaction route 4

When R ² in the formula (I) is an α-hydroxy substituted indenyl group, the compound of the formula (I) is the compound 15, wherein R ¹⁵ is H, alkyl with a, R ^1S d_ is alkyl with _6, and the alkyl with optionally substituted by NR ⁴ R ⁵ or phenyl which is optionally substituted by a halogen atom, R ¹³ is A thiol group, L is NR ⁴ , 0 or S, Z is CH, N or 0, and T, X, Y, RR ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined in claim 1. ;

Compound 16 is condensed with R ⁶ NR ⁷ R ³ to give compound 20;

Condensation of compound 19 with R ^s -Halo also gives compound 20;

Compound 18 is condensed with H ₂ NNR ⁴ R ⁵ to form compound 21;

Compound 18 reacts with R ^ls BrMg to yield compound 22.

16S