WO2014012428A1 - Oxazolidinone derivative, preparation method thereof and use thereof in medicine - Google Patents

Oxazolidinone derivative, preparation method thereof and use thereof in medicine Download PDF

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Publication number
WO2014012428A1
WO2014012428A1 PCT/CN2013/078563 CN2013078563W WO2014012428A1 WO 2014012428 A1 WO2014012428 A1 WO 2014012428A1 CN 2013078563 W CN2013078563 W CN 2013078563W WO 2014012428 A1 WO2014012428 A1 WO 2014012428A1
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group
alkyl
trifluoromethyl
aryl
cycloalkyl
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PCT/CN2013/078563
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French (fr)
Chinese (zh)
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杨方龙
董庆
张羚
沈光远
王春飞
应永铖
孙飘扬
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201380004048.3A priority Critical patent/CN103958484B/en
Publication of WO2014012428A1 publication Critical patent/WO2014012428A1/en

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    • 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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Abstract

The present invention relates to an oxazolidinone derivative, the preparation method thereof and the use thereof in medicine. In particular,the present invention relates to a new oxazolidinone derivative of general formula (I), the preparation method thereof and a pharmaceutical composition containing the derivative and the use thereof as a therapeutic agent, in particular the use as a cholesteryl ester transfer protein (CETP) inhibitor and the use for preparing a drug for treating diseases such as atherosis etc, wherein each substituent of general formula (I) is the same as the definition of the description.

Description

噁唑烷酮类衍生物、 其制备方法及其在医药上的应用 技术领域  Oxazolidinone derivatives, preparation method thereof and application thereof in medicine
本发明涉及一类新的噁唑烷酮衍生物、 其制备方法及含有该衍生物的药物组 合物以及其作为治疗剂特别是作为胆固醇酯转移蛋白 (CETP)抑制剂的用途和在制 备治疗和预防动脉粥样硬化等疾病的药物中的用途。 背景技术  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. Background technique
冠状动脉粥样硬化性心脏病简称冠心病 (coronary heart disease, CHD), 是由于 冠状动脉粥样硬化、 痉挛等因素造成的冠状动脉狭窄甚至完全堵塞， 引起心肌供 血、 供氧不足， 导致心绞痛乃至心肌梗死等临床症状的疾病。 据估计， 全球每年 约有 1700多万人死于 CHD， 随着 CHD患病人群平均年龄的增长以及由于肥胖症 和糖尿病的发病率大幅上升， 这个数字仍在不断上升。 虽然众多制药公司在冠心 病药物领域的研发竞争异常激烈， 然而鲜有能接受时间考验的药物问世。 目前全 球有许多新的冠心病药物正在进行临床试验。  Coronary heart disease (CHD) is a coronary heart disease (CHD) caused by coronary atherosclerosis, sputum and other factors, causing myocardial blood supply, insufficient oxygen supply, angina pectoris and even angina. A disease with clinical symptoms such as myocardial infarction. It is estimated that more than 17 million people die of CHD each year worldwide. This number is still rising as the average age of patients with CHD increases and the incidence of obesity and diabetes increases dramatically. Although many pharmaceutical companies are fiercely competitive in the research and development of coronary heart disease drugs, few time-tested drugs are available. There are many new coronary heart disease drugs in the world that are undergoing clinical trials.
长期研究认为， 哺乳动物循环系统中的多种脂蛋白与动脉粥样硬化、 CHD 发 生风险有一种对应关系。 流行病学和临床试验也已证实， 血脂障碍是诱发 CHD的 最重要危险因素， 而血脂障碍中最关键的因素是低密度脂蛋白胆固醇 (low density lipoprotein cholesterol, LDL-C) 水平升高及高密度脂蛋白胆固醇（high density lipoprotein cholesterol, HDL-C)水平降低。 对冠状动脉疾病而言， 低水平的 HDL-C 是一个重要的影响因子， 升高 HDL-C的水平要比降低 LDL-C的水平更能减少冠 脉疾病的发生， 因此近年来把升高 HDL-C水平作为减少 CHD发生的重要途径之 脂蛋白水平的代谢控制是牵涉多种因素的复杂的和动态的过程。人体内一个重 要的代谢调控蛋白是胆固醇酯转运蛋白 (cholesteryl ester transfer protein, CETP), 它是一个高度疏水的糖蛋白， 包含 476个氨基酸， 非极性氨基酸占 45%。 CETP在 肝、 小肠、 脾、 脂肪组织及巨噬细胞中均有表达。 游离胆固醇与 HDL结合后， 被 卵磷脂胆固醇脂酰转移酶 (lecithin-cholesterol acyl transferase, LCAT)酯化成胆固醇 酯， 移入 HDL 核心， 并可通过 CETP 转移给极低密度脂蛋白 (very low density lipoprotein, VLDL) LDL， 再被肝脏 LDL及 VLDL受体摄入肝细胞。 在这一逆向 胆固醇转运中， CETP促进胆固醇酯从 HDL转运到含载脂蛋白 B(apoB)的脂蛋白 颗粒中， 同时逆向转运甘油三脂， 因参与了血浆脂蛋白胆固醇水平的调控和脂蛋 白颗粒的重塑， CETP在脂蛋白代谢中的作用近年来倍受重视。 在人体内， 外周组 织中多余的胆固醇需要通过 HDL, 运送回肝脏并进一步代谢， CETP在这一逆转 运过程中起作用。 许多动物不具备 CETP这种蛋白， 包括一些体内 HDL水平较高 并具备抗 CHD能力动物， 比如啮齿类动物。 现在已有许多关于 CETP活性的自然 变异的流行病学研究正在进行中， 包括已知的少数无效突变。 这些研究清楚地表 明血液 HDL-C浓度和 CETP活性呈负相关关系， 得出假设， 通过抑制 CETP的脂 质转移活性， 提高 HDL- C水平同时降低 LDL， 进而发挥在人体内的效用， 成为 治疗 CHD的一个靶点。 Long-term studies suggest that there is a corresponding relationship between multiple lipoproteins in the mammalian circulatory system and the risk of atherosclerosis and CHD. Epidemiological and clinical trials have also confirmed that dyslipidemia is the most important risk factor for the induction of CHD, and the most critical factor in dyslipidemia is elevated and low density lipoprotein cholesterol (LDL-C) levels. The level of high density lipoprotein cholesterol (HDL-C) is decreased. For coronary artery disease, low levels of HDL-C are an important factor. Increasing HDL-C levels is more likely to reduce coronary artery disease than lowering LDL-C levels. The metabolic control of lipoprotein levels at HDL-C levels as an important pathway to reduce the occurrence of CHD is a complex and dynamic process involving multiple factors. An important metabolic regulatory protein in the human body is the cholesteryl ester transfer protein (CETP), a highly hydrophobic glycoprotein containing 476 amino acids and 45% non-polar amino acids. CETP is expressed in liver, small intestine, spleen, adipose tissue and macrophages. After binding to HDL, free cholesterol is esterified into cholesteryl ester by lecithin-cholesterol acyl transferase (LCAT), transferred to the HDL core, and transferred to very low density lipoprotein by CETP. VLDL) LDL, which is then taken up by liver LDL and VLDL receptors. In this reverse cholesterol transport, CETP promotes the transport of cholesteryl esters from HDL to lipoprotein particles containing apolipoprotein B (apoB), and reverse transport of triglycerides, which is involved in the regulation of plasma lipoprotein cholesterol levels and lipoproteins. Remodeling of particles, the role of CETP in lipoprotein metabolism has received much attention in recent years. In the human body, excess cholesterol in peripheral tissues needs to pass through HDL, transport it back to the liver and further metabolize, and CETP plays a role in this reverse transport process. Many animals do not have the CETP protein, including some animals with high HDL levels and anti-CHD capabilities, such as rodents. There are many natural things about CETP activity. Epidemiological studies of mutations are ongoing, including a few known null mutations. These studies clearly showed a negative correlation between blood HDL-C concentration and CETP activity, and hypothesized that by inhibiting the lipid transfer activity of CETP, increasing HDL-C levels and lowering LDL, the effect in humans becomes therapeutic. A target for CHD.
尽管一些他汀类药物， 如辛伐他汀 (舒降之@)表现出显著的治疗进展， 但在动 脉粥样硬化和随后的动脉粥样硬化性疾病事件的治疗和预防中只实现了大约三分 之一的危险降低。 目前， 这些他汀类和贝特类药物对 HDL-C水平提高有限， 鲜有 药物治疗能够达到治疗需要。 临床显示， 烟酸能明显提高 HDL-C水平， 但由于一 些副作用遇到了患者的依从性问题。 因此， 需要开发一个安全有效的药物， 通过 较好地升高 HDL-C水平， 显著改善血脂分布， 满足现有的治疗需求。 CETP 的抑 制为降低动脉粥样硬化发病率的比较有前途的新方法。 当前尚无 CETP抑制剂药 物上市， Pfizer公司 CETP抑制剂托彻普 (torcetrapib) III期临床试验因严重的不良 反应被迫停止。 有几个制药公司正在研究 CETP抑制剂或者处于临床试验中， 以 寻找更安全、 有效的 CETP抑制剂。  Although some statins, such as simvastatin (Suppressor @), show significant advances in treatment, only about three points are achieved in the treatment and prevention of atherosclerosis and subsequent atherosclerotic events. One of the dangers is reduced. At present, these statins and fibrates have limited HDL-C levels, and few medical treatments can meet the therapeutic needs. Clinically, niacin significantly increased HDL-C levels, but patient compliance problems were encountered due to some side effects. Therefore, there is a need to develop a safe and effective drug that significantly improves HDL-C levels and significantly improves blood lipid distribution to meet existing therapeutic needs. The inhibition of CETP is a promising new method for reducing the incidence of atherosclerosis. There are currently no CETP inhibitors on the market, and Pfizer's CETP inhibitor 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.
目前公开了一系列的 CETP 抑制剂的专利申请， 其中包括 WO0140190、 WO2005037796 WO2007005572或 WO2007041494等。  A series of patent applications for CETP inhibitors are disclosed, including WO0140190, WO2005037796 WO2007005572 or WO2007041494.
尽管目前已公开了一系列的治疗动脉粥样硬化疾病 CETP 抑制剂， 但仍需要 开发新的具有更好的药效的化合物， 经过不断努力， 本发明设计具有通式（I )所示 的结构的化合物， 并发现具有此类结构的化合物表现出优异的效果和作用。 发明内容  Although a series of CETP inhibitors for the treatment of atherosclerotic diseases have been disclosed, there is still a need to develop new compounds with better pharmacodynamics. With continuous efforts, the present invention has a structure represented by the general formula (I). The compound and the compound having such a structure were found to exhibit excellent effects and effects. Summary of the invention
本发明的目的在于提供一种通式（ I )所示的化合物， 以及它们的互变异构体、 外消旋体、 对映异构体、 非对映异构体、 混合物形式或可药用的盐， 以及代谢产 物或代谢前体或前药。  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.
Figure imgf000004_0001
Figure imgf000004_0001
其巾： Its towel:
A为 CH或氮原子；  A is CH or a nitrogen atom;
R或 R1各自独立地选自烷基、 氰基、 烯基、 块基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 - C OR6, 其中所述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基 或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 烷基、 卤 代烷基、 羟烷基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(0) NR7R -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基 所取代； 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 -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 substituent is substituted;
R3选自取代或未取代的环烷基、 杂环基、 芳基或杂芳基； R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
当 R3选自杂环基、 芳基或杂芳基， 其中所述杂环基、 芳基或杂芳基各自独立 地任选进一步被一个或多个选自卤素、 氰基、 羟基、 硝基、 氧代基、 烷基、 卤代 烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、 -OR -NR7R8、 -(CH2)pC(0) NR7R8, -S(0)mR6 -C(0)R6 -OC(0)R6或 -(CH2)pC(0)OR6的取代基所取代时， R2选自氢原 子、 烷基、 烯基、 块基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6， 其中所述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进 一步被一个或多个选自卤素、 氰基、 羟基、 烷基、 卤代烷基、 羟烷基、 环烷基、 杂环基、芳基、杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6 -C(0)R6 -OC(0)R6 -NR7C(0)R8 -NR7C(C OR8或 -C(0)OR6的取代基所取代； When 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 When 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) 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 , wherein Said alkyl, alkenyl, block, cycloalkyl, heterocyclyl, aryl or heteroaryl 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(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(C OR 8 or -C (0) substituted with a substituent of OR 6 ;
当 R3为环烷基， 其中所述环烷基进一步被一个或多个 -(CH2)pC(0)OR6的取代 基所取代时， R2为烷基； When 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;
R4选自氢原子、 烷基、 卤代烷基或卤素； R 4 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group or a halogen;
R5选自氢原子、 烷基、 卤代烷基、 羟基或卤素； R 5 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyl group or a halogen;
R6选自氢原子、 烷基、 烯基、 块基、 羟基、 卤素、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基， 其中所述的烷基、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基各自 独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代； 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;
R7或 R8各自独立地选自氢原子、 烷基、 环烷基、 杂环基、 芳基或杂芳基， 其 中所述的烷基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被一个或 多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代； 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或 z各自独立为 1、 2或 3 ;  n or z are each independently 1, 2 or 3;
p为 0、 1或 2; 且  p is 0, 1 or 2;
m为 0、 1或 2。 在本发明的一个具体实施方案中， 通式（I )所示的化合物或其互变异构体、 内 消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用 的盐为通式（ Π )所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐：
Figure imgf000006_0001
m is 0, 1, or 2. In a particular embodiment of the invention, the compound of formula (I) or a tautomer, mesogen, racemate, enantiomer, diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the formula ( Π ) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a conformation, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
( II )  (II)
其中： R， ^〜115、 A、 n、 z的定义如通式（I )中所定义。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中： R3为杂环基， 其中所述杂环基任选进一步被一个 或多个选自烷基、卤代烷基、羟烷基、-OR6、环 基、杂环基、芳基、杂芳基、 -S(0)2R6、 -C(0)R6或 -C(0)OR6的取代基所取代， 且 R6选自氢原子或烷基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R2选自氢原子、 烷基、 环烷基或 -C(0)R6， 其中所述 浣基或环烷基各自独立地任选进一步被 - C OR6所取代，且 R6选自氢原子或烷基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中： R3为环烷基， 其中所述环烷基进一步被一个或多 个 -(CH2)pC(0)OR6的取代基所取代； R6选自氢原子或烷基； p为 0或 1 ; 且 R2为 焼基。 在本发明的另一个具体实施方案中， 一种通式（ I )或通式（ II )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 A为 CH。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R4为氢原子。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R5为烷基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R1为一个或多个独立地选自烷基、 氰基、 卤代烷基 或卤代烷氧基的取代基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R1为三氟甲基、 三氟甲氧基或氰基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R为一个或多个独立地选自烷基、 氰基、 卤代烷基 或卤代烷氧基的取代基。 在本发明的另一个具体实施方案中， 一种通式（I )或通式（ Π )所示的化合物或 其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物 形式、 或其可药用的盐， 其中 R为三氟甲基或三氟甲氧基。 在本发明的优选实施方案中， 一种通式（ I )或通式（ II )所示的化合物或其互变 异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 其中所述的杂环基为饱和或部分不饱和的 3元至 20元， 含一个 或多个杂原子的单环或多环环状烃取代基； 其中所述的杂环基优选为 3元至 12元 的杂环基， 更优选 3元至 10元的杂环基， 最优选 5元至 6元的单环杂环基； 其中 所述的杂原子优选为 1-4个选自氮或氧的杂原子，更优选为 1-2个选自氮或氧的杂 原子。 本发明的典型化合物包括， 但不限于: Wherein: R, ^~11 5 , A, n, z are as defined in the general formula (I). In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: 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. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein 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. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: 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. In another embodiment of the present invention, a compound of the formula (I) or formula (II) 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 A is CH. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is alkyl. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof thereof, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is one or more substituents independently selected from alkyl, substituted with a cyano group, haloalkyl or haloalkoxy. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is trifluoromethyl, trifluoromethoxy or cyano. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is one or more substituents independently selected from alkyl, cyano, haloalkyl or haloalkoxy. In another embodiment of the present invention, a compound of the formula (I) or formula (Π) or a tautomer, a mesogen, a racemate, an enantiomer thereof a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is trifluoromethyl or trifluoromethoxy. In a preferred embodiment of the invention, a compound of the formula (I) or formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the 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:
实施例编号 化合物结构与命名  Example No. Compound Structure and Nomenclature
1 1
。  .
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 ( -四氢呋喃 -3- 基)氨基) -5- (三氟甲基)苯基)- 4-甲基噁唑 -2-酮
Figure imgf000008_0001
(4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl(-tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzene Base)- 4-methyloxazol-2-one
Figure imgf000008_0001
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁 唑烷 -3-基)甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己甲酸 Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) -4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexanic acid
(4WR)-5-(3，5-双 (三氟甲基)苯 ：基) -3-(2- (乙基 ((R)-四氢呋喃 -3- 基)氨基) -5- (三氟甲基)苯基)- 4-甲基噁唑 -2-酮 (4WR)-5-(3,5-bis(trifluoromethyl)benzene:yl)-3-(2-(ethyl((R)-tetrahydrofuran-3-yl)amino)-5-(trifluoro) Methyl)phenyl)-4-methyloxazol-2-one
。 .
(4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -3-(2-(甲基 (四氢 -2H- 吡喃 -4-基)氨基) -5- (三氟甲基)苯基)噁唑烷 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-(methyl(tetrahydro-2H-pyran-4-yl)amino) -5-(trifluoromethyl)phenyl)oxazolidin-2-one
(4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -3-(2- ((四氢 -2H-吡喃 (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-((tetrahydro-2H-pyran)
-4-基)氨基) -5- (三氟甲基)苯基)噁唑烷 -2-酮  4-yl)amino)-5-(trifluoromethyl)phenyl)oxazolidine-2-one
。 .
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-((2- (乙基 (四氢 -2H-吡 喃 -4-基)氨基) -5-三氟甲基)吡啶 -3-基)甲基)- 4-甲基噁唑 -2-酮 ( 4 WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(( 2 -(ethyl(tetrahydro- 2 H-pyran-4-yl)amino) -5 -trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
Figure imgf000009_0001
唑烷 -3-基)甲基) -5- (三氟甲基)吡啶 -2-基）（四氢 -2H-吡喃 -4-基） 氨基)丙酸乙酯
Figure imgf000009_0001
Ethylzol-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid ethyl ester
(4^5R)-5-(3，5-双 (三氟甲基)苯基) -3-((2- (乙基 (哌啶 -4-基)氨 基) -5- (三氟甲基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 (4^5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Pyridin-3-yl)methyl)-4-methyloxazol-2-one
(4WR)-3-((2-((l-乙酰哌啶 -4-基 X乙基)氨基) -5- (三氟甲基)吡啶 -3-基)甲基) -5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 (4WR)-3-((2-((l-acetylpiperidin-4-yl)ethyl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3 ,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one
(4WR)-3-((2-((l-乙酰哌啶 -4-基 X乙基)氨基) -5- (三氟甲基)吡啶 -3-基)甲基) -5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 (4WR)-3-((2-((l-acetylpiperidin-4-yl)ethyl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3 ,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one
3-((3-(((4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁 唑烷 -3-基)甲基) -5- (三氟甲基)吡啶 -2-基）（四氢 -2H-吡喃 -4-基） 氨基)丙酸 3-((3-((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl) -5-(Trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
物形式、 或其可药用的盐。 本发明涉及一种通式（IA )所 Form, or a pharmaceutically acceptable salt thereof. The invention relates to a general formula (IA)
Figure imgf000012_0002
Figure imgf000012_0002
( I-A )  ( I-A )
可作为合成通式（I )所示的化合物的中间体， 其中： It can be used as an intermediate for synthesizing a compound represented by the general formula (I), wherein:
A为 CH或氮原子；  A is CH or a nitrogen atom;
R1为一个或多个独立地选自烷基、 氰基、 烯基、 块基、 环烷基、 杂环基、 芳 基、杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 - C OR6的取代基， 其中所述烷基、 烯基、 块基、 环烷基、 杂环 基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 烷基、 卤代烷基、羟烷基、环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6 的取代基所取代； 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(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) substituted with a substituent of OR 6 ;
R3选自取代或未取代的环烷基、 杂环基、 芳基或杂芳基； R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
当 R3选自杂环基、 芳基或杂芳基， 其中所述杂环基、 芳基或杂芳基各自独立 地任选进一步被一个或多个选自卤素、 氰基、 羟基、 硝基、 氧代基、 烷基、 卤代 烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、 -OR -NR7R8、 -(CH2)pC(0) NR7R8, -S(0)mR6 -C(0)R6 -OC(0)R6或 -(CH2)pC(0)OR6的取代基所取代时， R2选自氢原 子、烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基、 -OR -NR7R8、 -C(0)NR7R\ -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6， 其中所 述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被 一个或多个选自卤素、 氰基、 羟基、 烷基、 卤代烷基、 羟烷基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8 -NR7C(C OR8或 -C(0)OR6的取代基所取代； When 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 When 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\ -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 , wherein the alkyl group Or an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl , cycloalkyl, heterocyclic, 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 (C oR 8 or -C (0) oR 6 substituent is substituted;
当 R3为环烷基， 其中所述环烷基进一步被一个或多个 -(CH2)pC(0)OR6的取代 基所取代时， R2为烷基； When 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;
R6选自氢原子、 烷基、 烯基、 块基、 羟基、 卤素、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基， 其中所述的烷基、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基各自 独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代； 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;
R7或 R8各自独立地选自氢原子、 烷基、 环烷基、 杂环基、 芳基或杂芳基， 其 中所述的烷基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被一个或 多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代； 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为 1、 2或 3;  n is 1, 2 or 3;
p为 0、 1或 2; 且  p is 0, 1 or 2;
m为 0、 1或 2;  m is 0, 1 or 2;
X为离去基团， 优选为卤素。 本发明的另一方面涉及一种制备根据权利要求 1所述的通式（I )所示的化合物 或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合 物形式、 或其可药用的盐的方法， 该方法包括以下步  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
Figure imgf000013_0001
Figure imgf000013_0001
通式 (I-A)化合物和通式 (I-B)化合物在溶剂中， 碱性条件下反应， 得到通式（I ) 化合物；  The compound of the formula (I-A) and the compound of the formula (I-B) are reacted in a solvent under basic conditions to give a compound of the formula (I);
其中： X为离去基团， 优选为卤素； 其中 R、 ^〜115、 A、 n、 z的定义如通式 ( I )中所定义。 进一步， 本发明的另一方面涉及一种药物组合物， 其含有治疗有效剂量的本 发明化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合 物形式、 或其可药用的盐和可药用的载体、 稀释剂或赋形剂。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物在制备胆固醇酯转移蛋白抑制剂中的用途。 所述的胆固醇酯转移蛋白抑 制剂导致 LDL-胆固醇的减少。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物， 其作为调控 CETP活性的药物， 优选作为抑制 CETP活性的药物， 其中 所述的 CETP活性的调控导致 LDL-胆固醇的减少。 本发明的另一方面涉及一种调控 CETP活性，优选抑制 CETP活性的方法，该 方法包括给予所需患者治疗有效量的通式 （I) 所示的化合物或其互变异构体、 外 消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用盐， 或包含 其的药物组合物。 本发明还涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构 体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药物组合物 在制备治疗或预防哺乳动物动脉粥样硬化的药物中的用途。 本发明还涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构 体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药物组合物， 在制备治疗或预防哺乳动物血脂障碍的药物中的用途。 本发明还涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构 体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药物组合物， 在制备降低哺乳动物血浆 LDL-胆固醇水平的药物中的用途。 本发明还涉及通式（I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物在制备提高哺乳动物血浆 HDL-胆固醇水平的药物中的用途。 本发明的另一方面涉及一种治疗或预防哺乳动物动脉粥样硬化疾病的方法， 该方法包括给予需要治疗的患者有效治疗量的通式 （I) 所示的化合物或其互变异 构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的 盐， 或包含其的药物组合物。 本发明的另一方面涉及一种治疗或预防哺乳动物血脂障碍疾病的方法， 该方 法包括给予需要治疗的患者有效治疗量的通式（I)所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或 包含其的药物组合物。 本发明的另一方面涉及一种降低哺乳动物血浆 LDL-胆固醇水平的方法， 该方 法包括给予需要治疗的患者有效治疗量的通式（I)所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或 包含其的药物组合物。 本发明的另一方面涉及一种提高哺乳动物血浆 HDL-胆固醇水平的方法， 该方 法包括给予需要治疗的患者有效治疗量的通式（I)所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或 包含其的药物组合物。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物， 其作为治疗或预防哺乳动物动脉粥样硬化疾病的药物。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物， 其作为治疗或预防哺乳动物动脉血脂障碍的药物。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物， 其作为降低哺乳动物血浆 LDL-胆固醇水平的药物。 本发明的另一方面涉及通式 （I) 所示的化合物或其互变异构体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 或包含其的药 物组合物， 其作为提高哺乳动物血浆 HDL-胆固醇水平的药物。 发明的详细说明 Wherein: X is a leaving group, preferably a halogen; wherein R, ^~11 5 , A, n, z are as defined in the formula (I). Further, another aspect of the invention relates to 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. Detailed description of the invention
除非有相反陈述， 否则下列用在说明书和权利要求书中的术语具有下述含义。 "烷基 "指饱和的脂族烃基团， 包括 1至 20个碳原子的直链和支链基团。 优 选含有 1至 10个碳原子的烷基， 更优选含有 1至 6个碳原子的烷基， 最优选含有 1至 4个碳原子的烷基。 非限制性实施例包括甲基、 乙基、 正丙基、 异丙基、 正丁 基、 异丁基、 叔丁基、 仲丁基、 正戊基、 U-二甲基丙基、 1，2-二甲基丙基、 2，2- 二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基丁基、 正己基、 1-乙基 -2-甲基丙基、 1，1，2-三甲基丙基、 1，1-二甲基丁基、 1，2-二甲基丁基、 2，2-二甲基丁基、 1，3-二甲基 丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2，3-二甲基丁基、 正庚 基、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2，3-二甲基戊基、 2，4-二 甲基戊基、 2，2-二甲基戊基、 3，3-二甲基戊基、 2-乙基戊基、 3-乙基戊基、 正辛基、 2，3-二甲基己基、 2，4-二甲基己基、 2，5-二甲基己基、 2，2-二甲基己基、 3，3-二甲基己 基、 4，4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己基、 2-甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基、 正壬基、 2-甲基 -2-乙基己基、 2-甲基 -3-乙基己基、 2，2-二乙基 戊基、 正癸基、 3，3-二乙基己基、 2，2-二乙基己基， 及其各种支链异构体等。 更优 选的是含有 1至 6个碳原子的低级烷基， 非限制性实施例包括甲基、 乙基、 正丙 基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1，1-二甲基丙基、 1，2- 二甲基丙基、 2，2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基丁基、 正己基、 1-乙基 -2-甲基丙基、 1，1，2-三甲基丙基、 1，1-二甲基丁基、 1，2-二甲基丁基、 2，2-二 甲基丁基、 1，3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2，3-二甲基丁基等。 烷基可以是取代的或未取代的， 当被取代时， 取代基可以在任 何可使用的连接点上被取代， 优选为一个或多个以下基团， 独立地选自烷基、 烯 基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷 基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 氧代、 -OR6、 -NR7R8、 -C(0) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, 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, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3 ,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-di Methylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2 , 2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Block 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 .
"环烷基"指饱和或部分不饱和单环或多环环状烃取代基， 其包括 3至 20个 碳原子， 优选包括 3至 12个碳原子， 更优选环烷基环包含 3至 10个碳原子， 最 优选环烷基环包含 3至 6个碳原子。 单环环烷基的非限制性实施例包含环丙基、 环丁基、 环戊基、 环戊烯基、 环己基、 环己烯基、 环己二烯基、 环庚基、 环庚三 烯基、 环辛基等。 多环环烷基包括螺环、 稠环和桥环的环烷基。  "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.
"螺环烷基"指 5至 20元， 单环之间共用一个碳原子 (称螺原子)的多环基团， 这些可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子系统。 优选 为 6至 14元， 更优选为 7至 10元。 根据环与环之间共用螺原子的数目将螺环烷 基分为单螺环烷基、 双螺环烷基基或多螺环烷基， 优选为单螺环烷基和双螺环烷 基。 更优选为 4元 /4元、 4元 /5元、 4元 /6元、 5元 /5元或 5元 /6元单螺环烷基。 螺环烷基的非限制性实
Figure imgf000016_0001
"Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting real
Figure imgf000016_0001
"稠环烷基"指 5至 20元， 系统中的每个环与体系中的其他环共享毗邻的一 对碳原子的全碳多环基团， 其中一个或多个环可以含有一个或多个双键， 但没有 一个环具有完全共轭的 π电子系统。 优选为 6至 14元， 更优选为 7至 10元。 根 据组成环的数目可以分为双环、 三环、 四环或多环稠环烷基， 优选为双环或三环， 更优 。 稠环烷基的非限制性实施例包含 "Fused cycloalkyl" means 5 to 20 members, each ring of the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. 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. Non-limiting examples of fused cycloalkyl groups include
Figure imgf000017_0001
Figure imgf000017_0001
"桥环烷基"指 5至 20元， 任意两个环共用两个不直接连接的碳原子的全碳 多环基团， 这些可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子 系统。 优选为 6至 14元， 更优选为 7至 10元。 根据组成环的数目可以分为双环、 三环、 四环或多环桥环烷基， 优选为双环、 三环或四环， 更有选为双环或三环。 桥环烷基的非 "Bridge cycloalkyl" means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π electronic system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Bridged cycloalkyl
Figure imgf000017_0002
Figure imgf000017_0002
所述环烷基环可以稠合于芳基、 杂芳基或杂环烷基环上， 其中与母体结构连接在 一起的环为环烷基， 非限制性实施例包括茚满基、 四氢萘基、 苯并环庚烷基等。 环烷基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多个以 下基团， 独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫 醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷 氧基、 环烷硫基、 杂环烷硫基、 氧代、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 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 .
"杂环基"指饱和或部分不饱和单环或多环环状烃取代基， 其包括 3 至 20 个环原子， 其中一个或多个环原子选自氮、氧或 S(0)m (其中 m是整数 0至 2)的杂 原子， 但不包括 -0-0-、 -0-S-或 -S-S-的环部分， 其余环原子为碳。 优选包括 3 至 12个环原子， 其中 1〜4个是杂原子， 更优选杂环烷基环包含 3至 10个环原子， 最优选杂环烷基环包含 5至 6个环原子。 单环杂环基的非限制性实施例包含吡咯 烷基、 哌啶基、 哌嗪基、 吗啉基、 硫代吗啉基、 高哌嗪基、 吡喃基、 四氢呋喃基 等。 多环杂环基包括螺环、 稠环和桥环的杂环基。 "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. Non-limiting examples of 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.
"螺杂环基"指 5至 20元， 单环之间共用一个原子 (称螺原子)的多环杂环基 团， 其中一个或多个环原子选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂原子， 其余环原子为碳。这些可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子系统。 优选为 6至 14元， 更优选为 7至 10元。 根据环与环之间共用螺原子 的数目将螺环烷基分为单螺杂环基、 双螺杂环基或多螺杂环基， 优选为单螺环烷 基和双螺环烷基。 更优选为 4元 /4元、 4元 /5元、 4元 /6元、 5元 /5元或 5元 /6元 单螺环烷基。 螺环烷 "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
Figure imgf000018_0001
Figure imgf000018_0001
"稠杂环基"指 5至 20元， 系统中的每个环与体系中的其他环共享毗邻的一 对原子的多环杂环基团， 一个或多个环可以含有一个或多个双键， 但没有一个环 具有完全共轭的 π电子系统， 其中一个或多个环原子选自氮、 氧或 S(0)m (其中 m 是整数 0至 2)的杂原子， 其余环原子为碳。 优选为 6至 14元， 更优选为 7至 10 元。 根据组成环的数目可以分为双环、 三环、 四环或多环稠杂环烷基， 优选为双 环或三环， 更优选为 5元 /5元或 5元 /6元双环稠杂环基。 稠杂环基的非限制性实 施例包含 "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 π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5-member/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. . Non-limiting examples of fused heterocyclic groups include
Figure imgf000018_0002
和 。
Figure imgf000018_0002
with.
"桥杂环基"指 5至 14元， 任意两个环共用两个不直接连接的原子的多环杂 环基团， 这些可以含有一个或多个双键， 但没有一个环具有完全共轭的 π 电子系 统， 其中一个或多个环原子选自氮、 氧或 S(0)m (其中 m是整数 0至 2)的杂原子， 其余环原子为碳。 优选为 6至 14元， 更优选为 7至 10元。 7至 10元。 根据组成 环的数目可以分为双环、 三环、 四环或多环桥环烷基， 优选为双环、 三环或四环， 更有选为双环或三环。 桥环烷基的非 施 ：
Figure imgf000018_0003
"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 π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan. 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. Non-application of bridged cycloalkyl groups:
Figure imgf000018_0003
所述杂环基环可以稠合于芳基、 杂芳基或环烷基环上， 其中与母体结构连接在- 起的环为杂环基， 非
Figure imgf000018_0004
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,
Figure imgf000018_0004
等。 杂环基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环 烷氧基、 环烷硫基、 杂环烷硫基、 氧代、 -OR6、 -NR7R8、 -C(O) NR7R8, -S(0)mR6 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 Wait. 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 .
"芳基"指具有共轭的 π电子体系的 6至 14元全碳单环或稠合多环 (也就是共 享毗邻碳原子对的环)基团， 优选为 6至 10元， 例如苯基和萘基。所述芳基环可以 稠合于杂芳基、 杂环基或环烷基环上， 其中与母体结构连接在一起的环为芳基环，  "Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as phenyl. And naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring,
Figure imgf000019_0001
Figure imgf000019_0001
芳基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个以下 基团， 独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、杂环烷硫基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane. Amino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, -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 .
"杂芳基"指包含 1至 4个杂原子， 5至 14个环原子的杂芳族体系， 其中杂 原子包括氧、 硫和氮。 优选为 5至 10元。 杂芳基优选为是 5元或 6元， 例如呋喃 基、 噻吩基、 吡啶基、 吡咯基、 N-烷基吡咯基、 嘧啶基、 吡嗪基、 咪唑基、 四唑 基等。 所述杂芳基环可以稠合于芳基、 杂环基或环烷基环上， 其中与母体结构连 一起的环为杂芳基环， 非限制性实施例包含：  "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:
Figure imgf000019_0002
Figure imgf000019_0002
杂芳基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多个以 下基团， 独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫 醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷 氧基、 环烷硫基、 杂环烷硫基、 -OR6、 -NR7R8、 -C(0) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 The 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 .
术语 "烯基"指由至少由两个碳原子和至少一个碳 -碳双键组成的如上定义的 烷基， 优选 C2_6烯基， 更优选 C2_4烯基。 例如乙烯基、 1-丙烯基、 2-丙烯基、 1-、 2-或 3-丁烯基等。烯基可以是取代的或非取代的， 当被取代时， 取代基优选为一个 或多个以下基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 -C(0)R6、 -C(0)OR6、 -S(0)mR6、 -NR7R8、 -C(0)NR7R8、 -NR7C(0)R8、 -NR7S(0)mR8或 -S(0)mNR7R8。 The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a C 2 -6 alkenyl group, more preferably a C 2 _ 4 alkenyl group. For example, 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 .
术语 "块基"指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的 烷基， 优选 C2_6块基， 更优选 C2_4块基。 例如乙块基、 1-丙块基、 2-丙块基、 1-、 2-或 3-丁块基等。块基可以是取代的或非取代的， 当被取代时， 取代基优选为一个 或多个以下基团， 其独立地选自烷基、 烯基、 块基、 烷氧基、 烷硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 -C(0)R6、 -C(0)OR6、 -S(0)mR6、 -NR7R8、 -C(0)NR7R8、 -NR7C(0)R8、 -NR7S(0)mR8或 -S(0)mNR7R8。 The term "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. For example, an ethyl group, a 1-propyl block group, a 2-propyl block group, a 1-, 2- or 3-butyl group, and the like. 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 .
"烷氧基" 指 -o- (浣基)和 -o- (未取代的环烷基)， 其中烷基的定义如上所述。 非限制性实施例包含甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环丁氧基、 环戊氧基、 环己氧基等。 烷氧基可以是任选取代的或未取代的， 当被取代时， 取 代基优选为一个或多个以下基团， 独立地选自为烷基、 烯基、 块基、 烷氧基、 烷 硫基、 烷基氨基、 卤素、 硫醇、 羟基、 硝基、 氰基、 环烷基、 杂环烷基、 芳基、 杂芳基、 环烷氧基、 杂环烷氧基、 环烷硫基、 杂环烷硫基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6。 "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. Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide Alkyl, heterocycloalkylthio, -OR 6 , -NR 7 R 8 , -C(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 .
"卤代烷基"指烷基被一个或多个卤素取代， 其中烷基的定义如上所述。 "羟基"指 -OH基团。  "Haloalkyl" means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. "Hydroxy" means an -OH group.
"羟烷基"指被羟基取代的烷基， 其中烷基的定义如上所述。  "Hydroxyalkyl" means an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
"卤素"指氟、 氯、 溴或碘。  "Halogen" means fluoro, chloro, bromo or iodo.
"氨基"指 -NH2。 "Amino" means -NH 2 .
"氰基"指 -CN。  "Cyano" means -CN.
"硝基"指 -N02。 "Nitro" means -N0 2 .
"苄基"指 -CH2-苯基。 "Benzyl" refers to -CH 2 - phenyl.
"氧代"指 =0。  "Oxo" means =0.
"羧基"指 -C(0)OH。  "Carboxy" means -C(0)OH.
"羧酸酯基"指 -C(0)0(烷基)或 (环烷基)， 其中烷基的定义如上所述。  "Carboxylic acid ester group" means -C(0)0(alkyl) or (cycloalkyl), wherein the alkyl group is as defined above.
"三氟甲氧基"指甲氧基在甲基被三个氟取代。  The "trifluoromethoxy" methoxy group is substituted by a three fluoro group in the methyl group.
"任选"或 "任选地"意味着随后所描述地事件或环境可以但不必发生， 该 说明包括该事件或环境发生或不发生地场合。例如， "任选被烷基取代的杂环基团" 意味着烷基可以但不必须存在， 该说明包括杂环基团被烷基取代的情形和杂环基 团不被烷基取代的情形。  "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "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. .
"取代的"指基团中的一个或多个氢原子， 优选为最多 5个， 更优选为 1〜3 个氢原子彼此独立地被相应数目的取代基取代。 不言而喻， 取代基仅处在它们的 可能的化学位置， 本领域技术人员能够在不付出过多努力的情况下确定 (通过实验 或理论)可能或不可能的取代。例如， 具有游离氢的氨基或羟基与具有不饱和 (如烯 属)键的碳原子结合时可能是不稳定的。 "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.
"药物组合物"表示含有一种或多种本文所述化合物或其生理学上 /可药用的 盐或前体药物与其他化学组分的混合物， 以及其他组分例如生理学 /可药用的载体 和赋形剂。 药物组合物的目的是促进对生物体的给药， 利于活性成分的吸收进而 发挥生物活性。  "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
m和 R6〜R8的定义如通式（ I )化合物中所述。 本发明化合物的合成方法 m and R 6 to R 8 are as defined in the compound of the formula (I). Method for synthesizing the compound of the present invention
为了完成本发明的目的， 本发明采用如下技术方案：  In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
本发明通式（I )所述的化合物或其互变异构体、 外消旋体、 对映异构体、 非对 映异构体、 或其混合物形式、 或其可药用盐的方法， 该方法包括以下步骤：  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 , the method includes the following steps:
(一)：
Figure imgf000021_0001
(One):
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0002
卤素、 羧基取代的化合物 (a)与氨基化合物 (b)在碱性条件下溶剂中反应得到氨 基、 羧基取代的化合物 (c)， 氨基、 羧基取代的化合物 (c)在甲醇中与氯化亚砜反应 得到甲酸酯化合物 (d)， 甲酸酯化合物 (d)在碱性条件下溶剂中与卤代化合物反应得 到氨基化合物 (e)， 氨基化合物 (e)在溶剂中与还原剂如氢化铝锂反应得到羟甲基化 合物 (i);或者卤素、 甲酰基取代的化合物 (f)在碱性条件下溶剂中，与氨基化合物 (g) 反应得到氨基、 甲酰基取代的化合物 (h)， 氨基、 甲酰基取代的化合物 (h)在溶剂中 与还原剂如硼氢化钠反应得到羟甲基化合物 (i)。进而羟甲基化合物 (i)在溶剂中与氯 化亚砜反应得到化合物 (0， 化合物 (0与噁唑酮类化合物 (k)在碱性条件下溶剂中反 应， 得到通式（I )化合物。 其中 X为离去基团， 优选为卤素， 更优选为氯； A、 n、 z、 R、 Ri〜R5的定义如通式（I )中所述。 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). Further, the 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). Wherein 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).
碱性条件的试剂包括有机碱和无机碱类， 所述的有机碱类包括但不限于六甲 基二硅基胺基钠、 三乙胺、 N，N-二异丙基乙基胺、 正丁基锂、 叔丁醇钾、 四丁基 溴化铵， 所述的无机碱类包括但不限于氢化钠、 碳酸钠、 碳酸氢钠、 碳酸钾、 碳 酸氢钾或碳酸铯。 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.
还原剂包括但不限于氢化铝锂或硼氢化钠。  Reducing agents include, but are not limited to, lithium aluminum hydride or sodium borohydride.
所用溶剂包括但不限于： N，N-二甲基甲酰胺、 甲苯、 醋酸、 甲醇、 乙醇、 四氢 呋喃、 二氯甲烷、 二甲基亚砜、 1，4-二氧六环或水。  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.
(二)：  (2):
Figure imgf000022_0001
Figure imgf000022_0001
碘代化合物 (m)与噁唑酮类化合物 (k)在碱性条件下溶剂中反应， 得到化合物 (n)。 化合物 (n)与氨基化合物 (g)在碱性条件下， 于溶剂中经催化剂催化进行反应， 得到通式 C O化合物。 其中 A、 n、 z、 R、 Ri〜R5的定义如通式（I )中所述。 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. Wherein A, n, z, R, Ri~R 5 are as defined in the formula (I).
碱性条件的试剂包括有机碱和无机碱类， 所述的有机碱类包括但不限于六甲 基二硅基胺基钠、 三乙胺、 N，N-二异丙基乙胺、 正丁基锂、 叔丁醇钾， 四丁基溴 化铵， 所述的无机碱类包括但不限于氢化钠、 碳酸钠、 碳酸氢钠、 碳酸钾、 碳酸 氢钾或碳酸铯。  The alkaline condition reagent includes an organic base and an inorganic base, and the organic base includes, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, and n-butyl Lithium hydride, potassium t-butoxide, tetrabutylammonium bromide, and the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
催化剂包括但不限于四-三苯基膦钯、 二氯化钯、 醋酸钯、 1，1 '-双 (二苄基磷) 二氯二戊铁钯或三 (二亚苄基丙酮)二钯。  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. .
所用溶剂包括但不限于： N，N-二甲基甲酰胺、 甲苯、 醋酸、 甲醇、 乙醇、 四氢 呋喃、 二氯甲烷、 二甲基亚砜、 1，4-二氧六环或水。 具体实施方式  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
以下结合实施例用于进一步描述本发明， 但这些实施例并非限制着本发明的 范围。  The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
本发明实施例中未注明具体条件的实验方法， 通常按照常规条件， 或按照原 料或商品制造厂商所建议的条件。 未注明具体来源的试剂， 为市场购买的常规试 剂。  The experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions recommended by the original material or the manufacturer of the article. Reagents without specific source are routinely purchased from the market.
实施例  Example
化合物的结构是通过核磁共振 (NMR)或 /和质谱 (MS)来确定的。 NMR位移 (δ) 以 10—6 (ppm)的单位给出。 NMR的测定是用 Bruker AVANCE-400核磁仪， 测定溶 剂为氘代二甲基亚砜 氘代氯仿 (CDC13)， 氘代甲醇 (CD3OD)， 内标为四 甲基硅烷 CTMS)。 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的测定用 FINMGAN LCQAd (ESI)质谱仪 (生产商： Thermo,型号： Finnigan LCQ advantage MAX)。 MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦 1200DAD高压液相色谱仪 (Sunfire C18 150x4.6mm色 谱柱)和 Waters 2695-2996高压液相色谱仪 (Gimini C18 150x4.6mm色谱柱）。  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).
激酶平均抑制率及 IC5Q值的测定用 NovoStar酶标仪 (德国 BMG公司）。 The average inhibition rate of the kinase and the IC 5Q value were determined using a NovoStar plate reader (BMG, Germany).
薄层层析硅胶板使用烟台黄海 HSGF254或青岛 GF254硅胶板， 薄层色谱法 (TLC)使用的硅胶板采用的规格是 0.15 mm〜0.2 mm, 薄层层析分离纯化产品采用 的规格是 0.4 mm〜0.5 mm。  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.
柱层析一般使用烟台黄海硅胶 200〜300目硅胶为载体。  Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as a carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买 自 ABCR GmbH & Co. KG、 Acros Organics、 Aldrich Chemical Company 韶远化学 科技 (Accela ChemBio Inc) 、 达瑞化学品等公司。  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.
实施例中无特殊说明， 反应能够均在氩气氛或氮气氛下进行。  Unless otherwise specified in the examples, the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约 1L容积的氩气或氮气气球。  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.
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氢化反应使用 Parr 3916EKX 型氢化仪和清蓝 QL-500 型氢气发生器或 HC2-SS型氢化仪。  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.
氢化反应通常抽真空， 充入氢气， 反复操作 3次。  The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
微波反应使用 CEM Discover-S 908860型微波反应器。  The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.
实施例中无特殊说明， 溶液是指水溶液。  There is no particular description in the examples, and the solution means an aqueous solution.
实施例中无特殊说明， 反应的温度为室温， 为 20°C〜30°C。  Unless otherwise specified in the examples, the reaction temperature is room temperature and is 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法 (TLC)， 反应所使用的展开剂的体 系有： A: 二氯甲烷和甲醇体系， B: 正己烷和乙酸乙酯体系， C: 石油醚和乙酸 乙酯体系， D: 丙酮， 溶剂的体积比根据化合物的极性不同而进行调节。  The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). 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.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括： A: 二 氯甲烷和甲醇体系， B: 正己烷和乙酸乙酯体系， C: 二氯甲烷和丙酮体系， 溶剂 的体积比根据化合物的极性不同而进行调节， 也可以加入少量的三乙胺和醋酸等 碱性或酸性试剂进行调节。 Purification compounds using column chromatography eluent systems and thin layer chromatography developers include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone In the system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
实施例 1  Example 1
(4&5R)-5-(3,5-双 (三氟甲基)苯基) -3-(2- (乙基 四氢呋喃 -3-基)氨基) -5- (三氟甲基) 苯基) - 4-甲基噁唑 -2-酮 (4&5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyltetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)phenyl) - 4-methyloxazol-2-one
Figure imgf000024_0001
第一步
Figure imgf000024_0001
first step
( -2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸 将 2-氟 -5- (三氟甲基)苯甲酸 la (560 mg， 2.70 mmol, 采用公知的方法 "专利 US2009306423"制备而得)溶解于 20 mL N，N-二甲基甲酰胺中， 加入 )-3-氨基四 氢呋喃对甲苯磺酸盐 C700mg， 2.70 mmol)和无水碳酸钾 (1.86 g， 13.50 mmol), 100 °〇搅拌反应 12小时。冷却至室温，滴加 1M盐酸至反应液 pH为 3〜4，加入 20mL 水， 用乙酸乙酯萃取 (30mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (30mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 ( -2- ((四氢呋喃 -3-基)氨 基) -5- (三氟甲基)苯甲酸 lb粗品 (743 mg， 黄色油状物)， 产物不经纯化直接用于下 步反应。  (-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid 2-fluoro-5-(trifluoromethyl)benzoic acid la (560 mg, 2.70 mmol, well known The method "Prepared by the patent US2009306423" is dissolved in 20 mL of N,N-dimethylformamide, and added with 3-aminotetrahydrofuran p-toluenesulfonate C 700 mg, 2.70 mmol) and anhydrous potassium carbonate (1.86 g). , 13.50 mmol), stir the reaction at 100 ° for 12 hours. After cooling to room temperature, 1 M hydrochloric acid was added dropwise to a pH of 3 to 4, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate Filtration and concentration of the filtrate under reduced pressure afforded the title product (2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid lb crude (743 mg, yellow oil) Purified directly for the next step of the reaction.
第二步  Second step
( -2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 将 ( -2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸 lb 粗品 （743 mg， 2.70 mmol)溶解于 15 mL甲醇中， 滴加氯化亚砜 (0.4 mL, 5.40 mmol), 50°C搅拌反应 12小时。 反应液减压浓縮， 加入 20mL水， 用乙酸乙酯萃取 (20mLx2)， 合并有机 相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 ( -2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 lc 粗品 (818 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。 Methyl (-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate (-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl) The crude benzoic acid lb (743 mg, 2.70 mmol) was dissolved in 15 mL of methanol, chlorosulfoxide (0.4 mL, 5.40 mmol) was added dropwise, and the reaction was stirred at 50 ° C for 12 hours. The mixture was extracted with EtOAc (EtOAc EtOAc. The title product (methyl -2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate </RTI> reaction.
MS m/z (ESI): 290.2 [M+l] MS m/z (ESI): 290.2 [M+l]
第三步  third step
(乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯  (ethyl (tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate
将 ( -2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 lc粗品 (818 mg， 2.70 mmol)溶解于 10 mL N，N-二甲基甲酰胺中， 加入氢化钠 (432 mg， 10.80 mmol), 搅 拌反应 1小时， 再加入碘乙烷 (4.20 g， 27 mmol), 继续反应 12小时。 加入 10 mL 水淬灭反应， 滴加 1 M盐酸至反应液 pH为 5〜6， 用乙酸乙酯萃取 (30 mLx3)， 合 并有机相， 用饱和氯化钠溶液洗涤 (30 mLx3)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮，用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物，得到标题产物 ( -2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 Id (400 mg， 淡黄色油状物)， 产率： 40.0%。  The crude methyl (-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate lc (818 mg, 2.70 mmol) was dissolved in 10 mL of N,N-dimethylformamide Add sodium hydride (432 mg, 10.80 mmol), stir the reaction for 1 hour, then add ethyl iodide (4.20 g, 27 mmol), and continue the reaction for 12 hours. Add 10 mL of water to quench the reaction and add 1 M hydrochloric acid. The pH of the reaction mixture was 5~6, and extracted with ethyl acetate (30 mL×3). The organic phase was combined and washed with saturated sodium chloride (30 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained was purified by column chromatography eluting to afford the title product (2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid methyl ester Id (400 mg) , pale yellow oil), Yield: 40.0%.
第四步  the fourth step
(乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯基甲醇  (Ethyl (tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)phenylmethanol
将 ( -2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 Id (331 mg， 1.20 mmol)溶解于 10 mL四氢呋喃中， 加入氢化铝锂 (46 mg， 2.40 mmol), 搅拌反应 1 小时。 向反应液中加入 10 mL饱和氯化铵溶液淬灭反应， 过滤， 用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 得到标题产物 ( -2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基) 苯基甲醇 le粗品 (350 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Methyl (-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate Id (331 mg, 1.20 mmol) was dissolved in 10 mL of THF. 46 mg, 2.40 mmol), stir the reaction for 1 hour. Add 10 mL of saturated ammonium chloride solution to the reaction mixture to quench the reaction, filter, extract with ethyl acetate (30 mL×2), and combine the organic phase with saturated sodium chloride solution After washing (20 mL×2), dried over anhydrous sodium sulfate, EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The crude methanol (350 mg, yellow oil) was used in the next step without purification.
MS m/z (ESI): 290.2 [M+l] MS m/z (ESI): 290.2 [M+l]
第五步  the fifth step
(氯甲基) -4- (三氟甲基)苯基) -N-乙基四氢呋喃 -3-胺  (chloromethyl)-4-(trifluoromethyl)phenyl)-N-ethyltetrahydrofuran-3-amine
将 ( -2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯基甲醇 le粗品 (350 mg， 1.20 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (186 mg， 1.56 mmol), 搅拌反应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (30 mLx2)， 合并有 机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 dN-(2- (氯甲基) -4- (三氟甲基)苯基) 乙基四氢呋喃 -3-胺 If 粗品 (370 mg, 黄色油状物)， 直接用于下步反应。  Dissolve (-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)phenylmethanol le (350 mg, 1.20 mmol) in 5 mL of N,N-dimethyl To the amide, add thionyl chloride (186 mg, 1.56 mmol), and stir the reaction for 1 hour. Add 30 mL of water to the reaction solution, extract with ethyl acetate (30 mL×2), and combine the organic phase with saturated sodium chloride solution After washing (20 mL×2), dried over anhydrous sodium sulfate -Amine If crude (370 mg, yellow oil) was used directly in the next step.
第六步  Step 6
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 (( -四氢呋喃 -3-基)氨基) -5- (三氟 甲基)苯基) - 4-甲基噁唑 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl((-tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)) Phenyl)-4-methyloxazol-2-one
将 dN-(2- (氯甲基) -4- (三氟甲基)苯基) 乙基四氢呋喃 -3-胺 If粗品 (370 mg, 1.20 mmol)溶解于 8 mL N，N-二甲基甲酰胺中， 加入 (4 5 -5-(3，5-双三氟甲基)苯 基)—4-甲基噁唑 -2-酮 lg (340 mg， 1.10 mmol,采用公知的方法"/ owma/ o/Me d Chemistry, 2011,54(13)， 4880-4895"制备而得)和无水碳酸钾 (456 mg， 3.30 mmol), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 10 mL水， 用乙酸乙酯萃取 (20 mLx2) , 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题 产物 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 ( -四氢呋喃 -3-基)氨基) -5- (三氟 甲基)苯基) - 4-甲基噁唑 -2-酮 1 (120 mg， 白色固体)， 产率： 17.2%。 Dissolve dN-(2-(chloromethyl)-4-(trifluoromethyl)phenyl)ethyltetrahydrofuran-3-amine If (370 mg, 1.20 mmol) in 8 mL of N,N-dimethyl To the formamide, (4 5 -5-(3,5-bistrifluoromethyl)phenyl)-4-methyloxazol-2-one lg (340 mg, 1.10 mmol, using a known method) / Owma/ o/Me d Chemistry, 2011, 54(13), 4880-4895 "Prepared" and anhydrous potassium carbonate (456 mg, 3.30 mmol), stirred at 70 ° C for 12 hours. Cooled to room temperature, 10 mL of water was added to the reaction mixture. The organic phase was extracted with ethyl acetate (20 mL×2), washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified to give the title product (4 WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl(-tetrahydrofuran-3-yl)amino) -5-(Trifluoromethyl)phenyl)-4-methyloxazol-2-one 1 (120 mg, white solid), yield: 17.2%.
MS m/z (ESI): 585.2 [M+l] 实施例 2 MS m/z (ESI): 585.2 [M+l] Example 2
反式 -4-((2-W 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲  Trans-4-((2-W 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolium-3-yl)-
Figure imgf000026_0001
Figure imgf000026_0001
第一步  First step
反式 -4- (乙基 (2-甲酰基 -4- (三氟甲基)苯基)氨基)环己甲酸甲酯 将 2-氟 -5- (三氟甲基)苯甲醛 la (576 mg， 3 mmol)和反式 -4- (乙胺)环己甲酸甲 酯 (667 mg， 3.60 mmol, 采用 "专利申请 WO200971509 " 公开的方法制备而得) 溶解于 10 mL甲苯中， 加入无水碳酸钾 C622 mg， 4.50 mmol), 150°C微波下反应 2 小时， 100°C继续搅拌反应 12小时。 过滤， 用乙酸乙酯萃取 (30 mLx2)， 合并有机 相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B 纯化所得残余物， 得到标题产物反式 -4- (乙基 (2- 甲酰基—4- (三氟甲基)苯基)氨基)环己甲酸甲酯 2a (390 mg, 黄色油状物)， 产率： 36.4%。 Trans-4-(ethyl(2-formyl-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylic acid methyl 2-fluoro-5-(trifluoromethyl)benzaldehyde la (576 Methyl, 3 mmol) and trans-4-(ethylamine)cyclohexanecarboxylate (667 mg, 3.60 mmol, prepared by the method disclosed in "Patent Application WO200971509") dissolved in 10 mL of toluene, added anhydrous Potassium carbonate C622 mg, 4.50 mmol), reaction at 150 ° C under microwave 2 The reaction was continued for stirring at 100 ° C for 12 hours. Filtration, extraction with ethyl acetate (30 mL×2), EtOAc (EtOAc) The resulting residue was purified to give the titled product, m.p. 4-(ethyl(2-formyl-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylate 2a (390 mg, yellow oil ()), Yield: 36.4%.
MS m/z (ESI): 358.3 [M+l]  MS m/z (ESI): 358.3 [M+l]
第二步  Second step
反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)环己甲酸甲酯 将反式—4- (乙基 (2-甲酰基 -4- (三氟甲基)苯基)氨基)环己甲酸甲酯 2a (390 mg, 1.09 mmol)溶解于 30 mL乙醇中， 加入硼氢化钠 (50 mg, 1.31 mmol), 搅拌反应 2 小时。 用 10 mL饱和氯化铵溶液淬灭反应， 用乙酸乙酯萃取 (50 mLx2)， 合并有机 相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4- (乙基 (2- (羟甲基 )-4- (三氟甲基)苯基)氨基)环己甲酸甲酯 2b粗 品 (420 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-(ethyl(2-formyl)- Methyl 4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylate 2a (390 mg, 1.09 mmol) was dissolved in 30 mL of ethanol, sodium borohydride (50 mg, 1.31 mmol), and the mixture was stirred for 2 hr. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The title product is obtained as a crude product of -4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylate 2b (420 mg, yellow oil) The product was used in the next step without purification.
MS m/z (ESI): 360.3[M+1] MS m/z (ESI): 360.3 [M+1]
第三步  third step
反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己甲酸甲酯 将反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)环己甲酸甲酯 2b 粗品 (392 mg, 1 mmol)溶解于 25 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (259 mg， 2 mmol), 搅拌反应 4小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己甲酸 甲酯 2c粗品 (460 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-(chloromethyl)-4-(trifluoromethyl)phenyl)ethyl)ethyl)cyclohexanecarboxylic acid methyl trans-4-(ethyl(2-(hydroxy) Methyl)-4-(trifluoromethyl)phenyl)amino)cyclohexanecarboxylic acid methyl ester 2b crude (392 mg, 1 mmol) dissolved in 25 mL of N,N-dimethylformamide Sulfone (259 mg, 2 mmol) was stirred for 4 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. Product title: trans-4-((2-(Chloromethyl)-4-(trifluoromethyl)phenyl)ethyl)ethyl)cyclohexanecarboxylate 2c crude (460 mg, yellow oil) It was used in the next step without purification.
第四步  the fourth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲基)苯基 X乙基)氨基)环己甲酸甲酯 将反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己甲酸甲酯 2c 粗品 (412 mg, 1.09 mmol)溶解于 10 mL N，N-二甲基甲酰胺中， 加入 ( ^，5R)-5-(3，5-双 (三 氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (313 mg, 1 mmol)和无水碳酸钾 (415 mg, 3 mmol), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 10 mL水， 用乙酸乙酯萃取 (50 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B纯化所得残余物， 得到标题产 物反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲 基) -4- (三氟甲基)苯基 X乙基)氨基)环己甲酸甲酯 2d (400 mg, 白色固体)， 产率： 61.1%。  Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl) 4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexanecarboxylic acid methyl trans-4-((2-(chloromethyl)-4-(trifluoromethyl)benzene Base X ethyl)amino)methyl cyclohexanecarboxylate 2c crude (412 mg, 1.09 mmol) was dissolved in 10 mL of N,N-dimethylformamide and (^,5R)-5-(3,5- Bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (313 mg, 1 mmol) and anhydrous potassium carbonate (415 mg, 3 mmol). After cooling to room temperature, 10 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate Concentration, the residue obtained was purified by EtOAc EtOAc (EtOAc) Phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xethyl)amino)methyl cyclohexanecarboxylate 2d (400 mg , white solid), Yield: 61.1%.
MS m/z (ESI): 655.4 [M+l] 第五步 MS m/z (ESI): 655.4 [M+l] the fifth step
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲基)苯基 X乙基)氨基)环己甲酸 将反式 -4-((2-(((4 5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基)—4- (三氟甲基)苯基 X乙基)氨基)环己甲酸甲酯 2d (400 mg， 0.61 mmol)溶解于 25 mL甲醇和水 < /V = 4: l)混合溶剂中， 加入氢氧化锂 (；51 mg， 1.22 mmol), 搅拌 反应 72 小时。 滴加饱和柠檬酸溶液至反应液 pH 为 3〜4， 用乙酸乙酯萃取 (50 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层层析以展开剂体系 B纯化所得残余物， 得到标题产物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟 甲基)苯基 X乙基)氨基)环己甲酸 2 (15 mg， 白色固体)， 产率： 29.7%。  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) 4-(3-trifluoromethyl)phenyl Xethyl)amino)cyclohexanecarboxylic acid trans-4-((2-((4 5R)-5-((3,5 5)-5-(3,5-bis(3) Fluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xethyl)amino)methyl cyclohexanecarboxylate 2d (400 mg, 0.61 mmol) was dissolved in a mixed solvent of 25 mL of methanol and water < /V = 4:1), and lithium hydroxide (51 mg, 1.22 mmol) was added, and the reaction was stirred for 72 hours. The saturated citric acid solution was added dropwise to a pH of 3 to 4, and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure, the residue obtained was purified using EtOAc EtOAc (EtOAc). Phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenylXethyl)amino)cyclohexanecarboxylic acid 2 (15 mg, White solid), Yield: 29.7%.
MS m/z (ESI): 641.4 [M+l] MS m/z (ESI): 641.4 [M+l]
1H NMR (400 MHz, CDC13): δ 7.90 (s, 1H), 7.79 (s, 2H), 7.62 (s, 1H), 7.54 (d, 1H)， 7.26 (d, 1H), 5.74 (d， 1H), 4.80 (d， 1H), 4.56 (d, 1H), 3.98 (t， 1H), 3.15 (t， 2H), 2.72 (t， 1H), 2.30-2.19 (m， 1H), 2.14-2.09 (m， 1H), 2.04-1.99 (m， 1H), 1.88 (t， 1H), 1.55-1.47 (m， 2H), 1.44-1.36 (m， 2H), 0.96-0.93 (m， 4H)， 0.69 (d， 3H) 实施例 3 1H NMR (400 MHz, CDC1 3 ): δ 7.90 (s, 1H), 7.79 (s, 2H), 7.62 (s, 1H), 7.54 (d, 1H), 7.26 (d, 1H), 5.74 (d, 1H), 4.80 (d, 1H), 4.56 (d, 1H), 3.98 (t, 1H), 3.15 (t, 2H), 2.72 (t, 1H), 2.30-2.19 (m, 1H), 2.14-2.09 (m, 1H), 2.04-1.99 (m, 1H), 1.88 (t, 1H), 1.55-1.47 (m, 2H), 1.44-1.36 (m, 2H), 0.96-0.93 (m, 4H), 0.69 (d, 3H) Example 3
(4&5R)-5-i3,5-双 (三氟甲基)苯基) -3-(2- (乙基 i(R)-四氢呋喃 -3-基)氨基) -5- (三氟甲基) 苯基) - 4-甲基噁唑 -2-酮  (4&5R)-5-i3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyli(R)-tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl Phenyl)-4-methyloxazol-2-one
Figure imgf000028_0001
Figure imgf000028_0001
Figure imgf000029_0001
第一步
Figure imgf000029_0001
first step
(R)-2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸 将 2-氟 -5- (三氟甲基)苯甲酸 la (416 mg， 2 mmol)溶解于 4 mL N，N-二甲基甲酰 胺中， 加入 (； R)-3-氨基四氢呋喃盐酸盐 (247 mg， 2 mmol)和无水碳酸钾 (1.38 g， 10 mmol), 置于封管中， 100°C搅拌反应 12小时。 冷却至室温， 滴加 1 M盐酸至反应 液 pH为 3〜4， 加入 20 mL水， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和 氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产 物 (R)-2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸 3a粗品 (400 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  (R)-2-((tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid 2-fluoro-5-(trifluoromethyl)benzoic acid la (416 mg, 2 mmol) Dissolved in 4 mL of N,N-dimethylformamide, (R)-3-aminotetrahydrofuran hydrochloride (247 mg, 2 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) In the sealed tube, the reaction was stirred at 100 ° C for 12 hours. After cooling to room temperature, 1 M hydrochloric acid was added dropwise until the pH of the reaction mixture was 3 to 4, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phase was combined and washed with saturated sodium chloride solution (30 mL×2), The aqueous solution was dried (MgSO4), filtered The oil was used in the next step without purification.
MS m/z (ESI): 276.1 [M+l] MS m/z (ESI): 276.1 [M+l]
第二步  Second step
(R)-2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 将 (R)-2- ((四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸 3a 粗品 （400 mg， 1.45 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氢化钠 (290 mg， 7.26 mmol), 搅拌 反应 1小时， 再加入碘乙烷 (2.84 g， 18.20 mmol), 继续反应 12小时。 用 20 mL水 淬灭反应， 用乙酸乙酯萃取 (10 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (10 mLx3), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 (R)-2- (乙基 (四氢呋 喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 3b粗品 (500 mg，黄色粘稠物)，直接用于下 步反应。  (R)-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoic acid methyl ester (R)-2-((tetrahydrofuran-3-yl)amino)-5 - (Trifluoromethyl)benzoic acid 3a crude (400 mg, 1.45 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (290 mg, 7.26 mmol) was added, and the reaction was stirred for 1 hour. Iodoethane (2.84 g, 18.20 mmol) was added and the reaction was continued for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The crude product (R)-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate 3b (500 mg, yellow viscous) was used directly for next step .
MS m/z (ESI): 332.2 [M+l]  MS m/z (ESI): 332.2 [M+l]
第三步  third step
(R)-2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲醇 冰浴下， 将 (R)-2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲酸甲酯 3b粗品 (500 mg， 1.45 mmol)溶解于 10 mL四氢呋喃中，加入氢化铝锂 (114 mg， 2.90 mmol), 升至室温搅拌反应 1小时。 用 0.3 mL饱和氯化铵淬灭反应， 过滤， 乙酸乙酯萃取 (50 mLx2) , 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题 产物 (R)-2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲醇 3c (150 mg， 无色油状 物)， 产率： 35.8%。 (R)-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzyl alcohol The crude (R)-2-(ethyl(tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)benzoate 3b (500 mg, 1.45 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium aluminum hydride (114 mg, 2.90 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The residue obtained was purified by silica gel column chromatography eluting elut elut elut 3c (150 mg, colorless oil), yield: 35.8%.
第四步  the fourth step
(R)-N-(2- (氯甲基) -4- (三氟甲基)苯基) 乙基四氢呋喃 -3-胺 将 (R)-2- (乙基 (四氢呋喃 -3-基)氨基) -5- (三氟甲基)苯甲醇 3c (150 mg， 0.52 mmol) 溶解于 2 mL二氯甲烷中， 加入氯化亚砜 C93 mg， 0.78 mmol), 搅拌反应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (30 mL)， 合并有机相， 用饱和氯化钠 溶液洗涤 (20 mL),无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物 (R)-N-(2- (氯 甲基)—4- (三氟甲基)苯基) 乙基四氢呋喃 -3-胺 3d粗品 (190 mg， 淡黄色油状物)， 产物不经纯化直接用于下步反应。  (R)-N-(2-(Chloromethyl)-4-(trifluoromethyl)phenyl)ethyltetrahydrofuran-3-amine (R)-2-(ethyl(tetrahydrofuran-3-yl) Amino)-5-(trifluoromethyl)benzyl alcohol 3c (150 mg, 0.52 mmol) was dissolved in dichloromethane (2 mL). After adding 30 mL of water to the reaction mixture, EtOAc (3 mL) The title product (R)-N-(2-(chloromethyl)-4-(trifluoromethyl)phenyl)ethyltetrahydrofuran-3-amine 3d crude (190 mg, pale yellow oil) Purification was used directly in the next step.
第五步  the fifth step
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 ((R)-四氢呋喃 -3-基)氨基) -5- (三氟 甲基)苯基) - 4-甲基噁唑 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl((R)-tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl) Phenyl)-4-methyloxazol-2-one
将 (R)-N-(2- (氯甲基) -4- (三氟甲基)苯基) 乙基四氢呋喃 -3-胺 3d粗品 (190 mg， 0.52 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入 (4 5 -5-(3，5-双 (；三氟甲基)苯 基) -4-甲基噁唑 -2-酮 lg (163 mg， 0.52 mmol)和无水碳酸钾（143 mg， 1.04 mmol), 70°C搅拌反应 48小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸乙酯萃取 (20 mLx3) , 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产 物 ( 5R)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 ((R)-四氢呋喃 -3-基)氨基) -5- (三氟甲 基)苯基) - 4-甲基噁唑 -2-酮 3 (100 mg， 白色固体)， 产率： 32.9%。  (R)-N-(2-(Chloromethyl)-4-(trifluoromethyl)phenyl)ethyltetrahydrofuran-3-amine 3d crude (190 mg, 0.52 mmol) was dissolved in 5 mL N, N In the dimethylformamide, (4 5 -5-(3,5-bis(;trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (163 mg, 0.52 mmol) Anhydrous potassium carbonate (143 mg, 1.04 mmol) was stirred at 70 ° C for 48 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, which was extracted with ethyl acetate (20 mL×3). The sodium chloride solution was washed (20 mL×2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, ,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl((R)-tetrahydrofuran-3-yl)amino)-5-(trifluoromethyl)phenyl)-4- Methyloxazol-2-one 3 (100 mg, white solid), Yield: 32.9%.
MS m/z (ESI): 585.3 [M+l] MS m/z (ESI): 585.3 [M+l]
1H NMR (400 MHz, CDC13) δ 7.89 (s, 1H), 7.80 (s, 2H), 7.59 (s, 1H), 7.56 (d， 1H)， 7.32 (s， 1H), 5.77 (d, 1H), 4.85 (d， 1H), 4.51 (d, 1H), 4.03-3.85 (m， 4H)， 3.76 (dd， 1H)， 3.63 (dd， 1H)， 3.10 (dd， 2H), 2.06 (m， 1H)， 1.81 (m， 1H)， 0.92 (t， 3H), 0.71(d, 3H) 实施例 4  1H NMR (400 MHz, CDC13) δ 7.89 (s, 1H), 7.80 (s, 2H), 7.59 (s, 1H), 7.56 (d, 1H), 7.32 (s, 1H), 5.77 (d, 1H) , 4.85 (d, 1H), 4.51 (d, 1H), 4.03-3.85 (m, 4H), 3.76 (dd, 1H), 3.63 (dd, 1H), 3.10 (dd, 2H), 2.06 (m, 1H) ), 1.81 (m, 1H), 0.92 (t, 3H), 0.71 (d, 3H) Example 4
(4&5R)-5-i3,5-双 (三氟甲基)苯基) -4-甲基 -3-(2-(甲基 (四氢 -2H-吡喃 -4-基)氨  (4&5R)-5-i3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-(methyl(tetrahydro-2H-pyran-4-yl)amine
基) -5- (三氟甲基)苯基)噁唑垸 -2-酮 -5-(trifluoromethyl)phenyl)oxazole-2-one
Figure imgf000031_0001
第一步
Figure imgf000031_0001
first step
2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯甲酸 将 2-氟 -5- (三氟甲基)苯甲酸 la (2.08 g， 10 mmol)溶解于 20 mL N，N-二甲基甲 酰胺中，加入四氢 -2H-吡喃 -4-胺 (1.52 g， 15 mmol)和无水碳酸钾 (4.15 g， 30 mmol), 置于封管中， 90°C搅拌反应 96小时。 冷却至室温， 倒入冰水中， 滴加 1 M盐酸至 反应液 ρΗ 为 3〜4， 析出固体， 过滤， 得到标题产物 2- ((四氢 -2H-吡喃 -4-基)氨 基) -5- (三氟甲基)苯甲酸 4a (2.38 g， 白色固体)， 产率： 82.4%。  2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)benzoic acid 2-fluoro-5-(trifluoromethyl)benzoic acid la (2.08 g, 10 Ment) dissolved in 20 mL of N,N-dimethylformamide, tetrahydro-2H-pyran-4-amine (1.52 g, 15 mmol) and anhydrous potassium carbonate (4.15 g, 30 mmol) The reaction was stirred at 90 ° C for 96 hours in a sealed tube. After cooling to room temperature, it was poured into ice water, and 1 M hydrochloric acid was added dropwise until the reaction liquid was 3 to 4, and the solid was precipitated and filtered to give the title product 2- ((tetrahydro-2H-pyran-4-yl)amino) - 5-(Trifluoromethyl)benzoic acid 4a (2.38 g, white solid), Yield: 82.4%.
MS m/z (ESI): 288.1 [M+l] MS m/z (ESI): 288.1 [M+l]
第二步  Second step
2-(甲基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯甲酸甲酯 将 2-((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯甲酸 4a (1.45 g， 5 mmol)溶解 于 25 mL N，N-二甲基甲酰胺中，加入氢化钠 C600 mg， 15 mmol),搅拌反应 10分钟， 再加入碘甲烷 C2.13 g， 15 mmol), 继续反应 12小时。 向反应液中加入 100 mL水， 用二氯甲烷萃取 (100 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx3)， 无 水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 2- (甲基 (四氢 -2H-吡喃 -4-基) 氨基) -5- (三氟甲基)苯甲酸甲酯 4b粗品 (2 g， 黄色油状物)， 产物不经纯化直接用于 下步反应。 Methyl 2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)benzoate 2-((tetrahydro-2H-pyran-4-yl) Amino) -5-(trifluoromethyl)benzoic acid 4a (1.45 g, 5 mmol) was dissolved in 25 mL of N,N-dimethylformamide, sodium hydride C 600 mg, 15 mmol Then add methyl iodide C2.13 g, 15 mmol) and continue the reaction for 12 hours. To the reaction mixture, 100 mL of water was added, and the mixture was extracted with methylene chloride (100 mL×2). The organic phase was combined and washed with saturated sodium chloride (50 mL×3), dried over anhydrous sodium sulfate, filtered, The title product 2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)benzoic acid methyl ester 4b crude (2 g, yellow oil) Directly used The next step is the reaction.
MS m/z (ESI): 318.2 [M+l]  MS m/z (ESI): 318.2 [M+l]
第三步  third step
(2- (甲基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)甲醇 冰浴下，将 2- (甲基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯甲酸甲酯 4b粗品 (1.59 g， 5 mmol)溶解于 50 mL四氢呋喃中， 加入氢化铝锂 (480 mg， 12.50 mmol), 恢复至室温搅拌反应 2小时。向反应液中加入 1 mL水，过滤，滤液加入 50 mL水， 用二氯甲烷萃取 (100 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无 水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 (2- (甲基 (四氢 -2H-吡喃 -4-基) 氨基) -5- (三氟甲基)苯基)甲醇 4c粗品 (1.96 g， 淡黄色油状物)， 产物不经纯化直接 用于下步反应。  (2-(Methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)methanol 2-(methyl(tetrahydro-2H-) The crude product of methyl pyran-4-yl)amino)-5-(trifluoromethyl)benzoate 4b (1.59 g, 5 mmol) was dissolved in 50 mL of tetrahydrofuran, and lithium aluminum hydride (480 mg, 12.50 mmol) was added. The reaction was stirred at room temperature for 2 hours. 1 mL of water was added to the reaction solution, and the filtrate was added to 50 mL of water and extracted with dichloromethane (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered The filtrate was concentrated under reduced pressure to give the title compound (2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)methanol 4c (1.96 g, Light yellow oil), the product was used in the next step without purification.
MS m/z (ESI): 290.2 [M+l]  MS m/z (ESI): 290.2 [M+l]
第四步  the fourth step
N-(2- (氯甲基) -4- (三氟甲基)苯基) -N-甲基四氢 -2H-吡喃 -4-胺 将 (2- (甲基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)甲醇 4c粗品 (95 mg， 0.33 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (79 mg， 0.66 mmol), 搅拌反应 1.5小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (30 mL)， 合并有 机相， 用饱和氯化钠溶液洗涤 (20 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 ΛΚ2- (氯甲基 )-4- (三氟甲基)苯基) 甲基四氢 -2H-吡喃 -4-胺 4d粗品 (150 mg, 淡黄色液体)， 产物不经纯化直接用于下步反应。  N-(2-(Chloromethyl)-4-(trifluoromethyl)phenyl)-N-methyltetrahydro-2H-pyran-4-amine (2-(methyl(tetrahydro-2H) -pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)methanol 4c crude (95 mg, 0.33 mmol) dissolved in 5 mL of N,N-dimethylformamide Sulfoxide (79 mg, 0.66 mmol) was stirred for 1.5 hours. After adding 30 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL). The title product is ΛΚ2-(chloromethyl)-4-(trifluoromethyl)phenyl)methyltetrahydro-2H-pyran-4-amine 4d crude (150 mg, pale yellow). Used in the next step of the reaction.
第五步  the fifth step
(4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -3-(2-(甲基 (四氢 -2H-吡喃 -4-基)氨 基) -5- (三氟甲基)苯基)噁唑烷 -2-酮 (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-(methyl(tetrahydro-2H-pyran-4-yl)amino) -5-(trifluoromethyl)phenyl)oxazolidine- 2 -one
将 ΛΚ2- (氯甲基) -4- (三氟甲基)苯基) 甲基四氢 -2H-吡喃 -4-胺 4d 粗品 (102 mg, 0.33 mmol)溶解于 5 mL N，N-二甲基甲酰胺中，加入 (4S，5R)-5-(3，5-双 (三氟甲基) 苯基)—4-甲基噁唑 -2-酮 lg (94 mg， 0.30 mmol)和无水碳酸钾 (124 mg， 0.90 mmol), 70°C搅拌反应 3小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸乙酯萃取 (30 mL), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B 纯化所得残余物， 得到标题产物 (45,5R)-5-(3,5-双（三氟甲基）苯基 )-4-甲基 -3-(2-(甲基（四氢 -2H-吡喃 -4-基）氨 基) -5- (三氟甲基)苯基)噁唑烷 -2-酮 4 (42 mg， 类白色固体)， 产率： 24.0%。  Dissolve ΛΚ2-(chloromethyl)-4-(trifluoromethyl)phenyl)methyltetrahydro-2H-pyran-4-amine 4d crude (102 mg, 0.33 mmol) in 5 mL of N,N- (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (94 mg, 0.30 mmol) was added to dimethylformamide Anhydrous potassium carbonate (124 mg, 0.90 mmol) was stirred at 70 ° C for 3 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate The residue was purified by EtOAc (EtOAc) elut elut 3-(2-(methyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)oxazolidin-2-one 4 (42 mg, white solid ), Yield: 24.0%.
MS m/z (ESI): 643.2 [M+l] MS m/z (ESI): 643.2 [M+l]
1H NMR (400 MHz, CDC13): δ 7.89 (s, 1H), 7.78 (s, 2H), 7.62 (s, 1H), 7.54 (d, 1H)， 7.26 (d, 1H), 5.72 (d， 1H), 4.79 (d， 1H), 4.50 (d， 1H), 4.04-3.93 (m， 3H), 3.42-3.29 (m， 2H), 2.97-2.92 (m， 1H), 2.70 (s， 3H), 1.79-1.59 (m， 4H)， 0.70 (d， 3H) 实施例 5 (4 & 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -3-(2-ίί四氢 -2H-吡喃 -4-基)氨基) -5- (三氟 1H NMR (400 MHz, CDC1 3 ): δ 7.89 (s, 1H), 7.78 (s, 2H), 7.62 (s, 1H), 7.54 (d, 1H), 7.26 (d, 1H), 5.72 (d, (H, 1H) , 1.79-1.59 (m, 4H), 0.70 (d, 3H) Example 5 (4 & 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-ίίtetrahydro-2H-pyran-4-yl)amino) - 5- (trifluoro
Figure imgf000033_0001
第一步
Figure imgf000033_0001
first step
(4S，5R)-5-(3，5-双 (三氟甲基)苯基) -3-(2-碘 -5- (三氟甲基)苯基) -4-甲基噁唑 -2-酮 将 ( ^，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (9.21 g， 29.40 mmol) 溶解于 20 mL N，N-二甲基甲酰胺中， 冷却到 -10°C〜- 15 °C， 滴加六甲基二硅基胺基 钠 (38.2 mL， 38.20 mmol), 搅拌反应 30分钟。 加入 2- (氯甲基) -1-碘 -4- (三氟甲基) 苯 5a C9.40 g， 29.40 mmol, 采用公知的方法 "专利 CN102372605 "制备而得)， 继 续搅拌 30分钟。 升到室温， 搅拌反应 36小时。 向反应液中加入 30 mL水， 滴加 3 M盐酸至反应液 ρΗ为 3〜4， 用乙酸乙酯萃取 (100 mIX3)， 合并有机相， 用饱和氯 化钠溶液洗涤 (100 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱 法以洗脱剂体系 B 纯化所得残余物， 得到标题产物 (4S，5R)-5-(3，5-双 (三氟甲基)苯 基) -3-(2-碘 -5- (三氟甲基)苯基) -4-甲基噁唑 -2-酮 5b (13.24 g， 浅黄色液体)， 产率： 75.3%。  (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-iodo-5-(trifluoromethyl)phenyl)-4-methyloxazole- 2-ketone (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (9.21 g, 29.40 mmol) dissolved in 20 mL In N,N-dimethylformamide, it was cooled to -10 ° C to - 15 ° C, and sodium hexamethyldisilazide (38.2 mL, 38.20 mmol) was added dropwise, and the reaction was stirred for 30 minutes. 2-(Chloromethyl)-1-iodo-4-(trifluoromethyl)benzene 5a C9.40 g, 29.40 mmol, was added by a known method "patent CN102372605", followed by stirring for 30 minutes. The temperature was raised to room temperature and the reaction was stirred for 36 hours. 30 mL of water was added to the reaction solution, 3 M hydrochloric acid was added dropwise to the reaction solution to obtain 3 to 4, extracted with ethyl acetate (100 mIX3), and the organic phase was combined and washed with a saturated sodium chloride solution (100 mL×2), The aqueous solution was dried over sodium sulfate, filtered, and the filtrate was evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Phenyl)-3-(2-iodo-5-(trifluoromethyl)phenyl)-4-methyloxazol-2-one 5b (13.24 g, pale yellow liquid), Yield: 75.3% .
MS m/z (ESI): 598.1 [M+l]  MS m/z (ESI): 598.1 [M+l]
第二步  Second step
( 5 -5-(3，5-双 (三氟甲基)苯基) -4-甲基 -3-(2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟 甲基)苯基)噁唑烷 -2-酮 将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -3-(2-碘 -5- (三氟甲基)苯基) -4-甲基噁唑 -2- 酮 5b (180 mg， 0.30 mmol)溶解于 2 mL甲苯中，依次加入 4-氨基四氢吡喃 (101 mg， 1 mmol), 碳酸铯 (200 mg， 0.60 mmol), 18-冠 -6 (36 mg， 0.06 mmol), 三 (二亚苄基 丙酮)二钯 (13.70 mg， 0.015 mmol)和 4,5-双 (二苯基膦) -9,9-二甲基氧杂蒽 (13.80 mg， 0.024 mmol)。 130°C微波下反应 30分钟。 反应液减压浓縮， 用薄层色谱法以洗脱 剂体系 B纯化所得残余物， 得到标题产物 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -3-(2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)噁唑烷 -2-酮 5 (80 mg， 黄色固 体)， 产率： 46.8%。 (5 -5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-5-- (trifluoromethyl)phenyl)oxazolidin-2-one (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-iodo-5-(trifluoromethyl)phenyl)-4-methyloxazole 2- Ketone 5b (180 mg, 0.30 mmol) was dissolved in 2 mL of toluene, followed by 4-aminotetrahydropyran (101 mg, 1 mmol), cesium carbonate (200 mg, 0.60 mmol), 18-crown- 6 (36 mg, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (13.70 mg, 0.015 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxaxime ( 13.80 mg, 0.024 mmol). The reaction was carried out in a microwave at 130 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj 4-methyl-3-(2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)oxazolidin-2-one 5 (80 mg, Yellow solid), Yield: 46.8%.
MS m/z (ESI): 571.2 [M+l] MS m/z (ESI): 571.2 [M+l]
1H NMR (400 MHz, CDC13): δ 7.89 (s, 1H), 7.73 (s, 2H), 7.49-7.43 (m， 1H), 7.24 (d， 1H), 6.69 (d, 1H)， 5.65 (d, 1H)， 5.45-5.31 (m， 1H)， 4.72 (d， 1H)， 4.13 (d, 1H)， 4.08-3.97 (m， 3H), 3.55 (d， 3H), 2.04 (s, 2H), 1.72-1.59 (m， 2H), 0.80 (d， 3H) 实施例 6 1H NMR (400 MHz, CDC1 3 ): δ 7.89 (s, 1H), 7.73 (s, 2H), 7.49-7.43 (m, 1H), 7.24 (d, 1H), 6.69 (d, 1H), 5.65 ( d, 1H), 5.45-5.31 (m, 1H), 4.72 (d, 1H), 4.13 (d, 1H), 4.08-3.97 (m, 3H), 3.55 (d, 3H), 2.04 (s, 2H) , 1.72-1.59 (m, 2H), 0.80 (d, 3H) Example 6
(4&5R)-5-i3,5-双 (三氟甲基)苯基) -3-((2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5-三氟 甲基)吡啶 -3-基)甲基) - 4-甲基噁唑 -2-酮  (4&5R)-5-i3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-trifluoro Methyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
Figure imgf000034_0001
第一步
Figure imgf000034_0001
first step
2-氯 -5- (三氟甲基) -3-吡啶甲醛  2-chloro-5-(trifluoromethyl)-3-pyridinecarboxaldehyde
将 3-溴 -2-氯 -5-三氟甲基吡啶 (2.6 g， 10 mmol, 韶远 (货号 SY012284))和 N，N-二 甲基甲酰胺 (950 mg， 13 mmol)溶解于 50 mL甲苯中， 冷却至 -78°C， 再滴加正丁基 锂， 滴加完毕， -78°C下搅拌反应 1.5小时， 用 1 M HC1淬灭反应， 用乙酸乙酯萃 取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物粗品 2-氯 -5- (三氟甲基) -3-吡啶甲醛 6a (2.30 g， 橙色油状物)， 产物不经纯化直接用于下步反应。  3-Bromo-2-chloro-5-trifluoromethylpyridine (2.6 g, 10 mmol, 韶yuan (Cat. No. SY012284)) and N,N-dimethylformamide (950 mg, 13 mmol) were dissolved in 50 In mL of toluene, cooled to -78 ° C, and then n-butyllithium was added dropwise. After the dropwise addition was completed, the reaction was stirred at -78 ° C for 1.5 hours, quenched with 1 M EtOAc, and extracted with ethyl acetate (50 mL×2) The organic phase was combined, washed with aq. EtOAc (EtOAc m. Pyridinecarboxaldehyde 6a (2.30 g, orange oil), product was used in the next step without purification.
第二步  Second step
2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 将粗品 2-氯 -5- (三氟甲基) -3-吡啶甲醛 6a (2.10 g， 10 mmol)溶解于 50 mL甲苯 中， 加入 N-乙基四氢 -2H-吡喃 -4-胺 6b (1.68 g， 13 mmol, 采用 "专利申请 WO9907702" 公开的方法制备而得)和无水碳酸钾 (4.15 g， 30 mmol), 90°C搅拌反 应 12小时。 冷却至室温， 过滤， 向反应液中加入 100 mL水， 用乙酸乙酯萃取 (30 mLx3), 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题产物 2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 6c (950 mg， 橙色油状物)， 产率： 31.5%。  2-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)nicotinal aldehyde crude 2-chloro-5-(trifluoromethyl)-3-pyridine Formaldehyde 6a (2.10 g, 10 mmol) was dissolved in 50 mL of toluene, and N-ethyltetrahydro-2H-pyran-4-amine 6b (1.68 g, 13 mmol) was added and prepared by the method disclosed in "Patent Application WO9907702" This was stirred with an anhydrous potassium carbonate (4.15 g, 30 mmol) at 90 ° C for 12 hours. The mixture was cooled to room temperature, filtered, and 100 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate The organic layer was concentrated under reduced pressure. Methyl) nicotinic aldehyde 6c (950 mg, orange oil), Yield: 31.5%.
第三步  third step
(2- (乙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 将 2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 6c (1.10 g， 3.64 mmol) 溶于 50 mL乙醇中，加入硼氢化钠 C0.17 g， 4.37 mmol),搅拌反应 12小时。用 50 mL 饱和氯化铵溶液淬灭反应， 用乙酸乙酯萃取 (50 mLx l)， 合并有机相， 用饱和氯化 钠溶液洗涤 (50 mLx l)，无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物 (2- (乙 基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 6d粗品 (1.15 g，淡黄色油 状物)， 产物不经纯化直接用于下步反应。  (2-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 2-(ethyl(tetrahydro-2H-pyran) 4-yl)amino)-5-(trifluoromethyl)nicotinaldehyde 6c (1.10 g, 3.64 mmol) dissolved in 50 mL of ethanol, sodium borohydride C 0.17 g, 4.37 mmol), stirring reaction 12 hour. The reaction was quenched with 50 mL of EtOAc EtOAc (EtOAc)EtOAc. Concentration by pressure gave the title product (2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol as a crude product (1. Yellow oil), the product was used in the next step without purification.
MS m/z (ESI): 305.5 [M+l] MS m/z (ESI): 305.5 [M+l]
第四步  the fourth step
3- (氯甲基) -N-乙基 -ΛΚ四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺  3-(Chloromethyl)-N-ethyl-indoletetrahydro-2Hpyran-4-yl)-5-(trifluoromethyl)pyridine-2-amine
将 (2- (乙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 6d粗品 (110 mg， 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (86 mg， 0.72 mmol), 搅拌反应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮，得到标题产物 3- (氯甲基) 乙基 -ΛΚ四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 6e粗品 (130 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Dissolve (2-(ethyl(tetrahydro-2Hpyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 6d crude (110 mg, 0.36 mmol) in 5 mL To the N,N-dimethylformamide, thionyl chloride (86 mg, 0.72 mmol) was added, and the mixture was stirred for 1 hour. To the reaction mixture, 30 mL of water was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Product title: 3-(Chloromethyl)ethyl-indoletetrahydro-2Hpyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine 6e crude (130 mg, yellow oil) It was used in the next step without purification.
MS m/z (ESI): 333.4 [M+l] 第五步 MS m/z (ESI): 333.4 [M+l] the fifth step
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基) 吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5- (three Fluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
将 3- (氯甲基) -N-乙基 -N- (四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 6e (116 mg， 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中，加入 (4S，5R)-5-(3，5-双 (三氟甲基） 苯基)—4-甲基噁唑 -2-酮 lg (94 mg， 0.30 mmol)和无水碳酸钾 (124 mg， 0.90 mmol), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸乙酯萃取 (20 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产 物 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲 基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 6 (117 mg， 白色固体)， 产率： 65.0%。  3-(Chloromethyl)-N-ethyl-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine 6e (116 mg, 0.36 mmol) Dissolved in 5 mL of N,N-dimethylformamide and added (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one Lg (94 mg, 0.30 mmol) and anhydrous potassium carbonate (124 mg, 0.90 mmol) were stirred at 70 ° C for 12 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered Concentration, the residue obtained was purified by EtOAc EtOAc (EtOAc) (tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one 6 (117 mg, White solid), Yield: 65.0%.
MS m/z (ESI): 600.4 [M+l] MS m/z (ESI): 600.4 [M+l]
1H NMR (400 MHz, CDC13): δ 8.56 (s， 1H)， 7.91 (s, 1H)， 7.85 (s， 1H)， 7.77 (s， 2H), 5.74 (d, 1H)， 4.80 (d, 1H)， 4.40 (d, 1H)， 4.05-3.94 (m， 3H), 3.52-3.26 (m， 5H)， 1.96-1.87 (m， 1H), 1.85-1.76 (m， 2H), 1.64 (d， 1H), 0.96 (t， 3H), 0.66 (d， 3H) 实施例 7 1H NMR (400 MHz, CDC1 3 ): δ 8.56 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.77 (s, 2H), 5.74 (d, 1H), 4.80 (d, 1H), 4.40 (d, 1H), 4.05-3.94 (m, 3H), 3.52-3.26 (m, 5H), 1.96-1.87 (m, 1H), 1.85-1.76 (m, 2H), 1.64 (d, 1H), 0.96 (t, 3H), 0.66 (d, 3H) Example 7
(4 & 5RV5-(3,5-双 (三氟甲基)苯基) -3-(2- (环丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三 氟甲基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮  (4 & 5RV5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(cyclopropyl(tetrahydro-2H-pyran-4-yl)amino)-5- (three Fluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
Figure imgf000036_0001
第一步
Figure imgf000036_0001
first step
2- (环丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 将 2-氯 -5- (；三氟甲基)烟碱醛 6a (650 mg， 3.11 mmol)溶解于 5 mL甲苯中， 加 入 N-环丙基四氢 -2H-吡喃 -4-胺 7a (570 mg， 4.04 mmol , 采用 "专利申请 WO2009072649" 公开的方法制备而得)和无水碳酸钾 (640 mg， 4.67 mmol), 150 °C微波下反应 3小时。过滤，向反应液中加入 50 mL水，用乙酸乙酯萃取 (20 mIX3)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题产物 2- (环丙 基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 7b (400 mg， 黄色油状物)， 产率： 40.8%。  2-(cyclopropyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)nicotinaldehyde 2-chloro-5-(;trifluoromethyl)nicotinaldehyde 6a (650 mg, 3.11 mmol) was dissolved in 5 mL of toluene and N-cyclopropyltetrahydro-2H-pyran-4-amine 7a (570 mg, 4.04 mmol) was prepared using the method disclosed in "Patent Application WO2009072649" And obtained with anhydrous potassium carbonate (640 mg, 4.67 mmol), and reacted under microwave at 150 °C for 3 hours. Filtration, 50 ml of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (20 m EtOAc). The residue obtained was purified by silica gel column chromatography elut elut elut elut elut Nicotinic aldehyde 7b (400 mg, yellow oil), Yield: 40.8%.
MS m/z (ESI): 315.4 [M+l]  MS m/z (ESI): 315.4 [M+l]
第二步  Second step
(2- (环丙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 将 2- (环丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 7b (400 mg， 1.27 mmol)溶于 20 mL乙醇中， 加入硼氢化钠 (；58 mg， 1.53 mmol), 搅拌反应 12小时。 用 20 mL饱和氯化铵溶液淬灭反应， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用 饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标 题产物 (2- (环丙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 7c粗品 (440 mg, 黄色油状物)， 产物不经纯化直接用于下步反应。  (2-(cyclopropyl(tetrahydro-2Hpyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 2-(cyclopropyl(tetrahydro-2H-) Pyran-4-yl)amino)-5-(trifluoromethyl)nicotinaldehyde 7b (400 mg, 1.27 mmol) was dissolved in 20 mL of ethanol, sodium borohydride (58 mg, 1.53 mmol) was added and stirred Reaction for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The title product (2-(cyclopropyl(tetrahydro-2Hpyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 7c crude (440 mg, yellow oil) The product was used in the next step without purification.
MS m/z (ESI): 317.4 [M+l] MS m/z (ESI): 317.4 [M+l]
第三步  third step
3- (氯甲基) -N-环丙基 -ΛΚ四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 将 (2- (环丙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 7c 粗品 (114 mg, 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中，加入氯化亚砜 (86 mg， 0.72 mmol), 搅拌反应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物 3- (氯甲基) 环丙基 -ΛΚ四氢 -2H吡喃 -4-基) -5- (三氟甲基) 吡啶 -2-胺 7d粗品 (130 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  3-(Chloromethyl)-N-cyclopropyl-indoletetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine (2-(cyclopropyl) Hydrogen-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 7c crude (114 mg, 0.36 mmol) dissolved in 5 mL of N,N-dimethylformamide Among them, thionyl chloride (86 mg, 0.72 mmol) was added, and the reaction was stirred for 1 hour. After adding 30 mL of water to the reaction mixture, the mixture was combined with EtOAc EtOAc (EtOAc) Product title: 3-(Chloromethyl)cyclopropyl-indoletetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine 7d crude (130 mg, yellow oil) The product was used in the next step without purification.
MS m/z (ESI): 331.5 [M+l] MS m/z (ESI): 331.5 [M+l]
第四步  the fourth step
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (环丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲 基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(cyclopropyl(tetrahydro-2H-pyran-4-yl)amino)-5- ( Trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
将 3- (氯甲基) -N-环丙基 -N- (四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 7d粗品 (121 mg, 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入 ( ^，5R)-5-(3，5-双 (三 氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (94 mg， 0.30 mmol)和无水碳酸钾 (124 mg， 0.90 mmol ), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸 乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠 干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以洗脱剂体系 A纯化所得残余物， 得 到标题产物 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (环丙基 (四氢 -2H-吡喃 -4-基)氨 基) -5- (三氟甲基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 7 (55 mg， 淡黄色固体)， 产率： 30.1%。 3-(Chloromethyl)-N-cyclopropyl-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine 7d crude (121 mg, 0.36 Methyl) was dissolved in 5 mL of N,N-dimethylformamide and (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazole-2 was added. The ketone lg (94 mg, 0.30 mmol) and anhydrous potassium carbonate (124 mg, 0.90 mmol) were stirred at 70 ° C for 12 hours. Cool to room temperature, add 50 mL of water to the reaction solution, use acetic acid Ethyl acetate extraction (20 mL×2), EtOAc (EtOAc) (EtOAc m. The residue obtained gave the title product (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(cyclopropyl(tetrahydro-2H-pyran-4-yl) Amino) -5-(trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one 7 (55 mg, pale yellow solid), yield: 30.1%.
MS m/z (ESI): 612.5 [M+l]  MS m/z (ESI): 612.5 [M+l]
1H NMR (400 MHz, CDC13): δ 8.55 (s， 1H)， 7.91 (s, 1H)， 7.80 (s， 1H)， 7.77 (s， 2H), 5.73 (d， 1H), 4.83 (d， 1H), 4.31 (d， 1H), 4.02 (t， 2H), 3.92-3.89 (m， 1H), 3.48-3.40 (m， 3H), 2.86-2.83 (m， 1H), 2.12-1.98 (m， 2H), 1.90 (d, 1H), 1.79 (d, 1H), 0.80-0.77 (m， 2H), 0.66 (d， 3H), 0.44-0.41 (m， 1H), 0.22-0.21 (m， 1H) 实施例 8 1H NMR (400 MHz, CDC1 3 ): δ 8.55 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.77 (s, 2H), 5.73 (d, 1H), 4.83 (d, 1H), 4.31 (d, 1H), 4.02 (t, 2H), 3.92-3.89 (m, 1H), 3.48-3.40 (m, 3H), 2.86-2.83 (m, 1H), 2.12-1.98 (m, 2H), 1.90 (d, 1H), 1.79 (d, 1H), 0.80-0.77 (m, 2H), 0.66 (d, 3H), 0.44-0.41 (m, 1H), 0.22-0.21 (m, 1H) Example 8
(4&5RV5-(3,5-双 (三氟甲基)苯基) -4-甲基 -3-((2- (丙基 (四氢 -2H-吡喃 -4-基)氨 基) -5- (三氟甲 -3-基)甲基)噁唑 -2-酮  (4&5RV5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-3-((2-(propyl(tetrahydro-2H-pyran-4-yl)amino))-5 - (Trifluoromethyl-3-yl)methyl)oxazole-2-one
Figure imgf000038_0001
第一步
Figure imgf000038_0001
first step
2- (丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 将 2-氯 -5- (；三氟甲基)烟碱醛 6a (650 mg， 3.11 mmol)溶解于 5 mL甲苯中， 加 入 N-丙基四氢 -2H-吡喃 -4-胺 8a (580 mg， 4.04 mmol,采用 "专利申请 WO9907702" 公开的方法制备而得)和无水碳酸钾 (640 mg， 4.67 mmol), 150°C微波下反应 3小 时。 过滤， 向反应液中加入 50 mL水， 用乙酸乙酯萃取 (20 mIX3)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅 胶柱色谱法以洗脱剂体系 B纯化所得残余物，得到标题产物 2- (丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 8b (424 mg， 黄色油状物)， 产率： 43.1%。 2-(propyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)nicotinaldehyde 2-chloro-5-(;trifluoromethyl)nicotinaldehyde 6a (650 mg, 3.11 mmol) dissolved in 5 mL of toluene, plus N-propyltetrahydro-2H-pyran-4-amine 8a (580 mg, 4.04 mmol, prepared by the method disclosed in "Patent Application WO9907702") and anhydrous potassium carbonate (640 mg, 4.67 mmol), The reaction was carried out for 3 hours under microwave at 150 °C. Filtration, 50 ml of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (20 m EtOAc). The residue obtained was purified by silica gel column chromatography eluting with eluent to afford the title product 2-(propyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl) Alkali aldehyde 8b (424 mg, yellow oil), Yield: 43.1%.
MS m/z (ESI): 317.5 [M+l] MS m/z (ESI): 317.5 [M+l]
第二步  Second step
(2- (丙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 将 2- (丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)烟碱醛 8b (424 mg， 1.34 mmol)溶于 20 mL乙醇中， 加入硼氢化钠 (61 mg， 1.61 mmol), 搅拌反应 12小时。 加入 30 mL水淬灭反应， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠 溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 (2- (丙 基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 8c粗品 (410 mg， 黄色粘 性油状物)， 产物不经纯化直接用于下步反应。  (2-(propyl(tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 2-(propyl(tetrahydro-2H-pyran) 4-yl)amino)-5-(trifluoromethyl)nicotinaldehyde 8b (424 mg, 1.34 mmol) was dissolved in 20 mL of ethanol, sodium borohydride (61 mg, 1.61 mmol) was added, and the reaction was stirred for 12 hours. . The reaction was quenched with EtOAc (3 mL) (EtOAc) Product (2-(propyl(tetrahydro-2Hpyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 8c crude (410 mg, yellow viscous oil) It was used in the next step without purification.
MS m/z (ESI): 377.4 [M+l] MS m/z (ESI): 377.4 [M+l]
第三步  third step
3- (氯甲基) -N-丙基 -N- (四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 将 (2- (丙基 (四氢 -2H吡喃 -4-基)氨基) -5- (三氟甲基)吡啶 -3-基)甲醇 8c粗品 (115 mg， 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (86 mg， 0.72 mmol), 搅拌反应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物 3- (氯甲基) -N-丙基 -N- (四氢 -2H吡喃 -4-基) -5- (三氟甲基)口比 啶 -2-胺 8d粗品 (130 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  3-(Chloromethyl)-N-propyl-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine (2-(propyl) Hydrogen-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methanol 8c crude (115 mg, 0.36 mmol) was dissolved in 5 mL of N,N-dimethylformamide Among them, thionyl chloride (86 mg, 0.72 mmol) was added, and the reaction was stirred for 1 hour. After adding 30 mL of water to the reaction mixture, the mixture was combined with EtOAc EtOAc (EtOAc) Product title: 3-(Chloromethyl)-N-propyl-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)- or pyridin-2-amine 8d crude (130 mg , yellow oil), the product was used in the next step without purification.
第四步  the fourth step
(4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (丙基 (四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基) 吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮  (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(propyl(tetrahydro-2H-pyran-4-yl)amino)-5- (three Fluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one
将 3- (氯甲基) -N-丙基 -N- (四氢 -2H吡喃 -4-基) -5- (三氟甲基)吡啶 -2-胺 8d粗品 (121 mg, 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入 ( ^，5R)-5-(3，5-双 (三 氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (94 mg， 0.30 mmol)和无水碳酸钾 (124 mg， 0.90 mmol ), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸 乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠 干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以洗脱剂体系 A纯化所得残余物， 得 到标题产物 ( 5 -5-(3，5-双 (三氟甲基)苯基) -3-(2- (丙基（四氢 -2H-吡喃 -4-基)氨 基) -5- (三氟甲基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 8 (115 mg， 类白色固体)， 产率： 62.5%。 MS m/z (ESI): 614.3 [M+l] 3-(Chloromethyl)-N-propyl-N-(tetrahydro-2H-pyran-4-yl)-5-(trifluoromethyl)pyridin-2-amine 8d crude (121 mg, 0.36 mmol Dissolved in 5 mL of N,N-dimethylformamide and added (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazole-2- The ketone lg (94 mg, 0.30 mmol) and anhydrous potassium carbonate (124 mg, 0.90 mmol) were stirred at 70 ° C for 12 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered The residue was purified by EtOAc (EtOAc) elute (tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one 8 (115 mg, Off-white solid), Yield: 62.5%. MS m/z (ESI): 614.3 [M+l]
1H NMR (400 MHz, CDC13): δ 8.52 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.77 (s, 2H): 5.75 (d, 1H)， 4.76 (d, 1H)， 4.35 (d, 1H)， 4.07-3.91 (m， 3H), 3.50-3.30 (m， 3H): 3.25-3.19 (m， 1H), 3.12-3.05 (m， 1H), 1.99-1.81 (m， 2H), 1.76 (d， 1H), 1.60 (d, 1H): 1.39-1.29 (m， 2H), 0.83(t, 3H), 0.64 (d， 3H) 实施例 9 1H NMR (400 MHz, CDC1 3 ): δ 8.52 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.77 (s, 2H) : 5.75 (d, 1H), 4.76 (d, 1H), 4.35 (d, 1H), 4.07-3.91 (m, 3H), 3.50-3.30 (m, 3H) : 3.25-3.19 (m, 1H), 3.12-3.05 (m, 1H), 1.99-1.81 ( m, 2H), 1.76 (d, 1H), 1.60 (d, 1H) : 1.39-1.29 (m, 2H), 0.83 (t, 3H), 0.64 (d, 3H) Example 9
N-i2-W4&5R 5-i3,5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟  N-i2-W4&5R 5-i3,5-bis(trifluoromethyl)phenyl 4-methyl-2-carbonyloxazolidine-3-yl)methyl)-4-(trifluoro
Figure imgf000040_0001
第一步
Figure imgf000040_0001
first step
(2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)甲醇 冰浴下， 将 2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯甲酸 4a (1.45 g， 5 mmol)溶解于 30 mL四氢呋喃中， 加入氢化铝锂 (190 mg， 5 mmol), 升至室温搅拌 反应 12小时。 加入 0.4 mL水淬灭反应， 过滤， 滤液用二氯甲烷萃取 (100 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 用硅胶柱色谱法以洗脱剂体系 B 纯化所得残余物， 得到标题产物 (2- ((四 氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)甲醇 9a (1 g，淡黄色固体)，产率： 73.0%。 (2-((tetrahydro-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)methanol 2-((tetrahydro-2H-pyran-4) in ice bath -Amino)amino-5-(trifluoromethyl)benzoic acid 4a (1.45 g, 5 mmol) was dissolved in 30 mL of tetrahydrofuran, lithium aluminum hydride (190 mg, 5 mmol) was added, and the mixture was stirred at room temperature for 12 hours. . The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained is purified by silica gel column chromatography eluting to afford the title product (2- ((4) Hydrogen-2H-pyran-4-yl)amino)-5-(trifluoromethyl)phenyl)methanol 9a (1 g, pale yellow solid), yield: 73.0%.
第二步  Second step
2-(ΛΚ四氢 -2H-吡喃 -4-基)乙酰氨基) -5- (三氟甲基)乙酸苄酯 将 (2- ((四氢 -2H-吡喃 -4-基)氨基) -5- (三氟甲基)苯基)甲醇 9a (350 mg， 1.27 mmol) 溶解于 5 mL乙酰氯中， 50°C搅拌反应 12小时。 冰浴下， 缓慢用 20 mL饱和碳酸 氢钠溶液淬灭反应， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液 洗涤 (30 mLx2), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 2-(N- (四 氢 -2H-吡喃 -4-基)乙酰氨基) -5- (三氟甲基)乙酸苄酯 9b粗品 (456 mg， 无色油状物)， 产物不经纯化直接用于下步反应。  Benzyl 2-(indolyl-2H-pyran-4-yl)acetamido)-5-(trifluoromethyl)acetate (2-((tetrahydro-2H-pyran-4-yl)amino) -5-(Trifluoromethyl)phenyl)methanol 9a (350 mg, 1.27 mmol) was dissolved in 5 mL of acetyl chloride and stirred at 50 ° C for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was concentrated under reduced pressure to give the titled product: 2-(N-(tetrahydro-2H-pyran-4-yl)acetylamino)-5-(trifluoromethyl)acetic acid benzyl ester 9b crude (456 mg, Color oil), the product was used in the next step without purification.
第三步  third step
ΛΚ2- (羟甲基) -4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酸铵 将 2-(ΛΚ四氢 -2H-吡喃 -4-基)乙酰氨基) -5- (三氟甲基)乙酸苄酯 9b粗品 (456 mg， 1.27 mmol)溶解于 8.8 mL甲醇和水 (V/V = 10: 1)混合溶剂中， 加入无水碳酸钾 (500 mg， 3.80 mmol), 搅拌反应 12小时。 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (30 mLx3), 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题 产物 N-(2- (羟甲基) -4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酸铵 9c (190 mg， 白色固体)， 产率： 47.5%。  2-(Hydroxymethyl)-4-(trifluoromethyl)phenyl)-indoletetrahydro-2H-pyran-4-yl)acetic acid ammonium 2-(indoletetrahydro-2H-pyran-4- Base acetylamino) -5-(trifluoromethyl)acetic acid benzyl ester 9b crude (456 mg, 1.27 mmol) was dissolved in 8.8 mL of a mixture of methanol and water (V/V = 10:1). Potassium (500 mg, 3.80 mmol) was stirred for 12 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut 4-Based ammonium acetate 9c (190 mg, white solid), Yield: 47.5%.
MS m/z (ESI): 318.4 [M+l] MS m/z (ESI): 318.4 [M+l]
第四步  the fourth step
N-(2- (氯甲基) -4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酸铵 将 N-(2- (羟甲基) -4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酸铵 9c (63 mg， 0.20 mmol)溶解于 1 mL二氯甲烷中， 加入氯化亚砜 (26 mg， 0.22 mmol), 搅拌反 应 1小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到 标题产物 ΛΚ2- (氯甲基 )-4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酸铵 9d粗品 (67 mg, 淡黄色固体)， 直接用于下步反应  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. After adding 30 mL of water to the reaction mixture, the mixture was combined with EtOAc EtOAc (EtOAc) Product title: ΛΚ2-(Chloromethyl)-4-(trifluoromethyl)phenyl)-indoletetrahydro-2H-pyran-4-yl)acetic acid ammonium 9d crude (67 mg, pale yellow solid). In the next step
第五步  the fifth step
N-(2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟 甲基)苯基) (四氢 -2H-吡喃 -4-基)乙酰胺  N-(2-(((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl) -4 -(Trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)acetamide
冰浴下， 将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (62 mg， 0.20 mmol)溶解于 l mL N，N-二甲基甲酰胺中， 加入六甲基二硅基胺基钠 (0.24 mL， 0.24 mmol), 搅拌反应 20分钟。 再加入 N-(2- (氯甲基) -4- (三氟甲基)苯基) -N-(四氢 -2H- 吡喃 -4-基)乙酸铵 9d (67 mg， 0.20 mmol), 恢复至室温搅拌反应 3小时。 向反应液 中加入 10 mL水， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱和氯化钠溶液洗 涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体 系 B纯化所得残余物， 得到标题产物 AK2-^4^5R)-5-C3，5-双 (三氟甲基)苯基) -4-甲 基 -2-噁唑烷酮 -3-基)甲基) -4- (三氟甲基)苯基) -ΛΚ四氢 -2H-吡喃 -4-基)乙酰胺 9 (40 mg， 白色固体)， 产率： 32.8%。 (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (62 mg, 0.20 mmol) was dissolved in l. To the N,N-dimethylformamide, sodium hexamethyldisilazide (0.24 mL, 0.24 mmol) was added, and the mixture was stirred for 20 min. Additional N-(2-(chloromethyl)-4-(trifluoromethyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)acetic acid ammonium 9d (67 mg, 0.20 mmol) The reaction was stirred at room temperature for 3 hours. To the reaction mixture, 10 mL of water was added, and the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate Thin layer chromatography The resulting residue was purified to give the title product AK2-^4^5R)-5-C3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxazolidin-3-yl Methyl)-4-(trifluoromethyl)phenyl)-indoletetrahydro-2H-pyran-4-yl)acetamide 9 (40 mg, white solid), yield: 32.8%.
MS m/z (ESI): 613.2 [M+l] 实施例 10 MS m/z (ESI): 613.2 [M+l] Example 10
4-ίί3-ίίί 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲 -5- (三氟甲基)吡啶 -2-基) (乙基)氨基)哌啶 -1-甲酸叔丁酯  4-ίί3-ίίί 5R)-5-(3,5-Bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolyl-3-yl)methyl-5- (trifluoromethyl) Tert-butyl pyridyl-2-yl)(ethyl)amino)piperidine-1-carboxylate
Figure imgf000042_0001
第一步
Figure imgf000042_0001
first step
4- (乙基 (3-甲酰基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 将 2-氯 -5- (三氟甲基)烟碱醛 6a (1.05 g， 5 mmol)溶解于 10 mL甲苯中， 加入 4- (乙氨基)哌啶 -1-甲酸叔丁酯 10a (1.48 g， 6.50 mmol,采用公知的方法" 'oorgfl 'c & Medicinal Chemistry Letters, 2008,18(1), 336-343 "制备而得)和无水碳酸钾（1.04 g， 7.5 mmol), 150°C微波下反应 3小时。 过滤， 向反应液中加入 100 mL水， 用乙酸 乙酯萃取 (30 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠 干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题产物 4- (乙基 (3-甲酰基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 10b (370 mg, 黄色油状物)， 产率： 18.4%。 4-(Ethyl(3-formyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 2-chloro-5-(trifluoromethyl) Alkali aldehyde 6a (1.05 g, 5 mmol) was dissolved in 10 mL of toluene, and 4-(ethylamino)piperidine-1-carboxylic acid tert-butyl ester 10a (1.48 g, 6.50 mmol, using a known method "'oorgfl'c& Medicinal Chemistry Letters, 2008, 18(1), 336-343 "Prepared" and anhydrous potassium carbonate (1.04 g, 7.5 mmol), reacted under microwave at 150 °C for 3 hours. Filtration, adding 100 mL of water to the reaction solution, extracting with ethyl acetate (30 mL×3), combining organic phases, washing with saturated sodium chloride solution (30 mL×2), anhydrous sodium sulfate The mixture was dried, filtered, and evaporated tolulujjjjjjjjjjjjj tert-Butyl 2-ethyl)amino)piperidine-1-carboxylate 10b (370 mg, yellow oil), yield: 18.4%.
MS m/z (ESI): 402.3 [M+l] MS m/z (ESI): 402.3 [M+l]
第二步  Second step
4- (乙基 (3-羟甲基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 将 4- (乙基 (3-甲酰基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 10b (370 mg, 0.92 mmol)溶于 20 mL乙醇中， 加入硼氢化钠 (42 mg， 1.11 mmol), 搅拌反应 12小时。 用 20 mL水液淬灭反应， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱 和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题 产物 4- (乙基 (3-羟甲基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 10c粗品 (374 mg, 黄色粘性油状物)， 产物不经纯化直接用于下步反应。  4-(Ethyl(3-hydroxymethyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 4-(ethyl(3-formyl-5) -(Trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 10b (370 mg, 0.92 mmol) dissolved in 20 mL of EtOAc (EtOAc) The reaction was stirred for 12 hours. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Title product 4-(ethyl(3-hydroxymethyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 10c crude (374 mg, yellow viscous oil) The product was used in the next step without purification.
MS m/z (ESI): 404.3 [M+l] MS m/z (ESI): 404.3 [M+l]
第三步  third step
4- (乙基 (3-氯甲基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 将 -4- (乙基 (3-羟甲基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸叔丁酯 10c粗品 (145 mg, 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中，加入氯化亚砜 (43 mg， 0.36 mmol), 搅拌反应 2小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物 4- (乙基 (3-氯甲基 -5- (三氟甲基)吡啶 -2-基)氨基)哌啶 -1-甲酸 叔丁酯 10d粗品 (160 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  4-(Ethyl(3-chloromethyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester -4-(ethyl(3-hydroxymethyl) -5-(Trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 10c crude (145 mg, 0.36 mmol) was dissolved in 5 mL of N,N-dimethylformamide. Thionyl chloride (43 mg, 0.36 mmol) was added and the reaction was stirred for 2 hours. After adding 30 mL of water to the reaction mixture, the mixture was combined with EtOAc EtOAc (EtOAc) The title product 4-(ethyl(3-chloromethyl-5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 10d crude (160 mg, yellow oil) The product was used in the next step without purification.
第四步  the fourth step
4-((3-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -5- (三氟 甲基)吡啶 -2-基) (乙基)氨基)哌啶 -1-甲酸叔丁酯 将 4- (乙基 (3-氯甲基 -5-(三氟甲基)吡啶 -2-基)氨基)哌啶小甲酸叔丁酯 10d粗品 (152 mg, 0.36 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入 (4S，5R)-5-(3，5-双 (三 氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (94 mg， 0.30 mmol)和无水碳酸钾 (124 mg， 0.90 mmol ), 70°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 50 mL水， 用乙酸 乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠 干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B纯化所得残余物， 得 到标题产物 4-((3-(((4 5R)-5-(3，5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲 基) -5- (三氟甲基)吡啶 -2-基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 10 (60 mg，类白色固体)， 产率： 28.6%。 4-((3-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl)) 4-(Trifluoromethyl)pyridin-2-yl)(ethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 4- (ethyl(3-chloromethyl-5-(trifluoromethyl)) Pyridyl- 2- (yl)amino)piperidine carboxylic acid tert-butyl ester 10d crude (152 mg, 0.36 mmol) was dissolved in 5 mL of N,N-dimethylformamide and (4S,5R)-5-(3) ,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (94 mg, 0.30 mmol) and anhydrous potassium carbonate (124 mg, 0.90 mmol), stirred at 70 ° C 12 hours. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered The residue was purified by EtOAc (EtOAc) elut elut 4-methyl-2-carbonyloxazolidin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-ylXethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 10 ( 60 mg, off-white solid), Yield: 28.6%.
MS m/z (ESI): 699.4 [M+l] MS m/z (ESI): 699.4 [M+l]
1H NMR (400 MHz, CDC13): δ 8.55 (s， 1H), 7.91 (s, 1H), 7.84 (s， 1H), 7.77 (s， 2H), 5.74 (d, 1H), 4.78 (d, 1H), 4.38 (d, 1H), 4.25-4.05 (m， 2H), 4.00-3.85 (m， 1H)， 3.57-3.39 (m， 1H), 3.28-3.12 (m， 2H), 2.82-2.52 (m， 2H), 1.86-1.69 (m， 2H), 1.69-1.57 (m， 2H), 1.45 (s， 9H)， 0.95 (t， 3H), 0.74 - 0.56 (m， 3H) 实施例 11 1H NMR (400 MHz, CDC1 3 ): δ 8.55 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.77 (s, 2H), 5.74 (d, 1H), 4.78 (d, 1H), 4.38 (d, 1H), 4.25-4.05 (m, 2H), 4.00-3.85 (m, 1H), 3.57-3.39 (m, 1H), 3.28-3.12 (m, 2H), 2.82-2.52 ( m, 2H), 1.86-1.69 (m, 2H), 1.69-1.57 (m, 2H), 1.45 (s, 9H), 0.95 (t, 3H), 0.74 - 0.56 (m, 3H) Example 11
3-ί(3-ίίί 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲 基) -5- (三氟甲基)吡啶 - -基）（四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯  3-ί(3-ίίί 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolium-3-yl)methyl)-5- (Trifluoromethyl)pyridine-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid ethyl ester
Figure imgf000044_0001
第一步
Figure imgf000044_0001
first step
3-((3-甲酰基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 将 2-氯 -5- (；三氟甲基)烟碱醛 6a (420 mg， 2 mmol)溶解于 8 mL甲苯中， 加入 3- ((四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 11a (600 mg， 3 mmol, 采用 "专利申请 WO2009067547 " 公开的方法制备而得)和无水碳酸钾 (553 mg， 4 mmol), 置于封 管中， 100°C搅拌反应 48 小时。 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂 体系 B纯化所得残余物， 得到标题产物 3-((3-甲酰基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 llb (160 mg， 黄色油状物)， 产率： 21.4%。 Ethyl 3-((3-formyl-5-(trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoate 2-chloro-5- (; Trifluoromethyl)nicotinic aldehyde 6a (420 mg, 2 mmol) was dissolved in 8 mL of toluene and added ethyl 3-((tetrahydro-2H-pyran-4-yl)amino)propanoate 11a (600 mg 3 mmol, prepared by the method disclosed in "Patent Application WO2009067547") and anhydrous potassium carbonate (553 mg, 4 mmol), placed in a sealed tube, and stirred at 100 ° C for 48 hours. Filtration, and the filtrate was concentrated under reduced pressure. Tetrahydrogen -2H-pyran-4-yl)amino)propionic acid ethyl ester llb (160 mg, yellow oil), yield: 21.4%.
MS m/z (ESI): 375.1 [M+l] MS m/z (ESI): 375.1 [M+l]
第二步  Second step
3-((3-羟甲基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 将 3-((3-甲酰基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 lib (160 mg， 0.43 mmol)溶于 6 mL乙醇中， 加入硼氢化钠 (20 mg， 0.51 mmol), 搅拌反应 12小时。 反应液减压浓縮， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用 饱和氯化钠溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标 题产物 3-((3-羟甲基 -5- (三氟甲基)吡啶 -2-基) (四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 11c 粗品 (140 mg， 淡黄色油状物)， 产物不经纯化直接用于下步反应。  Ethyl 3-((3-hydroxymethyl-5-(trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoate 3-((3-A) Acyl-5-(trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoic acid ethyl ester lib (160 mg, 0.43 mmol) dissolved in 6 mL of ethanol, added Sodium borohydride (20 mg, 0.51 mmol) was stirred for 12 hours. The reaction mixture was concentrated with EtOAc EtOAc (mjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 3-((3-Hydroxymethyl-5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid ethyl ester 11c crude (140 mg, dry Yellow oil), the product was used in the next step without purification.
MS m/z (ESI): 377.2 [M+l] MS m/z (ESI): 377.2 [M+l]
第三步  third step
3-((3-氯甲基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 将 3-((3-羟甲基 -5- (三氟甲基)吡啶 -2-基) (四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 11c 粗品 C140 mg， 0.37 mmol)溶解于 5 mL二氯甲烷中， 加入氯化亚砜 (57.5 mg， 0.48 mmol),搅拌反应 1.5小时。向反应液中加入 30 mL水，用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物 3-((3-氯甲基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基) 氨基)丙酸乙酯 lid粗品 (146 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Ethyl 3-((3-chloromethyl-5-(trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoate 3-((3-hydroxyl) Methyl-5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid ethyl ester 11c crude C140 mg, 0.37 mmol) dissolved in 5 mL of dichloro To the methane, thionyl chloride (57.5 mg, 0.48 mmol) was added, and the reaction was stirred for 1.5 hours. After adding 30 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (20 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The title product 3-((3-chloromethyl-5-(trifluoromethyl)pyridin-2-ylXtetrahydro-2H-pyran-4-yl)amino)propionic acid ethyl ester lide crude (146 mg, Yellow oil), the product was used in the next step without purification.
第四步  the fourth step
3-((3-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -5- (三氟 甲基)吡啶 -2-基）（四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 冰浴下，将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (116 mg， 0.37 mmol)溶解于 2 mL N，N-二甲基甲酰胺中， 加入六甲基二硅基胺基钠 (0.45 mL， 0.45 mmol), 搅拌反应 30分钟。 再加入 3-((3-氯甲基 -5- (三氟甲基)吡啶 -2-基 X四氢 -2H- 吡喃 -4-基)氨基)丙酸乙酯 lid粗品 (146 mg， 0.37 mmol), 恢复至室温搅拌反应 12 小时。 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (20 mLx3)， 合并有机相， 用饱 和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色 谱法以洗脱剂体系 A纯化所得残余物，得到标题产物 3-((3-(((4 5R)-5-(3，5-双 (三氟 甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -5- (三氟甲基)吡啶 -2-基） （四氢 -2H-吡 喃 -4-基)氨基)丙酸乙酯 11 (25 mg， 白色固体)， 产率： 10.0%。  3-((3-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl)- 5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propanoic acid ethyl ester (4S,5R)-5-(3,5) -Bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (116 mg, 0.37 mmol) dissolved in 2 mL of N,N-dimethylformamide, hexylmethyl Sodium silylamine (0.45 mL, 0.45 mmol) was stirred for 30 min. Further add 3-((3-chloromethyl-5-(trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoic acid ethyl ester lide crude (146 mg, 0.37 mmol), return to room temperature and stir for 12 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by eluent from EtOAc (EtOAc) (EtOAc) -Methyl-2-carbonyloxazolidin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propanoic acid Ethyl 11 (25 mg, white solid), Yield: 10.0%.
MS m/z (ESI): 672.3[M+1] MS m/z (ESI): 672.3 [M+1]
1H NMR (400 MHz, CDC13): δ 8.60-8.50 (m， 1H), 8.03-7.89 (m， 1H), 7.82 (s, 3H), 5.91-5.72 (m， 1H)， 4.83-4.66 (m， 1H)， 4.42-4.24 (m， 1H)， 4.07 (s， 4H)， 3.96-3.75 (m， 1H), 3.65-3.51 (m， 1H), 3.48-3.26 (m， 2H), 3.15-2.96 (m， 1H), 2.46-2.26 (m， 2H), 2.16-1.82 (m， 2H), 1.79-1.47 (m， 2H), 1.26 (m， 4H)， 0.69 (s， 3H) 实施例 12 1H NMR (400 MHz, CDC1 3 ): δ 8.60-8.50 (m, 1H), 8.03-7.89 (m, 1H), 7.82 (s, 3H), 5.91-5.72 (m, 1H), 4.83-4.66 (m , 1H), 4.42-4.24 (m, 1H), 4.07 (s, 4H), 3.96-3.75 (m, 1H), 3.65-3.51 (m, 1H), 3.48-3.26 (m, 2H), 3.15-2.96 (m, 1H), 2.46-2.26 (m, 2H), 2.16-1.82 (m, 2H), 1.79-1.47 (m, 2H), 1.26 (m, 4H), 0.69 (s, 3H) Example 12
(4&5R)-5-(3,5-双 (三氟甲基)苯基) -3-((2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基)吡啶 -3- -4-甲基噁唑 -2-酮  (4&5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Pyridine-3- -4-methyloxazol-2-one
Figure imgf000046_0001
Figure imgf000046_0001
将 4-((3-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷酮 -3-基）甲 基) -5- (三氟甲基)吡啶 -2-基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 10 (47 mg， 67 μηιοΐ)溶解 于 20 mL乙酸乙酯中， 加入 1 M盐酸乙酸乙酯溶液 3 mL， 搅拌反应 6小时。 反应 液减压浓縮， 得到标题产物 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -3-((2- (乙基 (哌啶 -4- 基)氨基) -5- (三氟甲基)吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 12 (40 mg， 淡黄色固体)， 产率： 93.7%。  4-((3-((4())))-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl -5-(Trifluoromethyl)pyridin-2-ylXethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 10 (47 mg, 67 μηιοΐ) dissolved in 20 mL of ethyl acetate, 1 M 3 mL of an ethyl acetate solution was stirred and the reaction was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure to give the title product (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(piperidin-4-yl)) Amino) -5-(trifluoromethyl)pyridin-3-yl)methyl)-4-methyloxazol-2-one 12 (40 mg, pale yellow solid), yield: 93.7%.
MS m/z (ESI): 599.3 [M+l] MS m/z (ESI): 599.3 [M+l]
1H NMR (400 MHz, MeOD): δ 8.56 (s， 1H), 8.04-7.97 (m， 4H)， 5.99 (d， 1H), 4.70 (d， 1H), 4.51 (d， 1H), 4.36 - 4.21 (m， 1H), 3.78 - 3.56 (m， 1H), 3.56 - 3.39 (m， 4H)， 3.18 - 3.03 (m， 2H), 2.19 - 2.02 (m， 4H)， 1.39 - 1.26 (m， 2H), 1.02 (t， 3H), 0.67 (m， 3H) 实施例 13  1H NMR (400 MHz, MeOD): δ 8.56 (s, 1H), 8.04-7.97 (m, 4H), 5.99 (d, 1H), 4.70 (d, 1H), 4.51 (d, 1H), 4.36 - 4.21 (m, 1H), 3.78 - 3.56 (m, 1H), 3.56 - 3.39 (m, 4H), 3.18 - 3.03 (m, 2H), 2.19 - 2.02 (m, 4H), 1.39 - 1.26 (m, 2H) , 1.02 (t, 3H), 0.67 (m, 3H) Example 13
(4&5R)-3-ii2- i-乙酰哌啶 -4-基) (乙基)氨基) -5- (三氟甲基)吡啶 -3-基)甲基) -5-(3,5- 双 (三氟 唑 -2-酮  (4&5R)-3-ii2-i-acetylpiperidin-4-yl)(ethyl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3,5- Bis(trifluoroazol-2-one
Figure imgf000046_0002
Figure imgf000046_0002
13 13
Figure imgf000047_0001
将 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-((2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基) 吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 12 (13 mg， 20 μηιοΐ)溶解于 5 mL二氯甲烷中，加 入三乙胺 (10 mg， 99 μηιο1)和乙酰氯 (5 mg， 59 μηιοΐ), 搅拌反应 2小时。 反应液用 饱和氯化钠溶液洗涤（10 mL) , 无水硫酸钠干燥， 过滤， 得到标题产物 (4WR)-3-((2-((l-乙酰哌啶 -4-基) (乙基)氨基) -5- (三氟甲基)吡啶 -3-基）甲基) -5-(3，5- 双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 13 (10 mg， 淡黄色固体)， 产率： 79.4%。
Figure imgf000047_0001
(4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Pyridin-3-yl)methyl)-4-methyloxazol-2-one 12 (13 mg, 20 μηιοΐ) dissolved in 5 mL of dichloromethane, added with triethylamine (10 mg, 99 μηιο1) and Acetyl chloride (5 mg, 59 μηιοΐ) was stirred for 2 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. Amino) -5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one 13 (10 mg, pale yellow solid), Yield: 79.4%.
MS m/z (ESI): 641.4 [M+l] MS m/z (ESI): 641.4 [M+l]
1H NMR (400 MHz, CDC13): δ 8.54 (s, 1H)， 7.91 (s, 1H)， 7.81 (s, 1H)， 7.77 (s, 2H), 5.75 (d, 1H)， 4.73 (d, 1H)， 4.32 (d, 1H)， 4.01-3.59 (m， 1H)， 3.60-3.33 (m， 1H)， 3.15-3.08 (m， 4H)， 2.61-2.43 (m， 1H), 2.06 (d， 3H), 1.88-1.72 (m， 5H)， 1.42 (t， 3H), 0.65 (t， 3H) 实施例 14 1H NMR (400 MHz, CDC1 3 ): δ 8.54 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.77 (s, 2H), 5.75 (d, 1H), 4.73 (d, 1H), 4.32 (d, 1H), 4.01-3.59 (m, 1H), 3.60-3.33 (m, 1H), 3.15-3.08 (m, 4H), 2.61-2.43 (m, 1H), 2.06 (d, 3H), 1.88-1.72 (m, 5H), 1.42 (t, 3H), 0.65 (t, 3H) Example 14
(4&5R)-3-ii2- i-乙酰哌啶 -4-基) (乙基)氨基) -5- (三氟甲基)吡啶 -3-基)甲基) -5-(3,5- -4-甲基噁唑 -2-酮  (4&5R)-3-ii2-i-acetylpiperidin-4-yl)(ethyl)amino)-5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3,5- -4-methyloxazol-2-one
Figure imgf000047_0002
将 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-((2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基) 吡啶 -3-基)甲基) -4-甲基噁唑 -2-酮 12 (13 mg， 21 μηιοΐ)溶解于 5 mL二氯甲烷中，加 入三乙胺 (l l mg， 104 μηιοΐ)和氯甲酸甲酯 (6 mg， 62 μηιοΐ), 搅拌反应 2小时。 反 应液用饱和氯化钠溶液洗涤 (10 mL) , 无水硫酸钠干燥， 过滤， 得到标题产物 (4WR)-3-((2-((l-乙酰哌啶 -4-基) (乙基)氨基) -5- (三氟甲基)吡啶 -3-基）甲基) -5-(3，5- 双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 14 (11 mg， 淡黄色固体)， 产率： 80.3%。
Figure imgf000047_0002
(4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Pyridin-3-yl)methyl)-4-methyloxazol-2-one 12 (13 mg, 21 μηιοΐ) dissolved in 5 mL of dichloromethane, plus Triethylamine (ll mg, 104 μηιοΐ) and methyl chloroformate (6 mg, 62 μηιοΐ) were added, and the reaction was stirred for 2 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. Amino) -5-(trifluoromethyl)pyridin-3-yl)methyl)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one 14 (11 mg, pale yellow solid), Yield: 80.3%.
MS m/z (ESI): 657.4 [M+l] MS m/z (ESI): 657.4 [M+l]
1H NMR (400 MHz, CDC13): δ 8.55 (s， 1H), 7.90 (s， 1H), 7.84 (s， 1H), 7.77 (s， 2H), 5.74 (d， 1H), 4.77 (d, 1H), 4.39 (d, 1H), 4.36-3.99 (m， 1H), 3.98-3.82 (m， 1H), 3.69 (s， 3H), 3.59-3.33 (m， 1H), 3.32-3.18 (m， 2H), 2.88-2.65 (m， 2H), 1.89-1.56 (m， 5H)， 0.94 (t， 3H), 0.65 (d, 3H) 实施例 15 1H NMR (400 MHz, CDC1 3 ): δ 8.55 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.77 (s, 2H), 5.74 (d, 1H), 4.77 (d, 1H), 4.39 (d, 1H), 4.36-3.99 (m, 1H), 3.98-3.82 (m, 1H), 3.69 (s, 3H), 3.59-3.33 (m, 1H), 3.32-3.18 (m, 2H), 2.88-2.65 (m, 2H), 1.89-1.56 (m, 5H), 0.94 (t, 3H), 0.65 (d, 3H) Example 15
3-ί(3-ίίί 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲 基) -5- (三氟甲基)吡 -2-基）（四氢 -2H-吡喃 -4-基)氨基)丙酸  3-ί(3-ίίί 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolium-3-yl)methyl)-5- (trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl)amino)propionic acid
Figure imgf000048_0001
Figure imgf000048_0001
将 3-((3-(((4WR)-5-(3，5-双 (三氟甲基）苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲 基) -5- (三氟甲基)吡啶 -2-基 X四氢 -2H-吡喃 -4-基)氨基)丙酸乙酯 11 (13 mg， 0.02 mmol)溶解于 1 mL甲醇中， 加入 2 M氢氧化锂溶液 0.1 mL, 搅拌反应 2小时。 滴 加 2 M盐酸是反应液 ρΗ为 3〜4， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱 和氯化钠溶液洗涤 (10 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色 谱法以展开剂体系 A纯化所得残余物，得到标题产物 3-((3-(((4 5R)-5-(3，5-双 (三氟 甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -5- (三氟甲基)吡啶 -2-基） （四氢 -2H-吡 喃 -4-基)氨基)丙酸 15 (10 mg， 白色固体)， 产率： 80.2%。 实施例 16 3-((3-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl) -5-(Trifluoromethyl)pyridin-2-ylxtetrahydro-2H-pyran-4-yl)amino)propanoic acid ethyl ester 11 (13 mg, 0.02 mmol) dissolved in 1 mL of methanol, added 2 0.1 mL of lithium hydroxide solution was stirred for 2 hours. Add 2 M hydrochloric acid to the reaction solution ρΗ is 3~4, extract with ethyl acetate (20 mL×2), combine the organic phase, wash with saturated sodium chloride solution (10 mL×2), dry over anhydrous sodium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by EtOAc EtOAc (EtOAc) -4-methyl-2-carbonyloxazolidin-3-yl)methyl)-5-(trifluoromethyl)pyridin-2-yl)(tetrahydro-2H-pyran-4-yl) Amino)propionic acid 15 (10 mg, white solid), Yield: 80.2%. Example 16
i4&5R)-3-i2-(n-i2H-四氮唑 -5-基)哌啶 -4-基) (乙基)氨基) -5- (三氟甲基)苄基 -5-(3,5- 双 (三氟甲基)苯基) -4-甲基噁唑烷酮 -2-酮I4&5R)-3-i2-(n-i2H-tetrazol-5-yl)piperidin-4-yl)(ethyl)amino)-5-(trifluoromethyl)benzyl-5-(3, 5-bis(trifluoromethyl)phenyl)-4-methyloxazolidinone-2-one
Figure imgf000049_0001
Figure imgf000050_0001
第一步
Figure imgf000049_0001
Figure imgf000050_0001
first step
2-((l-(叔丁氧碳基)哌啶 -4-基)氨基) -5- (三氟甲基)苯甲酸 将 2-氟 -5- (三氟甲基)苯甲酸 la (1 g， 5 mmol)溶解于 10 mL N，N-二甲基甲酰胺 中， 加入 4-氨基哌啶 -1-甲酸叔丁酯 (1.50 g， 7.50 mmol , 采用公知的方法文献 " Bioorganic & Medicinal Chemistry Letters 2011_21_983 - 988 "制备而得)和无水碳 酸钾 C2 g， 15 mmol),置于封管中， 100°C搅拌反应 12小时。向反应液中加入 20 mL 水， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物 2-((1- (叔丁氧碳基)哌啶 -4- 基)氨基) -5- (三氟甲基)苯甲酸 16a粗品 (1.94 g， 褐色油状物)， 产物不经纯化直接用 于下步反应。  2-((l-(tert-Butoxycarbonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)benzoic acid 2-fluoro-5-(trifluoromethyl)benzoic acid la ( 1 g, 5 mmol) was dissolved in 10 mL of N,N-dimethylformamide and tert-butyl 4-aminopiperidine-1-carboxylate (1.50 g, 7.50 mmol, using known methods) Bioorganic & Medicinal Chemistry Letters 2011_21_983 - 988 "Prepared" and anhydrous potassium carbonate C2 g, 15 mmol), placed in a sealed tube and stirred at 100 ° C for 12 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The title product is 2-((1-(tert-butoxycarbyl)piperidin-4-yl)amino)-5-(trifluoromethyl)benzoic acid 16a crude (1.94 g, brown oil). Used directly in the next step of the reaction.
第二步  Second step
4-((2- (乙酯基 )-4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 将 2- 1 叔丁氧碳基)哌啶 -4-基)氨基) -5- (三氟甲基)苯甲酸 16&粗品(1.94 g， 5 mmol)溶解于 50 mL N，N-二甲基甲酰胺中， 加入氢化钠 (；2 g， 50 mmol), 搅拌反应 5小时， 再加入碘乙烷 (8 mL， 100 mmol), 继续反应 12小时。 冷却至 0°C， 向反应 液中加入 100 mL水， 用乙酸乙酯萃取 (50 mIX3)， 合并有机相， 用饱和氯化钠溶 液洗涤 (30 mLx3)，无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物 4-((2- (乙 酯基)—4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 16b粗品 (2.20 g， 黄色油状 物)， 产物不经纯化直接用于下步反应。  4-((2-(Ethyl))-4-(trifluoromethyl)phenyl Xethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 2- 2-tert-butoxycarbonyl)piperidine- 4-yl)amino)-5-(trifluoromethyl)benzoic acid 16 & crude (1.94 g, 5 mmol) was dissolved in 50 mL of N,N-dimethylformamide and sodium hydride (2 g, 50 (mmol), the reaction was stirred for 5 hours, then ethyl iodide (8 mL, 100 mmol) was added and the reaction was continued for 12 hours. After cooling to 0 ° C, 100 mL of water was added to the reaction mixture, and extracted with ethyl acetate (50 mIX3). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×3), dried over anhydrous sodium sulfate Concentration under reduced pressure gave the title product 4-((2-(Ethyl)) 4-(trifluoromethyl)phenylethylethyl)ethyl)piperidine-1-carboxylic acid tert-butyl ester 16b (2.20 g , yellow oil), the product was used in the next step without purification.
第三步  third step
4- (乙基 (2- (羟甲基 )-4- (三氟甲基)苯基)氨基)哌啶小甲酸叔丁酯 将 4-((2- (乙酯基) -4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 16b粗品 (2 g， 4.50 mmol)溶解于 40 mL四氢呋喃中， 分批加入氢化铝锂 (342 mg， 9 mmol), 搅拌反应 2小时。 用 100 mL水铵淬灭反应， 过滤， 乙酸乙酯萃取 (50 mLx2)， 合 并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用硅胶柱色谱法以洗脱剂体系 B 纯化所得残余物， 得到标题产物 4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)哌啶 -1-甲酸叔丁酯 16c (300 mg，无色油状物)， 产率： 16.6%。  Tetrabutyl 4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)amino)piperidinecarboxylate 4-((2-(ethyl))-4-( Trifluoromethyl)phenyl Xethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 16b crude (2 g, 4.50 mmol) was dissolved in 40 mL of tetrahydrofuran, and lithium aluminum hydride (342 mg, 9 mmol) ), the reaction was stirred for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The obtained residue was purified to silica gel column chromatography elut elut elut elut - tert-butyl formate 16c (300 mg, colorless oil), yield: 16.6%.
MS m/z (ESI): 403.2[M+1] MS m/z (ESI): 403.2 [M+1]
第四步 4- (乙基 (2- (氯甲基 )-4- (三氟甲基)苯基)氨基)哌啶小甲酸叔丁酯 the fourth step 4-(Ethyl(2-(chloromethyl)-4-(trifluoromethyl)phenyl)amino)piperidinecarboxylic acid tert-butyl ester
将 4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)哌啶小甲酸叔丁酯 16c粗品 (300 mg， 0.75 mmol)溶解于 7 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (54 mg， 0.75 mmol), 搅拌反应 4小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (15 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮，得到标题产物 4- (乙基 (2- (氯甲基 )-4- (三氟甲基)苯基)氨基)哌啶 -1-甲酸叔丁 酯 16d粗品 (313 mg， 淡黄色油状物)， 产物不经纯化直接用于下步反应。  Dissolve 4-(ethyl(2-(hydroxymethyl))-4-(trifluoromethyl)phenyl)amino)piperidine carboxylic acid tert-butyl ester 16c (300 mg, 0.75 mmol) in 7 mL of N, To the N-dimethylformamide, thionyl chloride (54 mg, 0.75 mmol) was added, and the reaction was stirred for 4 hours. After adding 30 mL of water to the reaction mixture, the mixture was combined with EtOAc EtOAc (EtOAc) The title product 4-(ethyl(2-(chloromethyl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester 16d crude (313 mg, pale yellow oil) The product was used in the next step without purification.
第五步  the fifth step
4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟 甲基)苯基 X乙基)氨基)哌啶 - 1 -甲酸叔丁酯 将 4- (乙基 (2- (氯甲基) -4- (三氟甲基)苯基)氨基)哌啶 -1-甲酸叔丁酯 16d (313 mg， 0.75 mmol)溶解于 6 mL N，N-二甲基甲酰胺中，加入 (4S，5R)-5-(3，5-双 (三氟甲基) 苯基) -4-甲基噁唑 -2-酮 lg (235 mg， 0.75 mmol)和无水碳酸钾 (310 mg， 2.25 mmol), 75 °C搅拌反应 12小时。 冷却至室温， 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (30 mLx3), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产 物 4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三 氟甲基)苯基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 16e (190 mg，白色固体)，产率： 36.3%。 MS m/z (ESI): 698.4 [M+l]  4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl)- 4-(Ethyl(2-(chloromethyl)-4-(trifluoromethyl)phenyl) 4-(trifluoromethyl)phenyl Xethyl)amino)piperidine-1-carboxylic acid tert-butyl ester Amino) piperidine-1-carboxylic acid tert-butyl ester 16d (313 mg, 0.75 mmol) was dissolved in 6 mL of N,N-dimethylformamide, and (4S,5R)-5-(3,5-double (Trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (235 mg, 0.75 mmol) and anhydrous potassium carbonate (310 mg, 2.25 mmol), and stirred at 75 ° C for 12 hours. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered The residue was purified by EtOAc (EtOAc) elut elut 4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 16e (190 mg , white solid), Yield: 36.3%. MS m/z (ESI): 698.4 [M+l]
第六步  Step 6
( 5 -5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基)苄基) -4- 甲基噁唑 -2-酮  (5 -5-(3,5-Bis(trifluoromethyl)phenyl)-3-(2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl)benzyl ) -4-methyloxazol-2-one
将 4-((2-(((4WR)-5-(3，5-双 (三氟甲基）苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲 基) -4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-甲酸叔丁酯 16e (100 mg， 0.14 mmol)溶解 于 3 mL二氯甲烷中， 加入三氟乙酸 (0.11 mL， 1.40 mmol), 搅拌反应 2小时。 反 应液减压浓縮， 用乙酸乙酯萃取 (30 mL)， 合并有机相， 用饱和碳酸氢钠溶液洗涤 (25 mL),无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物 (4 5R)-5-(3，5-双 (三 氟甲基)苯基) -3-(2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基)苄基) -4-甲基噁唑 -2-酮 16f 粗品 (83 mg， 黄色固体)， 产物不经纯化直接用于下步反应。  4-((2-((4())))-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl) -4-(Trifluoromethyl)phenyl Xethyl)amino)piperidine-1-carboxylic acid tert-butyl ester 16e (100 mg, 0.14 mmol) was dissolved in 3 mL dichloromethane, then trifluoroacetic acid (0.11 mL) , 1.40 mmol), stir the reaction for 2 hours. The reaction mixture was concentrated with EtOAc EtOAc. (4 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Benzyl)-4-methyloxazol-2-one 16f crude (83 mg, yellow solid), product was used in the next step without purification.
第七步  Seventh step
4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟 甲基)苯基 X乙基)氨基)哌啶 - 1 -乙腈  4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl)- 4-(Trifluoromethyl)phenyl Xethyl)amino)piperidine-1 -acetonitrile
将 (4WR)-5-(3，5-双 (三氟甲基)苯基) -3-(2- (乙基 (哌啶 -4-基)氨基) -5- (三氟甲基) 苄基) -4-甲基噁唑 -2-酮 16f粗品 (73 mg， 0.12 mmol)溶解于 5 mL二氯甲烷中， 碳酸 氢钠 (42 mg， 0.50 mmol)用 4 mL水稀释后加入反应液， 再加入溴化氰 (14 mg， 0.13 mmol), 搅拌反应 12小时。 用二氯甲烷萃取 (10 mIX3)， 合并有机相， 用饱和氯化 钠溶液洗涤 (10 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法 以洗脱剂体系 B纯化所得残余物，得到标题产物 4-((2-(((4S，5R)-5-(3，5-双 (三氟甲基) 苯基)—4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-乙腈 16g (60 mg, 白色固体)， 产率： 80.0%。 (4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(ethyl(piperidin-4-yl)amino)-5-(trifluoromethyl) Benzyl)-4-methyloxazol-2-one 16f crude (73 mg, 0.12 mmol) was dissolved in 5 mL dichloromethane. NaHCO3 (42 mg, 0.50 mmol) Further, cyanogen bromide (14 mg, 0.13 mmol) was added, and the reaction was stirred for 12 hours. Extract with dichloromethane (10 mIX3), combine the organic phases, and chlorinate with saturated The sodium solution was washed (10 mL×2), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl Phenyl X ethyl)amino)piperidine-1-acetonitrile 16 g (60 mg, white solid), yield: 80.0%.
MS m/z (ESI): 623.2 [M+l] MS m/z (ESI): 623.2 [M+l]
第八步  Eighth step
(4WR)-3-(2-((l-(2H-四氮唑 -5-基)哌啶 -4-基 X乙基)氨基) -5- (三氟甲基)苄基 -5-(3，5- 双 (三氟甲基)苯基) -4-甲基噁唑烷 -2-酮  (4WR)-3-(2-((l-(2H-tetraazol-5-yl)piperidin-4-yl)ethyl)amino)-5-(trifluoromethyl)benzyl-5- (3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one
将 4-((2-(((4WR)-5-(3，5-双 (三氟甲基）苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲 基) -4- (三氟甲基)苯基 X乙基)氨基)哌啶 -1-乙腈 16g (62 mg, 0.10 mmol)溶解于 1 mL 甲苯中， 加入叠氮化钠 (7.8 mg， 0.12 mmol)和三乙胺盐酸盐 (17 mg， 0.12 mmol), 100°C搅拌反应 3小时。 冷却至室温， 向反应液中加入 5 mL水， 滴加 1 M盐酸至 反应液 ρΗ为 6〜7， 用乙酸乙酯萃取 (15 mIX3)， 合并有机相， 用饱和氯化钠溶液 洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以洗脱剂 体系 A 纯化所得残余物， 得到标题产物 (4 5R)-3-(2-((l-(2H-四氮唑 -5-基)哌啶 -4- 基 X乙基)氨基) -5- (三氟甲基)苄基 -5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑烷 -2-酮 16 (30 mg, 白色固体)， 产率： 45.4%。  4-((2-((4())))-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)methyl) -4-(Trifluoromethyl)phenyl Xethyl)amino)piperidine-1-acetonitrile 16 g (62 mg, 0.10 mmol) dissolved in 1 mL of toluene and sodium azide (7.8 mg, 0.12 mmol) Triethylamine hydrochloride (17 mg, 0.12 mmol) was stirred at 100 ° C for 3 hours. After cooling to room temperature, 5 mL of water was added to the reaction solution, and 1 M hydrochloric acid was added dropwise to the reaction solution to obtain 6 to 7 portions, which were extracted with ethyl acetate (15 mIX3), and the organic phases were combined and washed with a saturated sodium chloride solution (15) </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; (2H-tetraazol-5-yl)piperidin-4-ylXethyl)amino)-5-(trifluoromethyl)benzyl-5-(3,5-bis(trifluoromethyl)benzene -4-methyloxazolidin-2-one 16 (30 mg, white solid), Yield: 45.4%.
MS m/z (ESI): 666.4 [M+l] MS m/z (ESI): 666.4 [M+l]
1H NMR (400 MHz, CDC13): δ 8.00 - 7.88 (m， 1H), 7.87 - 7.75 (m， 2H), 7.63 - 7.57 (m: 1H), 7.56 - 7.48 (m， 1H), 7.29 - 7.22 (m， 1H), 5.88 - 5.72 (m， 1H), 4.85 - 4.71 (m， 1H)， 4.57 - 4.44 (m, 1H), 4.1 1 - 3.97 (m, 1H), 3.93 - 3.78 (m, 2H), 3.13 - 2.95 (m, 3H), 2.86 - 2.58 (m， 3H), 1.82 - 1.67 (m， 2H), 1.66 - 1.50 (m， 1H), 10.91 - 0.78 (m， 3H), 0.73 - 0.59 (m， 3H) 实施例 17 1H NMR (400 MHz, CDC1 3 ): δ 8.00 - 7.88 (m, 1H), 7.87 - 7.75 (m, 2H), 7.63 - 7.57 (m : 1H), 7.56 - 7.48 (m, 1H), 7.29 - 7.22 (m, 1H), 5.88 - 5.72 (m, 1H), 4.85 - 4.71 (m, 1H), 4.57 - 4.44 (m, 1H), 4.1 1 - 3.97 (m, 1H), 3.93 - 3.78 (m, 2H ), 3.13 - 2.95 (m, 3H), 2.86 - 2.58 (m, 3H), 1.82 - 1.67 (m, 2H), 1.66 - 1.50 (m, 1H), 10.91 - 0.78 (m, 3H), 0.73 - 0.59 (m, 3H) Example 17
反式 -4-((2-W 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲  Trans-4-((2-W 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolium-3-yl)-
基) -4- (三氟 基)环己甲酸  -4-(trifluoro)cyclohexanoic acid
Figure imgf000052_0001
Figure imgf000052_0001
17 17
Figure imgf000053_0001
Figure imgf000053_0001
17d  17d
第一步  First step
反式 -4-((2-甲酰基 -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 将 2-氟 -5- (三氟甲基)苯甲醛 la (460 mg, 2.40 mmol)和反式 -4- (甲胺)环己甲酸 甲酯 (600 mg， 3.50 mmol， 采用 "专利 EP1582521 " 公开的方法制备而得)混合 后， 加入无水碳酸钾 (500 mg， 3.60 mmol), 130°C下反应 2小时。 冷却至室温， 向 反应液中加入 20 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠 溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4-((2-甲酰基 -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17&粗品(824 mg, 黄色 油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-formyl-4-(trifluoromethyl)phenyl)methyl)amino)cyclohexanecarboxylic acid methyl 2-fluoro-5-(trifluoromethyl)benzaldehyde la ( 460 mg, 2.40 mmol) and methyl trans-4-(methylamine)cyclohexanecarboxylate (600 mg, 3.50 mmol, prepared by the method disclosed in "Patent EP1582521"), after mixing, anhydrous potassium carbonate (500) Mg, 3.60 mmol), reacted at 130 ° C for 2 hours. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered Concentration gave the title product trans-4-((2-formyl-4-(trifluoromethyl)phenyl)methyl)methyl)amino)cyclohexanecarboxylic acid methyl ester 17 & crude (824 mg, yellow oil). The product was used in the next step without purification.
MS m/z (ESI): 344.2 [M+l] MS m/z (ESI): 344.2 [M+l]
第二步  Second step
反式 -4-((2- (羟甲基) -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 将反式 -4-((2-甲酰基 -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17&粗品(800 mg, 2.33 mmol)溶于 20 mL甲醇和四氢呋喃 (V/V = 1 : 1)混合溶剂中， 加入硼氢化钠 (97 mg, 2.50 mmol), 搅拌反应 1.5小时。 向反应液中加入 30 mL水， 减压浓縮去 除大部分溶剂， 再用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液洗 涤 (30 mLx2)，无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物反式 -4-((2- (羟 甲基)—4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17b粗品 (800 mg,黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)methyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-((2-formyl-4) - (Trifluoromethyl)phenyl X methyl)amino)cyclohexanecarboxylic acid methyl ester 17 & crude (800 mg, 2.33 mmol) dissolved in 20 mL of methanol and tetrahydrofuran (V / V = 1:1) mixed solvent, added Sodium borohydride (97 mg, 2.50 mmol) was stirred for 1.5 h. To the reaction mixture, 30 mL of water was added, and the solvent was evaporated to dryness, and then evaporated to ethyl acetate (30 mL?), and the organic phase was combined and washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate Filtration and concentration of the filtrate under reduced pressure afforded the crude product of the title product trans-4-((2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)methyl)methyl)amino)cyclohexanecarboxylate 17b (800 mg, yellow oil), product was used in the next step without purification.
MS m/z (ESI): 346.2 [M+l] MS m/z (ESI): 346.2 [M+l]
第三步  third step
反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 将反式 -4-((2- (羟甲基) -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17b (800 mg， 2.33 mmol)溶解于 15 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (0.25 mL， 3.50 mmol), 搅拌反应 4小时。 向反应液中加入 30 mL水， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸 甲酯 17c粗品 (847 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。 Trans-4-((2-(chloromethyl)-4-(trifluoromethyl)phenyl)methyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-((2-(hydroxymethyl) ) methyl 4-(trifluoromethyl)phenyl Xmethyl)amino)cyclohexanecarboxylate 17b (800 Mg, 2.33 mmol) was dissolved in 15 mL of N,N-dimethylformamide, then chlorosulfoxide (0.25 mL, 3.50 mmol) was added and the mixture was stirred for 4 hr. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. Product title: trans-4-((2-(Chloromethyl)-4-(trifluoromethyl)phenyl)methyl)methyl)cyclohexanecarboxylate 17c crude (847 mg, yellow oil) It was used in the next step without purification.
第四步  the fourth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 冰浴下，将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (720 mg， 2.33 mmol)溶解于 15 mL N，N-二甲基甲酰胺中， 加入氢化钠 (111 mg， 2.80 mmol), 搅拌 反应 1小时， 加入 3 mL反式 -4-((2- (氯甲基 )-4- (三氟甲基)苯基 X甲基)氨基)环己甲 酸甲酯 17c粗品 (847 mg， 2.33 mmol)的 N，N-二甲基甲酰胺溶液， 加毕， 升至室温， 搅拌反应 30分钟。 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (30 mLx3)， 合并 有机相， 用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓 縮， 得到标题产物反式 -4 2-W4WR)-5-《3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁 唑烷 -3-基)甲基) -4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17d (320 mg, 白色固 体)， 产率： 21.5%。  Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl) 4-(trifluoromethyl)phenyl Xmethyl)amino)cyclohexanecarboxylic acid methyl ester (4S,5R)-5-(3,5-bis(trifluoromethyl) Phenyl)-4-methyloxazol-2-one lg (720 mg, 2.33 mmol) was dissolved in 15 mL of N,N-dimethylformamide, sodium hydride (111 mg, 2.80 mmol) 1 hour, add 3 mL of crude trans-4-((2-(chloromethyl)-4-(trifluoromethyl)phenyl)methyl)amino)cyclohexanecarboxylate 17c (847 mg, 2.33 mmol The solution of N,N-dimethylformamide was added, and the mixture was warmed to room temperature, and the reaction was stirred for 30 minutes. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The sodium chloride solution was washed (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product trans-4-4-W4WR)-5-"3,5-bis(trifluoromethyl) Phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenylXmethyl)amino)cyclohexanecarboxylic acid methyl ester 17d (320 mg, White solid), Rate: 21.5%.
第五步  the fifth step
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl))
基)—4- (三氟甲基)苯基 X甲基)氨基)环己甲酸 将反式 -4-((2-(((4S，5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基)—4- (三氟甲基)苯基 X甲基)氨基)环己甲酸甲酯 17d (320 mg， 0.50 mmol)溶解于 6 mL四氢呋喃和水 (V/V = 5: l)混合溶剂中， 加入氢氧化锂 (42 mg， 1 mmol), 搅拌 反应 12小时。滴加 1 M盐酸至反应液 pH为 3〜4， 用乙酸乙酯萃取 (15 mLx3)， 合 并有机相， 用饱和氯化钠溶液洗涤 (15 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用薄层色谱法以展开剂体系 A 纯化所得残余物， 得到标题产物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三氟 甲基)苯基 X甲基)氨基)环己甲酸 17 (100 mg， 白色固体)， 产率： 31.9%。  4-(3-trifluoromethyl)phenyl Xmethyl)amino)cyclohexanecarboxylic acid trans-4-((2-((4S,5R)-5-((3,5R)-5-((3,5-bis) Methyl trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xmethyl)amino)cyclohexanecarboxylate 17d (320 mg, 0.50 mmol) was dissolved in 6 mL of a mixture of tetrahydrofuran and water (V/V = 5:1). 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). The organic phase was combined and washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered, The resulting residue was purified by EtOAc (EtOAc) elut elut 4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xmethyl)amino)cyclohexanecarboxylic acid 17 (100 mg, white solid) : 31.9%.
MS m/z (ESI): 627.4[M+1] MS m/z (ESI): 627.4 [M+1]
1H NMR (400 MHz, CDC13): δ 7.93 (s， 1H), 7.81 (s， 2H), 7.64 (s， 1H), 7.61 - 7.51 (m， 1H), 7.29 (s， 1H), 5.76 (d， 1H), 4.91 - 4.78 (m， 1H), 4.65 - 4.43 (m， 1H), 4.08 - 3.88 (m: 1H), 2.76 (s, 4H)， 2.35 - 2.23 (m， 1H)， 2.21 - 2.05 (m， 2H), 2.05 - 1.93 (m， 1H)， 1.93 - 1.76 (m， 1H), 1.51 (d， 4H),0.91-0.96 (m， 1H), 0.72 (d， 3H) 实施例 18 1H NMR (400 MHz, CDC1 3 ): δ 7.93 (s, 1H), 7.81 (s, 2H), 7.64 (s, 1H), 7.61 - 7.51 (m, 1H), 7.29 (s, 1H), 5.76 ( d, 1H), 4.91 - 4.78 (m, 1H), 4.65 - 4.43 (m, 1H), 4.08 - 3.88 (m : 1H), 2.76 (s, 4H), 2.35 - 2.23 (m, 1H), 2.21 - 2.05 (m, 2H), 2.05 - 1.93 (m, 1H), 1.93 - 1.76 (m, 1H), 1.51 (d, 4H), 0.91-0.96 (m, 1H), 0.72 (d, 3H) Example 18
反式 -4-((2-W 5R)-5-(3,5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑垸 -3-基)甲  Trans-4-((2-W 5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolium-3-yl)-
基) -4- (三氟甲氧基)苯基) (乙基)氨基)环己甲酸 -4-(trifluoromethoxy)phenyl)(ethyl)amino)cyclohexanecarboxylic acid
Figure imgf000055_0001
第一步
Figure imgf000055_0001
first step
反式 -4- (乙基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 将 2-氟 -5- (三氟甲氧基)苯甲醛 (2.08 g， 10 mmol , 采用公知的方法 "专利 US2006128691 "制备而得)和反式 -4- (乙胺)环己甲酸甲酯 (2.22 g， 12 mmol，采用 "专 利申请 WO200971509" 公开的方法制备而得)混合后， 加入无水碳酸钾 P.07 g， 15 mmol), 130°C下反应 4小时。 冷却至室温， 过滤， 用二氯甲烷萃取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮，用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物，得到标题产物反式 -4- (乙 基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 18a (820 mg， 黄色油状物)， 产率： 22.0%。  Trans-4-(ethyl(2-formyl-4-(trifluoromethoxy)phenyl)amino)cyclohexanecarboxylic acid methyl ester 2-fluoro-5-(trifluoromethoxy)benzaldehyde ( 2.08 g, 10 mmol, prepared by the well-known method "patent US2006128691" and trans-4-(ethylamine) cyclohexanecarboxylate (2.22 g, 12 mmol, prepared by the method disclosed in "Patent Application WO200971509") After mixing, anhydrous potassium carbonate P.07 g, 15 mmol) was added, and the reaction was carried out at 130 ° C for 4 hours. The mixture was cooled to room temperature, filtered, and purified with methylene chloride (50 mL EtOAc). The residue obtained was purified by eluent B to give the title product, &lt;RTI ID=0.0&gt; 820 mg, yellow oil), Yield: 22.0%.
MS m/z (ESI): 374.5 [M+l] MS m/z (ESI): 374.5 [M+l]
第二步  Second step
反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 将反式 -4- (乙基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 18a (820 mg， 2.20 mmol)溶于 50 mL甲醇中， 加入硼氢化钠（100 mg， 2.64 mmol), 搅拌反 应 2小时。 用 20 mL水淬灭反应， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱 和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题 产物反式 -4- (乙基 (2- (羟甲基 )-4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 18b 粗品 (814 mg, 黄色油状物)， 产物不经纯化直接用于下步反应。 Trans-4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-(ethyl(2-formyl)) Methyl -4-(trifluoromethoxy)phenyl)amino)cyclohexanecarboxylate 18a (820 mg, 2.20 mmol) was dissolved in 50 mL of methanol, sodium borohydride (100 mg, 2.64 mmol). hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Product trans-4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexanecarboxylate 18b crude (814 mg, yellow oil), product Purified directly for the next step of the reaction.
MS m/z (ESI): 434.5[M+1] MS m/z (ESI): 434.5 [M+1]
第三步  third step
反式 -4-((2- (氯甲基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己甲酸甲酯 将反式 -4- (乙基 (2- (羟甲基 )-4- (三氟甲氧基)苯基)氨基)环己甲酸甲酯 18b 粗品 (230 mg, 0.61 mmol)溶解于5 mL N，N-二甲基甲酰胺中，加入氯化亚砜 (87 mg， 0.74 mmol), 搅拌反应 2小时。 向反应液中加入 10 mL水， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (10 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物反式 -4-((2- (氯甲基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己甲 酸甲酯 18c粗品 (240 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-(chloromethyl)-4-(trifluoromethoxy)phenylXethyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-(ethyl(2-( Methyl hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexanecarboxylate 18b crude (230 mg, 0.61 mmol) dissolved in 5 mL of N,N-dimethylformamide Sulfoxide (87 mg, 0.74 mmol) was stirred for 2 hours. After adding 10 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL×2), and the organic phase was combined and washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The title product is the crude product of trans-4-((2-(chloromethyl)-4-(trifluoromethoxy)phenyl)ethyl)ethyl)cyclohexanecarboxylate 18c (240 mg, yellow oil). The product was used in the next step without purification.
MS m/z (ESI): 390.3[M+1] MS m/z (ESI): 390.3 [M+1]
第四步  the fourth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲氧基)苯基 X乙基)氨基)环己甲酸甲酯 将 ( ^，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (192 mg, 0.61 mmol) 溶解于 5 mL N，N-二甲基甲酰胺中， 加入氢化钠 C29 mg, 0.74 mmol), 搅拌反应 1 小时， 加入 3 mL反式 -4-((2- (氯甲基) -4- (三氟甲氧基)苯基) (乙基)氨基)环己甲酸甲 酯 18c粗品 (240 mg， 0.61 mmol)的 N，N-二甲基甲酰胺溶液， 搅拌反应 0.5小时。 向 反应液中加入 10 mL水， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠 溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲基) -4- (三 氟甲氧基)苯基 X乙基)氨基)环己甲酸甲酯 18d粗品 (490 mg， 黄色固体)， 产物不经 纯化直接用于下步反应。  Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl) 4-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexanecarboxylic acid methyl ester (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl) -4-Methyloxazol-2-one lg (192 mg, 0.61 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (C29 mg, 0.74 mmol) was added, and the reaction was stirred for 1 hour. 3 mL of trans-4-((2-(chloromethyl)-4-(trifluoromethoxy)phenyl)(ethyl)amino)cyclohexanecarboxylate 18c crude (240 mg, 0.61 mmol) A solution of N,N-dimethylformamide was stirred for 0.5 hours. After adding 10 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered and evaporated. The title product trans-4-((2-((4))-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidine-3- Methyl)methyl)-4-(trifluoromethoxy)phenylXethyl)amino)cyclohexanecarboxylate 18d crude (490 mg, yellow solid), product was used in the next step without purification.
MS m/z (ESI): 671.4 [M+l] MS m/z (ESI): 671.4 [M+l]
第五步  the fifth step
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲氧基)苯基 X乙基)氨基)环己甲酸 将反式 -4-((2-(((4 5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己甲酸甲酯 18d粗品 (411 mg, 0.61 mmol) 溶解于 9 mL四氢呋喃和水 (V/V = 2:1)混合溶剂中， 加入氢氧化锂 (129 mg, 3.07 mmol), 搅拌反应 12小时。 滴加 1 M盐酸至反应液 pH为 3〜4， 用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 A纯化所得残余物， 得到标题产 物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基）苯基) -4-甲基 -2-羰基噁唑烷 -3-基）甲 基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己甲酸 18 (160 mg, 淡黄色固体)， 产率： 39.8%。 Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) 4-(3-trifluoromethoxy)phenyl Xethyl)amino)cyclohexanecarboxylic acid trans-4-((2-((4 5R)-5-((3,5-)) Trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexanecarboxylic acid The ester 18d crude product (411 mg, 0.61 mmol) was dissolved in a mixture of 9 mL of tetrahydrofuran and water (V/V = 2:1), and lithium hydroxide (129 mg, 3.07 mmol) was added, and the reaction was stirred for 12 hours. M hydrochloric acid until the pH of the reaction mixture is 3 to 4, and extracted with ethyl acetate (30 mL×2). The organic phase is combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, The resulting residue was purified by EtOAc (EtOAc) eluting -4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexanecarboxylic acid 18 (160 mg, pale yellow solid ), Yield: 39.8%.
MS m/z (ESI): 657.4[M+1]  MS m/z (ESI): 657.4 [M+1]
1H NMR (400 MHz, CDC13): δ 7.90 (s, 1H), 7.82 (s, 2H), 7.20 (d, 2H), 7.16 - 7.13 (m， 1H), 5.74 (d, 1H)， 4.88 - 4.70 (m， 1H)， 4.69 - 4.50 (m， 1H)， 4.15 - 3.95 (m， 1H)， 3.24 - 3.01 (m， 2H), 2.80 - 2.60 (m， 1H), 2.23 - 1.89 (m， 4H)， 1.55 - 1.34 (m， 4H)， 0.95 (m， 4H)， 0.72 (d， 3H) 实施例 19 1H NMR (400 MHz, CDC1 3 ): δ 7.90 (s, 1H), 7.82 (s, 2H), 7.20 (d, 2H), 7.16 - 7.13 (m, 1H), 5.74 (d, 1H), 4.88 - 4.70 (m, 1H), 4.69 - 4.50 (m, 1H), 4.15 - 3.95 (m, 1H), 3.24 - 3.01 (m, 2H), 2.80 - 2.60 (m, 1H), 2.23 - 1.89 (m, 4H ), 1.55 - 1.34 (m, 4H), 0.95 (m, 4H), 0.72 (d, 3H) Example 19
反式 -4-ii2-W4&5R 5-a5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲基 4-  Trans-4-i2-W4&5R 5-a5-bis(trifluoromethyl)phenyl 4-methyl-2-carbonyloxazolidine-3-yl)methyl 4-
Figure imgf000057_0001
Figure imgf000057_0001
第一步  First step
反式—4-((4-氰基 -2-甲酰苯基 X乙基)氨基)环己甲酸甲酯 将 4-氟 -3-甲酰苯甲腈 (400 mg， 2.70 mmol, 毕得，货号 B5661)和反式 -4- (；乙胺) 环己甲酸甲酯 (500 mg， 2.70 mmol， 采用 "专利申请 WO200971509" 公开的方 法制备而得)混合后， 加入无水碳酸钾 (560 mg， 4.05 mmol), 90°C下反应 12小时。 冷却至室温， 加入乙酸乙酯溶解， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱 剂体系 B纯化所得残余物， 得到标题产物反式 -4-((4-氰基 -2-甲酰苯基 )(乙基)氨基) 环己甲酸甲酯 19a (550 mg， 黄色固体)， 产率： 64.8%。 MS m/z (ESI): 315.2 [M+l] Trans-methyl 4-((4-cyano-2-formylphenylXethyl)amino)cyclohexanecarboxylate 4-fluoro-3-formylbenzonitrile (400 mg, 2.70 mmol, BET) , Item No. B5661) and trans-4-(;ethylamine) methyl cyclohexanecarboxylate (500 mg, 2.70 mmol, prepared by the method disclosed in "Patent Application WO200971509"), after mixing, anhydrous potassium carbonate (560) Mg, 4.05 mmol), reacted at 90 ° C for 12 hours. After cooling to room temperature, it was dissolved in ethyl acetate, filtered, and the filtrate was evaporated evaporated evaporated. -Formylphenyl)(ethyl)amino)methyl cyclohexanecarboxylate 19a (550 mg, yellow solid), Yield: 64.8%. MS m/z (ESI): 315.2 [M+l]
第二步  Second step
反式—4-((4-氰基 -2- (羟甲基)苯基 χ乙基)氨基)环己甲酸甲酯 将反式—4-((4-氰基 -2-甲酰苯基 X乙基)氨基)环己甲酸甲酯 19a (550 mg， 1.74 mmol)溶于 20 mL甲醇中， 加入硼氢化钠 (72 mg， 1.91 mmol), 搅拌反应 1小时。 用 20 mL水淬灭反应， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶 液洗涤 (30 mLx2)，无水硫酸钠干燥，过滤，滤液减压浓縮，得到标题产物反式 -4-((4- 氰基 -2- (羟甲基)苯基 X乙基)氨基)环己甲酸甲酯 19b粗品 (550 mg，黄色油状物)，产 物不经纯化直接用于下步反应。  Trans-methyl 4-((4-cyano-2-(hydroxymethyl)phenylphosphonium)amino)cyclohexanecarboxylate will be trans-4-((4-cyano-2-formylbenzene) The methyl group of ethyl 2-ethyl)amino)cyclohexanecarboxylate 19a (550 mg, 1.74 mmol) was dissolved in 20 mL of methanol, sodium borohydride (72 mg, 1.91 mmol) was added, and the reaction was stirred for 1 hour. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The crude product of trans-4-((4-cyano-2-(hydroxymethyl)phenyl)ethyl)ethyl)cyclohexanecarboxylate 19b (550 mg, yellow oil). In the next step of the reaction.
第三步  third step
反式 -4-((2- (氯甲基) -4-苯腈基 X乙基)氨基)环己甲酸甲酯 将反式 -4-((4-氰基 -2- (羟甲基)苯基 X乙基)氨基)环己甲酸甲酯 19b 粗品 (550 mg， 1.74 mmol)溶解于 10 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (310 mg， 2.60 mmol), 搅拌反应 2小时。 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (30 mLx3)， 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx3)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物反式 -4-((2- (氯甲基 )-4-苯腈基 X乙基)氨基)环己甲酸甲酯 19c 粗品 (580 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-(chloromethyl)-4-phenylcarbonitrile Xethyl)amino)cyclohexanecarboxylic acid methyl ester trans-4-((4-cyano-2-(hydroxymethyl) ) Phenyl X ethyl)amino)methyl cyclohexanecarboxylate 19b Crude (550 mg, 1.74 mmol) was dissolved in 10 mL of N,N-dimethylformamide, and thionyl chloride (310 mg, 2.60 mmol) The reaction was stirred for 2 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (30 mL×3), and the organic phase was combined, washed with a saturated sodium chloride solution (30 mL×3), dried over anhydrous sodium sulfate, filtered, The title product is trans-4-((2-(chloromethyl)-4-phenylcarbazyl Xethyl)amino)cyclohexanecarboxylic acid methyl ester 19c crude (580 mg, yellow oil). In the next step of the reaction.
第四步  the fourth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- 苯腈基 X乙基)氨基)环己甲酸甲酯 Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl)-4-benzonitrile-based Xethyl)amino)cyclohexanecarboxylic acid methyl ester
将 ( ^，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (532 mg， 1.70 mmol) 溶解于 10 mL N，N-二甲基甲酰胺中， 加入氢化钠 C82 mg， 2 mmol), 搅拌反应 1小 时，加入反式 -4-((2- (氯甲基) -4-苯腈基 X乙基)氨基)环己甲酸甲酯 19c粗品 (580 mg， 1.70 mmol), 搅拌反应 0.5小时。 向反应液中加入 20 mL水， 固体析出， 过滤， 用 20 mL 甲醇和水 (V/V = 1 :1)混合溶剂冲洗滤饼、 干燥， 得到标题产物反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4-苯腈 基 X乙基)氨基)环己甲酸甲酯 19d (650 mg， 白色固体)， 产率： 65.0%。  Dissolve (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (532 mg, 1.70 mmol) in 10 mL N,N To the dimethylformamide, sodium hydride (C82 mg, 2 mmol) was added, and the reaction was stirred for 1 hour, and trans-4-((2-(chloromethyl)-4-phenylcarbonitrile Xethyl)amino) was added. The crude methyl hexanoate 19c (580 mg, 1.70 mmol) was stirred for 0.5 h. 20 mL of water was added to the reaction mixture, and the solid was precipitated, filtered, and the filter cake was washed with 20 mL of a mixed solvent of methanol and water (V/V = 1:1) and dried to give the title product trans-4-((2-( ((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-phenylcarbonitrile X Ethyl)amino)methyl cyclohexanecarboxylate 19d (650 mg, white solid), Yield: 65.0%.
MS m/z (ESI): 612.2[M+1] MS m/z (ESI): 612.2 [M+1]
第五步  the fifth step
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- 苯甲腈 X乙基)氨基)环己甲酸  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Base -4-benzonitrile X ethyl)amino)cyclohexanic acid
将反式 -4-((2-(((4S，5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基) -4-苯腈基 X乙基)氨基)环己甲酸甲酯 19d (150 mg， 0.25 mmol)溶解于 3 mL四 氢呋喃和水 (； V/V = 2: 1)混合溶剂中， 加入氢氧化锂 C51 mg， 1.23 mmol), 搅拌反应 12小时。 滴加 1 M盐酸至反应液 pH为 3〜4， 用乙酸乙酯萃取 (20 mLx2)， 合并有 机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B 纯化所得残余物， 得到标题产物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4-苯甲 腈 X乙基)氨基)环己甲酸 19 (85 mg， 白色固体)， 产率： 58.2%。 Trans-4-((2-((4S,5R)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidine-3) Methyl)-4-phenylcarbonitrile Xethyl)amino)methyl cyclohexanecarboxylate 19d (150 mg, 0.25 mmol) dissolved in 3 mL of tetrahydrofuran and water (V/V = 2: 1) mixed solvent Lithium hydroxide C51 mg, 1.23 mmol) was added, and the reaction was stirred for 12 hours. 1 M hydrochloric acid was added dropwise to the pH of the reaction mixture was 3~4, and extracted with ethyl acetate (20 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate Pressure concentration, The resulting residue was purified by EtOAc EtOAc (EtOAc) 4-Methyl-2-carbonyloxazolidin-3-yl)methyl)-4-benzonitrile Xethyl)amino)cyclohexanecarboxylic acid 19 (85 mg, white solid), yield: 58.2%.
MS m/z (ESI): 598.4[M+1] MS m/z (ESI): 598.4 [M+1]
1H NMR (400 MHz, CDC13): δ 7.90 (s, 1H), 7.78 (s, 2H), 7.68 (s, 1H), 7.57 (d, 1H)， 7.23 (d, 1H), 5.79 (d， 1H), 4.80 (d， 1H), 4.46 (d， 1H), 4.02-3.93 (m， 1H), 3.29-3.08 (m， 2H), 2.79-2.68 (m， 1H), 2.28-2.20 (m， 1H), 2.15-2.08 (m， 1H), 2.08-1.96 (m， 2H), 1.87-1.79 (m， 1H), 1.63-1.45 (m， 2H), 1.45-1.34 (m， 2H), 1.00 - 0.83 (m， 4H)， 0.68 (d, 3H) 实施例 20 1H NMR (400 MHz, CDC1 3 ): δ 7.90 (s, 1H), 7.78 (s, 2H), 7.68 (s, 1H), 7.57 (d, 1H), 7.23 (d, 1H), 5.79 (d, 1H), 4.80 (d, 1H), 4.46 (d, 1H), 4.02-3.93 (m, 1H), 3.29-3.08 (m, 2H), 2.79-2.68 (m, 1H), 2.28-2.20 (m, 1H), 2.15-2.08 (m, 1H), 2.08-1.96 (m, 2H), 1.87-1.79 (m, 1H), 1.63-1.45 (m, 2H), 1.45-1.34 (m, 2H), 1.00 - 0.83 (m, 4H), 0.68 (d, 3H) Example 20
反式 -4-ii2-W4&5RV5-i3,5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲 基) -4- (三氟甲基)苯基) (乙基)氨基)环己乙酸  trans-4-ii2-W4&5RV5-i3,5-bis(trifluoromethyl)phenyl 4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl) Phenyl) (ethyl)amino)cyclohexanoic acid
Figure imgf000059_0001
Figure imgf000059_0002
第一步
Figure imgf000059_0001
Figure imgf000059_0002
first step
反式 -4- (乙胺)环己乙酸乙酯  Trans-4-(ethylamine)cyclohexylacetate
将反式 -4- (氨基)环己乙酸乙酯盐酸盐 (1.1 g， 5 mmol, 韶远， 货号 SY008639) 溶解于 20 mL乙醇中， 加入 40%乙醛溶液 (660 mg, 6 mmol)和钯 /碳 (200 mg, 1 mmol), 氢气置换三次， 搅拌反应 12 小时。 过滤， 滤液浓縮后， 滴加氨水至 PH 为 7〜8， 用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (30 mLx2), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4- (乙胺)环己 乙酸乙酯 20a粗品（1.0 g， 淡黄色油状物)， 产物不经纯化直接用于下步反应。  Dissolve trans-4-(amino)cyclohexylacetate hydrochloride (1.1 g, 5 mmol, 韶yuan, Cat. No. SY008639) in 20 mL of ethanol and add 40% acetaldehyde solution (660 mg, 6 mmol) It was replaced with palladium on carbon (200 mg, 1 mmol) three times with hydrogen and stirred for 12 hours. After filtration, the filtrate was concentrated, and then aqueous ammonia was added dropwise to pH 7 to 8 and extracted with ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered The filtrate was concentrated under reduced pressure to give purified crystals crystals crystals crystalssssssssssssssssssssssssssssss
第二步  Second step
反式 -4- (乙基 (2-甲酰基 -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 将 2-氟 -5- (三氟甲基）苯甲醛 la (600 mg， 3.12 mmol , 采用 "专利 t/52006128691 " 公开的方法制备而得)和反式 -4- (乙胺)环己乙酸乙酯 20a粗品 (1.0 g， 4.68 mmol)混合后，加入无水碳酸钾 (650 mg， 4.68 mmol), 130°C下反应 2小时。 冷却至室温， 加入 30 ml水， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯 化钠溶液洗涤 (50 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反 式 -4- (乙基 (2-甲酰基 -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 20b粗品（ 1.20 g， 黄色 油状物)， 产物不经纯化直接用于下步反应。  Trans-4-(ethyl(2-formyl-4-(trifluoromethyl)phenyl)amino)cyclohexylacetate 2-fluoro-5-(trifluoromethyl)benzaldehyde la (600 Mg, 3.12 mmol, prepared by the method disclosed in "Patent t/52006128691") and mixed with trans-4-(ethylamine)cyclohexylacetate 20a (1.0 g, 4.68 mmol), and then added anhydrous carbonate Potassium (650 mg, 4.68 mmol) was reacted at 130 ° C for 2 hours. After cooling to room temperature, 30 ml of water was added, and the mixture was combined with ethyl acetate (30 mL), and the organic phase was combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, The title product is trans-4-(ethyl(2-formyl-4-(trifluoromethyl)phenyl)amino)cyclohexaneacetic acid ethyl ester 20b crude ( 1.20 g, yellow oil). Used in the next step of the reaction.
MS m/z (ESI): 386.2 [M+l] MS m/z (ESI): 386.2 [M+l]
第三步  third step
反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 将反式—4- (乙基 (2-甲酰基 -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 20b粗品 (1.20 g， 3.11 mmol)溶于 30 mL甲醇和四氢呋喃 (V/V = 1 : 1)混合溶剂中， 加入硼氢化钠 (210 mg, 5.60 mmol), 搅拌反应 2小时。 向反应液中加入 20 mL水淬灭反应， 减 压浓縮去除大部分溶剂， 再用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱和氯化 钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反 式 -4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 20c粗品 (1.20 g， 黄色 油状物)， 产物不经纯化直接用于下步反应。  Trans-4-(Ethyl(2-(hydroxymethyl)-4-(trifluoromethyl)phenyl)amino)cyclohexylacetate to trans-4-(ethyl(2-formyl)- 4-(Trifluoromethyl)phenyl)amino)cyclohexaneacetic acid ethyl ester 20b crude (1.20 g, 3.11 mmol) was dissolved in 30 mL of methanol and tetrahydrofuran (V/V = 1:1) in a solvent mixture. Sodium (210 mg, 5.60 mmol) was stirred for 2 hours. The reaction mixture was quenched with water (20 mL). Drying over sodium sulfate, filtration, and EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 20c crude (1.20 g, yellow oil), product was used in the next step without purification.
第四步  the fourth step
反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己乙酸乙酯 将反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲基)苯基)氨基)环己乙酸乙酯 20c 粗品 (1.20 g， 3.11 mmol)溶解于 15 mL N，N-二甲基甲酰胺中，加入氯化亚砜 (558 mg， 4.65 mmol), 搅拌反应 2小时。 向反应液中加入 20 mL水， 用乙酸乙酯萃取 (50 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (50 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减 压浓縮， 得到标题产物反式 -4-((2- (氯甲基) -4- (三氟甲基)苯基) (乙基)氨基)环己乙酸 乙酯 20d粗品 (630 mg， 黄色油状物)， 产物不经纯化直接用于下步反应。  Trans-4-((2-(Chloromethyl)-4-(trifluoromethyl)phenyl)ethyl)ethyl)cyclohexylacetate to trans-4-(ethyl(2-(hydroxy) Methyl)-4-(trifluoromethyl)phenyl)amino)cyclohexylacetate 20c crude (1.20 g, 3.11 mmol) dissolved in 15 mL of N,N-dimethylformamide Sulfone (558 mg, 4.65 mmol) was stirred for 2 hours. After adding 20 mL of water to the reaction mixture, the mixture was combined with ethyl acetate (50 mL×2), and the organic phase was combined, washed with a saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, The title product is trans-4-((2-(chloromethyl)-4-(trifluoromethyl)phenyl)(ethyl)amino)cyclohexaneacetic acid ethyl ester 20d crude (630 mg, yellow oil). The product was used in the next step without purification.
第五步 反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基) -4- (三氟甲基)苯基 X乙基)氨基)环己乙酸乙酯 冰浴下，将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (485 mg， 1.55 mmol)溶解于 15 mL N，N-二甲基甲酰胺中， 加入氢化钠 (74 mg， 1.86 mmol), 搅拌 反应 1小时， 加入反式 -4-((2- (氯甲基 )-4- (三氟甲基)苯基 X乙基)氨基)环己乙酸乙酯 20d粗品 C630 mg， 1.55 mmol), 搅拌反应 0.5小时。 向反应液中加入 20 mL水淬灭 反应，用乙酸乙酯萃取 (30 mLx2)，合并有机相，用饱和氯化钠溶液洗涤 (30 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所 得残余物， 得到标题产物反式 -4-《2-^4WR)-5-《3，5-双 (三氟甲基)苯基) -4-甲基 -2- 羰基噁唑烷 -3-基）甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己乙酸乙酯 20e 粗品 (600mg, 淡黄色固体)， 产物不经纯化直接用于下步反应。 the fifth step Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) (4S,5R)-5-(3,5-bis(trifluoromethyl)ethyl -4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexylacetate under ice bath Phenyl)-4-methyloxazol-2-one lg (485 mg, 1.55 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and sodium hydride (74 mg, 1.86 mmol) was added and stirred. 1 hour, add trans-4-((2-(chloromethyl)-4-(trifluoromethyl)phenyl)ethyl)ethyl)cyclohexylacetate 20d crude C630 mg, 1.55 mmol), stir The reaction took 0.5 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The residue obtained was purified by silica gel column chromatography eluting to elute to afford the title product trans-4- "2-^4WR)-5-"3,5-bis(trifluoromethyl)phenyl) -4-Methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexylacetate 20e crude (600 mg, pale yellow solid The product was used in the next step without purification.
MS m/z (ESI): 683.3 [M+l] MS m/z (ESI): 683.3 [M+l]
第六步  Step 6
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl))
基) -4- (三氟甲基)苯基 X乙基)氨基)环己乙酸 将反式 -4-((2-(((4 5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基) -4- (三氟甲基)苯基 X乙基)氨基)环己乙酸乙酯 20e粗品 (300 mg， 0.29 mmol)溶 解于 4 mL 四氢呋喃和甲醇 (V/V = 3 : 1)混合溶剂中， 加入氢氧化钠 (24 mg， 0.60 mmol),搅拌反应 12小时。滴加 1M盐酸至反应液 pH为 3〜4，用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B纯化所得残余物， 得到标题产物反 式 -4-((2-《(4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- (三 氟甲基)苯基 X乙基)氨基)环己乙酸 20 (80 mg， 淡黄色固体)， 产率： 41.9%。  -4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexanoic acid will be trans-4-((2-((4 5R)-5-((3,5-)) Fluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenylXethyl)amino)ethyl cyclohexanoate 20e The crude product (300 mg, 0.29 mmol) was dissolved in 4 mL of a mixture of tetrahydrofuran and methanol (V/V = 3:1), sodium hydroxide (24 mg, 0.60 mmol) was added, and the reaction was stirred for 12 hours. The pH of the reaction mixture is 3 to 4, and the mixture is extracted with ethyl acetate (30 mL×2). The organic phase is combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, The resulting residue was purified by EtOAc to EtOAc (EtOAc). Methyl-2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethyl)phenyl Xethyl)amino)cyclohexaneacetic acid 20 (80 mg, pale yellow solid), yield: 41.9%.
MS m/z (ESI): [M+l] MS m/z (ESI): [M+l]
1H NMR (400 MHz, CDC13): δ 7.98 - 7.90 (m, 1H), 7.87 - 7.76 (m, 2H), 7.70 - 7.62 (m: 1H), 7.62 - 7.53 (m， 1H), 7.30 - 7.26 (m， 1H), 5.84 - 5.72 (m， 1H), 4.88 - 4.74 (m， 1H) 4.68 - 4.52 (m, 1H), 4.09 - 3.90 (m, 1H), 3.27 - 3.07 (m, 2H), 2.78 - 2.60 (m, 1H), 2.27 - 2.21 (m， 2H), 2.01 - 1.70 (m， 4H)， 1.68 - 1.40 (m， 4H)， 0.92 (m， 5H)， 0.76 - 0.64 (m， 3H) 实施例 21 1H NMR (400 MHz, CDC1 3 ): δ 7.98 - 7.90 (m, 1H), 7.87 - 7.76 (m, 2H), 7.70 - 7.62 (m : 1H), 7.62 - 7.53 (m, 1H), 7.30 - 7.26 (m, 1H), 5.84 - 5.72 (m, 1H), 4.88 - 4.74 (m, 1H) 4.68 - 4.52 (m, 1H), 4.09 - 3.90 (m, 1H), 3.27 - 3.07 (m, 2H), 2.78 - 2.60 (m, 1H), 2.27 - 2.21 (m, 2H), 2.01 - 1.70 (m, 4H), 1.68 - 1.40 (m, 4H), 0.92 (m, 5H), 0.76 - 0.64 (m, 3H Example 21
反式 -4-ii2-W4&5RV5-i3,5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲  Trans-4-i2-W4&5RV5-i3,5-bis(trifluoromethyl)phenyl 4-methyl-2-carbonyloxazolidine-3-yl)-
基) -4- (三氟甲氧基)苯基) (乙基)氨基)环己乙酸 -4-(trifluoromethoxy)phenyl)(ethyl)amino)cyclohexanoic acid
Figure imgf000062_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0002
Figure imgf000062_0003
第一步
Figure imgf000062_0003
first step
反式 -4- (乙基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己乙酸乙酯 将 2-氟 -5- (三氟甲氧基)苯甲醛 21a (416 mg， 2 mmol)和反式 -4- (乙胺)环己乙酸 乙酯 20a粗品 (426 mg， 2 mmol)混合后， 加入无水碳酸钾 (276 mg， 2 mmol), 130 °C下密封反应 12小时。 冷却至室温， 加入 5 mL水， 用乙酸乙酯萃取 C5 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (5 mL)， 无水硫酸钠干燥， 过滤， 滤液减压浓 縮， 得到标题产物反式 -4- (乙基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己乙酸乙酯 21b粗品（ 890 mg， 黄色固体)， 产物不经纯化直接用于下步反应。  Trans-4-(ethyl(2-formyl-4-(trifluoromethoxy)phenyl)amino)cyclohexylacetate 2-fluoro-5-(trifluoromethoxy)benzaldehyde 21a (416 mg, 2 mmol) and trans-4-(ethylamine)acetic acid ethyl acetate 20a crude (426 mg, 2 mmol). The reaction was sealed for 12 hours. After cooling to room temperature, 5 mL of water was added, and the mixture was combined with EtOAc EtOAc (EtOAc) The crude product of trans-4-(ethyl(2-formyl-4-(trifluoromethoxy)phenyl)amino)cyclohexaneacetate 21b (890 mg, yellow solid). In the next step of the reaction.
第二步  Second step
反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲氧基)苯基)氨基)环己乙酸乙酯 将反式 -4- (乙基 (2-甲酰基 -4- (三氟甲氧基)苯基)氨基)环己乙酸乙酯 21b 粗品 (800 mg, 2 mmol)溶于 10 mL甲醇中， 加入硼氢化钠 (90 mg， 2.40 mmol), 搅拌反 应 1小时。 向反应液中加入 10 mL水淬灭反应， 减压浓縮去除大部分溶剂， 再用 乙酸乙酯萃取 (30 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫 酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4- (乙基 (2- (羟甲基) -4- (三氟甲 氧基)苯基)氨基)环己乙酸乙酯 21c (70 mg， 黄色油状物)， 产率 8.9%。 Trans-4-(ethyl(2-(hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexylacetate to trans-4-(ethyl(2-formyl) -4-(Trifluoromethoxy)phenyl)amino)cyclohexylacetate 21b crude (800 mg, 2 mmol) dissolved in 10 mL of methanol, sodium borohydride (90 mg, 2.40 mmol) 1 hour. The reaction solution was quenched by adding 10 mL of water, and concentrated under reduced pressure to remove most solvent. Ethyl acetate (30 mL×2), EtOAc (EtOAc m. (2-(Hydroxymethyl)-4-(trifluoromethoxy)phenyl)amino)cyclohexylacetate 21c (70 mg, yellow oil).
第三步  third step
反式 -4-((2- (氯甲基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸乙酯 将反式—4- (乙基 (2- (羟甲基) -4- (三氟甲氧基)苯基)氨基)环己乙酸乙酯 21c (70 mg， 0.17 mmol)溶解于2 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (31 mg， 0.26 mmol), 搅拌反应 2小时。 向反应液中加入 10 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 依次用水 (20 mLx3)和饱和氯化钠溶液 (10 mLx2)洗涤， 无水硫酸钠干 燥，过滤，滤液减压浓縮，得到标题产物反式 -4-((2- (氯甲基) -4- (三氟甲氧基)苯基) (乙 基)氨基)环己乙酸乙酯 21d粗品 (72 mg，黄色油状物)，产物不经纯化直接用于下步 反应。  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). The organic phase was combined, washed sequentially with water (20 mL×3) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure gave the title product EtOAc EtOAc EtOAc Mg, yellow oil), the product was used in the next step without purification.
第四步  the fourth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸乙酯 将 ( ^，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (53 mg， 0.17 mmol)溶 解于 2 mL N，N-二甲基甲酰胺中， 加入 60%的氢化钠 C8 mg， 0.20 mmol), 搅拌反应 Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl) 4-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexylacetate to (^,5R)-5-(3,5-bis(trifluoromethyl)phenyl) -4-Methyloxazol-2-one lg (53 mg, 0.17 mmol) was dissolved in 2 mL of N,N-dimethylformamide, 60% sodium hydride C8 mg, 0.20 mmol)
1小时，加入 1 mL反式 -4-((2- (氯甲基 )-4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸乙 酯 21d粗品 (71 mg， 0.17 mmol)的 DMF溶液， 搅拌反应 2小时。 向反应液中加入 10 mL水淬灭反应， 用乙酸乙酯萃取 (30 mLx2)， 合并有机相， 依次用水 (20 mIX3) 和饱和氯化钠溶液 (10 mLx3)洗涤， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到 标题产物反式 -4-((2-(((4 5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基)—4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸乙酯 21e粗品 （120 mg， 黄色油状 物)， 产物不经纯化直接用于下步反应。 1 hour, add 1 mL of trans-4-((2-(chloromethyl)-4-(trifluoromethoxy)phenyl)ethyl)ethyl)cyclohexylacetate 21d crude (71 mg, 0.17 A solution of mmol of DMF was stirred for 2 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Filtration and concentration of the filtrate under reduced pressure afforded the title product trans-4-((2-((4(5)))-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl -2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethoxy)phenyl Xethyl)amino)cyclohexylacetate 21e crude (120 mg, yellow oil), product It was used in the next step without purification.
MS m/z (ESI): 699.2 [M+l] MS m/z (ESI): 699.2 [M+l]
第五步  the fifth step
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl))
基 M- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸 将反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基） 甲基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸乙酯 21e粗品 (80 mg， 0.11 mmol) 溶解于 5 mL四氢呋喃中， 加入 2 M氢氧化锂一水合物 (0.6 mL, 1.10 mmol)的水溶 液， 30°C搅拌反应 12小时。 滴加 1 M盐酸至反应液 pH为 3〜4， 用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过 滤， 滤液减压浓縮， 用薄层色谱法以展开剂体系 B纯化所得残余物， 得到标题产 物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基) -4- (三氟甲氧基)苯基 X乙基)氨基)环己乙酸 21 (40 mg,黄色固体)，产率： 54.8%。 MS m/z (ESI): 671.2[M+1] 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. Add 1 M hydrochloric acid to the pH of the reaction mixture. The mixture is extracted with ethyl acetate (30 mL×2). The combined organic phase is washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate and filtered. The obtained residue was purified to give the title product, trans-4-((2-(((((())))) 2-carbonyloxazolidin-3-yl)methyl)-4-(trifluoromethoxy)phenylXethyl)amino)cyclohexanoic acid 21 (40 mg, yellow solid), yield: 54.8% . MS m/z (ESI): 671.2 [M+1]
1H NMR (400 MHz, CDC13) δδ 7.89 (s, 1H), 7.78 (s, 2H), 7.19 (d, 2H), 7.11 (s, 1H)， 5.74 (d， 1H), 4.69 (d， 1H), 4.54(d， 1H), 4.01-3.94 (m， 1H), 3.11-3.05 (m， 2H), 2.60-2.54 (m， 1H), 2.21(d, 2H), 1.92-1.78(m, 4H)， 1.48-1.42 (m， 1H), 1.31-1.25 (m， 3H), 0.91-0.71 (m， 4H)， 0.70 (d, 3H) 实施例 22 1H NMR (400 MHz, CDC1 3 ) δδ 7.89 (s, 1H), 7.78 (s, 2H), 7.19 (d, 2H), 7.11 (s, 1H), 5.74 (d, 1H), 4.69 (d, 1H ), 4.54(d, 1H), 4.01-3.94 (m, 1H), 3.11-3.05 (m, 2H), 2.60-2.54 (m, 1H), 2.21(d, 2H), 1.92-1.78(m, 4H) ), 1.48-1.42 (m, 1H), 1.31-1.25 (m, 3H), 0.91-0.71 (m, 4H), 0.70 (d, 3H) Example 22
反式 -4-ii2-W4&5R 5-a5-双 (三氟甲基)苯基 4-甲基 -2-羰基噁唑烷 -3-基)甲基 4-  Trans-4-i2-W4&5R 5-a5-bis(trifluoromethyl)phenyl 4-methyl-2-carbonyloxazolidine-3-yl)methyl 4-
Figure imgf000064_0001
第一步
Figure imgf000064_0001
first step
反式—4-((4-溴 -2-甲酰基苯基 X乙基)氨基)环己乙酸乙酯 将 2-氟 -5-溴-苯甲醛 22a (500 mg， 2.46 mmol)和反式 -4- (乙胺)环己乙酸甲酯 (524 mg, 2.46 mmol, 采用 "专利 WO200971509" 公开的方法制备而得)混合后， 加入无水碳酸钾 (339 mg， 2.46 mmol), 120°C下密封反应 12小时。 冷却至室温， 加入 20 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机相， 用饱和氯化钠溶液洗涤 (5 mL), 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B 纯化所得残余物， 得到标题产物反式 -4-((4-溴 -2-甲酰基苯基) (乙基)氨基)环己乙酸 乙酯 22b ( 400 mg， 黄色油状物)， 产率 41%。 Trans-4-((4-bromo-2-formylphenylXethyl)amino)cyclohexylacetate 2-fluoro-5-bromo-benzaldehyde 22a (500 mg, 2.46 mmol) and trans Methyl 4-(ethylamine)cyclohexylacetate (524 mg, 2.46 mmol, prepared by the method disclosed in "Publication WO200971509"), after mixing, anhydrous potassium carbonate (339 mg, 2.46 mmol), 120 ° C The reaction was sealed for 12 hours. Cool to room temperature, add 20 mL of water, extract with ethyl acetate (20 mL×2), combine with organic phase and wash with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjjjj -formylphenyl)(ethyl)amino)ethyl cyclohexanoate 22b (400 mg, yellow oil), yield 41%.
MS m/z (ESI): 396.1 [M+1] MS m/z (ESI): 396.1 [M+1]
第二步  Second step
反式 -4- (乙基 (2- (羟甲基 )-4-甲苯基)氨基)环己乙酸甲酯 将反式—4-((4-溴 -2-甲酰基苯基 X乙基)氨基)环己乙酸乙酯 22b (400 mg， 1 mmol) 溶于 10 mL N，N-二甲基甲酰胺中，依次加入三甲基环三硼氧烷 (332 mg，2.65mmol)、 四三苯基膦钯 (115 mg， 0.10 mmol)和碳酸钾 (366 mg， 2.65 mmol), 90°C搅拌反应 12小时。 冷却至室温， 向反应液中加入 10 mL水淬灭反应， 用乙酸乙酯萃取 (30 mLx2), 合并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物， 得到标题产物 反式 -4- (乙基 (2- (羟甲基) -4-甲苯基)氨基)环己乙酸甲酯 22c (700 mg， 黄色油状物)， 产率 60.6%。  Trans-4-(ethyl(2-(hydroxymethyl)-4-methyl)amino)cyclohexaneacetate methyl trans-4-((4-bromo-2-formylphenyl Xethyl) Ethylaminoethyl cycloheximide 22b (400 mg, 1 mmol) dissolved in 10 mL of N,N-dimethylformamide, followed by trimethylcyclotriborane (332 mg, 2.65 mmol), four Triphenylphosphine palladium (115 mg, 0.10 mmol) and potassium carbonate (366 mg, 2.65 mmol) were stirred at 90 ° C for 12 hours. After cooling to room temperature, the reaction mixture was stirred with EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was concentrated under reduced pressure, and the residue obtained was purified to silica gel elute Methyl hexanoate 22c (700 mg, yellow oil), yield 60.6%.
MS m/z (ESI): 332.1 [M+1]  MS m/z (ESI): 332.1 [M+1]
第三步  third step
反式 -4- (乙基 (2- (羟甲基 )-4-甲苯基)氨基)环己乙酸甲酯 将反式—4- (乙基 (2- (羟甲基) -4-甲苯基)氨基)环己乙酸甲酯 22c (200 mg， 0.60 mmol)溶于 10 mL甲醇中， 加入硼氢化钠 (27 mg， 0.72 mmol), 搅拌反应 1小时。 向反应液中加入 10 mL丙酮淬灭反应， 减压浓縮去除大部分溶剂， 加入 20 mL乙 酸乙酯，有机相依次用水 (10 mL)和饱和氯化钠溶液洗涤 (10 mL)，无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题产物反式 -4- (乙基 (2- (羟甲基) -4-甲苯基)氨基)环己 乙酸甲酯 22d (200 mg， 无色油状物)， 产物不经纯化直接进行下一步反应。  Trans-4-(ethyl(2-(hydroxymethyl)-4-methyl)amino)cyclohexaneacetate methyl trans-4-(ethyl(2-(hydroxymethyl))-4-toluene The methylamino)cyclohexanacetate 22c (200 mg, 0.60 mmol) was dissolved in 10 mL of methanol, sodium borohydride (27 mg, 0.72 mmol) was added and the mixture was stirred for 1 hour. The 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.
MS m/z (ESI): 334.1 [M+1] MS m/z (ESI): 334.1 [M+1]
第四步  the fourth step
反式 -4-((2- (氯甲基 )-4-甲苯基 X乙基)氨基)环己乙酸甲酯 将反式—4- (乙基 (2- (羟甲基) -4-甲苯基)氨基)环己乙酸甲酯 22d (700 mg, 0.60 mmol)溶解于 5 mL N，N-二甲基甲酰胺中， 加入氯化亚砜 (107 mg， 0.90 mmol), 搅 拌反应 1小时。 向反应液中加入 10 mL水， 用乙酸乙酯萃取 (20 mLx2)， 合并有机 相，依次用水 (30 mLx3)和饱和氯化钠溶液 (10 mLx2)洗涤，无水硫酸钠干燥，过滤， 滤液减压浓縮，得到标题产物反式 -4-《2- (氯甲基) -4-甲苯基) (乙基)氨基)环己乙酸甲 酯 21e粗品 (210 mg， 无色油状物)， 产物不经纯化直接用于下步反应。  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). The organic phase was combined, washed sequentially with water (30 mL×3) and saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure afforded the title product: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The product was used in the next step without purification.
第五步  the fifth step
反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- 甲苯基 X乙基)氨基)环己乙酸甲酯 Trans-4-((2-((4WR)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) Methyl)-4-methylphenylethyl)ethyl)cyclohexaneacetate
将 (4S，5R)-5-(3，5-双 (三氟甲基)苯基) -4-甲基噁唑 -2-酮 lg (188 mg, 0.60 mmol) 溶解于 5 mL N，N-二甲基甲酰胺中， 加入 60%的氢化钠 (29 mg， 0.72 mmol), 搅拌 反应 1小时，加入 2 mL反式 -4-((2- (氯甲基) -4-甲苯基 X乙基)氨基)环己乙酸甲酯 21e 粗品 （210 mg， 0.60 mmol)的 DMF溶液，搅拌反应 2小时。 向反应液中加入 20 mL 水淬灭反应， 用乙酸乙酯萃取 (40 mLx2)， 合并有机相， 依次用水 (30 mLx3)和用饱 和氯化钠溶液 (20 mLx3)洗涤， 无水硫酸钠干燥， 过滤， 滤液减压浓縮， 得到标题 产物反式 -4-((2-(((4WR)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲 基)—4-甲苯基 X乙基)氨基)环己乙酸甲酯 21f (300 mg， 黄色油状物)， 产率 79.6%。 (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazol-2-one lg (188 mg, 0.60 mmol) Dissolved in 5 mL of N,N-dimethylformamide, added 60% sodium hydride (29 mg, 0.72 mmol), stirred for 1 hour, and added 2 mL of trans-4-((2-(chloromethyl) A solution of methyl 4-methylmethyl 4-ethyl)amino)cyclohexaneacetate 21e (210 mg, 0.60 mmol) in DMF. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Filtration and concentration of the filtrate under reduced pressure afforded the title product trans-4-((2-(((4)))-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl Methyl-2-oxooxazolidin-3-yl)methyl)- 4-methylphenyl Xethyl)amino)cyclohexanacetate 21f (300 mg, yellow oil).
第六步  Step 6
反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4- 甲苯基 X乙基)氨基)环己乙酸  Trans-4-((2-((4WR)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazol-3-yl)) -4-tolyl Xethyl)amino)cyclohexanoic acid
将反式 -4-((2-(((4S，5R)-5-((3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基) 甲基) -4-甲苯基 X乙基)氨基)环己乙酸甲酯 21f (300 mg， 0.47 mmol)溶解于 10 mL四 氢呋喃中， 加入 2 M氢氧化锂一水合物 C2.4 mL， 4.70 mmol)的水溶液， 30°C搅拌 反应 12小时。滴加 1 M盐酸至反应液 pH为 3〜4， 用乙酸乙酯萃取 (30 mLx2)， 合 并有机相， 用饱和氯化钠溶液洗涤 (20 mLx2)， 无水硫酸钠干燥， 过滤， 滤液减压 浓縮， 用薄层色谱法以展开剂体系 B 纯化所得残余物， 得到标题产物反式 -4-((2-(((4WR)-5-(3，5-双 (三氟甲基)苯基) -4-甲基 -2-羰基噁唑烷 -3-基)甲基) -4-甲苯 基 X乙基)氨基)环己乙酸 22 (100 mg， 白色固体)， 产率： 35.5%。  Trans-4-((2-((4S,5R)-5-((3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-carbonyloxazolidine-3) Methyl)-4-methylphenylethyl)ethyl)cyclohexylacetate 21f (300 mg, 0.47 mmol) dissolved in 10 mL of tetrahydrofuran, 2 M lithium hydroxide monohydrate C 2.4 mL An aqueous solution of 4.70 mmol) was stirred at 30 ° C for 12 hours. Add 1 M hydrochloric acid to the pH of the reaction solution 3~4, extract with ethyl acetate (30 mL×2), combine the organic phase, wash with saturated sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, filter, filtrate Concentration by pressure, the residue obtained was purified by EtOAc EtOAc (EtOAc) Phenyl)-4-methyl-2-carbonyloxazolidin-3-yl)methyl)-4-methylphenylethyl)ethyl)cyclohexaneacetic acid 22 (100 mg, white solid), yield: 35.5%.
MS m/z (ESI): 601.2[M+1] MS m/z (ESI): 601.2 [M+1]
1H NMR (400 MHz, CDC13) δ 7.87 (s， 1H), 7.77 (s， 2H), 7.16 (s， 1H), 7.07 (s， 2H), 5.76 (d， 1H)， 4.68 (d， 1H), 4.53(d, 1H), 4.01-3.94 (m， 1H), 3.10-2.99 (m， 2H), 2.59-2.54 (m， 1H), 2.34(s, 3H), 2.2 l(d, 2H), 1.92-1.78(m, 4H)， 1.48-1.42 (m， 1H)， 1.31-1.25 (m， 3H), 0.91-0.71 (m， 4H)， 0.70 (d, 3H) 测试例： 1H NMR (400 MHz, CDC1 3 ) δ 7.87 (s, 1H), 7.77 (s, 2H), 7.16 (s, 1H), 7.07 (s, 2H), 5.76 (d, 1H), 4.68 (d, 1H ), 4.53(d, 1H), 4.01-3.94 (m, 1H), 3.10-2.99 (m, 2H), 2.59-2.54 (m, 1H), 2.34(s, 3H), 2.2 l(d, 2H) , 1.92-1.78(m, 4H), 1.48-1.42 (m, 1H), 1.31-1.25 (m, 3H), 0.91-0.71 (m, 4H), 0.70 (d, 3H) Test example:
生物学评价  Biological evaluation
测试例 1 荧光法检测 CETP抑制剂的生物活性  Test Example 1 Fluorescence detection of biological activity of CETP inhibitor
首先制备荧光底物。 将 BODIPY®FLC12 标记的胆固醇 （Molecular Probes, D-3822 ) , 胆固醇油酸 （Sigma C-9253), 甘油三油酸脂 （Sigma T-7140), POPC (l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, Avanti Polar Lipids 850457)按摩 尔百分比 15:33:8:44 混合。 以氮气吹干原先溶剂后， 溶入二噁烷 (； dioxane, Allied Signal 087-1)中。最后用注射器将混合的二噁烷溶液缓缓加入 37°C的 40kHz超声中 水浴的缓冲液 （7.4 pH Tris， NaCl, EDTA) 中。 底物制成后在 4°C保存 （8个月 保存期）。  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. After purging the original solvent with nitrogen, it was dissolved in dioxane (dioxane, Allied Signal 087-1). Finally, the mixed dioxane solution was slowly added to a 37 ° C 40 kHz ultrasonic bath buffer (7.4 pH Tris, NaCl, EDTA) using a syringe. The substrate was prepared and stored at 4 ° C (8-month shelf life).
接着制备血浆。 抽取新鲜人类血液， 2000 转 /分钟离心 10分钟， 取上清分装 后低温冰箱保存， 使用前 37°C水浴解冻， 血浆澄清方可使用， 有絮状沉淀需离心 去除。 实验前， 需要将本发明化合物用二甲亚砜稀释成需要的浓度梯度（如 8个浓度 梯度： 1000 nM、 333.33 nM 111.11 nM 37.03 nM 12.34 nM 4.11 nM、 1.37 nM 和 0.46 nM)，然后将 96 μ1 人类血浆， 1 μΐ各梯度化合物混合， 37°C孵育 10分钟。 再各加入 3 μΐ 荧光底物，总共 100 μΐ的反应体系充分混合后荧光检测：激发光 544 nm， 放射光 595 nm。 37°C密封孵育 16小时后， 再次荧光检测。 两次荧光信号的 差值反映了体系内 CETP的活性， 从而可以计算出 IC 50值。 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 μΐ of each gradient compound was mixed and incubated at 37 ° C for 10 minutes. Then, 3 μΐ of the fluorescent substrate was added, and a total of 100 μΐ of the reaction system was thoroughly mixed and detected by fluorescence: excitation light was 544 nm, and emission light was 595 nm. After incubation for 16 hours at 37 ° C, the fluorescence was detected again. The difference between the two fluorescent signals reflects the activity of CETP in the system, so that the IC 50 value can be calculated.
Figure imgf000067_0001
Figure imgf000067_0001
本发明化合物对 CETP具有明显的抑制活性。 药代动力学评价  The compounds of the invention have significant inhibitory activity against CETP. Pharmacokinetic evaluation
测试例 2、 本发明化合物的药代动力学测试  Test Example 2. Pharmacokinetic test of the compound of the present invention
1、 摘要  1, abstract
以大鼠为受试动物， 应用 LC/MS/MS法测定了大鼠灌胃给予实施例 2化合物和 实施例 18化合物后不同时刻血浆中的药物浓度。 研究本发明的化合物在大鼠体内 的药代动力学行为， 评价其药动学特征。  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.
2、 试验方案  2. Test plan
2.1 试验药品  2.1 Test drugs
实施例 2化合物和实施例 18化合物。  Example 2 Compound and Example 18 compound.
2.2 试验动物  2.2 Test animals
健康成年 SD大鼠 8只， 雌雄各半， 平均分成 2组， 每组 4只， 购自上海西普尔- 必凯实验动物有限公司， 动物生产许可证号： SCXK (沪 )2008-0016。  Healthy adult SD rats, 8 males and females, divided into 2 groups, 4 in each group, purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.
2.3 药物配制  2.3 Drug preparation
称取适量样品， 加入 0.5% CMC-Na， 超声制成 0.5 mg/ml混悬液。 2.4 给药 An appropriate amount of the sample was weighed, 0.5% CMC-Na was added, and a 0.5 mg/ml suspension was prepared by ultrasonication. 2.4 Administration
SD大鼠 8只， 雌雄各半， 平均分成 2组， 禁食一夜后分别灌胃给药， 剂量为 5.0 mg/kg, 给药体积 10 ml/kg。  Eight SD rats, male and female, were divided into two groups. After fasting overnight, they were intragastrically administered at a dose of 5.0 mg/kg and a dose of 10 ml/kg.
3、 操作  3, operation
大鼠灌胃给药实施例 2化合物和实施例 18化合物， 于给药前及给药后 0.5、 1.0、 2.0、 3.0、 4.0、 6.0、 8.0、 11.0、 24.0 小时采血 0.1 ml, 置于肝素化试管中， 3500 rpm离心 5 min分离血浆， 乎 20°C保存。 给药后 2 小时进食。  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.
用 LC/MS/MS法测定不同化合物灌胃给药后大鼠血浆中的待测化合物含量。 方法的线性范围均为 1.00〜2000 ng/ml; 血浆样品经甲醇沉淀蛋白处理后进行分析。  The content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method. The linear range of the method was 1.00~2000 ng/ml; plasma samples were analyzed by methanol precipitation protein analysis.
4、 药代动力学参数结果  4, pharmacokinetic parameters results
本发明化合物的药代动力学参数如下：  The pharmacokinetic parameters of the compounds of the invention are as follows:
Figure imgf000068_0001
Figure imgf000068_0001
结论： 本发明化合物的药代吸收良好， 具有明显的药代动力学优势。  Conclusion: The compound of the present invention has good pharmacological absorption and has obvious pharmacokinetic advantages.

Claims

权利要求书: Claims:
1、 一种通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐： A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salt:
Figure imgf000069_0001
其巾：
Figure imgf000069_0001
Its towel:
A为 CH或氮原子；  A is CH or a nitrogen atom;
R或 R1各自独立地选自烷基、 氰基、 烯基、 块基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6， 其中所述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基 或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 烷基、 卤 代烷基、 羟烷基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8, -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基 所取代； 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(0)OR 6 , wherein the alkyl, alkenyl, block, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogens, Cyano, hydroxy, alkyl, haloalkyl, hydroxyalkyl, 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 (0) Substituted by a substituent of OR 6 ;
R3选自取代或未取代的环烷基、 杂环基、 芳基或杂芳基； R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
当 R3选自杂环基、 芳基或杂芳基， 其中所述杂环基、 芳基或杂芳基各自独立 地任选进一步被一个或多个选自卤素、 氰基、 羟基、 硝基、 氧代基、 烷基、 卤代 烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、 -OR6、 -NR7R8、 -(CH2)pC(0) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6或 -(CH2)pC(0)OR6的取代基所取代时， R2选自氢原 子、烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基、 -OR6、 -NR7R8、 -C(0)NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6， 其中所 述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被 一个或多个选自卤素、 氰基、 羟基、 烷基、 卤代烷基、 羟烷基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基所取代； When 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 Alkyl, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -NR 7 R 8 , -(CH 2 )pC(0) When 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, R 2 Selected from hydrogen atom, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , - S(0) m R 6 , -C(0)R 6 , -OC(0)R 6 , -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 wherein the alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group 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(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 substituent is substituted;
当 R3为环烷基， 其中所述环烷基进一步被一个或多个 -(CH2)pC(0)OR6的取代 基所取代时， R2为烷基； When 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;
R4选自氢原子、 烷基、 卤代烷基或卤素； R 4 is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group or a halogen;
R5选自氢原子、 烷基、 卤代烷基、 羟基或卤素； R6选自氢原子、 烷基、 烯基、 块基、 羟基、 卤素、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基， 其中所述的烷基、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基各自 独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代； 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;
R7或 R8各自独立地选自氢原子、 烷基、 环烷基、 杂环基、 芳基或杂芳基， 其 中所述的烷基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被一个或 多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代； 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或 z各自独立为 1、 2或 3;  n or z are each independently 1, 2 or 3;
p为 0、 1或 2; 且  p is 0, 1 or 2;
m为 0、 1或 2。  m is 0, 1, or 2.
2、 根据权利要求 1所述的通式（I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐， 其 为通式（II )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非 对映异构体、 或其混合物形式 或其可药用的盐： 2. A compound of the formula (I) according to claim 1 or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure imgf000070_0001
Figure imgf000070_0001
( I I )  ( I I )
其中： R、 1^〜1 5、 A、 n、 z的定义如权利要求 1中所述 ( Wherein: R, 1^~1 5 , A, n, z are as defined in claim 1 (
3、 根据权利要求 1或 2所述的通式（ I )所示的化合物或其互变异构体、 内消 旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的 盐， 其中： R3为杂环基， 所述杂环基任选进一步被一个或多个选自烷基、 卤代烷 基、羟烷基、 -OR6、环烷基、杂环基、芳基、杂芳基、 -S(0)2R6、 -C(0)R6或 -C(0)OR6 的取代基所取代， 且 R6选自氢原子或烷基。 3. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 or 2. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 is a heterocyclic group, and the heterocyclic group is optionally further selected from one or more selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, -OR 6, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (0) 2 R 6 , -C (0) R 6 or -C (0) oR 6 substituted with a substituent, and R 6 It is selected from a hydrogen atom or an alkyl group.
4、根据权利要求 1〜3任意一项所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐， 其中 R2选自氢原子、 烷基、 环烷基或 -C(0)R6， 其中所述烷基或环烷基各 自独立地任选进一步被 -C(0)OR6所取代； 且 R6选自氢原子或烷基。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 3; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or -C(0)R 6 , wherein the alkyl or cycloalkyl group Optionally, it is optionally further substituted with -C(0)OR 6 ; and R 6 is selected from a hydrogen atom or an alkyl group.
5、 根据权利要求 1或 2所述的通式（ I )所示的化合物或其互变异构体、 内消 旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药用的 盐， 其中： R3为环烷基， 其中所述环烷基进一步被一个或多个 -(CH2)pC(0)OR6的 取代基所取代； R6选自氢原子或烷基； p为 0或 1 ; 且 R2为烷基。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 or 2. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R 3 is a cycloalkyl group, wherein the cycloalkyl group is further substituted by one or more substituents of -(CH 2 )pC(0)OR 6 Substituted; R 6 is selected from a hydrogen atom or an alkyl group; p is 0 or 1; and R 2 is an alkyl group.
6、根据权利要求 1〜5任意一项所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐， 其中 A为 CH。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 5; Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein A is CH.
7、根据权利要求 1〜6任意一项所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐， 其中 R4为氢原子。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 6. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom.
8、根据权利要求 1〜7任意一项所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐， 其中 R5为烷基。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 7. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is alkyl.
9、根据权利要求 1〜8任意一项所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐， 其中 R1为一个或多个独立地选自烷基、 氰基、 卤代烷基或卤代烷氧基的 取代基。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 8. isomers, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is one or more substituents independently selected from alkyl, substituted with a cyano group, haloalkyl or haloalkoxy.
10、 根据权利要求 1〜9任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐， 其中 R为一个或多个独立地选自烷基、 氰基、 卤代烷基或卤代烷氧 基的取代基。 The compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 9. Isomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R is one or more substituents independently selected from alkyl, cyano, haloalkyl or haloalkoxy.
11、 根据权利要求 1〜10任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐， 其中该化合物为：
Figure imgf000072_0001
基、杂芳基、 -OR6、 -NR7R8、- C(O) NR7R8、- S (0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基， 其中所述烷基、 烯基、 块基、 环烷基、 杂环 基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、 -OR6、-NR7R8、-C(0)NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基 所取代； The compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 10. Isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is:
Figure imgf000072_0001
Base, 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 a substituent of -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 wherein the alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic ring The radically, aryl or heteroaryl 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, hetero Aryl, -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 Substituted by a substituent of 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 ;
R3选自取代或未取代的环烷基、 杂环基、 芳基或杂芳基； R 3 is selected from substituted or unsubstituted cycloalkyl, heterocyclic, aryl or heteroaryl;
当 R3选自杂环基、 芳基或杂芳基， 其中所述杂环基、 芳基或杂芳基各自独立 地任选进一步被一个或多个选自卤素、 氰基、 羟基、 硝基、 氧代基、 烷基、 卤代 烷基、羟烷基、环烷基、杂环基、芳基、杂芳基、 -OR6、 -NR7R8、 -(CH2)pC(0) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6或 -(CH2)pC(0)OR6的取代基所取代时， R2选自氢原 子、烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基、 -OR6、 -NR7R8、 -C(0)NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6， 其中所 述烷基、 烯基、 块基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被 一个或多个选自卤素、 氰基、 羟基、 烷基、 卤代烷基、 羟烷基、 环烷基、 杂环基、 芳基、 杂芳基、 -OR6、 -NR7R8、 -C(O) NR7R8、 -S(0)mR6、 -C(0)R6、 -OC(0)R6、 -NR7C(0)R8、 -NR7C(0)OR8或 -C(0)OR6的取代基所取代； When 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 Alkyl, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -NR 7 R 8 , -(CH 2 )pC(0) When 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, R 2 Selected from hydrogen atom, alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , - S(0) m R 6 , -C(0)R 6 , -OC(0)R 6 , -NR 7 C(0)R 8 , -NR 7 C(0)OR 8 or -C(0)OR 6 wherein the alkyl group, alkenyl group, blocked group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group 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(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 substituent is substituted;
当 R3为环烷基， 其中所述环烷基进一步被一个或多个 -(CH2)pC(0)OR6的取代 基所取代时， R2为烷基； When 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;
R6选自氢原子、 烷基、 烯基、 块基、 羟基、 卤素、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基， 其中所述的烷基、 烷氧基、 环烷基、 杂环基、 芳基或杂芳基各自 独立地任选进一步被一个或多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代； 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;
R7或 R8各自独立地选自氢原子、 烷基、 环烷基、 杂环基、 芳基或杂芳基， 其 中所述的烷基、 环烷基、 杂环基、 芳基或杂芳基各自独立地任选进一步被一个或 多个选自卤素、 氰基、 羟基、 氨基、 氧代基、 烷基、 卤代烷基、 羟烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代； 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为 1、 2或 3;  n is 1, 2 or 3;
p为 0、 1或 2; 且  p is 0, 1 or 2;
m为 0、 1或 2;  m is 0, 1 or 2;
X为卤素。  X is a halogen.
13、 一种制备根据权利要求 1所述的通式（ I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其可药 用的盐的方法， 该方法包括以下步骤： 通式 (I- A)化合物和通式 (I-B)化合物在溶剂中， 碱性条件下反应， 得到通式（I ) 化合物； 13. A compound of the formula (I) according to claim 1 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. A method of the body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising the steps of: The compound of the formula (I-A) and the compound of the formula (IB) are reacted in a solvent under basic conditions to obtain a compound of the formula (I);
其中： X为离去基团， 优选为卤素； 其中 R， Ι^〜Ι 5、 Α、 η、 ζ的定义如权利 要求 1中所述。 Wherein: X is a leaving group, preferably a halogen; wherein R, Ι^~Ι 5 , Α, η, ζ are as defined in claim 1.
14、一种药物组合物， 所述药物组合物含有治疗有效量的根据权利要求 1〜11 任意一项所述的通式（I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体、 或其混合物形式、 或其可药用的盐和药学上可接受的 载体、 稀释剂或赋形剂。 A pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) according to any one of claims 1 to 11 or a tautomer thereof, mesogenic a form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
15、 根据权利要求 1〜11任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐， 或根据权利要求 14所述的药物组合物在制备胆固醇酯转移蛋白抑制 剂中的用途。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 11. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 for the preparation of a cholesterol ester transfer protein inhibitor.
16、 根据权利要求 15所述的用途， 其中所述的胆固醇酯转移蛋白抑制剂导致 LDL-胆固醇的减少。 16. The use according to claim 15, wherein the cholesteryl ester transfer protein inhibitor results in a decrease in LDL-cholesterol.
17、 根据权利要求 1〜11任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐， 或根据权利要求 14所述的药物组合物在制备治疗或预防哺乳动物动 脉粥样硬化的药物中的用途。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 11. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a medicament for treating or preventing atherosclerosis in a mammal.
18、 根据权利要求 1〜11任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐， 或根据权利要求 14所述的药物组合物在制备治疗或预防哺乳动物血 脂障碍的药物中的用途。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 11. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a medicament for treating or preventing dyslipidemia in a mammal.
19、 根据权利要求 1〜11任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐，或根据权利要求 14所述的药物组合物在制备降低哺乳动物血浆 LDL- 胆固醇水平的药物中的用途。 The compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 11. The isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 is prepared to reduce plasma LDL in a mammal Use in cholesterol levels of drugs.
20、 根据权利要求 1〜11任意一项所述的通式（ I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 或其混合物形式、 或其 可药用的盐,或根据权利要求 14所述的药物组合物在制备提高哺乳动物血浆 HDL- 胆固醇水平的药物中的用途。 The compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to any one of claims 1 to 11. Use of the isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a medicament for increasing plasma HDL-cholesterol levels in a mammal.
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