Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• 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.
• 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.
• CETP cholesterol ester transfer protein
• Coronary heart disease 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.
• 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.
• 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.
• LDL-C low density lipoprotein cholesterol
• HDL-C high density lipoprotein cholesterol
• CETP cholesteryl ester transfer protein
• LCAT lecithin-cholesterol acyl transferase
• VLDL VLDL LDL
• 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.
• CETP activity 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.
• statins such as simvastatin (Suppressor @)
• Sircopin @ show significant advances in treatment
• One of the dangers is reduced.
• these statins and fibrates have limited HDL-C levels, and few medical treatments can meet the therapeutic needs.
• 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.
• CETP inhibitors 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.
• 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.
• 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:
• 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
• 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;
• 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 ( ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
• n is as defined in the general formula (I).
• a compound of the formula (I) or formula ( ⁇ ) 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.
• a compound of the formula (I) or formula ( ⁇ ) 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.
• 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.
• 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.
• 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.
• 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 N F ⁇ Factory Z
• 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
• 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);
• Ri ⁇ R 5 , n are as defined in the formula (I).
• 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
• 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.
• 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.
• 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.
• water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
• 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.
• 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.
• a phospholipid such as lecithin
• 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.
• preservatives such as ethylparaben or n-propylparaben
• coloring agents such as ethylparaben or n-propylparaben
• 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.
• 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.
• 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.
• 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.
• the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
• 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.
• sterile fixed oil as a solvent or suspension Floating medium.
• any blended fixed oil including synthetic mono- or diglycerides can be used.
• 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.
• suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
• 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.
• 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.
• 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,
• lower alkyl groups having 1 to 6 carbon atoms 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. ⁇ 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.
• 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 ⁇ -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 ⁇ 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.
• 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 ⁇ -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.
• fused heterocycloalkyl groups include 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.
• 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 ⁇ -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.
• bridge heterocycloalkyl preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
• 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
• 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 ⁇ -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.
• 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.
• 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.
• Haldroxy means an -OH group.
• Hydroalkyl means an alkyl group substituted by a hydroxy group.
• Halogen means fluoro, chloro, bromo or iodo.
• Amino means -NH 2 .
• Neitro means -N0 2 .
• Benzyl refers to -CH 2 - phenyl.
• 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.
• “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.
• 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.
• an imine compound (c) 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.
• the compound (f) 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.
• a reducing agent such as sodium triacetoxyborohydride
• 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
• 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 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).
• ESI FINMGAN LCQAd
• 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.
• 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.
• 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.
• the solution means an aqueous solution.
• reaction temperature is room temperature and is 20 ° C to 30 ° C.
• TLC thin layer chromatography
• 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
• A dichloromethane and methanol systems
• B n-hexane and ethyl acetate systems
• C dichloromethane and acetone
• 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.
• an alkaline or acidic reagent such as triethylamine or acetic acid
• 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.
• 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
• 5 mL of 1,2-dichloroethane were stirred and allowed to react for 16 hours.
• 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
• 5 mL of 1,1-dichloroethane were stirred and allowed to react for 16 hours.
• 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.
• 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.
• 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.
• 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 ⁇ of each gradient compound was mixed and incubated at 37 ° C for 10 minutes. Then, 3 ⁇ of the fluorescent substrate was added, and a total of 100 ⁇ 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.
• the desired concentration gradient eg 8 concentration gradients: 1000 nM, 333.33 nM 111.11 nM 37.03 nM 12.34
• 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.
• Example 2 Example 4, Example 6 and Example 13 compounds.
• 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.
• the pharmacokinetic parameters of the compounds of the invention are as follows:
• the compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

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