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CN105753814A - Substituted nitrogen heterocyclic derivative and application thereof - Google Patents

Substituted nitrogen heterocyclic derivative and application thereof Download PDF

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Publication number
CN105753814A
CN105753814A CN201511026661.2A CN201511026661A CN105753814A CN 105753814 A CN105753814 A CN 105753814A CN 201511026661 A CN201511026661 A CN 201511026661A CN 105753814 A CN105753814 A CN 105753814A
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compound
alkyl
cycloalkyl
heteroaryl
heterocyclic radical
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CN201511026661.2A
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Inventor
李德群
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Chengdu Beisi Kairui Biological Technology Co Ltd
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Chengdu Beisi Kairui Biological Technology Co Ltd
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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Abstract

The invention relates to a compound as shown in a formula (I) in the specification, a preparation method of the compound and medical application of the compound, in particular to a derivative of the compound as shown in the formula (I), a preparation method of the derivative and application of the derivative serving as a therapeutic agent to preparation of medicines for preventing and treating hyperlipemia, hypercholesterolemia, hypertriglyceridemia, liver fatty degeneration, Type-II diabetes, hyperglycemia, obesity or insulin resistance, metabolic syndrome and tumors.The compound is further capable of reducing total cholesterol, LDL (low density lipoprotein)-cholesterol and triglyceride, promoting liver LDL receptor expression and inhibiting PCSK9 expression.

Description

Substituted nitrogen heterocyclic ring derivatives and application thereof
Technical field
The technology of the present invention relates to treatment hyperlipemia (including hypertriglyceridemia and hypercholesterolemia), fatty degeneration of liver, type ii diabetes, hyperglycemia, insulin resistance, obesity, Metabolic syndrome is sought peace the purposes in antitumor, compound and compositions.
Background technology
Metabolism syndrome (MetabolicSyndrome, MS) is the pathological state of multiple Metabolite abnormal aggregation, is a complex set of metabolism disorder disease group, is cause diabetes, the risk factor of cardiovascular and cerebrovascular disease.
Cardiovascular and cerebrovascular disease is the number one killer of harm human health, its cause of disease is extremely complex, hyperlipidemia receives again the concern of most people as its very crucial risk factor, and along with the acceleration of the improvement of living standard and aging, the incidence rate of hyperlipidemia and mortality rate are obviously improved, more having pertinent literature to report, dyslipidemia is the main cause causing atherosclerosis, coronary heart disease, myocardial infarction etc..
Hyperlipidemia is often interpreted: the metabolism of fat or operating make one or more lipids in blood plasma be higher than normal extremely.And hyperlipidemia is the disease of kind of general, being often referred in serum T-CHOL (TC), triglyceride (TG) is too high or HDL-C (HDL-C) is too low, and modern medicine is referred to as dyslipidemia.Lipid is to be insoluble or poorly soluble in water, so lipoprotein must be formed with protein bound, therefore, hyperlipidemia is also commonly referred to as hyperlipoproteinemia.
Hyperlipidemia and cerebral infarction: Blood Cholesterol increases and easily forms arteriosclerosis plaque, when these specklees are piled up in arterial wall, can make tremulous pulse official jargon narrow, blocks blood and flows into corresponding position, will cause kinetic energy defect.When it occurs to cause cerebral infarction when cerebrovascular, medical evidence: long-term Lipid modulating can not only treat cerebral infarction, moreover it is possible to prevention cerebral infarction.
Hyperlipidemia and coronary heart disease: coronary heart disease is also called coronary atherosclerotic heart disease.Coronary artery is to the major arteries of heart blood supply, if excess fat deposition, will cause arteriosclerosis, so that blood flow is obstructed, cause heart ischemia, a series of symptom occur, i.e. coronary heart disease.The risk factor causing coronary heart disease is a lot, such as hyperlipidemia, smoking, obesity, hypertension, shortage physical exertion, diabetes, familial history of coronary artery disease etc., wherein, hyperlipidemia be again one of important risk factor causing coronary heart disease.So preventing and treating the most basic therapy of coronary heart disease is regulate blood fat, research shows that in serum, total cholesterol level declines 1%, then coronary heart disease incidence rate declines 2%.The long-term incidence rate and the mortality rate that coordinate Lipid modulating can reduce the angina pectoris of coronary heart disease, myocardial infarction etc..
Hyperlipidemia and fatty liver: fatty liver refers to that fat caused by a large amount of accumulation, often increases with blood fat in liver.Pathogenesis of fatty liver rate is up to 5-10%, and in adult body, Cyklokapren increased perosn about 35% is fatty liver, and part severe patient can develop into liver cirrhosis.Therefore, fatty liver treatment also should carry out adjusting the treatment of fat.
Hyperlipidemia and diabetes: hypertension, hyperlipidemia and hyperglycemia are commonly referred to as " three high ", be the principal element threatening diabetics healthy.Three is closely related, hyperlipidemia can increase the weight of the symptom of diabetes, most of diabeticss are with hyperlipidemia, more it is easily caused apoplexy, coronary heart disease, limb necrosis, retinopathy, nephropathy, neuropathy etc., therefore diabetics is wiped out and treated insect pests and plant diseases outside treatment hyperglycemia, should also be noted that Adjust-blood lipid, this is extremely important for reducing diabetics mortality rate and disability rate.
Hyperlipidemia is defined as blood fat disorder or dyslipidemia.It is often referred to blood in human body in lipid concentration beyond normal range.Raising including triglyceride (TG), serum total cholesterol (TC), C-VLDL (VLDL-C) or low-density lipoprotein cholesterol (LDL-C) level and HDL-C (HDL-C) level reduces along with the further investigation of hyperlipidemia Yu cardiovascular disease, people start to recognize that the risk reducing cardiovascular disease is had very important significance by blood fat reducing.
Blood lipid-lowering medicine conventional currently on the market mainly has Statins, fibrates, nicotinic acid class, cholic acid chelating agent class etc..
Statins represents medicine: atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin etc..This kind of medicine is development in recent years ratio fat-reducing medicament faster, is mainly the activity of rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase suppressed in serum total cholesterol (TC) route of synthesis, reduces TC synthesis；Low density lipoprotein receptor quantity is increased, accelerates LDL degraded, increase HDL content simultaneously, be conducive to removing and the transhipment of TC.
Weak point: its side effect brought is inevitable, as: rhabdomyolysis, the various enzymatic activity enhancings etc. of myositis and liver, some patients are additionally had to fail to well adapt to the treatment of statins, it is often more important that single Statins treatment also tends to reach intended ideal effect.
Fibrates represents medicine: clofibrate, gemfibrozil, FENOBRATE top grade.Such medicine is through long-term clinical practice, the medicine of the Regulation serum lipids have proven to a class better tolerance, having had.Its blood fat reducing approach also has the activity increasing lipoprotein lipase except similar with Statins, makes the removing of triglyceride (TG) increase；Reduce blood glucose, so that second coenzyme A and free fatty trend towards the synthesis of glucose, make lipid synthesis reduce.
Weak point: untoward reaction often occurs in digestive tract, there is anaphylaxis in occasional, and visual disorder, owing to such medicine adds cholesterol concentration in bile, so being also possible to cause cholelithiasis.
Nicotinic acid class represents medicine: nicotinic acid, inositol niacinate, acipimox etc..The formation of this kind of medicine decomposition and free fatty mainly through suppressing fat, it is suppressed that liver synthetic glycerine three ester (TG) and very low density lipoprotein (VLDL) (VLD-L) reduce blood fat.
Weak point: diabetics effect for reducing blood fat is inconspicuous, side effect such as liver poisoning, the untoward reaction such as hyperglycemia is comparatively obvious, skin epidemic disease often occurs, pruritus.
Cholic acid chelating agent class represents medicine: Ezetimibe (Ezetimibe), how rare unsaturated fatty acid etc..This kind of fat-reducing medicament can be divided into cholesterol absorption inhibitor and how rare unsaturated fatty acid two class.
(1), cholesterol absorption inhibitor (Ezetimibe): be combined with bile acid, hinder the heavily absorption of bile acid, thus promoting cholesterol to be converted into bile acid, combining at intestinal and this medicine and excreting.
(2), polyene unsaturated fatty acid: be combined into esters with cholesterol, promote cholesterol degradation be bile acid with bile excretion so that the concentration of blood bavin T-CHOL reduces.
Low density lipoprotein, LDL (LDL) level crosses high energy atherogenicity, reduces plasma LDL levels and prevention and treatment cardio-cerebrovascular diseases are had great importance.In blood, the LDL of about 70% is that the endocytosis mediated by low density lipoprotein receptor (LDLR) completes to remove, the expression of LDLR is subject to the impact of proprotein convertase subtilisin/kexin9 type (proproteinconvertasesubtilisin/kexintype9) (PCSK9), PCSK9 is a serine protease, main in liver synthesis, it can reduce LDLR quantity in hepatocyte.After PCSK9 and the LDLR being positioned at cell surface is combined, internalization, to cell, promotes LDLR degraded in lysosome.The activity suppressing PCSK9 can increase LDLR quantity, reduces LDL level in blood plasma.
The exploitation of PCSK9 inhibitor is the important directions that current large-scale transnational drugmaker makes great efforts research and development Novel cardiovascular disease medicament, expects that this kind of medicine surmounts the fat-reducing medicament that Statins is ripe.Big drug firm promotes PCSK9 inhibitor medicaments development just underway, current research work is concentrated mainly on the exploitation (such as following table) of biological medicine (including protein drug and long nucleic acid medicine), biological medicine and small-molecule drug are for when treating same disease, biological medicament has with high costs, the shortcomings such as limited preparation way such as ejection preparation can only be adopted, at present, clinical candidates is become but without little molecule PCSK9 inhibitor.
Disclose the micromolecular compound patent application of a series of PCSK9 inhibitor at present, including WO2010075469, WO2011006000, WO2011051961, WO2011152508, WO2012090220, JP2013136572, WO2013132509, WO2013137371, WO2014017569, WO2014002105, WO2014002106, WO2014150326, WO2014150395, WO2014139008 etc..
Although having been disclosed for a series of compound having and suppressing PCSK9 expression and lipid-lowering effect at present, but, need nonetheless remain for that exploitation is new has better drug effect, medicine is for the compound of result, through being continually striving to, present invention design has a compound of logical formula V structure and discovery has the compound of this class formation and shows effect and the effect of excellence, in a wider context, more deeply and all sidedly disclose and illustrate structure and the relation of activity usefulness, there is important using value.
Summary of the invention
It is an object of the invention to provide compound shown in a kind of logical formula V and their tautomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolic precursor thereof or prodrug.The compound of Formula V
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof；Wherein:
Y is selected from cycloalkyl, heterocyclic radical, aryl, heteroaryl, wherein,
Described cycloalkyl, heterocyclic radical, aryl, heteroaryl independently of one another by one or more selected from hydrogen, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, the substituent group of heterocyclic radical or heterocyclic radical is replaced；
R1, R2, R3, R4, R5, R6, R7, R8Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxo base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
M is nitrogen-atoms, or carbon atom；
W is nitrogen-atoms, or carbon atom；
Z is-O-,-S-,-NH-,-CR5R6-,-C (O) O-,-C (O) NR5-,-SO2O-,-SO2NR5-,-P (O) R5R6Or Z is not for any atom (chemical group namely, being connected with Z is directly connected to by chemical bond)；
Ring X is 3～10 rings, and 3～10 described ring X are selected from cycloalkyl, heterocyclic radical, aryl, heteroaryl, wherein,
Described cycloalkyl, heterocyclic radical, aryl, heteroaryl independently of one another by one or more selected from hydrogen, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNR ' (C=O) NR ' R " ,-S (O)nNR ' (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, the substituent group of heterocyclic radical or heterocyclic radical is replaced；
R ' and R " independent is hydrogen or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl,
At-NR ' R " ,-C (O) NR ' R " ,-OC (O) NR ' R " and ,-OS (O)nNR ' R " ,-OS (O)nNH (C=O) NR ' R " in, wherein NR ' R " can be 4 to 20 member heterocyclic ring containing nitrogen bases；
M=0,1,2；
N=1,2,3；
P=1,2,3；
Q=0,1,2,3,4,5,6；
S=0,1,2；
T=0,1,2.
The present invention relates to general formula compound compound (V), its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VI),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxo base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R5, R6, R7, R8, Z, M, q, t, ring X and ring Y is with described previously.
The present invention relates to general formula compound compound (V), its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VII),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R17, R18, R19, R20, R21It is hydrogen independently, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0- 6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R5, R6, R7, R8, R ', R ", Z, ring X, M, m, n, q, t are with described previously.
The present invention relates to general formula compound compound (VII), wherein, R9, R10, R11, R12, R13, R14, R15, R16It is-H independently, halogen, alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R17, R18, R19, R20, R21It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
The present invention relates to general formula compound compound (V), its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VIII),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R22, R23, R24, R25, R26It is hydrogen independently, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0- 6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical；
Ring Y, R1, R2, R3, R4, R5, R6, R7, R8, R ', R ", M, W, Z, m, n, p, q, s, t is with described previously.
The present invention relates to general formula compound compound (VIII), wherein, R22, R23, R24, R25, R26It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
The present invention relates to general formula compound compound (V), its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (IX),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21With described previously；
R22, R23, R24, R25, R26With described previously；
R5, R6, R7, R8, M, q, t is with described previously.
The present invention relates to general formula compound compound (IX), wherein, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
The compound that the present invention relates to, this compound is selected from following compound, but is not limited to following compound range:
Or its medicinal acceptable salt.
The present invention relates to the compound shown in logical formula V, its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X1 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound V by coupling；
Another kind of preparation method comprises the following steps:
X1 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X3 under certain reaction condition, prepare V by the reaction of reduction amination.
The present invention relates to compound shown in logical formula V, a kind of pharmaceutical composition of preparation, its compound comprising any one and pharmaceutically acceptable carrier.
The present invention relates to a kind of pharmaceutical composition of the composition of compound shown in logical formula V, described compositions includes the compound giving any one of the effective therapeutic dose of patient of needs treatment.
The present invention relates to any one compound purposes in the medicine of the lipid levels prepared for reducing patients blood plasma and/or liver in compound shown in logical formula V.
The present invention relates to any one compound in compound shown in logical formula V preparing for treating hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, metabolism syndrome, the purposes in antitumor drug.
The present invention relates to any one compound in compound shown in logical formula V and express and/or reduce the purposes in the PCSK9 medicine expressed in preparation for increasing LDLR.
The present invention relates to compound shown in logical formula V, compound disclosed by the invention has the advantages that
1, disclosed by the invention have logical formula V micromolecular compound, is suppressing PCSK9 gene expression, is increasing the expression of cell LDLR, strengthens hepatocyte to the remarkable effect in the picked-up ability of LDL, is expected to become a new generation's lipid lowerers.
PCSK9 inhibitor is the important directions that current large-scale transnational drugmaker makes great efforts research and development Novel cardiovascular disease medicament as the exploitation of fat-reducing medicament, expects that this kind of medicine surmounts the fat-reducing medicament that Statins is ripe.Big drug firm promotes PCSK9 inhibitor medicaments development just underway, current research work is concentrated mainly on the exploitation of biological medicine (including protein drug and long nucleic acid medicine), at present, clinical candidates is become but without little molecule PCSK9 inhibitor.Such as following table:
Biological medicine and small-molecule drug are for when treating same disease, biological medicament has with high costs, the shortcomings such as limited preparation way such as ejection preparation can only be adopted, and small-molecule drug has cheap for manufacturing cost, the advantages such as formulation method is various, disclosed by the invention have logical formula V micromolecular compound, shows significant suppression PCSK9 gene expression at cellular level, strengthen hepatocyte to the remarkable effect in the picked-up ability of LDL, be expected to become there is lipid lowerers of new generation.On the other hand, the formulation protocol of small-molecule drug selects face more extensive than biopharmaceutical macromolecular drug, is conducive to the exploitation of the multiple drug form of later stage drug development, compares biopharmaceutical macromolecular drug, can be supplied to as preparation type widely, meet the demand of people.
2, with existing patent documentation disclosed in the PCSK9 Compound Phase ratio of target spot for effect, disclosed by the invention have logical formula V compound, novel structure, there is brand-new architectural feature, it is expected to become the drug candidate that PCSK9 is had the novel mechanism of action, and eventually becomes a new generation there is the fat-reducing medicament of novel mechanism of action.
Existing patent document reports a few class and acts on the micromolecular compound of PCSK9 target spot, is summarized as follows with patent applicant's classification:
A, CVIPharmaceuticalLimited apply for a patent WO2010075469, WO2011006000 reports the micromolecular compound obtained based on natural product corydaline structure of modification, such is based on the micromolecular compound of Structures of Natural Products, its manufacturing process is complex, partial synthesis method needs to use the chemical reagent of severe toxicity, brings huge harm can to operator and natural environment.
B, CadilaHealthcareLimited apply for a patent WO2011051961, WO2012090220, WO2013132509, WO2014002105, reporting a few micromolecular compound in WO2014002106, these a few micromolecular compounds mainly contain a common chemical constitution fragment hexahydro pyrans methylamino structure fragment in molecular structure feature.This structure fragment is likely to play important role in compound structure with biological activity.
C, KowaCompanyLimited apply for a patent WO2011152508, JP2013136572, WO2013137371, WO2014017569 reports a few micromolecular compound, this kind of micromolecular compound molecular structure relative complex, general embodiment compound is possibly together with three chiral centres, and its manufacture difficulty is relatively large, and embodiment compound is it is generally required to six step chemical reactions (not including the structure of the structure fragment containing chiral centre) just can prepare target compound.
nulld、AmorchemHoldingsINC. apply for a patent in WO2014139008 and report small molecule compound，The section Example compound main structure of such micromolecular compound is in that containing " borate and boric acid " structure fragment，Although having listed multiple myeloma medicine bortezomib (containing " boric acid " structure fragment) at present，But " boric acid class " medicine is at non-therapeutic field of tumor (such as: diabetes，Hyperlipemia etc.) application nevertheless suffer from restriction，Main reason is that the potential neurotoxic side effects of boracic medicine，And its potential chemical characteristic (Chem.Res.Toxicol. with living organism " irreversible fixation ",2013,26(4),pp608–615)，Potential " carcinogenecity " being likely to result in SARS drug design of this chemical characteristic，" genotoxicity " has extensively been subject to the attention of Pharmaceutical Chemist.
E, ShifaBiomedicalCorporation apply for a patent WO2014150326, WO2014150395 reports two micromolecular compounds, the preparation method relative complex of these micromolecular compounds, the preparation of the compound that some expression activitiy is outstanding needs to use heavy metal catalyst reaction, and uses isocyanate compound.
Summarized above is exactly with the PCSK9 micromolecular compound being action target spot in current disclosed document.Compound disclosed by the invention is equally with PCSK9 for action target spot, and this compounds is all likely to become the newtype drug of following Based PC SK9 action target spot with a few micromolecular compounds of above-mentioned summary.
With existing patent documentation disclosed in the PCSK9 Compound Phase ratio of target spot for effect, disclosed by the invention have logical formula V compound, novel structure, there is brand-new unique structural feature, imply that the molecular structure feature of its novelty of compound disclosed by the invention, likely bring unexpected " quasi-medicated property feature ", be expected to become the drug candidate that PCSK9 is had the novel mechanism of action, and eventually become a new generation there is the fat-reducing medicament of novel mechanism of action.
3, disclosed by the invention have logical formula V compound, has raw material and is easy to get, and preparation process is simple to operate, advantage with low cost.
The micromolecular compound with logical formula V disclosed by the invention, the commercially available intermediate of main employing, then adopt simple chemical reaction to carry out fragment coupling reaction and prepare.For example with commercially available, there is " amine ", " aldehyde ", the starting material of the functional group such as " halogenated hydrocarbons ", then carry out a step chemical reaction and namely can prepare target compound.Therefore, disclosed by the invention have logical formula V compound, has raw material and is easy to get, and preparation process is simple to operate, advantage with low cost.
4, disclosed by the invention have logical formula V compound have activation the kinase whose activity of AMPK, prompting the compounds of this invention not only can be developed into a new generation's lipid lowerers, and the effect better controlling blood glucose can be played, in blood fat reducing and blood sugar lowering, obtain the existing single drugs with function more advantage of comprehensive benefit ratio for vast Metabolic Syndrome Patients.
General formula compound disclosed by the invention (V) preparation is prepared referring especially to following scheme,
Compound shown in logical formula V of the present invention, its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X1 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound V by coupling；
Another kind of preparation method comprises the following steps:
X1 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X3 under certain reaction condition, prepare V by the reaction of reduction amination.
Further, formula (VI):
Compound shown in formula of the present invention (VI), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X4 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X4 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VI by coupling；
Another kind of preparation method comprises the following steps:
X4 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X4 and X3 under certain reaction condition, prepare VI by the reaction of reduction amination.
Further, formula (VII):
Compound shown in formula of the present invention (VII), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X5 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X5 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VII by coupling；
Another kind of preparation method comprises the following steps:
X5 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X5 and X3 under certain reaction condition, prepare VII by the reaction of reduction amination.
Further, formula (VIII):
Compound shown in formula of the present invention (VIII), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X1 and X6 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X6, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VIII by coupling；
Another kind of preparation method comprises the following steps:
X1 and X7 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X7 under certain reaction condition, prepare VIII by the reaction of reduction amination.
Further, formula (IX):
Compound shown in formula of the present invention (IX), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X5 and X8 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X5 and X8, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound IX by coupling；
Another kind of preparation method comprises the following steps:
X5 and X9 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X5 and X9 under certain reaction condition, prepare IX by the reaction of reduction amination.
Accompanying drawing illustrates:
After Fig. 1 shows compound treatment, the fluorescence intensity that basis of microscopic observation arrives is evaluated sample and hepatocyte is absorbed the impact of LDL ability.
Fig. 2 shows high fat SD rat, is administered after surrounding through part of compounds oral administration gavage of the present invention, and in serum, the measurement result of low-density lipoprotein cholesterol (LDL-C) compares.
Fig. 3 shows high fat SD rat, is administered after surrounding through part of compounds oral administration gavage of the present invention, and in serum, the measurement result of T-CHOL (TC) compares.
Fig. 4 shows high fat SD rat, is administered after surrounding through part of compounds oral administration gavage of the present invention, and in serum, the measurement result of glutamate pyruvate transaminase (ALT) compares.
Fig. 5 shows high fat SD rat, is administered after surrounding through part of compounds oral administration gavage of the present invention, and in serum, the measurement result of glutamic oxaloacetic transaminase, GOT (AST) compares.
Detailed Description Of The Invention
In many aspects, present technology provides the compound of novelty and the purposes that this compound is in reducing the purposes of lipid levels of blood plasma and/or liver and treatment hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type ii diabetes, hyperglycemia, insulin resistance, obesity and metabolism syndrome.Compound provided herein can be formulated for the pharmaceutical composition in method disclosed herein and medicament.Present invention also offers described compound for preparing the purposes of pharmaceutical formulation and medicament, described compound purposes in the lipid levels reducing blood plasma and/or liver and described compound are in treatment hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver, type ii diabetes, hyperglycemia, the purposes in insulin resistance, obesity and metabolism syndrome.
Following term is middle in the whole text herein to be used with reference to following definitions.
Generally, mention certain element, for instance hydrogen or H, represent all isotopes including this element.Such as, if R group is defined to include hydrogen or H, it also includes deuterium and tritium.Comprise radiosiotope (such as tritium, C14、P32And S35) compound therefore also in the scope of the present invention.For by this type of labelling insert the present invention compound in means be that those skilled in the art are apparent based on disclosure herein.
Generally, " being substituted " represents such organic group (such as alkyl) as defined below, and the key of the connected non-hydrogen atom of the key of the one or more connection hydrogen wherein contained or non-carbon is replaced.The group being substituted also includes such group: wherein one or more keys connecting carbon atom or hydrogen atom are replaced by the heteroatomic key of one or more connections (including double or triple bonds).Thus, unless otherwise, the group being replaced is replaced by one or more substituent groups.In some embodiments, substituent group is replaced by 1,2,3,4,5 or 6 substituent groups.(namely the example of substituent group includes halogen, F, Cl, Br and I), hydroxyl, alkoxyl, alkene oxygen base, aryloxy, aralkyl oxy, heterocyclyloxy and heterocyclylalkoxy, carbonyl, carboxyl, ester, carbaminate/ester, oxime, hydroxylamine, alkoxyamine, aralkoxy amine, sulfur alcohol, sulfide, sulfoxide, sulfone, sulfonyl, sulfonamide, amine, N-oxide, hydrazine, hydrazides, hydrazone, azide, amide, urea, amidine, guanidine, enamine, acid imide, isocyanates/ester, isothiocyanate/ester, cyanate/ester, thiocyanate/ester, imines, nitro, nitrile etc..
The ring base being substituted, for instance cycloalkyl, aryl, heterocyclic radical and the heteroaryl being substituted, also includes the ring and the loop systems that wherein connect the key replacement of the connected carbon atom of key of hydrogen atom.Cycloalkyl, aryl, heterocyclic radical and the heteroaryl being substituted also can by defined below that be substituted or that be unsubstituted alkyl, thiazolinyl and alkynyl substituted.
Alkyl includes the straight or branched group comprising 1 to 20 carbon atom, it is preferable that containing the alkyl of 1 to 12 carbon atom.nullLimiting examples includes methyl、Ethyl、N-pro-pyl、Isopropyl、Normal-butyl、Isobutyl group、The tert-butyl group、Sec-butyl、N-pentyl、1，1-dimethyl propyl、1，2-dimethyl propyl、2，2-dimethyl propyl、1-ethyl propyl、2-methyl butyl、3-methyl butyl、N-hexyl、1-Ethyl-2-Methyl propyl group、1，1，2-thmethylpropyl、1，1-dimethylbutyl、1，2-dimethylbutyl、2，2-dimethylbutyl、1，3-dimethylbutyl、2-ethyl-butyl、2-methyl amyl、3-methyl amyl、4-methyl amyl、2，3-dimethylbutyl、N-heptyl、2-methylhexyl、3-methylhexyl、4-methylhexyl、5-methylhexyl、2，3-dimethyl amyl group、2，4-dimethyl amyl group、2，2-dimethyl amyl group、3，3-dimethyl amyl group、2-ethyl pentyl group、3-ethyl pentyl group、N-octyl、2，3-dimethylhexanyl、2，4-dimethylhexanyl、2，5-dimethylhexanyl、2，2-dimethylhexanyl、3，3-dimethylhexanyl、4，4-dimethylhexanyl、2-ethylhexyl、3-ethylhexyl、4-ethylhexyl、2-methyl-2-ethyl pentyl group、2-methyl-3-ethyl pentyl group、N-nonyl、2-methyl-2-ethylhexyl、2-methyl-3-ethylhexyl、2，2-diethyl amyl group、Positive decyl、3，3-diethylhexyl、2，2-diethylhexyl，And various branched chain isomers etc..More preferably contain the low alkyl group of 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc..Alkyl can be replace or non-substituted, when substituted, substituent group can be replaced on any spendable junction point, described substituent group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo ,-C (O) R ' ,-C (O) OR ' ,-S (O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR " or-S (O)mNR′R″。
Cycloalkyl-alkyl refers to the alkyl that the unsaturated monocycle of saturated or part or multi-ring cyclic hydrocarbon replace, and cycloalkyl ring comprises 3 to 20 carbon atoms, it is preferable that comprise 3 to 12 carbon atoms, more preferably comprises 3 to 10 carbon atoms.The limiting examples of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.；Polycyclic naphthene base includes the cycloalkyl of volution, condensed ring and bridged ring.
Thiazolinyl refers to by the unsaturated alkyl as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon double bond, for instance vinyl, 1-acrylic, 2-acrylic, 1-, 2-or 3-cyclobutenyl etc..Thiazolinyl can be replace or non-substituted, when substituted, substituent group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (O) R ' ,-C (O) OR ' ,-S (O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR " or-S (O)mNR′R″。
Cycloalkenyl group refers to include having at least one double bond being between two carbon atoms, unsaturated cycloalkyl as defined above.In some embodiments, cycloalkenyl group can have one, two or three double bonds but not including that aromatic compound.Cycloalkenyl group comprises 4 to 14 carbon atoms, or in some embodiments, comprises 5 to 14 carbon atoms, it is preferable that comprise 5 to 10 carbon atoms, more preferably comprises 5,6,7 or 8 carbon atoms.The example of cycloalkenyl group includes cyclohexenyl group, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl.
Alkynyl refers to the unsaturated alkyl as defined above being at least made up of two carbon atoms and at least one carbon-to-carbon triple bond, for instance acetenyl, 1-propinyl, 2-propynyl, 1-, 2-or 3-butynyl etc..Alkynyl can be replace or non-substituted, when substituted, substituent group is preferably one or more following group, and it is independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group ,-C (O) R ' ,-C (O) OR ' ,-S (O)mR′、-NR′R″、-C(O)NR′R″、-NR′C(O)R″、-NR′S(O)mR " or-S (O)mNR′R″。
Aryl is free from heteroatomic cyclic aromatic hydrocarbon.Aryl includes monocycle, bicyclo-and three-loop system in this article.Therefore, aryl includes but not limited to phenyl, azulene cyclopentacycloheptene base, diphenyl, fluorenyl, phenanthryl, anthryl, indenyl, indanyl, pentalene base and naphthyl.In some embodiments, aryl contains 6-14 carbon in the part of the ring of group, it is preferable that 6 to 12, more preferably 6-10 carbon atom.In some embodiments, aryl is phenyl or naphthyl.Although phrase " aryl " includes the group (such as indanyl, tetralyl etc.) containing the ring (the aromatic-aliphatic loop systems such as condensed) condensed, but its aryl not including there is other group (such as alkyl or halo group) being bonded with one of ring members.The groups such as tolyl are referred to as the aryl being substituted.The representational aryl being substituted can through mono-substituted or be replaced and exceed once.Such as, including but not limited to, through mono-substituted aryl, the phenyl or naphthyl that 2-, 3-, 4-, 5-or 6-replace, it can be replaced by such as substituent group listed above.
The alkyl that aralkyl is as defined above, wherein, the hydrogen of alkyl or carbon bond are connected the key of aryl defined above and are replaced.In some embodiments, aralkyl contains 7 to 16 carbon atoms, it is preferable that 7 to 14 carbon atoms, more preferably 7 to 10 carbon atoms.The aralkyl being substituted can be replaced in the part of alkyl, aryl, or is all replaced at alkyl and aryl moiety.Representational aralkyl includes but not limited to benzyl and phenethyl and (cycloalkylaryl) alkyl (such as 4-indanyl ethyl) condensed.The representational aralkyl being substituted can be replaced once or for several times by such as substituent group listed above.
Heterocyclic radical includes the aromatic series (being also referred to as heteroaryl) containing 3 or multiple ring members and non-aromatic cyclic compound, and one or more in its ring members are hetero atoms, for instance but it is not limited to N, O and S.In some embodiments, heterocyclic radical contains 1,2,3 or 4 hetero atoms.In some instances, heterocyclic radical include having 3 to 16 ring memberses single, two and three rings.Heterocyclic radical includes loop systems aromatic, that part is unsaturated and saturated, for instance, imidazole radicals, imidazolinyl and imidazolidinyl.Phrase " heterocyclic radical " includes the ring species class condensed, these those including comprising the aromatic series condensed and non-aromatic group, for instance benzotriazole base, 2,3-dihydrobenzos [Isosorbide-5-Nitrae] dialkyl group and benzo [1,3] dioxa cyclopentenyl.This phrase also include bridging containing heteroatomic multi-loop system, for instance but be not limited to quininuclidinyl.But, this phrase does not include the heterocyclic radical with other group (such as alkyl, oxo or halo group) being bonded with one of ring members.On the contrary, these are referred to as " heterocyclic radical being substituted ".nullHeterocyclic radical includes but not limited to aziridinyl、Azetidine base、Pyrrolidinyl、Imidazolidinyl、Pyrazolidinyl、Thiazolidinyl、Tetrahydrochysene thio-phenyl、Tetrahydrofuran base、Dioxa cyclopentenyl、Furyl、Thio-phenyl、Pyrrole radicals、Pyrrolinyl、Imidazole radicals、Imidazolinyl、Pyrazolyl、Pyrazolinyl、Triazolyl、Tetrazole radical、Azoles base、Isoxazole base、Thiazolyl、Thiazolinyl、Isothiazolyl、Thiadiazole base、Di azoly、Piperidyl、Piperazinyl、Morpholinyl、Thio-morpholinyl、THP trtrahydropyranyl、Tetrahydrochysene thiopyranyl、Thioxane、Dioxane base、Dithiane base、Pyranose、Pyridine radicals、Pyrimidine radicals、Pyridazinyl、Pyrazinyl、Triazine radical、Dihydropyridine base、Dihydro two thienyl、Dihydro dithione base、Homopiperazine base、Quininuclidinyl、Indyl、Indoline base、Isoindolyl、Azaindolyl (pyrrolopyridinyl)、Indazolyl、Indolizinyl、Benzotriazole base、Benzimidazolyl、Benzofuranyl、Benzo thio-phenyl、Benzothiazolyl、Benzodiazole base、Benzimidazole dihydrochloride base、Benzo two thienyl、Benzo thienyl、Benzothiazine base、Benzoxazolyl group、Benzothiazolyl、Benzothiadiazole base、Benzo [1,3] dioxa cyclopentenyl、Pyrazolopyridine base、Imidazopyridyl (azabenzimidazoles base)、Triazolopyridine base、Isoxazole pyridine radicals、Purine radicals、Xanthinyl、Adenyl、Guanyl-、Quinolyl、Isoquinolyl、Quinolizinyl、Quinoxalinyl、Quinazolyl、Phthalazinyl、Naphthyridinyl、Thianaphthenyl、Dihydrobenzo thiazinyl、Dihydro benzo furyl、Indolinyl、Dihydrobenzo dialkyl group、Tetrahydro indole base、Tetrahydrochysene indazole base、Four benzimidazolyls、Tetrahydro benzo triazolyl、Nafoxidine pyridine radicals、Tetrahydro-pyrazole pyridine radicals、Imidazolidine pyridine radicals、Tetrahydrochysene Triazolopyridine base and tetrahydric quinoline group.The representational heterocyclic radical being substituted can through monosubstituted or be replaced and exceed once, for instance but it is not limited to that 2-, 3-, 4-, 5-or 6-replace or by such as multiple substituent group Disubstituted pyridine base listed above or morpholinyl.
Heteroaryl is the aromatic ring compound containing 5 or more ring members atom, and wherein one or more ring memberses are hetero atoms, for instance but it is not limited to N, O and S.Heteroaryl includes but not limited to following radicals, such as, pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical, azoles base, isoxazole base, thiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, thio-phenyl, benzo thio-phenyl, furyl, benzofuranyl, indyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazoles base), Pyrazolopyridine base, Triazolopyridine base, benzotriazole base, benzoxazolyl group, benzothiazolyl, Benzothiadiazole base, imidazopyridyl, isoxazole pyridine radicals, thianaphthenyl, purine radicals, xanthinyl, adenyl, guanyl-, quinolyl, isoquinolyl, tetrahydric quinoline group, quinoxalinyl and quinazolyl.It is all aromatic fused ring compounds that heteroaryl includes all of which ring, for instance indyl, and it also includes only one of which ring is aromatic fused ring compounds, for instance 2,3-indolinyls.Although phrase " heteroaryl " includes the cycle compound condensed, but this phrase does not include the heteroaryl with other group (such as alkyl) being bonded with one of ring members.On the contrary, the heteroaryl with this type of replacement is referred to as " heteroaryl being substituted ".The representational heteroaryl being substituted can be replaced once or for several times by such as multiple substituent group listed above.
The alkyl that cycloheteroalkylalkyl is as defined above, but wherein, the hydrogen of alkyl or carbon bond are connected the key of heterocyclic radical defined above and are replaced.The cycloheteroalkylalkyl being substituted can be replaced in the part of alkyl, heterocyclic radical, or is all replaced at alkyl and heterocyclyl moieties.Representational cycloheteroalkylalkyl includes but not limited to morpholine-4-base-ethyl, furan-2-base-methyl, imidazol-4 yl-methyl, pyridin-3-yl-methyl, oxolane-2-base-ethyl and indole-2-base-propyl group.The representational cycloheteroalkylalkyl being substituted can be replaced once or for several times by such as substituent group listed above.
The alkyl that heteroarylalkyl is as defined above, wherein, the hydrogen of alkyl or carbon bond are connected the key of heteroaryl defined above and are replaced.The heteroarylalkyl being substituted can be replaced in the part of alkyl, heteroaryl, or is all replaced at alkyl and heteroaryl moieties.The representational heteroarylalkyl being substituted can be replaced once or for several times by such as substituent group listed above.
In the compound of the present invention, the group described herein with two or more junction point (i.e. bivalence, trivalent or multivalence) is named by prefix " Asia ".Such as, divalent alkyl is alkylidene, and divalent aryl is arlydene, and divalent heteroaryl radical is heteroarylidene, etc..The group being substituted with the compound of the present invention with single point of attachment does not use " Asia " to name.It is therefoie, for example, chloroethyl is not referred to as chlorethylidene in this article.
Oxo base refers to that the group being wherein connected with oxygen atom is the alkyl being substituted or being unsubstituted, aryl, heteroaryl, cycloalkyl, alkyl acyl, aryl-acyl, heteroaroyl by the substituted radical constituted that is connected with oxygen atom.Above group is connected with oxygen atom and namely may be constructed alkoxyl, aryloxy group, heteroaryloxy, cycloalkyl oxy, alkyl acyloxy, arylacyloxy, heteroaryl acyloxy group, cycloalkyl acyloxy.
Alkoxyl is the substituent group that in hydroxyl (-OH), the key of the carbon atom that the key of connection hydrogen atom is connected alkyl that is defined above that be substituted or that be unsubstituted is replaced.The example of linear alkoxide groups includes but not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy etc..The example of branched alkoxyl includes but not limited to isopropoxy, sec-butoxy, tert-butoxy, isoamoxy, different hexyloxy etc..The example of cycloalkyloxy includes but not limited to cyclopropyl oxygen, cyclobutyl oxygen, cyclopenta oxygen, cyclohexyl oxygen etc..The representational alkoxyl being substituted can be replaced once or for several times by such as substituent group listed above.
Term " alkanoyl " and " alkanoyl oxygen " refer to-C (O)-alkyl and-O-C (O)-alkyl respectively time used herein, each of which contains 2-5 carbon atom.
Term " aryl oxide " and " alkoxy aryl " refer to the substituent group that aryl that is that be substituted or that be unsubstituted is constituted with oxygen atoms bond, the substituent group that aralkyl that is that be substituted or that be unsubstituted is constituted with oxygen atoms bond respectively.Example includes but not limited to phenoxy group, naphthyl oxygen and benzyloxy.The representational aryl oxide being substituted and alkoxy aryl can be replaced once by such as substituent group listed above or for several times.
Term " carboxylic acid " refers to-COOH group time used herein.
Term " carboxylate " refers to-COOR ' group time used herein.R ' be as defined herein be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.
Term " amide " (or " amide groups ") includes C-amide group and N-amide group, is namely-C (O) NR ' R " and-NR ' C (O) R " group respectively.R ' and R " be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.Therefore amide groups includes but not limited to carbamoyl (-C (O) NH2) and carbonylamino group (-NHC (O) H).In some embodiments, amide is-NR ' C (O)-(C1-5Alkyl), this group is referred to as " carbonylamino ", and in other embodiments, amide is-NHC (O)-alkyl, and this group is referred to as " alkanoylamino ".
Term " nitrile " or " cyano group " refer to-CN group time used herein.
Carbaminate/ester includes N-carbamate groups and O-carbamate groups, is namely-NR ' C (O) OR " and-OC (O) NR ' R " group respectively.R ' and R " be independently as defined herein be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.R ' can also is that H.
Term " amine " (or " amino ") refer to-NR ' R time used herein " group, wherein R ' and R " be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.In some embodiments, amine is alkyl amino, dialkyl amido, arylamino or alkyl aryl amino.In some other embodiment, amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylcarbamic, isopropylamino, phenyl amino or benzylamino.
Term " sulfonamide " includes S-sulfuryl amine group and N-sulfuryl amine group, is namely-SO respectively2NR ' R " and-NR ' SO2R " group.R ' and R " be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, cycloheteroalkylalkyl or the heterocyclic radical that are unsubstituted.Therefore sulfuryl amine group includes but not limited to sulfonyl (-SO2NH2).In some embodiments herein, sulfonamide is-NHSO2-alkyl, it is referred to as " alkyl sulfonyl-amino ".
Term " mercaptan " refers to-SH group, and sulfide includes-SR ' group, and sulfoxide includes-S (O) R ' group, and sulfone includes-SO2R ' group, and sulfonyloxy includes-OSO2R ', sulphur acyloxy includes-OSO2OR′.R ' be independently as defined herein be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.In some embodiments, sulfide is alkylthiol groups ,-S-alkyl.
Term " urea " refers to-NR '-C (O)-NR ' R " group.R ' and R " group be independently hydrogen as defined herein or be substituted or the alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " amidine " refers to-C (NR ') NR ' R " and-NR ' C (NR ') R ", wherein, R ' and R " each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " guanidine " refers to-NR ' C (NR ') NR ' R ", wherein R ' and R " each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " enamine " refers to-C (R ')=C (R ') NR ' R " and-NR ' C (R ')=C (R ') R ", wherein R ' and R " each be hydrogen as defined herein independently, be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " halogen " or " halo " refer to bromine, chlorine, fluorine or iodine time used herein.In some embodiments, halogen is fluorine.In some other embodiment, halogen is chlorine or bromine.
Term " hydroxyl " can refer to-OH or its ionized form-O time used herein-。
Term " acid imide " refers to-C (O) NR ' C (O) R ", wherein R ' and R " each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted.
Term " nitrogen heterocycle " refers to the ring system containing nitrogen-atoms, this ring system can " a pair of horses going side by side close " fragrant and non-aromatic ring system, or pass through " spiral shell carbon atom " and link other ring systems, for instance following structure:
Etc..
Term " imines " refers to-CR ' (NR ") and-N (CR ' R ") group, wherein R ' and R " each be independently hydrogen as defined herein or be substituted or the alkyl, cycloalkyl, thiazolinyl, alkynyl, aralkyl base, heterocyclic radical or the cycloheteroalkylalkyl that are unsubstituted and meet: R ' and R " different time be hydrogen.
Term " nitro " refers to-NO time used herein2。
Term " trifluoromethyl " refers to-CF time used herein3。
Term " trifluoromethoxy " refers to-OCF time used herein3。
The officinal salt of compound described herein is within the scope of the invention, it includes such acid-addition salts or base addition salts, described salt maintains intended pharmacological activity and is not have potential ill effect (such as salt does not have undue toxicity, sensitization or zest, and is bioavailable) from angle biology.When the compound of the present invention has basic group (such as, amino) time, officinal salt can be formed with mineral acid (such as hydrochloric acid, hydrogen borate, nitric acid, sulphuric acid and phosphoric acid), organic acid (such as alginate, formic acid, acetic acid, benzoic acid, gluconic acid, Fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2 and p-methyl benzenesulfonic acid) or acidic amino acid (such as aspartic acid and glutamic acid).When the compound of the present invention has acidic-group, for instance during hydroxy-acid group, it can with metal, for instance alkali and alkaline earth metal ions (such as Na+、Li+、K+、Ca2+、Mg2+、Zn2+), ammonia or organic amine (such as dicyclohexylamine, Trimethylamine, triethylamine, pyridine, ethanolamine, diethanolamine, triethanolamine) or basic amino acid (such as arginine, lysine and ornithine) form salt.This type of salt " one kettle way " can be prepared during to the separation of compound and purification, or can prepare this type of salt by individually being reacted with suitable acid or alkali respectively and separate the salt being consequently formed by purified to free alkali or free acid rear compound.
Well known by persons skilled in the art, the compound of the present invention can show tautomerism, conformational isomerism, geometrical isomerism and/or stereomeric phenomenon.Although the formula figure in specification and claims only represents one of possible tautomerism, conformational isomerism, stereoisomerism or geometrical isomerism form, it is understood that the present invention include compound there is any tautomerism of one or more purposes described herein, conformational isomerism, stereoisomerism and/or geometrical isomerism form and these multiple multi-form mixture.
Those skilled in the art are understandable, and large-scale functional group and other structure can show tautomer, and all tautomers of compound described herein are within.
Spatial chemistry unless specifically indicated, the stereoisomer of compound, including all chiralitys of structure, diastereo-isomerism and racemic form.Therefore, the optical isomer in the enrichment of any or all asymmetric atom place or fractionation is included for the compound in the present invention.Raceme and diastereomeric mixtures, and each optical isomer, all can separated or synthesis, to be substantially free of its corresponding isomer or diastereomer, these stereoisomers are also within the scope of the invention.
The compound of the present invention can exist as solvate, especially as hydrate.Hydrate can be formed during the manufacture of compound or the compositions of inclusion compound, or hydrate can be formed due to the hygroscopic nature of compound over time.The compound of the present invention is alternatively arranged as organic solvate to be existed, including ether and solvate etc..Qualification and preparation to any specific solvate are all that synthesis is organic or medicinal chemistry art those of ordinary skill is known.
Lipid includes that synthesize and naturally occurring fat-soluble compound, and it includes neutrality and amphiphatic molecule.Both sexes lipid typically comprises hydrophilic component and hydrophobic components.Exemplary lipid includes fatty acid, triglyceride, neutral fat, phospholipid, candy fat, fatty alcohol, wax, terpene, steroid (such as cholesterol) and surfactant.
" lipid reduction reagent " has the compound of one or more following effects when referring to be administered to patient time used herein: the liver increasing LDLR is expressed；Increase the LDLRmRNA half-life in hepatocyte；Increase the liver picked-up to blood plasma LDL, cholesterol or triglyceride；Strengthen the fatty acid oxidation of liver, reduce triglyceride synthesis and the secretion of liver, and reduce blood plasma and/or the T-CHOL of liver, LDL-cholesterol, VLDL-cholesterol or triglyceride levels.Lipid disclosed herein reduces reagent and includes the compound in the present invention.
In one aspect, the invention provides the purposes utilizing the compounds of this invention manufacture in reducing the medicine of lipid levels of patients blood plasma and/or liver, reduce compound as described herein or the compositions of effective dose including using lipid to described patient.The lipid levels reduced can be one or more in T-CHOL, LDL-cholesterol (LDL-C), triglyceride (TG) and nonesterified long-chain fatty acid.
Compound described herein and compositions can be used for preventing or treat following disease, including such as, and hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty liver (fatty degeneration of liver), type ii diabetes, hyperglycemia, obesity or insulin resistance and metabolism syndrome.The method for the treatment of includes compound as herein described or the compositions of the experimenter's administering therapeutic effective dose to needs treatment.The compound of the present invention can be additionally used in treatment or prevention is characterised by the blood plasma that raises or liver cholesterol or triglyceride or the morbid state relevant to the blood plasma raised or liver cholesterol or triglyceride or morbid state.The technology of the present invention also provides for using the compounds of this invention manufacture treatment or prevention disease (such as, hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty liver, type ii diabetes, hyperglycemia, obesity or insulin resistance or metabolism syndrome) the purposes of effective dose medicine.
Compound disclosed herein and compositions are expressed by increasing the liver of LDLR, by increasing the stability of LDLRmRNA, by increasing LDLR genetic transcription, by suppressing the degraded of the LDLR albumen that mediates of proprotein convertase subtilisin/kexin9 type (proproteinconvertasesubtilisin/kexintype9) (PCSK9) or the whole of above-mentioned possible cell mechanism, reduce lipid levels.The LDLR level increased in liver adds picked-up and the processing of blood plasma LDL-C, thus causing that the blood plasma level of cholesterol, LDL-C and triglyceride reduces.Additionally, compound can pass through to activate the AMP protein kinase (AMPK) (key molecule of bio-energy Metabolism regulation) activated increases the phosphorylation of acetyl CoA carboxylase (ACC).The phosphorylation of the increase of ACC enhances the fatty acid oxidation in liver, the TG accumulation causing liver reduces, and cause that TG secretes with VLDL form, this additionally aids the blood plasma level reducing TG, LDL-C, T-CHOL and nonesterified long-chain fatty acid, thus preventing or treating the disease relevant to hyperlipemia.On the other hand, it is believed that, hereditism and pharmaceutical research show, AMPK is that body keeps necessary to glucose balance, and compound, by activating AMPK, finally plays treatment type ii diabetes, hyperglycemia, obesity or insulin resistance or metabolism syndrome.
In yet another aspect, compound provided by the invention has increases the LDLR purposes expressed, and including to needing its compound as herein described of experimenter's administering therapeutic effective dose or compositions, thus increases the LDLR in described experimenter and expresses.In another aspect of this invention, the invention provides a kind of purposes utilizing the compounds of this invention to reduce plasma LDL-cholesterol and/or plasma triglyceride, including to needing its compound as herein described of patient therapeuticallv's effective dose or compositions, thus reduce the plasma LDL-cholesterol of described patient.
In yet another aspect, the invention provides the lipid including compound and compositions thereof and reduce reagent.Compound and compositions can be used in method and the treatment of reduction lipid as herein described.In one embodiment, the invention provides Formula V compound, its stereoisomer, its tautomer, its solvate and/or its officinal salt.
In yet another aspect, present technology provides the pharmaceutical composition comprising any compound disclosed herein and pharmaceutically suitable carrier or one or more excipient or filler and medicament.In some embodiments, it is provided that the pharmaceutical composition of the patient's condition of the group of free hyperlipemia, hypercholesterolemia, hypertriglyceridemia, fatty degeneration of liver and metabolism syndrome composition is selected in treatment.Such composition includes lipid and reduces as herein described any compound of effective dose.In one embodiment, pharmaceutical composition is packaged into unit dosage form.When being administered to the experimenter needing it, unit dosage form can effectively reduce the lipid levels (at least one in such as T-CHOL, LDL-cholesterol, triglyceride and nonesterified long-chain fatty acid) in blood flow and/or liver.
Can pass through to mix one or more compounds of the present invention, its officinal salt, its stereoisomer, its tautomer or its solvate with pharmaceutically suitable carrier, excipient, binding agent, diluent etc., prepare pharmaceutical composition, to prevent or to treat the disease relevant to the lipid levels of the blood plasma increased and/or liver.Compound as herein described can be used for preparing formulation and the medicament of the blood plasma preventing or treating and increase and/or the relevant various disease conditions (such as hyperlipemia, hypercholesterolemia, fatty degeneration of liver and metabolism syndrome) of liver lipid levels with compositions.Such composition can be the form of such as granule, powder, tablet, capsule, syrup, suppository, injection, emulsion, elixir, suspension or solution.The compositions of the present invention can be formulated for the various forms of multiple route of administration, for instance, by oral, parenteral, locally, rectum, per nasal, vaginal application or used by the storage implanted.Parenteral or systemic administration include but not limited to subcutaneous, intravenous, intraperitoneal and intramuscular, injection.Following dosage form provides as an example, and it is not necessarily to be construed as the technology of the restriction present invention.
Pharmaceutical composition containing active component can apply to the form being administered orally, for instance tablet, dragee, lozenge, water or oil suspension, dispersibles powder or granule, emulsion, hard or soft capsule, or syrup or elixir.Can refer to any known method preparing Pharmaceutical composition in this area and prepare Orally administered composition, such composition can contain one or more selected from following composition: sweeting agent, correctives, coloring agent and preservative, to provide pleasing and good to eat pharmaceutical formulation.Tablet contains active component and the suitable nontoxic pharmaceutically useful excipient preparing tablet for mixing.These excipient can be inert excipient, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulating agent and disintegrating agent, for instance microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, corn starch or alginic acid；Binding agent, for instance starch, gelatin, polyvinylpyrrolidone or arabic gum and lubricant, for instance magnesium stearate, stearic acid or Pulvis Talci.These tablets can not maybe can pass through cover the taste of medicine or postpone disintegrate and absorption in the gastrointestinal tract by coating, thus provides the known technology of slow releasing function by its coating in a long time.Such as, water soluble taste can be used to shelter material, for instance hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or extend time material such as ethyl cellulose, acetylbutyrylcellulose.
Also can use wherein active component and the inert solid diluent hard gelatin capsule that such as calcium carbonate, calcium phosphate or Kaolin mix, or wherein active component provides oral formulations with water-solubility carrier such as Polyethylene Glycol or oil soluble matchmaker such as Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil Perle.
Water slurry contains active substance and the suitable excipient preparing water slurry for mixing.This type of excipient is suspending agent, for instance sodium carboxy methyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and arabic gum；Dispersant or wetting agent can be naturally-produced phospholipid such as lecithin, or the condensation product of alkylene oxide and fatty acid such as Myrj 45, or the condensation product of oxirane and long-chain fatty alcohol, such as 17 carbon ethyleneoxy group spermol, or oxirane and the condensation product by the derivative part ester of fatty acid and hexitol, such as polyoxyethylene sorbitol monoleate, or oxirane and the condensation product by the derivative partial ester of fatty acid and hexitan, for instance poly(ethylene oxide) Arlacel-80.Aqueous suspension can also contain one or more preservative such as ethyl hydroxybenzoate or nipalgin n-propyl, one or more coloring agent, one or more tender taste agent and one or more sweeting agents, for instance sucrose, saccharin or aspartame.
Oil suspension can pass through to make active component be suspended in vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois, or formulated in mineral oil such as liquid paraffin.Oil suspension can contain thickening agent, for instance Cera Flava, hard paraffin or spermol.Above-mentioned sweeting agent and tender taste agent can be added, to provide good to eat preparation.These compositionss can be preserved by addition antioxidant such as butylated hydroxyanisole or alpha-tocopherol.
Can make to be applicable to prepare water suspendible dispersible powder and granule also provide active component and for the dispersant mixed or wetting agent, suspending agent or one or more preservative by adding water.Suitable dispersant or wetting agent and suspending agent can illustrate above-mentioned example.Also other excipients such as sweeting agent, tender taste agent and coloring agent can be added.These compositionss are preserved by adding antioxidant such as ascorbic acid.
The pharmaceutical composition of the present invention can also be the form of oil in water emulsion.Oil phase can be vegetable oil such as olive oil or Oleum Arachidis hypogaeae semen, or mineral oil such as liquid paraffin or its mixture.Suitable emulsifying agent can be naturally-produced phospholipid, for instance soybean lecithin and by the derivative ester of fatty acid and hexitan or partial ester such as sorbitan monooleate, and the condensation product of described partial ester and oxirane, for instance polyoxyethylene sorbitol monoleate.Emulsion can also contain sweeting agent, tender taste agent, preservative and antioxidant.Available Sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose syrup blend and elixir.This type of preparation also can contain demulcent, preservative, coloring agent and antioxidant.
Pharmaceutical composition can be sterile injectable aqueous form.Water, ringer's solution and isotonic sodium chlorrde solution can be had in the acceptable solvent used and solvent.Aseptic injection preparation can be that wherein active component is dissolved in the aseptic injection oil-in-water microemulsion of oil phase.Such as active component is dissolved in the mixture of soybean oil and lecithin.Then oil solution is added process in the mixture of water and glycerol and forms microemulsion.The a large amount of injection in local can be passed through, injection or microemulsion are injected in the blood flow of patient.Or, it is desirable to solution and microemulsion is given by the mode that can keep the compounds of this invention constant circulating concentration.For keeping this constant density, continuous intravenous delivery device can be used.
Pharmaceutical composition could be for the aseptic injection water of intramuscular and subcutaneous administration or the form of oil suspension.Can by known technology, the dispersant suitable by those described above or wetting agent and suspending agent prepare this suspension.Aseptic injection preparation can also be aseptic injectable solution or the suspension of preparation in the acceptable diluent of nontoxic parenteral or solvent, for instance the solution of preparation in 1,3 butylene glycol.In addition, it is convenient to aseptic fixing oil as solvent or suspension media.For this purpose it is proposed, the fixing oil of any mediation including synthetic glycerine list or diester can be used.Additionally, fatty acid such as oleic acid can also prepare injection.
Dosage form for local (including buccal and Sublingual) or the compound of the transdermal administration present invention includes powder, spraying, ointment, paste, emulsifiable paste, washing liquid, gel, solution and paster.Active component can aseptically with pharmaceutically suitable carrier or excipient and be likely to any preservative of needing or buffer agent mixes.Powder and spraying can such as be prepared with excipient (such as the mixture of sugar, Muscovitum, silicic acid, sodium hydroxide, calcium silicates and polyamine powder or these materials).Ointment, paste, emulsifiable paste and gel also can contain following excipient, for instance, animal and plant fat, oil, wax, paraffin, starch, tragacanth, cellulose derivative, Polyethylene Glycol, silicone, bentonite, silicic acid, Muscovitum and zinc oxide or its mixture.It is also possible to use absorption enhancer, the compound increasing the present invention penetrates the flowing of skin.By providing rate controlling membranes (such as a part for percutaneous plaster) or compound can be scattered in the speed controlling this type of flowing in polymeric matrix or gel.
The compounds of this invention can be given by the suppository form for rectally.Can pass through by medicine be solid at normal temperatures but in the rectum for liquid, thus can dissolve in the rectum and discharge the suitable nonirritant excipient of medicine and mix and prepare these pharmaceutical compositions.This type of material includes the mixture of the fatty acid ester of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, the Polyethylene Glycol of various molecular weight and Polyethylene Glycol.
The compound of the present invention also can be used together with can be used for treating or prevent other traditional treatment agent of hyperlipemia disease.For including but not limited to that anti-inflammatory medicine, therapeutic antibodies and cholesterol reduce medicine with the exemplary treatment reagent of the combination treatment of one or more compounds of the present invention, for instance, statin.Can be used for the useful additional treatment reagent of formulated in combination thing and cooperation treatment to include, for instance, anti-hyperlipidemia reagent；Antilipemic exception reagent；Anti-diabetic reagent, includes but not limited to cholesteral biosynthesis inhibitor, for instance HMG-CoA reductase inhibitor (is also referred to as statin, lovastatin, simvastatin, pravastatin, fluvastatin, Rosuvastatin, Pitavastatin and atorvastatin)；HMG-CoA reduces synthase inhibitor；Squalene epoxidase inhibitor or inhibitor for squalene synthetic enzyme (being also known as squalene synthase inhibitor)；Microsomal triglyceride transfer protein (MTP) inhibitor；Cholic acid chelating agent anion exchange resin, includes but not limited to cholestyramine, cholestipol, the dialkylaminoalkyl derivative of colesevelam or crosslinked glucosan；Ldl receptor derivant；Fibrates, includes but not limited to clofibrate, bezafibrate, fenofibrate and gemfibrozil；Metformin, rosiglitazone, blood plasma HDL-elevating agent, include but not limited to nicotinic acid, fibrates；Anti-hypercholesterolemiccompounds reagent, includes but not limited to cholesterol-uptake inhibitor；Acyl-coenzyme a cholesterol acyltransferase (ACAT) inhibitor, includes but not limited to that amine of Merrill Lynch；Probucol；Nicotinic acid and salt thereof；Nicotiamide；Cholesterol absorption inhibitor, includes but not limited to cupreol or ezetimibe；Vitamin B6 (pyridoxol) and officinal salt thereof, for instance HCl salt；Vitamin B12(cobalamin)；Vitamin B3(nicotinic acid and nicotiamide)；Antioxidant vitamin, includes but not limited to vitamin C and vitamin E and bata-carotene；Beta receptor blockers；Angiotensin-ii receptor (AT1) antagonist；Angiotensin-convertion enzyme inhibitor, renin inhibitor；Anticoagulant, includes but not limited to fibrinogen deceptor antagonists, i.e. glycoprotein iib/iiia fibrinogen deceptor antagonists；Hormone, includes but not limited to estrogen；Insulin；Ion exchange resin；Ω-3 oil；Benfluorex；26 carbon 5 alkene acid ethyl ester and amlodipine.Adjunctive therapy may also include increase exercise, operation and change meals (such as becoming low cholesterol diet) some plant medicineses and also can be effectively used for formulated in combination thing and cooperation therapy, to treat hyperlipemia, for instance curcumin, balosam sterone, Bulbus Allii, Semen sojae atricolor, soluble fiber, fish oil, green tea, carnitine, chromium, coenzyme Q10, Semen Vitis viniferae extract, dimerization pantothenic acid, Monas cuspurpureus Went and Lac regis apis.
Berberine and related compound also can treat reagent as second, reduce with the lipid of the present invention together with reagent and use.Such as; berberine sulfate, berberine hydrochloride, berberine chloride, oxygen berberine, dihydroberberine, 8-cyano group dihydroberberine, N-1 N-oxide, N-1, protoberberine, 9-ethoxy carbonyl berberine, 9-N, N-formyl-dimethylamino berberine and 12-bromo berberine, berberine azide and berberine glycine betaine can be used.
Also can modify the compound of the present invention, for instance couple organic structure fragment by covalency or conjugate carries out, to improve pharmacokinetic property, toxicity or bioavailability (Half-life in vivo such as increased).Conjugate can be linear or branched hydrophilic polymer group, fatty acid group or fatty acid ester group.Polymer-based group can comprise the molecular weight that can be regulated by those skilled in the art, to improve, for instance pharmacokinetic property, toxicity or bioavailability.Exemplary conjugate can include poly-alkanol (such as Polyethylene Glycol (PEG), polypropylene glycol (PPG)), carbohydrate polymer, amino acid polymer or polyvinylpyrrolidone and fatty acid or fatty acid ester group, each of which can independently comprise about 8 to about 70 carbon atoms.Conjugate for using together with the compound of the present invention also acts as joint, for instance for any suitable substituent group or group, radioactive label (mark or label), halogen, albumen, enzyme, polypeptide, other treatment reagent (such as medicine or medicine), nucleoside, dyestuff, oligonucleotide, lipid, phospholipid and/or liposome.In one aspect, conjugate can include polyvinylamine (PEI), polyglycine, PEI and the crossbred of polyglycine, Polyethylene Glycol (PEG) or methoxy poly (ethylene glycol) (mPEG).The compound of the present invention also can be connected to by conjugate, for instance, labelling (that fluoresce or luminescence) or mark (radioactivity element, radiosiotope and/or isotope), to comprise the probe of the present invention.The conjugate used together with the compound of the present invention can improve Half-life in vivo in one aspect.
Term " link " and/or " combination " can represent and chemically or physically interact, for instance between compound and the target interested of the present invention.The example linked or interact includes covalent bond, ionic bond, hydrophilic-hydrophobic interacts, hydrophobic-hydrophobic interacts and complex." link " generally also may be referred to " combination " or " affinity ", and each of which is used equally to describe and multiple chemically or physically interacts.Measurement combination or affinity are also the routine techniquess of those skilled in the art.
Provided herein is the following examples to set forth advantages of the present invention, and assist those of ordinary skill in the art's preparation further or use the compound or its salt of the present invention, pharmaceutical composition, derivant, metabolite, prodrug, racemic mixture or tautomeric form.The embodiments herein is additionally operable to set forth preferred aspect of the present invention.Embodiment is not construed in any way as limiting the scope of the present invention defined by the appended claims.
Detailed description of the invention
The conventional method of the present invention explained further below, the compound of the present invention can be prepared by method as known in the art, is described in detail for the preparation flow of preferred compounds of the invention below but the preparation method of the compounds of this invention is not limited to this.
General formula compound disclosed by the invention (V) preparation is prepared referring especially to following scheme,
Compound shown in logical formula V of the present invention, its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X1 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound V by coupling；
Another kind of preparation method comprises the following steps:
X1 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X3 under certain reaction condition, prepare V by the reaction of reduction amination.
Further, formula (VI):
Compound shown in formula of the present invention (VI), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X4 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X4 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VI by coupling；
Another kind of preparation method comprises the following steps:
X4 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X4 and X3 under certain reaction condition, prepare VI by the reaction of reduction amination.
Further, formula (VII):
Compound shown in formula of the present invention (VII), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X5 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X5 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VII by coupling；
Another kind of preparation method comprises the following steps:
X5 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X5 and X3 under certain reaction condition, prepare VII by the reaction of reduction amination.
Further, formula (VIII):
Compound shown in formula of the present invention (VIII), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X1 and X6 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X6, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound VIII by coupling；
Another kind of preparation method comprises the following steps:
X1 and X7 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X7 under certain reaction condition, prepare VIII by the reaction of reduction amination.
Further, formula (IX):
Compound shown in formula of the present invention (IX), its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof, one of which preparation method comprises the following steps:
X5 and X8 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X5 and X8, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound IX by coupling；
Another kind of preparation method comprises the following steps:
X5 and X9 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X5 and X9 under certain reaction condition, prepare IX by the reaction of reduction amination.
Further illustrate the present invention below by specific embodiment, but those skilled in the art are it should be understood that the present invention is not limited in these embodiments.
The structure of compound is determined by nuclear magnetic resonance, NMR (NMR) or mass spectrum (MS).The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), being inside designated as tetramethylsilane (TMS), chemical shift is with 10-6(ppm) provide as unit.
The mensuration of MS is with FINNIGANLCQAd (ESI) mass spectrograph (manufacturer: Thremo model: FinniganLCQadvantageMAX)
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the silica gel plate that thin layer chromatography (TLC) uses is 0.15mm～0.2mm, and the specification that thin layer chromatography separation purified product adopts is 0.4mm～0.5mm silica gel plate.
It is carrier that column chromatography generally uses the Yantai Huanghai Sea 200～300 order silica gel.
The known initiation material of the present invention can adopt or synthesize with reference to methods known in the art, or commercially available from GmbH&Co.KG, AcrosOrgannics, AldrichChemicalCompany, TCIChemicals, pacifies the Xue Deng of resistance to Jilin Chemical company.
In embodiment if no special instructions, reaction all carries out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects argon ball or the nitrogen ball of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
The normal evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.
In embodiment if no special instructions, the temperature of reaction is room temperature, and temperature range is 20 DEG C～30 DEG C
The monitoring of the reaction process in embodiment adopts thin layer chromatography (TLC), the system of the developing solvent that reaction uses has: A: dichloromethane and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent is adjusted according to the polarity difference of compound, it is also possible to add a small amount of triethylamine and acidity or alkaline reagent etc. are adjusted.
The system of the system of the eluant of the column chromatography that purifying compounds adopts and the developing solvent of thin layer chromatography includes: A: dichloromethane and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent is adjusted according to the polarity difference of compound, it is also possible to add a small amount of triethylamine and acidity or alkaline reagent etc. are adjusted.
Embodiment 1
25ml round-bottomed flask adds compound 1A (200mg, 1.23mmol), compound 1B (327mg, 1.12mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (285mg, 1.34mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1), for eluant, obtains faint yellow solid product Compound 1 (227mg, productivity: 46.3%).1HNMR(400MHz,CDCl3) δ 7.93 7.79 (m, 3H), 7.75 7.64 (m, 2H), 7.27 7.16 (m, 2H), 6.94 (dd, J=15.1,3.0Hz, 2H), 6.86 6.70 (m, 4H), 3.83 (s, 3H), 3.71 (s, 2H), 3.19 (t, J=10.3Hz, 4H), 2.62 (t, J=10.3Hz, 4H)；MS(ESI)m/z[M+H]+: 439.24.
Embodiment 2
25ml round-bottomed flask adds compound 2A (208mg, 1.3mmol), compound 2B (250mg, 1.67mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (249mg, 1.40mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (8:1) is for eluant, obtain white solid product 2 (152mg, productivity: 32.5%).1HNMR(400MHz,CDCl3) δ 7.53 (d, J=7.4Hz, 1H), 7.34 7.26 (m, 8H), 7.23 (d, J=6.7Hz, 1H), 7.01 6.84 (m, 3H), 3.75 (s, 2H), 3.28 3.13 (m, 4H), 2.76 2.60 (m, 4H)；MS(ESI)m/z[M+H]+: 360.17.
Embodiment 3
Round-bottomed flask adds 3A (2.9g, 20mmol), adds CH2Cl2, after stirring and dissolving, add 3B (4.2g, 22mmol) and Et3N (3.3ml, 24mmol), stirring 12h under room temperature, thin layer detection adds water stirring 30min after reacting completely, be subsequently adding diluted ethyl acetate reactant liquor, organic facies is collected after layering, aqueous phase is extracted with ethyl acetate twice again, merges organic facies, uses saturated common salt water washing successively, anhydrous sodium sulfate dries, and finally concentration obtains crude product 3C (5.5g).
Weigh Compound 3C (1.5g, 5mmol) it is placed in round-bottomed flask, add THF, raw material 3D (0.81g is added after dissolving, 5mmol), stir 10min, be subsequently adding STAB (1.27g, 6mmol), reacting 3h under room temperature, thin layer detection adds saturated ammonium chloride solution cancellation reaction after reacting completely, reactant liquor is extracted with ethyl acetate three times, merge organic facies, using saturated common salt water washing successively, anhydrous sodium sulfate dries, last evaporating column chromatography purification, obtain product 3 (1.6g, 72%).1HNMR(400MHz,CDCl3) δ 8.00 (d, J=8.3Hz, 1H), 7.79 (d, J=8.4Hz, 2H), 7.73 (d, J=7.8Hz, 1H), 7.52 (s, 1H), 7.38 7.31 (m, 1H), 7.27 (dt, J=10.9,6.8Hz, 4H), 6.94 (d, J=7.9Hz, 2H), 6.87 (t, J=7.3Hz, 1H), 3.69 (s, 2H), 3.27 3.12 (m, 4H), 2.70 2.56 (m, 4H), 2.37 (s, 3H)；MS(ESI)m/z[M+H]+: 445.58.
Embodiment 4
25ml round-bottomed flask adds compound 4A (300mg, 1.86mmol), compound 4B (494mg, 1.69mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (430mg, 2.03mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1) is for eluant, obtain white solid product 4 (196mg, productivity: 42.2%).1HNMR(400MHz,CDCl3) δ 7.91 (d, J=7.8Hz, 2H), 7.67 (t, J=7.4Hz, 1H), 7.53 (t, J=7.7Hz, 2H), 7.33 (t, J=7.5Hz, 2H), 7.29 7.19 (m, 3H), 7.14 (d, J=8.1Hz, 1H), 6.96 6.85 (m, 2H), 3.57 (s, 3H), 3.51 (s, 2H), 2.99 (d, J=11.3Hz, 2H), 2.11 (td, J=11.2,3.3Hz, 2H), 1.91 1.77 (m, 4H)；MS(ESI)m/z[M+H]+: 439.41.
Embodiment 5
50ml round-bottomed flask adds compound 5A (980mg, 5.5mmol), compound 5B (831mg, 5.0mmol), ethyl acetate (5ml), under stirring, adds sodium triacetoxy borohydride (1272mg, 6mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Reacting with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1), for eluant, obtains faint yellow oil product 5C.
25ml round-bottomed flask adds compound 5C (413mg, 1.26mmol), compound 5D (264mg, 1.38mmol), triethylamine (255mg, 2.52mmol) with dichloromethane (5ml), at room temperature stir 4h, TLC and detect raw material 5C consumption completely.Reaction system is concentrated, through preparation TLC purification, (dichloromethane: methanol (15:1) is developing solvent), obtains white solid product 5 (426mg, productivity: 70.1%).1HNMR(400MHz,CDCl3) δ 7.66 (d, J=8.3Hz, 2H), 7.26 (d, J=8.0Hz, 2H), 6.91 (s, 1H), 6.88 6.77 (m, 4H), 6.76 6.69 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.47 (s, 2H), 3.18 3.08 (m, 4H), 2.60 2.51 (m, 4H), 2.41 (s, 3H)；MS(ESI)m/z[M+H]+: 483.05.
Embodiment 6
50ml round-bottomed flask adds compound 6A (980mg, 5.5mmol), compound 6B (831mg, 5.0mmol), ethyl acetate (5ml), under stirring, adds sodium triacetoxy borohydride (1272mg, 6mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Reacting with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1), for eluant, obtains faint yellow oil product 6C.
25ml round-bottomed flask adds compound 6C (615mg, 1.88mmol), compound 6D (258mg, 2.25mmol), triethylamine (380mg, 3.76mmol) with dichloromethane (5ml), at room temperature stir 4h, TLC and detect raw material 6C consumption completely.Reaction system is concentrated, through preparation TLC purification, (dichloromethane: methanol (20:1) is developing solvent), obtains white solid product 6 (574mg, productivity: 75.2%).1HNMR(400MHz,CDCl3) δ 7.20 7.12 (m, 2H), 6.93 (d, J=1.7Hz, 1H), 6.91 (d, J=2.2Hz, 1H), 6.90 6.85 (m, 2H), 6.83 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.51 (s, 2H), 3.23 3.16 (m, 4H), 3.09 (s, 3H), 2.63 2.55 (m, 4H)；MS(ESI)m/z[M+Na]+: 439.08.
Embodiment 7
25ml round-bottomed flask adds compound 7A (196mg, 1.1mmol), compound 7B (306mg, 1.0mmol), ethyl acetate (2ml), under stirring, adds sodium triacetoxy borohydride (254mg, 1.2mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 7 (189mg, productivity: 40.3%).1HNMR(400MHz,CDCl3) δ 7.80 7.71 (m, 2H), 7.52 7.45 (m, 2H), 6.81 (dd, J=8.9,6.0Hz, 2H), 6.67 6.60 (m, 3H), 6.59 6.53 (m, 2H), 3.83 (s, 3H), 3.66 (s, 2H), 3.19 (t, J=10.3Hz, 4H), 2.62 (t, J=10.3Hz, 4H), 2.43 (s, 3H)；MS(ESI)m/z[M+H]+: 469.11.
Embodiment 8
25ml round-bottomed flask adds compound 8A (400mg, 1.2mmol), compound 8B (213mg, 1.1mmol), ethyl acetate (2ml), under stirring, adds sodium triacetoxy borohydride (276mg, 1.3mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 8 (191mg, productivity: 34.3%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 6.92 6.75 (m, 5H), 6.26 6.14 (m, 2H), 3.67 (s, 2H), 3.34 (q, J=7.0Hz, 4H), 3.28 3.08 (m, 4H), 2.85 2.55 (m, 4H), 2.47 (s, 3H), 1.17 (t, J=7.0Hz, 6H)；MS(ESI)m/z[M+Na]+: 532.21.
Embodiment 9
25ml round-bottomed flask adds compound 9A (400mg, 1.2mmol), compound 9B (184mg, 1.1mmol), ethyl acetate (2ml), under stirring, adds sodium triacetoxy borohydride (276mg, 1.3mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain faint yellow solid product 9 (205mg, productivity: 38.5%).1HNMR(400MHz,CDCl3) δ 7.94 (d, J=8.9Hz, 1H), 7.70 (d, J=8.3Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 7.19 (d, J=2.6Hz, 1H), 6.88 6.79 (m, 2H), 6.79 6.70 (m, 3H), 3.89 (s, 2H), 3.20 3.05 (m, 4H), 2.74 2.58 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 484.21.
Embodiment 10
25ml round-bottomed flask adds compound 10A (400mg, 1.2mmol), compound 10B (214mg, 1.1mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (276mg, 1.3mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain faint yellow solid product 10 (238mg, productivity: 42.5%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 7.21 (dd, J=5.1,1.1Hz, 1H), 7.15 (dd, J=3.6,1.1Hz, 1H), 7.07 7.00 (m, 2H), 6.85 (dt, J=6.6,2.8Hz, 3H), 6.81 6.76 (m, 2H), 3.75 (s, 2H), 3.25 3.13 (m, 4H), 2.72 2.62 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+Na]+: 533.82.
Embodiment 11
25ml round-bottomed flask adds compound 11A (400mg, 1.2mmol), compound 11B (160mg, 1.1mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (276mg, 1.3mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 11 (178mg, productivity: 35.1%).1HNMR(400MHz,CDCl3) δ 7.72 (dd, J=12.5,8.1Hz, 3H), 7.40 (d, J=8.1Hz, 1H), 7.30 (d, J=8.1Hz, 2H), 7.26 (d, J=2.1Hz, 1H), 7.19 (dt, J=25.8,7.1Hz, 2H), 6.83 (d, J=9.1Hz, 2H), 6.72 (d, J=9.1Hz, 2H), 3.90 (s, 2H), 3.22 3.14 (m, 4H), 2.82 2.70 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 462.22.
Embodiment 12
25ml round-bottomed flask adds compound 12A (400mg, 1.2mmol), compound 12B (276mg, 1.1mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (276mg, 1.3mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 12 (200mg, productivity: 32.1%).1HNMR(400MHz,CDCl3) δ 7.69 (d, J=8.3Hz, 2H), 7.49 (dd, J=12.3,7.2Hz, 3H), 7.42 (dd, J=5.0,1.9Hz, 2H), 7.38 7.30 (m, 5H), 7.17 (d, J=2.0Hz, 1H), 6.85 6.79 (m, 2H), 6.65 (d, J=9.1Hz, 2H), 5.13 (s, 2H), 4.04 (s, 2H), 3.22 3.10 (m, 4H), 2.94 2.80 (m, 4H), 2.44 (s, 3H)；MS(ESI)m/z[M+H]+: 568.30.
Embodiment 13
25ml round-bottomed flask adds compound 13A (400mg, 1.2mmol), compound 13B (189mg, 1.1mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (276mg, 1.3mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 13 (164mg, productivity: 30.6%).1HNMR(400MHz,CDCl3) δ 7.86 (d, J=8.6Hz, 1H), 7.80 (d, J=7.9Hz, 1H), 7.73 (dd, J=8.6,4.5Hz, 3H), 7.52 7.44 (m, 1H), 7.33 (t, J=6.9Hz, 3H), 7.13 (d, J=8.8Hz, 1H), 6.92 6.86 (m, 2H), 6.83 6.77 (m, 2H), 4.24 (s, 2H), 3.40 3.10 (m, 4H), 2.97 2.62 (m, 4H),, 2.47 (s, 3H)；MS(ESI)m/z[M+H]+: 489.29.
Embodiment 14
25ml round-bottomed flask adds compound 14A (400mg, 1.2mmol), compound 14B (183mg, 1.1mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (276mg, 1.3mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (2:1) is for eluant, obtain white solid product 14 (218mg, productivity: 41.1%).1HNMR(400MHz,CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.36 7.27 (m, 2H), 7.07 6.97 (m, 2H), 6.87 (dd, J=7.9,1.7Hz, 1H), 6.86 6.82 (m, 2H), 6.79 6.74 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.64 (s, 2H), 3.23 3.09 (m, 4H), 2.73 2.61 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 483.23.
Embodiment 15
Adding 15A (249mg, 1.5mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, add oxalyl chloride (213 μ l, 2.5mmol) and DMF (1), react overnight under room temperature.Solvent evaporated and excessive oxalyl chloride, obtain crude product 15B.
Adding 15C (332mg, 1.0mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, and adds triethylamine (278 μ l, 2.0mmol).Being dissolved by crude product 15B dichloromethane (5ml), be slowly dropped into, overnight, it is complete that TLC detects raw material reaction to room temperature reaction.It is eluant through silica gel column chromatography (dichloromethane: methanol=50:1) after concentration, obtains product 15D (353mg, productivity 73.4%).
Adding 15D (353mg, 0.735mmol) in 50ml round-bottomed flask, oxolane (10ml) dissolves, and is slowly added to LiAlH in 0 DEG C4(112mg, 2.94mmol), reacts 1h at 70 DEG C.After being cooled to room temperature, react with methanol cancellation, be eventually adding saturated NaHCO3(1ml), filter, methanol washing leaching cake, after concentration, obtain product 15 (113mg, productivity 32.9%) through silica gel column chromatography (petroleum ether: ethyl acetate=1:1).1HNMR(400MHz,CDCl3) δ 7.72 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 7.16 (d, J=8.6Hz, 2H), 6.88 6.85 (m, 4H), 6.81 6.78 (m, 2H), 3.81 (s, 3H), 3.21 3.18 (m, 4H), 2.82-2.78 (m, 2H), 2.69 2.61 (m, 6H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 467.08.
Embodiment 16
100ml round-bottomed flask adds 16A (2.02g, 10mmol), DMSO (20ml) dissolve, under stirring, add piperazine (1.12g, 13mmol), K2CO3(2.07g, 15mmol) and TBAI (37mg, 0.1mmol), react 6h at 120 DEG C.After being cooled to room temperature, washing, extraction into ethyl acetate, merge organic layer, saturated NaCl washs, and anhydrous sodium sulfate dries, through silica gel column chromatography (first petroleum ether: ethyl acetate=5:1 after concentration；Rear dichloromethane: methanol=10:1) obtain yellow solid product 16B (1.14g, productivity 55.1%).
Adding 16B (622mg, 3.0mmol) in 50ml round-bottomed flask, dichloromethane (15ml) dissolves, and adds 16C (548mg, 3.3mmol) and NaBH (OAc) under stirring3(954mg, 4.5mmol), reacts overnight under room temperature.Saturated NaHCO3Cancellation is reacted, separatory, extraction into ethyl acetate, merges organic facies, obtains yellow solid product 16D (330mg, productivity 30.8%) through silica gel column chromatography (petroleum ether: ethyl acetate=1:1) after concentration.
Adding 16D (330mg, 0.92mmol) in 50ml round-bottomed flask, ethanol (20ml) dissolves, and is subsequently adding Pd/C (10mg, 0.09mmol), uses H2Take a breath 5 times (normal pressure), react overnight under room temperature.Filter, washing with alcohol filter cake, collect filtrate, solvent evaporated, obtain crude product 16E.
Adding crude product 16E in 50ml round-bottomed flask, dichloromethane (10mL) dissolves, and adds triethylamine (208 μ l, 1.5mmol) and TsCl (228mg, 1.2mmol), react overnight under room temperature under stirring.Product 16 (103mg, productivity 23.3%) is obtained through silica gel column chromatography (dichloromethane: methanol=50:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.59 (d, J=8.3Hz, 2H), 7.22 (d, J=8.1Hz, 2H), 6.96 6.92 (m, 3H), 6.88-6.82 (m, 2H), 6.80 6.77 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.51 (s, 2H), 3.17 3.15 (m, 4H), 2.60 2.58 (m, 4H), 2.40 (s, 3H)；MS(ESI)m/z[M+Na]+: 504.09.
Embodiment 17
25ml round-bottomed flask adds compound 17A (292mg, 1.79mmol), compound 17B (400mg, 1.63mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (416mg, 1.96mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain white solid product 17 (239mg, productivity: 37.5%).1HNMR(400MHz,CDCl3) δ 8.31 8.22 (m, 1H), 7.98 7.89 (m, 2H), 7.83 (d, J=7.6Hz, 1H), 7.62 (dd, J=14.6,7.3Hz, 2H), 7.57 7.45 (m, 3H), 7.33 (t, J=7.4Hz, 2H), 7.21 (dd, J=9.4,8.4Hz, 3H), 3.83 (s, 2H), 2.80 (d, J=11.4Hz, 2H), 2.44 (qd, J=12.0,3.6Hz, 1H), 2.06 1.89 (m, 2H), 1.71 (d, J=11.8Hz, 2H), 1.58 (qd, J=12.5,3.5Hz, 2H)；MS(ESI)m/z[M+H]+: 392.22.
Embodiment 18
25ml round-bottomed flask adds compound 18A (200mg, 0.6mmol), compound 18B (109mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (140mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain white solid product 18 (115mg, productivity: 40.7%).1HNMR(400MHz,CDCl3) δ 7.72 (d, J=8.3Hz, 2H), 7.42 7.27 (m, 5H), 7.18 7.07 (m, 3H), 7.07 7.02 (m, 2H), 6.94 (dd, J=8.1,1.7Hz, 1H), 6.90 6.84 (m, 2H), 6.82 6.74 (m, 2H), 3.56 (s, 2H), 3.21 3.11 (m, 4H), 2.65 2.55 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 515.11.
Embodiment 19
25ml round-bottomed flask adds compound 19A (200mg, 0.6mmol), compound 19B (135mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (140mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain white solid product 19 (121mg, productivity: 39.1%).1HNMR(400MHz,CDCl3) δ 7.88 (d, J=7.5Hz, 2H), 7.78 (d, J=7.6Hz, 1H), 7.70 (d, J=8.2Hz, 2H), 7.63 7.58 (m, 2H), 7.56 7.52 (m, 2H), 7.48 (t, J=7.5Hz, 3H), 7.31 (d, J=8.1Hz, 2H), 6.84 (d, J=9.1Hz, 2H), 6.71 (d, J=9.1Hz, 2H), 3.84 (s, 2H), 3.03 2.93 (m, 4H), 2.45 (s, 3H), 2.43 2.33 (m, 4H)；MS(ESI)m/z[M+H]+: 563.08.
Embodiment 20
25ml round-bottomed flask adds compound 20A (319mg, 1.79mmol), compound 20B (400mg, 1.63mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (416mg, 1.96mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (10:1) is for eluant, obtain white solid product 20 (194mg, productivity: 29.1%).1HNMR(400MHz,CDCl3) δ 8.24 (dd, J=7.9,1.1Hz, 1H), 7.89 (dd, J=5.3,3.4Hz, 2H), 7.77 (d, J=7.6Hz, 1H), 7.64 7.57 (m, 1H), 7.56 7.46 (m, 4H), 6.78 (d, J=9.0Hz, 2H), 6.72 (d, J=9.0Hz, 2H), 3.85 (s, 2H), 2.93 2.86 (m, 4H), 2.48 2.39 (m, 4H)；MS(ESI)m/z[M+H]+: 409.15.
Embodiment 21
25ml round-bottomed flask adds compound 21A (300mg, 0.90mmol), compound 21B (88mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 21 (137mg, productivity: 39.4%).1HNMR(400MHz,CDCl3) δ 8.58 (d, J=1.8Hz, 1H), 8.54 (dd, J=4.8,1.6Hz, 1H), 7.75 7.66 (m, 3H), 7.30 (dd, J=7.4,5.0Hz, 3H), 6.89 6.82 (m, 2H), 6.80 6.73 (m, 2H), 3.58 (s, 2H), 3.22 3.10 (m, 4H), 2.67 2.54 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 424.17.
Embodiment 22
25ml round-bottomed flask adds compound 22A (300mg, 0.90mmol), compound 22B (88mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 22 (128mg, productivity: 36.9%).1HNMR(400MHz,CDCl3) δ 8.57 (dd, J=4.5,1.5Hz, 2H), 7.74 7.67 (m, 2H), 7.32 7.30 (m, 3H), 6.92 6.83 (m, 2H), 6.82 6.75 (m, 2H), 3.57 (s, 2H), 3.23 3.13 (m, 4H), 2.65 2.54 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 424.15.
Embodiment 23
25ml round-bottomed flask adds compound 23A (300mg, 0.90mmol), compound 23B (88mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 23 (124mg, productivity: 35.6%).1HNMR(400MHz,CDCl3) δ 8.60 (dd, J=4.9,0.8Hz, 1H), 7.74 7.66 (m, 3H), 7.44 (d, J=7.8Hz, 1H), 7.31 (d, J=8.1Hz, 2H), 7.24 7.17 (m, 1H), 6.89 6.82 (m, 2H), 6.81 6.75 (m, 2H), 3.73 (s, 2H), 3.24 3.14 (m, 4H), 2.72 2.63 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 424.07.
Embodiment 24
25ml round-bottomed flask adds compound 24A (300mg, 0.90mmol), compound 24B (121mg, 0.90mmol) potassium carbonate (187mg, 1.36mmol), DMF (2ml), stirring overnight at 60 DEG C, it is complete that TLC detects raw material reaction.In reaction system, add the water of 2 times of volumes, then with dichloromethane extraction, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (10:1) is for eluant, obtain white solid product 24 (194mg, productivity: 50.1%).1HNMR (400MHz, DMSO) δ 11.35 (s, 1H), 11.27 (s, 1H), 7.71 (d, J=8.3Hz, 2H), 7.46 (d, J=8.3Hz, 2H), 6.91 6.84 (m, 2H), 6.83 6.78 (m, 2H), 3.32 (s, 2H), 3.16 3.06 (m, 4H), 2.58 2.48 (m, 4H), 2.42 (s, 3H)；MS(ESI)m/z[M-H]-: 428.24.
Embodiment 25
25ml round-bottomed flask adds compound 25A (200mg, 0.60mmol), compound 25B (53mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (139mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 25 (85mg, productivity: 37.7%).1HNMR(400MHz,CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.30 (d, J=8.1Hz, 2H), 7.03 (s, 2H), 6.89 6.80 (m, 2H), 6.79 6.72 (m, 2H), 3.71 (s, 2H), 3.17 3.08 (m, 4H), 2.69 2.57 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 413.04.
Embodiment 26
25ml round-bottomed flask adds compound 26A (200mg, 0.60mmol), compound 26B (53mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (139mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 26 (100mg, productivity: 43.9%).1HNMR(400MHz,CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.62 (d, J=0.8Hz, 1H), 7.31 (d, J=8.0Hz, 2H), 6.97 (s, 1H), 6.89 6.81 (m, 2H), 6.79 6.73 (m, 2H), 3.60 (s, 2H), 3.18 3.12 (m, 4H), 2.66 2.60 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 413.08.
Embodiment 27
25ml round-bottomed flask adds compound 27A (200mg, 0.60mmol), compound 27B (60mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (139mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (2:1) is for eluant, obtain white solid product 27 (98mg, productivity: 41.7%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.32 (d, J=8.0Hz, 2H), 6.90 6.83 (m, 2H), 6.81 6.74 (m, 2H), 6.66 6.62 (m, 1H), 6.10 6.02 (m, 2H), 3.68 (s, 3H), 3.50 (s, 2H), 3.19 3.07 (m, 4H), 2.63 2.52 (m, 4H), 2.47 (s, 3H)；MS(ESI)m/z[M]+: 426.07.
Embodiment 28
25ml round-bottomed flask adds compound 28A (300mg, 0.90mmol), compound 28B (90mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (212mg, 1.00mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (15:1) is for eluant, obtain white solid product 28 (142mg, productivity: 40.5%).1HNMR (400MHz, CDCl3) δ 7.68 (d, J=8.3Hz, 2H), 7.33 7.27 (m, 2H), 6.93 (d, J=1.1Hz, 1H), 6.87 (d, J=0.8Hz, 1H), 6.82 (t, J=6.2Hz, 2H), 6.75 (d, J=9.2Hz, 2H), 3.71 (s, 3H), 3.65 (s, 2H), 3.18 3.06 (m, 4H), 2.62 2.56 (m, 4H), 2.44 (s, 3H；MS(ESI)m/z[M+H]+: 427.68.
Embodiment 29
25ml round-bottomed flask adds compound 29A (200mg, 0.60mmol), compound 29B (52mg, 0.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (139mg, 0.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Saturated sodium bicarbonate aqueous solution cancellation is reacted, extraction into ethyl acetate, merges organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain yellow oil product 29 (90mg, productivity: 39.6%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 6.89 6.83 (m, 2H), 6.81 6.74 (m, 3H), 6.16 (dd, J=5.8,2.8Hz, 1H), 6.08 (s, 1H), 3.57 (s, 2H), 3.22 3.08 (m, 4H), 2.63 2.54 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M]+: 411.95.
Embodiment 30
25ml round-bottomed flask adds compound 30A (300mg, 0.90mmol), compound 30B (129mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 30 (121mg, productivity: 31.2%).1HNMR(400MHz,CDCl3) δ 8.88 (d, J=4.3Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 8.15 (d, J=8.4Hz, 1H), 7.79 7.64 (m, 3H), 7.58 (ddd, J=8.2,6.9,1.2Hz, 1H), 7.46 (d, J=4.4Hz, 1H), 7.30 (d, J=8.0Hz, 2H), 6.90 6.82 (m, 2H), 6.82 6.74 (m, 2H), 4.00 (s, 2H), 3.23 3.13 (m, 4H), 2.76 2.64 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 474.09.
Embodiment 31
50mL round-bottomed flask adds compound 31A (200mg, 0.609mmol), chloroform (6mL), between fluorophenylsulfonyl chloride 31B (324 μ L, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, colourless paste product 31 (257mg, productivity 86.7%) is obtained through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.64 7.59 (m, 1H), 7.56 7.46 (m, 2H), 7.35 (tdd, J=8.3,2.5,0.9Hz, 1H), 6.91 (d, J=1.6Hz, 1H), 6.87 6.73 (m, 6H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.20 3.09 (m, 4H), 2.63 2.50 (m, 4H)；MS(ESI)m/z[M+H]+: 487.03.
Embodiment 32
50mL round-bottomed flask adds compound 32A (200mg, 0.609mmol), chloroform (6mL), compound 32B (494mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, colourless paste product 32 (175mg, productivity 58.1%) is obtained through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.54 7.38 (m, 6H), 7.15 7.09 (m, 2H), 6.91 (d, J=1.5Hz, 1H), 6.88 6.79 (m, 5H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.21 3.12 (m, 4H), 2.63 2.51 (m, 4H)；MS(ESI)m/z[M+H]+: 495.05.
Embodiment 33
50mL round-bottomed flask adds compound 33A (200mg, 0.609mmol), chloroform (6mL), compound 33B (464mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, light yellow paste product 33 (156mg, productivity 53.1%) is obtained through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.48 7.38 (m, 5H), 7.04 6.98 (m, 2H), 6.92 (d, J=1.5Hz, 1H), 6.88 6.80 (m, 4H), 4.47 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.50 (s, 2H), 3.22 3.12 (m, 4H), 2.63 2.53 (m, 4H)；MS(ESI)m/z[M+H]+: 483.11.
Embodiment 34
50mL round-bottomed flask adds compound 34A (200mg, 0.609mmol), DMF (3mL) dissolves, ice bath stirs 5min, add sodium hydride (22mg, 0.913mmol), after ice bath stirs 10min, rise to and 30min is stirred at room temperature, add compound 34B (206 μ L, 1.22mmol), stir overnight under room temperature.Add water, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and obtains white solid product 34 (170mg, productivity 58.5%) through silica gel column chromatography (dichloromethane: methanol 70:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.18 7.12 (m, 2H), 6.92 (d, J=1.6Hz, 1H), 6.91 6.80 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.78 3.71 (m, 4H), 3.50 (s, 2H), 3.40 3.35 (m, 4H), 3.21 3.15 (m, 4H), 2.63 2.55 (m, 4H)；MS(ESI)m/z[M+H]+: 478.18.
Embodiment 35
50mL round-bottomed flask adds compound 35A (200mg, 0.609mmol), DMF (3mL) dissolves, ice bath stirs 5min, add sodium hydride (22mg, 0.913mmol), ice bath stirs 10min, rise to and 30min is stirred at room temperature, add compound 35B (131 μ L, 1.22mmol), stir overnight under room temperature.Add water, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and separates purification through silica gel column chromatography (dichloromethane: methanol 100:1) and obtain white solid product 35 (156mg, productivity 58.8%) after concentration.1HNMR(400MHz,CDCl3) δ 7.19 7.12 (m, 2H), 6.92 (d, J=1.5Hz, 1H), 6.90 6.80 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.50 (s, 2H), 3.22 3.14 (m, 4H), 2.94 (s, 6H), 2.63 2.54 (m, 4H)；MS(ESI)m/z[M+H]+: 436.15.
Embodiment 36
50mL round-bottomed flask adds compound 36A (200mg, 0.609mmol), DMF (3mL) dissolves, ice bath stirs 5min, add sodium hydride (22mg, 0.913mmol), ice bath stirs 10min, rise to and 30min is stirred at room temperature, add compound 36B (305mg, 1.22mmol), stir overnight under room temperature.Add water, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, separate purification obtain colorless oil as product 36 (25mg, productivity 7.6%) through silica gel column chromatography (dichloromethane: methanol 100:1) and preparation TLC (dichloromethane: methanol 50:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.21 7.15 (m, 2H), 6.94 6.80 (m, 5H), 3.90 (s, 3H), 3.88 (s, 3H), 3.77 (d, J=15.0Hz, 1H), 3.50 (s, 2H), 3.24 3.11 (m, 5H), 2.64 2.50 (m, 5H), 2.46 2.35 (m, 1H), 2.16 2.02 (m, 2H), 1.96 (d, J=18.5Hz, 1H), 1.75 1.65 (m, 1H), 1.49 1.40 (m, 1H), 1.16 (s, 3H), 0.90 (s, 3H)；MS(ESI)m/z[M+H]+: 543.37.
Embodiment 37
50mL round-bottomed flask adds compound 37A (200mg, 0.609mmol), is dissolved in dichloromethane (5mL), add compound 37B (174 μ L, 0.913mmol), triethylamine (127 μ L, 0.913mmol), stir overnight under room temperature.Evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and separates purification through silica gel column chromatography (dichloromethane: methanol 100:1) and obtain white solid product 37 (151mg, productivity 46.9%) after concentration.1HNMR(400MHz,CDCl3) δ 7.92 7.83 (m, 4H), 7.56 7.49 (m, 2H), 7.49 7.41 (m, 4H), 7.09 7.03 (m, 2H), 6.90 (d, J=1.5Hz, 1H), 6.87 6.73 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.13 3.03 (m, 4H), 2.60 2.50 (m, 4H)；MS(ESI)m/z[M+H]+: 29.15.
Embodiment 38
50mL round-bottomed flask adds compound 38A (200mg, 0.609mmol), chloroform (6mL), compound 38B (616mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain colourless paste product 38 (244mg, productivity 73.6%).1HNMR(400MHz,CDCl3)δ7.90–7.83(m,2H),7.75–7.68(m,2H),7.65–7.58(m,2H),7.53–7.40(m,3H),6.94–6.73(m,7H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.19–3.10(m,4H),2.62–2.50(m,4H)；MS(ESI)m/z[M+H]+: 545.09.
Embodiment 39
50mL round-bottomed flask adds compound 39A (200mg, 0.609mmol), chloroform (6mL), compound 39B (569mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 70:1) after concentration and obtain off-white color solid product 39 (127mg, productivity 39.7%).1HNMR(400MHz,CDCl3) δ 7.76 7.70 (m, 2H), 7.68 7.62 (m, 2H), 7.55 (brs, 1H), 6.91 (d, J=1.5Hz, 1H), 6.88 6.79 (m, 4H), 6.78 6.71 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19 3.09 (m, 4H), 2.61 2.51 (m, 4H), 2.22 (s, 3H)；MS(ESI)m/z[M+H]+: 526.08.
Embodiment 40
50mL round-bottomed flask adds compound 40A (200mg, 0.609mmol), chloroform (6mL), compound 40A (572mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain white solid product 40 (178mg, productivity 55.5%).1HNMR(400MHz,CDCl3) δ 7.36 (d, J=2.2Hz, 1H), 7.29 7.25 (m, 1H), 6.95 6.74 (m, 8H), 4.36 4.25 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H), 3.49 (s, 2H), 3.19 3.09 (m, 4H), 2.61 2.51 (m, 4H)；MS(ESI)m/z[M+H]+: 527.29.
Embodiment 41
50mL round-bottomed flask adds compound 41A (200mg, 0.609mmol), chloroform (6mL), compound 41B (491mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain light yellow paste product 41 (220mg, productivity 73.2%).1HNMR(400MHz,CDCl3) δ 7.96 7.89 (m, 2H), 7.84 7.77 (m, 2H), 6.90 (d, J=1.6Hz, 1H), 6.87 6.73 (m, 6H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.20 3.11 (m, 4H), 2.61 2.51 (m, 4H)；MS(ESI)m/z[M+H]+: 494.09.
Embodiment 42
50mL round-bottomed flask adds compound 42A (200mg, 0.609mmol), chloroform (6mL), compound 42B (635mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain colourless paste product 42 (263mg, productivity 78.2%).1HNMR(400MHz,CDCl3) δ 7.90 7.82 (m, 2H), 7.36 7.29 (m, 2H), 6.91 (d, J=1.6Hz, 1H), 6.88 6.73 (m, 6H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19 3.11 (m, 4H), 2.61 2.52 (m, 4H)；MS(ESI)m/z[M+H]+: 553.13.
Embodiment 43
50mL round-bottomed flask adds compound 43A (200mg, 0.609mmol), chloroform (6mL), compound 43B (657mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain product as light yellow solid 43 (80mg, productivity 23.4%).1HNMR(400MHz,CDCl3null)δ8.57(d,J=8.5Hz,1H),8.47(d,J=8.7Hz,1H),8.05(dd,J=7.3,1.2Hz,1H),7.66(dd,J=8.6,7.7Hz,1H),7.42(dd,J=8.5,7.4Hz,1H),7.24(d,J=7.5Hz,1H),6.89(d,J=1.4Hz,1H),6.86–6.77(m,2H),6.77–6.70(m,2H),6.68–6.61(m,2H),3.87(s,3H),3.87(s,3H),3.46(s,2H),3.13–3.03(m,4H),2.91(s,6H),2.57–2.46(m,4H)；MS (ESI) m/z [M+H]+: 562.13.
Embodiment 44
50mL round-bottomed flask adds compound 44A (200mg, 0.609mmol), chloroform (6mL), compound 44B (518mg, 2.44mmol), pyridine (0.5mL), 65 DEG C of oil baths are reacted 4h, evaporated under reduced pressure solvent, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, separate purification through silica gel column chromatography (dichloromethane: methanol 100:1) after concentration and obtain colourless paste product 44 (225mg, productivity 73.2%).1HNMR(400MHz,CDCl3) δ 7.82 7.73 (m, 1H), 7.05 6.92 (m, 4H), 6.90 (d, J=1.6Hz, 1H), 6.87 6.75 (m, 4H), 3.88 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.18 3.10 (m, 4H), 2.60 2.51 (m, 4H)；MS(ESI)m/z[M+H]+: 505.03.
Embodiment 45
50mL round-bottomed flask adds compound 45A (200mg, 0.609mmol), dissolve with DMF (3mL), ice bath stirs 5min, add sodium hydride (22mg, 0.913mmol), ice bath stirs 10min, rise to and 30min is stirred at room temperature, add compound 45B (139 μ L, 1.22mmol), stir overnight under room temperature.Add water, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and separates purification through silica gel column chromatography (dichloromethane: methanol 70:1) and obtain white solid product 45 (157mg, productivity 58.4%) after concentration.1HNMR(400MHz,CDCl3)δ7.02–6.95(m,2H),6.94–6.80(m,5H),3.89(s,3H),3.88(s,3H),3.77–3.70(m,4H),3.70–3.52(m,4H),3.50(s,2H),3.21–3.11(m,4H),2.64–2.54(m,4H)；MS(ESI)m/z[M+H]+: 442.13.
Embodiment 46
46B (2g, 11.7mmol) and 46A (3g, 35.1mmol) is dissolved in 20ml acetonitrile, adds potassium carbonate (3.23g, 23.4mmol) after allowing, be warming up to 100 degree of back flow reaction 3h.Removal of solvent under reduced pressure acetonitrile, adds 30ml water and is extracted with ethyl acetate twice, remove the impurity of two benzyls, then use dichloromethane extraction twice, and combined dichloromethane, with obtaining light yellow product 46C (1.5g, productivity 75%) after dried over sodium sulfate
By 46C (126.6mg, 0.718mmol) with 46D (200mg, 0.653mmol) it is dissolved in 1,2-dichloroethanes, under condition of ice bath, is slowly added to sodium triacetoxy borohydride (208mg, 0.980mmol), after rising to room temperature reaction 5h, filter through kieselguhr, silica gel column chromatography (dichloromethane: methanol=20:1) after removal of solvent under reduced pressure, obtain clear gummy solid 46 (105mg, 34.5%).1HNMR(400MHz,CDCl3) δ 7.77 (d, J=8.3Hz, 2H), 7.36 7.23 (m, 7H), 7.06 (d, J=8.1Hz, 1H), 6.86 (d, J=1.7Hz, 1H), 6.83 (dd, J=8.2,1.8Hz, 1H), 3.58 (s, 3H), 3.54 (s, 2H), 3.46 (s, 2H), 2.47 (brs, 8H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 467.18.
Embodiment 47
50mL round-bottomed flask adds compound 47A (200mg, 0.609mmol), chloroform (6mL), compound 47B (649mg, 2.44mmol), pyridine (0.5mL), reacting 4h in 65 DEG C of oil baths, reactant liquor is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification obtain off-white color solid 47 (38mg, productivity 11.2%) through preparing thin layer chromatography (dichloromethane: methanol 50:1).1HNMR(400MHz,CDCl3)δ7.07–6.99(m,2H),6.95–6.88(s,1H),6.88–6.77(m,4H),3.89(s,3H),3.88(s,3H),3.50(s,2H),3.26–3.11(m,4H),2.65–2.50(m,4H)；MS(ESI)m/z[M+H]+: 559.00.
Embodiment 48
25ml round-bottomed flask adds compound 48A (500mg, 2.81mmol), compound 48B (444mg, 2.55mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (649mg, 3.06mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain white solid product 48 (347mg, productivity: 40.5%).1HNMR (400MHz, CDCl3) δ 7.85 (d, J=7.8Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 6.89 (d, J=8.9Hz, 2H), 6.72 (d, J=8.8Hz, 2H), 3.79 (s, 2H), 3.20 3.07 (m, 4H), 2.82 2.67 (m, 4H)；MS(ESI)m/z[M+H]+: 337.88.
Embodiment 49
25ml round-bottomed flask adds compound 49A (300mg, 0.90mmol), compound 49B (124mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain yellow solid product 49 (164mg, productivity: 42.8%).1HNMR(400MHz,CDCl3) δ 8.20 (d, J=8.7Hz, 2H), 7.71 (d, J=8.3Hz, 2H), 7.56 (d, J=8.6Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 6.91 6.83 (m, 2H), 6.82 6.74 (m, 2H), 3.66 (s, 2H), 3.24 3.11 (m, 4H), 2.66 2.56 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 468.02.
Embodiment 50
25ml round-bottomed flask adds compound 50A (300mg, 0.90mmol), compound 50B (135mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (6:1) is for eluant, obtain white solid product 50 (174mg, productivity: 44.3%).1HNMR(400MHz,CDCl3) δ 8.02 (d, J=8.1Hz, 2H), 7.70 (d, J=8.2Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 6.90 6.81 (m, 2H), 6.77 (d, J=9.1Hz, 2H), 3.93 (s, 3H), 3.61 (s, 2H), 3.21 3.11 (m, 4H), 2.64 2.55 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 481.13.
Embodiment 51
25ml round-bottomed flask adds compound 51A (300mg, 0.90mmol), compound 51B (87mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (10:1) is for eluant, obtain white solid product 51 (167mg, productivity: 48.1%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.36 (s, 2H), 7.35 (d, J=2.2Hz, 2H), 7.32 (dd, J=7.3,3.5Hz, 3H), 6.88 6.83 (m, 2H), 6.79 6.75 (m, 2H), 3.59 (s, 2H), 3.19 3.15 (m, 4H), 2.63 2.59 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 423.57.
Embodiment 52
25ml round-bottomed flask adds compound 52A (300mg, 0.90mmol), compound 52B (122mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (209mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (2:1) is for eluant, obtain white solid product 52 (170mg, productivity: 44.5%).1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.31 (d, J=8.0Hz, 2H), 7.22 (d, J=8.6Hz, 2H), 6.90 6.82 (m, 2H), 6.81 6.75 (m, 2H), 6.73 (d, J=8.7Hz, 2H), 3.49 (s, 2H), 3.19 3.11 (m, 4H), 2.97 (s, 6H), 2.64 2.54 (m, 4H), 2.46 (s, 3H) .MS (ESI) m/z [M+H]+: 466.21.
Embodiment 53
100mL round-bottomed flask adds compound 53A (1g, 6.23mmol), sequentially add DMF (25mL), DMSO (5mL) stirring and dissolving, add potassium carbonate (1.72g, 12.5mmol), iodomethane (426 μ L, 6.85mmol), 25 DEG C of oil baths are stirred 16h.Reactant liquor adds water, and is extracted with ethyl acetate, and merges organic facies, and water washing, anhydrous sodium sulfate dries, and obtains white solid 53B (700mg, productivity 64.4%) after being spin-dried for.
100mL round-bottomed flask is sequentially added into compound 53B (700mg, 4.01mmol), 53C (1.12g, 6.02mmol), sodium bicarbonate (674mg, 8.02mmol), molecular sieve (20), ethanol (30mL), reflux 10h in 100 DEG C of oil baths.Reactant liquor sucking filtration, washing with alcohol, filtrate is spin-dried for, and the residue obtained obtains white solid 53D (697mg, productivity 53.6%) through column chromatography (dichloromethane: methanol 100:1).
100mL round-bottomed flask adds compound 53D (348mg, 1.07mmol), dissolve with dichloromethane (8mL), add TFA (2mL), stirring under room temperature overnight, reactant liquor is spin-dried for, and adds dichloromethane and be again spin-dried for, the colorless oil 53E obtained, is directly used in next step reaction.
50mL round-bottomed flask adds compound 53E, sequentially add dichloromethane (12mL), triethylamine (447 μ L, 3.21mmol), compound 53F (264mg, 1.07mmol), 2h is stirred at room temperature, add sodium triacetoxy borohydride (340mg, 1.61mmol), stir overnight in 25 DEG C of oil baths.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains white solid 53 (316mg, productivity 65.0%).1HNMR(400MHz,CDCl3) δ 8.21 (dd, J=7.9,1.1Hz, 1H), 7.88 7.81 (m, 2H), 7.70 7.65 (m, 1H), 7.64 7.54 (m, 2H), 7.54 7.45 (m, 3H), 5.12 (s, 1H), 3.85 (s, 2H), 3.32 (s, 3H), 3.31 (s, 3H), 2.82 2.62 (m, 4H), 2.50 2.30 (m, 4H)；MS(ESI)m/z[M+Na]+: 477.00.
Embodiment 54
Adding compound 54C (400mg, 1.22mmol), dichloromethane (2ml), triethylamine (246mg, 2.44mmol) in 25ml round-bottomed flask, stirring is lower adds compound 54D (222mg, 1.34mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, white solid product 54 (266mg, productivity: 47.5%).1HNMR (400MHz, DMSO) δ 8.01 (d, J=1.0Hz, 1H), 7.89 (d, J=0.9Hz, 1H), 6.92 6.88 (m, 2H), 6.88 6.79 (m, 5H), 3.73 (d, J=1.7Hz, 6H), 3.09 (s, 4H), 2.54 2.49 (m, 2H), 2.46 (d, J=4.2Hz, 4H)；MS(ESI)m/z[M+H]+: 459.04.
Embodiment 55
55A (166mg is added in 25ml round-bottomed flask, 0.5mmol) with methanol (10ml), 55B (82mg is added after stirring and dissolving, 0.5mmol), in 70 DEG C of stirrings overnight, TLC detection reacts completely, and obtains compound 55 (331mg, 92%) through silica gel column chromatography after concentration.1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 6.89 6.73 (m, 4H), 3.80 3.72 (m, 4H), 3.22 3.10 (m, 4H), 2.66 2.54 (m, 4H), 2.49 2.36 (m, 11H), 1.90 (s, 2H), 1.78 1.69 (m, 2H).
Embodiment 56
Adding 56A (583mg, 3.0mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, add addition oxalyl chloride (426 μ l, 5.0mmol) and DMF (1), react overnight under room temperature.Solvent evaporated and excessive oxalyl chloride, obtain crude product 56B.
Adding 56C (665mg, 2.0mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, and adds triethylamine (421 μ l, 3.0mmol).Being dissolved by crude product 56B dichloromethane (5ml), be slowly added dropwise, overnight, it is complete that TLC detects raw material reaction to room temperature reaction.Compound 56D (500mg, productivity 49.2%) is separated to obtain through silica gel column chromatography (dichloromethane: methanol=100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.72 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 7.12 (d, J=8.6Hz, 2H), 6.92 6.82 (m, 4H), 6.82 6.75 (m, 2H), 3.81 (s, 3H), 3.77 3.75 (m, 2H), 3.55 3.53 (m, 2H), 3.12 3.09 (m, 4H), 2.65 (t, J=7.4Hz, 2H), 2.47 (s, 3H), 2.38 2.34 (m, 2H), 2.02 1.94 (m, 2H)；MS(ESI)m/z[M+Na]+: 531.04.
Adding compound 56D (500mg, 0.983mmol) in 50ml round-bottomed flask, oxolane (10ml) dissolves, and is slowly added to LiAlH at 0 DEG C4(149mg, 3.93mmol), reacts 1h at 60 DEG C.After being cooled to room temperature, react with methanol cancellation, be eventually adding a small amount of saturated NaHCO3(1ml), after cancellation completely, add kieselguhr and filter, methanol washing leaching cake, separate to obtain product 56 (280mg, productivity 42.8%) through silica gel column chromatography (dichloromethane: methanol=100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 7.11 (d, J=8.5Hz, 2H), 6.87 6.83 (m, 4H), 6.79 6.77 (m, 2H), 3.81 (s, 3H), 3.17 3.15 (m, 4H), 2.62 2.56 (m, 6H), 2.46 (s, 3H), 2.43 2.39 (m, 2H), 1.64 1.52 (m, 4H)；MS(ESI)m/z[M+H]+: 495.13.
Embodiment 57
Adding 57A (225mg, 1.5mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, add oxalyl chloride (213 μ l, 2.5mmol) and DMF (1), react overnight under room temperature.Solvent evaporated and excessive oxalyl chloride, obtain crude product 57B.
Adding 57C (332mg, 1.0mmol) in 50ml round-bottomed flask, dichloromethane (10ml) dissolves, and is subsequently adding triethylamine (209 μ l, 1.5mmol).Being dissolved by crude product 57B dichloromethane (5ml), be slowly added dropwise, room temperature reaction is overnight.It is complete that TLC detects raw material reaction.Compound 57D (350mg, productivity 75.3%) is separated to obtain through silica gel column chromatography (dichloromethane: methanol=100:1) after concentration.
Adding 57D (350mg, 0.753mmol) in 50ml round-bottomed flask, oxolane (10ml) dissolves, and is slowly added to LiAlH at 0 DEG C4(114mg, 3.01mmol), reacts 1h at 60 DEG C.After being cooled to room temperature, react with methanol cancellation, be eventually adding a small amount of saturated NaHCO3(1ml), after cancellation completely, add kieselguhr and filter, methanol washing leaching cake, separate to obtain product 57 (200mg, productivity 59.0%) through silica gel column chromatography (dichloromethane: methanol=100:1) after concentration.1HNMR(400MHz,CDCl3) δ 7.71 (d, J=8.3Hz, 2H), 7.32 7.29 (m, 4H), 7.23-7.19 (m, 3H), 6.88 6.84 (m, 2H), 6.80 6.76 (m, 2H), 3.18 3.16 (m, 4H), 2.70 2.66 (m, 2H), 2.60 2.58 (m, 4H), 2.46 (s, 3H), 2.46-2.42 (m, 2H), 1.91-1.84 (m, 2H)；MS(ESI)m/z[M+H]+: 451.20.
Embodiment 58
25ml round-bottomed flask adds compound 58A (249mg, 1.52mmol), compound 58B (300mg, 1.38mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (351mg, 1.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 58 (202mg, productivity: 37.2%).1HNMR(400MHz,CDCl3) δ 8.25 (dd, J=9.9,6.3Hz, 3H), 7.90 7.82 (m, 2H), 7.78 (d, J=7.7Hz, 1H), 7.60 (t, J=7.5Hz, 1H), 7.53 (t, J=7.3Hz, 1H), 7.47 (q, J=7.1Hz, 3H), 6.45 (t, J=4.7Hz, 1H), 3.80 (s, 2H), 3.67 3.57 (m, 4H), 2.32 2.24 (m, 4H)；MS(ESI)m/z[M]+: 394.88.
Embodiment 59
25ml round-bottomed flask adds compound 59A (180mg, 1.10mmol), compound 59B (300mg, 098mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (254mg, 1.20mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain colorless oil as product 59 (157mg, productivity: 35.3%).1HNMR(400MHz,CDCl3) δ 8.28 (d, J=4.7Hz, 2H), 7.74 (d, J=8.3Hz, 2H), 7.33 7.25 (m, 2H), 7.07 (d, J=8.1Hz, 1H), 6.89 (d, J=1.6Hz, 1H), 6.84 (dd, J=8.2,1.7Hz, 1H), 6.47 (t, J=4.7Hz, 1H), 3.87 3.78 (m, 4H), 3.56 (s, 3H), 3.47 (s, 2H), 2.49 2.45 (m, 4H), 2.43 (s, 3H)；MS(ESI)m/z[M+H]+: 455.08.
Embodiment 60
25ml round-bottomed flask adds compound 60A (284mg, 1.52mmol), compound 60B (300mg, 1.38mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (351mg, 1.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (1:1) is for eluant, obtain colorless oil as product 60 (219mg, productivity: 38.1%).1HNMR(400MHz,CDCl3) δ 8.25 (dd, J=7.9,1.2Hz, 1H), 7.87 (dd, J=7.2,1.5Hz, 2H), 7.74 (d, J=7.2Hz, 1H), 7.58 (ddd, J=8.2,6.1,4.2Hz, 2H), 7.54 7.43 (m, 5H), 6.98 (td, J=7.6,0.8Hz, 1H), 6.92 (d, J=8.3Hz, 1H), 3.84 (s, 2H), 3.09 2.93 (m, 4H), 2.52 2.35 (m, 4H)；MS(ESI)m/z[M]+: 417.94.
Embodiment 61
25ml round-bottomed flask adds compound 61A (206mg, 1.10mmol), compound 61B (300mg, 0.98mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (254mg, 1.20mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (1:1) is for eluant, obtain white solid product 61 (206mg, productivity: 44.1%).1HNMR(400MHz,CDCl3) δ 7.79 (d, J=8.3Hz, 2H), 7.58 (dd, J=7.9,1.6Hz, 1H), 7.50 (dd, J=12.5,4.9Hz, 1H), 7.33 (d, J=8.1Hz, 2H), 7.09 (d, J=8.5Hz, 1H), 7.03 (dd, J=7.8,4.9Hz, 2H), 6.89 (d, J=6.9Hz, 2H), 3.61 (s, 3H), 3.54 (s, 2H), 3.25 (s, 4H), 2.67 (s, 4H), 2.47 (s, 3H)；MS(ESI)m/z[M+H]+: 478.04.
Embodiment 62
25ml round-bottomed flask adds compound 62A (249mg, 1.52mmol), compound 62B (300mg, 1.38mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (351mg, 1.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 62 (228mg, productivity: 41.9%).1HNMR(400MHz,CDCl3) δ 8.33 (dd, J=15.8,4.7Hz, 3H), 8.01 7.96 (m, 2H), 7.93 (d, J=8.4Hz, 2H), 7.53 (dt, J=6.9,3.1Hz, 4H), 6.50 (t, J=4.7Hz, 1H), 3.85 3.81 (m, 4H), 3.59 (s, 2H), 2.53 2.47 (m, 4H)；MS(ESI)m/z[M+H]+: 395.07.
Embodiment 63
25ml round-bottomed flask adds compound 63A (162mg, 0.99mmol), compound 63B (200mg, 0.92mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (234mg, 1.10mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1), for eluant, obtains white solid product compound 63 (163mg, productivity: 45.1%).1HNMR(400MHz,CDCl3) δ 8.26 (dd, J=7.9,1.1Hz, 1H), 8.18 (dd, J=4.9,1.2Hz, 1H), 7.95 7.85 (m, 2H), 7.81 (d, J=7.6Hz, 1H), 7.62 (td, J=7.6,1.2Hz, 1H), 7.59 7.41 (m, 5H), 6.68 6.54 (m, 2H), 3.83 (s, 2H), 3.48 3.29 (m, 4H), 2.45 2.29 (m, 4H)；MS(ESI)m/z[M+H]+: 394.27
Embodiment 64
25ml round-bottomed flask adds compound 64A (176mg, 1.08mmol), compound 64B (300mg, 0.98mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (250mg, 1.18mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (1:1), for eluant, obtains colorless oil as product compound 64 (189mg, productivity: 42.6%).1HNMR(400MHz,CDCl3) δ 8.19 (dd, J=4.9,1.4Hz, 1H), 7.77 (d, J=8.3Hz, 2H), 7.48 (ddd, J=8.8,7.2,2.0Hz, 1H), 7.30 (d, J=8.1Hz, 2H), 7.09 (d, J=8.1Hz, 1H), 6.91 (d, J=1.5Hz, 1H), 6.86 (dd, J=8.2,1.7Hz, 1H), 6.69 6.59 (m, 2H), 3.58 (s, 3H), 3.57 3.53 (m, 4H), 3.50 (s, 2H), 2.57 2.51 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 454.28.
Embodiment 65
25ml round-bottomed flask adds compound 65A (200mg, 0.64mmol), compound 65B (126mg, 0.58mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (148mg, 0.69mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (4:1), for eluant, obtains white solid product compound 65 (144mg, productivity: 45.6%).1HNMR(400MHz,CDCl3) δ 8.27 (dd, J=7.9,1.2Hz, 1H), 7.94 7.87 (m, 2H), 7.78 (d, J=7.3Hz, 1H), 7.65 7.56 (m, 2H), 7.55 7.47 (m, 3H), 7.39 (dd, J=8.7,2.6Hz, 1H), 7.25 (d, J=2.6Hz, 1H), 7.19 (d, J=8.6Hz, 1H), 7.16 7.06 (m, 3H), 7.04 6.97 (m, 1H), 3.87 (s, 2H), 3.45-3.25 (m, 4H), 2.45-2.25 (m, 4H)；MS(ESI)m/z[M+H]+: 544.23.
Embodiment 66
25ml round-bottomed flask adds compound 66A (200mg, 0.64mmol), compound 66B (96.3mg, 0.58mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (148mg, 0.69mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1), for eluant, obtains white solid product compound 66 (106mg,, productivity: 39.6%).1HNMR(400MHz,CDCl3) δ 7.38 (dd, J=8.6,2.6Hz, 1H), 7.33 (d, J=2.6Hz, 1H), 7.22 7.14 (m, 2H), 7.13 7.06 (m, 2H), 6.99 (td, J=7.6,1.7Hz, 1H), 6.95 (d, J=1.6Hz, 1H), 6.88 (dd, J=8.2,1.7Hz, 1H), 6.84 (d, J=8.1Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.65-3.45 (m, 4H), 3.53 (s, 2H), 2.65-2.45 (s, 4H)；MS(ESI)m/z[M+H]+: 464.30.
Embodiment 67
25ml round-bottomed flask adds compound 67A (200mg, 0.64mmol), compound 67B (177mg, 0.58mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (148mg, 0.69mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1) is for eluant, obtain white solid product 67 (146mg, productivity: 41.7%).1HNMR(400MHz,CDCl3) δ 7.78 (d, J=8.3Hz, 2H), 7.40 (dd, J=8.6,2.6Hz, 1H), 7.32 (d, J=9.0Hz, 3H), 7.20 (d, J=8.6Hz, 1H), 7.16 (dd, J=7.7,1.5Hz, 1H), 7.14 7.06 (m, 3H), 7.00 (td, J=7.6,1.7Hz, 1H), 6.92 (d, J=1.4Hz, 1H), 6.87 (d, J=8.2Hz, 1H), 3.59 (s, 3H), 3.58-3.51 (m, 4H), 3.53 (s, 2H), 2.65-2.51 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 604.25.
Embodiment 68
Being sequentially added into 68A (method of reference example 16 prepares) (104mg, 0.280mmol), palladium carbon (10mg), ethanol (20mL) in 100mL round-bottomed flask, room temperature under an atmosphere of hydrogen, atmospheric agitation is overnight.Reactant liquor sucking filtration, methanol washs, and merging filtrate is spin-dried for, obtains light brown paste 68B.It is directly used in next step reaction.
50mL round-bottomed flask adds 68B, it is dissolved in dichloromethane (10mL), add triethylamine (46 μ L, 0.329mmol), 68C (50mg, 0.264mmol), stir overnight under room temperature, reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution and extraction into ethyl acetate, and organic facies anhydrous sodium sulfate dries, and is spin-dried for, the residue obtained separates purification through preparation TLC (dichloromethane: methanol 50:1) and obtains colourless paste compound 68 (41mg, productivity 28.0%).1HNMR(400MHz,CDCl3null)δ7.52–7.47(m,2H),7.26–7.20(m,2H),6.93–6.84(m,4H),6.84–6.76(m,3H),4.05(d,J=13.0Hz,1H),3.90(s,3H),3.88(s,3H),3.53(q,J=7.1Hz,2H),3.46–3.39(m,1H),3.39–3.31(m,1H),3.13(d,J=13.1Hz,1H),2.92–2.78(m,2H),2.72(dd,J=11.4,9.3Hz,1H),2.64–2.54(m,1H),2.41(s,3H),2.25(td,J=11.0,3.1Hz,1H),1.23(d,J=6.1Hz,3H),1.05(t,J=7.1Hz,3H)；MS(ESI)m/z[M+H]+: 524.27.
Embodiment 69
Being sequentially added into 69A (method of reference example 16 prepares) (102mg, 0.275mmol), palladium carbon (25mg), ethanol (20mL) in 100mL round-bottomed flask, room temperature under an atmosphere of hydrogen, atmospheric agitation is overnight.Reactant liquor sucking filtration, methanol washs, and merging filtrate is spin-dried for, obtains light brown paste 69B.It is directly used in next step reaction.
50mL round-bottomed flask adds 69B, it is dissolved in dichloromethane (10mL), add triethylamine (66 μ L, 0.470mmol), 69C (72mg, 0.376mmol), stir overnight under room temperature, reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution and extraction into ethyl acetate, and organic facies anhydrous sodium sulfate dries, and is spin-dried for, the residue obtained separates purification through preparation TLC (dichloromethane: methanol 50:1) and obtains colourless paste compound 69 (53mg, productivity 36.8%).1HNMR(400MHz,CDCl3) δ 7.56 7.50 (m, 2H), 7.26 7.22 (m, 2H), 7.10 6.70 (m, 5H), 6.59 6.52 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.80 3.57 (m, 2H), 3.57 3.43 (m, 4H), 2.98 2.52 (m, 4H), 2.42 (s, 3H), 2.19 1.86 (m, 2H), 1.78 1.46 (m, 2H), 1.06 (t, J=7.1Hz, 3H)；MS(ESI)m/z[M+H]+: 524.19.
Embodiment 70
50mL round-bottomed flask adds compound 70A (200mg, 0.609mmol), dissolve with dichloromethane (10mL), it is placed in ice bath, stirs 5min, add pyridine (0.5mL), continue to stir 10min in ice bath, rise to and 30min is stirred at room temperature, add compound acetic anhydride (2mL), stir overnight under room temperature.Reactant liquor adds water and ethyl acetate, extracting and demixing, merges organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (petroleum ether: ethyl acetate 5:1) and obtains compound as white solid 70 (103mg, productivity 45.8%).1HNMR(400MHz,CDCl3)δ7.00–6.94(m,2H),6.94–6.80(m,5H),3.90(s,3H),3.88(s,3H),3.50(s,2H),3.22–3.11(m,4H),2.66–2.54(m,4H),2.27(s,3H)；MS(ESI)m/z[M+Na]+: 393.14.
Embodiment 71
50mL round-bottomed flask adds compound 71A (200mg, 0.609mmol), dissolve with DMF (4mL), be placed in ice bath, stirring 5min, add sodium hydride (22mg, 0.913mmol), continue to stir 10min in ice bath, rise to and 30min is stirred at room temperature, add compound 71B (142 μ L, 1.22mmol), stir overnight under room temperature.Reactant liquor adds water and ethyl acetate, extracting and demixing, merges organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains compound as white solid 71 (82mg, productivity 31.1%).1HNMR(400MHz,CDCl3) δ 8.22 8.15 (m, 2H), 7.66 7.59 (m, 1H), 7.54 7.46 (m, 2H), 7.13 7.07 (m, 2H), 7.00 6.91 (m, 3H), 6.87 (dd, J=8.2,1.6Hz, 1H), 6.83 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.52 (s, 2H), 3.26 3.15 (m, 4H), 2.68 2.56 (m, 4H)；MS(ESI)m/z[M+H]+: 433.10.
Embodiment 72
50mL round-bottomed flask adds compound 72A (200mg, 0.609mmol), chloroform (6mL), compound 72B (446mg, 2.44mmol), pyridine (0.5mL), reacting 4h in 65 DEG C of oil baths, reactant liquor is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains compound as white solid 72 (67mg, productivity 23.2%).1HNMR(400MHz,CDCl3) δ 7.69 (dd, J=5.0,1.3Hz, 1H), 7.56 (dd, J=3.8,1.3Hz, 1H), 7.08 (dd, J=5.0,3.8Hz, 1H), 6.94 6.75 (m, 7H), 3.89 (s, 3H), 3.88 (s, 3H), 3.49 (s, 2H), 3.21 3.10 (m, 4H), 2.61 2.52 (m, 4H)；MS(ESI)m/z[M+H]+: 475.15.
Embodiment 73
50mL round-bottomed flask adds compound 73A (200mg, 0.609mmol), dissolve with DMF (4mL), be placed in ice bath, stirring 5min, add sodium hydride (22mg, 0.913mmol), continue to stir 10min in ice bath, rise to and 30min is stirred at room temperature, add compound 73B (108 μ L, 0.913mmol), stir overnight under room temperature.Reactant liquor adds water and ethyl acetate, extracting and demixing, merges organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains compound as white solid 73 (89mg, productivity 34.9%).1HNMR(400MHz,CDCl3) δ 7.45 7.28 (m, 5H), 6.94 6.84 (m, 6H), 6.82 (d, J=8.1Hz, 1H), 5.01 (s, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.51 (s, 2H), 3.15 3.03 (m, 4H), 2.65 2.54 (m, 4H)；MS(ESI)m/z[M+H]+: 419.20.
Embodiment 74
74A (2g, 24.1mmol) and 74B (400mg, 2.41mmol) is dissolved in 10ml methanol, after 12h is stirred at room temperature, it is slowly added to sodium borohydride (109.4,2.892mmol), after reaction 15min, after kieselguhr filters after removal of solvent under reduced pressure, add water and be extracted with ethyl acetate twice removing impurity, then with 2 combined dichloromethanes of dichloromethane extraction, after adding dried over sodium sulfate, removal of solvent under reduced pressure obtains 74C (188.5mg, productivity 33%).
By 74C (188.5mg, 0.798mmol) with 74D (222mg, 0.725mg) it is dissolved in 5ml1,2-dichloroethanes, under condition of ice bath, is slowly added to sodium triacetoxy borohydride (230mg, 1.09mmol), after room temperature reaction 5h, filter through kieselguhr, silica gel column chromatography (dichloromethane: methanol=20:1), obtain product 74 (113mg, productivity 30.2%).1HNMR(400MHz,CDCl3) δ 7.77 (d, J=8.3Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 7.06 (d, J=8.1Hz, 1H), 6.90 (d, J=1.2Hz, 1H), 6.88 6.79 (m, 4H), 3.90 (s, 3H), 3.88 (s, 3H), 3.58 (s, 3H), 3.47 (s, 2H), 3.46 (s, 2H), 2.46 (m, 11H)；MS(ESI)m/z[M+H]+: 527.05.
Embodiment 75
50mL round-bottomed flask adds 75A (90mg, 0.731mmol), thionyl chloride (1mL), back flow reaction 2h in the oil bath of 80 DEG C, it is spin-dried for, obtain 75B, sequentially add 75C (200mg, 0.609mmol), THF (20mL), DMAP (10mg), TEA (102 μ L, 0.731mmol), stir overnight under room temperature, reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains compound as white solid 75 (28mg, productivity 10.6%).1HNMR(400MHz,CDCl3) δ 9.40 9.36 (m, 1H), 8.84 (dd, J=4.9,1.7Hz, 1H), 8.44 (dt, J=8.0,1.9Hz, 1H), 7.46 (ddd, J=8.0,4.9,0.7Hz, 1H), 7.16 7.07 (m, 2H), 6.99 6.92 (m, 3H), 6.87 (dd, J=8.1,1.7Hz, 1H), 6.83 (d, J=8.1Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.53 (s, 2H), 3.29 3.14 (m, 4H), 2.69 2.55 (s, 4H)；MS(ESI)m/z[M+H]+: 434.21.
Embodiment 76
50mL round-bottomed flask adds 76A (127mg, 0.731mmol), thionyl chloride (1mL), dichloromethane (2mL), 1 DMF, the oil bath of 35 DEG C is reacted 4h, it is spin-dried for, obtain 76B, sequentially add 76C (200mg, 0.609mmol), dichloromethane (12mL), TEA (127 μ L, 0.913mmol), 30min is stirred under room temperature, reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification obtain colourless paste compound 76 (57mg through preparing thin layer chromatography (dichloromethane: methanol 50:1), productivity 19.4%).1HNMR(400MHz,CDCl3) δ 9.41 (s, 1H), 8.74 (s, 1H), 8.13 8.07 (m, 1H), 8.05 7.99 (m, 1H), 7.86 7.76 (m, 2H), 7.24 7.16 (m, 2H), 7.04 6.91 (m, 3H), 6.87 (dd, J=8.2,1.6Hz, 1H), 6.83 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.52 (s, 2H), 3.27 3.15 (m, 4H), 2.67 2.55 (m, 4H)；MS(ESI)m/z[M+H]+: 484.26.
Embodiment 77
Experimental program and pertinent literature with reference to embodiment 76 prepare compound 77, MS (ESI) m/z [M+H]+: 511.25.
Embodiment 78
25ml round-bottomed flask adds compound 78A (300mg, 1.17mmol), ethyl acetate (5ml), triethylamine (161mg, 1.59mmol), stirring and dissolving is settled solution, add compound 78B (231mg, 1.06mmol), sodium triacetoxy borohydride (270mg, 1.27mmol) is added under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (4:1) is for eluant, obtain colorless oil as product 78 (208mg, productivity: 43.6%).1HNMR (400MHz, CDCl3) δ 8.23 (dd, J=7.9,1.0Hz, 1H), 7.92 7.89 (m, 2H), 7.82 (d, J=7.6Hz, 1H), 7.66 7.57 (m, 3H), 7.54 7.45 (m, 3H), 7.24 (dd, J=8.5,2.0Hz, 1H), 7.06 (td, J=8.8,2.1Hz, 1H), 3.83 (s, 2H), 3.04 2.92 (m, 1H), 2.82 (d, J=11.6Hz, 2H), 2.04 (td, J=11.4,2.6Hz, 2H), 1.98 1.84 (m, 4H)；MS(ESI)m/z[M+H]+: 451.91.
Embodiment 79
25ml round-bottomed flask adds compound 79A (300mg, 0.89mmol), compound 79B (108mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (208mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain white solid product 79 (174mg, productivity: 47.5%).1HNMR (400MHz, CDCl3) δ 7.71 (d, J=8.4Hz, 3H), 7.60 (dd, J=8.9,7.9Hz, 2H), 7.46 (t, J=7.7Hz, 1H), 7.32 (d, J=8.1Hz, 2H), 6.90 6.82 (m, 2H), 6.82 6.74 (m, 2H), 3.59 (s, 2H), 3.23 3.11 (m, 4H), 2.65 2.54 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+Na]+: 470.02.
Embodiment 80
25ml round-bottomed flask adds compound 80A (300mg, 1.17mmol), ethyl acetate (5ml), triethylamine (161mg, 1.59mmol), stirring and dissolving is settled solution, add compound 80B (324mg, 1.06mmol), sodium triacetoxy borohydride (270mg, 1.27mmol) is added under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (2:1) is for eluant, obtain colorless oil as product 80 (222mg, productivity: 41.2%).1nullHNMR(400MHz,CDCl3)δ7.75(d,J=8.3Hz,2H),7.69(dd,J=8.7,5.1Hz,1H),7.29(d,J=8.0Hz,2H),7.22(dd,J=8.5,2.0Hz,1H),7.06(ddd,J=15.8,7.6,3.2Hz,2H),6.91(d,J=1.6Hz,1H),6.85(dd,J=8.2,1.7Hz,1H),3.57(s,3H),3.50(s,2H),3.13–3.02(m,1H),2.98(d,J=11.3Hz,2H),2.44(s,3H),2.23–2.13(m,2H),2.06(dd,J=9.1,3.3Hz,4H)；MS(ESI)m/z[M]+: 510.88.
Embodiment 81
25ml round-bottomed flask adds chemical combination 81A (300mg, 0.89mmol), compound 81B (143mg, 0.82mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (208mg, 0.98mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (2:1) is for eluant, obtain white solid product 81 (183mg, productivity: 45.5%).1HNMR (400MHz, CDCl3) δ 7.83 (d, J=7.8Hz, 1H), 7.71 (d, J=8.3Hz, 2H), 7.66 (d, J=7.8Hz, 1H), 7.55 (t, J=7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.32 (d, J=8.1Hz, 2H), 6.90 6.83 (m, 2H), 6.82 6.75 (m, 2H), 3.73 (s, 2H), 3.21 3.14 (m, 4H), 2.67 2.61 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 490.96.
Embodiment 82
25ml round-bottomed flask adds compound 82A (200mg, 0.91mmol), compound 82B (254mg, 0.83mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (212mg, 1.00mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1), for eluant, obtains white solid product compound 82 (209mg, productivity: 49.5%).1HNMR(400MHz,CDCl3) δ 7.91 (d, J=8.2Hz, 1H), 7.81 (d, J=8.1Hz, 1H), 7.77 (d, J=8.3Hz, 2H), 7.50 7.44 (m, 1H), 7.40 7.33 (m, 1H), 7.32 7.28 (m, 2H), 7.10 (d, J=8.1Hz, 1H), 6.94 (d, J=1.6Hz, 1H), 6.87 (dd, J=8.2,1.8Hz, 1H), 3.59 (s, 3H), 3.57 (d, J=5.1Hz, 4H), 3.55 (s, 2H), 2.70 2.64 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 510.00.
Embodiment 83
25ml round-bottomed flask adds compound 83A (200mg, 0.91mmol), compound 83B (254mg, 0.83mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (212mg, 1.00mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1), for eluant, obtains white solid product compound 83 (181mg, productivity: 42.8%).1HNMR(400MHz,CDCl3) δ 7.92 (d, J=8.2Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.78 (d, J=8.3Hz, 2H), 7.48 (t, J=7.4Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 7.32 (d, J=8.2Hz, 2H), 7.23 7.19 (m, 1H), 7.18 (d, J=1.8Hz, 1H), 6.83 (d, J=8.3Hz, 1H), 3.59 (s, 3H), 3.58 3.53 (m, 4H), 3.52 (s, 2H), 2.68 2.61 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M]+: 509.83.
Embodiment 84
25ml round-bottomed flask adds compound 84A (200mg, 0.91mmol), compound 84B (181mg, 0.83mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (212mg, 1.00mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (4:1), for eluant, obtains white solid product compound 84 (170mg, productivity: 45.6%).1HNMR(400MHz,CDCl3) δ 8.26 (dd, J=7.9,1.2Hz, 1H), 7.91 (dd, J=5.3,3.3Hz, 2H), 7.86 (d, J=8.2Hz, 1H), 7.81 (dd, J=7.7,3.6Hz, 2H), 7.63 (td, J=7.6,1.3Hz, 1H), 7.58 (ddd, J=6.3,3.7,1.3Hz, 1H), 7.55 7.49 (m, 3H), 7.49 7.45 (m, 1H), 7.39 7.33 (m, 1H), 3.89 (s, 2H), 3.43 3.32 (m, 4H), 2.54 2.47 (m, 4H)；MS(ESI)m/z[M]+: 449.97.
Embodiment 85
25ml round-bottomed flask adds compound 85A (483mg, 1.45mmol), compound 85B (200mg, 1.2mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (382mg, 1.8mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (4:1) is for eluant, obtain white solid product 85 (275mg, productivity: 47.3%).1HNMR (400MHz, CDCl3) δ 7.74 (d, J=8.3Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 7.12 (t, J=8.2Hz, 1H), 6.93 (s, 1H), 6.89 6.83 (m, 2H), 6.77 (dd, J=8.4,2.2Hz, 1H), 6.54 (t, J=2.2Hz, 1H), 6.38 (dd, J=8.0,2.0Hz, 1H), 3.91 (d, J=5.4Hz, 6H), 3.51 (s, 2H), 3.17 3.07 (m, 4H), 2.61 2.51 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 483.03.
Embodiment 86
25ml round-bottomed flask adds compound 86A (375mg, 1.12mmol), compound 86B (100mg, 0.94mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (297mg, 1.41mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain white solid product 86 (179mg, productivity: 45.2%).1HNMR (400MHz, CDCl3) δ 8.56 (d, J=1.6Hz, 1H), 8.51 (dd, J=4.8,1.4Hz, 1H), 7.68 (dd, J=9.6,5.0Hz, 3H), 7.33 7.22 (m, 3H), 7.09 (t, J=8.2Hz, 1H), 6.73 (dd, J=8.4,2.1Hz, 1H), 6.48 (t, J=2.2Hz, 1H), 6.36 (dd, J=8.0,1.8Hz, 1H), 3.54 (s, 2H), 3.11 3.04 (m, 4H), 2.57 2.50 (m, 4H), 2.41 (s, 3H)；MS(ESI)m/z[M+H]+: 424.02.
Embodiment 87
50mL round-bottomed flask adds compound 87A (784mg, 2.39mmol), chloroform (6mL), compound 87B (2.28g, 9.55mmol), pyridine (0.5mL), reacting 6h in 65 DEG C of oil baths, reactant liquor is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains colourless paste 87C (170mg, productivity 12.0%).
25mL round-bottomed flask adds compound 87C (100mg, 0.168mmol), compound 87D (21mg, 0.168mmol), Pd (dppf) Cl2Dichloromethane complex (14mg; 0.017mmol); potassium acetate (49mg; 0.504mmol); THF/EtOH/ water (2mL/2mL/2mL) mixed solvent; react overnight in 80 DEG C of oil baths under nitrogen protection; reactant liquor is spin-dried for; residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merges organic facies; water washing; anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains off-white color solid 87 (41mg, productivity 44.7%).1HNMR(400MHz,CDCl3) δ 8.88 (d, J=1.9Hz, 1H), 8.68 (dd, J=4.8,1.5Hz, 1H), 7.97 7.86 (m, 3H), 7.75 7.68 (m, 2H), 7.43 (dd, J=7.7,4.9Hz, 1H), 6.94 6.73 (m, 7H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.21 3.09 (m, 4H), 2.61 2.50 (m, 4H)；MS(ESI)m/z[M+H]+: 545.94.
Embodiment 88
50mL round-bottomed flask adds 88A (436mg, 2.69mmol), it is dissolved in DMSO (6mL), sequentially add TBAI (8mg, 0.02mmol), potassium carbonate (464mg, 3.36mmol), 88B (452mg, 2.24mmol), stirring reaction 6h in 120 DEG C of oil baths, reactant liquor adds water, extraction into ethyl acetate, water washing, anhydrous sodium sulfate dries, and is spin-dried for, the residue obtained obtains light yellow oil 88C (339mg, productivity 53.4%) through column chromatography (dichloromethane: methanol 100:1) purification.
50mL round-bottomed flask adds compound 88C (200mg, 0.706mmol), it is dissolved in dichloromethane (12mL), add compound 88D (117mg, 0.706mmol), 2h is stirred at room temperature, adds sodium triacetoxy borohydride (195mg, 0.918mmol), stir overnight under room temperature.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (petroleum ether: ethyl acetate 4:1) and obtains yellow solid 88E (167mg, productivity 38.5%).
Being sequentially added into 88E (167mg, 0.385mmol), palladium carbon (40mg), ethanol (20mL), oxolane (5mL) in 100mL round-bottomed flask, room temperature under an atmosphere of hydrogen, atmospheric agitation is overnight.Reactant liquor sucking filtration, methanol washs, and merging filtrate is spin-dried for, obtains colourless paste 88F.It is directly used in next step reaction.
50mL round-bottomed flask adds compound 88F, is dissolved in dichloromethane (15mL), adds paratoluensulfonyl chloride (74mg, 0.387mmol), triethylamine (67 μ L, 0.483mmol), stir overnight under room temperature.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 150:1) and obtains compound as white solid 88 (131mg, productivity 72.9%).1HNMR(400MHz,CDCl3) δ 7.58 7.47 (m, 4H), 7.41 7.34 (m, 2H), 7.33 7.28 (m, 1H), 7.22 7.14 (m, 2H), 6.93 6.85 (m, 2H), 6.84 6.69 (m, 5H), 6.39 6.24 (m, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.77 (d, J=13.3Hz, 1H), 3.57 3.40 (m, 3H), 3.05 2.95 (m, 1H), 2.93 2.82 (m, 2H), 2.82 2.72 (m, 1H), 2.37 (s, 3H), 2.35 2.26 (m, 1H)；MS(ESI)m/z[M+H]+: 558.18.
Embodiment 89
Adding compound 89A (1000mg, 10.51mmol), dichloromethane (2ml), triethylamine (1592mg, 15.77mmol) in 50ml round-bottomed flask, stirring is lower adds compound 89B (2406mg, 12.62mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1), for eluant, obtains white solid product 89C.
25ml round-bottomed flask adds compound 89C (400mg, 1.61mmol), compound 89D (291mg, 1.77mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (409mg, 1.93mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, it is extracted with ethyl acetate again, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1), for eluant, obtains white solid product compound 89 (311mg, productivity: 48.6%).1HNMR(400MHz,CDCl3) δ 8.30 (d, J=4.7Hz, 2H), 7.85 (d, J=8.4Hz, 2H), 7.35 (dd, J=3.3,1.8Hz, 1H), 7.26 (d, J=8.1Hz, 2H), 6.48 (t, J=4.7Hz, 1H), 6.23 (t, J=3.3Hz, 1H), 6.19 6.15 (m, 1H), 3.65 (s, 2H), 3.60 3.52 (m, 4H), 2.43 2.39 (m, 4H), 2.37 (s, 3H)；MS(ESI)m/z[M+H]+: 398.40.
Embodiment 90
100ml round-bottomed flask adds compound 90A (3358mg, 18.15mmol), compound 90B (2000mg, 18.15mmol), Pd2(dba)3(833mg, 0.91mmol), Xantphos (1050mg, 1.82mmol), DIPEA (4691mg, 36.3mmol), dioxane (30ml), upper nitrogen protection.105 DEG C of stirring reactions overnight after, reaction system is down to room temperature, filters, through silica gel column chromatography after filtrate concentration, with petroleum ether: ethyl acetate (50:1), for eluant, obtains colorless oil 90C.
50ml round-bottomed flask adds compound 90C (1824mg, 8.52mmol), dichloromethane (20ml), in ice bath, 0 DEG C it is cooled to after stirring and dissolving, again by compound 90D (4412mg, 25.57mmol) be dividedly in some parts reaction system after, 0 DEG C continue reaction 2 hours, TLC detect raw material reaction complete.Reaction system is used saturated sodium bicarbonate aqueous solution successively, and saturated sodium-chloride water solution is washed, and anhydrous sodium sulfate dries.Through silica gel column chromatography after concentration, with dichloromethane: methanol (50:1), for eluant, obtains white solid product 90E.
25ml round-bottomed flask adds compound 90E (250mg, 1.02mmol), compound 90F (184mg, 1.12mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (259mg, 1.23mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain colorless oil as product 90 (185mg, productivity: 46.1%).1HNMR(400MHz,CDCl3) δ 8.31 (d, J=4.7Hz, 2H), 8.02 7.94 (m, 3H), 7.85 (d, J=7.9Hz, 1H), 7.58 (dd, J=10.5,4.4Hz, 2H), 7.51 (ddd, J=17.2,11.7,7.0Hz, 3H), 6.50 (t, J=4.7Hz, 1H), 3.89 3.78 (m, 4H), 3.59 (s, 2H), 2.56 2.42 (m, 4H)；MS(ESI)m/z[M+H]+: 395.16.
Embodiment 91
100ml round-bottomed flask adds compound 91A (2000mg, 10.34mmol), compound 91B (2118mg, 11.37mmol), potassium carbonate (2140mg, 15.51mmol), DMF (5ml), 70 DEG C of stirring reactions overnight after, reaction system is down to room temperature, after adding 100ml diluted ethyl acetate, washing 3 times successively, saturated sodium-chloride water solution washs, and anhydrous sodium sulfate dries, and concentration of organic layers obtains white solid product 91C.
50ml round-bottomed flask adds compound 91C (1764mg; 5.17mmol); compound 91D (1446mg; 5.69mmol), potassium acetate (1522mg, 15.51mmol); palladium (38mg; 0.17mmol), DMF (5ml), upper nitrogen protection; 70 DEG C of stirring reactions 16 hours; reaction system is down to room temperature, after adding 100ml diluted ethyl acetate, washing 3 times successively; saturated sodium-chloride water solution washs; anhydrous sodium sulfate dries, and concentration of organic layers obtains faint yellow solid product 91D, direct plunges into next step reaction.
50ml round-bottomed flask adds the product Compound E of previous step reaction, adds THF:H2O (1:1) solution 15ml, dispersed with stirring is suspension, add Dexol (1987mg, 12.9mmol), at room temperature stir overnight, it is spin-dried for reaction system, after adding 50ml diluted ethyl acetate, washing successively, saturated sodium-chloride water solution washs, anhydrous sodium sulfate dries, and concentration of organic layers obtains white solid product 91F.
Adding compound 91F (400mg, 1.05mmol), dichloromethane (2ml), triethylamine (159mg, 1.58mmol) in 25ml round-bottomed flask, stirring is lower adds compound 91G (230mg, 1.2mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1), for eluant, obtains white solid product 91H.
50ml round-bottomed flask adds compound 91H (400mg, 0.92mmol), dichloromethane (5ml), trifluoroacetic acid (1ml).Stirring 3 hours under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system being concentrated, the sodium hydrate aqueous solution of 1mol/L adjusts pH value to be 9-10, and extraction into ethyl acetate merges organic layer, and anhydrous sodium sulfate dries, and obtains white solid product 91I after concentration.
25ml round-bottomed flask adds compound 91I (150mg, 0.45mmol), compound 91J (45mg, 0.41mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (104mg, 0.49mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 91 (84mg, productivity: 48.3%).1HNMR (400MHz, CDCl3) δ 8.61 (d, J=1.3Hz, 1H), 8.56 (dd, J=4.8,1.2Hz, 1H), 7.91 (s, 2H), 7.74 (t, J=8.4Hz, 3H), 7.40 7.30 (m, 3H), 3.83 3.75 (m, 4H), 3.57 (s, 2H), 2.52 2.47 (m, 4H), 2.47 (s, 3H)；MS(ESI)m/z[M+H]+: 426.19.
Embodiment 92
25ml round-bottomed flask adds compound 92I (150mg, 0.45mmol), compound 92J (68mg, 0.41mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (104mg, 0.49mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain white solid product 92 (99mg, productivity: 50.1%).1HNMR (400MHz, CDCl3) δ 7.91 (s, 2H), 7.74 (d, J=8.3Hz, 2H), 7.36 (d, J=8.2Hz, 2H), 6.92 (d, J=1.3Hz, 1H), 6.87 6.82 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.82 3.74 (m, 4H), 3.49 (s, 2H), 2.48 (d, J=7.8Hz, 7H)；MS(ESI)m/z[M+H]+: 485.03.
Embodiment 93
25ml round-bottomed flask adds compound 93A (300mg, 1.84mmol), compound 93B (511mg, 1.67mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (425mg, 2mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (5:1) is for eluant, obtain white solid product 93 (345mg, productivity: 45.6%).1HNMR (400MHz, CDCl3) δ 8.28 (d, J=6.5Hz, 2H), 7.79 (d, J=8.3Hz, 2H), 7.32 (d, J=8.2Hz, 2H), 7.08 (d, J=8.1Hz, 1H), 6.90 (d, J=1.6Hz, 1H), 6.86 (dd, J=8.2,1.6Hz, 1H), 6.67 (dd, J=5.2,1.4Hz, 2H), 3.60 (s, 3H), 3.50 (s, 2H), 3.39 3.30 (m, 4H), 2.59 2.51 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+Na]+: 476.08.
Embodiment 94
25ml round-bottomed flask adds compound 94A (250mg, 1.52mmol), compound 94B (425mg, 1.39mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (353mg, 1.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain white solid product 94 (269mg, productivity: 42.6%).1HNMR(400MHz,CDCl3) δ 8.13 (d, J=1.3Hz, 1H), 8.05 (dd, J=2.5,1.5Hz, 1H), 7.84 (d, J=2.6Hz, 1H), 7.76 (d, J=8.3Hz, 2H), 7.30 (d, J=8.2Hz, 2H), 7.07 (d, J=8.1Hz, 1H), 6.89 (d, J=1.5Hz, 1H), 6.85 (dd, J=8.2,1.6Hz, 1H), 3.59 (d, J=4.9Hz, 4H), 3.57 (s, 3H), 3.49 (s, 2H), 2.56 2.50 (m, 4H), 2.44 (s, 3H)；MS(ESI)m/z[M+Na]+: 477.27.
Embodiment 95
25ml round-bottomed flask adds compound 95A (250mg, 1.52mmol), compound 95B (303mg, 1.39mmol), ethyl acetate (2ml), adds sodium triacetoxy borohydride (353mg, 1.66mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain colorless oil as product 95 (236mg, productivity: 43.1%).1HNMR(400MHz,CDCl3) δ 8.29 8.24 (m, 1H), 8.08 (d, J=1.1Hz, 1H), 8.07 8.03 (m, 1H), 7.92 7.87 (m, 2H), 7.85 (d, J=2.5Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.64 (dd, J=10.7,4.3Hz, 1H), 7.57 (t, J=7.4Hz, 1H), 7.54 7.47 (m, 3H), 3.84 (s, 2H), 3.47 3.36 (m, 4H), 2.43 2.32 (m, 4H)；MS(ESI)m/z[M+H]+: 395.13.
Embodiment 96
50mL round-bottomed flask adds compound 96A (784mg, 2.39mmol), chloroform (6mL), compound 96B (2.28g, 9.55mmol), pyridine (0.5mL), reacting 6h in 65 DEG C of oil baths, reactant liquor is spin-dried for, and adds saturated sodium bicarbonate aqueous solution in residue, extraction into ethyl acetate, merging organic facies, water washing, anhydrous sodium sulfate dries, the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains colourless paste 96C (170mg, productivity 12.0%).
25mL round-bottomed flask adds compound 96C (70mg, 0.118mmol), compound 96D (15mg, 0.118mmol), Pd (dppf) Cl2Dichloromethane complex (10mg; 0.012mmol); potassium acetate (35mg; 0.354mmol); THF/EtOH/ water (2mL/2mL/2mL) mixed solvent; react overnight in 80 DEG C of oil baths under nitrogen protection; reactant liquor is spin-dried for; residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merges organic facies; water washing; anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 100:1) and obtains off-white color solid 96 (59mg, productivity 91.5%).1HNMR(400MHz,CDCl3)δ9.29(s,1H),8.99(s,2H),7.99–7.94(m,2H),7.76–7.69(m,2H),6.94–6.73(m,7H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.20–3.10(m,4H),2.61–2.50(m,4H)；MS(ESI)m/z[M+H]+: 546.90.
Embodiment 97
50mL round-bottomed flask adds compound 97A (250mg, 0.761mmol), dissolve with DMF (4mL), be placed in ice bath, stirring 5min, add sodium hydride (27mg, 1.14mmol), continue to stir 10min in ice bath, rise to and 30min is stirred at room temperature, add compound 97B (214mg, 1.52mmol), stir overnight under room temperature.Reactant liquor adds water and ethyl acetate, extracting and demixing, merges organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains white solid 97 (107mg, productivity 32.5%).1HNMR(400MHz,CDCl3)δ7.21–7.14(m,2H),6.94–6.79(m,5H),3.90(s,3H),3.88(s,3H),3.50(s,2H),3.23–3.14(m,4H),2.63–2.51(m,5H),1.28–1.21(m,2H),1.12–1.05(m,2H)；MS(ESI)m/z[M+H]+: 433.03.
Embodiment 98
100mL round-bottomed flask adds compound 98A (1g, 6.23mmol), sequentially add DMF (25mL), DMSO (5mL) stirring and dissolving, add potassium carbonate (1.72g, 12.5mmol), iodomethane (426 μ L, 6.85mmol), 25 DEG C of oil baths are stirred 16h.Reactant liquor adds water, and is extracted with ethyl acetate, and merges organic facies, and water washing, anhydrous sodium sulfate dries, and obtains white solid 98B (700mg, productivity 64.4%) after being spin-dried for.
100mL round-bottomed flask is sequentially added into compound 98B (700mg, 4.01mmol), 98C (1.12g, 6.02mmol), sodium bicarbonate (674mg, 8.02mmol), molecular sieve (20), ethanol (30mL), reflux 10h in 100 DEG C of oil baths.Reactant liquor sucking filtration, washing with alcohol, filtrate is spin-dried for, and the residue obtained obtains white solid 98D (697mg, productivity 53.6%) through column chromatography (dichloromethane: methanol 100:1).
100mL round-bottomed flask adds compound 98D (348mg, 1.07mmol), dissolve with dichloromethane (8mL), add TFA (2mL), stirring under room temperature overnight, reactant liquor is spin-dried for, and adds dichloromethane and be again spin-dried for, the colorless oil 98E obtained, is directly used in next step reaction.
50mL round-bottomed flask adds compound 98E, sequentially add dichloromethane (12mL), triethylamine (447 μ L, 3.21mmol), compound 98F (328mg, 1.07mmol), 2h is stirred at room temperature, add sodium triacetoxy borohydride (340mg, 1.61mmol), stir overnight in 25 DEG C of oil baths.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains white solid 98 (347mg, productivity 63.0%).1HNMR(400MHz,CDCl3) δ 7.80 7.74 (m, 2H), 7.34 7.27 (m, 2H), 7.06 (d, J=8.1Hz, 1H), 6.86 (d, J=1.4Hz, 1H), 6.82 (dd, J=8.2,1.6Hz, 1H), 5.24 (s, 1H), 3.59 (s, 3H), 3.50 (s, 2H), 3.37 (s, 3H), 3.31 (s, 3H), 3.00 2.89 (m, 4H), 2.65 2.48 (m, 4H), 2.45 (s, 3H)；MS(ESI)m/z[M+H]+: 515.01.
Embodiment 99
50ml round-bottomed flask adds compound 99A (500mg, 2.40mmol), compound 99B (736mg, 2.40mmol), ethyl acetate (5ml), adds sodium triacetoxy borohydride (763mg, 3.60mmol) under stirring.Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.React with saturated sodium bicarbonate aqueous solution cancellation, then be extracted with ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1) is for eluant, obtain faint yellow solid product 99 (539mg, productivity: 45.1%).1HNMR (400MHz, CDCl3) δ 9.04 (d, J=2.7Hz, 1H), 8.20 (dd, J=9.5,2.8Hz, 1H), 7.79 (d, J=8.3Hz, 2H), 7.33 (d, J=8.1Hz, 2H), 7.09 (d, J=8.1Hz, 1H), 6.90 (s, 1H), 6.88 6.83 (m, 1H), 6.58 (d, J=9.5Hz, 1H), 3.83 3.75 (m, 4H), 3.61 (s, 3H), 3.51 (s, 2H), 2.57 2.51 (m, 4H), 2.47 (s, 3H)；MS(ESI)m/z[M]+: 498.97.
Embodiment 100
50mL round-bottomed flask adds compound 100A (250mg, 0.761mmol), dissolve with DMF (4mL), be placed in ice bath, stirring 5min, add sodium hydride (27mg, 1.14mmol), continue to stir 10min in ice bath, rise to and 30min is stirred at room temperature, add compound 100B (382mg, 1.52mmol), stir overnight under room temperature.Reactant liquor adds water and ethyl acetate, extracting and demixing, merges organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains off-white color solid 100 (79mg, productivity 19.1%).1HNMR(400MHz,CDCl3null)δ7.21–7.15(m,2H),7.00–6.80(m,5H),3.90(s,3H),3.88(s,3H),3.77(d,J=15.0Hz,1H),3.53(s,2H),3.27–3.17(m,4H),3.14(d,J=15.0Hz,1H),2.70–2.50(m,5H),2.46–2.36(m,1H),2.16–2.02(m,2H),1.96(d,J=18.5Hz,1H),1.70(ddd,J=13.9,9.3,4.6Hz,1H),1.45(ddd,J=13.2,9.4,3.9Hz,1H),1.16(s,3H),0.90(s,3H)；MS(ESI)m/z[M+H]+: 543.01.
Embodiment 101
Adding compound 101C (280mg, 0.85mmol), dichloromethane (2ml), triethylamine (173mg, 1.71mmol) in 25ml round-bottomed flask, stirring is lower adds compound 101D (152mg, 0.85mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (20:1) is for eluant, obtain colorless oil as product 101 (249mg, productivity: 62.5%).1HNMR(400MHz,CDCl3) δ 9.00 (d, J=2.3Hz, 1H), 8.89 (dd, J=4.9,1.6Hz, 1H), 8.14 8.10 (m, 1H), 7.51 7.47 (m, 1H), 6.91 6.77 (m, 7H), 3.91 (d, J=5.4Hz, 6H), 3.52 (s, 2H), 3.20 3.15 (m, 4H), 2.65 2.52 (m, 4H)；MS(ESI)m/z[M+H]+: 470.56.
Embodiment 102
Adding compound 102C (200mg, 0.74mmol), dichloromethane (2ml), triethylamine (132mg, 0.74mmol) in 25ml round-bottomed flask, stirring is lower adds compound 102D (149mg, 1.48mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain white solid product 102 (193mg, productivity: 63.6%).1HNMR(400MHz,CDCl3) δ 8.98 (d, J=2.1Hz, 1H), 8.87 (dd, J=4.9,1.6Hz, 1H), 8.57 (d, J=1.7Hz, 1H), 8.52 (dd, J=4.8,1.5Hz, 1H), 8.15 8.04 (m, 1H), 7.69 (d, J=7.8Hz, 1H), 7.48 (dd, J=8.0,4.9Hz, 1H), 7.33 7.23 (m, 1H), 6.90 6.81 (m, 2H), 6.81 6.72 (m, 2H), 3.56 (s, 2H), 3.20 3.09 (m, 4H), 2.65 2.52 (m, 4H)；MS(ESI)m/z[M+H]+: 410.28.
Embodiment 103
Adding compound 103C (180mg, 0.55mmol), dichloromethane (2ml), triethylamine (111mg, 1.10mmol) in 25ml round-bottomed flask, stirring is lower adds compound 103D (100mg, 0.55mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with petroleum ether: ethyl acetate (3:1) is for eluant, obtain colorless oil as product 103 (171mg, productivity: 65.7%).1HNMR(400MHz,CDCl3) δ 7.15 (d, J=9.1Hz, 2H), 6.97 6.81 (m, 5H), 3.91 (s, 3H), 3.90 (s, 3H), 3.52 (s, 2H), 3.24 3.12 (m, 5H), 2.64 2.56 (m, 4H), 2.33 (d, J=13.2Hz, 2H), 2.00 1.91 (m, 2H), 1.79 1.66 (m, 3H), 1.39 1.27 (m, 3H)；MS(ESI)m/z[M+H]+: 475.22.
Embodiment 104
Adding compound 104C (169mg, 0.51mmol), dichloromethane (2ml), triethylamine (104mg, 1.03mmol) in 25ml round-bottomed flask, stirring is lower adds compound 104D (100mg, 0.51mmol).Stirring overnight under room temperature, it is complete that TLC detects raw material reaction.Dilute with water after reaction system is concentrated, extraction into ethyl acetate, merge organic layer, anhydrous sodium sulfate dries, through silica gel column chromatography after concentration, with dichloromethane: methanol (30:1) is for eluant, obtain colorless oil as product 104 (151mg, productivity: 60.8%).1HNMR (400MHz, CDCl3) δ 7.34 (s, 1H), 7.09 7.00 (m, 2H), 6.93 (s, 1H), 6.89 6.78 (m, 4H), 3.91 (d, J=5.6Hz, 6H), 3.61 (s, 3H), 3.51 (s, 2H), 3.22 3.11 (m, 4H), 2.69 2.53 (m, 4H), 2.46 (s, 3H)；MS(ESI)m/z[M+H]+: 487.03.
Embodiment 105
Preparation scheme with reference to embodiment 103 prepares compound 105.MS(ESI)m/z[M+H]+: 461.61.
Embodiment 106
50mL round-bottomed flask adds compound 106A (500mg, 2.67mmol), sequentially add dichloromethane (12mL), compound 106B (818mg, 2.67mmol), 2h is stirred at room temperature, adds sodium triacetoxy borohydride (849mg, 4.00mmol), stir overnight in 25 DEG C of oil baths.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains colourless paste 106C (502mg, productivity 39.4%).
50mL round-bottomed flask adds compound 106C (205mg, 0.429mmol), sequentially adds azido trimethyl silicane (564 μ L, 4.29mmol), TBAF (1MTHF solution) (515 μ L, 0.515mmol), stirs 12h in 100 DEG C of oil baths.Reaction system adds water, stirring, precipitates out off-white color solid, sucking filtration, washing, collect filter cake, being dissolved in methylene chloride-methanol mixed solvent, sucking filtration, the filtrate obtained is spin-dried for, residue adds ethanol, sucking filtration, washing with alcohol, collect filter cake, obtain compound as white solid 106 (128mg, productivity 57.3%) after drying.1HNMR(400MHz,DMSO-d6) δ 7.90 7.82 (m, 2H), 7.73 7.65 (m, 2H), 7.50 7.41 (m, 2H), 7.14 7.06 (m, 2H), 7.04 (d, J=8.2Hz, 1H), 7.00 (d, J=1.3Hz, 1H), 6.91 (dd, J=8.2,1.4Hz, 1H), 3.52 (s, 1H), 3.49 (s, 2H), 3.32 3.26 (m, 4H), 3.16 (s, 3H), 2.55 2.50 (m, 4H), 2.41 (s, 3H)；MS(ESI)m/z[M+Na]+: 542.90.
Embodiment 107
100mL round-bottomed flask adds compound 107A (2g, 9.04mmol), it is dissolved in dichloromethane (50mL), add compound 107B (1.5g, 9.04mmol), 2h is stirred at room temperature, adds sodium triacetoxy borohydride (2.87g, 13.6mmol), stir overnight under room temperature.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains yellow solid 107C (1.73g, productivity 51.5%).
100mL round-bottomed flask is sequentially added into 107C (1.73g, 4.66mmol), palladium carbon (525mg), ethanol (20mL), oxolane (5mL), room temperature under an atmosphere of hydrogen, atmospheric agitation reaction 6h.Reactant liquor sucking filtration, washing with alcohol, merging filtrate, it is spin-dried for, obtains light brown paste 107D.It is directly used in next step reaction.
100mL round-bottomed flask is sequentially added into 107D, isopropanol (20mL), water (2mL), stirring and dissolving, sequentially adds acetaldehyde (40% aqueous solution) (471 μ L, 4.66mmol), palladium carbon (496mg), ammonium formate (2.94g, 46.6mmol), is stirred at room temperature reaction overnight.Reactant liquor sucking filtration, washing with alcohol, merging filtrate, it is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merges organic facies, water washing, anhydrous sodium sulfate dries, and obtains light brown paste 107E after being spin-dried for.It is directly used in next step reaction.
50mL round-bottomed flask adds compound 107E, is dissolved in dichloromethane (20mL), add compound 107F (499 μ L, 3.75mmol), triethylamine (523 μ L, 3.75mmol), under room temperature, stir 2h.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains compound as white solid 107 (579mg, productivity 23.6%).1HNMR(400MHz,CDCl3null)δ7.47–7.39(m,2H),7.36–7.31(m,1H),7.29–7.22(m,1H),6.93–6.76(m,7H),4.06(d,J=13.0Hz,1H),3.90(s,3H),3.88(s,3H),3.56(q,J=7.1Hz,2H),3.47–3.32(m,2H),3.12(d,J=13.0Hz,1H),2.93–2.78(m,2H),2.73(dd,J=11.5,9.3Hz,1H),2.64–2.54(m,1H),2.24(td,J=11.1,3.0Hz,1H),1.23(d,J=6.1Hz,3H),1.07(t,J=7.1Hz,3H)；MS(ESI)m/z[M+Na]+: 550.13.
Embodiment 108
100mL round-bottomed flask adds compound 108A (1.67g, 7.55mmol), it is dissolved in dichloromethane (50mL), add compound 108B (1.25g, 7.55mmol), 2h is stirred at room temperature, adds sodium triacetoxy borohydride (2.40g, 11.3mmol), stir overnight under room temperature.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains yellow solid 108C (1.60g, productivity 57.1%).
100mL round-bottomed flask is sequentially added into 108C (1.60g, 4.31mmol), palladium carbon (450mg), ethanol (20mL), oxolane (5mL), room temperature under an atmosphere of hydrogen, atmospheric agitation reaction 6h.Reactant liquor sucking filtration, washing with alcohol, merging filtrate, it is spin-dried for, obtains light brown paste 108D.It is directly used in next step reaction.
100mL round-bottomed flask is sequentially added into 108D, isopropanol (20mL), water (2mL), stirring and dissolving, sequentially adds acetaldehyde (40% aqueous solution) (435 μ L, 4.31mmol), palladium carbon (459mg), ammonium formate (2.72g, 43.1mmol), is stirred at room temperature reaction overnight.Reactant liquor sucking filtration, washing with alcohol, merging filtrate, it is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merges organic facies, water washing, anhydrous sodium sulfate dries, and obtains light brown paste 108E after being spin-dried for.It is directly used in next step reaction.
50mL round-bottomed flask adds compound 108E, is dissolved in dichloromethane (20mL), add compound 108F (479 μ L, 3.60mmol), triethylamine (502 μ L, 3.60mmol), under room temperature, stir 2h.Reactant liquor is spin-dried for, residue adds saturated sodium bicarbonate aqueous solution, extraction into ethyl acetate, merge organic facies, water washing, anhydrous sodium sulfate dries, and the residue obtained after being spin-dried for separates purification through column chromatography (dichloromethane: methanol 200:1) and obtains compound as white solid 108 (437mg, productivity 19.2%).1HNMR(400MHz,CDCl3null)δ7.47–7.38(m,2H),7.36–7.31(m,1H),7.29–7.22(m,1H),6.93–6.76(m,7H),4.06(d,J=13.0Hz,1H),3.56(q,J=7.1Hz,2H),3.47–3.32(m,2H),3.12(d,J=13.0Hz,1H),2.92–2.78(m,2H),2.73(dd,J=11.5,9.3Hz,1H),2.65–2.53(m,1H),2.24(td,J=11.2,3.1Hz,1H),1.23(d,J=6.1Hz,3H),1.07(t,J=7.1Hz,3H)；MS(ESI)m/z[M+H]+: 528.17.
Embodiment 109
Compound 109, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 497.60.
Embodiment 110
Compound 110, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 497.23.
Embodiment 111
Compound 111, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 511.21.
Embodiment 112
Compound 112, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 511.42.
Embodiment 113
Compound 113, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 511.43.
Embodiment 114
Compound 114, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 509.72.
Embodiment 115
Compound 115, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 509.23.
Embodiment 116
Compound 116, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 509.33.
Embodiment 117
Compound 117, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 497.26.
Embodiment 118
Compound 118, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 495.60.
Embodiment 119
Compound 119, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 510.64.
Embodiment 120
Compound 120, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 510.34.
Embodiment 121
Compound 121, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 510.46.
Embodiment 122
Compound 122, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 508.21.
Embodiment 123
Compound 123, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 514.46.
Embodiment 124
Compound 124, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 508.22.
Embodiment 125
Compound 125, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 501.60.
Embodiment 126
Compound 126 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR (400MHz, DMSO-d6) δ 11.43 (s1H), 10.16 (s, 1H), 7.63 7.55 (m, 1H), 7.55 7.41 (m, 4H), 7.09 (dd, J=8.2,1.7Hz, 1H), 7.02 6.93 (m, 3H), 6.91 6.83 (m, 2H), 4.27 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73 3.63 (m, 2H), 3.35 3.24 (m, 2H), 3.23 2.98 (m, 4H)；MS(ESI)m/z[M+H]+: 486.62.
Embodiment 127
Compound 127, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 483.23.
Embodiment 128
Compound 128, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 487.62.
Embodiment 129
Compound 129, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 486.23.
Embodiment 130
Compound 130, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 482.61.
Embodiment 131
Compound 131, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 482.32.
Embodiment 132
Compound 132, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 486.31.
Embodiment 133
Compound 133, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 483.60.
Embodiment 134
Compound 134, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 482.63.
Embodiment 135
Compound 135, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 486.72.
Embodiment 136
Compound 136, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 493.21.
Embodiment 137
Compound 137, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 517.24.
Embodiment 138
Compound 138, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 477.26.
Embodiment 139
Compound 139 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.81 7.76 (m, 2H), 7.74 7.68 (m, 2H), 7.46 (dd, J=3.6,0.9Hz, 1H), 7.42 (dd, J=5.1,0.8Hz, 1H), 7.14 (dd, J=5.0,3.7Hz, 1H), 6.96 6.73 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.50 (s, 2H), 3.21 3.10 (m, 4H), 2.64 2.50 (m, 4H) .MS (ESI) m/z [M+H]+: 550.90.
Embodiment 140
Compound 140 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3)δ8.76–8.70(m,2H),7.96–7.90(m,2H),7.79–7.72(m,2H),7.55–7.49(m,2H),6.94–6.74(m,7H),3.88(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.07(m,4H),2.62–2.49(m,4H).MS(ESI)m/z[M+H]+: 546.01；MS(ESI)m/z[M+H]+: 546.23.
Embodiment 141
Compound 141 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.82 7.73 (m, 4H), 7.56 7.54 (m, 1H), 6.90 (d, J=1.1Hz, 1H), 6.88 6.79 (m, 5H), 6.79 6.72 (m, 2H), 6.54 (dd, J=3.4,1.8Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 3.18 3.09 (m, 4H), 2.60 2.51 (m, 4H) .MS (ESI) m/z [M+H]+: 534.96.
Embodiment 142
Compound 142 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3)δ7.91–7.84(m,2H),7.72–7.65(m,2H),7.49–7.37(m,2H),7.30–7.23(m,1H),7.23–7.16(m,1H),6.94–6.74(m,7H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.10(m,4H),2.62–2.49(m,4H).MS(ESI)m/z[M+H]+: 563.01.
Embodiment 143
Compound 143 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.89 7.83 (m, 2H), 7.74 7.67 (m, 2H), 7.40 (t, J=8.0Hz, 1H), 7.22 7.17 (m, 1H), 7.15 7.11 (m, 1H), 7.00 6.95 (m, 1H), 6.93 6.73 (m, 7H), 3.89 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.19 3.09 (m, 4H), 2.61 2.49 (m, 4H) .MS (ESI) m/z [M+H]+: 575.05.
Embodiment 144
Compound 144 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.89 7.83 (m, 2H), 7.74 7.69 (m, 2H), 7.65 (d, J=4.0Hz, 1H), 7.41 (d, J=4.0Hz, 1H), 6.93 6.72 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.18 3.11 (m, 4H), 2.61 2.51 (m, 4H) .MS (ESI) m/z [M+H]+: 575.85.
Embodiment 145
Compound 145, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 500.37.
Embodiment 146
Compound 146 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.47 7.38 (m, 2H), 7.36 7.31 (m, 1H), 7.28 7.22 (m, 1H), 6.92 (d, J=1.6Hz, 1H), 6.90 6.77 (m, 6H), 3.89 (s, 3H), 3.88 (s, 3H), 3.56 (q, J=7.1Hz, 2H), 3.50 (s, 2H), 3.25 3.16 (m, 4H), 2.64 2.52 (m, 4H), 1.07 (t, J=7.1Hz, 3H) .MS (ESI) m/z [M+H]+: 514.08.
Embodiment 147
Compound 147, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 529.11.
Embodiment 148
Compound 16E is prepared with reference to embodiment 16, compound 16E300mg (0.916mmol) is dissolved in 15mL dichloromethane, it is subsequently adding triethylamine 140 μ L (1.01mmol), stir under room temperature, it is dividedly in some parts compound 148B223mg (1.01mmol) again, finish, react overnight under room temperature.Reactant liquor has solid to precipitate out, sucking filtration, the filter cake obtained obtains white solid through silica gel column chromatography (dichloromethane: methanol 10:1) purification, this solid 25mL dichloromethane disperses, and 1h, sucking filtration are stirred at room temperature, washed with dichloromethane, collect filter cake, obtain compound as white solid 148 (28mg, productivity 6.0%) after drying.1HNMR(400MHz,DMSO-d6)δ9.96(s,1H),8.09–8.02(m,2H),7.82–7.74(m,2H),6.97–6.75(m,7H),3.73(s,6H),3.47(s,2H),3.09–3.02(m,4H),2.52–2.45(m,4H).MS(ESI)m/z[M+H]+,512.2。
Embodiment 149
Compound 16E is prepared with reference to embodiment 16, compound 16E300mg (0.916mmol) is dissolved in 15mL dichloromethane, it is subsequently adding triethylamine 140 μ L (1.01mmol), stir under room temperature, it is dividedly in some parts compound 149B223mg (1.01mmol) again, finish, react overnight under room temperature.Reactant liquor has solid to precipitate out, sucking filtration, and the filter cake obtained obtains white solid through silica gel column chromatography (dichloromethane: methanol 10:1) purification, this solid 25mL dichloromethane disperses, and 1h, sucking filtration are stirred at room temperature, washed with dichloromethane, collects filter cake, and this solid 30mL methanol eddy dissolves, place and precipitate out solid, sucking filtration, methanol washs, and collects filter cake, obtain compound as white solid 149 (48mg, productivity 10.2%) after drying.1HNMR(400MHz,DMSO-d6) δ 9.94 (s, 1H), 8.28 8.23 (m, 1H), 8.15 8.09 (m, 1H), 7.90 7.82 (m, 1H), 7.66 (t, J=7.8Hz, 1H), 6.98 6.74 (m, 7H), 3.73 (s, 6H), 3.47 (s, 2H), 3.09 3.00 (m, 4H), 2.52 2.43 (m, 4H) .MS (ESI) m/z [M+H]+,512.1。
Embodiment 150
Compound 150, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 540.22.
Embodiment 151
5-formoxyl salicylic acid 151A (1.66g, 10.0mM) is dissolved in DMF (30mL), adds potassium carbonate (4.14g, 30mM) and iodomethane (2.18mL, 35mM), ambient temperature overnight.TLC monitoring reacts completely, and adds water and extraction into ethyl acetate, merges organic layer, uses saturated common salt water washing, and anhydrous sodium sulfate dries, and concentrate drying obtains product 151B.
Above product 151B is dissolved in dichloromethane (150mL), add 1-(4-nitrobenzophenone) piperazine (1.9g, 9.2mM), instill acetic acid (500 μ L), after stirring half an hour, it is dividedly in some parts sodium triacetoxy borohydride (3.18g, 15mM), stirred overnight at room temperature.TLC monitoring reacts completely, and adds saturated sodium bicarbonate aqueous solution, dichloromethane extraction, merges organic layer, and respectively with 5% aqueous citric acid solution, water and saturated common salt water washing, anhydrous sodium sulfate dries, and concentrate drying obtains oily product 151C.Precipitate out solid after standing 2h, pull an oar by petrol ether/ethyl acetate (2/1), filter, dry to obtain product 151C.
Being dissolved in methanol (100mL) by above product 151C, be slowly added dropwise water (25mL) solution of Lithium hydroxide monohydrate (2.1g, 50mM), be warming up to 45 DEG C under 0 DEG C of condition, stirring is overnight.TLC monitoring reacts completely, concentration, and addition water and ether extract, and with concentrated hydrochloric acid, aqueous phase pH are adjusted to 2, precipitate out solid, filter, and washs by water and ethyl acetate, dries and obtain product 151D.
In product 151D, add methanol (30mL), oxolane (30mL) and 10% palladium/carbon (150mg), react under hydrogen atmosphere.Reacting completely through TLC monitoring, kieselguhr filters, and concentrated filtrate obtains product 151E.
Compound 151E300mg (0.879mmol) is scattered in 15mL water, it is subsequently adding potassium carbonate 242mg (1.76mmol), stirs under room temperature, then be dividedly in some parts paratoluensulfonyl chloride 151F184mg (0.967mmol), finish, react overnight under room temperature.Reactant liquor 2MHCl regulates pH to 3, solid is had to precipitate out, sucking filtration, water washing, drain, wash with mixed solvent (dichloromethane: methanol 5:1), collect organic solvent washing liquid, it is spin-dried for, white solid is obtained through silica gel column chromatography (dichloromethane: methanol 10:1) purification, this solid 15mL dichloromethane disperses, 1h is stirred at room temperature, sucking filtration, washed with dichloromethane, collect filter cake, this solid moisture dissipates, dropping saturated sodium carbonate dissolves, drip dilute hydrochloric acid again and regulate pH to 6, precipitate out solid, sucking filtration, water washing, collect filter cake, obtain compound as white solid 151 (69mg after drying, productivity 15.8%).1HNMR(400MHz,DMSO-d6)δ9.75(s,1H),7.61–7.53(m,3H),7.47–7.39(m,1H),7.36–7.28(m,2H),7.11–7.05(m,1H),6.93–6.85(m,2H),6.82–6.73(m,2H),3.80(s,3H),3.47(s,2H),3.10–2.95(m,4H),2.52–2.40(m,4H),2.33(s,3H).MS(ESI)m/z[M+H]+,496.2。
Embodiment 152
Compound 152, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 496.25.
Embodiment 153
Compound 153, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 526.26.
Embodiment 154
Compound 154, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 558.12.
Embodiment 155
151E is prepared according to embodiment 151.Compound 151E300mg (0.879mmol) is scattered in 15mL water, it is subsequently adding potassium carbonate 242mg (1.76mmol), stirs under room temperature, then be dividedly in some parts dansyl chloride 155B283mg (1.05mmol), finish, react overnight under room temperature.Reactant liquor 2MHCl regulates pH to 3, has solid to precipitate out, sucking filtration, water washing, drains, and washs with mixed solvent (dichloromethane: methanol 5:1), collect organic solvent washing liquid, be spin-dried for, obtain white solid through silica gel column chromatography (dichloromethane: methanol 10:1) purification, this solid 15mL dichloromethane disperses, and 1h, sucking filtration are stirred at room temperature, washed with dichloromethane, collect filter cake, obtain compound as white solid 155 (10mg, productivity 2.0%) after drying.1HNMR(400MHz,DMSO-d6)δ10.18(s,1H),8.46–8.34(m,2H),8.12–8.05(m,1H),7.67–7.52(m,3H),7.44–7.37(m,1H),7.29–7.23(m,1H),7.10–7.03(m,1H),6.86–6.78(m,2H),6.75–6.66(m,2H),3.79(s,3H),3.42(s,2H),3.01–2.91(m,4H),2.81(s,6H),2.45–2.35(m,4H).MS(ESI)m/z[M+H]+,575.1。
Embodiment 156
151E is prepared according to embodiment 151.Compound 151E300mg (0.879mmol) is scattered in 15mL water, it is subsequently adding potassium carbonate 242mg (1.76mmol), stirs under room temperature, then be dividedly in some parts 2-naphthalene sulfonyl chloride 156B239mg (1.05mmol), finish, react overnight under room temperature.Reactant liquor 2MHCl regulates pH to 3, has solid to precipitate out, sucking filtration, water washing, drains, and washs with mixed solvent (dichloromethane: methanol 5:1), collect organic solvent washing liquid, be spin-dried for, obtain white solid through silica gel column chromatography (dichloromethane: methanol 10:1) purification, this solid 15mL dichloromethane disperses, and 1h, sucking filtration are stirred at room temperature, washed with dichloromethane, collect filter cake, obtain compound as white solid 156 (113mg, productivity 24.2%) after drying.1HNMR(400MHz,DMSO-d6) δ 9.97 (s, 1H), 8.32 (s, 1H), 8.13 8.05 (m, 2H), 8.01 (d, J=8.0Hz, 1H), 7.82 7.37 (m, 5H), 7.17 7.05 (m, 1H), 6.97 6.88 (m, 2H), 6.81 6.71 (m, 2H), 3.81 (s, 3H), 3.36 (s, 2H), 3.10 2.95 (m, 4H), 2.52 2.37 (m, 4H) .MS (ESI) m/z [M+H]+,532.2。
Embodiment 157
1-(4-nitrobenzophenone) piperazine 157A (1.036g, 5mM) is dissolved in methanol (10mL), under 0 DEG C of condition, instills methanol (5mL) solution of Bis(tert-butoxycarbonyl)oxide (1.24mL, 5.4mM) slowly.Monitoring through TLC and react completely, solvent is removed in concentration, pulls an oar by petrol ether/ethyl acetate (20/1), filters, and dries to obtain product 157B.
Above product 157B is dissolved in methanol (15mL), adds 10% palladium/carbon (150mg), react overnight under hydrogen atmosphere.Reacting completely through TLC monitoring, kieselguhr filters, and concentrated filtrate obtains product 157C.
Take above product 157C (720mg, 2.59mM) and be dissolved in dichloromethane (15mL), add triethylamine (542 μ L, 3.89mM) with 4-biphenyl sulfonic acid chloride (655mg, 2.59mM), react 2.5h, react completely through TLC monitoring, add 5% aqueous citric acid solution, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate dries, concentration, column chromatography (petrol ether/ethyl acetate=2/1) obtains product 157F.
Being dissolved in methanol (8mL) by above product 157F, instill 4MHCl/ methanol (8mL), react half an hour, react completely through TLC monitoring, concentration obtains product 157G.
Being dissolved in dichloromethane (8mL) by product 157G (150mg, 0.35mM), add triethylamine (146 μ L, 1.05mM) and the bromo-4 '-methoxyacetophenone of 2-(80mg, 0.35mM), stirring is overnight.TLC monitoring reacts completely, and concentration, column chromatography (methylene chloride/methanol=50/1) obtains compound 157 (71mg, productivity 37.5%).1HNMR(400MHz,CDCl3) δ 8.07 8.00 (m, 2H), 7.77 (d, J=8.5Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 7.63 7.57 (m, 2H), 7.49 (t, J=7.3Hz, 2H), 7.43 (d, 1H), 7.00 (d, J=8.9Hz, 2H), 6.96 (d, J=8.9Hz, 2H), 6.81 (d, J=8.9Hz, 2H), 6.42 (s, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 3.30 3.18 (m, 4H), 2.89 2.70 (m, 4H).
Embodiment 158
1-(4-nitrobenzophenone) piperazine 158A (1.036g, 5mM) is dissolved in methanol (10mL), under 0 DEG C of condition, instills methanol (5mL) solution of Bis(tert-butoxycarbonyl)oxide (1.24mL, 5.4mM) slowly.Monitoring through TLC and react completely, solvent is removed in concentration, pulls an oar by petrol ether/ethyl acetate (20/1), filters, and dries to obtain product 158B.
Above product 158B is dissolved in methanol (15mL), adds 10% palladium/carbon (150mg), react overnight under hydrogen atmosphere.Reacting completely through TLC monitoring, kieselguhr filters, and concentrated filtrate obtains product 158C.
Taking above product 158C (832mg, 3mM) and be dissolved in dichloromethane (20mL), add triethylamine (557 μ L, 4mM) and dansyl chloride (809mg, 3mM), reaction is overnight.Reacting completely through TLC monitoring, add 5% aqueous citric acid solution, with dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate dries, and concentration, column chromatography (petrol ether/ethyl acetate=3/1) obtains product 158D.
Being dissolved in methanol (10mL) by above product 158D, instill 4MHCl/ methanol (10mL), react half an hour, react completely through TLC monitoring, concentration obtains product 158E.
Being dissolved in dichloromethane (5mL) by product 158E (134mg, 0.30mM), add triethylamine (125 μ L, 0.9mM) and the bromo-4 '-methoxyacetophenone of 2-(69mg, 0.30mM), stirring is overnight.TLC monitoring reacts completely, and concentration, column chromatography (methylene chloride/methanol=40/1) obtains compound 158 (64mg, productivity 38.2%).1HNMR(400MHz,CDCl3null)δ8.50(d,J=8.5Hz,1H),8.35(d,J=8.6Hz,1H),8.07(dd,J=7.3,1.1Hz,1H),8.05–7.99(m,2H),7.65–7.56(m,1H),7.41(dd,J=8.5,7.4Hz,1H),7.21(d,J=7.4Hz,1H),6.95(d,J=8.9Hz,2H),6.77(d,J=9.0Hz,2H),6.66(d,J=9.0Hz,2H),6.53(s,1H),3.89(s,3H),3.82(s,2H),3.26–3.07(m,4H),2.91(s,6H),2.77–2.68(m,4H).
Embodiment 159
With reference to above embodiments embodiment and pertinent literature prepare compound 159, MS (ESI) m/z [M+H]+: 580.31.
Embodiment 160
160F (10mmol, 1.41g), 160G (15mmol, 1.5g) and triethylamine (15mmol, 2.08ml) are added in 50ml round-bottomed flask, dissolves with DMSO (15ml), at 100 DEG C, react 10h.To be cooled to room temperature, add water 100ml, has solid to precipitate out, and then adds 50ml ethyl acetate and continues stirring 10min, sucking filtration, washes with water 3 times, obtain compound 160H, yellow solid 1.67g, productivity 75.6%.1HNMR (400MHz, DMSO) δ 8.30 (s, 1H), 8.08 (d, J=9.4Hz, 2H), 6.97 (d, J=9.5Hz, 2H), 3.98 (s, 2H), 3.66-3.63 (m, 2H), 3.37-3.33 (m, 2H)
Veratraldehyde 160A (499mg, 3.0mM) is dissolved in methanol (10mL), it is dividedly in some parts sodium borohydride (170mg, 4.5mM), being stirred at room temperature 15 minutes, TLC monitoring reacts completely, add saturated aqueous ammonium chloride cancellation, concentration removes methanol, adds dichloromethane extraction, uses saturated common salt water washing, anhydrous sodium sulfate dries, and concentrate drying obtains product 160B.
Above product 160B is dissolved in ether (10mL), under 0 DEG C of condition, is slowly added dropwise ether (2mL) solution of tribromide squama (282 μ L, 3mM), stirred overnight at room temperature.TLC monitoring reacts completely, add saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, merge organic layer, respectively with water and saturated common salt water washing, anhydrous sodium sulfate dries, concentration, column chromatography (petrol ether/ethyl acetate=5/1) obtains product 160C (578mg, yield 83.3%).
nullBy 4-(4-nitrobenzophenone) piperazine-2-ketone (221mg,1.0mM) it is dissolved in oxolane (25mL)，Add potassium tert-butoxide (112mg,1.0mM)，Rise to 50 DEG C to stir 15 minutes，Add oxolane (5mL) solution of above-mentioned products obtained therefrom 160C，Stirring 3h is continued in 50 DEG C，Add water and dichloromethane extraction，Merge organic layer，Respectively with water and saturated common salt water washing，Anhydrous sodium sulfate dries，Concentration，Add a small amount of dichloromethane to dissolve，Under agitation it is slowly dropped into petrol ether/ethyl acetate (1/1)，Precipitate out solid，Eliminate unreacted 4-(4-nitrobenzophenone) piperazine 2-ketone，Filtrate concentrates，Repeat this operation and can precipitate out product 160D，Filter，Washing，Dry and obtain product 160D (105mg,Yield 28.3%).
In product 160D, add methanol (30mL) and 10% palladium/carbon (20mg), react under hydrogen atmosphere.Reacting completely through TLC monitoring, kieselguhr filters, and concentrated filtrate obtains product 160E.
Above product 160E is dissolved in dichloromethane (15mL), adds triethylamine (58 μ L, 0.42mM) and 4-biphenyl sulfonic acid chloride (71mg, 0.28mM), reaction 2.5h, reacts completely through TLC monitoring, adds 5% aqueous citric acid solution, with dichloromethane extraction, respectively with water and saturated common salt water washing, anhydrous sodium sulfate dries, concentration, column chromatography (methylene chloride/methanol=60/1) obtains product 160 (36mg, yield 23.1%).1HNMR(400MHz,CDCl3) δ 7.78 (d, J=8.3Hz, 2H), 7.64 (d, J=8.3Hz, 2H), 7.59 (d, J=7.2Hz, 2H), 7.48 (t, J=7.3Hz, 2H), 7.45 7.38 (m, 1H), 7.04 (d, J=8.8Hz, 2H), 6.91 6.79 (m, 4H), 6.74 (d, J=8.8Hz, 2H), 4.61 (s, 2H), 3.95 3.89 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.44 3.31 (m, 4H).
Embodiment 161
Compound 161 is prepared with reference to above embodiments 160 embodiment and pertinent literature,1HNMR (400MHz, MeOD) δ 7.87 (s, 1H), 7.81 7.70 (m, 5H), 7.65 (d, J=7.3Hz, 2H), 7.48 (t, J=7.4Hz, 2H), 7.40 (dd, J=13.2,5.8Hz, 3H), 7.35 7.30 (m, 2H), 7.03 (d, J=9.0Hz, 2H), 6.85 (d, J=8.9Hz, 2H), 4.66 (s, 2H), 3.92 3.85 (m, 2H), 3.41 (d, J=5.2Hz, 2H), 2.04 (m, 2H), MS (ESI) m/z [M+H]+: 498.23.
Embodiment 162
Compound 162, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 562.34.
Embodiment 163
Compound 163, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 554.34.
Embodiment 164
Compound 164, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 572.16.
Embodiment 165
Compound 165, MS (ESI) m/z [M+H] is prepared with reference to above embodiments embodiment and pertinent literature+: 504.23.
Embodiment 166
Compound 166 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,DMSO-d6) δ 11.47 (s, 1H), 10.27 (s, 1H), 7.98 7.93 (m, 2H), 7.92 7.87 (m, 2H), 7.44 (d, J=1.9Hz, 1H), 7.09 (dd, J=8.2,1.9Hz, 1H), 7.02 6.93 (m, 3H), 6.90 6.83 (m, 2H), 4.27 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.73 3.64 (m, 2H), 3.33 3.24 (m, 2H), 3.21 3.11 (m, 2H), 3.11 2.96 (m, 2H)；MS(ESI)m/z[M+H]+: 536.20.
Embodiment 167
Compound 167 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.58 7.50 (m, 2H), 7.03 6.96 (m, 2H), 6.93 (d, J=1.4Hz, 1H), 6.90 6.74 (m, 6H), 6.34 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.37 3.27 (m, 4H), 2.63 2.51 (m, 4H) .MS (ESI) m/z [M+H]+: 498.14.
Embodiment 168
Compound 168 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3)δ7.86–7.83(m,1H),7.82–7.76(m,2H),7.62–7.56(m,2H),7.55–7.51(m,1H),6.93–6.71(m,8H),3.89(s,3H),3.87(s,3H),3.49(s,2H),3.21–3.08(m,4H),2.64–2.48(m,4H).MS(ESI)m/z[M+H]+: 535.00.
Embodiment 169
Compound 169 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 7.85 7.78 (m, 2H), 7.74 7.67 (m, 2H), 7.62 (dd, J=2.9,1.4Hz, 1H), 7.48 7.40 (m, 2H), 6.94 6.70 (m, 7H), 3.89 (s, 3H), 3.87 (s, 3H), 3.49 (s, 2H), 3.20 3.08 (m, 4H), 2.63 2.49 (m, 4H) .MS (ESI) m/z [M+H]+: 550.95.
Embodiment 170
Compound 170 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3)δ8.77(s,2H),7.94–7.89(m,2H),7.69–7.63(m,2H),6.93–6.74(m,7H),4.09(s,3H),3.88(s,3H),3.87(s,3H),3.48(s,2H),3.20–3.10(m,4H),2.61–2.49(m,4H).MS(ESI)m/z[M+H]+: 577.05.
Embodiment 171
Compound 171 is prepared with reference to above embodiments embodiment and pertinent literature,1HNMR(400MHz,CDCl3) δ 8.01 7.95 (m, 2H), 6.90 (d, J=1.4Hz, 1H), 6.88 6.79 (m, 4H), 6.60 (s, 1H), 3.88 (s, 6H), 3.49 (s, 2H), 3.38 3.27 (m, 4H), 2.61 2.52 (m, 4H), 2.34 (s, 6H) .MS (ESI) m/z [M+H]+: 497.91.
Reference compound
Reference literature WO2010075469 prepares following compounds, and the spectroscopy data of following compound is consistent with document:
Reference literature WO2014150395 prepares following compounds, and the spectroscopy data of following compound is consistent with document:
Part of compounds biological test result of the present invention
One, the fluorescent quantitative PCR experiment detection medicine impact on hepatocyte PCSK9 gene expression dose
This experiment purpose is the reflection compound inhibitory action to PCSK9 gene expression, and compound is more strong to the inhibitory action of PCSK9 gene expression, it was shown that the potential fat-reducing effect of compound is more strong.
The detection medicine effect to HepG2 cell PCSK9mRNA:
By HepG2 cell (ATCC), by every hole 7 × 105The density of cells/well is seeded to 6 orifice plates, 37 DEG C, 5%CO2Overnight incubation.Next day, change liquid and add medicine to be measured and positive drug and process 24 hours.Extracting total serum IgE with Trizol reagent (Invitrogen), RNase-FreeDNase (Promega) processes.Every part of sample takes 1ugRNA, becomes cDNA as the template of real-time fluorescence quantitative PCR with M-MLV reverse transcriptase (Promega) reverse transcription.Use the PCSK9 quantification PCR primer through verifying, β-Actin quantification PCR primer as the primer of PCSK9 and reference gene β-Actin.The quantitative PCR reaction system of each sample is prepared with template, primer, PowerSYBRGreenPCRMasterMix (Invitrogen), quantitative PCR apparatus CFX96Real-TimePCRDetectionSystem (Bio-Rad) carries out real-time fluorescence quantitative PCR reaction by PCR instrument device description requirement, it is thus achieved that expression data.Δ Δ CT method is adopted to process expression data, with β-Actin for internal reference, the PCSK9 expression of blank is set as 1, try to achieve PCSK9 in all the other samples and, relative to the relative expression quantity (multiple relative to comparison) of comparison, assess the medicine impact on hepatocyte PCSK9 gene expression dose with this.
Experiments show that: the compounds of this invention, for instance: 1,5,9,10,11,12,13,14,16,17,21,22,25,27,28,29,32,33,34,38,39,41,42,43,44,46,47,50,51,52,54,55,56,57,58 etc., it is possible to PCSK9mRNA is expressed and plays strong inhibitory action.
Two, LDL uptake ratio test experiments:
The purpose of this experiment is the reflection compound effect to reducing LDL on a cellular level.LDL level crosses high energy atherogenicity.This experiment directly detects the ability of hepatocyte picked-up LDL from cellular level, can directly reflect the lipid-lowering effect of compound.
LDL uptake ratio cell model:
Surface of hepatocytes expresses ldl receptor, has the ability of picked-up LDL.Add the LDL (Dil-LDL) of fluorescent material Dil labelling in the medium, under fluorescence microscope, HepG2 hepatoma carcinoma cell be can be observed Dil-LDL is absorbed in cell.Medicine can make the amount of surface of hepatocytes ldl receptor increase thus strengthening the hepatocyte picked-up ability to LDL, therefore can be used on the fluorescence intensity that basis of microscopic observation arrives and evaluates sample hepatocyte absorbs the impact of LDL ability.
Cellar culture HepG2 cell (ATCC), is seeded to 96 orifice plates by the density of 2.5 × 104 cells in every hole, 37 DEG C, 5%CO2Overnight incubation.Next day, abandon supernatant, add sample and positive drug processes 20 hours.Abandoning supernatant, every hole adds the fresh culture of the epipolic Dil-LDL containing 2 μ g/ml (Invitrogen), at 37 DEG C, and 5%CO2Continue under condition to hatch 4 hours.Abandon supernatant, with PBS washed cell 2 times, change fresh culture, under fluorescence microscope (LeicaDMILLEDMicrosystems), observe the fluorescence intensity of every porocyte.To be not added with normal cell that sample and Dil-LDL process as negative control.Evaluate sample by the fluorescence intensity examined under a microscope and hepatocyte is absorbed the impact of LDL ability, and in addition classification, it is simple to compare.Stage division is as follows:
-represent compared with normal cell controls, without the fluorescence intensity increased；
+ represent compared with normal cell controls, the fluorescence intensity slightly increased；
++ represent compared with normal cell controls, the fluorescence intensity of medium increase；
+++ represent compared with normal cell controls, the fluorescence intensity strongly increased；
++++represent compared with normal cell controls, the fluorescence intensity strongly increased.
Test result indicate that: the compounds of this invention can strengthen the hepatocyte picked-up ability to LDL significantly.With compound C1 representative in document WO2010075469 and document WO2014150395, C2, C3, C4, C5 (structural formula sees above) compares, the hepatocyte that relatively low concentration the compounds of this invention processes is used to show the notable ability absorbing LDL, and the hepatocyte that reference compound processed at low concentration, to LDL almost without picked-up ability.Illustrate that the activity of the compounds of this invention increase hepatocyte picked-up LDL is significantly stronger than reference compound C1, C2, C3, C4, C5.
Three, the compound dual activation test experimental result to ERK and AMPK signal pathway:
With the compounds of this invention, HepG2 cell is processed, and detect the activation of ERK and AMPK.
Result shows: than undressed compared with control cells, dramatically increases at phosphorylated in the cell of compound treatment and activation ERK and AMPK.Including compound 5,8,9,14,16,21,22,25,27,28,29,31,32,33,34,38,39,41,42,43,44,46,50,51,52,54,55,56,57,59 etc..
Further, adopting the insulin resistant Mice model of obesity of High fat diet induction, the compounds of this invention has blood sugar lowering and reduces the effect of body weight, has and is obviously improved carbohydrate tolerance and insulin resistant, strengthens the feature of insulin sensitivity.
On the other hand, existing Research Literature shows: the activation of AMPK can suppress the downstream kinase of mTOR and Akt, and prompting AMPK/Akt/mTOR is probably the desirable target spot of oncotherapy.In existing Research Literature, cell experiment and zoopery are all pointed out, mTOR signal path can suppress the growth of tumor cell after suppressing, ERK and the AMPK of the compounds of this invention activation, can affecting the downstream kinase of mTOR and Akt further, prompting the compounds of this invention can be developed further into as antitumor drug.
Four, blood fat reducing experiment in SD rat model body:
Model is set up: customization fed with high SD rat, and normal group grows diet with common size Mus, gathers animal serum after 4 weeks, and Testing index changes.The rat of high lipid food induction is compared with normal rats, and in serum, LDL-C, TC equal size is increased significantly and has significant difference, it was demonstrated that high blood lipid model is successfully established.
Acute toxicity test: adopting single dose successive administration 7 days, test-compound, under the dosage of 500mg/kg, does not show apparent side effect.
Test group mediating recipe amount design: Normal group, hyperlipidemia model matched group, simvastatin group (8mg/kg), compound 31 groups (20mg/kg), compound 38 groups (20mg/kg), compound 160 groups (20mg/kg), compound 166 groups (20mg/kg).
Size of animal: often group 10.
Route of administration: oral administration gavage.
Administration frequency: once a day.
Administration time: 4 weeks.
Serum Indexes measures: after being administered 4 weeks, takes animal blood, is measured.
Measurement result induction and conclusion such as Fig. 2, Fig. 3, Fig. 4, Fig. 5.
The result of Fig. 2, Fig. 3, Fig. 4, Fig. 5 shows: the compounds of this invention 31, compound 38, compound 160, and compound 166 all can significantly reduce LDL-C and the TC of animal pattern.Fig. 4 and Fig. 5 shows, glutamate pyruvate transaminase and the glutamic oxaloacetic transaminase, GOT level of hyperlipidemia model group and simvastatin treated animal have significant rising, show abnormal liver function, but, the compounds of this invention, while showing notable internal Lipid-lowering activities, do not increase glutamate pyruvate transaminase and glutamic oxaloacetic transaminase, GOT level, compound 31, compound 38, compound 160, the glutamate pyruvate transaminase of compound 166 treated animal is consistent with normal diet treated animal with glutamic oxaloacetic transaminase, GOT level.Illustrate that the compounds of this invention is while blood fat reducing, liver is not caused damage by prompting, but simvastatin is while blood fat reducing, laboratory animal glutamate pyruvate transaminase and glutamic oxaloacetic transaminase, GOT level raise, illustrate that the animal pattern liver function taking simvastatin receives damage, also reveal that the obvious hepatotoxicity of statins.
Five, SD rat model nonalcoholic steatohepatitis experiment:
Zoologize explanation: what this experiment adopted zoologize uses animal for above-mentioned " in SD rat model body blood fat reducing experiment ", after animal serum index study completes, animal is put to death and dissects, take animal livers tissue, part formalin is fixed, partly-80 DEG C of freezen protective, carry out staining pathologic section (H&E dyeing, oil red-O dyeing) and check after being fixed for more than 48hr.Pay close attention to liver structure integrity, inflammatory cell infiltration and the fatty liver order of severity, and carry out (standards of grading: 0 grade: normal of marking；1 grade: < 20%；2 grades: 20-40%；3 grades: 40-60%；4 grades: 60-80%；5 grades: > 80%).Result is shown in following table.
Experimental animal group Empty bag degeneration Inflammation Fat Hyperemia under tunicle
Intact animal 0 0 0 0
High fat matched group 4 3 4 3 99 -->
Simvastatin group 4 3 4 2
Compound 31 groups 2 0 1 1
Compound 38 groups 1 1 1 1
Compound 160 groups 1 1 0 0
Compound 166 groups 1 0 0 1
Result shows, hyperlipidemia model group is compared with normal group, in liver, the volume of adipose cell significantly increases, Macrovesicular steatosis occurs, fatty builds up the heavy damage organizational structure of liver, causes liver vacuolar degeneration, and with massive inflammatory cells infiltrated, above phenomenon shows, nonalcoholic steatohepatitis modeling success.After animal gavage takes part of compounds of the present invention, mark from vacuolar degeneration, compound 31; compound 38, compound 160, liver structure is all had certain protective effect by compound 166; the hepar damnification caused due to adipose cell obtains certain reparation, reduces vacuolar degeneration degree；Compound 31, compound 38, compound 160, compound 166 can also significantly reduce inflammatory cell infiltration, reduces inflammation degree, and gathering and the adipose cell volume that can reduce fat increase, and liver fat degree alleviates.But, simvastatin treated animal liver anatomical, its liver structure integrity, inflammatory cell infiltration are consistent with hyperlipidemia model group with the fatty liver order of severity, and fatty liver symptom is not alleviated.Of the present inventionization compound 31, compound 38, compound 160, liver organization is all had certain protective effect by compound 166, and the compounds of this invention has the medical value for the treatment of fatty liver.
Above two experiments " in SD rat model body blood fat reducing experiment " and " experiment of SD rat model nonalcoholic steatohepatitis ", disclose the compounds of this invention and have a characteristic that
(1), the compounds of this invention show Lipid-lowering activities, without influence on liver normal function.In safe-dosaging limits, the compounds of this invention embodies the activity of internal blood fat reducing, does not cause the rising of rat transaminase level, and liver is not caused damage by prompting.But, simvastatin fat-reducing medicament, while showing Lipid-lowering activities, further such that the rising of animal transaminase level, illustrate that normal liver function receives damage, show obvious hepatotoxicity.The compounds of this invention blood fat reducing but do not affect the feature of liver function, in clinical practice, prompting the compounds of this invention has comparatively significant security advantages than statins.
(2), the compounds of this invention hyperlipidemia model Animal fat liver symptom is had potential therapeutical effect, and the lipid lowerers such as Statins do not have above curative effect.Can be seen that from " experiment of SD rat model nonalcoholic steatohepatitis ", the compounds of this invention reduces inflammation degree, gathering and the adipose cell volume that can reduce fat increase, liver fat degree alleviates, the hepar damnification that adipose cell causes obtains certain reparation, reduces vacuolar degeneration degree.But, simvastatin treated animal liver anatomical, its liver structure integrity, inflammatory cell infiltration are consistent with hyperlipidemia model group with the fatty liver order of severity, and fatty liver symptom is not alleviated.
Comprehensive above internal and Pharmacodynamics in vitro is tested, can be seen that, the compounds of this invention effect for reducing fat mechanism, it is different from existing listing fat-reducing medicament (such as: Statins, fibrates etc.), its excellent Lipid-lowering activities and its good security features, and the potential therapeutic value in fatty liver is treated, be expected to become vast cardiovascular patient and obtain the good fat-reducing medicament of new generation treating income.

Claims (17)

1. the compound of Formula V
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof；Wherein:
Y is selected from cycloalkyl, heterocyclic radical, aryl, heteroaryl, wherein,
Described cycloalkyl, heterocyclic radical, aryl, heteroaryl independently of one another by one or more selected from hydrogen, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, the substituent group of heterocyclic radical or heterocyclic radical is replaced；
R1, R2, R3, R4, R5, R6, R7, R8Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxo base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
M is nitrogen-atoms, or carbon atom；
W is nitrogen-atoms, or carbon atom；
Z is-O-,-S-,-NH-,-CR5R6-,-C (O) O-,-C (O) NR5-,-SO2O-,-SO2NR5-,-P (O) R5R6Or Z is not for any atom (chemical group namely, being connected with Z is directly connected to by chemical bond)；
Ring X is 3～10 rings, 3～10 described ring X be selected from cycloalkyl, heterocyclic radical, aryl, heteroaryl, wherein,
Described cycloalkyl, heterocyclic radical, aryl, heteroaryl independently of one another by one or more selected from hydrogen, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNR ' (C=O) NR ' R " ,-S (O)nNR ' (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, the substituent group of heterocyclic radical or heterocyclic radical is replaced；
R ' and R " independent is hydrogen or be substituted or the alkyl that is unsubstituted, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl,
At-NR ' R " ,-C (O) NR ' R " ,-OC (O) NR ' R " and ,-OS (O)nNR ' R " ,-OS (O)nNH (C=O) NR ' R " in, wherein NR ' R " can be 4 to 20 member heterocyclic ring containing nitrogen bases；
M=0,1,2；
N=1,2,3；
P=1,2,3；
Q=0,1,2,3,4,5,6；
S=0,1,2；
T=0,1,2.
2. general formula compound compound (V) according to claim 1, its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VI),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxo base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R5, R6, R7, R8, Z, M, q, t, ring X and ring Y is with claim 1.
3. general formula compound compound (V) according to claim 1, its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VII),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16Hydrogen independently, halogen, that be substituted or be unsubstituted silica-based, amino, nitro, oxygen base, sulfenyl, sulfuryl, cyano group, carbonyl, sulfonyloxy, phosphorus acyloxy, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R17, R18, R19, R20, R21It is hydrogen independently, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R5, R6, R7, R8, R ', R ", Z, ring X, M, m, n, q, t are with claim 1.
4. general formula compound compound (VII) according to claim 3, wherein, R9, R10, R11, R12, R13, R14, R15, R16It is-H independently, halogen, alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R17, R18, R19, R20, R21It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
5. general formula compound compound (V) according to claim 1, its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (VIII),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R22, R23, R24, R25, R26It is hydrogen independently, halogen ,-OH ,-NR ' R " ,-NO2,-Si (R ')3,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ,-OC (O) OR ' ,-OC (O) NR ' R " ,-S (O)mR ' ,-S (O)nNR ' R " ,-OS (O)nR ' ,-OS (O)nNR ' R ",-OS(O)nNH (C=O) NR ' R " ,-S (O)nNH (C=O) NR ' R " ,-NR ' S (O)nR " ,-NR ' S (O)nNR ' R ", alkyl that is that be substituted or that be unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical；
Ring Y, R1, R2, R3, R4, R5, R6, R7, R8, R ', R ", M, W, Z, m, n, p, q, s, t is with claim 1.
6. general formula compound compound (VIII) according to claim 5, wherein, R22, R23, R24, R25, R26It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
7. general formula compound compound (V) according to claim 1, its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, including general formula compound compound (IX),
Its stereoisomer, its tautomer, its solvate and medicinal acceptable salt thereof, wherein:
R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21With claim 3；
R22, R23, R24, R25, R26With claim 5；
R5, R6, R7, R8, M, q, t is with claim 1.
8. general formula compound compound (IX) according to claim 7, wherein, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26It is-H independently, halogen ,-OH ,-NO2,-CN ,-(CH2)0-6COOR ' ,-C (O) R ' ,-OC (O) R ' ,-C (O) NR ' R " ;-OC (O) OR ' ,-OC (O) NR ' R ", replacement or the amino that is unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl, be further selected from including:
R27Selected from phenyl, C1-6Alkyl, ring (C3-8) alkyl, thienyl, furyl, imidazole radicals, pyridine radicals, pyrimidine radicals, pyridazinyl, quinolyl, isoquinolyl, phenylacetylene base, benzyl, styryl, naphthyl, substituted-amino, morpholinyl, piperidyl, N methyl piperazine base, nafoxidine base, hexahydropyridine base, Camphora alkyl, p-methylphenyl
Wherein, C1-6Alkyl is optionally replaced by 0 to 13 substituent group,
Thienyl, furyl and imidazole radicals are optionally replaced by 0 to 3 substituent group,
Pyridine radicals is optionally replaced by 0 to 4 substituent group,
Pyrimidine radicals and pyridazinyl are optionally replaced by 0 to 3 substituent group,
Phenyl is optionally replaced by 0 to 5 substituent group,
Quinolyl and isoquinolyl naphthyl are selected for a post and are replaced by 0 to 6 substituent group,
Naphthyl is selected for a post and is replaced by 0 to 7 substituent group,
Above substituent group is selected from: hydroxyl, halogen, cyano group, and nitro is silica-based ,-COOH, carboxylic acid ester groups, the amino replaced or be unsubstituted, alkyl, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or cycloheteroalkylalkyl；
R28Selected from hydrogen, the alkyl replacing or being unsubstituted, alkoxyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical or heterocyclic radical.
9. the compound according to claim 1～8, this compound is selected from following compound, but is not limited to following compound range:
Or its medicinal acceptable salt.
10. preparing a logical compound shown in formula V, its stereoisomer, its tautomer, the method for its solvate and medicinal acceptable salt thereof described in claim 1, one of which preparation method comprises the following steps:
X1 and X2 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.X1 and X2, when certain reaction temperature, under certain alkaline reagent existent condition, obtains compound V by coupling；
Another kind of preparation method comprises the following steps:
X1 and X3 is the starting material of the program, it is possible to obtained by commercially available prod, or the method according to bibliographical information prepares.By X1 and X3 under certain reaction condition, prepare V by the reaction of reduction amination.
11. a pharmaceutical composition, its compound comprising any one in claim 1 to 9 and pharmaceutically acceptable carrier.
12. a pharmaceutical composition, described compositions includes giving the compound of any one in the claim 1 to 9 of the effective therapeutic dose of patient of needs treatment.
13. any one compound is used for the purposes reducing in the medicine of the lipid levels of patients blood plasma and/or liver in preparation in claim 1 to 9.
14. any one compound is used for treating hyperlipemia, hypercholesterolemia, hypertriglyceridemia, the disease of fatty degeneration of liver and metabolism syndrome composition or the purposes in the medicine of the patient's condition in preparation in claim 1 to 9.
15. the purposes in the PCSK9 medicine expressed is expressed and/or reduced to any one compound in preparation for increasing LDLR in claim 1 to 9.
16. any one compound is used for the purposes reducing in the medicine of LDL-cholesterol and/or plasma triglyceride in preparation in claim 1 to 9.
17. the compound according to claim 1 to 9 any one is used for treating type ii diabetes, hyperglycemia, obesity, insulin resistance or the purposes in antitumor drug in preparation.
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