WO2009062371A1 - Carbamate derivatives, and the use as medicament - Google Patents

Abstract

Carbamate derivatives of 5- or 6-membered ring represented by the general formula (I), a process for preparing them, pharmaceutical compositions comprising them, intermediates for preparing the general formula (I), and a process for preparing the intermediates, and their use as a medicament, especially for cholesterol ester transfer protein (CEPT) inhibitors.

Description

 Carbamate derivatives and their application in medicine

 The present invention relates to a novel class of five- and six-membered cyclic carbamate derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same and their use as therapeutic agents, particularly as cholesterol ester transfer protein inhibitors. Background technique

 Hypercholesterolemia, particularly high serum levels of low-density ester protein cholesterol, shows a risk of arteriosclerotic disease. At present, atherosclerosis and its associated coronary heart disease (CHD), stroke and peripheral vascular disease have become a huge obstacle to the global industrialization of the health care system. In the United States alone, approximately 13 million people have coronary heart disease (CHD), and the number of deaths per year exceeds 500,000, and this number is still growing. Despite attempts to treat dyslipidemia through proper diet and medications, coronary heart disease (CHD) is still the most common cause of death in the United States at 44% of all deaths, and 53% of them are atherosclerotic. Caused by hardening.

 The production of atherosclerosis is closely related to its blood lipid level. High levels of low-density lipoprotein (LDL) cholesterol are recognized as forms of dyslipidemia, but it is by no means the only cause of coronary heart disease (CHD). Low levels of high-density lipoprotein (HDL) cholesterol are also a contributing factor to coronary heart disease (CHD) (Gordon, DJ, et al., "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1 989), 79: 8-1 5). Increasing low-density lipoprotein (LDL) cholesterol levels increases the risk of atherosclerosis. Recently, epidemiological studies have shown that lowering high-density lipoprotein (HDL) cholesterol levels will also increase the risk of atherosclerosis.

 It is well known that increasing HDL cholesterol levels can prevent or treat arteriosclerotic diseases. However, there is currently no good high-density lipoprotein (HDL) drug. 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors and clofibrate can only partially increase high-density lipoprotein (HDL) cholesterol levels, and niacin derivatives can significantly increase HDL, but Serious tolerance problems. Therefore, there is a need for drugs that can significantly increase high-density lipoprotein (HDL) cholesterol levels and are well tolerated to prevent atherosclerosis.

Metabolic control of lipoprotein levels is a complex and dynamic process involving multiple factors. Many ester proteins in the patient's catabolic regulation mechanisms are related. Among them, cholesterol ester transfer protein (CETP) is an important lipoprotein level metabolic control factor, which is a 70,000 Dalton glycoprotein present in the plasma of humans and other animals. Transports cholesterol esters, triglycerides, and certain phospholipids between protoplast lipoprotein particles. The above lipoprotein microparticles include high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and chylomicrons. CETP catalyzes the transfer of cholesterol esters from high-density lipoprotein (HDL) to apoprotein-containing apoprotein B, especially to very low-density lipoproteins (Hesler, CB, et. al. (1987) Purification and Characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem.

262(5), 2275-2282). Under physiological conditions, the net reaction is a transfer of CELP with triglycerides from apoprotein B lipoprotein to high density lipoprotein (HDL) while transporting cholesterol esters from high density lipoprotein (HDL) to apoprotein Protein B lipoprotein exchange reaction. Some studies have clearly indicated that the plasma concentration of high density lipoprotein (HDL) cholesterol is relative to CETP activity. (Inazu, A., et. al. (2000)

Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4).

389-396), it is concluded that inhibition of CETP lipid transfer activity in pharmacy may increase high-density lipoprotein (HDL) cholesterol levels while lowering low-density lipoprotein (LDL) levels, which is beneficial to the human body.

 Clinical trials of CETP inhibitors have shown that the body can use this mechanism to increase circulating high-density lipoprotein (HDL) cholesterol levels. One study showed that using CETP inhibitors at a dose of 900 mg per day increased HDL cholesterol by 34% after 4 weeks (Circulation, 2002, 105: 2159). In another study of CETP inhibitors, the highest dose was administered twice a day at 120 mg twice daily, and high-density lipoprotein (HDL) cholesterol was increased by 106% after 4 weeks (N. Engl. J. Med. , 2004, 350: 1505-15). Increasing high-density lipoprotein (HDL) cholesterol levels in plasma by inhibiting CETP activity may give people the anti-atherosclerosis. Although CETP inhibitors have been shown to have anti-atherosclerotic effects in rabbits, this has not been confirmed in humans (Nature 2000, 406: 203-2071).

 Some pharmaceutical companies have been investigating new compounds that inhibit CETP, but no CETP inhibitors are currently available. There is a need to find new safer and more effective pharmaceutical compounds that can be used to treat lipid diseases through a single use or in combination with other drugs. Based on this, the present invention describes a process for the preparation of a series of five- and six-membered cyclic carbamate derivatives and their use in medicine, especially as a pharmaceutical application for CETP inhibitors. Summary of the invention

 In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel five- and six-membered cyclic carbamate compound of the formula (I), and tautomers thereof, Enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.

R ¹ R ² are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further Substituted by one or more alkyl, aryl, trifluoromethyl or heterocycloalkyl groups;

R ^{3 is} selected from a hydrogen atom, a fluorenyl group, an aryl group, an arylalkyl group or a heteroaryl group, wherein the alkyl group, the aryl group, the aryl fluorenyl group or the heteroaryl group is further substituted by one or more halogen or trifluoromethyl groups;

R ^{4 is} selected from a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group, a heteroaryl group or -C(=0)OR ⁷ _;

R ^{5 is} selected from the group consisting of a hydrogen atom, a halogen, a fluorenyl group, a cyclodecyl group, a trifluoromethyl group or a -C(=0)OR ⁷ _;

R ^{6 is} selected from a hydrogen atom, a halogen, a fluorenyl group, a cycloalkyl group, a trifluoromethyl group, a heterocyclic fluorenyl group, an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, An aryl group, an aryl fluorenyl group, a heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic acid esters;

R ^{7 is} selected from a hydrogen atom, a decyl group, an alkenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group; n is 1 work

 ~2.

 γ. -. .乂 ,

Typical compounds of the invention include, but are not limited to _:

 Example

 Structure name

 number

5-[5-C4-trifluoromethyl-phenyl)-2-one-acean

1 oxazo-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl

2

 -4-Trifluoromethyl-1 H-pyrrole-3-carboxylic acid ethyl ester

_F F 0 V 5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl

3

 -4-trifluoromethyl-1H-pyrrole-3-carboxylic acid B

F dec ester

5-[5-(2-trifluoromethyl-phenyl)-2-one-acean

4-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

5-[5-(3,5-di-trifluoromethyl-phenyl)-2-one

5-oxazol-3-yl-methyl}-3-trifluoromethyl

-1H-pyrrole-2-carboxylic acid ethyl ester 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl}-2-methyl-4-trifluoromethyl-1H- Ethyl pyrrol-3-carboxylate

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl}-4-iodo-3-trifluoromethyl-1H-pyrrole Ethyl 2-carboxylate

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- Pyrrole

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-iodine

人 5-[5-(4-三氟甲基-苯基) -4-甲基 5-[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl- 1 Ethyl H-pyrrole-3-carboxylate

Human 5-[5-(4-trifluoromethyl-phenyl)-4-methyl

 2-keto-oxazole 3-yl-methyl]-2-methyl-4-trifluoromethyl-1 H-pyrrole-3-carboxylic acid ethyl ester

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazole 3-yl-methyl]-1,2-dimethyl-4-ene

 Fluoromethyl-1H-pyrrole

FF 5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl- 1 H-pyrrol-2-yl-methyl) -oxazol-2-one

 F F

 5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)- Oxazol-2-one

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazole-3-yl-methyl}-4-phenyl-3-trifluoromethyl-1H-pyrrole Ethyl 2-carboxylate

5-(3,5-Di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-trifluoromethyl- 1H-pyrrol-2-yl-methyl)-4- Methyl-oxazol-2-one

(4S,5R)-5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl F, H

 -2-methyl-4-trifluoromethyl-1H-pyrrole

 Ethyl-3-carboxylate

在本发明的另一个方面， 是一种药物组合物，含有通式 (I)的五元及六元环氨 基甲酸酯类衍生物或其药学上可接受的盐、 载体或赋形剂。 (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2- Methyl-methyl)-oxazol-2-one

In another aspect of the invention, there is provided a pharmaceutical composition comprising a five- and six-membered cyclic carbamate derivative of the formula (I) or a pharmaceutically acceptable salt, carrier or excipient thereof.

 In another aspect of the invention, there is directed to an inhibitor of cholesteryl ester transfer protein activity, comprising a prophylactic or therapeutic agent for hyperlipidemia and a prophylactic or therapeutic agent for atherosclerosis.

 In another aspect of the invention, there is directed a cholesterol ester transfer protein activity inhibitor, comprising a prophylactic or therapeutic agent for hyperlipidemia and a prophylactic or therapeutic agent for atherosclerosis in a medicament for treating a cardiovascular-related disease the use of.

 In another aspect of the invention, there is directed a cholesterol ester transfer protein activity inhibitor, comprising a prophylactic or therapeutic agent for hyperlipidemia and a method for preparing a prophylactic or therapeutic agent for atherosclerosis, comprising the steps of:

 (1) An aqueous solution of 4,4,4-trifluoro-3-carbonyl-butyrate and sodium nitrite is reacted in an ice bath to obtain 4,4,4-trifluoro-2-indenyl 3-carbonyl- Ethyl butyrate, followed by reduction of zinc powder with 3-carbonyl-butyric acid-tert-butyl ester in glacial acetic acid to obtain the cyclized product trifluoromethylpyrrole diester;

 Under the protection of argon, trifluoromethylpyrrole diester is reduced in tetrahydrofuran and lithium aluminum hydrogen at room temperature to obtain trifluoromethylpyrrololate;

 At room temperature, trifluoromethylpyrrolidone is oxidized in dichloromethane and pyridinium chlorochromate to give trifluoromethylpyrrolidine.

(2) at room temperature, trifluoromethylpyrrolidine diester in a solution of dichloroacetic acid and trifluoroacetic acid to obtain a trifluoromethylpyrroleate;

 Trifluoromethylpyrrolate is reacted with a halogen under heating to obtain a halogen-substituted methylpyrrolidone;

 The halogen-substituted methylpyrrolidone is oxidized with cerium nitrate by heating under tetrahydrofuran/water/acetic acid, halogen-substituted pyrrole aldehyde;

 Wherein X is a halogen.

(3) At room temperature, trifluoromethylpyrrolidone is reduced in trichloromethane with trifluoroacetic acid to obtain: fluoromethylpyrrolidonic acid;

 Trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halotrifluoromethylpyrrolaldehyde;

Where X is a halogen _t

(4) Trifluoromethylpyrrolidonic acid is subjected to reduction reaction with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde.

(5)氮气氛下， 卤素取代的吡咯醛酯与芳基取代的硼酸， 发生 SuZuKi偶联反 应得到芳基吡咯醛酯；

(5) Under a nitrogen atmosphere, a halogen-substituted pyrrole aldehyde ester and an aryl-substituted boric acid are subjected to a SuZuKi coupling reaction to obtain an arylpyrrole aldehyde ester;

 Wherein X is a halogen; Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further substituted by one or more alkyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic acids Substituted by ester.

(6) under the ice salt bath, the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound;

Hydrogenation of the nitro compound to give an amino-substituted compound at room temperature.

(7) Under a nitrogen atmosphere, an anti-amination reaction of (S) benzyloxycarboaminopropionic acid with methoxy-methylamine in tetrahydrofuran to obtain a methoxyamino-substituted compound of the (S) configuration;

The (S) configuration of the aryl substituted compound is obtained by coupling a methoxyamino substituted compound of the (S) configuration with an aryl bromide in an ice bath under a nitrogen atmosphere;

The (S) configuration aryl substituted compound is reacted with Pd/C to obtain (1R, 2S) aryl substituted propanol at room temperature;

Wherein: R'-R ^{6 is} as defined above, and Ar is aryl, arylalkyl or heteroaryl, wherein aryl, aryl fluorenyl, The heteroaryl group is further substituted with one or more alkyl, aryl, decyloxy, carboxylic acid, carboxylic acid esters.

(8) At room temperature, aryl formaldehyde is cyclized with sodium hydride and trimethyl iodide to obtain aryl epoxide;

 O

 Ar^O

 Ar

The aryl epoxy oxime is subjected to ring-opening reaction with cyanotrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran to obtain a hydroxy-substituted arylpropionitrile;

 Hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran under a nitrogen atmosphere to obtain a hydroxy-substituted aryl propylamine;

 OH OH

Ar^^N Ar^^NH ₂ wherein Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further substituted by one or more fluorenyl groups, aryl groups, decyloxy groups, Substituted by a carboxylic acid or a carboxylic acid ester. (9) at room temperature, in the inventive step of the invention, 6, 8, with each polysubstituted pyrrole aldehyde, reductive amination to give a polysubstituted pyrrole methylamine;

Under the argon atmosphere, the polysubstituted pyrrole methylamine is cyclized with triphosgene, ruthenium, osmium-diisopropylethylamine to obtain five- and six-membered cyclic carbamates;

 Under the nitrogen atmosphere, the five-membered and six-membered cyclic carbamate reacted with a sodium hydride in tetrahydrofuran to react with a halogenated hydrazine to obtain a target compound N substituted five- and six-membered ring represented by the general formula (I). Carbamate compound;

Wherein R'-R ^{6 is} as defined above, and Ar is aryl, aralkyl or heteroaryl, wherein the aryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, aryl, decyloxy , substituted by carboxylic acid and carboxylic acid ester.

(10) a halogen-substituted pyrrole aldehyde ester in methanol with hydroxylamine hydrochloride, sodium acetate heated to reflux to obtain a polysubstituted pyrrolamine ester;

 The hydroxy-substituted arylacetic acid is reacted with methanol and azidotrimethylsilyl in benzene at room temperature to obtain a hydroxy-substituted arylethyl ester;

 0 0

 Ar

 OH Ar

 O

OH OH

At room temperature, the hydroxy-substituted arylethyl ester is brominated in tetrachloromethane with carbon tetrabromide and triphenylphosphine. Aryl hydrazine I

 The polysubstituted pyrrolamine ester is reacted with a bromoarylethyl ester in tetrahydrofuran to give an aryl-substituted pyrrolamine diester;

 The aryl-substituted pyrrolamine diester is reduced in tetrahydrofuran with a solution of lithium aluminum chloride in tetrahydrofuran to obtain an aryl-substituted pyrrolamine ester;

 Under the protection of nitrogen, the aryl-substituted pyrrolamine ester is cyclized with triphosgene, ruthenium, osmium-diisopropylethylamine in methylene chloride to obtain five- and six-membered cyclic carbamate compounds;

 Wherein X is a halogen; Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, alkoxy groups, carboxylic acids, carboxylic groups Substituted by an acid ester. Further, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present invention, a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the invention relates to a process for the preparation of a compound of the invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

 Multi-substituted pyrrole aldehyde at room temperature, reductive amination to give polysubstituted pyrrole methylamine;

 Under a argon atmosphere, a polysubstituted pyrrole methylamine is combined with triphosgene, ruthenium, osmium-diisopropylethylamine to give a 5- or 6-membered cyclic carbamate.

 Under the nitrogen atmosphere, the general 5- or 6-membered cyclic carbamate is reacted with a solution of sodium hydride in tetrahydrofuran to react with a halogenated hydrazine to obtain a target compound N substituted by the formula (1). Yuancyclic carbamate compound;

Wherein: R'-R ^{6 is} as defined above, and Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, and an alkane group. Substituted by a substituent of an oxy group, a carboxylic acid or a carboxylic acid ester. In another aspect, the invention relates to a method of preparing a compound of the invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

 a halogen-substituted pyrrolidine ester is heated in methanol with hydroxylamine hydrochloride and sodium acetate to obtain a polysubstituted pyrrolamine ester;

The hydroxy-substituted arylacetic acid is reacted with methanol and azidotrimethylsilane in benzene at room temperature to obtain a hydroxy-substituted arylethyl ester;

a hydroxy-substituted arylethyl ester in methylene chloride with carbon tetrabromide, triphenylphosphine to give a bromoarylethyl ester at room temperature;

 The polysubstituted pyrrolamine ester is reacted with a bromoarylethyl ester in tetrahydrofuran to give an aryl-substituted pyrrolamine diester;

 The aryl-substituted pyrrolamine diester is reduced in tetrahydrofuran with a solution of lithium aluminum hydrogen in tetrahydrofuran to obtain an aryl-substituted pyrrolamine ester;

 Under the protection of nitrogen, the aryl-substituted pyrrolamine ester is cyclized with triphosgene, hydrazine, hydrazine-ethylamine in methylene chloride to obtain five- and six-membered cyclic carbamate compounds;

Wherein X is a halogen; Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl group, the heteroaryl group The step is substituted with one or more substituents selected from the group consisting of fluorenyl, aryl, alkoxy, carboxylic acid or carboxylic acid esters. In another aspect, the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula

该中间体的制备方法包括以下步骤：

The preparation method of the intermediate comprises the following steps:

 An aqueous solution of 4,4,4-trifluoro-3-carbonyl-butyrate and sodium nitrite was reacted in an ice bath to obtain 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyric acid B. The ester, and the reduction of zinc powder with 3-carbonyl-butyric acid-tert-butyl ester in glacial acetic acid to obtain the cyclized product trifluoromethylpyrrole diester;

 Under the protection of argon, trifluoromethylpyrrolidine is reduced in tetrahydrofuran and lithium aluminum hydrogen at room temperature to obtain trifluoromethylpyrrololate;

 At room temperature, trifluoromethylpyrrolidone is oxidized in dichloromethane and pyridinium chlorochromate to give trifluoromethylpyrrolidine.

进一步， 本发明涉及合成本发明化合物的中间体， 其由如下结构通式表示:

Further, the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:

Wherein X is a halogen. The preparation method of the intermediate comprises the following steps:

 At room temperature, trifluoromethylpyrrole diester is selectively reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrrolate;

Trifluoromethylpyrrolate reacts with halogen under heating to give a halogen-substituted methylpyrrole I

 The halogen-substituted methylpyrrolidone is oxidized with cerium ammonium nitrate under heating in tetrahydrofuran/water/acetic acid, a halogen-substituted pyrrole aldehyde ester;

 Wherein X is a halogen. Further, the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:

 Wherein X is a halogen. The preparation method of the intermediate comprises the following steps:

 At room temperature, trifluoromethylpyrrolidine is reduced in trichloromethane with trifluoroacetic acid to obtain trifluoromethylpyrrolidonic acid;

三氟甲基吡咯醛酸在加热条件下与卤化钾反应得到卤代三氟甲基吡咯醛;

Trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halotrifluoromethylpyrrolaldehyde;

 Wherein X is a halogen. In a further aspect, the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:

该中间体的制备方法包括以下步骤：

The preparation method of the intermediate comprises the following steps:

 Trifluoromethylpyrrolidonic acid is reduced with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde

 Further, the present invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:

 Wherein X is a halogen; Ar is an aryl group, an aralkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by an acid ester. The preparation method of the intermediate comprises the following steps:

 Under a nitrogen atmosphere, a halogen-substituted pyrrole aldehyde ester and an aryl-substituted boric acid undergo a SuZuKi coupling reaction to obtain an arylpyrrole aldehyde ester;

其中 X是卤素； Ar是芳基、 芳垸基或杂芳基， 其中芳基、 芳垸基、 杂芳基 进一步被一个或多个垸基、 芳基、 垸氧基、 羧酸、 羧酸酯所取代。 另一方面，本发明涉及合成本发明化合物的中间体，其由如下结构通式表示:

Wherein X is a halogen; Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further one or more fluorenyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by ester. In another aspect, the invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:

Wherein I ¹ and R ² are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a trifluoromethyl group or a heterocycloalkane group. Substituted by a substituent. The preparation method of the intermediate comprises the following steps:

 Under ice salt bath, the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound;

: ¹

Hydrogenation reduction of nitro compounds to give amino substituted compounds at room temperature

Wherein RR ^{2 is} each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further substituted by one or more selected from the group consisting of an alkyl group, an aryl group, a trifluoromethyl group or a heterocycloalkyl group. Substituted by the base. Further, the present invention relates to an intermediate for the synthesis of a compound of the invention, which is represented by the following structural formula:

 Wherein: Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. The preparation method of the intermediate comprises the following steps:

氮气氛冰浴下，（S)构型的甲氧基氨基取代化合物与芳基溴偶联反应得到 (S) 构型芳基取代化合物；

Under reduced pressure in a nitrogen atmosphere, (S) benzyloxycarboaminopropionic acid is reductively aminated with methoxy-methylamine in tetrahydrofuran to obtain a methoxyamino-substituted compound of the (S) configuration;

The (S) configuration of the aryl substituted compound is obtained by coupling a methoxyamino substituted compound of the (S) configuration with an aryl bromide in an ice bath under a nitrogen atmosphere;

The (S) configuration aryl substituted compound is reacted with Pd/C to obtain (1R, 2S) aryl substituted propanol at room temperature;

 Wherein: Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. Further, the present invention relates to an intermediate for the synthesis of a compound of the present invention, which is represented by the following structural formula:

 OH

Ar^~^NH ₂ wherein: Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, and the heteroaryl group are further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, Substituted by a substituent of a carboxylic acid or a carboxylic acid ester. The preparation method of the intermediate comprises the following steps:

 At room temperature, aryl formaldehyde is cyclized with sodium hydride and trimethyl iodide to give aryl epoxy oxime.

Α" ~~ ^ Ar^

 The aryl epoxy oxime is subjected to ring-opening reaction with cyanotrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran to obtain a hydroxy-substituted arylpropionitrile;

 0 OH under a nitrogen atmosphere, a hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran to obtain a hydroxy-substituted aryl propylamine;

 OH OH

Ar^^N Ar^^ H ₂ wherein: Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, and an anthracene group. Substituted by a substituent of an oxy group, a carboxylic acid or a carboxylic acid ester. Further, the present invention relates to a pharmaceutical composition comprising a compound of the formula 1 of the present invention, a salt thereof or a pharmaceutically acceptable salt thereof.

 Further, the present invention relates to the use of the composition of the present invention for the preparation of a cholesterol ester transfer protein activity inhibitor, the use of the composition of the present invention for the preparation of a medicament for preventing or treating hyperlipidemia, and the preparation of the composition of the present invention for prevention or treatment Use in atherosclerosis drugs.

 In other words, the present invention relates to the use of a compound of the present invention for the preparation of a cholesterol ester transfer protein activity inhibitor, the use of the compound of the present invention for the preparation of a medicament for preventing or treating hyperlipidemia, and the preparation of a compound of the present invention for the prevention or treatment of atherosclerosis Use in hardened drugs.

 Finally, the present invention relates to a method for inhibiting the activity of a cholesterol ester transfer protein comprising administering to a patient a compound of the formula 1, a prodrug compound thereof, or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a method for preventing or treating hyperlipidemia comprising administering to a patient a compound represented by Formula 1, a prodrug compound thereof, or a pharmaceutically acceptable salt thereof, and the present invention relates to a prophylaxis Or a method of treating atherosclerosis, comprising administering to a patient a compound of formula 1, a prodrug compound thereof, or a pharmaceutically acceptable standard thereof

Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Mercapto" refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. A mercapto group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group, a pentyl group or the like is preferable. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The mercapto group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihaloalkyl, hydroxy, lower decyloxy, aryl, aryloxy, Heteroaryl, heterocyclic fluorenyl or -C(=0)OR ⁷ .

"Alkenyl" refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihalofluorenyl, hydroxy, lower decyloxy, aryl, aryloxy. , heteroaryl, heterocycloalkyl or -C(=0)OR ⁷ .

"Cyclopentyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring ("fused" ring system means each in the system The rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Examples of cyclodecyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexanyl, cyclohexadiene, adamantane, cycloheptadene, cycloheptatriene and the like. The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of lower fluorenyl, trihalofluorenyl, halogen, hydroxy, Lower decyloxy, aryl, heteroaryl, heterocyclic fluorenyl or -C(=0)OR ⁷ .

"Alkoxy" means -0-(alkyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The decyloxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an alkyl group, a halogen, a trihaloalkyl group, a hydroxyl group, a lower alkoxy group, and an aryl group. , aryloxy, heteroaryl, heterocycloalkyl, heteroaryl, heterocyclic fluorenyl or -C(=0)OR ⁷ .

"Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihaloalkyl, hydroxy, nitro, cyano, lower decyloxy, hydrazine. Base, heteroaryl, heterocyclic fluorenyl or -C(=0)OR ⁷ .

"Heteroaryl" means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring may be a 5- or 6-membered ring. Examples of the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihalofluorenyl, hydroxy, nitro, cyano, lower decyloxy, Alkyl, aryl, heterocycloalkyl or -C(=0)OR ⁷ .

"Heterocyclic fluorenyl" means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These rings may also have one or more double bonds. However, these rings do not have a fully conjugated _π- electron system. Unsubstituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl can be substituted or Unsubstituted. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, lower fluorenyl, trihaloalkyl, hydroxy, aryl, aryloxy, hetero Aryl, heterocycloalkyl, carboxy or -C(=0)OR ⁷ .

 "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"Trifluoromethyl" means -CF ₃ .

 "Carboxylic acid" means (alkyl) C(=0)OH.

"Carboxylic ester" means (alkyl) C(=0)0 R ⁸ , wherein R ⁸ is alkyl.

 "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:

冰浴下， 4,4,4-三氟 -3-羰基-丁酸乙酯和亚硝酸钠的水溶液反应， 得到 4,4,4- 三氟 -2-肟基 3-羰基 -丁酸乙酯， 再与 3-羰基-丁酸-叔丁酯在冰醋酸中加热条件下 锌粉还原得到环合产物三氟甲基吡咯二酯； 在氩气保护下， 三氟甲基吡咯二酯在 四氢呋喃和锂铝氢室温下还原得到三氟甲基吡咯醇酯； 室温下， 三氟甲基吡咯醇 酯在二氯甲垸中和氯铬酸吡啶盐氧化得到三氟甲基吡咯醛酯。 A method for preparing a five-membered and six-membered cyclic carbamate derivative of the formula (I) or a salt thereof,

An aqueous solution of 4,4,4-trifluoro-3-carbonyl-butyrate and sodium nitrite was reacted in an ice bath to obtain 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyric acid B. Reduction of zinc powder with ethyl 3-carbonyl-butyric acid-tert-butyl ester in glacial acetic acid to obtain the cyclized product trifluoromethylpyrrole diester; under argon protection, trifluoromethylpyrrolidine The tetrahydrofuran and lithium aluminum hydrogen are reduced at room temperature to obtain trifluoromethylpyrrololate; at room temperature, trifluoromethylpyrrololate is oxidized in dichloromethane and pyridinium chlorochromate to obtain trifluoromethylpyrrolidine.

(2)

 At room temperature, trifluoromethylpyrrolediester is selectively reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrroleate; trifluoromethylpyrrolate is reacted with halogen under heating to obtain halogen substitution. Methylpyrrolidone; halogen-substituted methylpyrrolidone is oxidized with cerium ammonium nitrate under heating in tetrahydrofuran/water/acetic acid, halogen-substituted pyrrole aldehyde.

 (3)

 At room temperature, trifluoromethylpyrrolidine is reduced with trifluoroacetic acid in dichloromethane to obtain trifluoromethylpyrrolidonic acid; trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halogenated three. Fluoromethylpyrrolaldehyde.

 (4)

 The trifluoromethylpyrrolidonic acid is subjected to a reduction reaction with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde.

(5)

 Under a nitrogen atmosphere, a halogen-substituted pyrrole aldehyde ester and a substituted boronic acid undergo a SuZuKi coupling reaction to obtain an arylpyrrolidinyl ester.

 (6)

 Under ice salt bath, the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound; at room temperature, the nitro compound is hydrogenated and reduced to obtain an amino-substituted compound.

氮气氛冰浴下， （s)苄氧基碳基氨基丙酸在四氢呋喃中与甲氧基 -甲胺发生还 原胺化反应得到 (S)构型的甲氧基氨基取代化合物； 氮气氛冰浴下， （S)构型的甲 氧基氨基取代化合物与芳基溴偶联反应得到 (S)构型芳基取代化合物；室温下， (S) 构型芳基取代化合物与 Pd/C还原反应得到 (1R,2S)的芳基取代丙醇。 (7)

Under a nitrogen atmosphere, the (s) benzyloxycarboaminopropionic acid is reductively aminated with methoxy-methylamine in tetrahydrofuran to obtain a methoxyamino-substituted compound of the (S) configuration; The (S) configuration of the methoxyamino-substituted compound is coupled with an aryl bromide to obtain an (S)-configuration aryl-substituted compound; at room temperature, the (S)-configuration aryl-substituted compound is reacted with Pd/C. An aryl substituted propanol of (1R, 2S) is obtained.

 (8)

NH

 At room temperature, aryl formaldehyde is cyclized with sodium hydride and trimethyl iodide to give aryl oxirane; aryl oxirane in tetrahydrofuran with cyanotrimethylsilane, tetrabutyl fluoride The ammonium ring-opening reaction gives a hydroxy-substituted arylpropionitrile; under a nitrogen atmosphere, a hydroxy-substituted arylpropionitrile is reacted with a solution of boron hydride in tetrahydrofuran to give a hydroxy-substituted aryl propylamine.

(9)

At room temperature, the synthesis step (6), (7), (8), and each polysubstituted pyrrole aldehyde, reductive amination to give a polysubstituted pyrrole methylamine; under argon atmosphere, polysubstituted pyrrole methylamine and Triphosgene, ruthenium, osmium-diisopropylethylamine cyclization to give five- and six-membered cyclic carbamates; hydrogenation of five- and six-membered cyclic carbamates in tetrahydrofuran under hydrogen atmosphere The sodium tetrahydrofuran solution is reacted with an alkyl halide to obtain a target compound quinone-substituted five- and six-membered cyclic carbamate compound represented by the formula (1).

 The invention further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula (I) according to the invention or a salt thereof and a pharmaceutically acceptable carrier.

 The invention further relates to the use of a compound of the formula (I) according to the invention or a salt thereof for the preparation of a cholesterol ester transfer protein inhibitor. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further described below in conjunction with the examples, but these examples do not limit the scope of the invention.

In the following examples, the structure of the compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated chloroform (CDC1 ₃ ), deuterated dimethyl sulfoxide (DMSO-D ₆ ), internal standard tetramethylsilane (TMS), chemical shift. It is given in units of l (T ⁶ (ppm).

 The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer.

 Thin layer silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.

 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

DMSO-D ₆ : deuterated dimethyl sulfoxide;

CDC1 ₃ : deuterated chloroform; Preparation examples:

 Example 1

 5-[5-(4-Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Ethyl carboxylate

第一步

first step

 4,4,4-trifluoro-2-indenyl 3-carbonyl-butyric acid ethyl ester

 4,4,4-trifluoro-3-carbonyl-butyrate ethyl la (3.822 g, in a 100 ml round bottom flask).

20.75 mmol) was dissolved in 6 ml of glacial acetic acid, and an aqueous solution of sodium nitrite (14.2 g, 20.75 mmol dissolved in 4 ml of water) was added dropwise with stirring to control the reaction temperature to 0 to 5 ° C. After the completion of the dropwise addition, Add 1 ml of water, react in an ice water bath for half an hour, remove the ice water bath, continue the reaction at room temperature for about 3 hours, track the plate until the material disappears, and follow the end of the point plate to obtain the standard product 4,4,4-three. A solution of fluoro-2-indenyl 3-carbonyl-butyric acid ethyl ester lb was directly subjected to the next reaction.

 Second step

 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester

9.3 011的冰醋酸中， 搅拌下升温至 65°C， 称量锌粉 (2.7 g, 41.5 mmol), 用滴液漏斗滴加上一步反应的产物 4,4,4-三氟 -2-肟基 3-羰基 -丁酸乙酯 lb的溶液， 分多次加入锌粉， 水浴控制体系温度保持在 75°C左右， 反应 2小时， 然后降低温度到 40〜45°C， 反应过夜。 点板跟踪点板跟踪反应结 束， 在反应液中加入 30 ml水和 20 ml乙酸乙酯， 室温搅拌 15分钟后， 用乙酸乙 酯 (50 mlx3)萃取反应液。合并有机相， 依次用水 (50 mlx2)、饱和碳酸氢钠水溶液 (50 mlx2)、饱和氯化钠水溶液 (50 mlx2)洗涤， 乙酸乙酯层用无水硫酸钠干燥， 过 滤，滤液减压浓缩，残余物用甲苯-正己垸重结晶得到产物 5-甲基 -3-三氟甲基 -1H- 吡咯 -2,4二羧酸 -4-叔丁酯 -2-乙酯 lc(3.66 g)， 产率： 55%。 In a 100 ml three-necked flask equipped with a thermometer and a dropping funnel, 3-carbonyl-butyric acid-tert-butyl ester (3.28 g,

In glacial acetic acid 9.3 011, the temperature is raised to 65 ° C with stirring, and the zinc powder is weighed. (2.7 g, 41.5 mmol), a solution of the one-step reaction product 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyric acid ethyl ester lb was added dropwise with a dropping funnel, and zinc powder was added in multiple portions. The temperature of the water bath control system was maintained at about 75 ° C, and the reaction was carried out for 2 hours, and then the temperature was lowered to 40 to 45 ° C, and the reaction was continued overnight. The spot plate was followed to track the completion of the reaction, and 30 ml of water and 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, and then the mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with EtOAc EtOAc EtOAc. The residue was recrystallized from toluene-n-hexane to give the product 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4dicarboxylic acid 4-tert-butyl ester-2-ethyl ester lc (3.66 g). Yield: 55%.

MS m/z (ESI): 320 [M-1]

 third step

 5-methyl-3-trifluoromethyl-1H-pyrrole-2-hydroxymethyl-4-carboxylic acid tert-butyl ester nitrogen atmosphere was dissolved in 16 ml of lithium aluminum hydrogen (0.39 g, 10 mmol) in an ice bath. In tetrahydrofuran, 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylate 4-tert-butyl ester 2-ethyl ester lc (3.214 g, 10 mmol) in tetrahydrofuran was slowly added dropwise. 10 ml) of the solution. After the dropwise addition, the reaction solution was allowed to warm to room temperature, and the reaction was stirred for 1 hour, and the reaction was completed by clicking on the plate. The reaction mixture was quenched with a small amount of water, and a small portion of ethyl acetate was added, filtered, and the filter cake was washed with ethyl acetate, and the obtained filter cake was purified by silica gel column chromatography to give the title product 5-methyl-3-trifluoromethyl- 1H-pyrrole-2-hydroxymethyl-4-carboxy acid tert-butyl ester ld (0.765 g), yield 50%.

MS m/z (ESI): 278 [M-1]

 the fourth step

 5-methyl-3-trifluoromethyl- 1 H-pyrrole-2-formyl-4-carboxy acid tert-butyl ester 5-methyl-3-trifluoromethyl-1H-pyrrole-2-hydroxyl Tert-butyl 4-carboxylic acid tert-butyl ester ld (0.636 g, 2.28 mmol) was dissolved in 10 ml of dichloromethane, then added chlorochromic acid pyridinium salt (736 mg, 3.418 mmol), stirred at room temperature for 2 hours, point plate tracking The reaction is over. The reaction mixture was diluted with 10 ml of acetone, filtered, and the filtered cake was washed with EtOAc (EtOAc). 2-formyl-4-carboxy acid tert-butyl ester le (0.359 g), yield 57.1%.

 MS m/z (ESI): 276 [M-1]

 the fifth step

 1-(4-trifluoromethyl-phenyl)-2-nitro-ethanol

4-Trifluoromethyl-benzaldehyde lf (182 mg, 1.046 mmol), nitroguanidine (223.5 mg, 3.06 mmol) was dissolved in 10 mL absolute ethanol and cooled to 0 ° C. Slowly add 44 mg of 10% sodium hydroxide solution, stir for 2.5 hours, add 63 mg of 2% acetic acid solution, warm to room temperature, stir the reaction for 1 hour, and click to track the end of the reaction. The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc). The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography. 1-(4-Trifluoromethyl-phenyl)-2-nitro-ethanol 1 _g (169 mg), yield 71.9%. .

MS m/z (ESI): 234 [M-1]

 Step 6

 L-(4-Trifluoromethyl-phenyl)-2-amino-ethanol

In a dry hydrogenated flask, 1-(4-trifluoromethyl-phenyl)-2-nitro-ethanol 1 _g (1.584 g, 6.74 mmol) was dissolved in 18 ml of ethanol and slowly added to 10%. Pd/C (150 mg), stirred at room temperature, 0.3 MPa overnight, and the plate was followed to end the reaction. Filter through celite and concentrate the filtrate under reduced pressure. The obtained residue was purified to silica gel elut372 elut elut elut elut elut elut

MS m/z (ESI): 206[M+1]

 Seventh step

 5-{[2-(4-Trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate Ethyl acetate

 1-(4-Trifluoromethyl-phenyl)-2-amino-ethanol 1 h (0.19 g, 0.927 mmol), 5-methyl-3-trifluoromethyl-1H-pyrrole-2-yl- tert-Butyl 4-carboxylate (0.234 g, 0.883 mmol) was dissolved in 5 ml of dichloromethane. After adding 0.585 g of 4 A molecular sieve and stirring for 6 hours, a solution of sodium borohydride (100.2 mg, 2.65 mmol) in methanol (1 ml) was added, and the reaction was stirred overnight, and the reaction was completed by clicking on the plate. Filtration, the reaction mixture was extracted with ethyl acetate (10 ml×1), and the organic layer was washed with dilute aqueous hydrochloric acid (10 ml×l), and the organic layer was washed with saturated aqueous sodium chloride (20 mix 1). The residue was dried over anhydrous sodium sulfate (MgSO4) Ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.231 g), yield 58.6%.

MS m/z (ESI): 467 [M+1]

 Eighth step

5-[5-(4-Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Ethyl carboxylate

5-{[2-(4-Trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl under a nitrogen salt bath -1H-pyrrole-3-carboxylic acid ethyl ester li (0.132 g, 0.283 mmol) was dissolved in 5 ml of dichloromethane, keeping the internal temperature less than 0 ° C, and slowly adding triphosgene (84.1 mg, 0.283 mmol) a solution of dichloromethane (2 ml), after stirring for 5 minutes, add 0.05 ml of N,N-dimercaptocarboxamide, and slowly add hydrazine, hydrazine-diisopropylethylamine (107.9 mg, 0.85 mmol) The reaction was stirred for 2 hours, and the point plate was followed to end the reaction. 2 ml of dilute hydrochloric acid was added to the reaction mixture, and after stirring for half an hour, the reaction mixture was concentrated under reduced pressure. ethyl acetate (50 ml×l), water (25 ml×l) The organic layer was washed with a saturated aqueous solution of sodium chloride (20 ml×1), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Purify the resulting residue to give the title Product 5-[5-(4-Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3 Ethyl carboxylate 1 (0.08 g, white solid), yield 57.5 %.

 MS m/z (ESI): 491 [M-1]

'HNMR (400MHz, CDC1 ₃ ) 59.39(S, lH), 7.66(d, 2H), 7.43(d, 2H), 5.57(t, 1H), 4.52(q, 2H), 3.97~3.47(t, 2H ), 2.46(s, 3H), 1.54(s, 9H). Example 2

 -[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl Ethyl-1 H-pyrrole-3-carboxylic acid ethyl ester

第一歩

First

 (3,5-di-trifluoromethyl-phenyl)-2-nitro-propanol

 3,5-di-trifluoromethyl-benzaldehyde 2a (5 g, 0.021 mmol), nitroacetamidine (5.76 g, in an ice-salt bath)

0.076 mmol) was dissolved in 100 ml of absolute ethanol and cooled to -0.2 Torr. Slowly add 8.8 ml of 10% sodium hydroxide solution, stir for 1 hour, warm to room temperature, and stir the reaction overnight. The point plate tracks the reaction. 66 ml of a 2% acetic acid solution was added, and the reaction solution was concentrated under reduced pressure. The residue was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The title product 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propanol 2b (6.66 g), yield 100% o

MS m/z (ESI): 316 [M-1] Second step

 L-(3,5-Di-trifluoromethyl-phenyl)-2-amino-propanol

 Dissolve 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propanol 2b (2.0 g, 6.3 mmol) in 2.2 ml/5 ml of methanol in a dry hydrogenated vial / Under water, slowly add 0.5 g Pd/C, stir at room temperature for 40 hours at 40 Psi, and follow the end of the reaction. Filter through celite and concentrate the filtrate under reduced pressure. Add 50 ml of water to the residue, adjust the pH to 9 to 10 with aqueous ammonia, and extract the residue with ethyl acetate (50 ml > < 3). The organic phase is combined and washed with saturated aqueous sodium chloride (20 ml×l) The organic layer was dried over anhydrous sodium sulfate (MgSO4). 2-amino-propanol 2c (0.68 g), yield 39.1%.

MS m/z (ESI): 288 [M+1]

 Third

 5-{[2-(3,5-di-trifluoromethyl-phenyl)小methyl-2-hydroxy-ethylamine]-methyl }-2-methyl-4-trifluoromethyl

 -1H-pyrrole-3-carboxylic acid ethyl ester

 1-(3,5-Di-trifluoromethyl-phenyl)-2-amino-propanol 2c (0.35 g, 1.22 mmol), 5-methyl-3-trifluoromethyl- 1H-pyrrole-2-formyl-4-carboxy acid tert-butyl ester le (0.225 g, 0.813 mmol) was dissolved in 10 ml of methanol. After adding a small amount of 4 A molecular sieve and stirring the reaction overnight, a solution of sodium borohydride (129 mg, 3.23 mmol) in methanol (2 ml) was added, and the mixture was stirred for 4 hr. Filtration, adding 20 ml of water to the filtrate, concentrating the filtrate under reduced pressure, and removing methanol, and extracting the residue with ethyl acetate (50 ml×3), and the organic phase was combined, and the organic layer was washed with saturated aqueous sodium chloride (20 ml×l) The ethyl ester layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl 1-methyl-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate 2d (0.2 g), yield 45 %.

MS m/z (ESI): 547 [M-1]

 the fourth step

5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoro Methyl-1 H-pyrrole-3-carboxylic acid ethyl ester

5-{[2-(3,5-Di-trifluoromethyl-phenyl)-1-methyl-2-hydroxy-ethylamine]-methyl}-2- under a nitrogen salt bath Ethyl methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate 2d (0.16 g, 0.292 mmol) was dissolved in 40 ml of dichloromethane, keeping the internal temperature less than 0 ° C, and then slowly dripping Add a solution of triphosgene (173.4 mg, 0.584 mmol) in dichloromethane (4 ml), hydrazine, hydrazine-diisopropylethylamine (222.5 mg, 1.752 mmol), warm to 0 ° C and stir for 1 hour. The temperature was raised to 15 ° C, and the reaction was stirred for 1 hour, and the point plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc. EtOAc (EtOAc mjjjjjjjjj Fluoromethyl-phenyl)-4-methyl-2-keto-oxazole-3- Ethyl-methyl] _-2 -methyl-4-trifluoromethyl-IH-pyrrole-3-carboxylic acid ethyl ester 2 (threo) (0.01 g, white solid), yield 11.9%.

 MS m/z (ESI): 573 [M-l]

lHNMR (400MHz, CDC1 ₃ ) 59.28 (brs, IH), 7.90 (s, IH), 7.75 (s, 2H), 5.10 (d, IH), 4.61 (d, IH), 4.48 (d, IH), 3.66 (m, IH), 2.46 (s, 3H), 1.53 (s, 9H), 1.48 (d, 3H). Example 3

 (4S,5R)-5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl -4-Methyl-1H-pyrrole-3-carboxylic acid ethyl ester

 First step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl-4-trifluoromethyl Base

 -1H-pyrrole-3-carboxylic acid ethyl ester

 The fourth step reaction of Example 2 of the present invention was repeated, and the compound obtained in Example 2 was used.

5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl Ethyl-1H-pyrrole-3-carboxylic acid ethyl ester 2d is reacted with triphosgene, hydrazine, hydrazine-diisopropylethylamine, and the obtained residue is purified by preparative chromatography to give the title product 5-[5-(3) ,5-di-trifluoromethyl-phenyl)-4-methyl-2-keto-oxazole-3-yl-methyl]-2-methyl-4-trifluoromethyl-1Η-pyrrole-3 Ethyl carboxylate 3 (erythro) (0.018 g, white solid), yield 21.4%.

 MS m/z (ESI): 573 [M-1]

lHNMR(400MHz, CDC1 ₃ ) 59.28(brs, IH), 7.9 l(s, IH), 7.73(s, 2H), 5.71(d, IH), 4.63(d, IH), 4.44(d, IH), 4.22 (m, IH), 2.48 (s, 3H), 1.55 (s, 9H), 0.82 (d, 3H). Example 4

5-[5-(2-Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1 H-pyrrole-3 -carboxylic acid ethyl ester

 4d

 First

 L-(2-trifluoromethyl-phenyl)-2-nitro-ethanol

 2-Trifluoromethyl-benzaldehyde 4a (1.067 g, 6.13 mmol), nitroformamidine (1.496 g,

2.45 mmol) was dissolved in 10 ml of absolute ethanol and cooled to 0 °C. Slowly add 258 mg of 10% sodium hydroxide solution, stir for 1 hour, add 387 mg of 2% acetic acid solution dropwise, warm to room temperature, stir the reaction overnight, and follow the end of the reaction. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjj

MS m/z (ESI): 234 [M-1]

 Second step

 1-(2-trifluoromethyl-phenyl)-2-amino-ethanol

 In a dry hydrogenation flask, 1-(2-trifluoromethyl-phenyl)-2-nitro-ethanol 4b (1.285 g, 5.47 mmol) was dissolved in 15 ml of ethanol and slowly added 480 mg Pd. /C, stirring at room temperature, 40PSi overnight, the spotting was followed to end the reaction. The mixture was filtered through EtOAc (EtOAc m.).

MS m/z (ESI): 206[M+1]

 third step

 5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate Ethyl acetate

1-(2-Trifluoromethyl-phenyl)-2-amino-ethanol 4c (0.178 g, 0.868 mmol), 5-methyl-3-trifluoromethyl-1H-pyrrole-2-yl- tert-Butyl 4-carboxylate (0.230 g, 0.868 mmol) was dissolved in 4 mL of dichloromethane. Add 0.550 g of 4 A molecular sieve, stir the reaction overnight, add sodium borohydride (99 mg, 2.61 mmol) A solution of methanol (1 ml) was stirred for 2 hours and the plate was followed to complete the reaction. A small amount of dilute hydrochloric acid was added, and after stirring for 15 minutes, it was filtered, and the filtrate was concentrated under reduced pressure. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc) Concentration gave the title product 5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4, -trifluoromethyl-1H - Pyrrole-3-carboxylate ethyl ester 4d, used directly in the next reaction. MS m/z (ESI): 492 [M+23]

 Fourth

 5-[5-(2-Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl- 1 H-pyrrole-3 -carboxylic acid ethyl ester

 5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl under a nitrogen salt bath

Ethyl 4-trifluoromethyl-1H-pyrrole-3-carboxylate 4d (0.332 g, 0.712 mmol) was dissolved in 8 ml of dichloromethane, keeping the internal temperature less than 0 ° C. Diisopropylethylamine (190 mg, 1.5 mmol) and a little sodium chloride, and slowly added dropwise a solution of triphosgene (148 mg, 0.5 mmol) in dichloromethane (2 ml). Track the end of the reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjj The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc) Trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 4 (0.118 g , white solid), yield 33.7%.

MS m/z (ESI): 491 [M-1]

 'H MR(400MHz, CDC) 59.73(s, 1H), 7.69(d, 1H), 7.63(m, 2H), 7.62(m, 1H), 5.9 l(t, 1H), 4.53(q, 2H) , 3.97(t, 1H), 3.33(t, 1H), 2.47(s, 3H), 1.54(s, 9H). Example 5

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl}-3-trifluoromethyl-1H-pyrrole-2-carboxylate Ethyl acetate

第一步

first step

 5-methyl-3-trifluoromethyl-1H-pyrrole-2 4 dicarboxylic acid -2-ethyl ester

 Dissolve 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester lc (0.95 g, 2.96 mmol) in 15 ml of dichloromethane Trifluoroacetic acid (2.4 ml, 32.3 mmol) was added and stirred at room temperature for 3 hours. Dichloromethane and trifluoroacetic acid were evaporated under reduced pressure. EtOAc (EtOAc m. -2,4-dicarboxylic acid-2-ethyl ester 5a (0.586 g, white solid), Yield: 74.7% ' MS m/z (ESI): 264 [M-1]

 Second step

 5-methyl-3-trifluoromethyl- 1 H-pyrrole-2-carboxylic acid ethyl ester-4-iodine

 Iodine (2.2 g, 8.68 mmol), potassium iodide (5.76 g, 34.72 mmol), dissolved in 5 ml of water, and added 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4 dicarboxyl with stirring a mixture of acid-2-ethyl ester 5a (2.3 g, 8.68 mmol), sodium bicarbonate (5.83 g 69.44 mmol), water (20 ml), heated to 90 ° C, a large amount of gas evolved after a period of time, and a large amount A white solid is formed. The color of the solution also changed from dark red to pale yellow, and the point plate was followed to end the reaction. The solid was collected by filtration and dried to give ethyl 5-methyl-3-trifluoromethyl-1H-pyrrole-2-carboxylate as standard. 4-iodo 5b (2.89 g, white solid), Yield: 96%

 MS m/z (ESI): 346 [M-1]

 third step

Ethyl 5-formyl-4-iodo-3-trifluoromethyl- 1H-pyrrole-2-carboxylate ethyl 5-methyl-3-trifluoromethyl-1H-pyrrole-2-carboxylate -4-iodo 5b (2.25 g, 6.48 mmol) was dissolved in 30 ml / 30 ml / 30 ml of tetrahydrofuran / water / acetic acid, added ammonium cerium nitrate (14.57 g, 26.57 mmol), added to 80 ° C, stirred After 2 hours of reaction, the spot plate was followed to end the reaction. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc) (EtOAc) The ethyl acetate layer was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjj g), yield 59%.

MS m/z (ESI): 362[M+1]

 the fourth step

 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propanol

 3,5-di-trifluoromethyl-benzaldehyde 2a (10 g, 0.0413 mmol), nitromethane (9.2 g, 0.151 mol) was dissolved in 200 ml of absolute ethanol under ice-bath and cooled to - 0.2 ° C. Slowly add 17.3 ml of 10% sodium hydroxide solution, keep the temperature below 3 °C, stir the reaction for 4 hours, add 130 ml of 2% acetic acid solution dropwise, keep the temperature below 5 °C, and raise to room temperature. The reaction was stirred overnight and the plate was followed to end the reaction. The reaction solution was concentrated under reduced pressure. A large amount of a yellow solid appeared, which was filtered, and the filtrate was extracted with ethyl acetate (50 ml×3), and the organic layer was combined, and the organic layer was washed with saturated aqueous sodium chloride (20 ml×l). The filtrate was concentrated under reduced pressure. EtOAc EtOAc m.

MS m/z (ESI): 302 [M-1]

 the fifth step

 L-(3,5-Di-trifluoromethyl-phenyl)-2-amino-ethanol

 In a dry hydrogenated bottle, 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-ethanol 5d (10.4 g, 34.3 mmol) was dissolved in 100 ml of methanol, slowly 2.5 g of Pd/C was added, and the reaction was stirred at 30 ° C for 17 hours at room temperature, and the reaction was stopped by clicking on the plate. Filter through celite and concentrate the filtrate under reduced pressure. The residue was recrystallized from ethyl acetate / hexane toieldieldielielielielielielielielielielielielielielielielielielielielielielielielieliel

MS m/z (ESI): 274 [M+1]

 Step 6

 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-carbyl-ethylamino]-methyl}-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid Ethyl ester

 The compound 5-formyl-4-iodo-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 5c (1.38 g, 3.82 mmol), 1-(3,5-di-trifluoromethyl -Phenyl)-2-amino-ethanol 5e (114 mg, 0.416 mmol) was dissolved in 3 ml of 1,2-dichloroethane, and the reaction was stirred overnight. Sodium borohydride (63 mg, 1.662 mmol) was slowly added with stirring. After stirring at room temperature for 1 hour, the reaction solution was filtered, and a dilute sodium hydroxide solution was added to the filtrate, and the filtrate was extracted with 50 ml of ethyl acetate. The organic layer was washed with aqueous sodium chloride (30 mL), and evaporated. -(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 5f (0.091 g , yellow solid), yield 81%.

MS m/z (ESI): 491 [Ml] Seventh step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl 3-trifluoromethyl-IH-pyrrole-2-carboxylic acid 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-3-trifluoromethyl-1H-pyrrole under ice-salt bath Ethyl 2-carboxylate 5f (0.091 g, 0.185 mmol), sodium chloride (17 mg) was dissolved in 30 ml of dichloromethane, keeping the internal temperature less than 0 ° C, and slowly adding triphos (53) Mg, 0.178 mmol) in dichloromethane (10 ml), hydrazine, hydrazine-diisopropylethylamine (141 mg, 1.11 mmol), warmed to 0 ° C, stirred for 2 hrs and warmed to room temperature. The reaction was stirred overnight and the plate was followed to end the reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc. EtOAc (EtOAc m. Ethyl trifluoromethyl-phenyl)-2-keto-oxazol-3-yl-methyl}-3-trifluoromethyl-1H-pyrrole-2-carboxylate 5 (0.056 g, white solid) The yield was 58.4%.

MS m/z (ESI): 517 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 510.84(s, IH), 7.88(s, IH), 7.84(s, 2H), 6.43(s, IH), 5.67(t IH), 4.37~4.64(m, 2H), 4.34(q, 2H), 4.00(t, IH), 3.43(t, IH), 1.35(t, 3H). Example 6

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl}-2-methyl-4-trifluoromethyl-IH- Pyrrole

 Ethyl-3-carboxylate

第一步

first step

5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole

Ethyl-3-carboxylate 1-(3,5-Di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (0.333 g, 1.22 mmol), 5-methyl-3-trifluoromethyl-1H under a nitrogen atmosphere - Pyrrole-2-formyl-4-carboxy acid tert-butyl ester le (0.225 g, 0.812 mmol) was dissolved in 10 ml of dichloromethane. After stirring the reaction at room temperature overnight, a solution of sodium borohydride (390 mg, 9.74 mmol) in methanol (3 ml) was added, and the mixture was stirred for 4 hr. After filtration, 20 ml of water was added to the filtrate, and a solid precipitated. After standing for 1 hour, it was filtered to remove the cake. The filtrate was concentrated under reduced pressure. EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjj The filtrate was filtered, and the filtrate was evaporated to dryness. Ethyl]methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6a (0.23 g), mp.

 MS m/z (ESI): 533 [M-1]

 Second step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- Pyrrole

 Ethyl-3-carboxylate

 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4- under a nitrogen salt bath Ethyl trifluoromethyl-1H-pyrrole-3-carboxylate 6a (0.23 g, 0.43 mmol) was dissolved in 30 ml of dichloromethane and sodium chloride (17 mg) was added to keep the internal temperature less than 0 Ό. A solution of triphosgene (76.8 mg, 0.258 mmol) in dichloromethane (10 ml) was added dropwise, and after stirring for half an hour, hydrazine, bis-diisopropylethylamine (327.7 mg, 2.58 mmol) was added. The temperature was less than 0 ° C, the reaction was stirred for 2 hours, the temperature was raised to room temperature, the reaction was stirred overnight, and the reaction was stopped by clicking on the plate. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAcjjjjjjjjj The mixture was washed with EtOAc. Ethyl 5-di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate 6 (0.13 g, white solid), yield 54%.

MS m/z (ESI): 559 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 59.50 (brs, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 5.65 (m, 1H), 4.60 (m, 2H), 4.06 (m, 1H), 3.47 (m, 1H), 2.46(s, 3H), 1.54(s, 9H). Example 7

-[5-(3,5-di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl}-4-iodo-3-trifluoromethyl-1H-pyrrole- 2-carboxylic acid ethyl ester

第一步

first step

5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-iodo-3-trifluoromethyl-1H-pyrrole-2 - Ethyl carboxylate

 The compound 5-formyl-4-iodo-3-trifluoromethyl-1 H-pyrrole-2-carboxylic acid ethyl ester 5c (0.433 g, 1.20 mmol), 2-amino-1-(3) ,5-di-trifluoromethyl-phenyl)-ethanol 5e (410 mg, 1.5 mmol) was dissolved in 12 ml of 1,2-dichloroacetamidine, a small amount of 4 A molecular sieve was added, and the reaction was stirred overnight, stirring Sodium cyanoborohydride (190 mg, 3 mmol) was slowly added, and the reaction was stirred at room temperature overnight, and the reaction was finished with a spot. The reaction solution was filtered, and an appropriate amount of a dilute sodium hydroxide solution was added to the filtrate, and the filtrate was extracted with 50 ml of ethyl acetate. The obtained organic layer was washed with aqueous sodium chloride (30 ml×l), The sodium was dried, filtered, and the filtrate was evaporated to dryness crystals crystals crystals crystals crystals crystals Ethyl (3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-iodo-3-trifluoromethyl-1H-pyrrole-2-carboxylate 7a (0.085 g, white solid), yield 81.4%.

MS m/z (ESI): 617 [M-1]

 Second step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-4-iodo-3-trifluoromethyl-1H-pyrrole Ethyl 2-carboxylate

5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4iodo-3-trifluoromethyl- under ice salt bath Ethyl 1H-pyrrole-2-carboxylate 7a (0.670 g, 1.08 mmol), sodium chloride (100 mg) was dissolved in 100 ml of dichloromethane, keeping the internal temperature less than 0 Ό, and slowly adding triphosgene ( A solution of 321 mg, 1.08 mmol) in dichloromethane (50 ml) was stirred and stirred for 2 h then EtOAc &lt;RTI ID=0.0&gt; The solution was stirred for 2 hours, then allowed to warm to room temperature, and the reaction was stirred overnight, and the reaction was completed by spotting. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc (EtOAc). The obtained residue was purified by silica gel column chromatography toield Ethyl 4-iodo-3-trifluoromethyl-1H-pyrrole-2-carboxylate 7 (0.3 g, white solid), yield 43%.

MS m/z (ESI): 643 [M-l]

lHNMR (400MHz, CDC1 ₃ ) 610.85(s, 1H), 7.90(s, 1H), 7.83(s, 2H), 5.67(t, 1H), 4.69~4.49(m, 2H), 4.37(q, 2H) , 4.09(t, 1H), 3.5 l(t, 1H), 1.37(t, 3H). Example 8

 -[5-(3,5-di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1 H- Pyrrole

第一歩

First

 5-methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-carboxy acid 5-methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-carboxyl The acid tert-butyl ester le (0.9 g, 3.25 mmol) was dissolved in 15 ml of dichloromethane, and a solution of trifluoroacetic acid (4.12 g, 36.1 mmol) in dichloromethane (5 ml) was added. The point plate tracks the reaction. The reaction mixture was concentrated under reduced pressure. hexane was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 0.675 g, white solid), yield 94%.

MS m/z (ESI): 220[M-1]

 Second

5-Methyl-3-trifluoromethyl-1 H-pyrrole-2-formyl-4-iodide Potassium iodide (775 mg, 3.05 mmol) was dissolved in 2 ml of water and potassium hydrogencarbonate (2.05 g, 23.4) Methyl) solution of water (2 ml) followed by 5-methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-carboxyl Acid 8a (0.675 g, 3.05 mmol) was stirred under reflux for 3 hours, and the reaction was stopped by spotting. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure gave the title product 5-methyl-3-trifluoromethyl-1H-pyr.

 MS m/z (ESI): 302 [M-1]

 Third

 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole

 -3-iodine

 1-(3,5-Di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (1.13 g, 4.15 mmol), under nitrogen

5-Methyl-3-trifluoromethyl-lH-pyrrole-2-formyl-4-iodo 8b (0.838 g, 2.77 mmol) was dissolved in 80 ml of dichloromethane. After stirring at room temperature for overnight, the temperature was raised to 40 ° C. After stirring for half an hour, the mixture was cooled to room temperature, sodium borohydride (1.33 g, 33.23 mmol) was added slowly, and 6 ml of methanol was added thereto. After stirring for 2 hours, the spotting was followed. . The filtrate was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAcjjjjjjjj The aqueous solution was dried over sodium sulfate, filtered, and evaporated, evaporated, evaporated,462462462462462462462462462462462462462462462462462462462462462462462462462 Hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-iodo 8c (1.25 g), yield 80.6%.

MS m/z (ESI): 559 [M-1]

 the fourth step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4 under a pyrrole nitrogen atmosphere ice salt bath -Trifluoromethyl-1H-pyrrole-3-iodine 8c (1.25 g, 2.23 mmol) was dissolved in 200 ml of dichloromethane, 100 mg of sodium chloride was added, and the internal temperature was kept below 0 °C. Add a solution of triphosgene (662.3 mg, 0.892 mmol) in dichloromethane (50 ml), hydrazine, hydrazine-diisopropylethylamine (1.7 g, 13.38 mmol), keep the temperature below 0 ° C, stir the reaction 1 After an hour, the temperature was raised to room temperature, and the reaction was stirred overnight, and the reaction was stopped by clicking on the plate. The reaction mixture was concentrated under reduced vacuo. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc (EtOAc) (EtOAcjjjjjjjjjjj -trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole 8 (0.32 g, pale yellow solid) The yield was 46.5 %. MS m/z (ESI): 459 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 59.14(brs, 1H), 7.89(s, 1H), 7.79(s, 2H), 6.00(d, 1H), 5.64(m, 1H), 4.55(m, 2H), 4.05 (m, 1H), 3.46(m, 1H), 2.23(s, 3H). Example 9

 5-[5-(3 ,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1Η- Pyrrole-3-iodine

第一步

first step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamine]-methyl}-2-methyl-4 under a pyrrole nitrogen atmosphere ice salt bath -Trifluoromethyl-1H-pyrrole-3-iodo 8c (0.095 g, 0.17 mmol) was dissolved in 50 ml of dichloromethane, sodium chloride (10 mg) was added, and the internal temperature was kept below 0 °C. A solution of triphosgene (20.2 mg, 0.068 mmol) in dichloromethane (10 ml), then hydrazine, bis-diisopropylethyleamine (1300 mg, 10.2 mmol), and stirred at room temperature overnight. . The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc, EtOAc (EtOAc mjjjjjjjj Fluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl- 1H-pyrrole-3-iodine 9 (0.077 g, pale yellow solid ), the yield is 75%.

MS m/z (ESI): 585 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 59.48 (brs, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 5.65 (m, 1H), 4.59 (m, 2H), 4.06 (m, 1H), 3.47 (m, 1H), 2.27(s, 3H). Example 10

 -[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H- Pyrrole

Ethyl-3-carboxylate

第一歩

First

 L-(4-Trifluoromethyl-phenyl)-2-nitro-propanol

 4-Trifluoromethyl-benzaldehyde lf (3.411 g, 19.6 mmol), nitroethane (5.88 g, 78.4 mmol) was dissolved in 40 ml of absolute ethanol and cooled to 0 ° C. Slowly add 784 mg of 10% sodium hydroxide solution, stir for 1.5 hours, add 7.176 g of 2% acetic acid solution, warm to room temperature, stir the reaction overnight, and follow the end of the reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj The residue was dried over anhydrous sodium sulfate (MgSO4). 3.86 g), yield 79%.

MS m/z (ESI): 238 [M-1]

 Second step

 L-(4-Trifluoromethyl-phenyl)-2-amino-propanol

In a dry hydrogenated vial, 1-(4-trifluoromethyl-phenyl)-2-nitro-propanol 10a (1.558 g, 6.34 mmol) was dissolved in 20 ml of ethanol and slowly added 157 mg. After Pd/C, stirring at room temperature for 0.3 MPa for 3 hours, the spot plate was followed to end the reaction. Filter through celite and concentrate the filtrate under reduced pressure. The obtained residue was purified to silica gel elut372 elut elut elut elut elut elut MS m/z (ESI): 220[M+1]

 third step

 5-{[2-(4-Trifluoromethyl-phenyl)小methyl-2-hydroxy-ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole- Ethyl 3-carboxylate

 1-(4-Trifluoromethyl-phenyl)-2-amino-propanol 10b (0.262 g, 1.2 mmol), 5-methyl-3-trifluoromethyl-1H-pyrrole-2-yl tert-Butyl -4-carboxylate (0.315 g, 1.14 mmol) was dissolved in 5 ml of dichloromethane. After adding 0.805 g of 4 A molecular sieve and stirring the reaction overnight, a solution of sodium borohydride (136 mg, 3.6 mmol) in methanol (1 ml) was added, and the reaction was stirred for 2 hours, and the reaction was completed by spotting. Filter and concentrate the filtrate under reduced pressure. The residue was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The layer was dried over anhydrous sodium sulfate, filtered and evaporated. Methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 10c (0.55 g) was used directly for the next reaction.

MS m/z (ESI): 481 [M+1]

 the fourth step

 5-[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1 H-pyrrole

 Ethyl-3-carboxylate

 5-{[2-(4-Trifluoromethyl-phenyl)-1-methyl-2-hydroxy-ethylamine]-methyl}-2-methyl-4 under a nitrogen salt bath -Trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 10c (0.550 g, 1.146 mmol) was dissolved in 5 ml of dichloromethane and 0.05 ml of hydrazine, hydrazine-dimethyl-formamide, , Ν-diisopropylethylamine (437 mg, 3.44 mmol), keeping the internal temperature less than 0 ° C, and slowly adding a solution of triphosgene (340 mg, 1.14 mmol) in dichloromethane (2 ml). The reaction was stirred for 2 hours, and the spotting was followed to end the reaction. The reaction mixture was concentrated under reduced pressure. ethyl acetate (50 ml··········· The organic layer was washed with a saturated aqueous solution of sodium chloride (20 ml), and then evaporated. The title product 5-[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-keto-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl Ethyl-1H-pyrrole-3-carboxylate 10 (threo) (0.2 g, white solid), yield 44.6%.

MS m/z (ESI): 505 [M-1]

'HNMR (400MHz, CDC1 ₃ ) 59.32(S, lH), 7.66(d, 2H), 7.42(d, 2H), 5.03(d, 1H), 4.49(q, 2H), 3.62(m, 1H), 2.46(s, 3H), 1.54(s, 9H), 1.42(d, 3H). Example 11

 5-[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H -pyrrole

Ethyl-3-carboxylate

 First step

 5-[5-(4-Trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl-4-trifluoromethyl- 1 H -pyrrole-3-carboxylic acid ethyl ester

 The fourth step of the reaction of Example 10 of the present invention was repeated, using the compound obtained in Example 10, 5-{[2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl -ethylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 10c is reacted with triphosgene, hydrazine, hydrazine-diisopropylethylamine, The obtained residue was purified by preparative chromatography chromatography to afford the title product 5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl] Ethyl 2-methyl-4-trifluoromethyl-l-pyrrole-3-carboxylate 11 (erythro) (0.2 g, white solid), yield 4.46.

 MS m/z (ESI): 505 [M-1]

'HNMR (400MHz, CDC1 ₃ ) 59.32(S, IH), 7.67(d, 2H), 7.38(d, 2H), 5.64(d, IH), 4.48(q _; 2H), 4.14(m, IH), 2.47(s, 3H), 1.55(s, 9H), 0.80(d, 3H). Example 12

 -[5-(3,5-di-trifluoromethyl-phenyl)-2-one-oxazole-3-yl-methyl]-1,2-.methyl-4-trifluoromethyl-1H -pyrrole

第一步

first step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazole-3-yl-methyl]-1,2-dimethyl-4-trifluoromethyl- Dissolve sodium hydride (80 mg, 3.33 mmol) in 5 ml of tetrahydrofuran solution in a 1H-pyrazine atmosphere ice salt bath, cool to 0 ° C, and add 5-[5-(3,5-di-three) Fluoromethyl-phenyl)-2-keto-oxazole-3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole 8 (0.06 g, 0.13 mmol) in tetrahydrofuran (20 ml The solution was kept at a temperature of less than 0 ° C. After stirring for half an hour, the temperature was raised to 50 ° C, and immediately cooled to 5 ° C. Iodomethyl hydrazine (37.5 mg, 0.264 mmol) was added immediately, and the reaction was stirred overnight. The point plate tracks the reaction. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjj The organic layer was washed with aq. EtOAc (EtOAc) (EtOAcjjjjjjjj Di-trifluoromethyl-phenyl)-2-one-oxazole 3-yl-methyl]-1,2-dimethyl-4-trifluoromethyl-1H-pyrrole 12 (0.028 g, light yellow Solid), yield 44%.

 MS m/z (ESI): 475 [M+l]

lHNMR (400MHz, CDC1 ₃ ) 67.88 (brs, 1H), 7.75 (s, 2H), 6.06 (s, 1H), 5.59 (m, 1H), 4.69 (d, 1H), 4.56 (d, 1H), 3.93 (m, 1H), 3.53 (s, 3H), 3.30 (m, 1H), 2.20 (s, 3H). Example 13

甲基 -3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-基-甲基) -噁唑

Methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-oxazole

 2-ketone

第一步

first step

 5-methyl-3-trifluoromethyl- 1 H-pyrrole-2-formyl

 Copper chromite (2.0 g) was dissolved in 2 ml of quinoline and heated to an oil bath temperature of 200~

205 Ό , heated to the system without gas evolution, add 5-methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-carboxy acid 8 _a (2 g, 9.05 mmol), immediately A lot of white smoke came out. While maintaining this temperature, the reaction was stirred for 30 minutes, and the spotting was followed to end the reaction. The system was cooled to about 160 Torr, the flask was washed with 30 ml of ethyl acetate, filtered, and the eluent was concentrated to 30 ml under reduced pressure. The organic phase was washed with 2 mol/L of dilute hydrochloric acid (10 ml×3), followed by saturated carbonic acid. The residue was washed with EtOAc (EtOAc m.) 1H-pyrrole-2-ylyl 13a (0.823 g), yield 57.4%.

MS m/z (ESI): 176 [M-1]

 Second step

 1-(3,5-Di-trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino]-propionium

 -1-hydroxyl

 1-(3,5-Di-Trifluoromethyl-phenyl)-2-amino-propanol 2c (0.33 g, 1.15 mmol), 5-methyl-3-trifluoromethyl-1H-pyrrole- 2-formyl 13a (0.136 g, 0.77 mmol) was dissolved in 10 ml of dichloromethane, and a small amount of 4 A molecular sieve was added thereto, and the reaction was stirred at room temperature overnight, and the reaction was completed by spotting. Sodium borohydride (176 mg) was added followed by 2 ml of methanol. The reaction was stirred at room temperature for 5 hours, and the spotting was followed to end the reaction. After filtration, the filtrate was concentrated under reduced pressure to remove dichloromethane and methanol. The organic layer was washed with EtOAc (EtOAc) (EtOAc m. The filtrate was concentrated under reduced vacuo. Methyl-1H-pyrrol-2-ylmethyl)-amino]-propan-1-hydroxy 13b (260 mg) was taken directly to the next step.

MS m/z (ESI): 447 [M-1]

third step 5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)- Oxazole

 2-ketone

 1-(3,5-Di-trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl) under a nitrogen salt bath -amino]-propion-1-hydroxyl 13b (260 mg, 0.58 mmol) dissolved in 80 ml of dichloromethane, added 34 mg of sodium chloride, kept at an internal temperature of less than 0 ° C, and slowly added dropwise Triphosgene (69 mg, 0.23 mmol) in dichloromethane (20 ml), N,N-diisopropylethylamine (442 mg, 3.48 mmol), keeping the temperature below 0 ° C, stirring for 1 hour After that, the temperature was raised to room temperature, and the reaction was stirred overnight, and the plate was followed to end the reaction. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAcjjjjjjjj The organic layer was washed with EtOAc (EtOAc m.) Methyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-oxazol-2-one 13 (erythro) (0.12 g, pale yellow solid), yield 87.2%.

 MS m/z (ESI): 473 [M-l]

lHNMR (400MHz, CDC1 ₃ ) 59.04 (brs, 1H), 7.9 (s, 1H), 7.73 (s, 2H), 6.00 (d, 1H), 5.70 (d, 1H), 4.65 (d, 1H), 4.32 (d, 1H), 4.2 l(m, 1H), 2.25(s, 3H), 0.8 l(d, 3H). Example 14

 5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)- Oxazole

 2-ketone

 First step

5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)- Oxazol-2-one The fourth step of the reaction of Example 13 of the present invention was repeated, using the compound 1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-) obtained in Example 13. Trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino]-propan-1-hydroxyl 13b is reacted with triphosgene, N,N-diisopropylethylamine, and the residue obtained by preparative chromatography To give the title product 5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl -Methyl)-oxazol-2-one 14 (threo) (0.023 g, pale yellow solid), yield 17.5%.

MS m/z (ESI): 473 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 59.14 (brs, 1H), 7.89 (s, 1H), 7.74 (s, 2H), 5.97 (d, 1H), 5.08 (d, 1H), 4.63 (d, 1H), 4.36 (d, 1H), 3.63(m, 1H), 2.23(s, 3H), 1.46(d, 3H). Example 15

 -[5-(3,5-di-trifluoromethyl-phenyl)-2-one-oxazole-3-yl-methyl}-4-phenyl-3-trifluoromethyl-1H-pyrrole- 2-carboxylic acid ethyl ester

第一歩

First

5-formyl-4-phenyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 5-formyl-4-iodo-3-trifluoromethyl- 1H- Ethyl pyrrol-2-carboxylate 5c (0.361 g, 1 mmol), phenylboronic acid (135 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium (558 mg, 0.5 mmol), potassium carbonate (318 mg, 2.3 Ment) dissolved in 2 ml / 2 ml of N, N-dimethylformamide / water mixture, heated to bring the internal temperature to 50 ~ 60 ° C, stirred reaction for 5 hours, the point plate tracking reaction ended . The reaction solution was extracted by adding 20 ml of water and 50 ml of ethyl acetate. Combine the organic phase with a saturated aqueous solution of sodium chloride (20 ml×1), the organic layer was washed with EtOAc EtOAcjjjjjjjjjjjjj Ethyl fluoromethyl-1H-pyrrole-2-carboxylate 15a (0.074 g), Yield: 23%.

MS m/z (ESI): 310 [M-1]

 Second step

 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl }-4-phenyl-3-trifluoromethyl-1Η-pyrrole

 Ethyl 2-carboxylate

 Under the nitrogen atmosphere, the compound 5-formyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 15a (0.074 g, 0.237 mmol), 1-(3,5-di -Trifluoromethyl-phenyl)-2-amino-ethanol 5e (97 mg, 0.355 mmol), dissolved in 5 ml of 1,2-dichloroethane, added a small amount of 4 molecular sieves, stirred overnight, stirred Sodium cyanoborohydride (45 mg, 0.71 mmol) was added slowly, and the reaction was stirred at room temperature overnight. The reaction solution was filtered, washed with aq. EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid Ethyl ester 15b (0.062 g), yield 46%.

MS m/z (ESI): 567 [M-1]

 third step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-4-phenyl-3-trifluoromethyl-1H- Ethyl pyrrol-2-carboxylate

 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-phenyl-3-trifluoromethyl Ethyl-1H-pyrrole-2-carboxylic acid ethyl ester 15b (0.062 g, 0.11 mmol), sodium chloride (20 mg) dissolved in 2 ml of methylene chloride, keeping the internal temperature less than 0 ° C, slowly A solution of triphosgene (70 mg, 0.23 mmol) in dichloromethane (2 ml) was added dropwise, and the mixture was stirred for 2 hr, then EtOAc, m. 2 ml) of the solution, the reaction was stirred for 2 hours, then allowed to warm to room temperature, and the reaction was stirred overnight, and the reaction was stopped by clicking on the plate. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc (EtOAc) (EtOAcjjjjjjjjjj -di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 15 (0.03 g, white solid), yield 46%.

 MS m/z (ESI): 595 [M+1]

lHNM (400MHz, CDC1 ₃ ) 510.70(s, 1H), 7.88(s, 1H), 7.76(s, 2H), 7.36(m, 3H), 7.20(m, 2H), 5.55(t, 1H), 4.48 ~4.26(m, 2H), 4.39(q, 2H), 3.72(t, 1H), 3.13(t, 1H), 1.37(t, 3H). Example 16

 (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-3-(l,5-dimethyl-3-trifluoromethyl-1H-pyrrol-2-yl- Methyl)-4-methyl-oxazol-2-one

第一步

first step

 (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-trifluoromethyl-1H-pyrrol-2-yl- Methyl)_4-methyl-oxazol-2-one

 Sodium hydride (80 mg) was dissolved in 5 ml of tetrahydrofuran under a nitrogen salt bath.

0, slowly adding (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl- 1H-pyrrol-2-yl-methyl)-oxazol-2-one 13 (0.06 g, 0.13 mmol) in tetrahydrofuran (5 ml), keeping the temperature at 0 ° C, stirring for 2 hours, adding 70 μM iodine Formazan, after 1 hour of incubation, warmed to room temperature, reacted overnight, and the plate was followed to end the reaction. 20 ml of water was added, and the reaction mixture was concentrated under reduced pressure. ethyl acetate (30 ml??) The organic layer was washed with aq. EtOAc (EtOAc m. R) 5-(3,5-Di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl) - 4-methyl-oxazol-2-one 16 (0.020 g, pale yellow solid), yield 68%.

MS m/z (ESI): 506 [M+18]

lHNMR (400MHz, CDC1 ₃ ) S7.88 (brs, 1H), 7.77 (s, 2H), 6.08 (s, 1H), 5.64 (d, 1H), 4.84 (d, 1H), 4.46 (d, 1H) , 4.02 (m, 1H), 3.55 (s, 3H), 2.23 (s, 3H), 0.72 (d, 3H). Example 17

(4S,5R)-5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazol-3-yl-methyl]-2-A Ethyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

第一步

first step

 (S)-[l-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester under nitrogen atmosphere, (S)-2-benzyloxycarbylamino-propionic acid 17a (13 g, 58 mmol), 1-hydroxy-benzotriazole-water (9.6 g, 71 mmol), methoxy-methylamine (6.8 g, 7.1 mmol) dissolved in 200 ml of THF and cooled. 0~10 ° C, slowly add N,N-diisopropylethylamine (25 ml, 15.3 mmol), control the temperature below 25 ° C, and slowly add 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (14 g, 7.3 mmol) was stirred at room temperature for 3.5 hours. 70 ml of 3N dilute hydrochloric acid solution was slowly added dropwise to the system, and the obtained reaction liquid was extracted with ethyl acetate (80 ml×l), the aqueous phase was extracted again with ethyl acetate (50 ml×2), and the organic phase was combined, and 20 ml of 3N was used in sequence. The organic layer was washed with aq. EtOAc (EtOAc m. S)-[l_(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester 17b (14.65 g), yield 95.0%.

MS m/z (ESI): 267 [M+1]

 Second step

(S)-[2-(3,5-Di-trifluoromethyl-phenyl)-1-methyl-2-one-ethyl]-carbamic acid benzyl ester under nitrogen atmosphere, (S) -[l-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester 17b (14.65 g, 55 mmol), 3,5-di-trifluoromethyl-phenyl bromide (11.9 Ml, 68.8 mmol) dissolved in 100 ml of tetrahydrofuran, cooled to -10 ° C, slowly added isopropyl magnesium chloride (68.8 ml, 137.5 mmol), keep the temperature not more than 1 ~ 5 ° C, after the completion of the addition, The temperature was raised to 20 ° C, and the reaction was stirred for 2 hours, and the reaction was stirred at room temperature overnight. The point plate tracks the reaction. To the system, 60 ml of a 5 N diluted hydrochloric acid solution was added, and the obtained mixture was extracted with ethyl acetate (80 ml×l), and then washed with a saturated aqueous solution of sodium chloride (20 ml×l), and the ethyl acetate layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product (S)-[2-(3,5-di-trifluoromethyl-benzene Benzyl)-1-methyl-2-keto-ethyl]-carbamic acid benzyl ester 17c (25.1 g), yield 100%, product used for the next reaction.

 MS m/z (ESI): 420 [M+1]

 third step

 (lR,2S)-l-(3,5-Di-trifluoromethyl-phenyl)-2-amino-propanol In a dry hydrogenated bottle, (S)-[2-(3,5- Di-trifluoromethyl-phenyl)-1-methyl-2-one-ethyl]-carbamic acid benzyl ester 17c (1.48 g, 3.53 mmol) was dissolved in 30 ml of methanol and 480 mg of Pd/C was added. After stirring for 4 hours at room temperature and 30 Psi, the spotting was followed to end the reaction. Filtration with celite, EtOAc (EtOAc m.) The rate is 86.6 %.

 MS m/z (ESI): 288 [M+1]

 the fourth step

 (lR,2S)-5-{[2-(3,5-:-trifluoromethyl-phenyl)methylene-2-hydroxy-ethylamine]-methyl}-2-methyl-4 -Trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

 (lR,2S)-l-(3,5-Di-trifluoromethyl-phenyl)-2-amino-propanol 17d (0.35 g, 1.22 mmol), 5-methyl-3 under a nitrogen atmosphere -Trifluoromethyl-1H-pyrrole-2-formyl-4-carboxy acid tert-butyl ester le (0.225 g, 0.813 mmol) was dissolved in 10 mL methanol. A small amount of 4 molecular sieves was added, and the reaction was stirred at room temperature overnight, then a solution of sodium borohydride (129 mg, 3.23 mmol) in methanol (2 ml). After filtration, 20 ml of water was added to the filtrate, and the filtrate was concentrated under reduced pressure. The residue was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Product (lR, 2S)-5-{[2-(3,5-Di-trifluoromethyl-phenyl)methanol-2-hydroxy-ethylamine]-methyl}-2-methyl- Ethyl 4-trifluoromethyl-1H-pyrrole-3-carboxylate 17e (0.47 g) was taken directly to the next step.

MS m/z (ESI): 547 [M-1]

 the fifth step

 (4S,5R)-5-[5-(3,5-Di-trifluoromethyl-phenyl)-4-methyl-2-one-oxazole-3-yl-methyl]-2-methyl -4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester

Under a nitrogen salt bath, (lR, 2S)-5-{[2-(3,5-di-trifluoromethyl-phenyl)methylene-2-hydroxy-ethylamine]-methyl }-2-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 17e (0.47 g, 0.86 mmol) was dissolved in 40 ml of dichloromethane, keeping the internal temperature less than 0 ° C, A solution of triphosgene (509 mg, 1.72 mmol) in dichloromethane (4 ml) was added dropwise, and the mixture was stirred for 1 hour, then hydrazine, bis-diisopropylethylamine (655 mg, 5.16 mmol) was added. The temperature was <5, and after stirring for 2 hours, the temperature was raised to 0 ° C, and the reaction was stirred overnight, and the reaction was stopped by the spot plate. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc (EtOAc). The obtained residue was purified by silica gel column chromatography toield Methyl oxazole 3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylate 17 (0.23 g, yellow solid), yield 48.6%.

MS m/z (ESI): 597 [M+23]

lHNMR (400MHz, CDC1 ₃ ) 69.30(s, IH), 7.90(s, IH), 7.73(s, 2H), 5.71(d, IH), 4.59(d IH), 4.45(d, IH), 4.20( m, IH), 2.48 (s, 3H), 1.57 (s, 9H), 0.82 (d, 3H). Example 18

 (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-IH-pyrrole-2- Methyl-methyl)-oxazol-2-one

第一步

first step

 (lR,2S)-l-(3,5-Di-trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl) -amino]-propane-1-hydroxyl

 (lR,2S)-l-(3,5-Di-trifluoromethyl-phenyl)-2-amino-propanol 17d (0.35 g, 1.22 mmol), 5-methyl-3 under nitrogen atmosphere -Trifluoromethyl-1H-pyrrole-2-formyl 13a (0.144 g, 0.813 mmol) was dissolved in 10 ml of dichloromethane, and a small amount of 4 molecular sieves was added thereto, and the reaction was stirred at room temperature overnight, and the reaction was completed by spotting. Add 185 mg of sodium borohydride and add 2 ml of methanol. The reaction was stirred at room temperature overnight, and the reaction was stopped by spotting. After filtration, the filtrate was concentrated under reduced pressure to remove dichloromethane and methanol. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc)EtOAc. Concentration under reduced pressure gave the title product (1,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -2-ylmethyl)-amino]-propan-1-hydroxy 18a (410 mg) was taken directly to the next step.

MS m/z (ESI): 447 [M-1]

Second step (4S,5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2- Methyl-methyl)-oxazol-2-one

 Under a nitrogen salt bath, (lR,2S)-l-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H- Pyrrol-2-ylmethyl)-amino]-propan-1-hydroxy 18a (410 mg, 0.915 mmol) was dissolved in 40 ml of dichloromethane, and a small amount of sodium chloride was added to maintain an internal temperature of less than 0 ° C. A solution of triphosgene (217 mg, 0.732 mmol) in dichloromethane (10 ml) was added dropwise, and the reaction was kept for half an hour, then hydrazine, hydrazine-diisopropylethylamine (697 mg, 5.49) was added. Methyl), keep the temperature below 0 ° C, stir the reaction for 1 hour, then warm to room temperature, stir the reaction overnight, and follow the end of the reaction. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The organic layer was washed with EtOAc (3 mL, EtOAc). -di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-oxazol-2-one 18 (0.18 g, yellow solid), yield 42%.

MS m/z (ESI): 473 [M-l]

lHNMR (400MHz, CDC1 ₃ ) 59.03 (brs, 1H), 7.9 (s, 1H), 7.73 (s, 2H), 6.00 (s, 1H), 5.70 (d, 1H), 4.65 (d, 1H), 4.32 (d, 1H), 4.22(m, 1H), 2.25(s, 3H), 0.8 l(d, 3H). Example 19

 3-[l-(3,5-Di-trifluoromethyl-phenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl]-5-(3, 5-di-trifluoromethyl-phenyl)-oxazol-2-one

重复本发明实施例 12第一步反应， 不同的是使用实施例 8中所得到的化合 物 5-[5-(3,5-二-三氟甲基 -苯基 )-2-酮 -噁唑 3-基-甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 8和 3,5-二 -三氟甲基-苄溴作原料， 得到标题产物 3-[1-(3,5-二-三氟甲基 -苯基 )-5- 甲基 -3-三氟甲基 -1H-吡咯 -2-基-甲基] -5-(3,5-二 -三氟甲基-苯基) -噁 -2-酮 19(92 mg, 白色固体)， 产率： 61.7%。

The first step reaction of Example 12 of the present invention was repeated except that the compound obtained in Example 8 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-keto-oxazole was used. 3-yl-methyl]-2-methyl-4-trifluoromethyl-1H-pyrrole 8 and 3,5-di-trifluoromethyl-benzyl bromide are used as starting materials to give the title product 3-[1-( 3,5-di-trifluoromethyl-phenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl]-5-(3,5-di-trifluoro Methyl-phenyl)-oxo-2-one 19 (92 mg, white solid), Yield: 61.7%.

MS m/z (ESI): 685 [M-l]

lHNMR (400MHz, CDC1 ₃ ) 58.1(s, 1H), 7.925(d, 3H), 7.374(s, 2H), 6.303(s, 1H), 5.468(s, 2H), 5.367(t, 1H), 4.486 (m, 2H), 3.774(t, 1H), 3.093(t, 1H), 2.094(s, 3H). Example 20 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazole-3-yl-methyl}-4-p-tolyl-3-trifluoromethyl-1H- Ethyl pyrrol-2-carboxylate

第一步

first step

 5-formyl-4-p-tolyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 5-formyl-4-iodo-3-trifluoromethyl- 1H under nitrogen atmosphere -pyrrole-2-carboxylic acid ethyl ester 5c (0.361 g, 1 mmol), p-toluene boronic acid (150 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium (558 mg, 0.5 mmol), potassium carbonate (318 mg) , 2.3 mmol) dissolved in 2 ml / 2 ml of hydrazine, hydrazine-dimethylformamide / water mixture, heated to bring the internal temperature to 50 ~ 60 ° C, stirred reaction overnight, the point plate to follow the end of the reaction. The reaction solution was extracted by adding 20 ml of water and 50 ml of ethyl acetate. The organic phase was combined, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated Ethyl-4-p-tolyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 20a (0.11 g), Yield: 34%.

MS m/z (ESI): 323 [M-l]

 Second

 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-p-tolyl-3-trifluoromethyl-1H-pyrrole Ethyl 2-carboxylate

 The compound 5-formyl-4-p-tolyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester under nitrogen atmosphere

20a (0.11 g, 0.338 mmol), 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (139 mg, 0.507 mmol), dissolved in 5 ml of 1,2- A small amount of 4 molecular sieves was added to the dichloroethane, and the reaction was stirred overnight. Slowly, sodium cyanoborohydride (64 mg, 1.014 mmol) was added with stirring, and the reaction was stirred at room temperature overnight. The trace reaction ends. The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated The title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-p-tolyl-3-trifluoromethane was obtained. Ethyl methyl-1H-pyrrole-2-carboxylate 20b (0.069 g), yield 35%.

 MS m/z (ESI): 583 [M+1]

 third step

 5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-4-p-tolyl-3-trifluoromethyl-1H -pyrrole-2-carboxylic acid ethyl ester

 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-p-tolyl-3-trifluoromethane under ice salt bath Ethyl methyl-1H-pyrrole-2-carboxylate 20b (0.069 g, 0.118 mmol), sodium chloride (20 mg) dissolved in 2 ml of methylene chloride, keeping the internal temperature less than 0 ° C, slow A solution of triphosgene (35 mg, 0.118 mmol) in dichloromethane (2 ml) was added dropwise, and the reaction was stirred for 2 hours, then N,N-diisopropylethylamine (90 mg, 0.711 mmol) was added. The solution of formazan (2 ml) was stirred for 2 hours, then allowed to warm to room temperature, and the reaction was stirred overnight, and the reaction was stopped by clicking on the plate. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The ethyl acetate layer was dried over anhydrous sodium sulfate (MgSO4), filtered, evaporated. Ethyl)-2-keto-oxazol-3-yl-methyl]-4-p-tolyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 20 (0.036 g, white solid) The yield was 50%. MS m/z (ESI): 609 [M+1]

lHNMR (400MHz, CDC1 ₃ ) 610.73(s, IH), 7.88(s, IH), 7.77(s, 2H), 7.17(d, 2H), 7.08(d, 2H), 5.56(t, IH), 4.48 ~4.26(m, 2H), 4.35(q, 2H), 3.72(t, IH), 3.14(t, IH), 2.37(s, 3H), 1.36(t, 3H).

5-[5-(3

第一步

first step

 5-formyl-4-(5-isopropyl-2-methoxy-phenyl)-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 5-formyl group under nitrogen atmosphere 4-iodo-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 5c (0.554 g,

1.53 mmol), 5-isopropyl-2-methoxy-benzeneboronic acid (327 mg, 1.68 mmol), tetrakis(triphenylphosphine)palladium (853 mg, 0.765 mmol), potassium carbonate (486 mg, 3.52 mmol Dissolve in 2 ml / 2 ml of hydrazine, hydrazine-dimethylformamide / water mixture, heat until the internal temperature reaches 50~60 ° C, stir the reaction overnight, and follow the end of the reaction. The reaction solution was extracted by adding 20 ml of water and 50 ml of ethyl acetate. The organic phase was combined, and the organic layer was washed with aq. Ethyl-4-(5-isopropyl-2-methoxy-phenyl)-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 21a (0.14 g), Yield: 23%. MS m/z (ESI): 382 [M-1]

 Second step

 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-(5-isopropyl-2-methoxy-benzene Ethyl 3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester

 The compound 5-formyl-4-(5-isopropyl-2-methoxy-phenyl)-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 21a (0.14) g, 0.365 mmol), 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (150 mg, 0.547 mmol), dissolved in 3 ml of 1,2-dichloro A small amount of 4 molecular sieves was added to the alkane, and the reaction was stirred overnight, and sodium cyanoborohydride (69 mg, U mmol) was slowly added with stirring, and the reaction was stirred at room temperature overnight, and the reaction was finished by spotting. The reaction solution was filtered, and the filtrate was extracted with 50 ml of ethyl acetate and 25 ml of saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate and filtered. The residue, ^^ gave the title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-(5-isopropyl Ethyl 2-bromo-phenyl)-3-trifluoromethyl-1H-pyrrole-2-carboxylate 21b (0.153 g), yield 66%.

MS m/z (ESI): 639 [M-1]

 Third

5-[5-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-4-(5-isopropyl-2-methoxy -phenyl)-3- Trifluoromethyl-IH-pyrrole-2-carboxylic acid ethyl ester

 5-{[2-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-4-(5-isopropyl-2) in an ice salt bath -Methoxy-phenyl)-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 21b (0.153 g, 0.239 mmol), sodium chloride (10 mg) dissolved in 9 ml of dichloromethane In the crucible, keep the internal temperature less than 0 °C, slowly add dropwise a solution of triphosgene (71 mg, 0.239 mmol) in dichloromethane (2 ml), stir the reaction for 2 hours, then add hydrazine, hydrazine-diisopropyl A solution of the amine (182 mg, 1.434 mmol) in dichloromethane (2 ml) was stirred for 2 hrs, then warmed to room temperature and stirred overnight. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The organic layer was dried over anhydrous sodium sulfate (MgSO4). 2-keto-oxazol-3-yl-methyl]-4-(5-isopropyl-2-methoxy-phenyl)-3-trifluoromethyl-1H-pyrrole-2-carboxylate Ethyl ester 21 (0.095 g, viscous liquid), yield 60%.

MS m/z (ESI): 667 [M+1]

lHNMR (400MHz, CDC1 ₃ ) 510.52(d, IH), 7.87(s, IH), 7.74(s, 2H), 7.18(m, IH), 6.97~6.92(d, IH), 6.84(m, IH) , 5.52(t, IH), 4.50~4.33(m, 2H), 4.35(q, 2H), 3.76~3.62(m, 1H), 3.75(s, 1.5H), 3.64(s, 1.5H), 3.21 ~3.09(m, IH), 2.86~2.83(m, IH), 1.38(t,3H), 1.23~1.21(m, 6H). Example 22

 -trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-IH-pyrrol-2-yl-methyl)-oxazole-2-one

第一步

first step

 1-(4-Trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino]-propanoid small hydroxyl group

1-(4-Trifluoromethyl-phenyl)-2-amino-propanol 10b (0.35 g, 1.22 mmol), 5-methyl-3-trifluoromethyl-1H-pyrrole under a nitrogen atmosphere 2-formyl 13a (0.144 g, 0.813 mmol) dissolved in 10 ml of dichloro In the methane, a small amount of 4 A molecular sieve was added, and the reaction was stirred at room temperature overnight, and the reaction was terminated by a spot plate. Add 185 mg of sodium borohydride and add 2 ml of methanol. The reaction was stirred at room temperature overnight, and the reaction was stopped by spotting. After filtration, the filtrate was concentrated under reduced pressure to remove dichloromethane and methanol. The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc m. Concentration by pressure gave the title product 1-(4-trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino] Propionin-1-hydroxy 22a (300 mg), directly into the next step.

MS m/z (ESI): 447 [M-1]

 Second

 (4S,5R)-5-(4-Trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl ) - Oxazol-2-one

1-(4-Trifluoromethyl-phenyl)-2-[(5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl)-amino group under a nitrogen salt bath ] -propan-1-hydroxy 22a (300 mg, 0.79 mmol) was dissolved in 10 ml of dichloromethane, a small amount of sodium chloride was added, the internal temperature was kept below 0 ° C, and triphosgene (470 mg, 1.58) was slowly added dropwise. Methylene chloride (10 ml) solution, after incubation for half an hour, add hydrazine, hydrazine-diisopropylethylamine (697 mg _: 5.49 mmol), keep the temperature below 0 °C, stir the reaction 10 After a minute, it was allowed to warm to room temperature, and the reaction was stirred overnight, and the plate was followed to end the reaction. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAcjjjjjjjj 20 mlx l) The organic layer was washed with ethyl acetate. EtOAcjjjjjjjjjjj -trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-oxazol-2-one 22 ( 0.018 g, yellow solid), yield 11.2%.

MS m/z (ESI): 405 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 67.67(d, 2H), 7.40(d, 2H), 5.98(s, IH), 5.63(d, IH), 4.58(s _: IH), 4.28(d, IH), 4.10 (m, IH), 2.23(d, 3H), 0.80(d, 3H). Example 23

 5-[6-(3,5-Di-trifluoromethyl-phenyl)-2-one-[1,3]oxazin-3-yl-methyl]-2-methyl-4-trifluoro Methyl-IH-pyrrole-3-carboxylic acid ethyl ester

第一步

first step

 2-(3,5-di-trifluoromethyl-phenyl)-ethylene oxide

 Sodium hydride (3.6 g, 90 mmol) was dissolved in 180 ml of DMSO, and trimethylsulfoxonium iodide was added dropwise.

(23.1 g, 105 mmol), stirring at room temperature for 8 minutes, then adding 3,5-di-trifluoromethyl-benzaldehyde 23a (7.26 g, 30 mmol) in DMSO (30 ml) dropwise. After stirring the reaction for 50 minutes at room temperature, the spot plate was followed to end the reaction. The reaction mixture was poured into 800 ml of ice water, and the mixture was extracted with n-pentyl hydrazine (300 ml><3), and the organic phase was combined. The organic layer was washed with saturated aqueous sodium chloride (50 ml×l). The residue was dried (MgSO4), filtered g, yellow oil), yield 21%.

 Second step

 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propanenitrile

 2-(3,5-Di-trifluoromethyl-phenyl)-epoxyacetam 23b (1.39 g, 5.1 mmol), cyanotrimethylsilyl (1.0 g, 10.2 mmol) was dissolved in 20 ml To the tetrahydrofuran, tetrabutylammonium fluoride (2.0 g) was added thereto with stirring at room temperature, and the reaction was stirred at room temperature overnight, and the reaction was stopped by spotting. The reaction mixture was concentrated under reduced pressure. ethyl acetate (30 ml??) 20 mlx l) The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc m. The residue was purified by silica gel column chromatography eluting elut elut elut elut Yield 29%

MS m/z (ESI): 282 [M-1]

 Third

 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine

Dissolve 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propanenitrile 23c (430 mg, 1.52 mmol) in 20 ml of tetrahydrofuran under nitrogen atmosphere, at room temperature, dropwise A solution of borofluorene in tetrahydrofuran (6.08 ml, 6.08 mmol) was stirred overnight, and the reaction was completed by spotting. Add 10 ml of methanol to the reaction solution. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The mixture was washed with aq. -(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine 23d (150 mg, pale yellow oil), yield 34.4%

MS m/z (ESI): 288 [M+l]

 the fourth step

 5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3 - tert-butyl carboxylate

 5-methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-carboxy acid tert-butyl ester le (132 mg, 0.476 mmol), 3-(3,5-di) -Trifluoromethyl-phenyl)-3-hydroxy-propylamine 23d (150 mg, 0.523 mmol), dissolved in 10 ml of dichloromethane, added a small amount of 4 molecular sieves, stirred at room temperature for 2 hours, point plate tracking The reaction is over. Add 114 mg of sodium borohydride and add 2 ml of methanol. After stirring at room temperature for 2 hours, the spot plate was followed to end the reaction. After filtration, the filtrate was concentrated under reduced pressure to remove methylene chloride and methanol. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc)EtOAc. The organic layer was concentrated under reduced pressure. 2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid tert-butyl ester 23e (150 mg, pale yellow oil), yield 57%

MS m/z (ESI): 549 [M+1]

 the fifth step

 5-[6-(3,5-Di-trifluoromethyl-phenyl)-2-one-[1,3]oxazin-3-yl-methyl]-2-methyl-4-trifluoro Ethyl methyl-1H-pyrrole-3-carboxylate

 5-{[3-(3,5-Di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl-4-trifluoromethane under a nitrogen salt bath Methyl-1H-pyrrole-3-carboxy acid tert-butyl ester 23e (150 mg, 0.274 mmol) was dissolved in 10 ml of dichloromethane, a small amount of sodium chloride was added, and the internal temperature was kept below 0 ° C. Add triphosgene (163 mg, 0.548 mmol) in dichloromethane (10 ml) and incubate for half an hour, then add hydrazine, hydrazine-diisopropylethylamine (208.6 mg, 1.64 mmol). The temperature was less than 0 ° C, and after stirring for 10 minutes, the temperature was raised to room temperature, and the reaction was stirred overnight, and the reaction was completed by clicking on the plate. The reaction mixture was concentrated under reduced EtOAc (EtOAc m. 20 mlx l) The organic layer was washed with ethyl acetate. EtOAcjjjjjjjjjjjjjj Di-trifluoromethyl-phenyl)-2-one-[1 ,3]oxazin-3-yl-methyl]-2-methyl-4-trifluoromethyl- 1 H-pyrrole-3- Ethyl carboxylate 23 (0.015 g, yellow solid), yield 9.6%.

MS m/z (ESI): 574 [M-1] lHNMR (400MHz, CDC1 ₃ ) S9.6(s, 1H), 7.88(s, 1H), 7.83(s, 1H), 5.40(m, 1H), 4.69(d 1H), 4.5 l(d, 1H) , 3.61 (m, 1H), 3.40 (m, 1H), 2.46 (s, 3H), 2.32 (m, 1H), 2.17 (m, 1.55 (s, 9H). Example 24

 6-(3,5-Di-trifluoromethyl-phenyl)-3-(4-iodo-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-2 Ketone

 -[1,3]oxazine

 First step

 5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole-3 - Iodine

 5-Methyl-3-trifluoromethyl-1H-pyrrole-2-formyl-4-iodo 8b (116 mg, 0.381 mmol), 3-(3,5-di-trifluoromethyl) under a nitrogen atmosphere The base-phenyl)-3-hydroxy-propylamine 23d (164 mg, 0.571 mmol) was dissolved in 10 ml of methanol, and a small amount of 4 molecular sieves was added thereto, and the reaction was stirred at room temperature overnight, and the reaction was completed by spotting. 2 ml of sodium cyanoborohydride (49.5 mg, 0.762 mmol) in methanol was added. The reaction was stirred at room temperature overnight, and the reaction was stopped by spotting. After filtration, the filtrate was concentrated under reduced pressure to remove methanol. The organic layer was washed with aq. EtOAc (EtOAc (EtOAc)EtOAc. The organic layer was concentrated under reduced pressure. - Methyl-4-trifluoromethyl-1H-pyrrole-3-iodine 24a (170 mg, white solid), taken directly to the next reaction.

 Second step

 6-(3,5-Di-trifluoromethyl-phenyl)-3-(4-iodo-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-2 Ketone

 -[1,3]oxazine

5-{[3-(3,5-Di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl-4-trifluoromethyl- under a nitrogen atmosphere 1H-pyrrole-3-iodine 24a (170 mg, 0.296 mmol) was dissolved in 10 ml of hydrazine, hydrazine-dimethylformamide, and 20 ml of hydrazine, hydrazine-carbonyldiimidazole (53 mg, 0.326) was added dropwise with stirring at room temperature. A solution of hydrazine, hydrazine-dimethylformamide was stirred overnight, and the reaction was stopped by spotting. Concentrate the reaction solution under reduced pressure with ethyl acetate (30) The resulting residue was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The layer was dried over anhydrous sodium sulfate (MgSO4). 4-iodo-5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-2-one-[1,3]oxazine 24 (0.022 g, yellow solid), yield 12.4%.

MS m/z (ESI): 599 [M-1]

lHNM (400MHz, CDC1 ₃ ) S9.57(s, IH), 7.88(s, IH), 7.83(s, 2H), 5.40(m, IH), 4.68(d, IH), 4.46(d, IH) , 3.61 (m, IH), 3.47 (m, IH), 2.26 (s, 3H), 2.35 (m, 1H), 2.16 (m: IH). Example 25

 -[4-(3,5-di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-3-trifluoromethyl-IH-pyrrole-2-carboxylic acid Ethyl ester

第一步

first step

 5-aminomethyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester

 Ethyl 5-formyl-4-iodo-3-trifluoromethyl-1H-pyrrole-2-carboxylate 5c (600 mg, 1.66 mmol), hydroxylamine hydrochloride (238 mg, 3.57 mmol), sodium acetate (293 The mg, 3.57 mmol) was dissolved in 15 ml of methanol, and the reaction was stirred under reflux for 2 hours. In a separate vial, 10 ml of concentrated hydrochloric acid, 30 ml of water, zinc powder (906 mg, 13.94 mmol) were added in sequence, and a small amount of methanol was added to dissolve it. The above hydrochloric acid reaction solution was added dropwise with stirring, and reacted at room temperature for 3 hours, and the spotting was followed to complete the reaction. The reaction solution was poured into an open beaker, and saturated sodium bicarbonate solution was added until a large amount of white solid was formed and filtered. The filtrate was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) Ethyl trifluoromethyl- 1H-pyrrole-2-carboxylate 25a (0.27 g, white solid), yield 69%.

MS m/z (ESI): 235 [M-1]

 Second step

 (3,5-Di-trifluoromethyl-phenyl)-hydroxy-acetic acid methyl ester (3,5-di-trifluoromethyl-phenyl)-hydroxy-acetic acid 25b (1.44 g, 5.0 mmol Dissolved in 25 ml of benzene, methanol (4.0 ml, 100 mmol), azide trimethylsilyl (613 mg, 6.0 mmol), and stirred at room temperature for 3 hours. Acetic acid was added dropwise to the reaction mixture, and the solution was changed from pale yellow to EtOAc (EtOAc). Methyl-phenyl)-hydroxy-methyl acetate 25c (1.493 g, colorless oil), yield 98.8%.

 MS m/z (ESI): 301 [M-1]

 third step

 (3,5-Di-trifluoromethyl-phenyl)-hydroxy-acetic acid methyl ester 25c (3,5-di-trifluoromethyl-phenyl)-bromo-acetic acid methyl ester ice salt bath 1.493 g, 4.94 mmol) was dissolved in 30 ml of dichloromethane. After adding carbon tetrabromide (1.799 g, 5.43 mmol), all dissolved, triphenylphosphine (1.425 g, 5.43 mmol) was added portionwise, and the reaction was stirred for 4 hours, and the reaction was completed by spotting. The reaction mixture was concentrated under reduced pressure and purified title crystallijjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , yield 45%.

MS m/z (ESI): 285 [M-80]

 Fourth

 5-({[(3,5-di-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino}-methyl}-trifluoromethyl- 1H-pyrrole-2-carboxylic acid Ethyl ester

Ethyl 5-aminomethyl-3-trifluoromethyl-1H-pyrrole-2-carboxylate 25a (0.082 g, 0.347 mmol) was dissolved in 20 ml of tetrahydrofuran and (3,5-di-trifluoro Methyl-phenyl)-bromo-acetic acid methyl ester 25d (0.507 g, 1.388 mmol), triethylamine (350 mg, 3.47 mmol). Point plate tracking reaction Bunch. The reaction mixture was concentrated under reduced EtOAc (EtOAc m. The organic layer was washed with EtOAc (EtOAc m.) -trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino}-methyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 25e (0.1 g), yield 55 %.

MS m/z (ESI): 519 [M-1]

 the fifth step

 5-{[l-(3,5-di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid Ester

 Lithium aluminum hydrogen (170 mg, 4.47 mmol) was dissolved in 50 ml of tetrahydrofuran in a dry ice bath.

5-({[(3,5-di-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino}-methyl-3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid Ethyl acetate 25e (0.1 g, 0.192 mmol) in tetrahydrofuran (10 ml) was stirred for half an hour. The reaction was quenched by the addition of 1 ml of water. The reaction was completed by spotting. The reaction mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated. Ethyl-phenyl)-2-hydroxy-ethylamino]-methyl 3-trifluoromethyl- 1H-pyrrole-2-carboxylic acid ethyl ester 25f (0.025 g, pale yellow solid), yield 27%.

MS m/z (ESI): 491 [M-l]

 Step 6

 5-[4-(3,5-Di-trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-3-trifluoromethyl-1Η-pyrrole-2-carboxylate Ethyl acetate

 5-{[1-(3,5-Di-trifluoromethyl-phenyl)-2-hydroxy-ethylamino]-methyl}-3-trifluoromethyl- 1H under a nitrogen salt bath - Pyrrole-2-carboxylate ethyl ester 25f (25 mg, 0.05 mmol) was dissolved in 2 ml of dichloromethane, a small amount of sodium chloride was added, the internal temperature was kept below 0 °C, and triphosgene (15 mg) was slowly added dropwise. , 0.05 mmol) in dichloromethane (2 ml), after incubation for half an hour, add hydrazine, hydrazine-diisopropylethylamine (38 mg, 0.3 mmol), keep the temperature below 0 °C, stir After reacting for 10 minutes, it was allowed to warm to room temperature, and the reaction was stirred overnight, and the reaction was stopped by clicking on the plate. The reaction mixture was concentrated under reduced EtOAc (EtOAc m. The organic layer was washed with EtOAc (EtOAc m.). -trifluoromethyl-phenyl)-2-one-oxazol-3-yl-methyl]-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid ethyl ester 25 (0.012 g, white solid) , yield 46%.

MS m/z (ESI): 517 [M-1]

lHNMR (400MHz, CDC1 ₃ ) 510.14(s, 1H), 7.90(s, 1H), 7.70(s, 2H), 6.00(s, 1H), 4.89-4.7 l(m, 2H), 4.47~4.43(d, 1H), 4.35(q, 2H), 4.175-4.136(m, 2H), 1.37(t, 3H). Example 26

 6-(3,5-Di-trifluoromethyl-phenyl)-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-2-one-[ 1,3] evil

第一步

first step

 5-{[3-(3,5-Di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl-4-trifluoromethyl-1H-pyrrole nitrogen atmosphere Next, 5-methyl-3-trifluoromethyl-1H-pyrrole-2-ylyl 13a (143 mg, 0.808 mmol), 3-(3,5-di-trifluoromethyl-phenyl)- 3-Hydroxy-propylamine 23d (300 mg, 1.05 mmol), dissolved in 10 ml of methanol, added a small amount of 4 molecular sieves, stirred at room temperature overnight, and the plate was followed to complete the reaction. Sodium cyanoborohydride (315 mg, 4.848 mmol) was added, and the reaction was stirred at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure to remove methanol. The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc). The mixture was concentrated under reduced pressure. 2-methyl-4-trifluoromethyl-1H-pyrrole 26a (170 mg, pale yellow solid), yield 47.2%

 Second step

6-(3,5-Di-trifluoromethyl-phenyl)-3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-yl-methyl)-2-one-[ 1,5] 5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl}-2-methyl under a nitrogen salt atmosphere -4-Trifluoromethyl-1H-pyrrole 26a (145 mg, 0.323 mmol) was dissolved in 20 ml of methylene chloride, a small amount of sodium chloride was added, and the internal temperature was kept below 0 Ό, and the phosgene was slowly added dropwise (193). Mg, 0.648 mmol) in methylene chloride (20 ml), after incubation for half an hour, add N,N-diisopropylethylamine (164 mg, 1.3 mmol) to keep the temperature below (TC, After stirring for 10 minutes, it was allowed to warm to room temperature, and the reaction was stirred overnight, and the mixture was applied to the end of the reaction. The reaction mixture was concentrated under reduced pressure, ethyl acetate (30 ml×3), water (20 ml×l) The residue was obtained, the aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The organic layer was concentrated under reduced vacuolulululululululululululu -1H-pyrrol-2-yl-methyl)-2-one-[1,3]oxazine 26 (0.1 g, pale yellow solid), yield 67%

 MS m/z (ESI): 475 [M+l]

lHNMR (400MHz, CDC1 ₃ ) 69.26(s, IH), 7.88(s, 2H), 7.83(s, IH), 5.99(s, IH), 5.40(m _; IH), 4.65(d, IH), 4.39 (d, IH), 3.6 l(m, IH), 3.48(m, IH), 2.34(m, IH), 2.23(s, 3H), 2.15(m, IH). Test example:

 Biological evaluation

Example 1 CETP inhibition cell proliferation test

 The following in vitro assays are used to determine the in vitro inhibition of CETP activity of the compounds of the invention in whole plasma.

 Cholesterol lipid transfer protein (CETP) plays an important role in lipid metabolism, which catalyzes the transfer of cholesterol lipids from high-density lipoprotein (HDL) to apolipoprotein B (apoB). The principle of CETP inhibitor screening in this experiment is as follows: In the reaction system, the donor molecule containing the fluorescent self-quenching neutral lipid is transferred to the acceptor molecule under the guidance of CETP, thereby losing the inhibition. , causing the system to increase in fluorescence. Inhibition of CETP inhibits lipid transfer, thereby reducing system fluorescence intensity. Reagents and methods

 Compositions using CETP inhibitor screening reagents include: donor molecule, receptor molecule, reaction buffer, rabbit serum (CETP enzyme source).

 Experimental steps:

 1. All test compounds were dissolved in DMSO at a concentration of 1 mM (final reaction concentration 50 uM;).

2. Prepare the reaction system according to the following table, use 200 uL PCR tube, seal and place for 5 minutes.

 Table 1. Mixture 1

3. 将给体分子、 受体分子、 反应缓冲液以 1:1 :2的比例配置适量的混合液， 混匀， 每管 20 uL加到混合物 1中。 密封， 混匀。

3. Configure the donor molecule, the acceptor molecule, and the reaction buffer in an appropriate ratio of 1:1:2. Mix well and add 20 uL per tube to Mix 1. Seal and mix.

 4. Incubate at 37 ° C for 45 minutes.

 5. Pipette 95 uL of the reaction solution into a 96-well plate and measure the fluorescence (excitation wavelength 465 nm; emission wavelength 535 nm).

 The inhibition rate of each compound was calculated by comparing the fluorescence intensities of the tube to be tested and the positive control tube. Activity of the compounds of the invention

 The biochemical activity of the compound of the present invention was measured by the above test, and the ratio of the inhibition ratios measured is shown in the following table.

Claims

Claims: A compound represented by the formula (I), a prodrug thereof or a pharmaceutically acceptable salt thereof:

among them- Each of RR ^{2 is} independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further substituted by one or more substituents selected from the group consisting of a fluorenyl group, an aryl group, a trifluoromethyl group or a heterocycloalkyl group. Replace R ^{3 is} selected from a hydrogen atom, a fluorenyl group, an aryl group, an arylalkyl group or a heteroaryl group, wherein the fluorenyl group, the aryl group, the arylalkyl group or the heteroaryl group is further further selected from one or more selected from halogen or trifluoromethyl. Substituted by a substituent; R ^{4 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, an aryl group, a heteroaryl group or -C(=0)OR ⁷ ; R ^{5 is} selected from the group consisting of a hydrogen atom, a halogen, a fluorenyl group, a cyclodecyl group, a trifluoromethyl group or a -C(=0)OR ⁷ ; R ^{6 is} selected from a hydrogen atom, a halogen, a fluorenyl group, a cyclodecyl group, a trifluoromethyl group, a heterocycloalkyl group, an aryl group, an arylalkyl group or a heteroaryl group, wherein a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, An aryl group, an aryl fluorenyl group, a heteroaryl group is further substituted with one or more substituents selected from the group consisting of a fluorenyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester; R ^{7 is} selected from a hydrogen atom, a decyl group, an alkenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group; n is a b. 2. The compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising:

4. A method of preparing a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:  Multi-substituted pyrrole aldehyde at room temperature, reductive amination to give polysubstituted pyrrole methylamine;

 Under a argon atmosphere, a polysubstituted pyrrole methylamine is cyclized with triphosgene, ruthenium, osmium-diisopropylethylamine to obtain a five- or six-membered cyclic carbamate;

Under the nitrogen atmosphere, the general 5- or 6-membered cyclic carbamate is reacted with a solution of sodium hydride in tetrahydrofuran to react with a halogenated hydrazine to obtain a target compound N substituted by the formula (1). Yuancyclic carbamate compound;

 Wherein: Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. 5. A method of preparing a compound according to claim 1, a prodrug thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of:  a halogen-substituted pyrrolidine ester is heated in methanol with hydroxylamine hydrochloride and sodium acetate to obtain a polysubstituted pyrrolamine ester;

 The hydroxy-substituted arylacetic acid is reacted with methanol and azidotrimethylsilane in benzene at room temperature to obtain a hydroxy-substituted arylethyl ester;  O 0  Ar Ar  OH O OH OH  a hydroxy-substituted arylethyl ester in methylene chloride with carbon tetrabromide, triphenylphosphine to give a bromoarylethyl ester at room temperature;  0 0  Ar Ar  O O OH Br  The polysubstituted pyrrolamine ester is reacted with a bromoarylethyl ester in tetrahydrofuran to give an aryl-substituted pyrrolamine diester;

 The aryl-substituted pyrrolamine diester is reduced in tetrahydrofuran with a solution of lithium aluminum hydrogen in tetrahydrofuran to obtain an aryl-substituted pyrrolamine ester;

Under the protection of nitrogen, the aryl-substituted pyrrolamine ester is cyclized with triphosgene, hydrazine, hydrazine-diisopropylethylamine in dichloromethane to obtain five- and six-membered cyclic carbamate compounds;

Wherein X is a halogen; Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group is further further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, a carboxylic acid or Substituted by a substituent of the carboxylic acid ester. An intermediate for synthesizing the compound of the formula (I) according to claim 1, which is represented by the following structural formula

7. A method of preparing an intermediate according to claim 6, the method comprising the steps of:  An aqueous solution of 4,4,4-trifluoro-3-carbonyl-butyrate and sodium nitrite was reacted in an ice bath to obtain 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyric acid B. The ester, and the reduction of zinc powder with 3-carbonyl-butyric acid-tert-butyl ester in glacial acetic acid to obtain the cyclized product trifluoromethylpyrrole diester;

 Under the protection of argon, trifluoromethylpyrrole diester is reduced in tetrahydrofuran and lithium aluminum hydrogen at room temperature to obtain trifluoromethylpyrrololate;

 Trifluoromethylpyrrololate is oxidized in dichloromethane with pyridinium chlorochromate to give trifluoromethylpyrrolidine ester at room temperature.

8. An intermediate for synthesizing the compound of the formula (I) according to claim 1, which is represented by the following structural formula:

 Where X is a halogen < 9. A process for the preparation of an intermediate according to claim 8, which comprises the steps of: selectively reducing the reaction of trifluoromethylpyrrolediester with trifluoroacetic acid in methylene chloride at room temperature. Fluoromethylpyrrolate;

 : fluoromethylpyrrolate is reacted with a halogen under heating to obtain a halogen-substituted methylpyrrolidone;

 The halogen-substituted methylpyrrolidone is oxidized with cerium nitrate by heating under tetrahydrofuran/water/acetic acid, halogen-substituted pyrrole aldehyde;

 Wherein X is a halogen. 10. An intermediate for synthesizing the compound of the formula (I) according to claim 1, which is represented by the following structural formula:

Wherein X is a halogen. 11. A process for the preparation of an intermediate according to claim 10, which comprises the steps of: trifluoromethylpyrrolidine ester is reduced in trichloromethane with trifluoroacetic acid at room temperature to obtain trifluoromethyl Pyrrolidonic acid;

 Trifluoromethylpyrrolidonic acid is reacted with potassium halide under heating to obtain halotrifluoromethylpyrrolaldehyde;

 Wherein X is a halogen. 12. An intermediate for the synthesis of a compound of the formula (I) according to claim 1, which is represented by the following structural formula:

13. A process for the preparation of an intermediate according to claim 12, which comprises the steps of: reducing the reaction of trifluoromethylpyrrolidonic acid with copper chromite under heating to obtain trifluoromethylpyrrolaldehyde

An intermediate for synthesizing the compound of the formula (I) according to claim 1, which is represented by the following structural formula:

Wherein X is a halogen; Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group is further substituted with one or more fluorenyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by an acid ester. 15. A process for the preparation of an intermediate according to claim 14, which comprises the steps of: substituting a SuZuKi coupling reaction with a halogen-substituted pyrrole aldehyde and an aryl-substituted boric acid under a nitrogen atmosphere to obtain an arylpyrrole aldehyde Ester

 Wherein X is a halogen; Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group is further further substituted by one or more alkyl groups, aryl groups, decyloxy groups, carboxylic acids, carboxylic acids Substituted by ester. 16. An intermediate for the synthesis of a compound of formula (I) as claimed in claim 1, which is represented by the following structural formula:

Wherein I ¹ and R ² are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a trifluoromethyl group or a heterocycloalkane group. Substituted by a substituent. 17. A method of preparing an intermediate according to claim 16, the method comprising the steps of: Under ice salt bath, the substituted aldehyde is nitrated at room temperature to obtain a nitro-substituted compound;

Hydrogenation reduction of nitro compounds to give amino substituted compounds at room temperature

Wherein R> and R ² are each independently selected from a hydrogen atom, an aryl group or a heteroaryl group, wherein the aryl or heteroaryl group is further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a trifluoromethyl group or a heterocyclic ring. Substituted by a thiol group. 18. An intermediate for the synthesis of a compound of formula (I) as claimed in claim 1, which is represented by the following structural formula:

Wherein: A _Γ is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, and the heteroaryl group are further Substituted by one or more substituents selected from alkyl, aryl, alkoxy, carboxylic acid or carboxylic acid esters. 19. A process for the preparation of an intermediate according to claim 18, which comprises the steps of: (S) benzyloxycarbamidopropionic acid in tetrahydrofuran with methoxy-methylamine under nitrogen atmosphere in an ice bath Reductive amination reaction to give a methoxyamino substituted compound in the (S) configuration;

The (S) configuration of the aryl substituted compound is obtained by coupling a methoxyamino substituted compound of the (S) configuration with an aryl bromide in an ice bath under a nitrogen atmosphere;

The (S) configuration aryl substituted compound is reacted with Pd/C to obtain (1R, 2S) aryl substituted propanol at room temperature;

 Wherein: Ar is an aryl group, an aryl fluorenyl group or a heteroaryl group, wherein the aryl group, the aryl fluorenyl group, the heteroaryl group is further further selected from one or more selected from the group consisting of a fluorenyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. 20. An intermediate which synthesizes a compound of the formula (I) according to claim 1 which is represented by the following structural formula:

 Wherein: Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group are further further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a decyloxy group, a carboxylic acid or a carboxylic acid ester. Substituted by a substituent. 21. A process for the preparation of an intermediate according to claim 20, which comprises the steps of: arylation of aryl formaldehyde with sodium hydride and trimethyl iodide at room temperature to obtain an aryl epoxy B-burning

The aryl oxirane is reacted with cyanotrimethylsilyl fluorene in tetrahydrofuran to form a aryl aryl nitrile; O OH  Ar^ ^ Ar^^N Under a nitrogen atmosphere, a hydroxy-substituted arylpropionitrile is reacted with a solution of borane in tetrahydrofuran to obtain a hydroxy-substituted aryl propylamine;  OH OH Ar^^N Ar^^NH ₂ wherein: Ar is an aryl group, an arylalkyl group or a heteroaryl group, wherein the aryl group, the aralkyl group, the heteroaryl group are further selected from one or more selected from the group consisting of an anthracenyl group, an aryl group, and an anthracene group. Substituted by a substituent of an oxy group, a carboxylic acid or a carboxylic acid ester. 22. Use of a composition according to claim 3 in the preparation of a cholesterol ester transfer protein activity inhibitor. 23. Use of a composition according to claim 3 in the manufacture of a medicament for the prevention or treatment of hyperlipidemia. 24. Use of a composition according to claim 3 in the manufacture of a medicament for the prevention or treatment of atherosclerosis. 25. Use of a compound according to claim 1 for the preparation of a cholesterol ester transfer protein activity inhibitor. 26. Use of a compound according to claim 1 for the manufacture of a medicament for the prevention or treatment of hyperlipidemia. 27. Use of a compound according to claim 1 for the manufacture of a medicament for the prevention or treatment of atherosclerosis.