WO2014012401A1 - Benzo-seven-member heterocyclic derivative and preparation method of benzo-seven-member heterocyclic derivative and medical application of benzo-seven-member heterocyclic derivative - Google Patents

Description

 Benzo seven-membered heterocyclic derivative, preparation method thereof and application thereof in medicine

Technical field

 The present invention relates to a novel class of benzo seven-membered heterocyclic derivatives, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a cholesterol ester transfer protein (CETP) inhibitor and in the preparation of a therapeutic And use in drugs for preventing diseases such as atherosclerosis. Background technique

 Coronary heart disease (CHD) is a coronary heart disease (CHD) caused by coronary atherosclerosis, sputum and other factors, causing myocardial blood supply, insufficient oxygen supply, angina pectoris and even angina. A disease with clinical symptoms such as myocardial infarction. It is estimated that more than 17 million people die of CHD each year worldwide. This number is still rising as the average age of patients with CHD increases and the incidence of obesity and diabetes increases dramatically. Although many pharmaceutical companies are fiercely competitive in the research and development of coronary heart disease drugs, few time-tested drugs are available. There are many new coronary heart disease drugs in the world that are undergoing clinical trials.

Long-term studies suggest that there is a corresponding relationship between multiple lipoproteins in the mammalian circulatory system and the risk of atherosclerosis and CHD. Epidemiological and clinical trials have also confirmed that dyslipidemia is the most important risk factor for the induction of CHD, and the most critical factor in dyslipidemia is elevated and low density lipoprotein cholesterol (LDL-C) levels. The level of high density lipoprotein cholesterol (HDL-C) is decreased. For coronary artery disease, low levels of HDL-C are an important factor. Increasing HDL-C levels is more likely to reduce coronary artery disease than lowering LDL-C levels. The metabolic control of lipoprotein levels at HDL-C levels as an important pathway to reduce the occurrence of CHD is a complex and dynamic process involving multiple factors. An important metabolic regulatory protein in the human body is the cholesteryl ester transfer protein (CETP), a highly hydrophobic glycoprotein containing 476 amino acids and 45% non-polar amino acids. CETP is expressed in liver, small intestine, spleen, adipose tissue and macrophages. After binding to HDL, free cholesterol is esterified into cholesteryl ester by lecithin-cholesterol acyl transferase (LCAT), transferred to the HDL core, and transferred to very low density lipoprotein by CETP. VLDL) LDL, which is then taken up by liver LDL and VLDL receptors. In this reverse cholesterol transport, CETP promotes the transport of cholesteryl esters from HDL to lipoprotein particles containing apolipoprotein B (apoB), and reverse transport of triglycerides, which is involved in the regulation of plasma lipoprotein cholesterol levels and lipoproteins. Remodeling of particles, the role of CETP in lipoprotein metabolism has received much attention in recent years. In the human body, excess cholesterol in peripheral tissues needs to pass through HDL, transport it back to the liver and further metabolize, and CETP plays a role in this reverse transport process. Many animals do not have the CETP protein, including some animals with high HDL levels and anti-CHD capabilities, such as rodents. There are many natural things about CETP activity. Epidemiological studies of mutations are ongoing, including a few known null mutations. These studies clearly showed a negative correlation between blood HDL-C concentration and CETP activity, and hypothesized that by inhibiting the lipid transfer activity of CETP, increasing HDL-C levels and lowering LDL, and then exerting its effects in humans, it becomes a treatment. A target for CHD.

 Although some statins, such as simvastatin (Suppressor @), show significant advances in treatment, only about three points are achieved in the treatment and prevention of atherosclerosis and subsequent atherosclerotic events. One of the dangers is reduced. At present, these statins and fibrates have limited HDL-C levels, and few medical treatments can meet the therapeutic needs. Clinically, niacin significantly increased HDL-C levels, but patient compliance problems were encountered due to some side effects. Therefore, there is a need to develop a safe and effective drug that significantly improves HDL-C levels and significantly improves blood lipid distribution to meet existing therapeutic needs. The inhibition of CETP is a promising new method for reducing the incidence of atherosclerosis. There are currently no CETP inhibitors on the market, and Pfizer's CETP inhibitor tocherep (the torcetrapib) phase III trial was forced to stop due to serious adverse events. Several pharmaceutical companies are investigating CETP inhibitors or are in clinical trials to find safer and more effective CETP inhibitors.

 A series of patent applications for CETP inhibitors are disclosed, including WO0140190, WO2005037796 WO2007005572 or WO2007041494.

 Although a series of CETP inhibitors for the treatment of atherosclerotic diseases have been disclosed, there is still a need to develop new compounds with better pharmacodynamics. With continuous efforts, the present invention has a structure represented by the general formula (I). The compound and the compound having such a structure were found to exhibit excellent effects and effects. Summary of the invention

 The object of the present invention is to provide a compound represented by the formula (I), and tautomers, mesomers, racemates, enantiomers, diastereomers thereof, Mixture forms and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. as follows:

其巾：

Its towel:

R ^{1 is} selected from heterocycloalkyl or heteroaryl, wherein each of said heterocycloalkyl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, alkyl, haloalkyl, Hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O) NR ⁷ R ⁸ , -S(0) _m R ⁶ -C Substituting (0) a substituent of R ⁶ -OC(0)R ⁶ or -C(0)OR ⁶ ; R ^{2 is} selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected by one or more From halogen, cyano, hydroxy, amino, oxo, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ^{8, -C (O) NR 7} R 8, -S (0) m R 6, -C (0) R 6, -OC (0) R 6 or -C (0) oR ⁶ substituent is substituted;

R is selected from the group consisting of -Cl- ₆ , the base of the base, the -Cl- ₆ , the heterocyclic base, the -C ₆ -based aryl, the -Ci- ₆ , the heteroaryl, the -c _{2 -6} alkenyl ring alkyl, ₂ _ ₆ alkenyl heterocycloalkyl, -C ₂ _ ₆ alkenyl, aryl, or -C ₂ _ ₆ alkenyl heteroaryl, wherein said alkyl -d_ ₆ cycloalkyl, alkoxy -d_ ₆ Heterocycloalkyl, -d- ₆ alkylaryl, -d- ₆ alkylheteroaryl,

_ ₂ -C ₆ alkenyl cycloalkyl, ₂ _ ₆ alkenyl heterocycloalkyl, -C ₂ _ ₆ alkenyl, aryl, or -C ₂ _ ₆ alkenyl heteroaryl are each independently optionally substituted with one or more a plurality selected from halo, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or -CCR ⁶ (C oR ⁶ group is substituted with substituents;

R ⁴ or R ⁵ are each independently selected from a hydrogen atom, halogen, cyano, nitro, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein The alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each, independently, optionally further substituted with one or more substituents selected from hydroxy, halo or alkyl;

R ^{6 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the hetero group The cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, Substituted by a substituent of a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate group;

R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group Or heteroaryl groups, each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycle Substituted by a substituent of an alkyl, aryl, heteroaryl, carboxy or carboxylate group; n is 1, 2 or 3;

m is 0, 1, or 2. In a particular embodiment of the invention, the compound of formula (I) or a tautomer, mesogen, racemate, enantiomer, diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the formula ( Π ) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

 ( I I )

Wherein: ^~11 ⁵ , n is as defined in the general formula (I). In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof Or diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is heteroaryl, wherein said heteroaryl is optionally further selected from one or more selected from alkyl or hydroxy Substituted by a substituent of an alkyl group. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof Or diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is tetrazolyl, wherein said tetrazolyl is further further selected from one or more selected from alkyl or hydroxy The substituent of the alkyl group is substituted, preferably by one or more alkyl groups. In another embodiment of the present invention, a compound of the formula (I) or formula (()) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ or R ⁵ are each independently an alkyl group, preferably an alkyl group having 1 to 6 carbon atoms, more preferably An alkyl group of 1 to 4 carbon atoms, most preferably a methyl group. In another embodiment of the present invention, a compound of the formula (I) or formula (()) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is -d- ₆ alkylaryl, preferably -d- ₆ alkylphenyl, more preferably -d- ₄ alkylphenyl, most preferably a benzyl group, the aryl group -d_ ₆ alkyl optionally further substituted with one or more substituents selected from halo, alkyl, haloalkyl substituents. In another embodiment of the present invention, a compound of the formula (I) or formula (()) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is heterocycloalkyl, wherein said heterocycloalkyl is optionally further And one or more selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(0 Substituting a substituent of NR ⁷ R ⁸ , -C(0)R ⁶ or -C(0)OR ⁶ ;

R ^{6 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a cycloalkyl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group or heterocycloalkyl group are each independently optionally further selected from one or more selected from halogen. Substituted with a substituent of a cyano group, a hydroxy group, an amino group, an alkyl group, an alkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group or a heterocycloalkyl group;

R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group or heterocycloalkyl group are each independently optionally further one or more Substituents selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl or heterocycloalkyl are substituted. In a preferred embodiment of the invention, a compound of the formula (I) or formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl group is a saturated or partially unsaturated 3- to 20-membered single, one or more heteroatoms a cyclic or polycyclic cyclic hydrocarbon substituent; wherein the heterocycloalkyl group is preferably a 3- to 12-membered heterocycloalkyl group, more preferably a 3- to 10-membered heterocycloalkyl group, and most preferably 4 to 6 Monocyclic heterocycloalkyl; wherein the hetero atom is preferably from 1 to 4 heteroatoms selected from nitrogen or oxygen, more preferably from 1 to 2 heteroatoms selected from nitrogen or oxygen. Typical compounds of the invention include, but are not limited to:

N-(3，5-二 (三氟甲基)苄基) -7，9-二甲基 -ΛΚ2-甲基 -2H-四氮唑 -5- 基) 四氢呋喃 -2-基)甲基) -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 -5-胺

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)tetrahydrofuran-2-yl)methyl) -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine

N=N ^F \Factory ^Z

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)sodium-tetrahydrofuran-2-yl) -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine

5-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 ,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)tetrahydro-2H-pyran-2-carboxylic acid

(-4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl -2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidinemethyl formate

( -4-((5-((3，5-二 (三氟甲基)苄基 )(2-甲基 -2H-四氮唑 -5-基)氨基) -7，9-二 甲基 -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓小基)甲基)哌啶小甲酸乙酯 或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合 物形式、 或其可药用的盐。 本发明的另一方面涉及一种制备通式（I )所示的化合物或其互变异构体、 内消 旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的 盐的方法， 该方法

(-4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl -2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidine acetonate or its tautomers, meso, racemic a body, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a compound of the formula (I) or a mutual a method of an isomer, a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method

 ( I-A ) ( l-B) ( I )

 The compound of the formula (I-A) and the compound of the formula (I-B) are subjected to a reduction-reduction reaction with a reducing agent under acidic conditions in a solvent to obtain a compound of the formula (I);

Wherein: Ri~R ⁵ , n are as defined in the formula (I). Further, another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the formula (I) or a tautomer thereof, a mesogen, a foreign body A rot, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof Use of a salt, or a pharmaceutical composition comprising the same, in the preparation of a cholesterol ester transfer protein inhibitor. The cholesterol ester transfer protein inhibitor results in a decrease in LDL-cholesterol. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof a salt, or a pharmaceutical composition comprising the same, as a drug for regulating CETP activity; preferably as a drug for inhibiting CETP activity, wherein Regulation of CETP activity leads to a decrease in LDL-cholesterol. Another aspect of the invention relates to a method of modulating CETP activity, preferably inhibiting CETP activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a foreign body A rot, an enantiomer, a diastereomer, a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The present invention also relates to a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof, Or use of a pharmaceutical composition comprising the same in the manufacture of a medicament for treating or preventing atherosclerosis in a mammal. The present invention also relates to a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for treating or preventing dyslipidemia in a mammal. The present invention also relates to a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof, Or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for lowering plasma LDL-cholesterol levels in a mammal. The present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for increasing plasma HDL-cholesterol levels in a mammal. Another aspect of the invention relates to a method of treating or preventing atherosclerotic disease in a mammal, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof , a racemate, an enantiomer, a diastereomer, a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Another aspect of the invention relates to a method for treating or preventing a dyslipidemia disorder in a mammal, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, Racemate, enantiomer, diastereomer, mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Another aspect of the invention relates to a method of reducing plasma LDL-cholesterol levels in a mammal comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, Racemate, enantiomer, diastereomer, mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Another aspect of the invention relates to a method of increasing plasma HDL-cholesterol levels in a mammal comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, Racemate, enantiomer, diastereomer, mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, as a medicament for treating or preventing atherosclerotic diseases in a mammal. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, as a medicament for treating or preventing arterial dyslipidemia in a mammal. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, as a medicament for lowering plasma LDL-cholesterol levels in a mammal. Another aspect of the invention relates to a compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer, mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, as a medicament for increasing plasma HDL-cholesterol levels in a mammal. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations. The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecyl ethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.

 The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or (X-tocopherol).

 Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of aqueous dispersions in the presence of a dispersible or wetting agent, a suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

 The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

 The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, it is convenient to use sterile fixed oil as a solvent or suspension Floating medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

 The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

 As is well known to those skilled in the art, the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the performance of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt may be Validated according to traditional treatment protocols. Detailed description of the invention

 Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2-methyl-2-ethylpentyl, 2 -methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl , 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Block, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁶ , -NR ⁷ R ⁸ , -C(O) NR ⁷ R ⁸ , -S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0)R ⁶ , -NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0) OR ⁶ .

 "Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains 5 to 6 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

"Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting real

 "Fused cycloalkyl" means 5 to 20 members, each ring of the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic ring, the tricyclic ring, the tetracyclic ring or the polycyclic fused ring alkyl group may be classified according to the number of the constituent rings, and preferably a bicyclic ring or a tricyclic ring, more preferably. Non-limiting examples of fused cycloalkyl groups include

"Bridge cycloalkyl" means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π electronic system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Bridged cycloalkyl

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached The ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, oxo, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0 R ⁶ , -NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

"Heterocycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) _m A hetero atom (where m is an integer of 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein 1 to 4 are heteroatoms; more preferably the heterocycloalkyl ring contains from 3 to 10 ring atoms, and most preferably the heterocycloalkyl ring contains from 4 to 6 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydropyranyl,

 Polycyclic heterocycloalkyl groups include spiro, fused, and bridged heterocycloalkyl groups.

"Spirocycloalkyl" means a polycyclic heterocycloalkyl group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S (0). _m ) (where m is an integer 0 to 2) of a hetero atom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocycloalkyl group is classified into a monospirocycloalkyl group, a dispirocycloalkylene group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a double, depending on the number of shared spiro atoms between the ring and the ring. Spiroheterocycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single example includes

"Fused heterocycloalkyl" means 5 to 20 members, each ring in the system sharing an adjacent pair of atoms of a polycyclic heterocycloalkyl group with other rings in the system, one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) _m (where m is an integer 0 to 2) heteroatoms, and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5- to 5- or 5-membered/6-membered bicyclic fused heterocycloalkane. base. Non-limiting examples of fused heterocycloalkyl groups include

"Bridge heterocycloalkyl" refers to a polycyclic heterocycloalkyl group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings are completely A conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Non-application of bridge heterocycloalkyl:

杂环烷基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或 多个以下基团， 独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤 素、 巯基、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、环烷硫基、杂环烷硫基、氧代、 -OR⁶、 -NR⁷R⁸、 -C(0) NR⁷R⁸, -S(0)_mR⁶ -C(0)R⁶、 -OC(0)R⁶、 -NR⁷C(0)R⁸、 -NR⁷C(0)OR⁸或 -C(0)OR⁶。 The heterocycloalkyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic ring. Non-limiting examples include:

The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkane Thio group, alkylamino group, halogen, fluorenyl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkylthio group ,heterocycloalkylthio,oxo, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ -C(0)R ⁶ , -OC(0 R ⁶ , -NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

 "Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as phenyl. And naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl group.

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, arginyl, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0)R ⁶ , - NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

 "Heteroaryl" means a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen, preferably from 5 to 10 members. The heteroaryl group is preferably a 5- or 6-membered compound such as a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group or the like. The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0)R ⁶ -NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

"Alkoxy" means -CM alkyl) and -CM unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group. Thio group, alkylamino group, sulfonate, fluorenyl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide Alkyl, heterocycloalkylthio, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ , -C(0)R ⁶ , -OC(0) R ⁶ , -NR ⁷ C(0)R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or a butenyl group or the like; preferably a C _{2 -6} alkenyl group, more preferably a C ₂ _ ₄ alkenyl group. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamine Base, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl Base, -OR ⁶ , -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -S(0) _m R ⁶ -C(0)R ⁶ , -OC(0)R ⁶ , -NR ⁷ C (0) R ⁸ , -NR ⁷ C(0)OR ⁸ or -C(0)OR ⁶ .

"-C^alkylcycloalkyl" refers to a d- ₆ alkyl group substituted by a cycloalkyl group, preferably a d- ₄ alkyl group substituted with a cycloalkyl group, more preferably a methylene group substituted with a cycloalkyl group;

"-d_ ₆ alkyl heterocycloalkyl" refers to a heterocycloalkyl group substituted d_ ₆ alkyl group, preferably an alkyl-substituted heterocyclyl d_ ₄ alkyl group, and more preferably a methylene substituted heterocycloalkyl group;

"-d_ ₆ alkyl aryl" refers to an aryl group substituted with d_ ₆ alkyl, preferably substituted by phenyl d_ ₄ alkyl, more preferably phenyl substituted methylene;

"-d_ ₆ alkyl heteroaryl" refers to an aryl-substituted heteroaryl d_ ₆ alkyl, preferably substituted heteroaryl d_ ₄ alkyl group, more preferably a heteroaryl group substituted methylene;

"-C _{2 -6} alkenylcycloalkyl" refers to a c _{2 -6} alkenyl group substituted by a cycloalkyl group, preferably a c ₂ _ ₄ alkenyl group;

_"2 _ ₆ alkenyl heterocycloalkyl" refers to heterocycloalkyl substituted C ₂ _ ₆ alkenyl, preferably C ₂ _ ₄ alkenyl group;

"-C _{2 -6} alkenylaryl" means a c _{2 -6} alkenyl group substituted by an aryl group, preferably a c ₂ _ ₄ alkenyl group;

"-C _{2 -6} alkenylheteroaryl" means a c _{2 -6} alkenyl group substituted by a heteroaryl group, preferably a c ₂ _ ₄ alkenyl group;

 "Haloalkyl" means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. "Haloalkoxy" means an alkoxy group substituted on the alkyl group with one or more halogens.

 "Hydroxy" means an -OH group.

 "Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.

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

"Amino" means -NH ₂ .

 "Cyano" means -CN.

"Nitro" means -N0 ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

 "Oxo" means =0.

 "Carboxy" means -C(0)OH.

 The "carboxylate group" means -C(0)0(alkyl) or (cycloalkyl), wherein the alkyl group and the cycloalkyl group are as defined above. "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocycloalkyl group optionally substituted by alkyl" means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocycloalkyl group is substituted with an alkyl group and the heterocycloalkyl group is not substituted with an alkyl group. The situation of substitution.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond. "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.

m and R ^{6 to} R ⁸ are as defined in the compound of the formula (; I ). Method for synthesizing the compound of the present invention

 In order to accomplish the synthetic purposes of the present invention, the present invention employs the following synthetic technical solutions:

 A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the process comprising:

苯并 [b]氮杂卓甲酸苄酯类化合物 (a)与胺基化合物 (b)在酸性条件下溶剂中反 应得到亚胺化合物 (c)， 亚胺化合物 (c)在溶剂中与还原剂如硼氢化钠反应得到胺基 取代的苯并 [b]氮杂卓类化合物 (d)，胺基取代的苯并 [b]氮杂卓类化合物 (d)与^代化 合物 (e)在碱性条件下溶剂中反应得到化合物 (f)， 化合物 (f)在溶剂中， 催化剂作用 下， 氢化脱保护得到苯并 [b]氮杂卓类化合物 (g)， 苯并 [b]氮杂卓类化合物 (g)与 R¹ 取代甲醛 0 在酸性条件下溶剂中， 与还原剂如三乙酰氧基硼氢化钠反应， 还原胺 化得到通式（I )化合物。 其中 X为卤素； n、 ^〜11⁵的定义如通式（I )中所述。

The benzo[b]azepinecarboxylic acid benzyl ester compound (a) is reacted with the amine compound (b) in a solvent under acidic conditions to obtain an imine compound (c), the imine compound (c) in a solvent and a reducing agent. For example, sodium borohydride is reacted to obtain an amine-substituted benzo[b]azepine compound (d), an amine-substituted benzo[b]azepine compound (d) and a compound (e) in a base. Under the condition of the solvent, the compound (f) is obtained, and the compound (f) is deprotected by hydrogenation under the action of a catalyst to obtain a benzo[b]azepine compound (g), benzo[b]azepine. The compound (g) and the substituted compound of R ^{1 are} reacted with a reducing agent such as sodium triacetoxyborohydride in a solvent under acidic conditions to obtain a compound of the formula (I) by reductive amination. Wherein X is a halogen; and n, ^~11 ⁵ are as defined in the formula (I).

 Agents that provide acidic conditions include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid.

 The alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and tetrabutylene. Ammonium bromide, the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.

 Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1 '-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylideneacetone) dipalladium , palladium / carbon, Raney nickel.

Reducing agents include, but are not limited to, Fe powder, Zn powder, H ₂ , sodium borohydride, sodium triacetoxyborohydride, nitrile Sodium borohydride or lithium aluminum hydride.

 Solvents used include, but are not limited to: toluene, methanol, ethanol, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N, N -dimethylformamide. detailed description

 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions recommended by the original material or the manufacturer of the article. Reagents without specific source are routinely purchased from the market.

 Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10- ⁶ (ppm) a. The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide deuterated chloroform (CDC1 ₃ ), deuterated methanol (CD ₃ OD), and internal standard was tetramethylsilane (CTMS).

 The MS was assayed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

 The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average inhibition rate of the kinase and the IC _5Q value were determined using a NovoStar plate reader (BMG, Germany).

 The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm~0.2 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ~0.5 mm.

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

 The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

 Unless otherwise specified in the examples, the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

 An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

 The pressurized hydrogenation reaction uses a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.

 The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

 The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.

 There is no particular description in the examples, and the solution means an aqueous solution.

 Unless otherwise specified in the examples, the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the body of the developing agent used in the reaction. There are: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and ethyl acetate systems, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

Purification compounds using column chromatography eluent systems and thin layer chromatography developers include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone In the system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment. Example 1

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3, 4, 5 - four

 First step

 (E)-7,9-Dimethyl-5-"2-methyl-2H-tetraazol-5-yl)imide) -2,3,4,5-tetrahydro-1H-benzo[ b] Benzene-1-carboxylate

7,9-Dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine benzyl formate l (56.1 g, 0.17 mol, patented Prepared by the method disclosed in "WO2011002696", 2-methyl-2H-tetrazol-5-amine (25.8 g, 0.26 mol) and 5.2 mL of trifluoroacetic acid (7.89 g, 69 mmol) dissolved in 1 L In toluene, the mixture was heated to 135 ° C, refluxed by a water separator for 6 hours, and further reacted at 110 ° C for 6 days, and the reaction was completed. Obtained crude (E)-7,9-dimethyl-5-((2-methyl-2H-tetrazol-5-yl)imide)-2,3,4,5-tetrahydro-1H- Benzo[b]azepine-1- The reaction solution of benzyl formate lb, which was cooled and used directly in the next step.

 Second step

 7,9-Dimethyl-5-((2-methyl-2H-tetrazol-5-yl)amino)-2,3,4,5-tetrahydro-1H-benzo[b]nitrogen Benzene-1-carboxylic acid benzyl ester

Sodium borohydride (19.6 g, 0.52 mmol) was dissolved in the above crude (E)-7,9-dimethyl-5-((2-methyl-2H-tetrazol-5-yl)imide)- _In the reaction solution of 2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylic acid benzyl ester lb, methanol was slowly added dropwise under ice bath, and the mixture was added dropwise, and stirred at room temperature for 30 minutes. The reaction is complete. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjj -Alkyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylic acid benzyl ester lc (39.9 g, yellow oil), yield: 56.8%.

MS m/z (ESI): 407.2 [M+l]

 third step

 5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3, 4,5-tetrahydrogen

 -1H-benzo[b]azepine-1-benzyl formate

 7,9-Dimethyl-5-((2-methyl-2H-tetrazol-5-yl)amino)-2,3,4,5-tetrahydro-1H-benzo[b] The aza-l-carboxylic acid ester lc (39.9 g, 98 mmol) was dissolved in 300 mL of tetrahydrofuran, stirred for 15 minutes in an ice bath, and sodium hydride (11.8 g, 295 mmol) was added slowly in portions. After stirring for 1 hour in a bath, 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (60.2 g, 196 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of 100 mL of a saturated aqueous solution of ammonium chloride, and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was combined and washed with saturated sodium chloride solution (150 mL) The organic layer was dried (MgSO4), filtered, evaporated, evaporated 2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1 - Benzyl formate Id (27.2 g, yellow oil), Yield: 43.9%.

MS m/z (ESI): 633.2 [M+l]

 the fourth step

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4 ,5-tetrahydro-1H-benzo[b]azepine-5-amine

5-((3,5-Di(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3 , 4,5-tetrahydro-1H-benzo[b]azepine-1-carboxylic acid benzyl ester Id (27.2 g, 43 mmol) dissolved in 250 mL of methanol, palladium on carbon (10%, cat.) The hydrogen was replaced three times, and the reaction was stirred for 16 hours. The reaction mixture was filtered with EtOAc (EtOAc) (EtOAcjjjjjjjjjj bis (trifluoromethyl) benzyl) -7,9-dimethyl -N- (2- methyl--2H- tetrazol-5-yl) - _2, 3,4,5-tetrahydro -1H -Benzo[b]azepine-5-amine le (17.0 g, yellow solid), Yield: 79.4%

 MS m/z (ESI): 499.4 [M+l]

the fifth step 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 ,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid methyl ester N-(3,5-bis(trifluoromethyl) Benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -5-amine le (100 mg, 0.20 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and methyl 4-formylpiperidin-1-carboxylate If (51.51 mg, 0.30 mg, using well-known Method literature "Eur. J. Org. Chem. 2012, 260-263" prepared, stirred for 30 minutes, then added sodium triacetoxyborohydride (84.80 mg, 0.40 mmol), then add 5 drops of acetic acid, stir The reaction was continued for 16 hours. A small amount of potassium carbonate was added to the reaction mixture, stirred for 10 minutes, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjjjjjjjjjj -2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine)methyl) Piperidine methyl formate 1 (40 mg, white solid), Yield: 30.8%.

MS m/z (ESI): 654.3 [M+l]

1H NMR (400 MHz, CDC1 ₃ ): δ 7.81 (s, 3H), 6.92 (s, 1H), 6.56 (s, 1H), 5.64 (s, 1H), 5.19 (s, 1H), 4.88 (d, 1H), 4.21 (t, 2H), 4.16 (s, 3H), 3.74 (s, 1H), 3.72 (s, 3H), 3.24 (d, 2H), 2.95-2.77 (m, 4H), 2.29 (s , 3H), 2.24 (s, 3H), 1.98-1.90 (m, 6H), 1.73-1.71 (m, 2H) Example 2

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -((tetrahydro-2H) -pyridyl

将 N-(3，5-二 (三氟甲基)苄基) -7,9-二甲基 -ΛΚ2-甲基 -2H-四氮唑 -5-基) -2，3，4，5-四 氢 -1H-苯并 [b]氮杂卓 -5-胺 le (150 mg, 0.30 mmol)和四氢 -2H-吡喃 -4-甲醛 2a (399 mg, 3.50 mmol, 采用专利申请 "WO2010021680" 中公开的方法制备而得)溶解于 12 mL l，2-二氯乙烷中， 滴加 5滴醋酸， 搅拌反应 1小时， 再加入三乙酰氧基硼氢 化钠 (160 mg， 0.75 mmol), 搅拌反应 48小时。 加入 50 mL饱和碳酸氢钠溶液淬灭 反应， 分液， 有机相用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 C 纯化所得残余物， 得到标题产物 N-(3，5-二 (三氟甲基)苄基) -7,9-二甲基 -ΛΚ2-甲基 -2H-四氮唑 -5-基) -1-((四氢 -2H-吡 喃 -4-基)甲基) -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 -5-胺 2 (98 mg， 白色固体 产率： 54.8%。

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-2,3,4,5 -tetrahydro-1H-benzo[b]azepine-5-amine le (150 mg, 0.30 mmol) and tetrahydro-2H-pyran-4-carbaldehyde 2a (399 mg, 3.50 mmol, using patent application) Dissolved in the method disclosed in WO2010021680" To 12 mL of 1,2-dichloroethane, 5 drops of acetic acid were added dropwise, and the reaction was stirred for 1 hour, and then sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added, and the reaction was stirred for 48 hours. The reaction was quenched by the addition of 50 mL of EtOAc EtOAc (EtOAc m. The resulting residue was purified to give the title product N-(3,5-di(trifluoromethyl)benzyl)-7,9-dimethyl-indole-2-methyl-2H-tetrazole-5- -1((tetrahydro-2H-pyran-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 2 ( 98 mg, white solid yield: 54.8%.

 MS m/z (ESI): 597.6 [M+l]

1H NMR (400 MHz, CDC1 ₃ ): δ 7.78 (s, 3H), 6.90 (s, 1H), 6.54 (s, 1H), 5.60 (s, 1H), 5.15 (s, 1H), 4.85 (d, 1H), 4.12 (s, 3H), 3.96 (s, 2H), 3.30-3.50 (m, 2H), 3.10-3.30 (m, 2H), 2.80-3.0 (s, 2H), 2.25-2.40 (s, 3H), 2.21 (s, 3H), 1.95 (s, 3H), 1.65-1.94 (m, 3H), 1.55 (s, 3H) Example 3, 4

 (R)-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)- 1 -((tetrahydro-2H-pyran-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine

(-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -((tetrahydro) -2H-

将 N-(3，5-二 (三氟甲基)苄基) -7,9-二甲基 -ΛΚ2-甲基 -2H-四氮唑 -5-基) -1- ((四氢 -2H-吡喃 -4-基)甲基) -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 -5-胺 2 (193 mg， 32 mmol) 进 行手性拆分， 采用 HPLC法， 用制备设备和手性柱对手性异构体进行分离 (分离条 件： 手性柱 CHIRALCEL OZ-H, 流动相： 正己烷： 异丙醇 =98: 2, 流速： 1.5 mL/ 分钟)， 收集其相应组分， 旋转蒸发除去溶剂， 得到标题产物 (R)-N-(3，5-二 (三氟甲 基）苄基 )-7，9-二甲基 -N-(2-甲基 -2H-四氮唑 -5-基 )-1-((四氢 -2H-吡喃 -4-基）甲 基) -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 -5-胺 3 (86 mg， 14 mmol)和 ( -N-(3，5-二 (三氟甲 基）苄基 )-7，9-二甲基 -N-(2-甲基 -2H-四氮唑 -5-基 )-1-((四氢 -2H-吡喃 -4-基）甲 基) -2，3，4，5-四氢 -1H-苯并 [b]氮杂卓 -5-胺 4 (106 mg， 18 mmol)。

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-1-((tetrahydro- 2H-Pyr-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 2 (193 mg, 32 mmol) for chiral demolition Separation by HPLC method using preparative equipment and chiral column chiral isomers (separation conditions: chiral column CHIRALCEL OZ-H, mobile phase: n-hexane: isopropanol = 98: 2, flow rate: 1.5 mL /min), collect the corresponding components, remove the solvent by rotary evaporation to obtain the title product (R)-N-(3,5-di(trifluoromethyl) Benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)- -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 3 (86 mg, 14 mmol) and (-N-(3,5-di(trifluoro) Methyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl) Methyl) -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 4 (106 mg, 18 mmol).

 3: MS m/z (ESI): 597.3 [M+l], retention time 9.335 minutes, ee value > 99.0%.

 4: MS m/z (ESI): 597.3 [M+l] , retention time 11.247 minutes, ee value > 99.0%.

 3: IHNMR (400 MHz, CDC13): δ 7.82 (s, 3H), 6.91 (s, 1H), 6.56 (s, 1H), 5.71 (s, 1H),

5.21 (s, 1H), 4.88 (d, 1H), 4.51 (d, 1H), 4.16 (s, 3H), 3.75 (t, 1H), 3.56-3.51 (m, 3H),

3.24-3.16 (m, 3H), 2.93 (s, 2H), 2.71 (s, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 2.03-1.82 (m,

6H)

 4: IHNMR (400 MHz, CDC13): δ 7.81 (s, 3H), 6.93 (s, 1H), 6.57 (s, 1H), 5.73 (s, 1H), 5.23 (s, lH), 4.88 (d, 1H), 4.20 (d, 1H), 4.18 (s, 3H), 4.00 (s, 1H), 3.46-3.41 (m, 3H), 3.28-3.16 (m, 3H), 2.93 (s, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.20 (s, 1H), 1.99-1.78 (m, 6H) Example 5

 N-(3 bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazole-5-yl)- 1 -((tetrahydrofuran-2-

Tetrahydrofuran-2-carbaldehyde (600 mg, 4.90 mmol), N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-) was added to the reaction flask. Methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (50 mg, 0.10 mmol), triacetyl Sodium oxyborohydride (42 mg, 0.20 mmol) and 5 mL of 1,2-dichloroethane were stirred and allowed to react for 16 hours. Add 10 mL of 1,2-dichloroethane and 10 mL of saturated sodium bicarbonate solution, and separate. The organic phase is washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by thin layer chromatography to afford the title product N-(3,5-di(s) Fluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-1-((tetrahydrofuran-2-yl)methyl)-2 , 3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 5 (12 mg, white solid), yield: 20.6%.

MS m/z (ESI): 583.3 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.82 (t, 3H), 6.91 (s, 1H), 6.65-6.52 (d, 1H), 5.56 (br, 1H), 5.16-4.85 (m, 2H), 4.17 ( s, 3H), 4.10-3.95 (m, 1H), 3.90-3.60 (m, 2H), 3.43-3.30 (m, 1H), 3.26-3.16 (m, 1H), 3.15-3.09 (m, 1H), 3.01-2.85 (m, 1H), 2.34-2.24 (d, 3H), 2.23-2.16 (d, 3H), 2.08-1.92 (m, 3H), 1.90-1.80 (m, 2H), 1.55-1.44 (m , 1H), 1.40-1.22 (m, 2H) Example 6

 N-(3 bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazole-5-yl)- 1 -((tetrahydrofuran -3-

 Tetrahydrofuran-3-carbaldehyde (150 mg, 1.47 mmol), N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-) was added to the reaction flask. Methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (50 mg, 0.10 mmol), triacetyl Sodium oxyborohydride (42 mg, 0.20 mmol) and 5 mL of 1,1-dichloroethane were stirred and allowed to react for 16 hours. Add 10 mL of 1,2-dichloroethane and 10 mL of saturated sodium bicarbonate solution, and separate. The organic phase is washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate and filtered. The resulting residue was purified by EtOAc (EtOAc) elut elut Methyl-2H-tetrazol-5-yl)-1-((tetrahydrofuran-3-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 5-amine 6 (45 mg, white solid), Yield: 77.2%.

MS m/z (ESI): 583.3 [M+l]

1HNMR (400 MHz, CDC13): δ 7.82 (s, 3H), 6.92 (s, 1H), 6.57 (s, 1H), 5.64-5.48 (m, 1H), 5.27-5.10 (m, 1H), 4.98- 4.82 (m, 1H), 4.16 (s, 3H), 3.96-3.72 (m, 3H), 3.64-3.53 (m, 1H), 3.35-3.00 (m, 3H), 2.94-2.83 (m, 1H), 2.58-2.44 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 2.10-1.83 (m, 4H), 1.40-1.23 (m, 2H) Example 7

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3, 4, 5 - four

 First step

4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid benzyl ester N-(3,5-bis(trifluoromethyl) Benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -5-amine le (800 mg, 1.61 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and benzyl 4-formylpiperidine-1-carboxylate 7a (684 mg, 3.22 mmol, using "patent" Application WO2008021375 "Prepared by the disclosed method", after stirring for 30 minutes, sodium triacetoxyborohydride C683 mg, 3.22 mmol) and B 1 mL acetic acid were added, and the reaction was stirred for 16 hours. A small amount of potassium carbonate was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the potassium carbonate was removed by filtration. The filtrate was concentrated under reduced pressure. 3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetra Hydrogen-1H-benzo[b]azepineyl)methyl)piperidine benzyl formate 7b (1.05 g, white solid), yield: 90.5%. MS m/z (ESI): 696.3 [M+l]

 Second step

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)amino)-1- ( Piperidin-4-yl-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 4-((5-((3,5-) (trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzene And [b]azetazinyl)methyl)piperidine benzoic acid benzyl ester 7b (1.05 g, 1.51 mmol) was dissolved in 100 mL of hydrochloric acid in dioxane, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure toieldield of of of of of of of of of of of of of of of of of of of of of of of of Amino)-1-(piperidin-4-yl-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 7c (850 mg, white Solid), the product was used in the next step without purification.

 third step

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 ,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid ethyl ester crude N-(3,5-di(trifluoromethyl) Benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)amino)small (; piperidin-4-yl-methyl)-2,3,4 ,5-tetrahydro-1H-benzo[b]azepine-5-amine 7c (90 mg, 0.15 mmol) and triethylamine (63 mL, 0.45 mmol) dissolved in 10 mL dichloromethane Ethyl formate (33 mg, 0.30 mmol) was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. Methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl Ethyl piperidine ethyl formate 7 (35 mg, white solid), Yield: 34.7%.

MS m/z (ESI): 668.4 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.80-7.81 (m, 3H), 6.94 (s, 1H), 6.58 (s, 1H), 5.65-5.60 (m, 1H), 5.25-5.20 (m, 1H), 4.89-4.85 (m, 1H), 4.16 (s, 3H), 4.19-4.13 (m, 3H), 3.32-3.20 (m, 2H), 3.00-2.97 (m, 2H), 2.82-2.76 (m, 2H ), 2.34 (s, 3H), 2.24 (s, 3H), 2.05-1.61 (m, 10H), 1.31-1.27 (t, 3H) Example 8

 N-(3 bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazole-5-yl)- 1 -(((R)-tetrahydrofuran

 -2-yl)methyl)-2, [b]azepine-5-amine

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl) was added sequentially to the reaction flask. -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (150 mg, 0.30 mmol), (R)-tetrahydrofuran-2-carbaldehyde (150 mg, 1.47 mmol Sodium triacetoxyborohydride (128 mg, 0.60 mmol) and 5 mL of 1,2-dichloroethane were stirred for 16 hours. The mixture was washed with aq. The residue obtained gave the title product N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl. - 1 -(((R)-tetrahydrofuran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 8 (75 mg, Yield of yellow oil: 42.8%.

MS m/z (ESI): 583.3 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.82 (t, 3H), 6.91 (s, 1H), 6.65-6.50 (d, 1H), 5.73-5.45 (m, 1H), 5.15-4.86 (m, 2H), 4.22-4.13 (d, 3H), 4.11-3.96 (m, 1H), 3.91-3.61 (m, 2H), 3.45-3.33 (m, 1H), 3.31-3.20 (m, 1H), 3.17-3.11 (m , 1H), 3.03-2.86 (m, 1H), 2.34-2.26 (d, 3H), 2.25-2.16 (d, 3H), 2.06-1.93 (m, 3H), 1.93-1.78 (m, 3H), 1.63 -1.45 (m, 2H) Example 9

 N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -(((5)- Tetrahydrofuran

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazine was added sequentially to the reaction flask. Zyrid-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (150 mg, 0.30 mmol), (^-tetrahydrofuran-2-carbaldehyde ( 300 mg, 3 mmol), sodium triacetoxyborohydride (128 mg, 0.60 mmol) and 5 mL of 1,2-dichloroethane, stirred for 16 hours. Add 10 mL of dichloromethane with saturated sodium bicarbonate The solution was washed (20 mL×2), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-1-(((-tetrahydrofuran-2-yl)) -2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 9 (105 mg, white solid), yield: 60.0%.

MS m/z (ESI): 583.3 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.82 (t, 3H), 6.91 (s, 1H), 6.65-6.50 (d, 1H), 5.73-5.43 (m, 1H), 5.15-4.84 (m, 2H), 4.22-4.13 (d, 3H), 4.10-3.96 (m, 1H), 3.90-3.61 (m, 2H), 3.44-3.33 (m, 1H), 3.30-3.20 (m, 1H), 3.17-3.10 (m , 1H), 3.01-2.86 (m, 1H), 2.34-2.26 (d, 3H), 2.25-2.16 (d, 3H), 2.05-1.93 (m, 3H), 1.92-1.78 (m, 3H), 1.64 -1.45 (m, 2H) Example 10

 5-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3, 4, 5 - four

 First step

 (6-(iodomethyl)tetrahydro-2H-pyran-3-yl)methanol

Iodine (8.8 g, 35 mmol), sodium bicarbonate (2.9 g, 34 mmol) and 30 mL of B were added sequentially to the reaction flask. a mixed solvent of alcohol and water (V/V = 4:1), and 2-(butyl-3-en-1-yl)propane-1,3-diol 10a 3.0 g, 23 mmol, was added dropwise in an ice water bath. The ethanol solution of the patent application US2007197615 "prepared by the disclosed method" was stirred at room temperature for 16 hours. The mixture was stirred for 10 min. The obtained residue was purified to silicagel elut elut elut elut elut elut elut Yield: 84.7%

 Second step

(5-(Hydroxymethyl)tetrahydro- ² H-pyran- ² -yl)methylacetate (6-(iodomethyl)tetrahydro-2H-pyran-3-yl)methanol 10b (5.0 g, 19.50 mmol), potassium acetate (2.0 g, 19.50 mmol) and 18-crown-6 (515 mg, 1.95 mmol) dissolved in 15 mL of N,N-dimethylformamide, heated to 80 ° C The reaction was stirred for 16 hours. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Liquid), Yield: 54.5%.

MS m/z (ESI): 189.0 [M+l]

 third step

 (5-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)methyl acetate 10c (5-formyltetrahydro-2H-pyran-2-yl)methyl acetate 200 mg, 1.06 mmol) was dissolved in 10 mL of dichloromethane and stirred for 2 hours. The reaction mixture was suction filtered, and the filtrate was evaporated to dryness crystals crystals crystals crystals Purification was used directly in the next step.

 the fourth step

 5-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 ,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)methyl acetate in the reaction bottle Adding N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3, 4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (100 mg, 0.21 mmol), crude (5-formyltetrahydro-2H-pyran-2-yl)methyl Acetate 10d (80 mg, 0.43 mmol), sodium triacetoxyborohydride (137 mg, 0.64 mmol) and 20 mL of 1,2-dichloroethane were stirred at 60 ° C for 16 hours. The reaction mixture was poured into a solution of 20 mL of aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Filtration, and the filtrate was concentrated under reduced pressure. -methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl Methyl)tetrahydro-2H-pyran-2-yl)methyl acetate 10e (70 mg, white solid), yield: 48.6%.

 MS m/z (ESI): 669.3 [M+l]

the fifth step 5-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)methanol was added to the reaction flask in sequence 5-- (5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3, 4,5-tetrahydro-1H-benzo[b]azapine)methyl)tetrahydro-2H-pyran-2-yl)methyl acetate 10e (70 mg, 0.10 mmol), hydrogen A mixed solvent of sodium oxide (12 mg, 0.30 mmol) and 10 mL of methanol and water (V/V = 5:1) was stirred at 50 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjj (benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b] Aza-l-yl)methyl)tetrahydro-2H-pyran-2-yl)methanol 10f (40 mg, pale yellow solid), product was used in the next step without purification.

MS m/z (ESI): 627.3 [M+l]

 Step 6

 5-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)tetrahydro-2H-pyran-2-carboxylic acid was added to the reaction flask in turn to the crude 5-((5- ((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5 -tetrahydro-1H-benzo[b]azapine)methyl)tetrahydro-2H-pyran-2-yl)methanol 10f (40 mg, 64 mmol), sodium hydroxide (0.5 mg, O .Olmmol) and 20 mL of acetonitrile and water (V/V = 5:1) were mixed with a solvent, stirred for 5 minutes, then potassium permanganate (20 mg, 0.13 mmol) was added, and the reaction was stirred for 1 hour. After adding 20 mL of aqueous sodium thiosulfate solution, and extracting with ethyl acetate (30 mL×3), the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. Purification by HPLC to give the title compound (5-((3,5-bis(trifluoromethyl)benzyl) (2-methyl-2H-tetrazole). -5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-yl)methyl)tetrahydro-2H- Pyran-2-carboxylic acid 10 (7.6 mg, white solid), Yield: 18.5%.

MS m/z (ESI): 641.5 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.83-7.81 (m, 3H), 7.06 (s, 1H), 6.73-6.71 (m, 1H), 5.65-5.62 (m, 1H), 5.42-5.38 (m, 1H ), 4.92-4.93 (m, 1H), 4.39-4.27 (m, 1H), 4.18-4.17 (m, 3H), 3.67-3.32 (m, 4H), 2.32 (s, 2H), 2.28 (s, 3H) ), 2.21-2.16 (m, 3H), 1.75-1.53 (m, 9H) Example 11, 12

 (-4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl -2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid methyl ester

(R)-4-((5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-di Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylate

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl- Methyl 2,3,4,5-tetrahydro-1H-benzo[b]azepine)methyl)piperidinecarboxylate 1 (1.38 g, 2.11 mmol) for chiral resolution by HPLC Separation by preparative equipment and chiral column chiral isomers (separation conditions: chiral column CHIRALPAKAD-H, mobile phase: n-hexane: isopropanol = 90: 10, flow rate: 1.0 mL / min), collect it The solvent was removed by rotary evaporation to give the title product (4-((5-(3,5-bis(trifluoromethyl)benzyl)) (2-methyl-2H-tetrazole-5-) Amino)amino-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidinemethyl formate 11 (658 mg , 1.01 mmol) and (R)-4-((5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetraazol-5-yl)amino)) 7,9-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidinemethyl formate 12 (730 mg, 1.12 mmol ).

11: MS m/z (ESI): 654.5 [M+l], retention time 4.486 minutes, ee value > 99.0%.

12: MS m/z (ESI): 654.5 [M+l], retention time 7.145 minutes, ee value > 99.0%.

11: IHNMR (400 MHz, CDC13): δ 7.81 (s, 3H), 6.92 (s, 1H), 6.57 (s, 1H), 5.65-5.64 (m, 1H), 5.22-5.19 (m, 1H), 4.90-4.85 (m, 1H), 4.25-4.20 (m, 1H), 4.16 (s, 3H), 4.08-4.05 (m, 1H), 3.72 (s, 3H), 3.27-3.18 (m, 2H), 2.92-2.90 (m, 2H), 2.82-2.77 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H), 1.98-1.64 (m, 9H)

 12: IHNMR (400 MHz, CDC13): δ 7.81 (s, 3H), 6.92 (s, 1H), 6.57 (s, 1H), 5.65-5.64 (m, 1H), 5.22-5.19 (m, 1H), 4.90-4.85 (m, 1H), 4.25-4.20 (m, 1H), 4.16 (s, 3H), 4.09-4.06 (m, 1H), 3.72 (s, 3H), 3.26-3.16 (m, 2H), 2.92-2.90 (m, 2H), 2.80-2.77 (m, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 1.98-1.60 (m, 9H) Example 13

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)- 1 -(( 1 -(2-methyl-2H-tetrazol-5-yl)piperidin-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine- 5-amine

 First step

 4-formylpiperidine-1-carboxylic acid tert-butyl ester

 4-(Hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.64 mmol, Belling, NO 100275), PCC oxidant (1.5 g, 6.97 mmol), diatomaceous earth (2.0) was added to the reaction flask. g) and 20 mL of dichloromethane, the reaction was stirred for 3 hours. The reaction mixture was filtered and evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

 Second step

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 , 3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester was added to the reaction flask in turn to the crude 4-formylpiperidine tert-Butyl-l-carboxylate 13a (660 mg, 4.64 mmol), N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl- 2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine le (1.4 g, 2.80 mmol), 2 drops of acetic acid (cat .), sodium triacetoxyborohydride (2.0 g, 90 mmol) and 20 mL of 1,2-dichloroethane were stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl) Methyl)piperidine-1-carboxylic acid tert-butyl ester 13b (700 mg, yellow solid), yield: 23.5%.

third step N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-1-(piperidine) 4-(4-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride 4-((5-((3,5-) Bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H- Benzo[b]azetazinyl)methyl)piperidineminic acid tert-butyl ester 13b (700 mg, 1 mmol) was dissolved in 20 mL of dioxane hydrochloride solution and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure toieldield of of of of of of of of of of of of of of of of of of of of of of of of -1-(piperidin-4-yl-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride 13c (600 mg, Yellow oil), the product was used in the next step without purification.

 the fourth step

 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2 ,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carbonitrile crude N-(3,5-bis(trifluoromethyl) Benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-1-(piperidin-4-yl-methyl)-2,3,4,5 -tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride 13c (600 mg, 1 mmol) and sodium bicarbonate (170 mg, 2 mmol) dissolved in 5 mL of ethanol, bromo Formaldehyde (128 mg, 1.20 mmol) was stirred for 8 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl Piperidine small carbonitrile 13d (541 mg, yellow oil), product was used in the next step without purification.

 the fifth step

 1-((1-(2H-tetraazol-5-yl)piperidin-4-yl)methyl)-N-(3,5-bis(trifluoromethyl)benzyl)-7,9- Dimethyl-indole 2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine in the reaction bottle Add the crude 4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl -2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carbonitrile 13d (541 mg, 0.87 mmol), azide The silane (200 mg, 1.70 mmol), triethylamine (260 mg, 2.60 mmol) and 10 mL of tetrahydrofuran were stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj -N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl) -2,3,4 , 5-tetrahydro-1H-benzo[b]azepine-5-amine 13e (200 mg, white solid), yield: 34.6%.

MS m/z (ESI): 664.4 [M+l]

 Step 6

N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -(( 1 -(2) -methyl-2H-tetrazol-5-yl)piperidin-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 1 - "1 -(2H-tetraazol-5-yl)piperidin-4-yl)methyl)-N-(3,5-bis(trifluoromethyl)benzyl)-7,9- Dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 13e ( 100 mg, 0.15 mmol), methyl iodide (0.75 mL, 0.45 mmol) and tetrabutylammonium bromide (9.70 mg, 0.03 mmol) dissolved in 2 mL of dichloromethane, 10% sodium hydroxide dropwise at 0 °C Solution (2.5 mL, 0.45 mmol), stirring at room temperature 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj -ΛΚ2-methyl-2H-tetrazol-5-yl)-1-((1-(2-methyl-2H-tetrazolyl-5-yl)piperidin-4-yl)methyl) - 2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 13 (40 mg, white solid), Yield: 40.0%

MS m/z (ESI): 678.7 [M+l]

 1HNMR (400 MHz, CDC13): δ 7.78 (s, 3H), 6.91 (s, 1H), 6.55 (s, 1H), 5.61-5.51 (m, 1H), 5.31-5.25 (m, 1H), 4.83- 4.79 (m, 1H), 4.24-4.21 (m, 1H), 4.16 (s, 3H), 4.14 (s, 3H) 4.07-4.04 (m, 2H), 2.96-2.86 (m, 3H), 2.34 (s , 3H), 2.22 (s, 3H), 2.1-1.9 (m, 3H), 1.9-1.5 (m, 2H), 1.68-1.52 (m, 6H) Example 14

 (-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -((1- (2-methyl

 First step

(-4-((5-(3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl -2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester 4-formylpiperidine-1-carboxylic acid tert-butyl ester 13a (1.70 g, 7.97 mmol, was prepared in the reaction flask by a known method "Bioorganic & Medicinal Chemistry Letters, 22 (9), 3157-3162; 2012". And), (S)-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene-2-methyl-2H-tetrazol-5-yl) 2,3,4,5-tetrahydro-1 fluorene-benzo[b]azepine-5-amine 14a (2 g, 4 mmol, prepared by the known method patent "US20100331309A1", 2 drops of acetic acid ( The reaction was stirred for 16 hours with sodium triacetoxyborohydride (1.53 g, 7.21 mmol) and 20 mL dichloromethane. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjj (2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1 Methyl)piperidine-1-carboxylic acid tert-butyl ester 14 M 2.53 g, white solid), yield: 91%.

 Second step

 (-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-indole 2-methyl-2H-tetrazol-5-yl)- 1 - (piperidine- 4-yl-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride (-4-((5-((3,5) - bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4,5-tetrahydro-1H -Benzo[b]azetazinyl)methyl)piperidineminic acid tert-butyl ester 14b (2.53 g, 3.64 mmol) was dissolved in 40 mL of dioxane hydrochloride solution and stirred at 0 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness crystals crystals crystalssssssssssssssssss 5-yl)-1-(piperidin-4-yl-methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride 14c (3 g, light yellow solid), product was used in the next step without purification.

 third step

 (5)-4-((5-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-di Methyl

-2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidinecarbonitrile The crude product (-N-(3,5-bis(trifluoromethyl)) Benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-1-(piperidin-4-yl-methyl)-2,3, 4,5-Tetrahydro-1H-benzo[b]azepine-5-amine hydrochloride 14c (2.30 g, 3.64 mmol) was dissolved in 20 mL of ethanol and then sodium hydrogen carbonate (1.10 g, 12.70 mmol) And bromocarbonitrile (0.50 g _: 4.74 mmol), the reaction was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. -((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)-7,9-dimethyl-2,3,4, 5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidinecarbonitrile 14d (2.20 g, yellow solid), yield 97.7%.

 the fourth step

 (-1 -((1 -(2H-tetraazol-5-yl)piperidin-4-yl)methyl)-N-(3,5-bis(trifluoromethyl)benzyl)-7, 9-Dimethyl-hydrazine 2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine

The crude product (-4-((5,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)) was added in the reaction flask. 7,9-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepineyl)methyl)piperidinecarbonitrile 14d (2.20 g, 3.55 mmol), stack Nitrotrimethylsilane (820 mg, 7 mmol), triethylamine (1.10 g, 10 mmol) and 20 mL of tetrahydrofuran were stirred for 16 hours. The reaction was concentrated under reduced pressure. The obtained residue was purified to give the title product (-1-((2-(2H-tetraazol-5-yl)piperidin-4-yl)) -N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2, 3,4,5-Tetrahydro-1H-benzo[b]azepine-5-amine 14e (1.54 g, white solid), Yield: 65.5%.

 the fifth step

 (-N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-anthracene 2-methyl-2H-tetrazol-5-yl)- 1 -((1- (2-methyl-2H-tetrazol-5-yl)piperidin-4-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5 -amine (-l-((l-(2H-tetrazolyl-5-yl)piperidin-4-yl)methyl)-N-(3,5-bis(trifluoromethyl)benzyl) -7,9-Dimethyl-hydrazine 2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-amine 14e (1.54 g, 2.32 mmol), iodomethane (0.44 mL, 6.96 mmol) and tetrabutylammonium bromide (149 mg, 0.46 mmol) were added to 10 mL of dichloromethane and 10% hydr. Sodium solution (278 mg, 6.96 mmol) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjj -ΛΚ2-methyl-2H-tetrazol-5-yl)-1-((1-(2-methyl-2H-tetrazolyl-5-yl)piperidin-4-yl)methyl) - 2,3,4,5-Tetrahydro-1H-benzo[b]azepine-5-amine 14 (1 g, white solid), Yield: 63.7%.

 MS m/z (ESI): 678.6 [M+1]

 1H NMR (400 MHz, CDC13): 1H NMR (400 MHz, CDC13) δ 7.78 (s, 3H), 6.93 (s, 1H), 6.56 (s, 1H), 5.61-5.51 (m, 1H), 5.31-5.25 (m, 1H), 4.83-4.79 (m, 1H), 4.32-4.23 (m, 1H), 4.16 (s, 3H), 4.07-4.05 (m, 3H), 4.05-3.95 (m, 2H), 2.93 -2.89 (m, 3H), 2.40-2.25 (m, 3H), 2.22 (s, 3H), 2.05 (s, 3H), 1.85-1.55 (m, 4H), 1.50-1.25 (m, 4H). Compounds 15-28 can be prepared according to the present invention by the technical scheme of the compound of the formula (I), which are prepared from the appropriate starting compounds in accordance with the synthetic route of Examples 1-14:

测试例：

Test case:

Biological Evaluation Test Example 1 Fluorometric detection of biological activity of CETP inhibitors A fluorogenic substrate is first prepared. BODIPY® FLC12 labeled cholesterol (Molecular Probes, D-3822), cholesterol oleic acid (Sigma C-9253), glycerol trioleate (Sigma T-7140), POPC (l-palmitoyl-2-oleoyl-sn- Glyco-3-phosphocholine, Avanti Polar Lipids 850457) molar percentage 15 : 33: 8: 44 mixed. After purging the original solvent with nitrogen, it was dissolved in dioxane (dioxane, Allied Signal 087-1). Finally, the mixed dioxane solution was slowly added to a 37 ° C 40 kHz ultrasonic water bath buffer (7.4 pH Tris, NaCl, EDTA) with a syringe. The substrate was prepared and stored at 4 ° C (8-month shelf life).

 Plasma is then prepared. Fresh human blood is drawn and centrifuged at 2000 rpm for 10 minutes. The supernatant is stored in a low-temperature refrigerator and thawed in a 37 °C water bath before use. The plasma is clarified and can be removed by centrifugation.

Prior to the experiment, the compound of the invention was diluted with dimethyl sulfoxide to the desired concentration gradient (eg 8 concentration gradients: 1000 nM, 333.33 nM 111.11 nM 37.03 nM 12.34 nM 4.11 nM, 1.37 nM and 0.46 nM), then 96 11 Human plasma, 1 μΐ of each gradient compound was mixed and incubated at 37 ° C for 10 minutes. Then, 3 μΐ of the fluorescent substrate was added, and a total of 100 μΐ of the reaction system was thoroughly mixed and detected by fluorescence: excitation light was 544 nm, and emission light was 595 nm. After incubation for 16 hours at 37 ° C, the fluorescence was detected again. The difference between the two fluorescent signals reflects the activity of CETP in the system, so that the IC _5Q value can be calculated.

结论： 本发明化合物对 CETP具有明显的抑制活性。 药代动力学评价

Conclusion: The compounds of the present invention have significant inhibitory activity against CETP. Pharmacokinetic evaluation

 Test Example 2. Pharmacokinetic test of the compound of the present invention

 1, abstract

 Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compounds of Example 2, Example 4, Example 6 and Example 13 by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.

 2. Test plan

 2.1 Test drugs

 Example 2, Example 4, Example 6 and Example 13 compounds.

 2.2 Test animals

 Healthy adult SD rats, 16 males and females, divided into 4 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

 2.3 Drug preparation

 An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication.

 2.4 Administration

 Sixteen SD rats, male and female, were divided into 4 groups. After fasting overnight, they were intragastrically administered at a dose of 5.0 mg/kg and a dose of 10 ml/kg.

 3, operation

 Rats were administered intragastrically with Example 2, Example 4, Example 6 and Example 13 compounds, before and after administration 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours of blood collection. 0.1 ml, placed in heparinized tubes, centrifuged at 3500 rpm for 5 min to separate plasma, and stored at 20 °C. Eat 2 hours after administration.

 The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method. The linear range of the method was 1.00~2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.

 4, pharmacokinetic parameters results

 The pharmacokinetic parameters of the compounds of the invention are as follows:

 Conclusion: The compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

Claims

 Claims: A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a salt thereof:

Its towel: R ^{1 is} selected from heterocycloalkyl or heteroaryl, wherein each of said heterocycloalkyl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, alkyl, haloalkyl, Hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(O) NR ⁷ R ⁸ , -S(0) _m R ⁶ , - Substituted by a substituent of C(0)R ⁶ , -OC(0)R ⁶ or -C(0)OR ⁶ ; R ^{2 is} selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected by one or more From halogen, cyano, hydroxy, amino, oxo, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ^{8, -C (O) NR 7} R 8, -S (0) m R 6, -C (0) R 6, -OC (0) R 6 or -C (0) oR ⁶ substituent is substituted; R ³ is selected from -D-6 alkylcycloalkyl, - - 6 alkyl heterocycloalkyl, _C6-alkyl aryl, _-D-6 alkylheteroaryl, -C ₂ - ₆ alkenyl, cycloalkyl , -C ₂ - ₆ alkenyl heterocycloalkyl, -C ₂ - ₆ alkenylaryl or -C ₂ - ₆ alkenyl heteroaryl, wherein the ₆ alkylcycloalkyl, -d- ₆ alkyl heterocycloalkyl, _alkyl aryl, _-D-6 alkylheteroaryl, -C ₂ - ₆ alkenyl cycloalkyl, -C ₂ - ₆ alkenyl heterocycloalkyl, -C ₂ - ₆ alkenyl The aryl or -C ₂ - ₆ alkenyl heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, Substituted with alkoxy, haloalkoxy, -OC(0)R ⁶ or -C(0)OR ⁶ substituents; R ⁴ or R ⁵ are each independently selected from a hydrogen atom, halogen, cyano, nitro, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein The alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each, independently, optionally further substituted with one or more substituents selected from hydroxy, halo or alkyl; R ^{6 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the hetero group The cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, Substituted by a substituent of a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxy or carboxylate group; R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group Or heteroaryl groups, each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycle Substituted by a substituent of an alkyl, aryl, heteroaryl, carboxy or carboxylate group; n is 1, 2 or 3;  m is 0, 1, or 2. 2. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, or mixtures thereof,

 ( I I ) Wherein: Ι^~Ι ⁵ , η is as defined in claim 1. 3. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 or 2. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein η is 1. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 3; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is heteroaryl, wherein said heteroaryl is optionally further substituted by one or more substituents selected from alkyl or hydroxyalkyl Replaced. 5. A compound of the formula (I) according to claim 4 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a tetrazolyl group, wherein the tetrazolyl group is optionally further substituted with one or more substituents selected from an alkyl group or a hydroxyalkyl group, preferably Substituted by one or more alkyl groups. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 5; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ or R ⁵ are each independently alkyl. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 6. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is -Ci- ₆ alkylaryl, preferably -d- ₆ alkylphenyl, more preferably -d- ₄ alkyl The phenyl group, most preferably a benzyl group, is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, haloalkyl. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 7. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is heterocycloalkyl, wherein the heterocycloalkyl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NR ⁷ R ⁸ , -C(0) NR ⁷ R ⁸ , -C(0)R ⁶ Substituted by a substituent of -C(0)OR ⁶ ; R ^{6 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a cycloalkyl group or a heterocycloalkyl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group are each independently optionally further one or more selected from halogen Substituted with a substituent of a cyano group, a hydroxyl group, an amino group, an alkyl group, an alkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group or a heterocycloalkyl group; R ⁷ or R ⁸ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group are each independently optionally further one or more Substituted by a substituent selected from the group consisting of halogen, cyano, hydroxy, amino, alkyl, alkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl. The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 8. Isomer, or a mixture thereof, or a drug thereof

 ( l-A ) ( l-B) ( I )  The compound of the formula (I-A) and the compound of the formula (I-B) are subjected to a reduction-reduction reaction with a reducing agent under acidic conditions in a solvent to obtain a compound of the formula (I); Wherein: Ι^~Ι ⁵ , η is as defined in claim 1. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a tautomer thereof, a mesogen, a racemate, a pair The enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients. 12. A compound according to any one of claims 1 to 9 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition according to claim 11 for the preparation of a cholesterol ester transfer protein inhibitor. 13. The use according to claim 12, wherein the cholesterol ester transfer protein inhibitor results in a decrease in LDL-cholesterol. 14. A compound according to any one of claims 1 to 9 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition according to claim 11 for the manufacture of a medicament for treating or preventing atherosclerosis in a mammal. The compound according to any one of claims 1 to 9, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition according to claim 11 for the manufacture of a medicament for treating or preventing dyslipidemia in a mammal. 16. A compound according to any one of claims 1 to 9 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 11 for use in the manufacture of a medicament for lowering plasma LDL-cholesterol levels in a mammal. 17. A compound according to any one of claims 1 to 9 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition according to claim 11 for the manufacture of a medicament for increasing plasma HDL-cholesterol levels in a mammal.