CN104870429B - Benzofuran derivative, preparation method therefor, and medical application thereof - Google Patents

Benzofuran derivative, preparation method therefor, and medical application thereof Download PDF

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CN104870429B
CN104870429B CN201480003531.4A CN201480003531A CN104870429B CN 104870429 B CN104870429 B CN 104870429B CN 201480003531 A CN201480003531 A CN 201480003531A CN 104870429 B CN104870429 B CN 104870429B
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alkoxyl
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张晨
王健民
何平
雷鸣
叶飞
魏用刚
邓炳初
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Sichuan Haisco Pharmaceutical Co Ltd
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Abstract

Disclosed are a benzofuran derivative, a preparation method therefor, and a medical application thereof, specifically relating to a compound represented by general formula (I), a stereoisomer thereof, a hydrate thereof, a solvate thereof, an eutecticum thereof, a pharmaceutically accepted salt or prodrug thereof, a preparation method therefor, a pharmaceutical composition comprising the benzofuran derivative, and a medical application of the compound or pharmaceutical composition, especially as a GPR40 receptor (G-protein coupled receptor) agonist, wherein definitions of substituent groups in general formula (I) are the same as definitions in the specification (img file='DDA0000739175360000011. TIF' wi='784' he='394' /).

Description

Benzofuran derivatives, its preparation method and its in application pharmaceutically
Technical field
The present invention relates to a kind of benzofuran derivatives, its preparation method and its in application pharmaceutically, and in particular to one Plant the novel benzofuran derivatives with g protein coupled receptor 40 (GPR40) function of receptors adjustment effect or its solid is different Structure body, hydrate, solvate, eutectic, pharmaceutically acceptable salt or prodrug, its preparation method and the medicine comprising it Compositionss and its in application pharmaceutically.
Background technology
Diabetes and its complication have had a strong impact on the quality of life of people, and become cause death major reason it One, too high blood sugar level causes patient the classical symptom of polyuria, polydipsia and polyphagia, the complication of diabetes occur in diabetes Such as injury of kidney, diabetes ketoacidosiss and heart disease can threat to life.Type ii diabetes are a modal paradiabetess, main Occur in the adult phase, be mainly shown as that (i.e. body tissue can not be effectively internal for hypoinsulinism or insulin resistant Property insulin in source is made a response), the factors such as h and E can cause insulin resistant.
If diabeticss are unable to effective control blood glucose by diet and exercise, need to inject hormone medicine or oral Antidiabetic drug.The oral antidiabetic drug of approved listing at present includes sulfonylurea, biguanideses, thiazolidinedioneses (TZDs), α-Portugal Polyglycoside enzyme inhibitor, dextrin analog, depeptidyl peptidase inhibitors (DPP-IV), sodium glucose co-transporter 2 white 2 (SGLT-2) the class medicine such as inhibitor.However, the above antidiabetic drug has side effect, such as hypoglycemia, increased weight, cardiovascular (Vinod S.Deshmukh etc. (2013) the .International Journal of such as risk and urogenital infections Basic＆Clinical Pharmacology, 2,4-11), these side effect have further increased the burden of diabeticss, because This, needs of new generation antidiabetic drug of the exploitation with new mechanism of action.
G protein coupled receptor 40 (GPR40) be one have blood sugar lowering urinate potentiality novel targets, the high table in beta Cell of islet Reach.GPR40, also known as FAA 1 (FFAR1), is a membrane receptor for belonging to homologous g protein coupled receptor superfamily, many Plant species camber to guard.G protein coupled receptor has 7 transmembrane structures, can experience extracellular signal, and activation intracellular signal transduction leads to Road, and finally cause cell response, GPR40 can activate (Itoh Y etc. (2003) by middle long-chain free fatty acids (FFAs) .Nature, 422,173-176).FFAs is also a kind of important signaling molecule in addition to originating as energy, can promote islets of langerhans Element secretion, what the function was mainly realized by GPR40.After FFAs and GPR40 interactions, can be by beta Cell of islet PLC or L-type Ca2+Channel signal path improves Ca2+Flow, and then cause cell response (Fujiwara etc. (2005) .Am J Physiol Endocrinol Metab, 289, E670-E677).Research shows, in animal model, exciting GPR40 can be effective Reduce blood glucose；In clinical trial, patient's short-term and life-time service GPR40 agonist are treated and can promote glucose induction Insulin secretion, and glucose tolerance (K Nagasumi etc. (2009) .Diabetes, 58,1067-1076) can be improved, and by Can just promote insulin secretion only in the case of high-level blood glucose in GPR40, therefore it is low to produce hypoglycemic risk.
Fasiglifam hemihydrate (TAK-875) are to have been enter into three phases clinic at present and be proved to effective GPR40 agonist.Research shows：In diabetes animal model, fasiglifam hemihydrate (TAK-875) can promote Insulin secretion and can effective control blood glucose, and will not then promote insulin secretion (Tsujihata Y etc. in normal rat (2010) .Diabetes, 59, A165)；In clinical trial, fasiglifam hemihydrate (TAK-875) also show Obvious hypoglycemic effect, while with relatively low risk of hypoglycemia (T.Araki etc. (2012) .Diabetes, Obesity and Metabolism14,271-278).Some other GPR40 agonist is also developed in succession, such as JTT-851, LY-2881835.
In sum, GPR40 is the oral antidiabetic drug novel targets of a safe and feasible, and the exploitation of GPR40 agonist has Highly important researching value and application prospect.At present some are disclosed in succession with regard to the related Research Literature of GPR40 agonist.
(1) describe can be used as the prevention of insulin secretion stimulators and diabetes and/or curative for US2006258722 GPR40 receptor modulators, its structural formula is as follows：
Wherein, the cyclic group of the optionally substituted bases of Ar, the cyclic group of the optionally substituted bases of A, and not by thiazole, oxazoles, miaow Azoles and pyrazoles are replaced, and Xa and Xb is each independently selected from key or the chain comprising 1-5 atom, and Xc is selected from O, S, SO or SO2, Xd choosings From key, CH or CH2, D is selected from phenyl ring, thiophene or thiazole, and B is selected from 5 to 7 yuan of ring, R1Selected from hydroxyl.It is not considered as have in this patent Body description is the part of the present invention.
(2) describe can be used as the prevention of insulin secretion stimulators and diabetes and/or curative for CN101616913 The fused ring compound of GPR40 function of receptors adjustment effects, its structural formula is as follows：
Wherein, R1Selected from-SO2-R6, R6Selected from C1-6Alkyl or optionally substituted 1,1- dioxotetrahydros thiapyran base, X Selected from key or bivalent hydrocarbon radical；R2And R3Selected from H, halogen atom, substituted alkyl or substituted hydroxyl；R4And R5Selected from by hydroxyl The C that base replaces1-6Alkyl；A is selected from phenyl ring, and B is selected from 5 to 7 yuan of rings, and Y is selected from hydroxyl selected from key or CH2, R.In being not considered as this patent Specific descriptions are the parts of the present invention.
(3) US7786165 describes GPR40 receptor function modulators, and its structural formula is as follows：
Wherein, the cyclic group of the optionally substituted bases of Ar, and do not replaced by 4- piperidyls, the cyclic group of the optionally substituted bases of B, And not by the replacement of thiazole Huo oxazoles, V is selected from key or the chain containing 1-3 atom, and this chain is not-N=N- groups, and W is selected from key Or C1-6Alkyl, X, Xa are selected from O or CR selected from CH or N, Y6R7, R1And R1aSelected from H, halogen, C1-6Alkyl or C1-6Alkoxyl, R2Choosing From H, C1-6Alkyl or optionally substituted acyl group, R3And R4Selected from H or halogen, R5Selected from replace hydroxyl or substituted amido, no Think that the compound specifically described in US7786165 is the part of the present invention.
(4) describe can be used as the prevention of insulin secretion stimulators and diabetes and/or curative for WO2010143733 GPR40 receptor modulators, its structural formula is as follows：
Wherein, R1Selected from halogen, hydroxyl, optionally substituted C1-6Alkyl or optionally substituted C1-6Alkoxyl；R2Selected from replacement Hydroxyl, R3Selected from H, halogen or optionally substituted C1-6Alkyl, X is CH2, Y is selected from CH2, NH or O, Z be selected from selected from CH or N, A Halogen, optionally substituted amido or 4-13 yuan of rings.It is not considered as that the compound specifically described in WO2010143733 is of the invention A part.
The content of the invention
The present invention provides a class formation the novel compound as led to shown in formula (I), shows through research, the compounds of this invention Excellent drug activity is shown as GPR40 agonist.
Preferred version of the present invention, the compound or its stereoisomer, hydrate, ester, solvation shown in a kind of logical formula (I) Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R is selected from H, C1-8Alkyl or PEG, preferred H or C1-6Alkyl, more preferably H or C1-4Alkyl, further preferred H；
Ring Q is selected from 5 to 8 yuan of carbocylic radicals or heterocyclic radical, preferably 5 to 6 yuan carbocylic radicals or heterocyclic radical, more preferably 5 yuan carbocylic radicals Or heterocyclic radical, further preferably select 5 circle heterocycles bases, described heterocyclic radical to contain 1 to 4 N, O or S (=O)nAtom or group (wherein when containing multiple N, O or S (=O)nWhen atom or group, each hetero atom may be the same or different, and what is be hereinafter similar to retouches State with identical implication, repeat no more), preferably 1 to 3 N, O or S (=O)nAtom or group, more preferably 1 to 2 N, O Or S (=O)nAtom or group, described carbocylic radical or heterocyclic radical optionally further by 0 to 4 selected from F, Cl, Br, I ,= O, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynes Base-R12,-O-C (=O)-O-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-R12、-(CH2)m- S (=O)n-R12 Or-NR13R13aSubstituent group replace that (wherein when with multiple substituent groups, each substituent group may be the same or different, hereinafter Similar description has identical implication, repeats no more), preferably 0 to 3 is selected from F, Cl, Br, I ,=O, cyano group, isocyano group, ammonia Base, nitro, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-O-C (=O)-O-R12、-(CH2)m- C (=O)-O-R12、- (CH2)m- C (=O)-R12、-(CH2)m- S (=O)n-R12Or-NR13R13a, more preferably 0 to 3 selected from F, Cl, Br, I ,=O, Cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-6Alkyl or C1-6Alkoxyl, further preferred 0 to 2 selected from F, Cl, Br, I ,=O, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-4Alkyl or C1-4Alkoxyl, further preferred F, C1-3Alkane Base or C1-3Alkoxyl；
R1、R2、R3And R4Each it is individually optional from H, F, Cl, Br, I, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl or C1-8Alkoxyl, preferred H, F, Cl, Br, I, cyano group, amino, nitro, hydroxyl, C1-6Alkyl or C1-6Alkoxyl, more It is preferred that H, F, Cl, Br, I, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, further preferred H, F, Cl, cyano group, hydroxyl, C1-3Alkane Base or C1-3Alkoxyl, further preferred H, F, Cl, C1-2Alkyl or C1-2Alkoxyl, further preferred H, F or Cl, wherein described Alkyl, alkoxyl or amino are independently of one another optionally further by 0 to 4 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyanogen Base, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl- R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)m- S (=O)n- R12,-O-C (=O)-O-R12Or-NR13R13aSubstituent group replaced, preferably 0 to 3 be selected from F, Cl, Br, I ,-CH2F、- CHF2、-CF3, cyano group, nitro, hydroxyl, C1-6Alkyl or C1-6Alkoxyl, more preferably 0 to 3 selected from F, Cl, Br, I ,- CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, further preferred 0 to 2 selected from F, Cl ,- CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred F, C1-2Alkyl or C1-2Alkoxyl；
R5、R6、R7、R8、R9、R10And R11It is each independently selected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, it is cyano group, different Cyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- thiazolinyl- R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、- (CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12、-(CH2)mS (= O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbon Ring group) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 10 yuan are miscellaneous Ring group), preferred H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-6Alkyl, C1-6Alkoxyl ,-C1-6Alkyl-O- C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (=O)nR12、-(CH2)m- (3 to 6 yuan of carbocyclic rings Base) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles Base), more preferably H, F, Cl, Br ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O- C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (=O)nR12、-(CH2)m- (3 to 6 yuan of carbocyclic rings Base) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles Base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl ,- (CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkane Base-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 4 yuan Carbocylic radical) or-O- (CH2)m- (3 to 4 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4 Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred H, C1-4Alkyl, C1-4Alkoxyl or Person-C1-4Alkyl-O-C1-4Alkyl, described heterocyclic radical contains 1 to 4 N, O or S (=O)nAtom or group, preferably 1 to 3 The individual hetero atom selected from N, O or S, more preferably 1 to 2 hetero atom selected from N, O or S, described alkyl, alkoxyl, thiazolinyl, alkynes Base, carbocylic radical or heterocyclic radical are optionally further by 0 to 4 selected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, it is cyano group, different Cyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- thiazolinyl- R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、- (CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12、-(CH2)mS (= O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbon Ring group) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 10 yuan are miscellaneous Ring group) substituent group replaced, preferably 0 to 3 be selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, amino, nitro, hydroxyl Base, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13aOr-(CH2)mS (=O)nR12, more preferably 0 to 3 is selected from F、Cl、Br、I、-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 2 is selected from F、Cl、Br、-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, Cl, cyano group, hydroxyl Base, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7(=O) or=CR can be formed12R12b, it is preferably formed as (=O)；
Alternatively, R8And R9(=O) or=CR can be formed12R12b, it is preferably formed as (=O)；
Alternatively, R6With R7、R6With R8、R6With R9、R7With R8、R7With R9、R8With R9Any one group can form one 3 To 8 yuan of carbocyclic rings or 3 to 8 circle heterocycles, 3 to 6 yuan of carbocyclic rings or 3 to 6 circle heterocycles, more preferably R are preferably formed as6With R7、R8With R9's Any one group can form 3 to 6 yuan of carbocyclic rings or 3 to 6 circle heterocycles, further preferred 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, Further preferred 3 yuan of carbocyclic rings or 3 circle heterocycles, further preferred 3 yuan of carbocyclic rings, described heterocycle contains 1 to 4 N, O or S (=O)n Atom or group, preferably 1 to 3 is selected from N, O or S (=O)nAtom or group, more preferably 1 to 2 selected from N, O or S (= O)nAtom or group, described carbocyclic ring or heterocycle is optional further by 0 to 4 R12aSubstituent group replace and (wherein work as tool There are multiple R12aWhen, each R12aCan be identical or different in the scope), preferably 0 to 3 is selected from 0 to 3 R12a, more preferably 0 to 2 Individual R12a；
R12aSelected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl, C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)- NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12、-(CH2)mS (=O)nR12、-N(R12b) C (=O) NR13R13a、-N (R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbocylic radicals) ,-(CH2)m- (3 to 10 circle heterocycles Base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 10 circle heterocycles base), preferred F, Cl, Br, I ,=O, Hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl- R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)mC (=O)-NR13R13a、- (CH2)mS (=O)nR12、-(CH2)m- (3 to 6 yuan of carbocylic radicals) or-(CH2)m- (3 to 6 circle heterocycles base), more preferably F, Cl, Br, I, =O, hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynes Base-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)mC (=O)- NR13R13aOr-(CH2)mS (=O)nR12, further preferred F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, C1-4Alkane Base-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl Or C1-4Alkyl O-C1-4Alkyl, further preferred F ,=O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkane Base, preferred F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, described heterocycle contain 1 to 4 N, O or S (= O)nAtom or group, preferably 1 to 3 hetero atom selected from N, O or S, more preferably 1 to 2 hetero atom selected from N, O or S, Described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical optionally further by 0 to 4 selected from F, Cl, Br, I ,- CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O- C1-8Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12、-O-C (=O)-O-R12、-(CH2)mS (=O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (= O)OR12、-(CH2)m- (3 to 10 yuan of carbocylic radicals) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) Or-O- (CH2)mThe substituent group of-(3 to 10 circle heterocycles base) is replaced, and preferably 0 to 3 is selected from F, Cl, Br, I ,-CH2F、- CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkane Base ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m-C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O- R12Or-(CH2)mS (=O)nR12, more preferably 0 to 3 is selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-4Alkyl, C1-4 Alkoxyl, further preferred 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further It is preferred that 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 1 is selected from F、Cl、Br、-CF3、C1-3Alkyl or C1-3Alkoxyl, preferably 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alkoxyl；
Alternatively, as two R12aWhen being connected on same atom, together with the atom that can be connected with them one is formed 3 to 8 yuan of carbocyclic rings or 3 to 8 circle heterocycles, preferably 3 to 6 yuan of carbocyclic ring or 3 to 6 yuan of heterocycle, more preferably 3 to 6 yuan of heterocycle, it is described Heterocycle contain 1 to 4 N, O or S (=O)nAtom or group, preferably 1 to 3 hetero atom selected from N, O or S, more preferably 1 To 2 hetero atoms selected from N, O or S, described carbocyclic ring or heterocycle optionally further by 0 to 4 selected from F, Cl, Br, I ,- CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O- C1-8Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12、-O-C (=O)-O-R12、-(CH2)mS (=O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbocylic radicals) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or Person-O- (CH2)mThe substituent group of-(3 to 10 circle heterocycles base) is replaced, preferably 0 to 3 selected from F, Cl, Br, I, hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl or-C (=O)-C1-4Alkyl, more preferably 0 to 2 is selected from F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl Or C1-4Alkoxyl, further preferred 0 to 2 is selected from F, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F、C1-2Alkyl or C1-2Alkoxyl；
R12、R12b、R13And R13aSelected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, sulfydryl, isocyano group, amino, Nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl, 3 to 10 yuan of carbocylic radicals or 3 to 10 circle heterocycles bases, preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C1-6Alkyl, C1-6Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, more preferably H, F, Cl, Br, hydroxyl, sulfydryl, cyano group, amino, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, further It is preferred that H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, further preferred H, F, Cl, Br、C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-3Alkyl, C1-3Alkoxyl, 3 To 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, preferred C1-2Alkyl or C1-2Alkoxyl, described heterocyclic radical contains 1 to 4 N, O or S (=O)nAtom or group, preferably 1 to 3 is selected from N, O or S (=O)nAtom or group, more preferably 1 to 2 is selected from N, O Or S (=O)nAtom or group, described alkyl, alkoxyl, carbocylic radical or heterocyclic radical are optionally further selected from by 0 to 4 F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alcoxyl Base ,-C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m-C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (= O)-R12,-O-C (=O)-O-R12、-(CH2)mS (=O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N (R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbocylic radicals) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 First carbocylic radical) or-O- (CH2)mThe substituent group of-(3 to 10 circle heterocycles base) is replaced, preferably 0 to 3 selected from F, Cl, Br, I ,- CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-C1-6Alkyl-O- C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、- (CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12、-O-C (=O)-O-R12Or-(CH2)mS (=O)nR12, more preferably 0 to 3 is selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-4 Alkyl, C1-4Alkoxyl, further preferred 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alcoxyl Base, further preferred 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 F, Cl, Br ,-CF are selected to 13、C1-3Alkyl or C1-3Alkoxyl, preferably 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alcoxyl Base；
Alternatively, R12With R12b、R13With R13a3 to 8 yuan of carbocyclic rings or 3 to 8 circle heterocycles can be formed, preferably 3 to 6 yuan Carbocyclic ring or 3 to 6 yuan of heterocycle, more preferably 3 to 6 yuan of heterocycle, described heterocycle contains 1 to 4 N, O or S (=O)nAtom or Person's group, preferably 1 to 3 is selected from N, O or S (=O)nAtom or group, more preferably 1 to 2 is selected from N, O or S (=O)nAtom Or group, described carbocyclic ring or heterocycle is optional to be further selected from F, Cl, Br, I ,-CH by 0 to 42F、-CHF2、-CF3, cyanogen Base, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- alkene Base-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、- (CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12、-(CH2)mS (= O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbon Ring group) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 10 yuan are miscellaneous Ring group) substituent group replaced, preferably 0 to 3 be selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, Nitro, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynes Base-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)- NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12Or-(CH2)mS (=O)nR12, it is more excellent 0 to 3 is selected selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-4Alkyl, C1-4Alkoxyl, further preferred 0 to 3 is selected from F、Cl、Br、-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 2 selected from F, Cl, Br ,- CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 1 is selected from F, Cl, Br ,-CF3、C1-3Alkyl or Person C1-3Alkoxyl, preferably 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alkoxyl；
P be selected from 0,1,2 or 3, preferably 0,1 or 2, more preferably 0 or 1, further preferred 0；
Q be selected from 0,1,2,3 or 4, preferably 0,1 or 2, more preferably 0 or 1, further preferred 0；
T is selected from 0,1 or 2, preferably 0 or 1, more preferably 1；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
In the present invention, described " alternatively " refers to the scheme after " alternatively " and the side before " alternatively " Case is choice relation arranged side by side, rather than is the further selection in aforementioned schemes.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R1、R2、R3And R4It is each individually optional from H, F, Cl, Br, I, cyano group, amino, nitro, hydroxyl, C1-6Alkyl or C1-6 Alkoxyl, preferred H, F, Cl, Br, I, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, more preferably H, F, cyano group, hydroxyl, C1-3Alkane Base or C1-3Alkoxyl, further preferred H, C1-2Alkyl or C1-2Alkoxyl, further preferred H, wherein the alkyl, alkoxyl Or amino is independently of one another optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, nitro, hydroxyl Base, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced, and preferably 0 to 3 is selected from F, Cl, Br, I ,-CH2F、-CHF2、- CF3、C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and more preferably 0 to 2 is selected from F, Cl ,-CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred F, C1-2Alkyl or C1-2Alkoxyl, further preferred C1-2Alkoxyl；
R5、R10And R11It is each individually optional from H, F, Cl, Br, I, cyano group, hydroxyl, C1-6Alkyl, C1-6Alkoxyl or C1-6 Alkyl-O-C1-6Alkyl, preferred H, F, Cl, Br, I, C1-4Alkyl or C1-4Alkoxyl, more preferably H, F, C1-3Alkyl or C1-3Alcoxyl Base, further preferred H, F, C1-2Alkyl or C1-2Alkoxyl, further preferred H or C1-2Alkyl, the alkyl, alkoxyl are each Independently optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-6Alkyl or C1-6Alkoxyl Substituent group is replaced, and preferably 0 to 2 is selected from F, Cl, Br, I, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, more excellent 0 to 2 is selected selected from F, C1-3Alkyl or C1-3Alkoxyl, further preferred F, C1-2Alkyl or C1-2Alkoxyl, it is further excellent Select C1-2Alkoxyl.
Preferred version of the present invention, including it is the compound shown in logical formula (I) or all its stereoisomers, hydrate, ester, molten Agent compound, pharmaceutically acceptable salt or prodrug, wherein：
R1、R2、R3And R4It is each individually optional from H, F, Cl, Br, I, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, it is excellent Select H, F, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably H, C1-2Alkyl or C1-2Alkoxyl, further preferred H, its Described in alkyl or alkoxyl optionally further by 0 to 3 be selected from F, Cl, Br, I ,-CH independently of one another2F、-CHF2、-CF3、 C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl ,-CF3、C1-3Alkyl or C1-3Alcoxyl Base, more preferably F, C1-2Alkyl or C1-2Alkoxyl, further preferred C1-2Alkoxyl；
R5、R10And R11It is each individually optional from H, F, Cl, Br, I, C1-4Alkyl or C1-4Alkoxyl, preferred H, F, C1-3Alkyl Or C1-3Alkoxyl, more preferably H, F, C1-2Alkyl or C1-2Alkoxyl, further preferred H or C1-2Alkyl, the alkyl or alkane Epoxide is independently of one another optionally further by 0 to 2 selected from F, Cl, Br, I, C1-4Alkyl or C1-4The substituent group institute of alkoxyl Replace, preferably 0 to 2 is selected from F, C1-3Alkyl or C1-3Alkoxyl, more preferably F, C1-2Alkyl or C1-2Alkoxyl, further It is preferred that C1-2Alkoxyl.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R1、R5、R10And R11It is each independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl group, isopropyl, butyl, methoxy Base, ethyoxyl, propoxyl group, methoxy, methoxy ethyl, methoxy-propyl, ethoxyl methyl or ethoxyethyl group, it is excellent H, F, methyl, ethyl, methoxyl group, ethyoxyl, methoxy, methoxy ethyl, ethoxyl methyl or ethoxyethyl group are selected, More preferably H, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-6Alkane Base, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (= O)mR12、-(CH2)m- (3 to 6 yuan of carbocylic radicals) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or Person-O- (CH2)m- (3 to 6 circle heterocycles base), preferred H, F, Cl, Br ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl, C1-4 Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、- (CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (=O)nR12、- (CH2)m- (3 to 6 yuan of carbocylic radicals) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles base), more preferably H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O- C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan of carbocyclic rings Base) or-O- (CH2)m- (3 to 6 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alcoxyl Base ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O- (CH2)m- (3 to 4 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 4 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyanogen Base, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred H, C1-4Alkane Base, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkyl, described heterocyclic radical contains 1 to 3 hetero atom selected from N, O or S, It is preferred that 1 to 2 hetero atom selected from N, O or S, described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical are each only It is vertical optional further by 0 to 3 selected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, amino, nitro, hydroxyl, carboxylic Base, C1-6Alkyl, C1-6Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13aOr-(CH2)mS (=O)nR12Substituent group replaced, preferably 0 to 3 Selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 is selected from F、Cl、Br、-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, Cl, cyano group, hydroxyl Base, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R6With R8、R6With R9、R7With R8、R7With R9、R8With R9Any one group can form one 3 To 6 yuan of carbocyclic rings or 3 to 6 circle heterocycles, preferred R6With R7、R8With R9Any one group can form 3 to 6 yuan of carbocyclic rings or 3 to 6 Circle heterocycles, more preferably 3 to 4 yuan carbocyclic rings or 3 to 4 circle heterocycles, further preferred 3 yuan of carbocyclic rings or 3 circle heterocycles, further preferred 3 yuan Carbocyclic ring, described heterocycle contains 1 to 3 N, O or S atom, preferably 1 to 2 hetero atom selected from N, O or S, described carbocyclic ring or Heterocycle is optionally further by 0 to 3 R12aSubstituent group replaced, preferably 0 to 2 R12a；
R12aSelected from F, Cl, Br, I ,=O, hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl-O-C1-6Alkyl ,- (CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)- O-R12、-(CH2)mC (=O)-NR13R13a、-(CH2)mS (=O)nR12、-(CH2)m- (3 to 6 yuan of carbocylic radicals) or-(CH2)m- (3 to 6 circle heterocycles bases) substituent group replaced；It is preferred that F, Cl, Br, I ,=O, hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkane Base-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)- R12、-(CH2)m- C (=O)-O-R12、-(CH2)mC (=O)-NR13R13aOr-(CH2)mS (=O)nR12, more preferably F, Cl, Br, =O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O-C1-4Alkyl, further preferred F ,=O, hydroxyl, C1-3 Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkyl, further preferred F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O- C1-2Alkyl, described heterocycle contains 1 to 3 N, O or S atom, preferably 1 to 2 hetero atom selected from N, O or S, described alkane Base, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical are optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、- CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkane Base ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m-C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O- R12Or-(CH2)mS (=O)nR12Substituent group replaced, preferably 0 to 3 be selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、 C1-4Alkyl, C1-4Alkoxyl, more preferably 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, Further preferred 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 1 It is individual selected from F, Cl, Br ,-CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or this C1-2 Alkoxyl；
Alternatively, as two R12aWhen being connected on same atom, together with the atom that can be connected with them 3 to 6 are formed First carbocyclic ring or 3 to 6 yuan of heterocycle, preferably 3 to 6 yuan of heterocycle, the heterocycle contains 1 to 3 hetero atom selected from N, O or S, excellent 1 to 2 hetero atom selected from N, O or S is selected, the heterocycle or carbocyclic ring are optionally further by 0 to 3 selected from F, Cl, Br, I, hydroxyl Base, cyano group, C1-6Alkyl, C1-6Alkoxyl or-C (=O)-C1-4The substituent group of alkyl is replaced, preferably 0 to 2 selected from F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 is selected from F, C1-3Alkyl or C1-3Alkoxyl, enters one Step preferably 0 to 1 is selected from F, C1-2Alkyl or C1-2Alkoxyl；
R12、R13And R13aSelected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C1-6Alkyl, C1-6Alkoxyl, (3 to 6 yuan of carbocylic radicals) or 3 to 6 circle heterocycles bases, preferred H, F, Cl, Br, hydroxyl, sulfydryl, cyano group, amino, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, more preferably H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 To 6 circle heterocycles bases, further preferred H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, Further preferably C1-3Alkyl, C1-3Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-2Alkyl or C1-2 Alkoxyl；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, I, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4 Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, preferred H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkane Base, more preferably H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, further preferred H, C1-3Alkoxyl or- C1-3Alkyl-O-C1-3Alkyl, further preferred H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl, described alkyl, alcoxyl Base is each individually optional to be further selected from-CH by 0 to 32F、-CHF2、-CF3, cyano group, amino, nitro, hydroxyl, carboxyl or C1-4 The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br ,-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alcoxyl Base, more preferably 0 to 1 is selected from F, Cl, cyano group, hydroxyl, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 selected from F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9In any one group can form 3 to 6 yuan of carbocyclic rings or 3 to 6 circle heterocycles, it is excellent 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, more preferably 3 yuan carbocyclic rings or 3 circle heterocycles, further preferred 3 yuan of carbocyclic rings, the heterocycle are selected to contain There are 1 to 3 hetero atom selected from N, O or S, preferably 1 to 2 hetero atom selected from N, O or S, and the carbocyclic ring for being formed Or heterocycle can optionally further by 0 to 3 R12aSubstituent group replaced, preferably 0 to 2 R12a；
R12aSelected from F, Cl, Br, I ,=O, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl, C1-4Alcoxyl-O-C1-4Alkyl or Person-(CH2)mS (=O)nR12, preferred F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O-C1-4Alkyl, More preferably F ,=O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkyl, further preferred F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, further preferred F, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, it is described Alkyl or alkoxyl optionally further by 0 to 3 be selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, amino, nitro, Hydroxyl, carboxyl, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 3 is selected from F, Cl, Br, I ,-CH2F、- CHF2、-CF3、C1-4Alkyl, C1-4Alkoxyl, more preferably 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, enters one Step preferably 0 to 1 is selected from F, Cl, Br ,-CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkane Base or this C1-2Alkoxyl；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7、R8And R9Be each independently selected from H, F, methyl, ethyl, propyl group, isopropyl, butyl, methoxyl group, ethyoxyl, Propoxyl group, methoxy, methoxy ethyl, methoxy-propyl, ethoxyl methyl or ethoxyethyl group, preferred H, methyl, Methoxyl group, ethyoxyl, methoxy, ethoxyl methyl, methoxy ethyl or ethoxyethyl group, more preferably H, methoxyl group, second Epoxide, methoxy or ethoxyl methyl, further preferred H；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9Arbitrary group can form 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, preferably 3 yuan Carbocyclic ring or 3 circle heterocycles, more preferably 3 yuan carbocyclic rings, described heterocycle contains the hetero atom of 1 to 3 O, N or S, preferably 1 to 2 choosing From the hetero atom of N, O or S, and the carbocyclic ring that formed or heterocycle can optionally further by 0 to 3 selected from F, Cl, Br, I, Methyl, ethyl, propyl group, isopropyl, butyl, methoxyl group, ethyoxyl, propoxyl group, methoxy, methoxy ethyl, methoxyl group The substituent group of propyl group, ethoxyl methyl or ethoxyethyl group is replaced, and preferably 0 to 2 selected from F, methyl, ethyl, propyl group, different Propyl group, methoxyl group, ethyoxyl, methoxy, methoxy ethyl, ethoxyl methyl or ethoxyethyl group, more preferably 0 to 1 It is individual selected from F, methyl, ethyl, methoxyl group, ethyoxyl, methoxy, methoxy ethyl, ethoxyl methyl or ethyoxyl second Base, further preferred methoxyl group, ethyoxyl, methoxy, methoxy ethyl or ethoxyl methyl.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
Ring Q is selected fromOrIt is preferred thatOrMore preferablyOrFurther preferablyAnd ring Q can be further by 0 to 3 optionally from F, Cl, Br, I ,=O, amino, hydroxyl, C1-6Alkyl or C1-6Alcoxyl The substituent group of base is replaced, and preferably 0 to 3 optionally from F, Cl ,=O, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 optionally From F, Cl ,=O, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 2 optionally from F, Cl ,=O, C1-2Alkyl or C1-2Alcoxyl Base, further preferred 0 to 2 optionally from F ,=O or C1-2Alkoxyl.
Preferred version of the present invention, including the compound shown in logical formula (I) or its stereoisomer, hydrate, ester, solvation Thing, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
Ring Q is selected fromOrIt is preferred that
Preferred version of the present invention, the compound or its stereoisomer, hydrate, ester, solvent shown in a kind of logical formula (II) Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R is selected from H or C1-6Alkyl, preferred H or C1-4Alkyl, more preferably H；
Ring Q is selected fromOrIt is preferred thatOrMore preferablyAnd ring Q can With further by 0 to 3 optionally from F, Cl, Br, I ,=O, amino, hydroxyl, C1-6Alkyl or C1-6The substituent group of alkoxyl is taken In generation, preferably 0 to 3 optionally from F, Cl ,=O, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 optionally from F, Cl ,=O, C1-3 Alkyl or C1-3Alkoxyl, further preferred 0 to 2 optionally from F, Cl ,=O, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 It is optional from F ,=O or C to 21-2Alkoxyl；
R1Selected from H, F, Cl, Br, I, cyano group, amino, nitro, hydroxyl, C1-6Alkyl or C1-6Alkoxyl, preferred H, F, Cl, Br, cyano group, amino, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, more preferably H, F, Cl, Br, cyano group, amino, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, further preferred H, F, C1-2Alkyl or C1-2Alkoxyl, further preferred H, wherein the alkyl, alkoxyl or Amino is independently of one another optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, nitro, hydroxyl, C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced, and preferably 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3, cyanogen Base, nitro, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3, cyanogen Base, nitro, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 2 is selected from F ,-CF3、C1-2Alkyl or C1-2Alkane Epoxide；
R5、R10And R11It is each individually optional from H, F, Cl, Br, I, cyano group, hydroxyl, C1-6Alkyl, C1-6Alkoxyl or C1-6 Alkyl-O-C1-6Alkyl, preferred H, F, Cl, Br, C1-4Alkyl or C1-4Alkoxyl, more preferably H, F, Cl, Br, C1-3Alkyl or C1-3Alkoxyl, further preferred H, F, Cl, Br, C1-2Alkyl or C1-2Alkoxyl, further preferred H, F, C1-2Alkyl or C1-2Alkane Epoxide, the alkyl or alkoxyl are independently of one another optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、- CF3、C1-6Alkyl or C1-6The substituent group of alkoxyl is replaced, and preferably 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、 C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 is selected from F, Cl, Br, C1-4Alkyl or C1-4The substituent group of alkoxyl is taken In generation, further preferred 0 to 2 is selected from F, Cl, Br, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2 Alkyl or C1-2Alkoxyl；
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-6Alkane Base, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (= O)nR12、-(CH2)m- (3 to 6 yuan of carbocylic radicals) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or Person-O- (CH2)m- (3 to 6 circle heterocycles base), preferred H, F, Cl, Br ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl, C1-4 Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、- (CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (=O)nR12、- (CH2)m- (3 to 6 yuan of carbocylic radicals) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles base), more preferably H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O- C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan of carbocyclic rings Base) or-O- (CH2)m- (3 to 6 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alcoxyl Base ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O- (CH2)m- (3 to 4 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 4 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyanogen Base, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred H, C1-4Alkane Base, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkyl, it is excellent that described heterocyclic radical contains 1 to 3 hetero atom selected from N, O or S Select 1 to 2 hetero atom selected from N, O or S, described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical are each independent Optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, amino, nitro, hydroxyl, carboxyl, C1-6 Alkyl, C1-6Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (= O)-O-R12、-(CH2)m- C (=O)-NR13R13aOr-(CH2)mS (=O)nR12Substituent group replaced, preferably 0 to 3 is selected from F、Cl、Br、I、-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 selected from F, Cl、Br、-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 selected from F, Cl, cyano group, hydroxyl, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R7With R8、R8With R9、R6With R8、R6With R9Any one group can form one 3 to 6 yuan Carbocyclic ring or 3 to 6 circle heterocycles, preferred R6With R7、R8With R9Any one group can form 3 to 6 yuan of carbocyclic rings or 3 to 6 yuan miscellaneous Ring, more preferably 3 to 4 yuan carbocyclic rings or 3 to 4 circle heterocycles, further preferred 3 yuan of carbocyclic rings or 3 circle heterocycles, further preferred 3 yuan of carbocyclic rings, Described heterocycle contains 1 to 3 N, O or S atom, preferably 1 to 2 hetero atom selected from N, O or S, described carbocyclic ring or miscellaneous Ring is optionally further by 0 to 3 R12aSubstituent group replaced, preferably 0 to 2 R12a；
R12aSelected from F, Cl, Br, I ,=O, hydroxyl, cyano group, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl-O-C1-6Alkyl ,- (CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)- O-R12、-(CH2)mC (=O)-NR13R13aOr-(CH2)mS (=O)nR12Substituent group replaced；It is preferred that F, Cl, Br ,=O, hydroxyl Base, C1-4Alkyl, C1-4Alkoxyl, C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, more preferably F, Cl, Br ,=O, Hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O-C1-4Alkyl, further preferred F ,=O, hydroxyl, C1-3Alkyl, C1-3Alkane Epoxide or C1-3Alkyl O-C1-3Alkyl, further preferred F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, enters One step preferred F, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, described alkyl, alkoxyl, thiazolinyl, alkynyl are optionally further F, Cl, Br, I ,-CH are selected from by 0 to 32F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-6Alkane Base, C1-6Alkoxyl ,-C1-6Alkyl-O-C1-6Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a,-O-C (=O)- NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12Or-(CH2)mS (=O)nR12Substituent group replaced, preferably 0 to 3 It is individual selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-4Alkyl, C1-4Alkoxyl, more preferably 0 to 3 selected from F, Cl, Br ,- CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、- CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 1 is selected from F, Cl, Br ,-CF3、C1-3Alkyl or C1-3Alkoxyl, Further preferred 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alkoxyl；
Alternatively, as two R12aWhen being connected on same atom, the miscellaneous of 3 to 6 yuan of carbocyclic rings or 3 to 6 yuan can be formed Ring, preferably 3 to 6 yuan of heterocycle, the heterocycle contains 1 to 3 hetero atom selected from N, O or S, and preferably 1 to 2 is selected from N, O or S Hetero atom, the heterocycle or carbocyclic ring optionally further by 0 to 3 are selected from F, Cl, Br, I, CF3, hydroxyl, cyano group, C1-6Alkane Base or C1-6The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br, CF3, hydroxyl, cyano group, C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 is selected from F, C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkane Base or C1-2Alkoxyl；
R12、R13And R13aSelected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C1-6Alkyl, C1-6Alkoxyl, 3 to 6 First carbocylic radical or 3 to 6 circle heterocycles bases, preferred H, F, Cl, Br, hydroxyl, sulfydryl, cyano group, amino, C1-4Alkyl, C1-4Alkoxyl, 3 To 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, more preferably H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, further preferred H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, enter The preferred C of one step1-3Alkyl, C1-3Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-2Alkyl or C1-2Alkane Epoxide；
P is selected from 0,1 or 2, preferably 0 or 1, more preferably 0；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (II) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R is selected from H or C1-4Alkyl, preferred H；
Ring Q is selected fromOrIt is preferred thatAndOrCan further by 0 to 3 optionally from F, Cl ,=O, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 optionally from F, Cl ,=O, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 2 optionally from F, Cl ,=O, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 2 optionally From F ,=O or C1-2Alkoxyl；
R1Selected from H, F, Cl, Br, cyano group, amino, hydroxyl, C1-4Alkyl or C1-4Alkoxyl, preferred H, F, Cl, Br, cyano group, Amino, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably H, F, C1-2Alkyl or C1-2Alkoxyl, wherein further preferred H, institute Alkyl, alkoxyl or amino are stated independently of one another optionally further by 0 to 3 selected from F, Cl, Br ,-CH2F、-CHF2、-CF3, cyanogen Base, nitro, hydroxyl, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br ,-CH2F、- CHF2、-CF3, cyano group, nitro, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 2 is selected from F ,-CF3、C1-2Alkyl or Person C1-2Alkoxyl；
R5、R10And R11It is each individually optional from H, F, Cl, Br, C1-4Alkyl or C1-4Alkoxyl, preferred H, F, Cl, Br, C1-3Alkyl or C1-3Alkoxyl, more preferably H, F, Cl, Br, C1-2Alkyl or C1-2Alkoxyl, further preferred H, F, C1-2Alkyl or C1-2Alkoxyl, the alkyl or alkoxyl are independently of one another optionally further by 0 to 3 selected from F, Cl, Br ,-CH2F、- CHF2、-CF3、C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and more preferably 0 to 2 is selected from F, Cl, Br, C1-3Alkyl or C1-3Alkoxyl, it is further excellent 0 to 1 is selected selected from F, C1-2Alkyl or C1-2Alkoxyl；
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br ,-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、- (CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)mS (=O)nR12、- (CH2)m- (3 to 6 yuan of carbocylic radicals) ,-(CH2)m- (3 to 6 circle heterocycles base) ,-O- (CH2)m- (3 to 6 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 6 circle heterocycles base), preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4 Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan of carbocylic radicals) Or-O- (CH2)m- (3 to 6 circle heterocycles base), more preferably H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4 Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 4 First carbocylic radical) or-O- (CH2)m- (3 to 4 circle heterocycles base), further preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred H, C1-4Alkyl, C1-4Alkoxyl Or-C1-4Alkyl-O-C1-4Alkyl, described heterocyclic radical contains 1 to 3 hetero atom selected from N, O or S, preferably 1 to 2 choosing From the hetero atom of N, O or S, described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical each it is individually optional further F, Cl, Br, I ,-CH are selected from by 0 to 32F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4The substituent group of alkoxyl Replaced, preferably 0 to 2 is selected from F, Cl, Br ,-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 1 Selected from F, Cl, cyano group, hydroxyl, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or C1-2 Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9Any one group can form 3 to 6 yuan of carbocyclic rings or 3 to 6 circle heterocycles, it is excellent Select 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, more preferably 3 yuan carbocyclic rings or 3 circle heterocycles, further preferred 3 yuan of carbocyclic rings, described heterocycle Containing 1 to 3 N, O or S atom, preferably 1 to 2 hetero atom selected from N, O or S, described carbocyclic ring or heterocycle optionally enters one Step is by 0 to 3 R12aSubstituent group replaced, preferably 0 to 2 R12a；
R12aSelected from F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12Substituent group replaced, preferred F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O- C1-4Alkyl, more preferably F ,=O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkyl, further preferred F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, further preferred F, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkane Base；
R12、R13And R13aSelected from H, F, Cl, Br, hydroxyl, sulfydryl, cyano group, amino, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan Carbocylic radical or 3 to 6 circle heterocycles bases, preferred H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles Base, more preferably H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-3 Alkyl, C1-3Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-2Alkyl or C1-2Alkoxyl；
P is selected from 0,1 or 2, preferably 0 or 1, more preferably 0；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (III) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R5、R10And R11It is each individually optional from H, F, Cl, Br, C1-4Alkyl or C1-4Alkoxyl, preferred H, F, Cl, Br, C1-3 Alkyl or C1-3Alkoxyl, more preferably H, F, Cl, Br, C1-2Alkyl or C1-2Alkoxyl, further preferred H, F, C1-2Alkyl or C1-2 Alkoxyl, the alkyl or alkoxyl are independently of one another optionally further by 0 to 2 selected from F, Cl, Br, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 1 It is individual selected from F, C1-2Alkyl or C1-2Alkoxyl；
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkane Base-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan Carbocylic radical) or-O- (CH2)m- (3 to 6 circle heterocycles base), preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alcoxyl Base ,-C1-4Alkyl-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O- (CH2)m- (3 to 4 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 4 circle heterocycles base), more preferably H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, further preferred H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkyl, further preferred H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O- C1-3Alkyl, described heterocyclic radical contains 1 to 3 hetero atom selected from N, O or S, preferably 1 to the 2 miscellaneous original selected from N, O or S Son, described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical each it is individually optional further by 0 to 3 selected from F, Cl、Br、-CH2F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4The substituent group of alkoxyl is replaced, preferably 0 to 2 Selected from F, Cl, Br ,-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 1 is selected from F, Cl, cyano group, hydroxyl Base, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9In any one group can form 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, it is excellent 3 yuan of carbocyclic rings or 3 circle heterocycles, more preferably 3 yuan carbocyclic rings, the heterocycle are selected to contain 1 to 2 hetero atom selected from N, O or S, and The carbocyclic ring for being formed or heterocycle can optionally further by 0 to 2 R12aSubstituent group replaced；
R12aSelected from F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O-C1-4Alkyl, preferred F, =O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkyl, more preferably F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, further preferred F, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl；Described alkyl or alkoxyl Optionally further by 0 to 3 selected from F, Cl, Br, I ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4The substituent group institute of alkoxyl Replace, preferably 0 to 3 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 2 choosing From F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, further preferred 0 to 1 selected from F, Cl, Br ,- CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alkoxyl；
R12Selected from H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, preferred H, F, Cl、Br、C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, more preferably C1-3Alkyl, C1-3Alkoxyl, 3 To 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-2Alkyl or C1-2Alkoxyl；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (III) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R5、R10And R11It is each independently selected from H, F, methyl or ethyl.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkane Base-O-C1-4Alkyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)mS (=O)nR12、-O-(CH2)m- (3 to 6 yuan Carbocylic radical) or-O- (CH2)m- (3 to 6 circle heterocycles base), preferred H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alcoxyl Base ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)mS (=O)nR12, more preferably H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkane Base-O-C1-4Alkyl, further preferred H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, further preferred H, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, described heterocyclic radical contains 1 to 3 hetero atom selected from N, O or S, preferably 1 to 2 hetero atom selected from N, O or S, described alkyl, alkoxyl, thiazolinyl, alkynyl, carbocylic radical or heterocyclic radical are each independently appointed Choosing is further selected from F, Cl, Br ,-CH by 0 to 32F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or C1-4Alkoxyl Substituent group is replaced, and preferably 0 to 2 is selected from F, Cl, Br ,-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 1 is selected from F, Cl, cyano group, hydroxyl, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or Person C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9In any one group can form 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, it is excellent 3 yuan of carbocyclic rings or 3 circle heterocycles, more preferably 3 yuan carbocyclic rings, the heterocycle are selected to contain 1 to 3 hetero atom selected from N, O or S, and The carbocyclic ring for being formed or heterocycle can optionally further by 0 to 3 R12aSubstituent group replaced；
R12aSelected from F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl O-C1-4Alkyl, preferred F, =O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl O-C1-3Alkyl, more preferably F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl, further preferred F, C1-2Alkoxyl or C1-2Alkyl O-C1-2Alkyl；Described alkyl, alkoxyl Optionally further by 0 to 3 selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4The substituent group of alkoxyl is taken In generation, preferably 0 to 2 is selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4Alkoxyl, more preferably 0 to 1 is selected from F、Cl、Br、-CF3、C1-3Alkyl or C1-3Alkoxyl, further preferred 0 to 1 is selected from F, C1-2Alkyl or this C1-2Alkoxyl；
R12Selected from H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 6 yuan of carbocylic radicals or 3 to 6 circle heterocycles bases, preferred H, F, Cl、Br、C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, more preferably C1-3Alkyl, C1-3Alkoxyl, 3 To 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, further preferred C1-2Alkyl or C1-2Alkoxyl；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7、R8And R9It is each independently selected from H, F, Cl, Br, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkane Base-O-C1-4Alkyl or-(CH2)mS (=O)nR12, preferred H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkane Base, more preferably H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, further preferred H, C1-3Alkoxyl or- C1-3Alkyl-O-C1-3Alkyl, further preferred H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl, described alkyl or alkane Epoxide is each individually optional to be further selected from F, Cl, Br ,-CH by 0 to 32F、-CHF2、-CF3, cyano group, hydroxyl, C1-4Alkyl or Person C1-4The substituent group of alkoxyl is replaced, and preferably 0 to 2 is selected from F, Cl, Br ,-CF3, cyano group, hydroxyl, C1-3Alkyl or C1-3 Alkoxyl, more preferably 0 to 1 is selected from F, Cl, cyano group, hydroxyl, C1-2Alkyl or C1-2Alkoxyl, further preferred 0 to 1 choosing From F, C1-2Alkyl or C1-2Alkoxyl；
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R8With R9In any one group can form 3 to 4 yuan of carbocyclic rings or 3 to 4 circle heterocycles, it is excellent 3 yuan of carbocyclic rings or 3 circle heterocycles, more preferably 3 yuan carbocyclic rings, the heterocycle are selected to contain 1 to 2 hetero atom selected from N, O or S, and The carbocyclic ring for being formed or heterocycle can optionally further by 0 to 2 R12aSubstituent group replaced；
R12aSelected from F, Cl, Br ,=O, hydroxyl, C1-4Alkyl, C1-4Alkoxyl or C1-4Alkyl-O-C1-4Alkyl, preferred F, =O, hydroxyl, C1-3Alkyl, C1-3Alkoxyl or C1-3Alkyl-O-C1-3Alkyl, more preferably F, C1-2Alkyl, C1-2Alkoxyl or C1-2Alkyl-O-C1-2Alkyl, further preferred F, C1-2Alkoxyl or C1-2Alkyl-O-C1-2Alkyl；Described alkyl or alcoxyl Base is optionally further by 0 to 2 selected from F, Cl, Br ,-CH2F、-CHF2、-CF3、C1-4Alkyl or C1-4The substituent group institute of alkoxyl Replace, preferably 0 to 1 is selected from F, Cl, Br ,-CF3、C1-3Alkyl or C1-3Alkoxyl, more preferably 0 to 1 is selected from F, C1-2Alkane Base or this C1-2Alkoxyl；
R12Selected from H, F, Cl, Br, C1-4Alkyl, C1-4Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, preferred C1-3 Alkyl, C1-3Alkoxyl, 3 to 5 yuan of carbocylic radicals or 3 to 5 circle heterocycles bases, more preferably C1-2Alkyl or C1-2Alkoxyl；
M be selected from 0,1,2,3 or 4, preferably 0,1,2 or 3, more preferably 0,1 or 2；
N is selected from 0,1 or 2.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkyl, preferred H, C1-3 Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, more preferably H, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, Further preferred H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl, further preferred H；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl or-C1-4Alkyl-O-C1-4Alkyl, preferred H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, more preferably H, C1-2Alkyl, C1-2Alkoxyl or-C1-2Alkane Base-O-C1-2Alkyl, further preferred H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl；
Alternatively, R8With R93 yuan of carbocyclic rings can be formed.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7It is each independently selected from H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, preferred H, C1-3 Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, more preferably H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl, it is further excellent Select H；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H, C1-3Alkyl, C1-3Alkoxyl or-C1-3Alkyl-O-C1-3Alkyl, preferred H, C1-2Alkyl, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkyl, more preferably H, C1-2Alkoxyl or-C1-2Alkyl-O-C1-2Alkane Base；
Alternatively, R8With R93 yuan of carbocyclic rings can be formed.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6And R7It is each individually optional from H, methyl, methoxyl group, ethyoxyl, methoxy, ethoxyl methyl, methoxyl group Ethyl or ethoxyethyl group, more preferably preferred H, methoxy or ethoxy, H；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each individually optional from H, methyl, methoxyl group, ethyoxyl, methoxy, ethoxyl methyl or methoxyl group Ethyl, preferred H, methyl, methoxy or ethoxyl methyl, more preferably H, methoxy or ethoxyl methyl；
Alternatively, R8And R93 yuan of carbocyclic rings can be formed.
Preferred version of the present invention, including the compound shown in logical formula (IV) or its stereoisomer, hydrate, ester, solvent Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6And R7Selected from H；Or, R6And R7One=O can be formed；
R8And R9It is each individually optional from H, methoxy or ethoxyl methyl；Or, it is alternatively that, R8And R9Can shape Into 3 yuan of carbocyclic rings.
Preferred version of the present invention, there is provided as led to compound or its stereoisomer, hydrate, ester, solvent shown in formula (I) Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R is selected from H or C1-8Alkyl；
Ring Q contains 1 to 4 N, O or S (=O) selected from 5 to 8 yuan of carbocylic radicals or heterocyclic radical, described heterocyclic radicalnAtom or Person's group, described carbocylic radical or heterocyclic radical is optional to be further selected from F, Cl, Br, I ,=O, cyano group, isocyano group, ammonia by 0 to 4 Base, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12,-O-C (=O)- O-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-R12、-(CH2)m- S (=O)n-R12Or-NR13R13aReplacement Base is replaced；
R1And R4It is each individually optional from F, Cl, Br, I, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl Or C1-8Alkoxyl, wherein the alkyl, alkoxyl or amino independently of one another optionally further by 0 to 4 selected from F, Cl, Br, I、-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-(CH2)m- alkene Base-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)- NR13R13a、-(CH2)m- S (=O)n-R12,-O-C (=O)-O-R12Or-NR13R13aSubstituent group replaced；
R2And R3It is each individually optional from H, F, Cl, Br, I, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkane Base or C1-8Alkoxyl, wherein the alkyl, alkoxyl or amino independently of one another optionally further by 0 to 4 selected from F, Cl, Br、I、-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl or C1-8The replacement of alkoxyl Base is replaced；
R5、R6、R7、R8、R9、R10And R11It is each independently selected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, it is cyano group, different Cyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl ,-C1-8Alkyl-O-C1-8Alkyl ,-(CH2)m- thiazolinyl- R12、-(CH2)m- alkynyl-R12、-(CH2)m-NR13R13a、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、- (CH2)m- C (=O)-NR13R13a,-O-C (=O)-NR13R13a,-O-C (=O)-R12,-O-C (=O)-O-R12、-(CH2)mS (= O)nR12、-N(R12b) C (=O) NR13R13a、-N(R12b) C (=O) R12、-N(R12b) C (=O) OR12、-(CH2)m- (3 to 10 yuan of carbon Ring group) ,-(CH2)m- (3 to 10 circle heterocycles base) ,-O- (CH2)m- (3 to 10 yuan of carbocylic radicals) or-O- (CH2)m- (3 to 10 yuan are miscellaneous Ring group), described heterocyclic radical contains 1 to 4 N, O or S (=O)nAtom or group, described alkyl, alkoxyl, thiazolinyl, Alkynyl, carbocylic radical or heterocyclic radical are optionally further by 0 to 4 selected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, Isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl or-C1-8Alkyl-O-C1-8The substituent group of alkyl is taken Generation；
Alternatively, R6And R7(=O) or=CR can be formed12R12b；
Alternatively, R8And R9(=O) or=CR can be formed12R12b；
Alternatively, R6With R7、R6With R8、R6With R9、R7With R8、R7With R9、R8With R9Any one group can form one 3 To 8 yuan of carbocyclic rings or 3 to 8 circle heterocycles, described heterocycle contains 1 to 4 N, O or S (=O)nAtom or group, described carbocyclic ring Or heterocycle is optionally further by 0 to 4 R12aSubstituent group replaced；
R12aSelected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkoxyl or C1-8Alkyl-O-C1-8Alkyl；
R12And R12bSelected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, sulfydryl, isocyano group, amino, nitro, hydroxyl Base, carboxyl, C1-8Alkyl, C1-8Alkoxyl, 3 to 10 yuan of carbocylic radicals or 3 to 10 circle heterocycles bases, described heterocyclic radical contains 1 to 4 N, O or S (=O)nAtom or group, described alkyl, alkoxyl, carbocylic radical or heterocyclic radical are optionally further by 0 to 4 choosing From F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkane Epoxide or-C1-8Alkyl-O-C1-8The substituent group of alkyl is replaced；
R13And R13aSelected from H, F, Cl, Br, I ,-CH2F、-CHF2、-CF3, cyano group, sulfydryl, isocyano group, amino, nitro, hydroxyl Base, carboxyl, C1-8Alkyl, C1-8Alkoxyl, 3 to 10 yuan of carbocylic radicals or 3 to 10 circle heterocycles bases, described heterocyclic radical contains 1 to 4 N, O or S (=O)nAtom or group, described alkyl, alkoxyl, carbocylic radical or heterocyclic radical are optionally further by 0 to 4 choosing From F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, cyano group, isocyano group, amino, nitro, hydroxyl, carboxyl, C1-8Alkyl, C1-8Alkane Epoxide ,-C1-8Alkyl-O-C1-8Alkyl or-(CH2)mS (=O)nR12Substituent group replaced；
P is selected from 0,1,2 or 3；
Q is selected from 0,1,2,3 or 4；
T is selected from 0,1 or 2；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, lead to formula (I) described in compound or its stereoisomer, hydrate, ester, solvate, Eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R1And R4It is each individually optional from F, Cl, Br or C1-4Alkyl, preferred F or Cl；
R2And R3It is each individually optional from H, F, Cl, Br or C1-4Alkyl, preferred H；
R5、R10And R11It is each individually optional from H, F, Cl, Br, I or C1-4Alkyl, preferred H, F or methyl.
Preferred version of the present invention, lead to formula (I) described in compound or its stereoisomer, hydrate, ester, solvate, Eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6、R7、R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl Or-(CH2)m-NR13R13a, preferred H ,-CH2OH, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8And R9Can be formed (=O)；
Alternatively, R6With R7、R6With R8、R6With R9、R7With R8、R7With R9、R8With R9Any one group can form one 3 To 6 yuan of carbocyclic rings, preferably 3 to 4 yuan carbocyclic rings, more preferably 3 yuan carbocyclic rings；
R13And R13aSelected from H or C1-6Alkyl, preferred H or C1-4Alkyl, described alkyl can further by 0 to 2 choosing From-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from H or C1-6Alkyl, preferred H or methyl；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, leads to compound or its stereoisomer described in formula (I), hydrate, ester, solvate, altogether Crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
Ring Q is selected fromOrIt is preferred thatAnd ring Q can be further by 0 to 3 optionally from F, Cl, Br, I ,=O, amino, hydroxyl, C1-6Alkyl or C1-6Alkoxyl Substituent group replaced.
Preferred version of the present invention, leads to compound or its stereoisomer described in formula (I), hydrate, ester, solvate, altogether Crystal, metabolite, pharmaceutically acceptable salt or prodrug, it is the compound or its stereoisomerism shown in following logical formula (II)s Body, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R is selected from H or C1-4Alkyl, preferred H：
Ring Q isAnd ring Q can be further by 0 to 3 optionally from F ,=O, amino, hydroxyl, C1-4Alkyl or C1-4Alkane The substituent group of epoxide is replaced；
R1Selected from F, Cl or Br, preferred F or Cl；
R5、R10And R11It is each individually optional from H, F, Cl, Br or C1-4Alkyl, preferred H, F or methyl；
R6、R7、R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl Or-(CH2)m-NR13R13a, preferred H ,-CH2OH, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R6With R7、R6With R8、R6With R9、R7With R8、R7With R9、R8With R9Any one group can form one 3 To 6 yuan of carbocyclic rings, preferably 3 to 4 yuan carbocyclic rings, more preferably 3 yuan carbocyclic rings；
R13And R13aSelected from H or C1-4Alkyl, described alkyl can be further by 0 to 2 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from H or C1-4Alkyl, preferred H or methyl；
P is selected from 0,1 or 2；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, lead to formula (I) described in compound or its stereoisomer, hydrate, ester, solvate, Eutectic, metabolite, pharmaceutically acceptable salt or prodrug, it is the compound or its stereoisomerism shown in logical formula (III) Body, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R5、R10And R11It is each individually optional from H, F, Cl, Br or C1-4Alkyl, preferred H, F or methyl；
R6、R7、R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl Or-(CH2)m-NR13R13a, preferred H ,-CH2OH, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aSelected from H or C1-4Alkyl, described alkyl can be further by 0 to 2 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from H or C1-4Alkyl, preferred H or methyl；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, leads to compound or its stereoisomer described in formula (I), hydrate, ester, solvate, altogether Crystal, metabolite, pharmaceutically acceptable salt or prodrug, its be compound or its stereoisomer shown in logical formula (IV), Hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R6、R7、R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl Or-(CH2)m-NR13R13a, preferred H ,-CH2OH, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aSelected from H or C1-4Alkyl, described alkyl can be further by 0 to 2 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from H or C1-4Alkyl, preferred H or methyl；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, lead to formula (IV) shown in compound or its stereoisomer, hydrate, ester, solvate, Eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6And R7Each it is individually optional from H, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each individually optional from H ,-CH2OH, methyl,Or
Alternatively, R8And R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings.
Preferred version of the present invention, leads to the compound or its stereoisomer, hydrate, ester, solvent of compound described in formula (I) Compound, eutectic, metabolite, pharmaceutically acceptable salt or prodrug, it is that the compound or its solid led to shown in formula V is different Structure body, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug：
Wherein：
R4Selected from H, F or Cl, preferred H or F；
R5、R10And R11It is each individually optional from H, F, Cl or C1-4Alkyl, preferred H, F or methyl；
R6、R7、R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl Or-(CH2)m-NR13R13a, preferred H ,-CH2OH, methyl, methoxyl group, ethyoxyl,Or
Alternatively, R6And R7Can be formed (=O)；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aSelected from H or C1-4Alkyl, described alkyl can be further by 0 to 2 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from H or C1-4Alkyl, preferred H or methyl；
M is selected from 0,1,2,3 or 4；
N is selected from 0,1 or 2.
Preferred version of the present invention, lead to formula V described in compound or its stereoisomer, hydrate, ester, solvate, Eutectic, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R4Selected from H, F or Cl, preferred H or F；
R5And R11For methyl；
R10Selected from H or F, preferred H；
R6And R7Each it is individually optional from H, methyl, methoxyl group, ethyoxyl,OrOr R6With R7Formed (=O), preferred H or R6And R7Formed (=O), more preferably R6And R7Formed (=O)；
R8And R9It is each individually optional from H ,-CH2OH, methyl,OrOr R8And R9It is coupled Carbon atom formed 3 yuan of carbocyclic rings, preferred R8And R9Coupled carbon atom forms 3 yuan of carbocyclic rings；
Preferred version of the present invention, leads to compound or its stereoisomer described in formula V, hydrate, ester, solvate, altogether Crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein：
R6And R7For H or R6And R7Formed (=O), preferred R6And R7Formed (=O)；
R8And R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings.
Preferred version of the present invention, lead to formula (I) shown in compound or its stereoisomer, hydrate, solvate, ester, Metabolite, eutectic, pharmaceutically acceptable salt or prodrug, wherein compound are included but is not limited to：
The present invention relates to the suitable pharmaceutically acceptable salt of compound shown in logical formula (I) include, but are not limited to sodium salt, Potassium salt, aluminium salt, lithium salts, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, front three amine salt, tetramethyl ammonium, diethylamine salt, triethylamine Salt, isopropyl amine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl amine salt, pyridiniujm, first Yl pyridines salt, 2,6- lutidines salt, coffee alkali salt, procaine salt, choline salt, Radix Betae alkali salt, cocoa alkali salt, purine Salt, piperazine salt, piperidinium salt, N-ethylpiperidine salt, polyamino resin salt, benethamine penicillin salt, hydrochlorate, hydrobromate, sulfate, Nitrate, phosphate, formates, acetate, oxyacetate, propionate, 2 hydroxy propanoic acid salt, malonate, trifluoroacetate, Mesylate, esilate, fluoroform sulphonate, vinyl sulfonate, benzene sulfonate, tosilate, benzoate, benzene second Hydrochlorate, alginate, anthranilate, Camphora hydrochlorate, maleate, tartrate, citrate, succinate, mandelate, Fumarate, malate, oxalates, salicylate, glucuronate salt, galacturonic acid hydrochlorate, citrate, aspartic acid Salt, glutamate, Glu, cinnamate, combinations thereof.Particular certain cancers, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine Salt, hydrochlorate, hydrobromate, sulfate, phosphate, trifluoroacetate, acetate, maleate, aspartate, glutamic acid Salt, malate or combinations thereof.
The invention further relates to the method for preparing compound shown in described logical formula (I), those skilled in the art will know that this Bright compound can be synthesized by various preparation methoies.Preferred method includes, but are not limited to method discussed below.This The technical staff in field is it will be appreciated that the feature shown on molecule should be consistent with the conversion planned.In order to obtain this The required compound of invention, it is sometimes desirable to which a kind of judgement is changing the order of synthesis step or select a kind of specific technique side Case.Rational protection group is selected in order to be protected to reactive functional group present in compound described in the invention Group.Specifically, the one kind of the preparation method of logical formula (I) compound of the invention in following methods：
Method one：
Formula (I-a) compound passes sequentially through Horner-Wadsworth-Emmons reactions (or wittig reactions), reduction Reaction and alkylated reaction are converted into formula (I-b) compound；Or formula (I-a) compound is turned by reduction elimination reaction Turn to formula (I-b) compound；
Formula (I-b) compound is converted into formula (I-c) chemical combination by suzuki coupling reactions and hydrogenation reduction Thing；
Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions and hydrolysis； Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；
Method two：
Formula (I-d) compound is converted into formula (I-e) chemical combination by nucleophilic substitution and Claisen rearangement reaction Thing.
Formula (I-e) compound is converted into formula (I-f) compound by epoxidation reaction and ring-opening reaction；Or it is logical Formula (I-e) compound is converted into formula (I-f) compound by nucleophilic substitution；
Formula (I-f) compound passes through suzuki coupling reaction formula (I-c) compounds；Or formula (I-f) compound Formula (I-c) compound is converted into by suzuki coupling reactions and hydrogenation reduction；
Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions and hydrolysis； Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；
Method three：
Formula (I-g) compound is converted into formula (I-a) compound by Adol reactions；Or formula (I-g) compound Formula (I-a) compound is converted into by nucleophilic substitution；
Formula (I-a) compound is converted into formula (I-f) compound by reduction reaction；Or formula (I-a) compound Formula (I-f) compound is converted into by reduction reaction and decarboxylation reaction；
Formula (I-f) compound passes through suzuki coupling reaction formula (I-c) compounds；Or formula (I-f) compound Formula (I-c) compound is converted into by suzuki coupling reactions and hydrogenation reduction；
Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions and hydrolysis； Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；
Method four：
Formula (I-a) compound is converted into formula (I-h) compound by suzuki coupling reactions；Or formula (I-a) Compound is converted into formula (I-h) compound by suzuki coupling reactions and hydrogenation reduction；
Formula (I-h) compound is converted into formula (1-i) compound by reduction amination；
Formula (1-i) compound is converted into logical by nucleophilic substitution, Mitsunobu condensation reactions and hydrolysis Formula (I) compound, or formula (I-i) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；Wherein：
L is selected from F, Cl, Br or I；
R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11, Q, p, q and t be as defined in the present invention；
R16、R17And R18Selected from H, hydroxyl, methyl or ethyl.
More specifically, the one kind of the preparation method of logical formula (I) compound of the invention in following methods：
Method one：
In the basic conditions, with tetrahydrofuran as solvent, formula (I-a) compound is anti-with diethoxy cyanogen methyl phosphorodithioate Should, by cyano reduction it is then aldehyde radical with diisobutyl aluminium hydride, further react with reducing agent, then in alkalescence condition Under, further obtain formula (I-b) compound with alkylating reagent reaction；Or formula (I-a) compound reacts with reducing agent, Further in the presence of concentrated sulphuric acid, there is elimination reaction and obtain formula (I-b) compound；Wherein described alkali selected from sodium hydrogen, Sodamide., potassium tert-butoxide, butyl lithium or lithium diisopropyl amido；Reducing agent is selected from sodium borohydride, potassium borohydride, aluminum hydride Lithium, thio sodium borohydride or 3-sec-butyl lithium borohydride；Alkylating reagent is selected from iodomethane, methyl tosylate, sulphuric acid Dimethyl ester, bromoethane, ethyl p-toluenesulfonate or dithyl sulfate；
With toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, carbon Under sour sodium or potassium phosphate existence condition, under palladium catalyst effect, formula (I-b) compound occurs with 3- formylphenylboronic acids Suzuki coupling reactions, then under reducing agent effect, hydrogenating reduction obtains formula (I-c) compound；Wherein described palladium is urged Agent is selected from [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride two Chloromethanes complex, tetrakis triphenylphosphine palladium, palladium chloride, palladium or bi triphenyl phosphorus palladium chloride, described reduction Agent is as described above；
With dichloromethane or tetrahydrofuran as solvent, under the conditions of tri-butyl phosphine, diisopropyl azodiformate or In the presence of 1,1- (azo dicarbapentaborane) two piperidines, formula (I-c) compound and 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- Base) there is Mitsunobu reactions and obtain logical formula (I) compound in ethyl acetate；Or formula (I-c) compound is under these conditions Logical formula (I) compound is converted into by Mitsunobu condensation reactions and hydrolysis；
Method two：
With acetonitrile, tetrahydrofuran, toluene or 1,2- dichloroethanes for solvent, in the presence of potassium carbonate, formula (I-d) chemical combination Thing instead gives birth to nucleophilic displacement of fluorine with 3- bromopropenes, then at 180 DEG C, by Claisen rearangement formula (I-e) compound is obtained；
With dichloromethane or 1,2- dichloroethanes for solvent, formula (I-e) compound occurs with metachloroperbenzoic acid Epoxidation reaction, is then heated to reflux obtaining formula (I-f) compound with 1,2- dichloroethanes for solvent；Or with dichloromethane Or 1,2- dichloroethanes are solvent, in the presence of trifluoromethanesulfonic acid, there is nucleophilic substitution and obtain in formula (I-e) compound Formula (I-f) compound；
With toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, carbon Under sour sodium or potassium phosphate existence condition, under palladium catalyst effect, formula (I-f) compound occurs with 3- hydroxymethyls phenylboric acid Suzuki coupling reactions obtain formula (I-c) compound, or with toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water Or tetrahydrofuran/water is solvent, under potassium carbonate, sodium carbonate or potassium phosphate existence condition, under palladium catalyst effect, formula (I-f) with 3- formylphenylboronic acids there is suzuki coupling reactions in compound, and then under reducing agent effect, hydrogenating reduction is obtained Formula (I-c) compound, wherein described palladium catalyst and reducing agent are as defined above；
With dichloromethane or tetrahydrofuran as solvent, under the conditions of tri-butyl phosphine, diisopropyl azodiformate or In the presence of 1,1- (azo dicarbapentaborane) two piperidines, formula (I-c) compound and 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- Base) there is Mitsunobu reactions and obtain logical formula (I) compound in ethyl acetate；Or formula (I-c) compound is under these conditions Logical formula (I) compound is converted into by Mitsunobu condensation reactions and hydrolysis；
Method three：
With first alcohol and water as solvent, in the presence of potassium carbonate, there is Adol reactions and led in formula (I-g) compound with formaldehyde Formula (I-a) compound；Or with tetrahydrofuran, DMF as solvent, in the presence of sodium hydrogen, formula (I-g) is changed Formula (I-a) compound obtained and nucleophilic substitution with iodomethane or glycol dibromide in compound there is；
With tetrahydrofuran as solvent, in the presence of aluminum chloride, formula (I-a) compound obtains formula with Lithium Aluminium Hydride reaction (I-f) compound；Or formula (I-a) compound hydrogenating reduction under reducing agent effect, further slough hydroxyl and led to Formula (I-f) compound, wherein dehydroxylating agent are selected from triethyl silicane, palladium/charcoal, TMSCl/NaI or CS2/ NaH, TMSCl are Refer to trim,ethylchlorosilane, wherein described reducing agent is as described above；
With toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, carbon Under sour sodium or potassium phosphate existence condition, under palladium catalyst effect, formula (I-f) compound occurs with 3- hydroxymethyls phenylboric acid Suzuki coupling reactions obtain formula (I-c) compound, or with toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water Or tetrahydrofuran/water is solvent, under potassium carbonate, sodium carbonate or potassium phosphate existence condition, under palladium catalyst effect, formula (I-f) with 3- formylphenylboronic acids there is suzuki coupling reactions in compound, and then under reducing agent effect, hydrogenating reduction is obtained Formula (I-c) compound, wherein described palladium catalyst and reducing agent are as defined above；
With dichloromethane or tetrahydrofuran as solvent, under the conditions of tri-butyl phosphine, diisopropyl azodiformate or In the presence of 1,1- (azo dicarbapentaborane) two piperidines, formula (I-c) compound and 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- Base) there is Mitsunobu reactions and obtain logical formula (I) compound in ethyl acetate；Or formula (I-c) compound is under these conditions Logical formula (I) compound is converted into by Mitsunobu condensation reactions and hydrolysis；
Method four：
With toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, carbon Under sour sodium or potassium phosphate existence condition, under palladium catalyst effect, formula (I-a) compound occurs with 3- hydroxymethyls phenylboric acid Suzuki coupling reactions obtain formula (I-h) compound, or with toluene/ethanol/water, acetonitrile/water, Isosorbide-5-Nitrae-dioxane/water Or tetrahydrofuran/water is solvent, under potassium carbonate, sodium carbonate or potassium phosphate existence condition, under palladium catalyst effect, formula (I-a) with 3- formylphenylboronic acids there is suzuki coupling reactions in compound, and then under reducing agent effect, hydrogenating reduction is obtained Formula (I-h) compound, wherein described palladium catalyst and reducing agent are as defined above；
With methanol/water, ethanol/water, isopropanol/water as solvent, what sodium hydroxide, potassium hydroxide or Lithium hydrate were present Under the conditions of, formula (I-h) is condensed with oxammonium hydrochloride., then under reducing agent Lithium Aluminium Hydride, borine effect or in blue Buddhist nun Nickel, the lower hydrogenating reduction of palladium carbon effect obtain formula (1-i) compound.
With acetonitrile, DMF as solvent, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, hydroxide In the presence of lithium, triethylamine, DIPEA, there is nucleophilic substitution in formula (1-i), then with dichloromethane or Tetrahydrofuran is solvent, under the conditions of tri-butyl phosphine, diisopropyl azodiformate or 1,1- (azo dicarbapentaborane) two piperidines In the presence of, there is Mitsunobu reactions with 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) ethyl acetate and obtain logical formula (I) Compound；Or formula (I-i) compound under these conditions further hydrolysis are logical formula (I) compound.Wherein, L Selected from F, Cl, Br or I；
R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11, Q, p, q and t definition and it is heretofore described define one Cause；R16、R17、R18Selected from H, hydroxyl, methyl or ethyl.
The invention further relates to a kind of pharmaceutical composition, described compositionss include：Chemical combination shown in the logical formula (I) of effective dose Thing or its all stereoisomer, hydrate, solvate, ester, metabolite, eutectic, pharmaceutically acceptable salt or front Medicine, and pharmaceutically acceptable carrier, diluent, adjuvant or excipient.Described compositionss can also further include one kind or Various other therapeutic agents.Wherein described other therapeutic agents include：
(a) GPR40 agonist or pharmaceutically acceptable salt, and/or
(b) DPP-IV inhibitor or pharmaceutically acceptable salt, and/or
(c) SGLT-2 inhibitor or pharmaceutically acceptable salt, and/or
(d)PPARγAgonist and partial agonist or pharmaceutically acceptable salt, and/or
(e)PPARα/γDual agonists or pharmaceutically acceptable salt, and/or
(f)PPARδAgonist or pharmaceutically acceptable salt, and/or
(g) insulin or insulin mimetic or pharmaceutically acceptable salt, and/or
(h) Protein tyrosine phosphatase-1B (PTP-1B) inhibitor or pharmaceutically acceptable salt, and/or
(i) Sulfonylureas Inhibitors or pharmaceutically acceptable salt, and/or
(j) Alpha-glucosidase inhibitor or pharmaceutically acceptable salt, and/or
(k) GLP-1, GLP-1 analog, GIP-1, HSD-1 or pharmaceutically acceptable salt, and/or
(l) glucagon receptor antagonist or pharmaceutically acceptable salt, and/or
(m) anti-inflammatory agent, and/or
(n) ileal bile acid transporter inhibitor or pharmaceutically acceptable salt, and/or
(o) appetrol, and/or
P () improves the medicine of patient's lipid profile, the medicine is chelated selected from HMG-CoA reductase inhibitor, bile acid Agent, nicotine, nicotinic acid or its salt, PPARαAgonist, cholesterol absorption inhibitor, acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitor, CETP inhibitor or phenolic antioxidant or pharmaceutically acceptable salt, and/or
(q) biguanideses, thiazolidinedioneses, row how class or its pharmaceutically acceptable salt or prodrug, and/or
(r) PARP inhibitor.
Preferred version of the present invention, described GPR40 agonist selected from fasiglifam hemihydrate or its pharmaceutically Acceptable salt or prodrug.Described DDPIV inhibitor is selected from linagliptin (BI 1356), omarigliptin (MK- 3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (Egelieting), Saxagliptin (BMS-477118), denagliptin (Ge Lieting), Carmegliptin, Melogliptin (Metro profit Spit of fland), Dutogliptin, Teneligliptin (teneligliptin), Gemigliptin or Trelagliptin.Described SGLT-2 inhibitor selected from dapagliflozin, propanediol, empagliflozin, ertugliflozin, Ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin.Described PARP inhibitor choosing From bezafibrate, fenofibrate, pioglitazone, azelaic acid, rosiglitazone or saroglitazar.Described biguanideses therapeutic agent is selected from metformin or diethyl biguanide.Described thiazolidinedioneses are controlled Treat agent and be selected from ciglitazone, pioglitazone, rosiglitazone, troglitazone, Fa Gelie ketone or darglitazone.Described sulfonylureas Class therapeutic agent is selected from glimepiride, Tolglybutamide, glibornuride, glibenclamide, Gliquidone, Glipizide or lattice Lie Qite.How class therapeutic agent is selected from Nateglinide, Repaglinide or Mitiglinide to described row.Described alpha-glucosidase Inhibitor is selected from Acarbose, voglibose or miglitol.Described GLP-1 analog is selected from exendin or profit Draw Shandong peptide.
The invention further relates to compound shown in logical formula (I) or its stereoisomer, hydrate, solvate, ester, metabolism product The purposes of thing, eutectic, pharmaceutically acceptable salt or prodrug as a kind of agonist of g protein coupled receptor 40 medically, Further relate to described include compound shown in logical formula (I) or its stereoisomer, hydrate, solvate, ester, metabolite, altogether The pharmaceutical composition of crystal, pharmaceutically acceptable salt or prodrug purposes medically, shown in the logical formula (I) of the preferred present invention Compound or its stereoisomer, hydrate, solvate, ester, metabolite, eutectic, pharmaceutically acceptable salt or front Medicine is to be used to prepare the medicine system for treating and/or preventing metabolic disease as a kind of agonist of g protein coupled receptor 40 Agent.Described metabolic disease for example can be to include diabetes, type ii diabetes, diabetic retinopathy, diabetic Neuropathy, diabetic nephropathy, diabetic complication, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipemia, height Triglycerides mass formed by blood stasis, hypertension, hyperlipoproteinemia, high LDL-C, low HDL cholesterol, hypoglycemia, dyslipidemia, The elevated level of thrombotic disease, cardiovascular disease, kidney disease, ketoacidosiss, fatty acid or glycerol, lipoatrophy, Lipotoxicity, obesity, metabolic syndrome, X syndromes, insulin resistance, insulin allergy disease, glucose intolerance, skin One or more in skin disease, atherosclerosiss and its sequela angina pectoriss, limping, heart attack or apoplexy.Further It is preferred that compound or its stereoisomer, hydrate, solvate, ester, metabolite, eutectic shown in the logical formula (I) of the present invention Body, pharmaceutically acceptable salt or prodrug be as a kind of agonist of g protein coupled receptor 40 be used for prepare for treatment and/or The pharmaceutical preparation of prevention type ii diabetes.
The invention further relates to a kind for the treatment of and/or the method for preventing the metabolic disease, the method includes giving experimenter Compound or its stereoisomer, hydrate, ester, solvate, eutectic shown in the of the present invention logical formula (I) of effective dose Body, metabolite, pharmaceutically acceptable salt or prodrug, or the described pharmaceutical composition including it.
Unless there are contrary statement, the term for using in the present invention has following implications.
Involved carbon, hydrogen, oxygen, sulfur, nitrogen or halogen include their same position in group of the present invention and compound Involved carbon, hydrogen, oxygen, sulfur or nitrogen are optionally further by one or many in plain situation, and group of the present invention and compound Individual their corresponding isotopes are substituted, and the isotope of wherein carbon includes12C、13C and14C, the isotope of hydrogen includes protium (H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen includes16O、17O and18O, the isotope of sulfur includes32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine includes17F and19F, the isotope of chlorine includes35Cl and37Cl, bromine Isotope include79Br and81Br。
" alkyl " refers to the straight or branched saturated aliphatic hydrocarbons containing 1 to 20 carbon atom, preferably 1 to 8 carbon original The alkyl of son, the alkyl of more preferably 1 to 6 carbon atom, the alkyl of more preferably 1 to 4 carbon atom.Non-limiting reality Example is applied including methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, 2- amyl groups, 3- amyl groups, 2- Methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 3- methyl -3- amyl groups, 2- methyl -3- amyl groups, 2,3- diformazans Base -2- butyl, 3,3- dimethyl -2- butyl, n-heptyl, n-octyl and its various branched chain isomers；Described alkyl can appoint Choosing is further selected from F, Cl, Br, I ,=O ,-CH by 0 to 52F、-CHF2、-CF3, hydroxyl, sulfydryl ,-SR14,-S (=O) R14、- S (=O)2R14, nitro, cyano group, isocyano group, aldehyde radical, carboxyl, amino, alkyl amine group, amide groups, thiazolinyl, alkynyl, alkyl, hydroxyl Alkyl, alkoxyl, carbocylic radical, heterocyclic radical, carboxylate, carboxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)m- S (=O)n-R12,-O-C (= O)-O-R12Or-NR13R13aSubstituent group replaced, wherein R14Alkyl, 3 to 10 carbon atoms selected from 1 to 8 carbon atom Carbocylic radical or 3 to 10 carbon atoms heterocyclic radical, R12、R13And R13aIt is herein presented as defined with claim 1 Alkyl, its is as defined above.
" alkoxyl " refers to-O- alkyl, and non-limiting example includes methoxyl group, ethyoxyl, 1- propoxyl group, the oxygen of 2- third Base, 1- butoxy, 2- methyl isophthalic acids-propoxyl group, 2- butoxy, 2- methyl -2- propoxyl group, 1- amoxys, 2- amoxys, the oxygen of 3- penta Base, 2- methyl -2- butoxy, 3- methyl -2- butoxy, 3- methyl isophthalic acids-butoxy and 2-methyl-1-butene epoxide.Described alkane Base can optionally further by 0 to 5 selected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, hydroxyl, sulfydryl ,-SR14、-S (=O) R14,-S (=O)2R14, nitro, cyano group, isocyano group, aldehyde radical, carboxyl, amino, alkyl amine group, amide groups, thiazolinyl, alkynyl, Alkyl, hydroxy alkyl, alkoxyl, carbocylic radical, heterocyclic radical, carboxylate, carboxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl- R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)m- S (=O)n- R12,-O-C (=O)-O-R12Or-NR13R13aSubstituent group replaced, wherein R14It is as defined above, R12、R13And R13aAs Defined with claim 1.
" thiazolinyl " is referred to containing 1 to 3 carbon-to-carbon double bond, and the straight chain being made up of 2-20 carbon atom or side chain are unsaturated Aliphatic alkyl, the thiazolinyl of preferred 2-12 carbon atom, the thiazolinyl of more preferably 2-8 carbon atom.Non-limiting example includes Vinyl, propylene-2- bases, butene-2-base, 2-pentenyl, amylene-4- bases, hexene-2- bases, the base of hexene-3, heptene-2- bases, Teracrylic acid-base, heptene -4- bases, octene -3- bases, nonene -3- bases, decene -4- bases and hendecene -3- bases.Described thiazolinyl can be with Optionally further by 0 to 4 selected from F, Cl, Br, I, alkyl, alkoxyl, straight-chain alkenyl, straight-chain alkynyl, amino, nitro, cyano group, The substituent group of sulfydryl, amide groups, carbocylic radical or heterocyclic radical is replaced.
" alkynyl " is referred to containing 1 to 3 key of carbon-to-carbon three, the straight chain being made up of 2-20 carbon atom or side chain unsaturation Aliphatic alkyl, the alkynyl of preferred 2-12 carbon atom, the alkynyl of more preferably 2-8 carbon atom.Non-limiting example includes Acetenyl, propine -1- bases, propine -2- bases, butine -1- bases, crotonylene-base, butine -3- bases, 3,3- dimethyl butine -2- bases, Pentyne -1- bases, pentyne -2- bases, hexin -1- bases, 1- heptyne -1- bases, heptyne -3- bases, heptyne -4- bases, octyne -3- bases, n-heptylacetylene - 3- bases, decine -4- bases, undecyne -3- bases, dodecyne -4- bases.Described alkynyl can optionally further by 0 to 4 selected from F, Cl, Br, I, alkyl, alkoxyl, straight-chain alkenyl, straight-chain alkynyl, amino, nitro, cyano group, sulfydryl, amide groups, carbocylic radical or miscellaneous The substituent group of ring group is replaced.
" carbocylic radical " refers to saturation either undersaturated aromatic rings or non-aromatic ring, and aromatic rings or non-aromatic ring can be with It is 3 to 10 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, carbocylic radical can be connected with bridged ring or volution, Non-limiting example include cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- thiazolinyls, phenyl, 1- cyclopenta -2- thiazolinyls, 1- cyclopenta -3- thiazolinyls, cyclohexyl, 1- cyclohexyl -2- thiazolinyls, 1- cyclohexyl -3- thiazolinyls, cyclohexenyl group, cyclohexadienyl, ring Heptyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl,Described carbon Ring group can optionally further by 0 to 8 selected from F, Cl, Br, I ,=O ,-CH2F、-CHF2、-CF3, hydroxyl, sulfydryl ,-SR14、-S (=O) R14,-S (=O)2R14, nitro, cyano group, isocyano group, aldehyde radical, carboxyl, amino, alkyl amine group, amide groups, thiazolinyl, alkynyl, Alkyl, hydroxy alkyl, alkoxyl, carbocylic radical, heterocyclic radical, carboxylate, carboxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl- R12、-(CH2)m- C (=O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)m- S (=O)n- R12,-O-C (=O)-O-R12Or-NR13R13aSubstituent group replaced, wherein R14It is as defined above, R12、R13And R13aAs Defined with claim 1.
" heterocyclic radical " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or Person's non-aromatic ring can be 3 to 10 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and comprising 1 to 4 choosing From the hetero atom of N, O or S, preferably 3 to 8 circle heterocycles bases, N, S that selectivity replaces in the ring of heterocyclic radical can be oxidized to various oxygen Change state.Heterocyclic radical can be connected on hetero atom or carbon atom, and heterocyclic radical can be connected with bridged ring or volution, non-limiting Embodiment include epoxy ethyl, glycidyl, aziridinyl, oxetanylmethoxy, azelidinyl, thietanyl, 1,3- Dioxolanyl, Isosorbide-5-Nitrae-dioxolanyl, 1,3- dioxane bases, azacycloheptyl, oxepane base, thia suberyl, oxygen Azatropylidene base, diazepine base, sulfur azatropylidene base, pyridine radicals, piperidyl, homopiperidinyl, furyl, thienyl, pyranose, N- Alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, piperazinyl, homopiperazine base, imidazole radicals, piperidyl, piperazine sting base, morpholinyl, Thio-morpholinyl, thioxane bases, the thiophene bases of 1,3- bis-, dihydrofuran base, dihydro pyranyl, the ring group of two thiophene penta, tetrahydrofuran base, Tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, nafoxidine base, imidazolidine base, tetrahydro-thiazoles base, THP trtrahydropyranyl, Benzimidazolyl, benzo pyridine radicals, pyrrolopyridinyl, coumaran base, 2- pyrrolinyls, 3- pyrrolinyls, dihydro Indyl, 2H- pyranoses, 4H- pyranoses, dioxacyclohexyl, 1,3- dioxy amyl groups, pyrazolinyl, dithiane base, dithiode Alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 3- azabicyclos [3.1.0] hexyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H- indyl quinolizinyl, N- pyridines Base carbamide, 1,1- dioxidothiomorpholinyls, azabicyclic [3.2.1] octyl, azabicyclic [5.2.0] nonyl, oxa- three Ring [5.3.1.1] dodecyl, azaadamantane base and oxa- spiroheptane base.Described heterocyclic radical can optionally enter one Step is selected from F, Cl, Br, I ,=O ,-CH by 0 to 82F、-CHF2、-CF3, hydroxyl, sulfydryl ,-SR14,-S (=O) R14,-S (=O)2R14, nitro, cyano group, isocyano group, aldehyde radical, carboxyl, amino, alkyl amine group, amide groups, thiazolinyl, alkynyl, alkyl, hydroxy alkyl, Alkoxyl, carbocylic radical, heterocyclic radical, carboxylate, carboxyl ,-(CH2)m- thiazolinyl-R12、-(CH2)m- alkynyl-R12、-(CH2)m- C (= O)-R12、-(CH2)m- C (=O)-O-R12、-(CH2)m- C (=O)-NR13R13a、-(CH2)m- S (=O)n-R12,-O-C (=O)- O-R12Or-NR13R13aSubstituent group replaced, wherein R14It is as defined above.
" PEG " is referred to containing truePolymer, wherein n is the integer in the range of 2～about 1000, preferably 2～ About 500, more preferably 2～about 250, more preferably 2～about 125, more preferably 2～about 50, further preferred 2～about 25 In the range of integer.
" amino " refers to-NH2。
" alkyl amine group " refers to the amino group with one or two alkyl substituents.
" cyano group " is referred to
" isocyano group " is referred to
" nitro " refers to-NO2。
" hydroxyl " refers to-OH.
" sulfydryl " refers to-SH.
" aldehyde radical " refers to-C (=O) H.
" carboxyl " refers to-COOH.
" carboxylate " refer to--COOR15, wherein R15For alkyl.
" amide groups " refer to-CONR13R13a, R13And R13aAs defined with claim 1.
"=O " be this area ordinary practice usage, refer to double bond be connected oxygen atom, for example in carbonyl with carbon atom phase Double bond oxygen atom even.
" hydroxy alkyl " refers to the alkyl replaced by 1,2 or 3 hydroxyls, and described alkyl is preferably C1-4 alkyl.It is non- Restricted embodiment includes hydroxymethyl, 1- hydroxyethyls, 2- hydroxyethyls, 1,2- dihydroxypropyls, 1,3- dihydroxypropyls With 2,3- dihydroxypropyls.
" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to that the compounds of this invention keeps free acid Or the biological effectiveness and characteristic of free alkali, and described free acid by with nontoxic inorganic base or organic base, it is described Free alkali by the salt that obtains with nontoxic mineral acid or organic acid reaction.The non-limiting example of described inorganic base Including sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, barium；The non-limiting example of described organic base includes ammonia, trimethylamine, tetramethyl Ammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, first Yl pyridines, 2,6- lutidines, caffeine, procaine, choline, glycine betaine, theobromine, purine, piperazine, piperidines, N- second Phenylpiperidines, polyamino resin, benethamine penicillin salt；Described mineral acid and the non-limiting example hydrochloric acid of organic acid, hydrobromic acid, Sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic, propanoic acid, 2 hydroxy propanoic acid, malonic acid, trifluoroacetic acid, methanesulfonic acid, second sulphur Acid, trifluoromethanesulfonic acid, vinyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, phenylacetic acid, alginic acid, anthranilic acid, dextrocamphoric acid., Maleic acid, tartaric acid, citric acid, succinic acid, mandelic acid, fumaric acid, malic acid, oxalic acid, salicylic acid, glucuronic acid, gala Alduronic acid, citric acid, aspartic acid, glutamic acid, cinnamic acid,
" carrier " refer to will not to organism produce obvious stimulation and will not eliminate given compound biological activity and The material of characteristic.
" excipient " refers to and is added in pharmaceutical composition to promote the inert substance of compound administration.Non-limiting enforcement Example includes Calcium Carbonate, calcium phosphate, sugar, starch, cellulose derivative (including Microcrystalline Cellulose), gelatin, vegetable oil, Polyethylene Glycol Class, diluent, granulating agent, lubricant, binding agent and disintegrating agent.
" adjuvant " is nonspecific immunity strengthening agent, when injecting together with antigen or being previously implanted body, can strengthen machine Immunne response or change type of immune response of the body to antigen.
" diluent " is also named " filler ".When active compound is processed into powder, or in order to make it easy to spray entering of being added The inert substance of row dilution.Such as：Clay, Kaolin, potter's clay, Pulvis Talci etc..
" prodrug " refer to can Jing biotransformationin vivos be the compounds of this invention with biological activity.The prodrug of the present invention leads to Preparing, the modification can pass through conventional operation or be removed in vivo the functional group crossed in modification the compounds of this invention Go, and obtain parent compound.Prodrug includes that hydroxyl, amino or a sulfydryl in the compounds of this invention are connected to any collection The compound formed in group, when the prodrug of the present invention is delivered to mammalian subject, prodrug is isolated and is formed trip respectively From hydroxyl, free amino or free sulfydryl.The example of prodrug is included but is not limited to, the hydroxyl in the compounds of this invention Or the compound that amino-functional group is formed with formic acid, acetic acid or benzoic acid.
" eutectic " refer to active pharmaceutical ingredient and eutectic formation in the presence of hydrogen bond or other non-covalent bonds combine and Into crystal, the pure state of wherein active pharmaceutical ingredient (API) and eutectic formation (CCF) is at room temperature solid, and respectively There is fixed stoichiometric proportion between component.Eutectic is a kind of multicomponent crystal, both comprising formation between two kinds of neutral solids Binary eutectic, the multi-element eutectic for also being formed comprising neutral solid and salt or solvate.Non-limiting example eutectic formation bag Include alanine, L-Valine, leucine, isoleucine, proline, Phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, L-Tyrosine, agedoite, glutamine, lysine, arginine, histidine, aspartic acid, door winter ammonia Acid, glutamic acid, pyroglutamic acid, sulphuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propanoic acid, benzenesulfonic acid, benzoic acid, benzene Acetic acid, salicylic acid, alginic acid, anthranilic acid, dextrocamphoric acid., citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, Portugal It is grape alduronic acid, glutamic acid, glycolic, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, general Acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-methyl benzenesulfonic acid, malonic acid, 2 hydroxy propanoic acid, oxalic acid, glycolic, Fructus Vitis viniferae Alduronic acid, galacturonic acid, citric acid, cinnamic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropyl Base amine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2- dimethylaminos Base ethanol, 2- DEAE diethylaminoethanols, dicyclohexylamine, caffeine, procaine, choline, glycine betaine, benethamine penicillin, second Diamidogen, glucamine, methylglucosamine, theobromine, triethanolamine, trometamol, purine, piperazine, piperidines and N-ethylpiperidine.
" stereoisomer " refers to the isomer by produced by the spatially arrangement mode difference of atom in molecule, including suitable Trans isomer, enantiomer and conformer.
" optional " or " optionally " or " selective " or " optionally " refer to that subsequently described event or situation can be with But may not occur, the description includes the situation and wherein nonevent situation that the event or situation wherein occur.For example, " select Property ground by alkyl-substituted heterocyclic radical " refer to the alkyl can with but may not exist, the description is taken including wherein heterocyclic radical by alkyl The situation in generation, and wherein heterocyclic radical is not by alkyl-substituted situation." pharmaceutical composition " represents one or more described hereinization The combination of compound or its physiology/pharmaceutically acceptable salt or prodrug or/and one or more other therapeutic agent and Pharmaceutically acceptable excipient, adjuvant, diluent and carrier.
“EC50" medium effective concentration, refer to concentration when reaching maximum drug effect half.
Specific embodiment
The implementation process for describing the present invention in detail below by way of specific embodiment and the beneficial effect for producing, it is intended to which help is read Reader more fully understand the present invention essence and feature, not as to this case can practical range restriction.
In the present invention, the structure of compound by nuclear magnetic resonance, NMR (NMR) or (and) mass spectrum (MS) to be determining.NMR positions (δ) is moved with 10-6(ppm) unit is given.The measure of NMR is with (Bruker Avance III 400 and Bruker Avance300) nuclear magnetic resonance spectrometer, measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
The measure of MS uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
The measure of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax 100 × 4.6mm of SB-C18).
Tlc silica gel plate is made using Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin layer chromatography (TLC) The specification that silica gel plate is adopted is 0.15mm～0.20mm, thin layer chromatography isolate and purify the specification of product employing be 0.4mm～ 0.5mm。
It is carrier that column chromatography generally uses the mesh silica gel of Yantai Huanghai Sea silica gel 200～300.
Oneself initiation material known of the present invention can be adopted or synthesized according to methods known in the art, or it is commercially available in The company such as safe smooth science and technology, silent pacify resistance to Jilin Chemical, Shanghai moral, Chengdu section dragon chemical industry, splendid remote chemistry science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
The usual evacuation of hydrogenation, is filled with hydrogen, repeatable operation 3 times.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C～30 DEG C.
Other symbols used herein have following meaning：
s：It is unimodal
d：Doublet
t：Triplet
q：Quartet
m：Multiplet
br：Broad peak
J：Coupling constant
Hz：Hertz
Bn：Benzyl
Me：Methyl
Et：Ethyl
TBS：T-Butyldimethylsilyl
Intermediate 1：2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (1E)
Methyl 2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetate
The first step：4- (chloromethyl) -7- hydroxyls -2H- chromen-2-ones (1B)
4-(chloromethyl)-7-hydroxy-2H-chromen-2-one
At 0 DEG C, resorcinol 1A (17.62g, 160.02mmol) point of aliquot ground is added dissolved with chloroformyl ethyl acetate In the concentrated sulphuric acid (60mL) of (28.00g, 170.12mmol), reaction 2 hours is stirred at room temperature.Reactant liquor is poured in frozen water, will be mixed Compound is filtered, and filter cake is washed with water (100mL × 3) and is dried, and obtains the crude product of offwhite solid, is directly used in next step anti- Should.
Second step：2- (6- hydroxyl benzofuran -3- bases) acetic acid (1C)
2-(6-hydroxybenzofuran-3-yl)acetic acid
By 4- (chloromethyl) -7- hydroxyl -2H- chromen-2-one 1B crude products be dissolved in sodium hydrate aqueous solution (1000mL, In 1M), heating reflux reaction 2 hours.Reaction terminates, with concentrated sulphuric acid acidification reaction liquid, ethyl acetate (250mL × 3) extraction, nothing Water magnesium sulfate is dried, and filters concentrating under reduced pressure, obtains the compound 1C (16.00g, yield 52%) of brown solid.
3rd step：2- (6- hydroxyl benzofuran -3- bases) methyl acetate (1D)
methyl 2-(6-hydroxybenzofuran-3-yl)acetate
2- (6- hydroxyl benzofuran -3- bases) acetic acid 1C (16.00g, 83.26mmol) is dissolved in methanol (75mL), is dripped Plus concentrated sulphuric acid (8mL), by mixture heating reflux reaction 4 hours.Reaction terminates, and reactant liquor concentration is spin-dried for, and uses dichloromethane (30mL) dissolve, washed with water (100mL × 3) and saturated aqueous common salt (100mL × 3) successively, anhydrous magnesium sulfate is dried, filter, By filtrate reduced in volume.Residue obtains pale yellow colored solid with silica gel column chromatography separating purification (petrol ether/ethyl acetate=4/1) The compound 1D (8.37g, yield 48%) of body shape.
4th step：2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (1E)
Methyl 2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetate
By palladium carbon, (10%) 1.38g, 3.60mmol add 2- (6- hydroxyl benzofuran -3- bases) methyl acetate 1D In methanol (65mL) solution of (7.38g, 35.79mmol), with hydrogen exchange reaction system 3 times, hydrogen, stirring reaction 18 are passed through Hour.Reacting liquid filtering, decompression are spin-dried for.Residue with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1), Obtain the compound 1E (4.50g, yield 60.4%) of white solid.
Intermediate 2：Bromo- 2,2,4,6- tetramethyl -2 of 5-, 3- Dihydrobenzofuranes -3- alcohol (2G)
5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol
The first step：Bromo- 3, the 5- dimethyl phenyl acetic acids esters (2B) of 4-
4-bromo-3,5-dimethylphenyl acetate
By acetic anhydride (12.10g, 119mmol), triethylamine (12.00g, 119mmol) adds bromo- 3, the 5- xylenols 2A of 4- In dichloromethane (50mL) solution of (20.00g, 99mmol), stirring reaction 2 hours under room temperature.Frozen water is added in reactant liquor (100mL) reaction is quenched, is extracted with dichloromethane (100mL × 3), merge organic faciess, saturated nacl aqueous solution (100mL × 3) Washing, uses anhydrous sodium sulfate drying organic faciess, filters, and concentrates the crude product that filtrate obtains brown liquid shape, is directly used in next Step reaction.
Second step：1- (bromo- 6- hydroxyl -2 of 3-, 4- dimethyl benzenes) ethyl ketone (2C)
1- (3-bromo-6-hydroxy-2,4-dimethylphenyl) ethanone
Bromo- 3,5- dimethyl phenyl acetic acids ester crude products 2B of 4- and aluminum chloride (19.7g, 148.1mmol) are added to In 1,2- dichloroethanes (200mL), backflow is warming up to, stirring reaction 2.5 hours, reaction system darkens.Mixture is used Ice-water bath is cooled to 0 DEG C, is slowly added dropwise 1M HC1 terminating reactions, water (100mL) dilution is added, with dichloromethane (100mL × 3) Extraction, merges organic faciess, saturated sodium-chloride water solution (200mL × 3) washing, anhydrous sodium sulfate drying, filtering and concentrating.Residue With petroleum ether/recrystallize with dichloromethane, White Flocculus 2C (16.0g, two step yields 66%) is obtained.
MS m/z(ESI)：241.0,243.0 [M-1]
1H NMR (300MHz, CDC13) δ 10.99 (s, 1H), 6.77 (s, 1H), 2.61 (s, 6H), 2.40 (s, 3H).
3rd step：Bromo- (bromo- 6- hydroxyl -2 of 3-, the 4- dimethyl benzenes) ethyl ketones (2D) of 2-
2-bromo-1- (3-bromo-6-hydroxy-2,4-dimethylphenyl) ethanone
By 1- (bromo- 6- hydroxyl -2 of 3-, 4- dimethyl benzenes) ethyl ketone 2C (10.0g, 41.14mmol), copper bromide (15.6g, In 69.85mmol) being dissolved in chloroform (100mL) and ethyl acetate (50mL) mixed solvent, stirring reaction is heated to reflux 4 hours.Instead Should terminate, reactant liquor ice-water bath is cooled to into room temperature, filter.Add water (100mL) dilution in filtrate, with ethyl acetate (100mL × 3) extract, merge organic faciess, washed with saturated sodium-chloride water solution (200mL × 1), anhydrous sodium sulfate drying organic faciess, mistake Filter, filtrate reduced in volume obtains crude product, is directly used in next step reaction.
4th step：Bromo- 4,6- dimethyl benzofurans -3 (2H) -one (2E) of 5-
5-bromo-4,6-dimethylbenzofuran-3 (2H)-one
It is bromo- (bromo- 6- hydroxyl -2 of 3-, 4- dimethyl benzenes) by product 2- is walked in sodium acetate (10.1g, 123.3mmol) addition In methanol (150mL) solution of ethyl ketone crude product 2D, stirring reaction 2 hours under room temperature.Reaction terminates, and adds water in reactant liquor (50mL) reaction is quenched, mixture concentrating under reduced pressure is removed into part methanol, 100mL is diluted with water to, with ethyl acetate (100mL × 3) extract, merge organic faciess, washed with saturated sodium-chloride water solution (200mL × 1), anhydrous magnesium sulfate is dried, and filters, and will filter Liquid concentrating under reduced pressure.Residue obtains faint yellow solid shape with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1) Compound 2E (5.4g, two step yields 55%).
1H NMR (300MHz, DMSO) δ 7.22 (s, 1H), 4.83 (s, 2H), 2.61 (s, 6H).
13C NMR (75MHz, CDCl3) δ 199.31,172.98,148.75,139.18,121.13,118.19,112.51, 75.11,25.54,17.64.
5th step：Bromo- (2H) -one (2F) of 2,2,4,6- tetramethyl benzofuran -3 of 5-
5-bromo-2,2,4,6-tetramethylbenzofuran-3 (2H)-one
Anhydrous and oxygen-free atmosphere, at -30 DEG C, by sodium hydride (125mg, 5.21mmol) bromo- 4, the 6- dimethyl of 5- is added to In dry tetrahydrofuran (20mL) solution of benzofuran -3 (2H) -one 2E (500mg, 2.07mmol), stir 20 minutes.To mixed Iodomethane (1.5g, 10.57mmol) is added in compound, reaction 3 hours is warmed to room temperature.Saturated ammonium chloride is added in reaction system Aqueous solution (50mL) is quenched reaction, and add water (10mL) dilution, is extracted with ethyl acetate (100mL × 3), merges organic faciess, with nothing Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure.Residue with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1), Obtain faint yellow solid shape compound 2F (482mg, yield 85%).
1H NMR (300MHz, CDC13) δ 6.83 (s, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 1.43 (s, 6H).
6th step：Bromo- 2,2,4,6- tetramethyl -2 of 5-, 3- Dihydrobenzofuranes -3- alcohol (2G)
5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol
Bromo- (2H) -one 2F (482mg, 1.79mmol) of 2,2,4,6- tetramethyl benzofuran -3 of 5- is dissolved in into methanol (4mL) In tetrahydrofuran (16mL) mixed solvent, under ice bath, point aliquot adds sodium borohydride (339mg, 8.96mmol), stirs under room temperature Mix reaction 0.5 hour.Reaction terminates, add water in mixture (15mL) be quenched reaction, concentration removes part reactant liquor, adds salt Sour (10mL, 1M) acidifying, is extracted with ethyl acetate (50mL × 3), merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate Concentrating under reduced pressure.Residue obtains white solid chemical combination with silica gel column chromatography separating purification (petroleum ether/dichloromethane=2/1) Thing 2G (450mg, yield 92%).
Intermediate 3：(S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (3D)
(S)-methyl 2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetate
The first step：
(S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid (R) phenethylamine salt (3B)
(R) -1-phenylethanaminium (S) -2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetate
2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid 3A (9.32g, 48mmol) is dissolved in into acetone (80mL) In, under being heated to reflux state, by the acetone soln (2.91g, 24mmol, 13mL) of R- phenethylamines, slow instillation reacts molten In liquid.After completion of dropwise addition, heating is closed so as to be slowly dropped to room temperature, be stirred overnight.Filter, precipitation uses a small amount of washing with acetone.Again 1N dilute hydrochloric acid is added thereto to, PH ＜ 2, plus ethyl acetate extraction, concentration is adjusted.Concentrate is dissolved in acetone (35mL) again, plus Heat is slow to instill in reaction solution by the acetone soln (1.53g, 12.7mmol) of R- phenethylamines to reflux state.Deca After end, heating is closed so as to be slowly dropped to room temperature, be stirred overnight.Filter, precipitation uses a small amount of washing with acetone, and this is precipitated Be dissolved in acetone (25mL), recrystallization obtain compound 3B (600mg, 60%).
Second step：(S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid (3C)
(S) -2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetic acid
(S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid (R) phenethylamine salt 3B is dissolved in into 1M hydrochloric acid water-soluble In liquid, ethyl acetate (50mL × 3) extraction is added, merge organic layer, anhydrous sodium sulfate drying is concentrated to give compound 3C (370mg, 99%),
3rd step：(S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (3D)
(S)-methyl 2- (6-hydroxy-2,3-dihydrobenzofuran-3-yl) acetate
Under room temperature, (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) acetic acid 3C is dissolved in methanol, the dense sulfur of Deca Sour 0.2mL, after being warming up to 50 DEG C of reactions 2 hours, plus saturated sodium bicarbonate aqueous solution terminating reaction, plus ethyl acetate (50mL × 3) extract, merge organic layer, anhydrous sodium sulfate drying, concentration, column chromatographic isolation and purification (silica gel 6.0g, petrol ether/ethyl acetate =5/1) eluting, obtains compound as white solid 3D (317mg, 80%, ee%=99%).
The absolute configuration of product is according to document (ACS Med.Chem.Lett.2010,1,290-294) and retention time It is determined that.
Embodiment 1
2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid (compound 1)
2- (6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：Bromo- 3- methoxyl group -2 of 5-, 2,4,6- tetramethyl -2,3- Dihydrobenzofuranes (1a)
5-bromo-3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran
Anhydrous and oxygen-free atmosphere, under ice-water bath, by sodium hydride (48mg, 1.99mmol) bromo- 2,2,4, the 6- tetramethyls of 5- is added Base -2, in dry tetrahydrofuran (15mL) solution of 3- Dihydrobenzofuranes -3- alcohol 2G (450mg, 1.66mmol), stir 20 points Clock.Iodomethane (471mg, 3.32mmol) is added in mixture, reaction 1 hour is warmed to room temperature.Reaction terminates, and adds saturation chlorine Change aqueous ammonium (15mL) and reaction is quenched, add water (25mL), extracted with ethyl acetate (30mL × 3).Merge organic faciess, use saturation Saline solution (30mL × 1) is washed, anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.Residue is separated with silica gel column chromatography Purification (petrol ether/ethyl acetate=4/1), obtains the compound 1a (360mg, yield 77%) of pale yellow oily liquid shape.
1H NMR (300MHz, CDCl3) δ 6.56 (s, 1H), 4.44 (s, 1H), 3.38 (s, 3H), 2.38 (d, 6H), 1.53 (s, 3H), 1.33 (s, 3H).
Second step：3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde (1b)
3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
By bromo- 3- methoxyl group -2 of 5-, 2,4,6- tetramethyl -2,3- Dihydrobenzofuranes 1a (350mg, 1.30mmol) and 3- Formylphenylboronic acid (210mg, 1.40mmol) is dissolved in aqueous sodium carbonate (10mL, 1M), adds toluene (15mL) and ethanol (5mL).With reaction system with nitrogen, tetrakis triphenylphosphine palladium (81mg, 0.07mmol) is added.Nitrogen atmosphere is kept, is heated up React 15 hours to 80 DEG C.Reaction terminates, and adds water in reactant liquor (5mL) and ethyl acetate (40mL), is filtered with kieselguhr.Filter Liquid is washed with saturated common salt aqueous solution (20mL × 3), anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.Residue silicon Plastic column chromatography isolates and purifies (petrol ether/ethyl acetate=14/1), obtains compound 1b (335mg, the product of pale yellow oily liquid Rate 83%).
3rd step：(3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol (1c)
(3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
By 3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde 1b (335mg, In 1.08mmol) being dissolved in methanol (4mL) and tetrahydrofuran (16mL) mixed solution, under ice bath, divide aliquot by sodium borohydride (204mg, 5.40mmol) is added in mixture, is warmed to room temperature reaction 1 hour.Reaction terminates, and adds water in reactant liquor (10mL) Reaction is quenched, concentrating under reduced pressure removes part reactant liquor.Add hydrochloric acid (6mL, 1M) in mixture, with ethyl acetate (30mL × 3) Extraction, merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.Residue silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1), obtains faint yellow thick solid 1c (322mg, yield 95%).
1H NMR (400MHz, CDCl3) δ 7.41 (t, 1H), 7.34 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 1H), 6.54 (s, 1H), 4.73 (d, 2H), 4.45 (d, 1H), 3.49 (s, 1H), 3.41 (d, 3H), 1.98 (d, 6H), 1.57 (s, 3H), 1.39 (s, 3H).
4th step：2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (1d)
Methyl 2- (6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
By (3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol 1c (130mg, 0.4mmol) and 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (100mg, 0.48mmol) is molten In dichloromethane (15mL).Reaction system with nitrogen, by tributylphosphine (178mg, 0.88mmol) and 1,1 '-(azo two Carbonyl) two piperidines (222mg, 0.88mmol) add mixture in, stirring reaction 2 hours under room temperature.Add in reactant liquor few Amount normal hexane, filters, and filtrate is concentrated.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=8/1) To faint yellow thick solid 1d (165mg, yield 82.1%).
5th step：2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 1)
2- (6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
Sodium hydroxide solution (1mL, 2M) is added into 2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- dihydros Benzofuran -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1d (200mg, 0.40mmol) is in first In alcohol (2mL) and tetrahydrofuran (4mL) mixed solvent, stirring reaction 2 hours under room temperature.Reaction terminates, and add water (20mL) dilution Reaction, it is 1 to be acidified to PH with the aqueous hydrochloric acid solution of 1M, and ethyl acetate (30mL × 3) extraction merges organic faciess, anhydrous sodium sulfate It is dried, filters, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=2/1) To the compound 1 (178mg, yield 91.3%) of white solid.
MS m/z(ESI)：487.0[M-1]
1H NMR (400MHz, DMSO) δ 12.33 (s, 1H), 7.44 (td, 1H), 7.38 (d, 1H), 7.14 (s, 1H), 7.08 (dd, 2H), 6.52 (s, 1H), 6.50-6.41 (m, 2H), 5.10 (d, 2H), 4.68 (t, 1H), 4.47 (s, 1H), 4.23- 4.10 (m, 1H), 3.75-3.55 (m, 1H), 3.36 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.90 (dd, 6H), 1.46 (s, 3H), 1.31 (s, 3H).
Embodiment 2
2- (6- ((3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid (compound 2)
2- (6- ((3- (3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofur an-3-yl) acetic acid
The first step：Bromo- 3- ethyoxyl -2 of 5-, 2,4,6- tetramethyl -2,3- Dihydrobenzofuranes (2a)
5-bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran
Anhydrous and oxygen-free atmosphere, under ice bath, by sodium hydride (80mg, 3.32mmol) bromo- 2,2,4,6- tetramethyl -2 of 5- is added, In dry tetrahydrofuran (20mL) solution of 3- Dihydrobenzofuranes -3- alcohol 2G (750mg, 2.76mmol), 20 points of stirring reaction Clock.Iodoethane (0.45mL, 3.52mmol) is added in mixture, reaction 5 hours is warmed to room temperature, is heated to reflux continuing to react 2 Hour, reaction terminates.Add water (20mL) dilute reaction solution, plus saturated aqueous ammonium chloride (10mL), with ethyl acetate (30mL × 3) extract.Merge organic faciess, with anhydrous sodium sulfate drying, filter, by filtrate reduced in volume.Residue is separated with silica gel column chromatography Purification (petrol ether/ethyl acetate=3/1), obtains the compound 2a (532mg, yield 64.4%) of weak yellow liquid shape.
1H NMR (400MHz, CDCl3) δ 6.55 (s, 1H), 4.51 (s, 1H), 3.56 (q, 2H), 2.37 (d, 6H), 1.52 (s, 3H), 1.34 (s, 3H), 1.22 (t, 3H).
Second step：3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde (2b)
3- (3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
By bromo- 3- ethyoxyl -2 of 5-, 2,4,6- tetramethyl -2,3- Dihydrobenzofuranes 2a (500mg, 1.67mmol) and 3- Formylphenylboronic acid (334mg, 2.23mmol) is dissolved in the mixing of sodium carbonate liquor (11mL, 1M), toluene (15mL) and ethanol (4mL) In solvent.With reaction system with nitrogen, tetrakis triphenylphosphine palladium (127mg, 0.11mmol) is added in mixture, keep nitrogen Atmosphere is enclosed, and is warming up to 80 DEG C of stirring reactions 21 hours.Reaction terminates, and add water (10mL) and ethyl acetate in reactant liquor (50mL), filtered with kieselguhr.Filtrate is washed with saturated common salt aqueous solution (30mL × 3), anhydrous sodium sulfate drying, is filtered, will Filtrate reduced in volume.Residue obtains faint yellow sticky with silica gel column chromatography separating purification (petrol ether/ethyl acetate=20/1) Solid, shaped compound 2b (435mg, yield 80.1%).
3rd step：3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol (2c)
(3- (3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
Under frozen water, in batches by sodium borohydride (254mg, 6.70mmol) add 3- (3- ethyoxyl -2,2,4,6- tetramethyls - 2,3- Dihydrobenzofuranes -5- bases) benzaldehyde 2b (435mg, 1.34mmol) mixes in methanol (5mL) and tetrahydrofuran (10mL) In solvent, stirring reaction is warmed to room temperature 0.5 hour.Reaction terminates, add water in reactant liquor (10mL) reaction, concentrating under reduced pressure is quenched Part reactant liquor is removed, saturated ammonium chloride solution (10mL) is added.Mixture is extracted with ethyl acetate (30mL × 3), is associated with Machine phase, with anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Residue with silica gel column chromatography separating purification (petroleum ether/ Ethyl acetate=8/1), obtain thick white shape solid 2c (400mg, yield 91.5%).
1H NMR (400MHz, DMSO) δ 7.38 (td, 1H), 7.28 (d, 1H), 7.04 (d, 1H), 7.00-6.93 (m, 1H), 6.51 (s, 1H), 5.21 (dd, 1H), 4.55 (d, 2H), 4.53 (s, 1H), 3.59 (tt, 2H), 1.91 (d, 6H), 1.45 (s, 3H), 1.31 (s, 3H), 1.12 (t, 3H).
4th step：2- (6- ((3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (2d)
Methyl 2- (6- ((3- (3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
By 3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol 2c (150mg, 0.46mmol) it is dissolved in dichloro with 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (115mg, 0.55mmol) In methane (15mL).Reaction system with nitrogen, by tributylphosphine (202mg, 1.00mmol) and 1,1 '-(azo dicarbapentaborane) two Piperidines (252mg, 1.00mmol) is added in mixture, stirring reaction 2 hours under room temperature.Add in reactant liquor it is a small amount of just oneself Alkane, filters, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=8/1) Colourless transparent oil liquid 2d (185mg, yield 77.9%).
5th step：2- (6- ((3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 2)
2- (6- ((3- (3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofur an-3-yl) acetic acid
Sodium hydrate aqueous solution (0.9mL, 2M) is added into 2- (6- ((3- (3- ethyoxyl -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 2d (185mg, 0.36mmoL) In methanol (2mL) and tetrahydrofuran (4mL) mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, to reactant liquor In add water (20mL) reaction is quenched, be acidified to pH for 1 with 1M aqueous hydrochloric acid solutions, extracted with ethyl acetate (30mL × 3), be associated with Machine phase, anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.Residue silica gel column chromatography separating purification (petroleum ether/second Acetoacetic ester=1.5/1), obtain the compound 2 (150mg, yield 83.4%) of white solid.
MS m/z(ESI)：501.2[M-1]
1H NMR (400MHz, CDCl3) δ 7.40 (dt, 2H), 7.18 (s, 1H), 7.08 (dd, 2H), 6.55-6.41 (m, 3H), 5.06 (s, 2H), 4.76 (t, 1H), 4.53 (d, 1H), 4.29 (dd, 1H), 3.91-3.74 (m, 1H), 3.67-3.48 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 1.97 (dd, 6H), 1.55 (s, 3H), 1.39 (s, 3H), 1.24 (t, 3H).
Embodiment 3
2- (6- ((3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) - 2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 3)
2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydroben zofuran-3-yl) acetic acid
The first step：2- (bromo- 4, the 6- dimethyl benzofurans -3- bases of 5-) acetonitrile (3a)
2- (5-bromo-4,6-dimethylbenzofuran-3-yl) acetonitrile
Anhydrous and oxygen-free atmosphere, at 0 DEG C, diethoxy cyanogen methyl phosphorodithioate (1.1g, 6.22mmol) is slowly added dropwise to hydrogen In changing tetrahydrofuran (20mL) solution of sodium (149mg, 6.22mmol), stir 10 minutes, by bromo- 4, the 6- dimethylbiphenyls furans of 5- The tetrahydrofuran solution of -3 (2H) -one 2E (1.0g, 4.15mmol) of muttering is slowly dropped in mixture, is risen to 35 DEG C and is continued to stir Reaction 3 hours.Saturated ammonium chloride solution (20mL) and water (20mL) are added in reactant liquor, is extracted with ethyl acetate (20mL × 3) Take, merge organic faciess, washed with saturated aqueous common salt (50mL × 1), anhydrous sodium sulfate drying organic faciess, filter, by filtrate decompression Concentration, uses petroleum ether.Residue with ethyl acetate recrystallization, obtains faint yellow solid shape compound 3a (870mg, yield 82.9%).
1H NMR (300MHz, DMSO) δ 7.95 (s, 1H), 7.52 (s, 1H), 4.26 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3H).
Second step：2- (bromo- 4, the 6- dimethyl benzofurans -3- bases of 5-) acetaldehyde (3b)
2- (5-bromo-4,6-dimethylbenzofuran-3-yl) acetaldehyde
Nitrogen atmosphere, at 0 DEG C, diisobutyl aluminium hydride (434mg, 3.05mmol) is slowly added dropwise to 2- (5- bromo- 4,6- Dimethyl benzofuran -3- bases) acetonitrile 3a (0.73g, 2.78mmol) toluene (30mL) solution in, stirring reaction 1.5 hours. Reaction terminates, and ether (10mL) and water (0.12mL) is added in reactant liquor, add sodium hydroxide solution (0.12mL, 15%), continue to stir 15 minutes.Add water again (3mL), continues to stir 15 minutes.Mixture is dried with anhydrous magnesium sulfate, is taken out Filter, by filtrate reduced in volume.Residue obtains pale red with silica gel column chromatography separating purification (petroleum ether/dichloromethane=2/1) Thick thing 3b (400mg, yield 52.6%).
1H NMR (300MHz, DMSO) δ 9.79 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 4.06 (s, 2H), 2.50 (s, 6H).
3rd step：2- (bromo- 4, the 6- dimethyl benzofurans -3- bases of 5-) ethanol (3c)
2- (5-bromo-4,6-dimethylbenzofuran-3-yl) ethanol
2- (bromo- 4, the 6- dimethyl benzofurans -3- bases of 5-) acetaldehyde 2b is dissolved in methanol (3mL) and tetrahydrofuran (10mL) In mixed solvent, at 0 DEG C, sodium borohydride (124mg, 3.28mmol) is added in mixture, stirring reaction 0.5 hour.Reaction Terminate, add water in reactant liquor (5mL) be quenched reaction, concentration of reaction solution removing part organic solvent.Add water (10mL) dilution, uses Ethyl acetate (10mL × 3) is extracted, and merges organic faciess, is washed with saturated aqueous common salt (30mL × 1), and anhydrous sodium sulfate drying is organic Phase, silica gel column chromatography separating purification (petrol ether/ethyl acetate=9/1) obtains faint yellow solid 3c (251mg, yield 71.3%).
4th step：Bromo- 3- methoxyethyl -4 of 5-, 6- dimethyl benzofurans (3d)
5-bromo-3- (2-methoxyethyl) -4,6-dimethylbenzofuran
In nitrogen atmosphere, iodomethane (198mg, 1.40mmol) is added into 2- (bromo- 4, the 6- dimethyl benzofurans -3- of 5- Base) ethanol 3c (251mg, 0.93mmol) tetrahydrofuran (10mL) solution in, stir 20 minutes.By sodium hydride (34mg, 1.40mmol) add in mixed solution, be warming up to 40 DEG C of stirring reactions 5 hours, be heated to backflow and continue to react 2 hours.Reaction Terminate, saturated ammonium chloride solution (5mL) and water (10mL) are added in reactant liquor, extracted with petroleum ether (30mL × 3), be associated with Machine phase, is washed, anhydrous sodium sulfate drying organic faciess with saturated aqueous common salt (30mL × 1), is filtered, by filtrate reduced in volume.Residual Thing with silica gel column chromatography separating purification (petroleum ether/dichloromethane=3/1), obtain faint yellow solid shape compound 3d (260mg, Yield 98%).
1H NMR (400MHz, DMSO) δ 7.71 (s, 1H), 7.43 (s, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 3.00 (t, 2H), 2.64 (s, 3H), 2.44 (s, 3H).
5th step：3- (3- (2- methoxyethyls) -4,6- dimethyl benzofuran -5- bases) benzaldehyde (3e)
3- (3- (2-methoxyethyl) -4,6-dimethylbenzofuran-5-yl) benzaldehyde
By bromo- 3- methoxyethyl -4 of 5-, 6- dimethyl benzofuran 3d (260mg, 0.92mmol) and 3- formoxyl benzene boron Sour (151mg, 1.01mmol) is dissolved in aqueous sodium carbonate (2.8mL, 1M), adds toluene (5mL) and ethanol (5mL).Use nitrogen Gas replaces reaction system, and tetrakis triphenylphosphine palladium (53mg, 0.045mmol) is added in mixture.Nitrogen atmosphere is kept, is heated up To 80 DEG C of stirring reactions 24 hours.Reaction terminates, and saturated ammonium chloride solution (20mL) and water (5mL) are added in reactant liquor, uses Ethyl acetate (30mL × 3) is extracted, and merges organic faciess, and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying is organic Phase, filters, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=14/1) Colorless viscous shape thing shape compound 3e (170mg, yield 60%).
1H NMR (400MHz, DMSO) δ 10.07 (s, 1H), 7.94 (d, 1H), 7.74-7.68 (m, 3H), 7.52 (dd, 1H), 7.35 (s, 1H), 3.62 (t, 2H), 3.29 (s, 3H), 3.02 (t, 2H), 2.23 (s, 3H), 2.01 (s, 3H).
6th step：(3- (3- (2- methoxyethyls) -4,6- dimethyl benzofuran -5- bases) phenyl) methanol (3f)
(3- (3- (2-methoxyethyl) -4,6-dimethylbenzofuran-5-yl) phenyl) methanol
Under condition of ice bath, sodium borohydride (42mg, 1.10mmol) is added into 3- (3- (2- methoxyethyls) -4,6- dimethyl Benzofuran -5- bases) benzaldehyde 3e (170mg, 0.55mmol) is in the mixed solvent of tetrahydrofuran (5mL) and methanol (2mL) Solution in, stirring reaction 0.5 hour.(13mL) termination that adds water in reactant liquor is quenched reaction, with ethyl acetate (10mL × 3) Extraction, organic layer is washed with saturated aqueous common salt (30mL × 1), with anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.It is residual Stay thing silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1), obtain colorless viscous shape compound 3f (151mg, Yield 88%).
7th step：(3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol (3g)
(3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl)methanol
By (3- (3- (2- methoxyethyls) -4,6- dimethyl benzofuran -5- bases) phenyl) methanol 3f (151mg, In 0.49mmol) being dissolved in methanol (6mL) and tetrahydrofuran (3mL) mixed solvent, by palladium carbon (30mg, palladium content w/w=10%) In being added to mixture.Hydrogen exchange reaction system, is stirred at room temperature reaction 1 hour, is warming up to 55 DEG C of continuation reactions 7 little When.With ethyl acetate (15mL) dilute reaction solution, kieselguhr filtration, add water in filtrate (10mL).With ethyl acetate (10mL × 3) Extraction, organic layer is washed with saturated aqueous common salt (30mL × 1), anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.Residual Thing obtains colorless oil compound 3g (91mg, yield with silica gel column chromatography separating purification (petroleum ether/dichloromethane=1/1) 59%).
1H NMR (400MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.08-6.91 (m, 2H), 6.55 (s, 1H), 5.20 (t, 1H), 4.53 (dd, 2H), 4.42 (d, 2H), 3.47-3.36 (m, 4H), 3.24 (s, 3H), 1.89 (s, 6H).
8th step：2- (6- ((3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (3h)
Methyl 2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, at 0 DEG C, (3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) Phenyl) methanol 3g (82mg, 0.26mmoL), 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (66mg, In 0.32mmoL) being dissolved in dry dichloromethane (10mL) solution, by tributylphosphine (115mg, 0.57mmoL), 1,1 '-(azo Dicarbapentaborane) two piperidines (144mg, 0.57mmoL) add mixture in, be warmed to room temperature stirring reaction 6 hours, TLC plates tracking reaction Terminate.By reactant liquor concentrating under reduced pressure, residue silica gel column chromatography analysis purification (petrol ether/ethyl acetate=6/1), obtain Colorless oil 3h (92mg, yield 70.2%).
9th step：2- (6- ((3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 3)
2- (6- ((3- (3- (2-methoxyethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydroben zofuran-3-yl) acetic acid
Sodium hydrate aqueous solution (1mL, 1M) is added into 2- (6- ((3- (3- (2- methoxyethyls) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3h (92mg, 0.18mmoL) Tetrahydrofuran (5mL) solution in, stirring reaction 1 hour under room temperature.Reactant liquor concentration is removed into partial solvent, it is molten with 1M hydrochloric acid Liquid adjusts pH≤3, is extracted with ethyl acetate (10mL × 2), merges organic faciess, saturated aqueous common salt (10mL × 1) washing, with anhydrous Sodium sulfate is dried, and filters, by filtrate reduced in volume.Residue silica gel column chromatography isolate and purify (methylene chloride/methanol= 10/1) white solid compound 3 (71mg, yield 79%), is obtained.
ESIMS[M+H]+：489.0.
1H NMR (400MHz, DMSO) δ 12.36 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.08 (dt, 3H), 6.55 (s, 1H), 6.46 (t, 2H), 5.09 (s, 2H), 4.68 (t, 1H), 4.42 (d, 2H), 4.18 (dd, 1H), 3.71-3.60 (m, 1H), 3.483.36 (m, 3H), 3.24 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.86 (s, 6H), 1.90-1.78 (m, 1H), 1.63 (m, 1H).
Embodiment 4
2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydrobenzo furans Mutter -3- bases) acetic acid (compound 4)
2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2,3- dihydrobenzofuran-3-yl)acetic acid
The first step：Bromo- 4,6- dimethyl -2 of 5-, 3- Dihydrobenzofuranes -3- alcohol (4a)
5-bromo-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol
Under ice bath, sodium borohydride (0.24g, 6.22mmol) is added in batches bromo- 4, the 6- dimethyl benzofurans -3 of 5- (2H) in mixed solution of -one 2E (0.50g, 2.07mmol) in tetrahydrofuran (10mL) and methanol (2mL) mixed solvent, rise React 0.5 hour to being stirred at room temperature.Add water (15mL) dilution in reactant liquor, is extracted with ethyl acetate (20mL × 3), organic layer Washed with saturated aqueous common salt (50mL × 1), with anhydrous sodium sulfate drying, filtered, by filtrate reduced in volume.Residue silicagel column Chromatography purification (petrol ether/ethyl acetate=6/1), obtains white solid compound 4a (400mg, yield 79%).
Second step：Bromo- 4, the 6- dimethyl benzofurans (4b) of 5-
5-bromo-4,6-dimethylbenzofuran
P-methyl benzenesulfonic acid (568mg, 3.30mmol) is added into bromo- 4,6- dimethyl -2 of 5-, 3- Dihydrobenzofuranes -3- alcohol In toluene (20mL) solution of 4a (400mg, 1.65mmol), stirring reaction is heated to reflux 15 minutes, reaction terminates.By reactant liquor Room temperature is cooled to, add water (15mL) dilution, is extracted with petroleum ether (10mL × 3), saturated aqueous common salt (30mL × 1) washing, with nothing Aqueous sodium persulfate is dried, and filters, by filtrate reduced in volume.Residue obtains colourless with silica gel column chromatography separating purification (petroleum ether) Liquid shape compound 4b (363mg, yield 97%).
1H NMR (400MHz, DMSO) δ 7.96 (d, 1H), 7.49 (s, 1H), 7.07 (d, 1H), 2.54 (s, 3H), 2.46 (s, 3H).
3rd step：3- (4,6- dimethyl benzofuran -5- bases) benzaldehyde (4c)
3- (4,6-dimethylbenzofuran-5-yl) benzaldehyde
Toluene (10mL) and ethanol (5mL) are added into bromo- 4, the 6- dimethyl benzofurans 4b (363mg, 1.61mmol) of 5- In the sodium carbonate liquor (4.8mL, 1M) of 3- formylphenylboronic acids (266mg, 1.77mmol).With reaction system with nitrogen, Tetrakis triphenylphosphine palladium (93mg, 0.08mmol) is added in mixture.Nitrogen atmosphere is kept, 80 DEG C of stirring reactions 24 are warming up to Hour.Reaction terminates, and mixture is filtered, filtrate add water (10mL) dilution, with ethyl acetate (30mL × 3) extract, be associated with Machine phase, is washed, anhydrous sodium sulfate drying organic faciess with saturated aqueous common salt (50mL × 1), is filtered, by filtrate reduced in volume.Residual Thing obtains colorless oil 4c (249mg, yield with silica gel column chromatography separating purification (petrol ether/ethyl acetate=8/1) 61.8%).
1H NMR (400MHz, DMSO) δ 10.07 (s, 1H), 7.94 (t, 2H), 7.74-7.69 (m, 2H), 7.54 (d, 1H), 7.40 (s, 1H), 7.02 (d, 1H), 2.13 (s, 3H), 2.05 (s, 3H).
4th step：(3- (4,6- dimethyl benzofuran -5- bases) phenyl) methanol (4d)
(3- (4,6-dimethylbenzofuran-5-yl) phenyl) methanol
Under condition of ice bath, sodium borohydride (112mg, 2.96mmol) is added into 3- (4,6- dimethyl benzofuran -5- bases) Benzaldehyde 4c (247mg, 0.99mmol) is in the mixed solvent of tetrahydrofuran (10mL) and methanol (3mL), and stirring reaction 0.5 is little When.Add water in reactant liquor (15mL) reaction is quenched, with ethyl acetate (10mL × 3) extract, organic layer saturated aqueous common salt (30mL × 1) washs, and with anhydrous sodium sulfate drying, filters, and by filtrate reduced in volume, (241mg is produced to obtain colorless oil 4d Rate 96%).
ESIMS[M+H]+：255.1.
5th step：(3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol (4e)
(3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
(3- (4,6- dimethyl benzofuran -5- bases) phenyl) methanol 4d (241mg, 0.96mmol) is dissolved in methanol (10mL) In tetrahydrofuran (5mL) mixed solvent, by palladium carbon, (10%) 48mg is added in mixture.Hydrogen exchange reaction system is used, Stirring reaction 24 hours at 35 DEG C, are warming up to 55 DEG C and continue to react 48 hours.With ethyl acetate (15mL) dilute reaction solution, diatom Soil is filtered, by filtrate reduced in volume.Residue obtains nothing with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1) Color grease 4e (190mg, yield 78%).
6th step：2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydros Benzofuran -3- bases) methyl acetate (4f)
Methyl 2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy)- 2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, at 0 DEG C, (3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol 4e (130mg, 0.51mmoL), 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (128mg, 0.61mmoL) is molten In dry dichloromethane (10mL), by tributylphosphine (227mg, 1.12mmoL), 1,1 '-(azo dicarbapentaborane) two piperidines (283mg, 1.12mmoL) is added in mixture, is warmed to room temperature reaction 2 hours.Reacting liquid filtering is removed into insoluble matter, by filtrate Concentrating under reduced pressure, residue silica gel column chromatography analysis purification (petrol ether/ethyl acetate=7/1), obtains pale yellow oil 4f (190mg, yield 84%).
7th step：2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydros Benzofuran -3- bases) acetic acid (compound 4)
2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2,3- dihydrobenzofuran-3-yl)acetic acid
Sodium hydrate aqueous solution (5mL, 2M) is added into 2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 4f (190mg, 0.43mmoL) tetrahydrofuran (5mL) In solution, reaction is stirred at room temperature overnight.PH≤2 of reactant liquor are adjusted with dilute hydrochloric acid, is extracted with ethyl acetate (10mL × 3), closed And organic faciess, saturated aqueous common salt (50mL × 1) washing, with anhydrous sodium sulfate drying, filter, by filtrate reduced in volume.Residue (petrol ether/ethyl acetate=1.5/1) is isolated and purified with silica gel column chromatography, (170mg is produced to obtain white solid compound 4 Rate 92.4%).
ESIMS[M-H]-：429.1.
1H NMR (400MHz, DMSO) δ 12.35 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.16-7.01 (m, 3H), 6.53 (s, 1H), 6.47 (m, 2H), 5.09 (s, 2H), 4.68 (t, 1H), 4.52 (t, 2H), 3.66 (m, 1H), 3.34 (s, 2H), 3.09 (t, 2H), 2.69 (dd, 1H), 1.87 (s, 3H), 1.83 (s, 3H).
Embodiment 5
2- (6- ((3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) oxygen Base) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 5)
2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：Bromo- 2, the 2- bis- (methylol) of 5- -4,6- dimethyl benzofurans -3 (2H) -one (5a)
5-bromo-2,2-bis (hydroxymethyl) -4,6-dimethylbenzofuran-3 (2H)-one
Potassium carbonate (1.2g, 8.69mmol), methanol (20mL) and water (20mL) are added to into bromo- 4, the 6- dimethylbiphenyls of 5- In tetrahydrofuran (40mL) solution of furan -3 (2H) -one 2E (1.0g, 4.16mmol), then by formalin (0.85g, 10.41mmol, 37.6%) adds in mixture, stirring reaction 0.5 hour under room temperature.Reactant liquor concentration is removed into partial solvent, Add water (50mL) dilution, with ethyl acetate (60mL × 3) extract, merge organic faciess, and successively with saturated aqueous common salt (100mL × 2) wash with water (100mL × 2).Anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is spin-dried for, and obtains white solid Compound 5a (1.18g, yield 94%).
MS m/z(ESI)：252.9,255.0 [M-31]
1H NMR (300MHz, DMSO) δ 7.15 (s, 1H), 5.08 (t, 2H), 3.67 (d, 4H), 2.57 (s, 3H), 2.45 (s, 3H).
Tetra A., 2008,19,2497-2507
Second step：Bromo- 2, the 2- bis- (methoxyl methyl) of 5- -4,6- Dimethvl-benzofurans -3 (2H) -one (5b)
5-bromo-2,2-bis (methoxymethyl) -4,6-dimethylbenzofuran-3 (2H)-one
Anhydrous and oxygen-free atmosphere, under ice bath, by sodium hydride, (60%) 0.5g, 12.45mmol add in batches 5- bromo- 2,2- The dry tetrahydrofuran (38mL) of two (methylol) -4,6- dimethyl benzofurans -3 (2H) -one 5a (1.59g, 4.98mmol) In solution, stirring reaction 20 minutes, then iodomethane (1.5mL, 24.90mmol) is added in mixture.It is warmed to room temperature and continues to stir Reaction 3 hours is mixed, reaction terminates.Water (25mL) and saturated ammonium chloride solution (25mL) are added in reactant liquor, ethyl acetate is used (50mL × 3) extract, and merge organic faciess and are washed with saturated aqueous common salt (100mL × 2).Anhydrous sodium sulfate drying, filters, and will filter Liquid concentrating under reduced pressure.Residue obtains white solid with silica gel column chromatography separating purification (petrol ether/ethyl acetate=14/1) Compound 5b (734mg, yield 46%).
MS m/z(ESI)：329.0,330.9 [M+1]
1H NMR (400MHz, DMSO) δ 7.18 (s, 1H), 3.65 (s, 4H), 3.17 (s, 6H), 2.57 (s, 3H), 2.44 (s, 3H).
3rd step：Bromo- 2, the 2- bis- (methoxyl methyl) of 5- -- 4,6- dimethyl -2,3- Dihydrobenzofuranes -3- alcohol (5c)
5-bromo-2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-3- ol
Under ice bath, sodium borohydride (328mg, 8.66mmol) point aliquot is added into bromo- 2, the 2- bis- (methoxyl methyl) -4,6- of 5- The methanol (5mL) and tetrahydrofuran (10mL) mixed solution of Dimethvl-benzofuran -3 (2H) -one 5b (570mg, 1.73mmol) In, it is warmed to room temperature reaction 0.5 hour.Add water in reaction system (10mL) be quenched reaction, add saturated ammonium chloride solution (15mL), extracted with ethyl acetate (20mL × 3), merge organic faciess and washed with water (50mL × 2), anhydrous sodium sulfate drying, Filter, by reactant liquor concentrating under reduced pressure.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=10/1) Colorless and transparent liquid 5c (572mg, yield 99%).
4th step：Bromo- 2,2- bis- (methoxyl methyl) -4,6- dimethyl -2 of 5-, 3- Dihydrobenzofuranes (5d)
5-bromo-2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran
Anhydrous and oxygen-free atmosphere, under ice bath, by triethyl group hydrogen silane (16.3mL, 102.10mmol) bromo- 2, the 2- bis- of 5- is added (methoxyl methyl) -- 4,6- dimethyl -2, the dry methylene chloride of 3- Dihydrobenzofuranes -3- alcohol 5c (573mg, 1.73mmol) (20mL) in, then trifluoroacetic acid (1.03mL, 13.80mmol) is slowly added dropwise, stirring reaction 2 hours.Two are added in reactant liquor Chloromethanes (20mL) and saturated sodium bicarbonate solution (20mL), stir 10 minutes, add water (10mL), point liquid.Water layer acetic acid Ethyl ester (30mL × 2) is extracted, and merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.Residue silica gel Column chromatographic isolation and purification (petrol ether/ethyl acetate=30/1), obtains white solid 5d (480mg, yield 88%).
1H NMR (400MHz, DMSO) δ 6.61 (s, 1H), 3.46 (d, 4H), 3.28 (s, 6H), 3.01 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H)
5th step：3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde (5e)
3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
3- formylphenylboronic acids (247.4mg, 1.65mmol) and sodium carbonate liquor (6.5mL, 1M) are added into 5- bromo- 2,2- Two (methoxyl methyl) -4,6- dimethyl -2, in toluene (15mL) solution of 3- Dihydrobenzofuranes 5d (510mg, 1.62mmol), Add ethanol (3mL).Under nitrogen atmosphere, tetrakis triphenylphosphine palladium (93.6mg, 0.08mmol) is added in reaction system, risen Warm to 80 DEG C, stirring reaction 18 hours.Reaction terminates, and add water (10mL) dilution in reactant liquor, plus ethyl acetate (50mL) is dilute Release.Filtered with kieselguhr, organic layer is washed with saturated aqueous common salt (20mL × 3), anhydrous sodium sulfate drying, filtered, filtrate is subtracted Pressure concentration.Residue obtains colourless transparent oil liquid with silica gel column chromatography separating purification (petrol ether/ethyl acetate=12/1) 5e (410mg, yield 74%).
6th step：(3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol (5f)
(3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl)methanol
Under condition of ice bath, sodium borohydride (228mg, 6.03mmol) is dividedly in some parts into 3- (2,2- bis- (methoxyl methyl) -4,6- Dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde 5e (410mg, 1.20mmol) tetrahydrofuran (8mL) and methanol (4mL) in mixed solvent.Reaction 15 minutes is stirred at room temperature.Add water in reactant liquor (10mL) be quenched reaction, remove partial solvent, Saturated ammonium chloride solution (15mL) is added, is extracted with ethyl acetate (25mL × 3), merged organic faciess and done with anhydrous sodium sulfate It is dry, filter, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1) Colourless transparent oil liquid 5f (380mg, yield 92%).
1H NMR (400MHz, DMSO) δ 7.37 (t, 1H), 7.27 (d, 1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.49 (s, 1H), 5.19 (t, 1H), 4.53 (d, 2H), 3.57-3.42 (m, 4H), 3.31 (s, 6H), 2.95 (s, 2H), 1.88 (s, 3H), 1.81 (s, 3H).
7th step：2- (6- ((3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (5g)
Methyl2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) 2,3-dihydrobenzofuran-3-yl) acetate
2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (110mg, 0.53mmol) is added into (3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol 5f's (150mg, 0.44mmol) In dry methylene chloride (15mL) solution, under nitrogen atmosphere, by tributylphosphine (0.24mL, 0.97mmol) and the formyl two of azo two Piperidines (245mg, 0.97mmol) is added in mixed liquor.Stirring reaction 2 hours under room temperature, add in reactant liquor it is a small amount of just oneself Alkane, mixture is filtered, filtrate reduced in volume.Rapid column chromatography (petrol ether/ethyl acetate=6/1) obtains crude product and straight Connect for next step reaction.Med.Chem.lett., 2010,1,290-294
8th step：2- (6- ((3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 5)
2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The methanol (2mL) and tetrahydrofuran of reacting coarse product will be walked in sodium hydrate aqueous solution (1.1mL, 2M) addition (4mL) in mixed solvent, stirring reaction 1.5 hours under room temperature.By reactant liquor concentrating under reduced pressure, add water (20mL) dilution, uses 1M salt It is 1 that acid is acidified to pH, is extracted with ethyl acetate (30mL × 3), merges organic faciess and simultaneously uses anhydrous sodium sulfate drying, is filtered, and will be filtered Liquid concentrating under reduced pressure.Residue obtains compound as white solid with silica gel column chromatography separating purification (methylene chloride/methanol=40/1) 5 (168mg, two step yields 73%).
MS m/z(ESI)：517.2[M-1]
1H NMR (400MHz, CDCl3) δ 7.45-7.33 (m, 2H), 7.16 (s, 1H), 7.06 (t, 2H), 6.57 (s, 1H), 6.53-6.42 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.81 (dt, 1H), 3.68-3.51 (m, 4H), 3.44 (s, 6H), 3.00 (s, 2H), 2.89-2.74 (m, 1H), 2.61 (dd, 1H), 1.91 (d, 6H).
Embodiment 6
2- (6- (3- (2- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid (compound 6)
2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：Bromo- 1, the 3- dimethyl benzenes (6a) of 5- allyloxy -2-
5- (allyloxy) -2-bromo-1,3-dimethylbenzene
Potassium carbonate (20.6g, 0.15mol) and 3- bromopropenes (8.6mL, 0.10mol) are added into bromo- 3, the 5- xylenols 2A of 4- In acetonitrile (200mL) solution of (10.0g, 0.05mol), stirring reaction is heated to reflux 6 hours.Reaction terminates, by reaction mixing Thing is filtered, filtrate reduced in volume.Residue obtains light with silica gel column chromatography separating purification (petrol ether/ethyl acetate=50/1) Yellow oily liquid 6a (10.9g, yield 90%).
1H NMR (400MHz, CDCl3) δ 6.66 (s, 2H), 6.03 (ddd, 1H), 5.33 (dd, 2H), 4.48 (d, 2H), 2.37 (s, 6H).
Second step：The bromo- MXs of 2- pi-allyl -4- (6b)
2-allyl-4-bromo-3,5-dimethylphenol
Anhydrous and oxygen-free atmosphere, by bromo- 1, the 3- dimethyl benzenes 6a (7.5g, 0.03mol) of 5- allyloxy -2- 180 are heated to DEG C reaction 6 hours.Reaction system is cooled to into room temperature, dichloromethane (50mL) is added, solution decompression is concentrated, residue silicon Plastic column chromatography isolates and purifies (petrol ether/ethyl acetate=20/1), obtains pale yellow solid shape compound 6b (1.94g, yield 25%).
1H NMR (400MHz, DMSO) δ 9.44 (s, 1H), 6.68 (s, 1H), 5.82 (dt, 1H), 5.00-4.79 (m, 2H), 3.38 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H).
3rd step：(bromo- 4,6- dimethyl -2 of 5-, 3 Dihydrobenzofuranes -2- bases) methanol (6c)
(5-bromo-4,6-dimethyl-2,3-dihydrobenzofuran-2-yl) methanol
Metachloroperbenzoic acid (538mg, 3.11mol) is added into the bromo- MX 6b of 2- pi-allyl -4- In 1,2- dichloroethanes (20mL) solution of (500mg, 2.07mol), 70 DEG C of stirring reactions are heated to 4 hours.Reaction terminates, will Reactant liquor is cooled to room temperature, adds saturated sodium thiosulfate solution (10mL), stirs 15 minutes.Saturated carbon is added in mixed liquor Acid sodium solution (30mL), continues to stir 30 minutes.Extracted with ethyl acetate (40mL × 3), merge organic faciess, saturated sodium carbonate is molten Liquid (30mL × 2) is washed, anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.Residue silica gel column chromatography separating purification (petrol ether/ethyl acetate=10/1-6/1), obtains white solid compound 6c (286mg, yield 53%).
1H NMR (400MHz, DMSO) δ 6.61 (s, 1H), 4.99 (t, 1H), 4.84-4.73 (m, 1H), 3.60-3.48 (m, 2H), 3.16 (dd, 1H), 2.93 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).
4th step：The bromo- 2- of 5- (methoxyl methyl) -4,6- dimethyl -2,3 Dihydrobenzofuranes (6d)
5-bromo-2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran
Anhydrous and oxygen-free atmosphere, under ice bath, sodium hydride (40mg, 1.67mmol) is dividedly in some parts (bromo- 4, the 6- dimethyl of 5-- 2,3 Dihydrobenzofuranes -2- bases) methanol 6c (286mg, 1.11mmol) dry tetrahydrofuran (20mL) solution in, stirring 20 Minute.Iodomethane (788mg, 5.55mmol) is added in mixed liquor, stirring reaction is warmed to room temperature 2 hours.Add in reactant liquor Water (10mL) is quenched reaction, plus saturated ammonium chloride solution (15mL), is extracted with ethyl acetate (25mL × 3), and organic faciess are with anhydrous Sodium sulfate is dried, and filters, by filtrate reduced in volume.Residue with silica gel column chromatography separating purification (petrol ether/ethyl acetate= 10/1) colourless transparent oil liquid 6d (270mg, yield 89%), is obtained.
1H NMR (400MHz, DMSO) δ 6.62 (s, 1H), 4.93 (ddt, 1H), 3.50 (dd, 2H), 3.29 (s, 3H), 3.21 (dd, 1H), 2.90 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).
5th step：3- (2- (methyl methoxy base) -4,6- dimethyl -2,3 Dihydrobenzofuranes -5- bases) benzaldehyde (6e)
3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
By sodium carbonate liquor (4.8mL, 1M) and ethanol (2.5mL) add bromo- 2- (methoxyl methyl) -4, the 6- dimethyl of 5- - The toluene (10mL) of 2,3 Dihydrobenzofuranes 6d (260mg, 0.96mmol) and 3- formylphenylboronic acids (159mg, 1.06mmol) In solution, bubbling 30 minutes and nitrogen atmosphere is kept in mixed liquor with nitrogen, by tetrakis triphenylphosphine palladium (58mg, 0.05mmol) add in mixture.Reactant liquor is heated to into 80 DEG C, stirring reaction 18 hours is cooled to room temperature.To in mixture Add water (8mL) and ethyl acetate (40mL), filtered with kieselguhr, filtrate layered, organic layer saturated aqueous common salt (30mL × 2) is washed Wash, anhydrous sodium sulfate drying, filter, by filtrate reduced in volume.Residue silica gel column chromatography isolates and purifies (petroleum ether/second Acetoacetic ester for=14/1), obtain pale yellow oily liquid 6e (260mg, yield 91%).
6th step：(3- (2- (methyl methoxy base) -4,6- dimethyl -2,3 Dihydrobenzofuranes -5- bases) benzyl alcohol (6f)
(3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
Under condition of ice bath, sodium borohydride (134mg, 3.55mmol) is dividedly in some parts into 3- (2- (methyl methoxy base) -4,6- bis- Methyl -2,3 Dihydrobenzofuranes -5- bases) benzaldehyde 6e (260mg, 0.71mmol) tetrahydrofuran (6mL) and methanol (3mL) In mixed solvent, stirring reaction is warmed to room temperature 0.5 hour.Add water in reactant liquor (5mL) be quenched reaction, remove partial solvent, Add saturated ammonium chloride solution (15mL).Extracted with ethyl acetate (20mL × 3), anhydrous sodium sulfate drying, filtered, filtrate is subtracted Pressure concentration.Residue silica gel column chromatography isolates and purifies (petrol ether/ethyl acetate is=5/1), obtains water white transparency oily Liquid 6f (255mg, yield 97%).
7th step：2- (6- ((3- (2- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (6g)
Methyl 2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.13mL, 0.52mmol) and azodicarbonyldipiperidine (130.9mg, 0.52mmol) add (3- (2- (methyl methoxy base) -4,6- dimethyl -2,3 Dihydrobenzofuranes -5- bases) benzyl alcohol 6f (70.0mg, 0.23mmol) and 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (58.9mg, In dry methylene chloride (8mL) solution 0.28mmol).Reactant liquor is warmed to room temperature, stirring reaction 2 hours.To in reactant liquor A small amount of normal hexane is added, insoluble matter in mixture, concentrating under reduced pressure filtrate is filtered to remove.Residue silica gel column chromatography analyzes pure Change (petrol ether/ethyl acetate=6/1), obtain white solid compound 6g (90mg, yield 78%).
1H NMR (400MHz, DMSO) δ 7.44 (t, 1H), 7.37 (d, 1H), 7.16-6.99 (m, 3H), 6.51 (s, 1H), 6.47 (d, 2H), 5.09 (s, 2H), 4.98-4.89 (m, 1H), 4.67 (t, 1H), 4.20 (dd, 1H), 3.77-3.66 (m, 1H), 3.63 (s, 3H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, 1H), 2.84 (dd, 1H), 2.77 (dd, 1H), 2.59 (dd, 1H), 1.86 (s, 3H), 1.80 (s, 3H).
8th step：2- (6- ((3- (2- (methoxyl methyl)-(4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 6)
2- (6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenz ofuran-3-yl) acetic acid
Sodium hydroxide solution (0.87mL, 2M) is added into 2- (6- ((3- (2- (methoxyl methyl) -4,6- dimethyl -2,3- bis- Hydrogen benzofuran -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 6g (170mg, 0.35mmol) In methanol (2mL) and tetrahydrofuran (4mL) mixed solvent.Stirring reaction 1.5 hours under room temperature, add water in reactant liquor (20mL) it is 1, to adjust pH with 1M hydrochloric acid.Extracted with ethyl acetate (30mL × 3), organic faciess anhydrous sodium sulfate drying, filtered, will Filtrate reduced in volume is spin-dried for.Residue obtains white solid with silica gel column chromatography separating purification (methylene chloride/methanol=50/1) Shape compound 6 (155mg, yield 93%).
MS m/z(ESI)：473.2[M-1]
1H NMR (400MHz, CDCl3) δ 7.40 (dd, 2H), 7.16 (d, 1H), 7.06 (dd, 2H), 6.59 (s, 1H), 6.536.43 (m, 2H), 5.05 (s, 2H), 5.02-4.91 (m, 1H), 4.76 (t, 1H), 4.29 (dd, 1H), 3.81 (td, 1H), 3.63 (ddd, 2H), 3.46 (s, 3H), 3.19 (dd, 1H), 2.89 (dd, 1H), 2.81 (dd, 1H), 2.62 (dd, 1H), 1.95 (s, 3H), 1.88 (s, 3H).
Embodiment 7
(3S) 2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) oxygen Base) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 7)
(3S) 2- (- 6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5- Yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：(3S) 2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate
(3S) methyl 2- (- 6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate (7a)
By (3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol 1c (100mg, 0.32mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (80mg, In 0.38mmol) being dissolved in dichloromethane (10mL).Reaction system with nitrogen, by tributylphosphine (142mg, 0.70mmol) and 1, 1 '-(azo dicarbapentaborane) two piperidines (178mg, 0.70mmol) is added in mixture, stirring reaction 2 hours under room temperature.To reaction A small amount of normal hexane is added in liquid, is filtered, by filtrate reduced in volume.Residue silica gel rapid column chromatography (petrol ether/ethyl acetate =8/1), obtain colourless transparent oil liquid crude product.
Second step：(3S) 2- (6- ((3- (3- methoxyl group -2,2,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 7)
(3S) 2- (- 6- ((3- (3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5- Yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The methanol (2mL) and tetrahydrofuran (4mL) of the crude product of reaction will be walked in sodium hydroxide solution (0.8mL, 2M) addition In mixed solvent, stirring reaction 2 hours under room temperature.Reaction terminates, and add water (20mL) diluting reaction, with the aqueous hydrochloric acid solution acid of 1M It is 1 to change to PH, ethyl acetate (30mL × 3) extraction, merges organic faciess, and anhydrous sodium sulfate drying is filtered, and filtrate decompression is dense Contracting.Residue obtains the compound 7 of white solid with silica gel column chromatography separating purification (methylene chloride/methanol=70/1) (130mg, two step yields 83.3%).
MS m/z(ESI)：487.2[M-1]
1H NMR (400MHz, CDCl3) δ 7.47-7.33 (m, 2H), 7.17 (d, 1H), 7.08 (dd, 2H), 6.54 (s, 1H), 6.51-6.40 (m, 2H), 5.06 (s, 2H), 4.76 (t, 1H), 4.46 (d, 1H), 4.29 (dd, 1H), 3.86-3.75 (m, 1H), 3.42 (s, 3H), 2.81 (dd, 1H), 2.61 (dd, 1H), 1.96 (dt, 6H), 1.56 (s, 3H), 1.39 (s, 3H).
Embodiment 8
(S) 2- (6- (3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzene second Base) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 8)
(S) -2- (6- (3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) phenethyl) -2,3-dihyd robenzofuran-3-yl) acetic acid
The first step：(S) 2- (6- (3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) Phenethyl) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 8a
(S)-methyl 2- (6- (3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) phenethyl) -2,3-dihydrobenzofuran-3-yl) acetate
By (3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol 5f (120mg, 0.35mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (87mg, In 0.42mmol) being dissolved in dichloromethane (10mL).Reaction system with nitrogen, by tributylphosphine (156mg, 0.77mmol) and 1, 1 '-(azo dicarbapentaborane) two piperidines (192mg, 0.77mmol) is added in mixture, stirring reaction 2 hours under room temperature.To reaction A small amount of normal hexane is added in liquid, is filtered, by filtrate reduced in volume.Residue silica gel rapid column chromatography (petrol ether/ethyl acetate =6/1), and colourless transparent oil liquid crude product is obtained, it is directly used in next step.
Second step：(S) 2- (6- (3- (2,2- bis- (methoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) Phenethyl) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 8)
(S) -2- (6- (3- (2,2-bis (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) phenethyl) -2,3-dihyd robenzofuran-3-yl) acetic acid
Methanol (2mL) and tetrahydrofuran (4mL) that crude product is walked in sodium hydroxide solution (0.9mL, 2M) addition are mixed into molten In agent, stirring reaction 1.5 hours under room temperature.Reaction terminates, add water (20mL) reaction is quenched, be acidified to the aqueous hydrochloric acid solution of 1M PH is 1, ethyl acetate (25mL × 3) extraction, merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.It is residual Thing silica gel column chromatography separating purification (methylene chloride/methanol=60/1) is stayed, the compound 8 of white blister solid is obtained (140mg, two step yields 77.6%).
MS m/z(ESI)：5172[M-1]
1H NMR (400MHz, DMSO) δ 12.32 (s, 1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.16-7.01 (m, 3H), 6.54-6.42 (m, 3H), 5.09 (s, 2H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.76-3.59 (m, 1H), 3.54- 3.43 (m, 4H), 3.30 (s, 6H), 2.95 (s, 2H), 2.69 (dd, 1H), 2.49-2.41 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H).
Embodiment 9
2- (6- ((3- (4,6- dimethyl -3- oxo -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydros Benzofuran -3- bases) acetic acid (compound 9)
2- (6- ((3- (4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl) benzyl) oxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：5- (3- hyd roxymethyl phenyls) -4,6- Dimethvl-benzofurans -3 (2H) -one (9a)
5- (3- (hydroxymethyl) phenyl) -4,6-dimethylbenzofuran-3 (2H)-one
3- methylol phenylboric acids (2.8g, 18.3mmol) and sodium carbonate liquor (83.0mL, 1M) are added into bromo- 4, the 6- bis- of 5- In toluene (100mL) solution of methyl benzofuran -3 (2H) -one 2E (4.0g, 16.6mmol), ethanol (40mL) is added.Nitrogen Under atmosphere is enclosed, tetrakis triphenylphosphine palladium (1.0g, 0.8mmol) is added in reaction system, be warming up to 80 DEG C, stirring reaction 24 is little When.Reaction terminates, and add water (30mL) diluting reaction in reactant liquor, plus ethyl acetate (200mL) dilution.Filtered with kieselguhr, Organic layer is washed with saturated aqueous common salt (50mL × 3), anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.Residue silicon Plastic column chromatography isolates and purifies (petrol ether/ethyl acetate=6/1-4/1), obtains pale yellow oily liquid 9a (3.3g, yield 74%).
1H NMR (400MHz, CDCl3) δ 7.44 (t, 1H), 7.38 (d, 1H), 7.11 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H), 4.75 (s, 2H), 4.61 (s, 2H), 2.28 (s, 3H), 2.07 (s, 3H)
Second step：2- (6- ((3- (4,6- dimethyl -3- oxo -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) - 2,3- Dihydrobenzofuranes -3- bases) methyl acetate (9b)
Methyl 2- (6- ((3- (4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.41mL, 1.64mmol) and azodicarbonyldipiperidine (413.8mg, 1.64mmol) add 5- (3- hyd roxymethyl phenyls) -4,6- Dimethvl-benzofurans -3 (2H) -one 9a (200mg, 0.75mmol) with the drying of 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 1E (186.1mg, 0.89mmol) In dichloromethane (15mL) solution.Reactant liquor is stirred at room temperature into reaction 2 hours.A small amount of normal hexane, mistake are added in reactant liquor Filter insoluble matter in mixture, concentrating under reduced pressure filtrate.Residue silica gel rapid column chromatography (petrol ether/ethyl acetate=6/ 1) pale yellow transparent oily liquids crude product 9b, is obtained.
3rd step：2- (6- ((3- (4,6- dimethyl -3- oxo -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) - 2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 9)
2- (6- ((3- (4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl) benzyl) oxy)- 2,3-dihydrobenzofuran-3-yl) acetic acid
Sodium hydroxide solution (1.9mL, 2M) is added into 2- (6- ((3- (4,6- dimethyl -3- oxo -2,3- dihydrobenzos Furan -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 9b methanol (2mL) and tetrahydrofuran (4mL) in mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, and add water (20mL) diluting reaction, with the hydrochloric acid of 1M It is 1 that aqueous solution is acidified to PH, ethyl acetate (30mL × 3) extraction, merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate Concentrating under reduced pressure.Residue obtains the change of faint yellow solid shape with silica gel column chromatography separating purification (methylene chloride/methanol=60/1) Compound 9 (140mg, two step yields 36.4%).
MS m/z(ESI)：443.1[M-1]
1H NMR (400MHz, CDCl3) δ 7.49-7.39 (m, 2H), 7.13 (s, 1H), 7.05 (d, 2H), 6.86 (s, 1H), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.61 (s, 2H), 4.29 (dd, 1H), 3.81 (td, 1H), 2.80 (dd, 1H), 2.62 (dd, 1H), 2.26 (s, 3H), 2.06 (s, 3H).
Embodiment 10
(S) 2- (6- ((3- (4,6- dimethyl -3- oxo -3- hydrogen -2,1 '-cyclopropyl benzofuran -5- bases) benzyl) oxygen Base) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 10)
(S) -2- (6- ((3- (4,6-dimethyl-3-oxo-3H-spiro [benzofuran-2,1 ' - Cyclopropan] -5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：5- (3- (((t-Butyldimethylsilyl) epoxide) methyl) phenyl) -4,6- dimethyl -2- hydrogen benzo furans Mutter -3- ketone (10a)
5- (3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4,6- dimethylbenzofuran-3(2H)-one
Add in single port bottle 5- (3- hyd roxymethyl phenyls) -4,6- Dimethvl-benzofurans -3 (2H) -one 9a (3.3g, 12.3mmol), tert-butyl chloro-silicane (3.71g, 24.6mmol), imidazoles (2.51g, 36.9mmol) and dichloromethane (40mL) 40 minutes, are stirred at room temperature.After reaction terminates, 70mL water quenchings are added to go out reaction.Add and divide after 250mL ethyl acetate Layer, takes organic layer.Organic layer is washed with water (100mL × 2), anhydrous sodium sulfate drying, concentration, column chromatography (petroleum ether/dichloromethane =2/1), obtain pale yellow oily liquid 10a (4.68g, yield 99%).
Second step：5- (3- (((t-Butyldimethylsilyl) epoxide) methyl) phenyl) -4,6- dimethyl -3H- spiral shells-[benzene And furan -2,1 '-cyclopropyl] -3- ketone (10b)
5- (3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4,6-dimethyl-3H- Spiro [benzofuran-2,1 '-cyclopropan] -3-one
Anhydrous and oxygen-free atmosphere, at -30 DEG C, by 5- (3- (((t-Butyldimethylsilyl) epoxide) methyl) phenyl) -4,6- Dimethyl -2- hydrogen benzofuran -3- ketone 10a (2.5g, 6.54mmol) is added in the tetrahydrofuran of 100mL dryings.Add 60% sodium hydride (1.31g, 32.68mmol), stirs 20 minutes.Glycol dibromide (3.68g, 19.6mmol) is slowly added dropwise, React 16 hours at 50 DEG C are warming up to after adding.After reaction terminates, 0 DEG C is cooled to, is slowly added to 25mL water quenchings and goes out reaction, then plus Enter 75mL saturated aqueous ammonium chlorides, be extracted with ethyl acetate (100mL × 3).Merge organic layer, with anhydrous sodium sulfate drying, Concentration.Silica gel column chromatography (petroleum ether/dichloromethane=1/1) obtains brown oil liquid 10b (1.08g, yield 40%).
1H NMR (400MHz, DMSO) δ 7.49 (t, 1H), 7.38 (d, 1H), 7.13 (d, 2H), 7.07 (d, 1H), 4.81 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 1.78 (dd, 2H), 1.44 (dd, 2H), 0.91 (s, 9H), 0.10 (s, 6H).
3rd step：5- (3- hyd roxymethyl phenyls) -4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -3- ketone (10c)
5- (3- (hydroxymethyl) phenyl) -4,6-dimethyl-3H-spiro [benzofuran-2,1 ' - cyclopropan]-3-one
5- (3- (((t-Butyldimethylsilyl) epoxide) methyl) phenyl) -4,6- dimethyl -3H- are added in single port bottle Spiral shell-[benzofuran -2,1 '-cyclopropyl] -3- ketone 10b (449mg, 1.1mmol), tetrahydrofuran solvent 10mL and the tetrabutyl are fluorinated Ammonium (863mg, 3.3mmol), stirs 30 minutes under room temperature.Add water 10mL stirrings reaction to be quenched in 10 minutes, extracted with ethyl acetate Take (15mL × 3), merge organic layer, anhydrous sodium sulfate drying, concentration.Silica gel column chromatography (petrol ether/ethyl acetate=3/1) To white blister solid 10c (270mg, yield 84%).
4th step：(S) 2- (6- ((3- (4,6- dimethyl -3- oxo -3H- spiral shells-[benzofuran -2,1 '-cyclopropyl] -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (10d)
(S)-methyl 2- (6- ((3- (4,6-dimethyl-3-oxo-3H-spiro [benzofuran-2,1 '- Cyclopropan] -5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.3mL, 1.20mmol) and azodicarbonyldipiperidine (302mg, 1.20mmoL) Addition 5- (3- hyd roxymethyl phenyls) -4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -3- ketone 10c (160mg, It is 0.54mmol) dry with (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (136mg, 0.65mmoL) In dry dichloromethane (15mL) solution.Reactant liquor is stirred at room temperature into reaction 2 hours.A small amount of normal hexane is added in reactant liquor, It is filtered to remove insoluble matter in mixture, concentrating under reduced pressure filtrate.Residue with silica gel rapid column chromatography (petrol ether/ethyl acetate= 6/1) pale yellow transparent oily liquids crude product 10d, is obtained.
5th step：(S) 2- (6- ((3- (4,6- dimethyl -3- oxo -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 10)
(S) -2- (6- ((3- (4,6-dimethyl-3-oxo-3H-spiro [benzofuran-2,1 ' - Cyclopropan] -5-yl) benzyl) oxy) -2,3-dihy-drobenzofuran-3-yl) acetic acid
Sodium hydroxide solution (1.4mL, 2M) is added into (S) 2- (6- ((3- (4,6- dimethyl -3- oxo -3H- spiral shells-[benzene And furan -2,1 '-cyclopropyl] -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) and methyl acetate 10d methanol (3mL) and in tetrahydrofuran (6mL) mixed solvent, stirring reaction 2 hours under room temperature.Reaction terminates, and (20mL) dilution that adds water is anti- Should, it is 1 to be acidified to PH with the aqueous hydrochloric acid solution of 1M, and ethyl acetate (25mL × 3) extraction merges organic faciess, and anhydrous sodium sulfate is done It is dry, filter, by filtrate reduced in volume.Residue obtains white with silica gel column chromatography separating purification (methylene chloride/methanol=70/1) Color blister solid chemical compound 10 (215mg, two step yields 84%).
MS m/z(ESI)：469.1[M-1]
1H NMR (400MHz, DMSO) δ 12.35 (s, 1H), 7.55-7.40 (m, 2H), 7.18 (d, 1H), 7.11 (d, 3H), 6.47 (d, 2H), 5.06 (s, 2H), 4.68 (t, 1H), 4.23-4.11 (m, 1H), 3.74-3.61 (m, 1H), 2.70 (dd, 1H), 2.50-2.41 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H), 1.75 (dd, 2H), 1.41 (q, 2H).
Embodiment 11
(S) 2- (6- ((3- (2,2- bis- (methoxy) -4,6- dimethyl -3- oxo -2,3- Dihydrobenzofuranes -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 11)
(S) -2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-3-oxo-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：5- (3- (hydroxymethyl) phenyl) -2,2- bis- (methoxy) -4,6- dimethyl benzofurans -3 (2H) -one (11a)
5- (3- (hydroxymethyl) phenyl) -2,2-bis (methoxymethyl) -4,6- dimethylbenzofuran-3(2H)-one
By 3- methylol phenylboric acids (150mg, 0.97mmol) and sodium carbonate liquor (8.1mL, 1M) add 4,6- dimethyl- In toluene (10mL) solution of bromo- benzofuran -3 (2H) -one 5b (265mg, 0.81mmol) of 2,2- bis- (methoxyl methyl) -5-, Add ethanol (4mL).Under nitrogen atmosphere, tetrakis triphenylphosphine palladium (46mg, 0.04mmol) is added in reaction system, heated up To 80 DEG C, stirring reaction 42 hours.Reaction terminates, and add water (10mL) diluting reaction in reactant liquor, plus ethyl acetate (50mL) Dilution.Filtered with kieselguhr, organic layer is washed with saturated aqueous common salt (10mL × 3), anhydrous sodium sulfate drying, filtered, by filtrate Concentrating under reduced pressure.Residue obtains faint yellow oily with silica gel column chromatography separating purification (petrol ether/ethyl acetate=6/1-5/1) Liquid 11a (240mg, yield 83%).
1H NMR (400MHz, DMSO) δ 7.43 (t, 1H), 7.34 (d, 1H), 7.08 (s, 1H), 7.02 (d, 2H), 5.23 (t, 1H), 4.55 (d, 2H), 3.66 (s, 4H), 3.21 (s, 6H), 2.03 (s, 3H), 1.99 (s, 2H).
Second step：(S) 2- (6- ((3- (2,2- bis- (methoxy) -4,6- dimethyl -3- oxo -2,3- dihydrobenzos Furan -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (11b)
(S)-methyl 2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-3-oxo-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.34mL, 1.36mmol) and azodicarbonyldipiperidine (343mg, 1.36mmol) add 5- (3- (hydroxymethyl) phenyl) -2,2- bis- (methoxy) -4,6- dimethyl benzofurans -3 (2H) -one 11a (220mg, 0.62mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D In dry methylene chloride (15mL) solution of (154mg, 0.74mmol).Reactant liquor is stirred at room temperature into reaction 1 hour.To reaction A small amount of normal hexane is added in liquid, insoluble matter in mixture, concentrating under reduced pressure filtrate is filtered to remove.Residue silica gel rapid column chromatography (dichloromethane/ethyl acetate=60/1), obtains colourless transparent oil liquid crude product 11b.
3rd step：(S) 2- (6- ((3- (2,2- bis- (methoxy) -4,6- dimethyl -3- oxo -2,3- dihydrobenzos Furan -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 11)
(S) -2- (6- ((3- (2,2-bis (methoxymethyl) -4,6-dimethyl-3-oxo-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
Sodium hydroxide solution (1.5mL, 2M) is added into (S) 2- (6- ((3- (2,2- bis- (methoxy) -4,6- diformazans Base -3- oxo -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 11b In methanol (4mL) and tetrahydrofuran (8mL) mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, and adds water (20mL) reaction is quenched, it is 1 to be acidified to pH with the aqueous hydrochloric acid solution of 1M, ethyl acetate (25mL × 3) extraction merges organic faciess, Anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Residue with silica gel column chromatography separating purification (methylene chloride/methanol= 80/1) white blister solid chemical compound 11 (160mg, two step yields 49%), is obtained.
MS m/z(ESI)：533.2[M+1]
1H NMR (400MHz, CDCl3) δ 7.48-7.37 (m, 2H), 7.14 (s, 1H), 7.08-7.03 (m, 2H), 6.91 (s, 1H), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.29 (dd, 1H), 3.81 (dd, 3H), 3.70 (dd, 2H), 3.36 (s, 6H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.24 (s, 3H), 2.05 (s, 3H).
Embodiment 12
(S) 2- (6- ((3- (2- (methoxy) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) oxygen Base) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 12)
(3S) 2- (- 6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：(S) 2- (6- ((3- (2- (methoxy) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) Benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (12a)
(3S) methyl 2- (- 6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.33mL, 1.33mmol) and azodicarbonyldipiperidine (336mg, 1.33mmol) add (3- (2- (methyl methoxy base) -4,6- dimethyl -2,3 Dihydrobenzofuranes -5- bases) benzyl alcohol 6f (180mg, 0.60mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (150mg, In dry methylene chloride (15mL) solution 0.72mmol).Reactant liquor is stirred at room temperature into reaction 2 hours.Add in reactant liquor Enter a small amount of normal hexane, be filtered to remove insoluble matter in mixture, concentrating under reduced pressure filtrate.Residue silica gel rapid column chromatography (oil Ether/ethyl acetate=6/1), obtain pale yellow transparent oily liquids crude product 12a.
Second step：(S) 2- (6- ((3- (2- (methoxy) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) Benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 12)
(3S) 2- (- 6- ((3- (2- (methoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran- 5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
By sodium hydroxide solution (1.5mL, 2M) add (S) 2- (6- ((3- (2- (methoxy) -4,6- dimethyl -2, 3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 12a methanol (3mL) and In tetrahydrofuran (6mL) mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, add water (20mL) reaction is quenched, use It is 1 that the aqueous hydrochloric acid solution of 1M is acidified to PH, ethyl acetate (25mL × 3) extraction, merges organic faciess, anhydrous sodium sulfate drying, mistake Filter, by filtrate reduced in volume.Residue obtains white bubble with silica gel column chromatography separating purification (methylene chloride/methanol=60/1) Shape solid chemical compound 11 (215mg, two step yields 75.4%).
MS m/z(ESI)：473.1[M-1]
1H NMR (400MHz, DMSO) δ 12.32 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.11 (t, 2H), 7.04 (t, 1H), 6.51 (s, 1H), 6.47 (d, 2H), 5.09 (s, 2H), 5.00-4.87 (m, 1H), 4.68 (t, 1H), 4.28-4.12 (m, 1H), 3.76-3.60 (m, 1H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, 1H), 2.84 (dd, 1H), 2.69 (dd, 1H), 2.49-2.41 (m, 1H), 1.83 (d, 6H).
Embodiment 13
(3S) 2- (6- ((3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydros Benzofuran -3- bases) acetic acid (compound 13)
(3S) 2- (- 6- ((3- (2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) Oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：2,4,5,6- tetramethyl -2,3- Dihydrobenzofuranes (13a)
2,4,5,6-tetramethyl-2,3-dihydrobenzofuran
Trifluoromethanesulfonic acid (32mg, 0.2mmol) is dissolved in 5mL dichloromethane, is then slowly dropped to and is dissolved with 2- In the 15mL dichloromethane solutions of the bromo- MX 6b (480mg, 2.0mmol) of pi-allyl -4-, it is warming up to after adding React 3 hours at 60 DEG C.Room temperature is down in reaction after terminating, add 15mL saturated sodium bicarbonate aqueous solutions and 5mL water, uses dichloromethane Alkane extracts (20mL × 2), merges organic faciess, anhydrous sodium sulfate drying, concentration.Residue silica gel column chromatography (petroleum ether/dichloromethane Alkane=4/1) obtain pale yellow transparent oily liquids 13a (360mg, yield 75%).
1H NMR (400MHz, DMSO) δ 6.60 (s, 1H), 5.02-4.80 (m, 1H), 3.28 (dd, 1H), 2.73 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.36 (d, 3H).
Second step：3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde (13b)
3- (2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
Toluene (20mL) and ethanol (5mL) are added into 2,4,5,6- tetramethyl -2,3- Dihydrobenzofuranes 13a (350mg, 1.45mmol) and the sodium carbonate liquor (14.5mL, 1M) of 3- formylphenylboronic acids (253mg, 1.60mmol) in.Use nitrogen displacement Reaction system, tetrakis triphenylphosphine palladium (173mg, 0.10mmol) is added in mixture.Nitrogen atmosphere is kept, 80 DEG C are warming up to Stirring reaction 15 hours.Reaction terminates, and mixture is filtered, and filtrate adds water (10mL) dilution, adds 50mL ethyl acetate, with full With saline solution (20mL × 3) washing, anhydrous sodium sulfate drying organic faciess, filter, by filtrate reduced in volume.Residue is fast with silica gel Fast column chromatography (petrol ether/ethyl acetate=20/1), obtains yellow oil crude product 13b.
3rd step：(3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl methanol (13c)
(3- (2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
Under condition of ice bath, sodium borohydride (275mg, 7.25mmol) is added into 3- (2,4,6- trimethyl -2,3- dihydrobenzos Furan -5- bases) benzaldehyde 13b crude products in the mixed solvent of tetrahydrofuran (12mL) and methanol (3mL), are warming up to and are stirred at room temperature Reaction 0.5 hour.Add water in reactant liquor (10mL) be quenched reaction, add saturated aqueous ammonium chloride 20mL and ethyl acetate 35mL.After layering, water is mutually extracted with ethyl acetate (30mL × 2), merges organic faciess, with anhydrous sodium sulfate drying, filters, and will filter Liquid concentrating under reduced pressure, residue silica gel column chromatography (petrol ether/ethyl acetate=10/1) obtains pale yellow oil 13c (315mg, two step yields 81%).
MS m/z(ESI)：269.1[M+1]
4th step：(3S) 2- (6- ((3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) methyl acetate (compound 13d)
(3S) methyl 2- (6- ((3- (2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydrobenzo-furan-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.3mL, 1.23mmol) and azodicarbonyldipiperidine (317mg, 1.23mmol) Add (3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl methanols (13c) (150mg, 0.56mmol) and (S) The dry methylene chloride of 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (129mg, 0.62mmol) (12mL) in solution.Reactant liquor is stirred at room temperature into reaction 1.5 hours.A small amount of normal hexane is added in reactant liquor, is filtered to remove Insoluble matter in mixture, concentrating under reduced pressure filtrate.Products therefrom directly carries out next step reaction.
5th step：(3S) 2- (6- ((3- (2,4,6- trimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid (compound 13)
(3S) 2- (- 6- ((3- (2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) Oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
Sodium hydroxide solution (1.4mL, 2M) is added into (3S) 2- (6- ((3- (2,4,6- trimethyl -2,3- dihydrobenzo furans Mutter -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 13d (235mg, 0.51mmol) is in methanol (3mL) and in tetrahydrofuran (6mL) mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, add water (25mL) be quenched Reaction, it is 1 to be acidified to PH with the aqueous hydrochloric acid solution of 1M, and ethyl acetate (25mL × 3) extraction merges organic faciess, anhydrous sodium sulfate It is dried, filters, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (methylene chloride/methanol=60/1) White blister solid chemical compound 13 (190mg, yield 84%).
MS m/z(ESI)：443.1[M-1]
1H NMR (400MHz, DMSO) δ 12.35 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.11 (t, 2H), 7.04 (t, 1H), 6.47 (dd, 3H), 5.09 (s, 2H), 4.91 (dd, 1H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.74-3.60 (m, 1H), 3.24 (dd, 1H), 2.71 (t, 1H), 2.68-2.63 (m, 1H), 2.46 (dd, 1H), 1.83 (d, 6H), 1.39 (d, 3H).
Embodiment 14
(3S) 2- (6- ((3- (2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyls Base) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 14)
(S) -2- (6- ((3- (2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：Bromo- 2, the 2- bis- (ethoxyl methyl) of 5- -4,6- dimethyl Dihydrobenzofuranes -3 (2H) -one (14a)
5-bromo-2,2-bis (ethoxymethyl) -4,6-dimethylbenzofuran-3 (2H)-one
Anhydrous and oxygen-free atmosphere, under ice bath, by sodium hydride (700mg, 17.5mmol hydrogenate sodium content w/w=60%) in batches The drying of bromo- 2,2- bis- (methylol) -4,6- dimethyl benzofurans -3 (2H) -one 5a (2.11g, 7.0mmol) of secondary addition 5- In DMF (50mL), stirring reaction 20 minutes, then iodoethane (2.8mL, 25.0mmol) is added into mixture In.0 DEG C of stirring reaction 0.5 hour, reaction terminates.Water (50mL) and saturated ammonium chloride solution (25mL) are added in reactant liquor, Extracted with ethyl acetate (80mL × 3), merge organic faciess and washed with saturated aqueous common salt (100mL × 2).Anhydrous sodium sulfate is done It is dry, filter, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=16/1) Oily liquids 14a (450mg, yield 18%).
1H NMR (400MHz, DMSO) δ 7.17 (s, 1H), 3.69 (s, 4H), 3.38 (q, 4H), 2.57 (s, 3H), 2.44 (s, 3H), 0.96 (t, 6H).
Second step：Bromo- 2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2 of 5-, 3- Dihydrobenzofuranes -3- alcohol (14b)
5-bromo-2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-3-ol
Under ice bath, sodium borohydride (238mg, 6.30mmol) is dividedly in some parts into bromo- 2, the 2- bis- (ethoxyl methyl) -4,6- of 5- The methanol (3mL) of dimethyl Dihydrobenzofuranes -3 (2H) -one 14a (450mg, 1.26mmol) and tetrahydrofuran (6mL) mix In solution, reaction 1.5 hours is warmed to room temperature.Add water in reaction system (5mL) be quenched reaction, add saturated ammonium chloride solution (15mL), extracted with ethyl acetate (20mL × 3), merge organic faciess, anhydrous sodium sulfate drying is filtered, and reactant liquor is reduced pressure into dense Contracting.Residue obtains colorless and transparent liquid 14b with silica gel column chromatography separating purification (petrol ether/ethyl acetate=15/1) (315mg, yield 70%).
3rd step：Bromo- 2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2 of 5-, 3- Dihydrobenzofuranes (14c)
5-bromo-2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran
Anhydrous and oxygen-free atmosphere, under ice bath, by hydrogen silane (7.7mL, 48.2mmol) 4,6- dimethyl -2,2- diethoxies is added In the dry methylene chloride (10mL) of bromo- 2, the 3- Dihydrobenzofuranes 14b (315mg, 0.88mmol) of ylmethyl -3- hydroxyl -5-, Trifluoroacetic acid (0.52mL, 7.0mmol), stirring reaction 2.5 hours are slowly added dropwise again.Dichloromethane is added in reactant liquor (10mL) with saturated sodium bicarbonate solution (10mL), stir 10 minutes, add water (10mL), point liquid.Water layer dichloromethane (20mL × 2) extract, and merge organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.Residue silica gel column layer Analysis isolates and purifies (petrol ether/ethyl acetate=40/1), obtains the 14c (210mg, yield 70%) of colourless transparent liquid shape.
4th step：3- (2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde (14d)
3- (2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzaldehyde
3- formylphenylboronic acids (106mg, 0.67mmol) and sodium carbonate liquor (6.1mL, 1M) are added into bromo- 2, the 2- bis- of 5- (ethoxyl methyl) -4,6- dimethyl -2, in toluene (15mL) solution of 3- Dihydrobenzofuranes 14c (210mg, 061mmol), Add ethanol (3mL).Under nitrogen atmosphere, tetrakis triphenylphosphine palladium (70mg, 0.1mmol) is added in reaction system, heated up To 80 DEG C, stirring reaction 18 hours.Reaction terminates, add water in reactant liquor (10mL) reaction, plus ethyl acetate (50mL) is quenched Dilution.Filtered with kieselguhr, organic layer is washed with saturated aqueous common salt (20mL × 3), anhydrous sodium sulfate drying, filtered, by filtrate Concentrating under reduced pressure.Residue obtains pale yellow oily liquid with silica gel column chromatography separating purification (petrol ether/ethyl acetate=20/1) 14d (150mg, yield 68%).
5th step：3- (2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol (14e)
(3- (2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) phenyl)methanol
Under condition of ice bath, by sodium borohydride (78mg, 2.05mmol) be dividedly in some parts 3- (2,2- bis- (ethoxyl methyl) -4, 6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzaldehyde 14d (150mg, 0.4mmol) tetrahydrofuran (4mL) and methanol (2mL) in mixed solvent.Reaction 30 minutes is stirred at room temperature.Add water (5mL) diluting reaction in reactant liquor, removes partial solvent, Saturated ammonium chloride solution (15mL) is added, is extracted with ethyl acetate (20mL × 3), merged organic faciess and done with anhydrous sodium sulfate It is dry, filter, by filtrate reduced in volume.Residue is obtained with silica gel column chromatography separating purification (petrol ether/ethyl acetate=5/1) Colourless transparent oil liquid 14e (140mg, yield 93%).
MS m/z(ESI)：371.3[M+1]
6th step：(S) 2- (6- ((3- (2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (14f)
(S)-methyl 2- (6- ((3- (2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.21mL, 0.83mmol) and azodicarbonyldipiperidine (214mg, 0.83mmol) add 3- (2,2- bis- (ethoxyl methyl) -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl alcohol 14e (140mg, 0.38mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (94mg, In dry methylene chloride (12mL) solution 0.45mmoL).Reactant liquor is stirred at room temperature into reaction 2 hours.Add in reactant liquor Enter a small amount of normal hexane, be filtered to remove insoluble matter in mixture, concentrating under reduced pressure filtrate.Products therefrom directly carries out next step reaction.
7th step：(3S) 2- (6- ((3- (2,2- diethoxymethyl -4,6- dimethyl -2,3- Dihydrobenzofuranes -5- Base) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 14)
(S) -2- (6- ((3- (2,2-bis (ethoxymethyl) -4,6-dimethyl-2,3- Dihydrobenzofuran-5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
By sodium hydroxide solution (0.8mL, 2M) add (S) 2- (6- ((3- (and 2,2- diethoxymethyl -4,6- dimethyl - 2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 14f (180mg, 0.32mmol) in methanol (3mL) and tetrahydrofuran (6mL) mixed solvent, stirring reaction 1.5 hours under room temperature.Reaction terminates, Add water (20mL) reaction is quenched, be acidified to PH for 1 with the aqueous hydrochloric acid solution of 1M, ethyl acetate (25mL × 3) extraction merges organic Phase, anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume.Residue silica gel column chromatography separating purification (petroleum ether/acetic acid Ethyl ester=1/1), obtain white blister solid chemical compound 14 (138mg, yield 79%).
MS m/z(ESI)：545.3[M-1]
1H NMR (400MHz, CDCl3) δ 7.44-7.32 (m, 2H), 7.16 (s, 1H), 7.06 (dd, 2H), 6.56 (s, 1H), 6.51-6.43 (m, 2H), 5.05 (s, 2H), 4.75 (t, 1H), 4.28 (dd, 1H), 3.80 (ddd, 1H), 3.69 (d, 2H), 3.663.48 (m, 6H), 2.99 (s, 2H), 2.80 (dd, 1H), 2.61 (dd, 1H), 1.94 (s, 3H), 1.87 (s, 3H), 1.21 (t, 6H).
Embodiment 15
(S) 2- (6- ((3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] 5- yls) benzyl) epoxide) -2, 3- Dihydrobenzofuranes -3- bases) acetic acid (compound 15)
(S) -2- (6- ((3- (4,6-dimethyl-3H-spiro [benzofuran-2,1 '-cyclopropan] -5- Yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：The tert-butyl group (3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) phenyl) oxygen Base) dimethyl-silicon ether (15a)
Tert-butyl ((3- (4,6-dimethyl-3H-spiro [benzofuran-2,1 '-cyclopropan] -5- yl)benzyl)oxy)dimethylsilane
Anhydrous and oxygen-free atmosphere, under ice-water bath, is added to aluminum chloride (420mg, 3.15mmol) 20mL and is dried tetrahydrochysene furan In muttering, Lithium Aluminium Hydride (114mg, 3.0mmol) is charged with, is stirred 15 minutes.By 4, the 6- dimethyl -5- (3- (((tert-butyl groups Dimethyl silicon substrate) epoxide) methyl) phenyl) -2- hydrogen -2,1 '-cyclopropyl benzofuran -3- ketone 10b (625mg, 1.53mmol) matches somebody with somebody Dry tetrahydrofuran (10mL) solution is made, in being added drop-wise to reactant liquor, then heats to be reacted 1 hour under room temperature.Reaction knot Shu Hou, ice-water bath cooling, is slowly added dropwise 0.5N sodium hydrate aqueous solution 15mL, stirs 10 minutes, adds water 15mL.Use acetic acid second Ester extracts (30mL × 3), merges organic faciess, and with saturated common salt (30mL × 3) are washed.Organic faciess have anhydrous sodium sulfate drying, dense Contracting.Residue silica gel column chromatography (petroleum ether/dichloromethane=7/1) obtains colourless transparent oil liquid 15a (450mg, yield 76%).
1H NMR (400MHz, DMSO) δ 7.40 (t, 1H), 7.27 (d, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.52 (s, 1H), 4.75 (s, 2H), 3.23 (s, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.08 (q, 2H), 0.88 (s, 9H), 0.77 (q, 2H), 0.06 (s, 6H).
Second step：(3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) benzyl alcohol (15b)
(3- (4,6-dimethyl-3H-spiro [benzofuran-2,1 '-cyclopropan] -5-yl) phenyl) methanol
The tert-butyl group (3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) benzene is added in single port bottle Base) epoxide) dimethyl-silicon ether 15a (500mg, 1.3mmol), tetrahydrofuran solvent 12mL and tetrabutyl ammonium fluoride (994mg, 3.8mmol), stir 30 minutes under room temperature.Water 20mL stirrings are added reaction to be quenched in 10 minutes, be extracted with ethyl acetate (20mL × 4) organic layer, anhydrous sodium sulfate drying, concentration, are merged.Silica gel column chromatography (petrol ether/ethyl acetate=4/1) obtains faint yellow Oily liquids 15b (353mg, yield 99%).
1H NMR (400MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 6.51 (s, 1H), 5.17 (t, 1H), 4.54 (d, 2H), 3.22 (s, 2H), 1.90 (s, 3H), 1.84 (s, 3H), 1.08 (t, 2H), 0.80-0.74 (m, 2H).
3rd step：(S) 2- (6- ((3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (15c)
(S)-methyl 2- (6- ((3- (4,6-dimethyl-3H-spiro [benzofuran-2,1 '- Cyclopropan] -5-yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetate
Nitrogen atmosphere, by tributylphosphine (0.34mL, 1.34mmol) and azodicarbonyldipiperidine (338mg, 1.34mmol) add (3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) benzyl alcohol 15b (170mg, It is 0.61mmol) dry with (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (139mg, 0.67mmoL) In dry dichloromethane (12mL) solution.Reactant liquor is stirred at room temperature into reaction 2 hours.A small amount of normal hexane is added in reactant liquor, It is filtered to remove insoluble matter in mixture, concentrating under reduced pressure filtrate.Residue with silica gel rapid column chromatography (petrol ether/ethyl acetate= 9/1), obtain colourless transparent oil liquid 15c (230mg, 80%).
4th step：(S) 2- (6- ((3- (4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropyl] -5- bases) benzyl) Epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 15)
(S) -2- (6- ((3- (4,6-dimethyl-3H-spiro [benzofuran-2,1 '-cyclopropan] -5- Yl) benzyl) oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
By sodium hydroxide solution (1.2mL, 2M) add (S) 2- (6- ((3- (4,6- dimethyl -3H- spiral shells [benzofuran -2, 1 '-cyclopropyl] -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 15c (230mg, 0.49mmol) In methanol (3mL) and tetrahydrofuran (6mL) mixed solvent, stirring reaction 1.0 hours under room temperature.Reaction terminates, and adds water (20mL) diluting reaction, it is 3 to be acidified to PH with the aqueous hydrochloric acid solution of 1M, and ethyl acetate (20mL × 3) extraction merges organic faciess, Anhydrous sodium sulfate drying, filters, by filtrate reduced in volume.Residue silica gel column chromatography separating purification (petrol ether/ethyl acetate =2/1), obtain white blister solid chemical compound 15 (200mg, yield 90%).
MS m/z(ESI)：455.2[M-1]
1H NMR (400MHz, DMSO) δ 12.30 (s, 1H), 7.44 (t, 1H), 7.38 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 2H), 6.52 (s, 1H), 6.50-6.44 (m, 2H), 5.10 (s, 2H), 4.67 (t, 1H), 4.18 (dd, 1H), 3.71- 3.63 (m, 1H), 3.22 (s, 2H), 2.68 (dd, 1H), 2.46 (d, 1H), 1.88 (s, 3H), 1.82 (s, 3H), 1.08 (t, 2H), 0.77 (t, 2H).
Embodiment 16
(S) 2- (6- ((3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydros Benzofuran -3- bases) acetic acid (compound 16)
(S) -2- (6- ((3- (3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzyl) Oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
The first step：Bromo- 1, the 3- dimethyl -5- of 2- ((2- methacrylics) epoxide benzene (16b)
2-bromo-1,3-dimethyl-5- ((2-methylallyl) oxy) benzene
Under room temperature, by the bromo- MX 16a (8.04g, 40mmol) of 4-, the chloro- propylene of 2- methyl -3- (3.62g, 40mmol) it is added in acetonitrile (80mL) with Anhydrous potassium carbonate (11.06g, 80mmol), is warming up to 95 DEG C of back flow reaction 15 little When, TLC shows that reaction is complete.Ethyl acetate (200mL), water (200mL) are added in reaction system, is stirred 10 minutes, point liquid, Organic faciess are dried with anhydrous sodium sulfate (10g), concentration, silica gel column chromatography separating purification (petrol ether/ethyl acetate=30/1) To brown liquid 16b (8.0g, yield 80%).
Second step：Bromo- 3,3,4,6- tetramethyl -2 of 5-, 3- Dihydrobenzofuranes (16c)
5-bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran
Under room temperature, by bromo- 1, the 3- dimethyl -5- of 2-, ((2- methacrylics) epoxide benzene 16b (18.0g, 31mmol) is added To in dichloromethane (100mL), 0 DEG C is cooled to, adds aluminum trichloride (anhydrous) (208mg, 1.57mmol), be warmed to room temperature reaction, React after 30 minutes complete.Water (10mL) is added in reaction system, is stirred 5 minutes, point liquid, organic faciess concentration, silica gel column layer Analysis isolates and purifies (petrol ether/ethyl acetate=30/1), obtains brown liquid 16c (3.2g, yield 40%).
3rd step：(3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) methanol (16d)
(3- (3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) phenyl) methanol
Under room temperature, by bromo- 3,3,4,6- tetramethyl -2 of 5-, 3- Dihydrobenzofuranes 16c (2.55g, 10mmol), 3- hydroxyl first Base phenylboric acid (1.52g, 10mmol), tetra-triphenylphosphine palladium (578mg, 0.5mmol) and natrium carbonicum calcinatum (3.18g, 30mmol) In being added to toluene (50mL), 100 DEG C of reactions are warming up to, react complete after 22 hours.Ethyl acetate is added in reaction system (100mL) with water (100mL), point liquid, organic phases washed with water (50mL × 3), anhydrous sodium sulfate (10g) is dried, concentration, silicagel column Chromatography purification (petrol ether/ethyl acetate=5/1), obtains white solid 16d (565mg, yield 20%).
1H NMR (400MHz, CDCl3) δ 7.39 (t, 1H), 7.33 (d, 1H), 7.12 (s, 1H), 7.08 (d, 1H), 6.51 (s, 1H), 4.71 (s, 2H), 2.94 (s, 2H), 1.97 (s, 3H), 1.87 (s, 3H), 1.50 (s, 6H).
4th step：(S) 2- (6- ((3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) - 2,3- Dihydrobenzofuranes -3- bases) methyl acetate (16e)
(S)-methyl 2- (6- ((3- (3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) Benzyl) oxy) -2,3-dihydro benzofuran-3-yl) acetate
Under room temperature, by (3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) methanol 16d (565mg, 2mmol), (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3C (416mg, 2mmol) and the formyl of azo two Two piperidines (1.05g, 4mmol) are added in dichloromethane (30mL), instill tributylphosphine (809mg, 4mmol).After dripping off, 2 Hour reaction is complete.Reaction system is concentrated to dryness, silica gel column chromatography separating purification (petrol ether/ethyl acetate=1/1).Obtain in vain Color solid 16e (472mg, yield 50%).
5th step：(S) 2- (6- ((3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) - 2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 16)
(S) -2- (6- ((3- (3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzyl) Oxy) -2,3-dihydrobenzofuran-3-yl) acetic acid
Under room temperature, by (S) 2- (6- ((3- (3,3,4,6- tetramethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) oxygen Base) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 16e (472mg, 1mmol) is suspended in methanol (10mL), adds hydrogen-oxygen Change water (1mL) solution of sodium (800mg, 20mmol), room temperature reaction 15 hours.Reactant liquor is concentrated into into 2mL, water is added (10mL), PH ＜ 4 are adjusted with hydrochloric acid, is extracted with ethyl acetate (10mL × 3), merge organic faciess, wash (10mL), anhydrous slufuric acid with water Sodium (1g) is dried, concentration, silica gel column chromatography separating purification (petrol ether/ethyl acetate=1/2).Obtain compound as white solid 16 (220mg, yield 48%, HPLC purity 97.96%).
MS m/z(ESI)：459.3[M+1]
1H NMR (400MHz, CDCl3) δ 7.37 (m, 2H), 7.18 (s, 1H), 7.06 (m, 2H), 6.50 (m, 3H), 5.06 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.80 (m, 1H), 2.94 (s, 2H), 2.83 (dd, 1H), 2.63 (dd, 1H), 1.96 (s, 3H), 1.86 (s, 3H), 1.50 (s, 6H).
Embodiment 17
(S) 2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- dihydrobenzos Furan -3- bases) acetic acid (compound 17)
(S) -2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl)acetic acid
The first step：(S) 2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate (17a)
(S)-methyl 2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) Oxy) -2,3-dihydrobenzo furan-3-yl) acetate
Nitrogen atmosphere, at 0 DEG C, by (3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol 4e (180mg, 0.71mmol) and (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (162mg, In 0.78mmol) being dissolved in dry dichloromethane (10mL), by tributylphosphine (315mg, 1.56mmol), 1, the 1 '-(carbonyl of azo two Base) two piperidines (393mg, 1.56mmol) add mixture in, be warmed to room temperature reaction 2 hours.Reacting liquid filtering is removed insoluble Thing, by filtrate reduced in volume, residue silica gel column chromatography analysis purification (petrol ether/ethyl acetate=7/1), obtains yellowish Color grease 17a (231mg, yield 73%).
Second step：(S) 2- (6- ((3- (4,6- dimethyl -2,3- Dihydrobenzofuranes -5- bases) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) acetic acid (compound 17)
(S) -2- (6- ((3- (4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy) -2, 3-dihydrobenzofuran-3-yl)acetic acid
By sodium hydrate aqueous solution (5mL, 2M) add (S) 2- (6- ((3- (and 4,6- dimethyl -2,3- Dihydrobenzofuranes - 5- yls) benzyl) epoxide) -2,3- Dihydrobenzofuranes -3- bases) methyl acetate 17a (231mg, 0.52mmol) tetrahydrofuran (5mL) in solution, reaction is stirred at room temperature overnight.PH≤2 of reactant liquor are adjusted with dilute hydrochloric acid, is extracted with ethyl acetate (10mL × 3) Take, merge organic faciess, saturated aqueous common salt (50mL × 1) washing, with anhydrous sodium sulfate drying, is filtered, by filtrate reduced in volume.It is residual Stay thing silica gel column chromatography to isolate and purify (petrol ether/ethyl acetate=1.5/1), obtain compound as white solid 17 (175mg, yield 78%).
MS m/z(ESI)：[M-1]-：429.3.
1H NMR (400MHz, CDCl3) δ 12.22 (s, 1H), 7.35 (t, 1H), 7.29 (d, 1H), 7.06-6.98 (m, 2H), 6.95 (d, 1H), 6.44 (s, 1H), 6.41-6.34 (m, 2H), 5.01 (s, 2H), 4.59 (t, 1H), 4.44 (t, 2H), 4.10 (dd, 1H), 3.59 (td, 1H), 3.00 (t, 2H), 2.60 (dd, 1H), 2.37 (d, 1H), 1.79 (s, 3H), 1.74 (s, 3H).
Embodiment 18
2- [(3S) -6- [[3- (fluoro- 4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases of 7-) Phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 18)
2- [(3S) -6- [[3- (7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
The first step：The fluoro- MXs of the bromo- 2- of 4- (18b)
4-bromo-2-fluoro-3,5-dimethylphenol
By the bromo- MX 2A (5.0g, 24.8mmol) of 4- and trifluoromethanesulfonic acid N- pyridine (15.3g, In 62.0mmol) being added to 1,2- dichloroethanes (50mL), back flow reaction 24 hours under nitrogen atmosphere.Reaction adds full after terminating With sodium thiosulfate solution (50mL), stir 5 minutes.With dichloromethane aqueous layer extracted (50ml × 2), merge organic faciess, nothing Aqueous sodium persulfate is dried, and filters, by filtrate reduced in volume, residue silica gel column chromatography separating purification (petroleum ether/dichloromethane (v/ V)=1/1), obtain the fluoro- MX 18b of the bromo- 2- of 4- (2.1g, yield 38.7%) of yellow solid.
Second step：The fluoro- MX acetass (18c) of the bromo- 2- of 4-
4-bromo-2-fluoro-3,5-dimethylphenyl acetate
Sequentially add in reaction bulb the fluoro- MXs (2.0g, 9.1mmol) of the bromo- 2- of 4-, acetic anhydride (1.4g, 1.37mmol), in triethylamine (1.39g, 1.37mmol) and dichloromethane (30mL), 2 hours are stirred at room temperature.Reaction adds after terminating Enter water (50mL), with dichloromethane aqueous layer extracted (30mL × 2), merge organic faciess, anhydrous sodium sulfate drying is filtered, by filtrate Concentrating under reduced pressure, residue silica gel column chromatography separating purification (petroleum ether/dichloromethane (v/v)=10/1) obtains faint yellow oily The fluoro- MX acetass 18c of the bromo- 2- of 4- (2.4g, yield 100%).
3rd step：1- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) ethyl ketone (18d)
1- (3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl) ethanone
The fluoro- MX acetass (2.35g, 9.0mmol) of the bromo- 2- of 4-, trichlorine are sequentially added in reaction bulb Change aluminum (3.6g, 27.0mmol) and 1,2 dichloroethanes (25mL), back flow reaction 2 hours.After reaction terminates, room temperature is cooled to, will Reactant liquor is poured in frozen water (200mL), is 3 with 6N hydrochloric acid acidifying pH, with dichloromethane aqueous layer extracted (200mL × 3).It is associated with Machine phase, anhydrous sodium sulfate drying is filtered, and by filtrate reduced in volume, residue is with silica gel column chromatography separating purification (petroleum ether/bis- Chloromethanes (v/v)=1/1) obtain 1- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) the ethyl ketone 18d of yellow solid (0.91g, yield 38%).
1H NMR (400MHz, DMSO) δ 10.23 (t, 1H), 2.45 (s, 3H), 2.29 (d, 3H), 2.14 (s, 3H).
4th step：The bromo- 1- of 2- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) ethyl ketone (18e)
2-bromo-1- (3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl) ethanone
Sequentially add in reaction bulb 1- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) ethyl ketone 18d (900mg, 3.45mmol), copper bromide (1.15g, 5.17mmol), chloroform (15mL) and ethyl acetate (10mL), back flow reaction 18 hours.Instead After should terminating, room temperature is cooled to, is filtered, washed with water (15mL × 1), collect filtrate, anhydrous sodium sulfate drying, by filtrate decompression Concentration.Residue silica gel column chromatography separating purification (petroleum ether/dichloromethane (v/v)=1/1) obtains the 2- of brown-red solid shape Bromo- 1- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) ethyl ketone 18e crude products (1.17g), direct plunges into the next step.
5th step：Fluoro- 4, the 6- Dimethvl-benzofurans -3- ketone (18f) of the bromo- 7- of 5-
5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one
The bromo- 1- of 2- (fluoro- 6- hydroxyl -2 of the bromo- 5- of 3-, 4- 3,5-dimethylphenyls) ethyl ketone 18e crude products are sequentially added in reaction bulb (1.17g, 3.45mmol), sodium acetate (848mg, 10.34mmol) and methanol (15mL), are stirred at room temperature 3 days.After reaction terminates, Water (15mL) is added, is extracted with ethyl acetate (15mL × 3), merge organic faciess, anhydrous sodium sulfate drying filters, filtrate is subtracted Pressure concentration, residue silica gel column chromatography separating purification (petroleum ether/dichloromethane (v/v)=2/1) obtains yellow solid Fluoro- 4, the 6- Dimethvl-benzofurans -3- ketone 18f of the bromo- 7- of 5- (530mg, the 4th step and the 5th step gross production rate 59%).
6th step：Fluoro- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone (18g) of the bromo- 7- of 5-
5-bromo-7-fluoro-4,6-dimethyl-spiro [benzofuran-2,1 '-cyclopropane] -3- one
Under the protection of anhydrous and oxygen-free nitrogen, fluoro- 4, the 6- Dimethvl-benzofurans -3- of the bromo- 7- of 5- are sequentially added in reaction bulb Ketone 18f (530mg, 2.0mmol) and anhydrous tetrahydro furan (15mL), add sodium hydride (410mg, 10.2mmol) by -30 DEG C, stir Mix 20 minutes.Stirring 20 minutes is warmed to room temperature, then is warming up to 35 DEG C, be slowly added dropwise 1,2 ,-Bromofume (0.53ml, 6.1mmol), after adding, stir 10 minutes.React 30 hours at being warming up to 45 DEG C.Reaction terminates, and is cooled to 0 DEG C, is slowly added to Saturated aqueous ammonium chloride (15mL), is extracted with ethyl acetate water layer (15ml × 4), merges organic faciess, anhydrous sodium sulfate drying, Filter, by filtrate reduced in volume, residue silica gel column chromatography separating purification (petroleum ether/dichloromethane (v/v)=2/1) is obtained (260mg is produced fluoro- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 18g of the bromo- 7- of 5- of pink solid shape Rate 45%).
7th step：The fluoro- 5- of 7- [3- (methylol) phenyl] -4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- Ketone (18h)
7-fluoro-5- [3- (hydroxymethyl) phenyl] -4,6-dimethyl-spiro [benzofuran-2, 1′-cyclopropane]-3-one
By fluoro- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 18g of the bromo- 7- of 5- (250mg, 0.88mmol), 3- methylols phenylboric acid (160mg, 1.05mmol) is added in DMF (5mL), adds 2M Wet chemical (1.75mL), nitrogen displacement reaction, adds [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (32mg, 0.04mmol), 90 DEG C are reacted 1 hour.Reaction terminates, and is cooled to room temperature, adds ethyl acetate (30mL), filters, and uses Water washing (10ml × 3), anhydrous sodium sulfate drying organic layer is filtered, by filtrate reduced in volume, residue silica gel column chromatography point The fluoro- 5- of 7- [3- (methylol) phenyl] -4 of yellow oily liquid are obtained from purification (petrol ether/ethyl acetate (v/v)=4/1), 6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 18h (220mg, yield 81%).
8th step：Methyl 2- [(3S) -6- [[3- (fluoro- 4, the 6- dimethyl -3- oxos of 7--spiral shell [benzofuran -2,1 '-rings Propane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate (18i)
Methyl2- [(3S) -6- [[3- (7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane] -5-yl) phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetate
By the fluoro- 5- of 7- [3- (methylol) phenyl] -4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 18h (220mg, 0.71mmol) is added in dichloromethane (15mL), adds (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- Base) methyl acetate 3D (162.4mg, 0.78mmol), nitrogen displacement.Sequentially add at 0 DEG C tributylphosphine (0.39mL, 1.56mmol) with 1,1 '-(azo dicarbapentaborane) two piperidines (393mg, 1.56mmol), 3 hours are stirred at room temperature.Filter, by filtrate It is concentrated under reduced pressure to give methyl 2- [(3S) -6- [[3- (fluoro- 4, the 6- dimethyl -3- oxos of 7--spiral shell [benzo furan of faint yellow oily Mutter -2,1 '-cyclopropane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate 18i crude products, directly For the next step.
9th step：2- [(3S) -6- [[3- (7- fluoro- 4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-rings third Alkane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 18)
2- [(3S) -6- [[3- (7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By upper step crude product methyl 2- [(3S) -6- [[3- (fluoro- 4, the 6- dimethyl -3- oxos-spiral shells of 7- [benzofuran -2, 1 '-cyclopropane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] and methyl acetate 18i be dissolved in methanol (2mL) and In the mixed solution of tetrahydrofuran (5mL), the sodium hydroxide solution (1.7mL) of 2M is added, is stirred at room temperature 2 hours, concentrating under reduced pressure, Water (10mL) is added in reactant liquor, Deca 1M dilute hydrochloric acid to reactant liquor pH is 3, is extracted with ethyl acetate (15mL × 3), is merged Organic faciess simultaneously use anhydrous sodium sulfate drying, filter, by filtrate reduced in volume.Residue silica gel column chromatography separating-purifying (dichloro Methane/methanol (v/v)=100/1) obtain 2- [(3S) -6- [[3- (fluoro- 4, the 6- dimethyl -3- oxygen of 7- of white blister solid, shaped Generation-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases) phenyl] methoxyl group] -2-2,3- Dihydrobenzofuranes -3- bases] acetoxylation (225mg, the 8th step and the 9th step total recovery are 65%, HPLC to compound 18：97.39%).
MS：487.2[M-1]
1H NMR (400MHz, DMSO) δ 12.28 (s, 1H), 7.50 (m, 2H), 7.21 (s, 1H), 7.11 (m, 2H), 6.47 (dt, 2H), 5.12 (s, 2H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.67 (m, 1H), 2.69 (dd, 1H), 2.46 (m, 1H), 2.18 (s, 3H), 1.97 (d, 3H), 1.86 (dd, 2H), 1.47 (q, 2H).
Embodiment 19
2- [(3S) -6- [[3- [2,2- double (methylol) -4,6- dimethyl -3- oxos-benzofuran -5- bases] phenyl] first Epoxide] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid (compound 19)
2- [(3S) -6- [[3- [2,2-bis (hydroxymethyl) -4,6-dimethyl-3-oxo-benzofuran- 5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
The first step：Double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4, the 6- dimethyl-benzo of bromo- 2, the 2- of 5- Furan -3- ketone (19a)
5-bromo-2,2-bis [[tert-butyl (dimethyl) silyl] oxymethyl] -4,6-dimethyl- benzofuran-3-one
Bromo- 2, the 2- bis- (methylol) of 5- -4,6- dimethyl benzofurans -3 (2H) -one 5a is sequentially added in reaction bulb (603mg, 2.0mmol), methyl tertbutyl chlorosilane (1.2g, 8.0mmol), imidazoles (816mg, 12.0mmol) and N, N- diformazan In base Methanamide (8mL), stir 30 minutes under room temperature.After reaction terminates, water (10mL) and ethyl acetate (50mL), layering are added Afterwards, organic layer (30mL × 2) is washed with water, organic layer anhydrous sodium sulfate drying is filtered, and by filtrate reduced in volume, residue is used Silica gel column chromatography separating purification (petroleum ether) obtains the double [[tert-butyl group (dimethyl) monosilanes of bromo- 2, the 2- of 5- of faint yellow oily Base] epoxide methyl] -4,6- Dimethvl-benzofurans -3- ketone 19a (1.05g, yield 99%).
Second step：2,2- double [tert-butyl group (dimethyl) silicyl] epoxide methyl] -5- [3- (methylol) phenyl] -4, 6- Dimethvl-benzofurans -3- ketone (19b)
2,2-bis [[tert-butyl (dimethyl) silyl] oxymethyl] -5- [3- (hydroxymethyl) Phenyl] -4,6-dimethyl-benzofuran-3-one
By double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4, the 6- Dimethvl-benzofurans of bromo- 2, the 2- of 5- - 3- ketone 19a (1.0g, 1.89mmol), 3- methylol phenylboric acid (344mg, 2.27mmol) are added to DMF (15ml) in, 2M wet chemicals (3.78mL), nitrogen displacement is added to react, [1,1 '-bis- (diphenylphosphinos) two are luxuriant for addition Ferrum] palladium chloride (69mg, 0.05mmol), reacts 1 hour at 90 DEG C.Reaction terminates, and is cooled to room temperature, adds ethyl acetate (50mL), filter, filtrate water washing (20mL × 3), anhydrous sodium sulfate drying organic layer is filtered, residual by filtrate reduced in volume Thing silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10/1) is stayed to obtain double [the tertiary fourths of 2,2- of yellow oily Base (dimethyl) silicyl] epoxide methyl] -5- [3- (methylol) phenyl] -4,6- Dimethvl-benzofuran -3- ketone 19b (1.03g, yield 99%).
1H NMR (400MHz, DMSO) δ 7.45 (d, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 7.02 (s, 1H), 6.92 (d, 1H), 5.22 (t, 1H), 4.57 (d, 2H), 3.92 (d, 4H), 2.16 (s, 3H), 2.04 (s, 3H), 0.72 (d, 18H) ,- 0.00 (t, 12H).
3rd step：Methyl -2- [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] - 4,6- dimethyl -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (19c)
Methyl 2- [(3S) -6- [[3- [2,2-bis [[tert-butyl (dimethyl) silyl] oxymethyl] - 4,6-dimethyl-3-oxo-benzofuran-5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3- yl]acetate
By double [tert-butyl group (dimethyl) silicyl] the epoxide methyl of 2,2-] -5- [3- (methylol) phenyl] -4,6- diformazans Base-benzofuran -3- ketone 19b (1.05g, 1.88mmol) is added in dichloromethane (20mL), addition (S) 2- (6- hydroxyl -2, 3- Dihydrobenzofuranes -3- bases) methyl acetate 3D (396.4mg, 1.9mmol), nitrogen displacement sequentially adds tributyl at 0 DEG C Phosphine (1.04ml, 4.15mmol) and 1,1 '-(azo dicarbapentaborane) two piperidines (1.05g, 4.15mmol), is stirred at room temperature 3 hours, mistake Filter, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10/1) is obtained Methyl -2- [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4,6- bis- of yellow oily Methyl -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] (1.2g is produced acetic acid 19c Rate 87%).
4th step：2- [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4,6- bis- Methyl -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (19d)
2- [(3S) -6- [[3- [2,2-bis [[tert-butyl (dimethyl) silyl] oxymethyl] -4,6- Dimethyl-3-oxo-benzofuran-5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By methyl -2- [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4,6- bis- Methyl -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid 19c (1.2g, In 1.6mmol) being dissolved in the mixed solution of methanol (3mL) and tetrahydrofuran (9mL), 2M sodium hydroxide solutions (2.2mL), room are added Temperature stirring 2 hours, concentrating under reduced pressure adds water (10mL), Deca 1M dilute hydrochloric acid (5mL), with ethyl acetate (15mL in reactant liquor × 3) extract, merge organic faciess and use anhydrous sodium sulfate drying, filter, filtrate reduced in volume is obtained into the 2- of faint yellow oily [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4,6- dimethyl -3- oxos-benzos Furan -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid 19d (1.08g).
5th step：2- [(3S) -6- [[3- [2,2- double (methylol) -4,6- dimethyl -3- oxos-benzofuran -5- bases] Phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid (compound 19)
2- [(3S) -6- [[3- [2,2-bis (hydroxymethyl) -4,6-dimethyl-3-oxo-benzofuran- 5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By upper step 2- [(3S) -6- [[3- [2,2- double [[tert-butyl group (dimethyl) silicyl] epoxide methyl] -4,6- bis- Methyl -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid 19d crude product (1.08g, 1.47mmol) is dissolved into tetrahydrofuran (10mL), add tetrabutyl ammonium fluoride trihydrate (2.32g, 7.35mmol), stir 45 minutes under room temperature.Reaction terminates, and adds water (20mL) that reaction is quenched, and is extracted with ethyl acetate water layer (20mL × 3), merge organic faciess, anhydrous sodium sulfate drying, concentrating under reduced pressure.Residue silica gel column chromatography separating-purifying (oil Ether/ethyl acetate (v/v)=1/1) obtain 2- [(3S) -6- [[3- [2,2- double (methylol) -4,6- diformazans of faint yellow blister Base -3- oxos-benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid compound 19 (470mg, the 4th step and the 5th step gross production rate are 63.4%, HPLC：96.33%).
MS m/z(ESI)：527.3[M+23]；503.2[M-1].
1H NMR (400MHz, DMSO) δ 12.31 (s, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.19 (s, 1H), 7.09 (m, 2H), 7.01 (d, 1H), 6.47 (dt, 2H), 5.10 (s, 2H), 5.03 (s, 2H), 4.67 (d, 1H), 4.18 (dd, 1H), 3.68 (m, 5H), 2.69 (dd, 1H), 2.46 (d, 1H), 2.14 (s, 3H), 2.01 (s, 3H).
Embodiment 20
2- [(3S) -6- [[3- [4,6- dimethyl -3- (3- methanesulfonylpropyl amino) -2,3- Dihydrobenzofuranes -5- Base] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid (compound 20)
2- [(3S) -6- [[3- [4,6-dimethyl-3- (3-methylsulfonylpropylamino) -2,3- Dihydrobenzofuran-5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
The first step：4,6- dimethyl -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] benzofuran -3- ketone (20a)
4,6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl] benzofuran-3- one
4,6- dimethyl -5- (3- hyd roxymethyl phenyls) benzofuran -3- ketone 9a (1.30g, 4.8mmol) are dissolved in into dichloro In methane (20mL), add 3,4- dihydropyran (0.5mL, 5.8mmol) and p-methyl benzenesulfonic acid pyridiniujm (125mg, 0.5mmol), stir 30 minutes under room temperature.After reaction terminates, saturated sodium bicarbonate aqueous solution (20mL) is added, use dichloromethane Aqueous layer extracted (20mL × 3), merges organic faciess, and anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume, residue silicagel column Chromatography purification (petrol ether/ethyl acetate (v/v)=5/1) obtains 4, the 6- dimethyl -5- [3- (tetrahydrochysenes of faint yellow oily Pyrans -2- yloxymethyls) phenyl] benzofuran -3- ketone 20a (1.59g, yield 94%).
Second step：4,6- dimethyl -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] -2,3- Dihydrobenzofuranes -3- Amine (20b)
4,6-dimethyl-5- [3- (tetrahydropyran-2-yloxymethyl) phenyl] -2,3- dihydrobenzofuran-3-amine
By 4,6- dimethyl -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] benzofuran -3- ketone 20a (563mg, 1.6mmol) it is added in methanol (10mL) with oxammonium hydrochloride. (333mg, 4.8mmol), in reaction bulb sodium hydroxide is added Water (3mL) solution of (211mg, 5.28mmol), reacts 4 hours, concentrating under reduced pressure at 80 DEG C, and water (20mL) is added in residue With dichloromethane (50mL), organic layer washes with water (10mL × 2), collects organic faciess, and anhydrous sodium sulfate drying is filtered, will filtered Liquid concentrating under reduced pressure, residue is dissolved into again (10mL) in methanol, adds nickel (120mg), and 24 hours are stirred at room temperature under nitrogen atmosphere. Filter, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50/1) is obtained 4,6- dimethyl -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] -2, the 3- Dihydrobenzofuranes -3- amine of faint yellow oily 20b (240mg, yield 68%).
3rd step：4,6- dimethyl-N -s (3- methanesulfonylpropyls) -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] - 2,3- Dihydrobenzofuranes -3- amine (20c)
4,6-dimethyl-N- (3-methylsulfonylpropyl) -5- [3- (tetrahydropyran-2- Yloxymethyl) phenyl] -2,3-dihydrobenzofuran-3-amine
By 4,6- dimethyl -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] -2,3- Dihydrobenzofuranes -3- amine 20b (240mg, 0.68mmol), 3- (methyl sulphonyl) propyl group 4- toluene sulfonic acides (226mg, 0.82mmol), potassium carbonate (188mg, In 1.36mmol) being added to acetonitrile (10mL), react 48 hours at 90 DEG C.After reaction terminates, filter, filtrate reduced in volume is obtained To faint yellow oily 4,6- dimethyl-N -s (3- methanesulfonylpropyls) -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] - 2,3- Dihydrobenzofuranes -3- amine 20c crude products, are directly used in the next step.
4th step：(3- (4,6- dimethyl -3- ((3- (methyl sulphonyl) propyl group) amino) -2,3- Dihydrobenzofuranes - 5- yls) phenyl) methanol (20d)
[3- [4,6-dimethyl-3- (3-methylsulfonylpropylamino) -2,3- dihydrobenzofuran-5-yl]phenyl]methanol
By upper step 4,6- dimethyl-N -s (3- methanesulfonylpropyls) -5- [3- (Pentamethylene oxide. -2- yloxymethyls) phenyl] - 2,3- Dihydrobenzofuranes -3- amine 20c dissolving crude products are added in the mixed solvent of tetrahydrofuran (5mL) and methanol (3mL) The hydrochloric acid (1mL) of 12N, is stirred at room temperature 30 minutes.Saturated sodium bicarbonate solution (15mL) is added, (15mL is extracted with ethyl acetate × 3), and merging organic faciess, anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=60/1) obtains (3- (4,6- dimethyl-the 3- ((3- (methyl sulphonyl) third of faint yellow oily Base) amino) -2,3- Dihydrobenzofuranes -5- bases) phenyl) methanol 20d (175mg, the 3rd step and the 4th step gross production rate 66%).
5th step：Methyl 2- [(3S) -6- [[3- [4,6- dimethyl -3- (3- methanesulfonylpropyl amino) -2,3- dihydros Benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] methyl acetate (20e)
Methyl2- [(3S) -6- [[3- [4,6-dimethyl-3- (3-methylsulfonylpropylamino) -2, 3-dihydrobenzofuran-5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetate
By (3- (4,6- dimethyl -3- ((3- (methyl sulphonyl) propyl group) amino) -2,3- Dihydrobenzofuranes -5- bases) Phenyl) methanol 20d (167mg, 43mmol) is added in dichloromethane (10mL), adds (S) 2- (6- hydroxyl -2,3- dihydrobenzenes And furan -3- bases) methyl acetate 3D (98.3mg, 0.47mmol), nitrogen displacement at 0 DEG C, sequentially adds tributylphosphine (0.24mL, 0.94mmol) and 1,1 '-(azo dicarbapentaborane) two piperidines (238mg, 0.94mmol), is stirred at room temperature 2 hours.Cross Filter, by filtrate reduced in volume methyl 2- [(3S) -6- [[3- [4,6- dimethyl -3- (the 3- mesyls of faint yellow oily are obtained Propylcarbamic) -2,3- Dihydrobenzofuranes -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid first Ester 20e crude products, are directly used in the next step.
6th step：2- [(3S) -6- [[3- [4,6- dimethyl -3- (3- methanesulfonylpropyl amino) -2,3- dihydrobenzos Furan -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid (compound 20)
2- [(3S) -6- [[3- [4,6-dimethyl-3- (3-methylsulfonylpropylamino) -2,3- Dihydrobenzofuran-5-yl] phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By upper step crude product methyl 2- [(3S) -6- [[3- [4,6- dimethyl -3- (3- methanesulfonylpropyl amino) -2,3- bis- Hydrogen benzofuran -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] methyl acetate 20e is added to tetrahydrochysene In furan (6mL) and methanol (3mL), 2M sodium hydroxide solutions (1.05mL) are added, be stirred at room temperature 2 hours, reaction terminates, added 2M hydrochloric acid (1.5mL), adds potassium phosphate to adjust pH to 6-7, adds water (10mL), is extracted with ethyl acetate (15mL × 3), is associated with Machine phase, anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume, residue with silica gel column chromatography separating-purifying (dichloromethane/ Methanol (v/v)=50/1) obtain 2- [(3S) -6- [[3- [4,6- dimethyl -3- (the 3- methanesulfonylpropyl ammonia of yellow solid Base) -2,3- Dihydrobenzofuranes -5- bases] phenyl] methoxyl group] -2,3- Dihydrobenzofuranes pyridin-3-yls] acetic acid compound 20 (170mg, the 5th step and the 6th step gross production rate 70%, HPLC：99.75%).
MS m/z(ESI)：564.3[M-1].
1H NMR (400MHz, DMSO) 87.44 (td, 1H), 7.38 (d, 1H), 7.08 (m, 3H), 6.57 (s, 1H), 6.47 (ddd, 2H), 5.09 (s, 2H), 4.67 (t, 1H), 4.38 (m, 3H), 4.18 (t, 1H), 3.67 (m, 1H), 3.13 (dd, 2H), 2.92 (s, 3H), 2.69 (dd, 1H), 2.59 (m, 2H), 2.46 (d, 1H), 1.95 (d, 3H), 1.88 (s, 3H), 1.80 (m, 2H).
Embodiment 21
[(3S) [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases) -2- is fluoro- for -6- for 2- Phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 21)
2- [(3S) -6- [[5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) -2-fluoro-phenyl] methoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid
The first step：Bromo- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone (21a) of 5-
5-bromo-4,6-dimethyl-spiro [benzofuran-2,1 '-cyclopropane] -3-one
Anhydrous and oxygen-free nitrogen protection under, by bromo- 4,6- dimethyl benzofurans -3 (2H) -one 2E of 5- (12.05g, In 50mmol) being added to tetrahydrofuran (150mL), at -30 DEG C, sodium hydride (10g, 60%wt, 250mmol), stirring 30 are added Minute, stirring 30 minutes at being to slowly warm up to 35 DEG C, Deca glycol dibromide (13mL, 150mmol) is warming up to 45 after adding React 24 hours at DEG C.Reaction is cooled to -20 DEG C after terminating, and is slowly added to water quenching and goes out reaction (50mL).Add saturated ammonium chloride Aqueous solution (50mL), is extracted with ethyl acetate (80mL × 3), merges organic faciess, and anhydrous sodium sulfate drying filters, filtrate is subtracted Pressure concentration, residue silica gel column chromatography separating-purifying (petroleum ether/dichloromethane (v/v)=1/1) obtains pink solid shape Bromo- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 21a (8.78g, yield 65.8%) of 5-.
1H NMR (400MHz, DMSO) δ 7.23 (s, 1H), 2.62 (s, 3H), 2.46 (s, 3H), 1.77 (q, 2H), 1.43 (q, 2H).
Second step：4,6- dimethyl -5- (4,4,5,5- tetramethyl -1, the ring -2- bases of 3,2- dioxy boron penta) spiral shell [benzo furan Mutter -2,1 '-cyclopropane] -3- ketone (21b)
4,6-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) spiro [benzofuran-2,1 '-cyclopropane] -3-one
By bromo- 4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 21a (5.34g, 20mmol) of 5-, join boron Sour pinacol ester (5.59g, 22mmol), [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (818mg, 1mmol), potassium acetate (5.89g, 60mmol), in being added to ethanol solution (100mL), nitrogen displacement, back flow reaction 16 hours.After reaction terminates, somewhat concentration of reaction solution, addition water (100mL) extracts (100mL × 3) with dichloromethane, merges Organic faciess, anhydrous sodium sulfate drying is filtered, by filtrate reduced in volume, residue with silica gel column chromatography separating-purifying (petroleum ether/ Dichloromethane (v/v)=1/1) obtain 4,6- dimethyl -5- (4,4,5,5- tetramethyl -1,3, the 2- dioxies of faint yellow solid shape Ring -2- the bases of boron penta) spiral shell [benzofuran -2,1 '-cyclopropane] -3- ketone 21b (3.7g, yield 59%).
1H NMR (400MHz, DMSO) δ 6.94 (s, 1H), 2.60 (s, 3H), 2.42 (s, 3H), 1.71 (q, 2H), 1.37 (dd, 2H), 1.34 (s, 12H).
The bromo- 2- fluorophenyl methanols (21d) of 3rd step 5-
(5-bromo-2-fluorophenyl)methanol
The bromo- 2- fluorobenzaldehydes 21c (1.015g, 5.0mmol) of 5- are dissolved in into the mixed of methanol (5mL) and tetrahydrofuran (10mL) In closing solution, sodium borohydride (378mg, 10mmol) is added at 0 DEG C, continue to stir 15 minutes after adding.Water (10mL) is added to quench Go out reaction.Somewhat concentration of reaction solution, adds saturated aqueous ammonium chloride (10mL), is extracted with ethyl acetate (20mL × 3), merges Organic faciess, wash successively (50mL × 1), water washing (50mL × 1) with saturated ammonium chloride solution, merge organic faciess, concentrating under reduced pressure Obtain the bromo- 2- fluorophenyl methanols 21d of the 5- (1.1g, yield 99%) of white solid.
4th step 5- [4- fluoro- 3- (methylol) phenyl] -4,6- dimethyl-spiral shell [benzofuran -2,1 '-cyclopropane] -3- Ketone (21e)
5- [4-fluoro-3- (hydroxymethyl) phenyl] -4,6-dimethyl-spiro [benzofuran-2, 1′-cyclopropane]-3-one
By 4,6- dimethyl -5- (4,4,5,5- tetramethyl -1, the ring -2- bases of 3,2- dioxy boron penta) spiral shell [benzofuran -2, 1 '-cyclopropane] the bromo- 2- fluorophenyl methanols 21d (615mg, 3.0mmol) of -3- ketone 21b (628mg, 2.0mmol) and 5- are added to N, In dinethylformamide (5mL), 2M solution of potassium carbonate (5mL), nitrogen displacement reaction is added to add [1,1 '-bis- (diphenyl Phosphine) ferrocene] palladium chloride (73mg, 0.1mmol), react 1 hour at 90 DEG C, ethyl acetate is added, filter, filtrate water is washed Wash (10mL × 3), anhydrous sodium sulfate drying, filter, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (stone Oily ether/ethyl acetate (v/v)=5/1) obtain 5- [4- fluoro- 3- (methylol) phenyl] -4, the 6- dimethyl-spiral shell of yellow oily [benzofuran -2,1 '-cyclopropane] -3- ketone 21e (462mg, yield 74%).
1H NMR (400MHz, DMSO) δ 7.23 (ddd, 2H), 7.11 (s, 1H), 7.10-7.05 (m, 1H), 5.28 (t, 1H), 4.60 (d, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.74 (q, 2H), 1.41 (q, 2H).
5th step：Methyl 2- [(3S) -6- [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] - 5- yls) -2- fluoro-phenyls] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate (21f)
Methyl
2- [(3S) -6- [[5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) -2-fluoro-phenyl] metho xy] -2,3-dihydrobenzofuran-3-yl] acetate
Sequentially add in reaction bulb 5- [4- fluoro- 3- (methylol) phenyl] -4,6- dimethyl-spiral shell [benzofuran -2, 1 '-cyclopropane] -3- ketone 21e (300mg, 0.96mmol), dichloromethane (15mL) and (S) 2- (6- hydroxyl -2,3- dihydrobenzos Furan -3- bases) methyl acetate 3D (210mg, 1.01mmol), nitrogen protection under, sequentially add at 0 DEG C tributylphosphine (0.53mL, 2.11mmol) with 1,1 '-(azo dicarbapentaborane) two piperidines (532mg, 2.11mmol), it is stirred at room temperature 3 hours, filters, by filtrate Be concentrated under reduced pressure to give faint yellow oily methyl 2- [(3S) -6- [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2, 1 '-cyclopropane] -5- bases) -2- fluoro-phenyls] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate 21f crude products, directly For the next step.
6th step 2- [(3S) -6- [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- Base) -2- fluoro-phenyls] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 21)
2- [(3S) -6- [[5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) -2-fluoro-phenyl] metho xy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By methyl 2- [(3S) -6- [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2, the 1 '-rings third of upper step Alkane] -5- bases) -2- fluoro-phenyls] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate 21f crude products are dissolved in methanol (5mL) and in the mixed solution of tetrahydrofuran (10mL), 2M sodium hydroxide solutions (2.4mL) are added, is stirred at room temperature 2 hours, subtracted Pressure concentration, water (10mL) is added in reactant liquor, and Deca 1M dilute hydrochloric acid to reactant liquor pH is 1, is extracted with ethyl acetate (15mL × 3) Take, merge organic faciess and use anhydrous sodium sulfate drying, filter, by filtrate reduced in volume, residue silica gel column chromatography is separated and carried Pure (petrol ether/ethyl acetate (v/v)=4: 1 → methylene chloride/methanol (v/v)=70: 1) obtain yellow blister 2- [(3S)- 6- [[5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases) -2- fluoro-phenyls] methoxyl group] -2, 3- Dihydrobenzofuranes -3- bases] acetic acid compound 21 (366mg, the 5th step and the 6th step total recovery 78%).
MS m/z(ESI)：487.1[M-1].
1H NMR (400MHz, DMSO) δ 12.29 (s, 1H), 7.39-7.27 (m, 2H), 7.23-7.15 (m, 1H), 7.11 (t, 2H), 6.49 (dd, 2H), 5.14 (s, 2H), 4.68 (t, 1H), 4.19 (dd, 1H), 3.73-3.61 (m, 1H), 2.69 (dd, 1H), 2.47 (dd, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.74 (dd, 2H), 1.41 (q, 2H).
Embodiment 22
2- [(3S) -6- [[the chloro- 5- of 2- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases) Phenyl] methoxyl group] -2-2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 22)
2- [(3S) -6- [[2-chloro-5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) phenyl] metho xy] -2,3-dihydrobenzofuran-3-yl] acetic acid
The first step：(the bromo- 2- chlorphenyls of 5-) methanol (22b)
(5-bromo-2-chlorophenyl)methanol
The chloro- 2- fluorobenzaldehydes (1.10g, 5.0mmol) of 5- are dissolved in methanol (5mL) and tetrahydrofuran (10mL), at 0 DEG C Sodium borohydride (378mg, 10mmol) is added, continues to stir 15 minutes after adding.Add water (10mL) that reaction is quenched, somewhat concentrate Reactant liquor, adds saturated ammonium chloride solution (10mL), is extracted with ethyl acetate (20mL × 3), merges organic faciess, and saturation is used successively Ammonium chloride solution washing (50mL × 1), water washing (50mL × 1), organic faciess be concentrated under reduced pressure to give white solid (5- is bromo- 2- chlorphenyls) methanol 22b (1.15g, yield 99%).
Second step：5- (4- chloro- 3- (methylol) phenyl) -4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-ring third Alkane] -3- ketone (22c)
5- (4-chloro-3- (hydroxymethyl) phenyl) -4,6-dimethyl-3H-spiro [benzofuran-2,1 '-cyclopropan] -3-one
By 4,6- dimethyl -5- (4,4,5,5- tetramethyl -1, the ring -2- bases of 3,2- dioxy boron penta) spiral shell [benzofuran -2, 1 '-cyclopropane] -3- ketone 21b (628mg, 2.0mmol) and (the bromo- 2- chlorphenyls of 5-) methanol 22b (615mg, 3.0mmol) additions To in DMF (5mL), 2M solution of potassium carbonate (5mL), nitrogen displacement reaction is added to add [1,1 '-bis- (two Phenylphosphine) ferrocene] palladium chloride (73mg, 0.1mmol), react 2 hours at 90 DEG C, ethyl acetate is added, to filter, filtrate is used Water washing (10mL × 3), anhydrous sodium sulfate drying organic layer is filtered, by filtrate reduced in volume, residue silica gel column chromatography point 5- (4- chloro- 3- (methylol) phenyl) -4, the 6- bis- of yellow oily is obtained from purification (petrol ether/ethyl acetate (v/v)=5/1) Methyl -3H- spiral shells [benzofuran -2,1 '-cyclopropane] -3- ketone 22c (500mg, yield 76%).
MS m/z(ESI)：331.1[M+1].
3rd step：Methyl 2- [(3S) -6- [[the chloro- 5- of 2- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-rings Propane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate (22d)
Methyl2- [(3S) -6- [[2-chloro-5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane] -5-yl) phenyl] methoxy] -2,3-dihydro benzofuran-3-yl] acetate
By 5- (4- chloro- 3- (methylol) phenyl) -4,6- dimethyl -3H- spiral shells [benzofuran -2,1 '-cyclopropane] -3- ketone In 22c (490mg, 1.49mmol) dichloromethane (15mL), (S) 2- (6- hydroxyl -2,3- Dihydrobenzofuranes -3- bases) second is added Sour methyl ester 3D (326mg, 1.57mmol, intermediate), nitrogen protection under, under 0 degree, sequentially add tributylphosphine (0.82ml, 3.28mmol) with 1,1 '-(azo dicarbapentaborane) two piperidines (828mg, 3.28mmol), it is stirred at room temperature 3 hours, filters, by filtrate It is concentrated under reduced pressure to give methyl 2- [(3S) -6- [[the chloro- 5- of 2- (4, the 6- dimethyl -3- oxos-spiral shell [benzo furan of faint yellow oily Mutter -2,1 '-cyclopropane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] methyl acetate 22d crude products, directly For the next step.
6th step：2- [(3S) -6- [[the chloro- 5- of 2- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-rings third Alkane] -5- bases) phenyl] methoxyl group] -2-2,3- Dihydrobenzofuranes -3- bases] acetic acid (compound 22)
2- [(3S) -6- [[2-chloro-5- (4,6-dimethyl-3-oxo-spiro [benzofuran-2,1 ' - Cyclopropane] -5-yl) phenyl] metho xy] -2,3-dihydrobenzofuran-3-yl] acetic acid
By upper step (methyl 2- [(3S) -6- [[the chloro- 5- of 2- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-rings Propane] -5- bases) phenyl] methoxyl group] -2,3- Dihydrobenzofuranes -3- bases] and methyl acetate 22d crude products be dissolved in methanol (5mL) and In the mixed solution of tetrahydrofuran (10mL), 2M sodium hydroxide solutions (3.7mL) are added, are stirred at room temperature 2 hours, concentrating under reduced pressure, Water (10mL) is added in reactant liquor, Deca 1M dilute hydrochloric acid to reactant liquor pH is 1, is extracted with ethyl acetate (15mL × 3), is merged Organic faciess simultaneously use anhydrous sodium sulfate drying, filter, by filtrate reduced in volume, residue silica gel column chromatography separating-purifying (oil Ether/ethyl acetate (v/v)=4: 1 → methylene chloride/methanol (v/v)=70: 1) obtain 2- [(3S)-the 6- [[2- of yellow blister Chloro- 5- (4,6- dimethyl -3- oxos-spiral shell [benzofuran -2,1 '-cyclopropane] -5- bases) phenyl] methoxyl group] -2-2,3- dihydros Benzofuran -3- bases] acetic acid compound 22 (595mg, the 5th step and the 6th step total recovery for 79%),
MS m/z(ESI)：506.0[M+1].
1HNMR (400MHz, DMSO) δ 12.31 (s, 1H), 7.60 (d, 1H), 7.33 (s, 1H), 7.18 (dd, 1H), 7.11 (t, 2H), 6.47 (d, 2H), 5.16 (s, 2H), 4.68 (t, 1H), 4.24-4.16 (m, 1H), 3.75-3.60 (m, 1H), 2.69 (dd, 1H), 2.50-2.42 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.74 (dd, 2H), 1.41 (dd, 2H).
Biological test example
1.GPR40 luciferase reporter genes are tested
Using the activity of GPR40 luciferase reporter gene experimental test the compounds of this invention, process of the test is as follows：
Compound is configured to the storing liquid of 10mM with DMSO, then it is stand-by by 3 times of gradient dilutions.By stably expressing cell line HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elk1 are inoculated in 96 orifice plates with suitable density.Second day, treat that cell converges It is right to reach 70% or so, it is replaced by serum-free medium, overnight starvation.3rd day, add and contain the tested chemical combination of variable concentrations The DMEM culture medium of thing, per the μ l of hole 200, is put into cell culture incubator and is incubated 5 hours.Using Luciferase Assay System Test kit detects uciferase activity.Analysis is fitted to fluorescence data using the softwares of Origin 7, each compound is calculated EC50, result of the test is shown in Table 1.
The luciferase reporter gene result of the test of table 1
Conclusion：The compounds of this invention has obvious agonist activity to people GPR40.
2. oral glucose tolerance test
Hypoglycemic effect of the compounds of this invention in glucose load mice is evaluated using oral glucose tolerance test (OGTT). Process of the test is as follows：
The animal for using is SPF level ICR mices, and 18-22g is female, purchased from the limited public affairs of Beijing China Fukang biotechnology share Department, animal productiong quality certification number：SCXK (capital) 2009-0004.The mice of purchase is induced 25 days with high lipid food, fasting Night.It is grouped according to the basal plasma glucose value after fasting, 10 per group.Test-compound is with 5%DMSO-15%solutol-80% lifes Suspension of the reason saline into 2mg/ml.Gastric infusion, dosage is 20mg/kg.Blank control group gives 5%DMSO- 15%solutol-80% normal saline.Give 20% D/W (1g/kg) after administration 15min, and 0,15, 30th, 45 the blood glucose value of each mice, 60, is determined during 120min using the steady person of outstanding talent's Instrument for Measuring Blood Sugar of Johnson ＆ Johnson, area under drug-time curve is calculated (AUC) ratio is reduced.Result of the test is shown in Table 2.
The oral glucose tolerance test result of table 2
Conclusion：The compounds of this invention has good hypoglycemic effect.

Claims (19)

1. the compound or its pharmaceutically acceptable salt shown in a kind of logical formula (I)：
Wherein：
R is selected from H；
R1Selected from F, Cl or Br；
R4Selected from F, Cl, Br, I；
R2And R3It is each individually optional from H；
R5、R10And R11It is each independently selected from H, F, Cl, Br, I, C1-6Alkyl；
P is selected from 0；
Q is selected from 0 or 1；
T is selected from 1；
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)m-NR13R13a；
Alternatively, R6And R7Can be formed (=O)；
R13And R13aIn arbitrary group be selected from H, another group be selected from C1-6Alkyl, the alkyl is further by 1-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from C1-6Alkyl；
R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl or-C1-4Alkyl-O-C1-4Alkyl；
Alternatively R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
M is selected from 0；
N is selected from 2；
Ring Q is selected from
2. compound according to claim 1 or its pharmaceutically acceptable salt, it is the change shown in following logical formula (II)s Compound or its pharmaceutically acceptable salt：
Wherein：
R is selected from H；
Ring Q is
R1Selected from F, Cl or Br；
R5、R10And R11It is each individually optional from H, F, Cl, Br or C1-4Alkyl；
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)m-NR13R13a；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl or-C1-4Alkyl-O-C1-4Alkyl；
Alternatively, R8With R9Coupled carbon atom can form 3 yuan of carbocyclic rings；
R13And R13aIn arbitrary group be selected from H, another group be selected from C1-4Alkyl, the alkyl is further by 1 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from C1-4Alkyl；
P is selected from 0；
M is selected from 0；
N is selected from 2.
3. compound according to claim 1 or its pharmaceutically acceptable salt, it is the compound shown in logical formula (III) Or its pharmaceutically acceptable salt：
Wherein：
R5And R11It is each individually optional from H, F, Cl, Br or C1-4Alkyl；
R10Selected from H, F, Cl or Br；
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)m-NR13R13a；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl or-C1-4Alkyl-O-C1-4Alkyl；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aIn arbitrary group be selected from H, another group be selected from C1-4Alkyl, the alkyl is further by 1 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from C1-4Alkyl；
M is selected from 0；
N is selected from 2.
4. compound according to claim 1 or its pharmaceutically acceptable salt, it is the compound shown in logical formula (IV) Or its pharmaceutically acceptable salt：
Wherein：
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)m-NR13R13a；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl or-C1-4Alkyl-O-C1-4Alkyl；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aIn arbitrary group be selected from H, another group be selected from C1-4Alkyl, the alkyl is further by 1 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from C1-4Alkyl；
M is selected from 0；
N is selected from 2.
5. compound according to claim 4 or its pharmaceutically acceptable salt, wherein：
R6And R7Each it is individually optional from H, methyl, methoxyl group, ethyoxyl,
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each individually optional from H ,-CH2OH, methyl,
Alternatively, R8And R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings.
6. compound according to claim 1 or its pharmaceutically acceptable salt, its be the compound shown in logical formula V or Its pharmaceutically acceptable salt：
Wherein：
R4Selected from H, F or Cl；
R5、R10And R11It is each individually optional from H, F, Cl or C1-4Alkyl；
R6、R7It is each independently selected from H, C1-4Alkyl, C1-4Alkoxyl ,-C1-4Alkyl-O-C1-4Alkyl or-(CH2)m-NR13R13a；
Alternatively, R6And R7Can be formed (=O)；
R8And R9It is each independently selected from H ,-CH2OH、C1-4Alkyl or-C1-4Alkyl-O-C1-4Alkyl；
Alternatively, R8With R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings；
R13And R13aIn arbitrary group be selected from H, another group be selected from C1-4Alkyl, the alkyl is further by 1 selected from-(CH2)mS (=O)nR12Substituent group replaced；
R12Selected from C1-4Alkyl；
M is selected from 0；
N is selected from 2.
7. compound according to claim 6 or its pharmaceutically acceptable salt, wherein：
R4Selected from H, F or Cl；
R5And R11For methyl；
R10Selected from H or F；
R6And R7Each it is individually optional from H, methyl, methoxyl group, ethyoxyl,Or R6And R7Shape Into (=O)；
R8And R9It is each individually optional from H ,-CH2OH, methyl,
Alternatively, R8And R9Carbon atom that can be coupled forms 3 yuan of carbocyclic rings.
8. compound according to claim 7 or its pharmaceutically acceptable salt, wherein：
R6And R7For H or R6And R7Formed (=O)；
R8And R9Coupled carbon atom forms 3 yuan of carbocyclic rings.
9. compound according to claim 1 or its pharmaceutically acceptable salt, wherein compound is selected from：
10. the stereoisomer of the compound described in claim 9.
11. compounds according to any one of claim 1～9 or its pharmaceutically acceptable salt, wherein described salt Selected from sodium salt, potassium salt, aluminium salt, lithium salts, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, front three amine salt, tetramethyl ammonium, diethylamine Salt, triethylamine salt, isopropyl amine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexyl amine salt, Pyridiniujm, picoline salt, 2,6- lutidines salt, coffee alkali salt, procaine salt, choline salt, Radix Betae alkali salt, theobromine Salt, purine salt, piperazine salt, piperidinium salt, N-ethylpiperidine salt, polyamino resin salt, benethamine penicillin salt, hydrochlorate, hydrobromate, Sulfate, nitrate, phosphate, formates, acetate, oxyacetate, propionate, 2 hydroxy propanoic acid salt, malonate, trifluoro Acetate, mesylate, esilate, fluoroform sulphonate, vinyl sulfonate, benzene sulfonate, tosilate, benzoic acid It is salt, phenylacetate, alginate, anthranilate, Camphora hydrochlorate, maleate, tartrate, citrate, succinate, flat Fructus Persicae hydrochlorate, fumarate, malate, oxalates, salicylate, glucuronate salt, galacturonic acid hydrochlorate, citrate, Aspartate, glutamate, Glu, cinnamate or combinations thereof.
12. compounds according to claim 11 or pharmaceutically acceptable salt, wherein described salt is selected from sodium salt, potassium Salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochlorate, hydrobromate, sulfate, phosphate, trifluoroacetic acid Salt, acetate, maleate, aspartate, glutamate, Glu, malate or combinations thereof.
13. prepare the method according to compound described in any one of claim 1～12, and the method may be selected from comprising the following steps Method one, method two, method three or method four：
Method one：
Formula (I-a) compound pass sequentially through Horner-Wadsworth-Emmons reaction or wittig reaction, reduction reaction with And alkylated reaction is converted into formula (I-b) compound；Or formula (I-a) compound by reduce elimination reaction be converted into it is logical Formula (I-b) compound；
Formula (I-b) compound is converted into formula (I-c) compound by suzuki coupling reactions and hydrogenation reduction；
Formula (I-c) compound is reacted by Mitsunobu and hydrolysis are converted into logical formula (I) compound；Or formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu reactions；
Method two：
Formula (I-d) compound is converted into formula (I-e) compound by nucleophilic substitution and Claisen rearangement reaction；
Formula (I-e) compound is converted into formula (I-f) compound by epoxidation reaction and ring-opening reaction；Or formula (I-e) compound is converted into formula (I-f) compound by nucleophilic substitution；
Formula (I-f) compound passes through suzuki coupling reaction formula (I-c) compounds；Or formula (I-f) compound passes through Suzuki coupling reactions and hydrogenation reduction are converted into formula (I-c) compound；
Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions and hydrolysis；Or Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；
Method three：
Formula (I-g) compound is converted into formula (I-a) compound by Adol reactions；Or formula (I-g) compound passes through Nucleophilic substitution is converted into formula (I-a) compound；
Formula (I-a) compound is converted into formula (I-f) compound by reduction reaction；Or formula (I-a) compound passes through Reduction reaction and decarboxylation reaction are converted into formula (I-f) compound；
Formula (I-f) compound passes through suzuki coupling reaction formula (I-c) compounds；Or formula (I-f) compound passes through Suzuki coupling reactions and hydrogenation reduction are converted into formula (I-c) compound；
Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions and hydrolysis；Or Formula (I-c) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；
Method four：
Formula (I-a) compound is converted into formula (I-h) compound by suzuki coupling reactions；Or formula (I-a) chemical combination Thing is converted into formula (I-h) compound by suzuki coupling reactions and hydrogenation reduction；
Formula (I-h) compound is converted into formula (1-i) compound by reduction amination；
Formula (1-i) compound is converted into formula by nucleophilic substitution, Mitsunobu condensation reactions and hydrolysis (I) compound, or formula (I-i) compound is converted into logical formula (I) compound by Mitsunobu condensation reactions；Wherein：
L is selected from F, Cl, Br or I；
R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11, Q, p, q and t be with any one of claim 1～11 as determined Justice；
R16、R17And R18Selected from H, OH, methyl or ethyl.
A kind of 14. pharmaceutical compositions, described compositionss include：Effective dose according to arbitrary in claim 1～9,11,12 The stereoisomer described in compound or its pharmaceutically acceptable salt or claim 10 described in, and pharmaceutically can connect Carrier, diluent, adjuvant or the excipient received.
15. claim 1～9, the compound any one of 11,12 or its pharmaceutically acceptable salt or claim 10 Pharmaceutical composition described in described stereoisomer or claim 14 is in the agonist of g protein coupled receptor 40 is prepared Purposes.
16. purposes according to claim 15, wherein, the purposes is claim 1-9, any one of 11,12 Compound or its pharmaceutically acceptable salt or stereoisomer or claim 14 described in claim 10 described in Pharmaceutical composition is being prepared for the purposes in treatment and/or the pharmaceutical preparation of preventing metabolic diseases.
17. purposes according to claim 16, wherein, the metabolic disease is diabetes, diabetic complication, high gallbladder are consolidated The sour lipidemia of alcoholemia, hyperglycemia, hyperinsulinemia, hyperlipemia, high glycerine three, hypertension, hyperlipoproteinemia, height LDL-C, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketosis acid Poisoning, lipoatrophy, lipotoxicity, obesity, metabolism syndrome, X syndromes, insulin resistance, insulin allergy disease, Fructus Vitis viniferae One kind in sugared Intolerance, dermatosiss, atherosclerosiss and its sequela angina pectoriss, limping, heart attack or apoplexy Or it is various.
18. purposes according to claim 17, wherein, the diabetic complication is diabetic retinopathy, glycosuria One or more in characteristic of disease neuropathy or diabetic nephropathy.
19. purposes according to claim 16, wherein, the metabolic disease is type ii diabetes.
CN201480003531.4A 2013-05-22 2014-05-22 Benzofuran derivative, preparation method therefor, and medical application thereof Expired - Fee Related CN104870429B (en)

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