Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • 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
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/22—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/14—Nitrogen atoms not forming part of a nitro radical
• • 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
  • C07D401/02—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 two hetero rings
  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • C07D405/02—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 two hetero rings
  • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• Oxazolidinone derivatives preparation method thereof and application thereof in medicine
• the present invention relates to a novel class of oxazolidinone derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use as therapeutic agents, particularly as cholesterol ester transfer protein (CETP) inhibitors, in the preparation of therapeutic and Use in medicines for preventing diseases such as atherosclerosis.
• CTP 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, the effect in humans becomes therapeutic. 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 torcetrapib phase III clinical trial was forced to stop due to serious adverse events. Several pharmaceutical companies are investigating CETP inhibitors or 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, racemates, enantiomers, diastereomers, mixtures thereof or pharmaceutically acceptable substances thereof. Salts used, as well as metabolites or metabolic precursors or prodrugs.
• A is CH or a nitrogen atom
• R or R 1 are each independently selected from alkyl, cyano, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -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 OR 6 , wherein the alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group Or the heteroaryl groups are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 6 , -NR 7 R 8 , -C(0) NR 7 R -
• R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
• R 3 is selected from a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aryl group or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, and nitro , oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR-NR 7 R 8 , -(CH 2 )pC(0) NR 7
• R 8 , -S(0) m R 6 -C(0)R 6 -OC(0)R 6 or -(CH 2 )pC(0)OR 6 is substituted with a substituent
• R 2 is selected from a hydrogen atom , alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -NR 7 R 8 , -C(O
• R 3 is a cycloalkyl group, wherein the cycloalkyl group is further substituted with one or more substituents of -(CH 2 )pC(0)OR 6 , R 2 is an alkyl group;
• R 4 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group or a halogen;
• R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group or a halogen;
• R 6 is selected from a hydrogen atom, an alkyl group, an alkenyl group, a blocked group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group,
• the cycloalkyl, heterocyclyl, 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, Substituted with a substituent of an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
• R 7 or R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
• the aryl groups 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, cycloalkyl, heterocyclyl, Substituted by a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
• n or z are each independently 1, 2 or 3;
• p 0, 1 or 2;
• 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:
• R, ⁇ 11 5 , A, n, z are 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 a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein: R 3 is a heterocyclic group, wherein the heterocyclic group is further further selected from one or more selected from the group consisting of an alkyl group, Haloalkyl, hydroxyalkyl, -OR 6 , cyclo, heterocyclyl, aryl, heteroaryl, -S(0) 2 R 6 , -C(0)R 6 or -C(0)OR 6 Substituted by a substituent, and R 6 is selected from a hydrogen atom or an alkyl 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 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or -C(0)R 6 , wherein the fluorenyl group or cycloalkyl are each independently optionally further substituted - C oR 6 substituted, and R 6 is selected from a hydrogen atom or an alkyl 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 cycloalkyl, wherein the cycloalkyl group is further further substituted by one or more -(CH 2 )pC ( 0) Substituted by a substituent of OR 6 ; R 6 is selected from a hydrogen atom or an alkyl group; p is 0 or 1; and R 2 is a fluorenyl group.
• 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 heterocyclic group is a saturated or partially unsaturated 3 to 20 membered monocyclic ring containing one or more hetero atoms Or a polycyclic cyclic hydrocarbon substituent; wherein the heterocyclic group is preferably a 3- to 12-membered heterocyclic group, more preferably a 3- to 10-membered heterocyclic group, and most preferably a 5- to 6-membered single ring.
• Heterocyclic group; wherein the hetero atom is preferably from 1 to 4 hetero atoms selected from nitrogen or oxygen, more preferably from 1 to 2 hetero atoms selected from nitrogen or oxygen.
• Typical compounds of the invention include, but are not limited to:
• the invention relates to a general formula (IA)
• A is CH or a nitrogen atom
• R 1 is one or more independently selected from the group consisting of alkyl, cyano, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -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) a substituent of OR 8 or -C OR 6 wherein the alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more Halogen, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -NR 7 R 8 , -C(O) NR 7 R 8 - -S
• R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
• R 3 is selected from a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aryl group or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, and nitro , oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR-NR 7 R 8 , -(CH 2 )pC(0) NR 7
• R 8 , -S(0) m R 6 -C(0)R 6 -OC(0)R 6 or -(CH 2 )pC(0)OR 6 is substituted with a substituent
• R 2 is selected from a hydrogen atom , alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR-NR 7 R 8 , -C(0)NR 7 R ⁇
• R 3 is a cycloalkyl group, wherein the cycloalkyl group is further substituted with one or more substituents of -(CH 2 )pC(0)OR 6 , R 2 is an alkyl group;
• R 6 is selected from a hydrogen atom, an alkyl group, an alkenyl group, a blocked group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group,
• the cycloalkyl, heterocyclyl, 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, Substituted with a substituent of an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
• R 7 or R 8 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
• the aryl groups 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, cycloalkyl, heterocyclyl, Substituted by a substituent of an aryl, heteroaryl, carboxy or carboxylate group;
• n 1, 2 or 3;
• p 0, 1 or 2;
• n 0, 1 or 2;
• X is a leaving group, preferably a halogen.
• Another aspect of the invention relates to a compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer thereof, a method of diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps
• X is a leaving group, preferably a halogen; wherein R, ⁇ 11 5 , A, n, z are as defined in the formula (I).
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer, diastereomer thereof, 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 thereof, a racemate thereof, Use of an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, which is a drug for regulating CETP activity, preferably a drug which inhibits CETP activity, wherein the regulation of CETP activity results in 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 pharmaceutically acceptable salt, enantiomer, diastereomer, or mixture thereof, 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 thereof, or a mixture thereof, or a pharmaceutically acceptable compound thereof Use of a salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment or prevention of 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 thereof, or a mixture thereof, or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment or prevention of 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 thereof, or a mixture thereof, or a pharmaceutically acceptable compound thereof A salt, 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 mesomer, a racemate, an enantiomer, a diastereomer, 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, or a mixture thereof, 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, A racemic form, enantiomer, diastereomer, or a mixture thereof, 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, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
• Another aspect of the invention relates to a method for 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, a racemate, an enantiomer, a diastereomer, or a mixture thereof, 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable 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, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as a medicament for increasing plasma HDL-cholesterol levels in a mammal.
• 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, an alkyl group having 1 to 6 carbon atoms is more preferred, and an alkyl group having 1 to 4 carbon atoms is most preferred.
• Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, U-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl , 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,
• 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 group, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Cycloalkoxy, 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 .
• 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 from 3 to 6 carbon 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. According to the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring. better.
• 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 ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, 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, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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 .
• Heterocyclyl 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 ( Wherein m is a hetero atom of the integer 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 from 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 5 to 6 ring atoms.
• monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
• the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a heterocyclic group of a bridged ring.
• spiroheterocyclyl means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) m A hetero atom (where m is an integer from 0 to 2), 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 spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the rings, preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan Monospirocycloalkyl. Spirocycloalkane
• “Fused heterocyclic group” means 5 to 20 members, each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more a bond, 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 from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• fused heterocyclic groups include
• “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, and these may contain one or more double bonds, but none of the rings have a complete conjugation
• a ⁇ -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. 7 to 10 yuan.
• 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.
• the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group,
• the heterocyclic 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, Thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxygen Generation, -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 .
• 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, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring,
• 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, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
• 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, heterocyclic 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, thiol, 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 .
• alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a C 2 -6 alkenyl group, more preferably a C 2 _ 4 alkenyl group.
• a vinyl group a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, and the like.
• 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, Alkylamino, Halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , -C(0)R 6 , -C(0)OR 6 , -S(0) m R 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -NR 7 C(0)R 8 , -NR 7 S(0) m R 8 or -S(0) m NR 7 R 8 .
• block group refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a C 2 -6 block group, more preferably a C 2 _ 4 block group.
• a C 2 -6 block group preferably a C 2 _ 4 block group.
• the block 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, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, -C(0)R 6 , -C(0)OR 6 , -S(0) m R 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -NR 7 C (0) R 8 , -NR 7 S(0) m R 8 or -S(0) m NR 7 R 8 .
• the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block,
• Alkoxy means -o-(indenyl) and -o-(unsubstituted cycloalkyl), wherein alkyl is 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.
• Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
• Hydrogens means an -OH group.
• Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
• 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.
• Carboxylic acid ester group means -C(0)0(alkyl) or (cycloalkyl), wherein the alkyl group is as defined above.
• the "trifluoromethoxy" methoxy group is substituted by a three fluoro group in the methyl group.
• heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
• 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 are able to determine without much effort (by experimentation). Or theory) may or may not be replaced. 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.
• Method for the compound of the formula (I) or a tautomer, racemate, enantiomer, diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, of the present invention includes the following steps:
• a halogen, a carboxy-substituted compound (a) is reacted with an amino compound (b) in a solvent under basic conditions to give an amino group, a carboxy-substituted compound (c), an amino group, a carboxy-substituted compound (c) in methanol and a chloride
• the sulfone reaction gives a formate compound (d), and the formate compound (d) is reacted with a halogenated compound in a solvent under basic conditions to obtain an amino compound (e), and the amino compound (e) is hydrogenated in a solvent with a reducing agent such as hydrogenation.
• Aluminium lithium is reacted to obtain a methylol compound (i); or a halogen, formyl-substituted compound (f) is reacted with an amino compound (g) in a solvent under basic conditions to obtain an amino group, formyl-substituted compound (h),
• the amino group, formyl substituted compound (h) is reacted with a reducing agent such as sodium borohydride in a solvent to obtain a methylol compound (i).
• methylol compound (i) is reacted with thionyl chloride in a solvent to obtain a compound (0, a compound (0) is reacted with an oxazolone compound (k) in a solvent under basic conditions to obtain a compound of the formula (I).
• X is a leaving group, preferably a halogen, more preferably chlorine; and
• A, n, z, R, Ri ⁇ R 5 are as defined in the formula (I).
• the alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes but is not limited to the six Sodium dialkylamino sodium, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, tetrabutylammonium bromide, said inorganic bases including but not Limited to sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate.
• Reducing agents include, but are not limited to, lithium aluminum hydride or sodium borohydride.
• Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.
• the iodo compound (m) is reacted with the oxazolone compound (k) in a solvent under basic conditions to obtain a compound (n).
• the compound (n) and the amino compound (g) are subjected to catalytic catalysis in a solvent under basic conditions to obtain a compound of the formula CO.
• A, n, z, R, Ri ⁇ R 5 are as defined in the formula (I).
• the alkaline condition reagent includes an organic base and an inorganic base
• the organic base includes, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, and n-butyl Lithium hydride, potassium t-butoxide, tetrabutylammonium 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 or tris(dibenzylideneacetone) dipalladium. .
• Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water. 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).
• MS was measured 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.
• 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, Rui Chemicals and other companies.
• 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.
• the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
• TLC thin layer chromatography
• the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, 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
• 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.
• N-(2-(Chloromethyl)-4-(trifluoromethyl)phenyl)-indoletetrahydro-2H-pyran-4-yl)acetic acid ammonium N-(2-(hydroxymethyl)- 4-(Trifluoromethyl)phenyl)-indoletetrahydro-2H-pyran-4-yl)acetic acid ammonium 9c (63 mg, 0.20 mmol) was dissolved in 1 mL of dichloromethane and then filtered. 26 mg, 0.22 mmol), stirred for 1 hour.
• Lithium hydroxide (42 mg, 1 mmol) was added and the reaction was stirred for 12 hours. 1 M hydrochloric acid was added dropwise. The pH of the reaction mixture was 3 ⁇ 4, and extracted with ethyl acetate (15 mL ⁇ 3).
• Trans-4-((2-(Chloromethyl)-4-(trifluoromethoxy)phenylXethyl)amino)cyclohexylacetate will be trans-4-(ethyl(2-( Hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexylacetate 21c (70 mg, 0.17 mmol) dissolved in 2 mL of N,N-dimethylformamide Sulfoxide (31 mg, 0.26 mmol) was stirred for 2 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2).
• M-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexanoic acid will be trans-4-((2-((4WR)-5-((3,5-bis)) Benzyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethoxy)phenylXethyl)amino)cyclohexylacetate 21e crude (80 mg, 0.11 mmol) dissolved in 5 mL of tetrahydrofuran, added 2 M aqueous solution of lithium hydroxide monohydrate (0.6 mL, 1.10 mmol), and stirred for 12 hours at 30 ° C.
• reaction mixture was quenched by the addition of 10 mL of acetone, and the mixture was evaporated to dryness to remove the solvent, and the mixture was evaporated to ethyl acetate (20 mL) and the organic phase was washed with water (10 mL) and saturated sodium chloride solution (10 mL) Dry over Na2SO4, EtOAc (EtOAc m. Color oil), the product was directly subjected to the next reaction without purification.
• Trans-4-((2-(chloromethyl)-4-methylphenyl)ethyl)amino)cyclohexanacetate will be trans-4-(ethyl(2-(hydroxymethyl))-4- Methyl tolyl)amino)cyclohexanacetate 22d (700 mg, 0.60 mmol) was dissolved in 5 mL of N,N-dimethylformamide, then chlorosulfoxide (107 mg, 0.90 mmol) was added and the reaction was stirred for 1 hour. . 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 2).
• 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)
• the molar percentage is 15:33:8:44.
• dioxane dioxane, Allied Signal 087-1).
• the mixed dioxane solution was slowly added to a 37 ° C 40 kHz ultrasonic bath buffer (7.4 pH Tris, NaCl, EDTA) using a syringe.
• the substrate was prepared and stored at 4 ° C (8-month shelf life).
• Plasma is then prepared. Fresh human blood was drawn and centrifuged at 2000 rpm for 10 minutes. The supernatant was stored in a low-temperature refrigerator and thawed in a 37 °C water bath before use. The plasma was clarified and used, and the flocculent precipitate was 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 ⁇ of each gradient compound was mixed and incubated at 37 ° C for 10 minutes.
• 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
• the compounds of the invention have significant inhibitory activity against CETP. Pharmacokinetic evaluation
• Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compound of Example 2 and the compound of Example 18 by intragastric administration was determined by LC/MS/MS.
• the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
• Example 2 Compound and Example 18 compound.
• Example 2 The compound of Example 2 and the compound of Example 18 were administered by intragastric administration, and 0.1 ml of blood was collected before and 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration, and heparinized.
• the tubes were separated by centrifugation at 3500 rpm for 5 min in a test tube 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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