CN108602811A - FXR receptor stimulating agents - Google Patents

FXR receptor stimulating agents Download PDF

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CN108602811A
CN108602811A CN201780007789.5A CN201780007789A CN108602811A CN 108602811 A CN108602811 A CN 108602811A CN 201780007789 A CN201780007789 A CN 201780007789A CN 108602811 A CN108602811 A CN 108602811A
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amino
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hydroxyl
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CN108602811B (en
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吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
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Xuanzhu Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides the following general formula (1) compound represented, its pharmaceutically acceptable salt, its ester or its stereoisomer, the present invention also provides the preparation method of above compound and is preparing for preventing and/or treating the purposes in nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and the drug of malignant tumour.Wherein, R1、R2、R3、R4, m, n, W, A, Z, E, F, X, Y be defined as in the description.

Description

FXR receptor stimulating agent Technical field
The present invention relates to FXR receptor stimulating agent, its pharmaceutically acceptable salt, its ester and their stereoisomers, containing the pharmaceutical preparation of these compounds and the compound, its pharmaceutically acceptable salt, its ester and their stereoisomer the purposes in the drug by related diseases such as the receptor-mediated nonalcoholic fatty liver of FXR, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumours is treated and/or prevented in preparation.
Background technique
FXR receptor (farnesoid X receptor) belongs to ligand-activated transcription factor nuclear receptor family member, with typical nuclear receptor structure, the i.e. highly conserved combined area DNA (DBD) of amino terminal, carboxyl terminal ligand binding domain (LBD), amino terminal ligand-independent transcriptional activation function area (AF1), carboxyl terminal ligand-dependent transcriptional activation functional areas (AF2) and foot chain area.FXR can form heterodimer with retinoid X receptor (RXR), after ligand is in conjunction with the region LBD of FXR, FXR conformation can change, the combined area of DNA is integrated to the FXR response element (IR-1) of target gene promoters above, it discharges Corepressors (such as NCOR), co-activator is recruited, to play transcriptional control effect.
FXR has expression, including adipose tissue, liver, gastrointestinal tract, kidney etc. in multiple organ-tissues, and wherein expression quantity is the abundantest in liver.FXR signal path, the expression of multiple downstream genes can directly or indirectly be adjusted, such as BSEP, SHP, CYP7A1, FGFR4, OST α/β, SREBP-1C gene, and then adjust multiple metabolic pathways, such as: the metabolism of triglycerides, cholesterol, blood glucose and energy stability metabolism cholic acid has the function of the diseases such as treating cancer, nonalcoholic fatty liver, metabolic disorder, inflammation.By inhibiting synthesis, combination and the transhipment of cholic acid, its metabolism is adjusted, is the main attemperator of internal cholic acid balance.
The natural Cholic acids compound in part can excitement FXR receptor, such as the glycine conjugates of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and taurine and these cholic acid.Natural compound is removed, the FXR agonist researched and developed in the world at present can be broadly divided into two major classes, and one kind is steroid, using the shellfish cholic acid difficult to understand of Intercept company as representative (obeticholicacid, OCA), for nonalcoholic fatty liver indication, it is in the clinic III phase；Another kind of is novel molecular entity, the compound such as GW4604 (WO2000/037077) of early stage research and development, Although have stronger agonist activity, its to photo-labile and bioavilability it is lower, in addition, Phenex company research and development PX-104 (WO2011020615A1) be assigned to Gilead company, be currently in clinical II phase conceptual phase.
But it still wants to develop the preferably novel FXR receptor stimulating agent of efficient, less toxic and stability at present.
Summary of the invention
The issue of the present invention is to provide the compounds with new molecular architecture, can effectively excitement FXR receptor, promotion BSEP and SHP gene expression dose, while the expression of effectively inhibition CYP7A1 gene.In addition, better meeting the market demand to achieve the purpose that better therapeutic effect, it is also desirable to be capable of providing the preferable FXR receptor stimulating agent of efficient, less toxic and stability.
Specifically, the purpose of the present invention is to provide a kind of new structural FXR receptor stimulating agents, it provides possibility for treating nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumour with good drug effect, for FXR receptor stimulating agent.
Other objects of the present invention are to provide the preparation method of above-mentioned FXR receptor stimulating agent.
Another object of the present invention is to provide the pharmaceutical compositions and preparation that contain above-mentioned FXR receptor stimulating agent.
A further object of the present invention is to provide above-mentioned FXR receptor stimulating agent in preparation for preventing and/or treating the purposes in nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and the drug of malignant tumour.
The present inventor persistently careful studies to achieve the goals above, as a result, it has been found that the following general formula (I) compound, its pharmaceutically acceptable salt, its ester and their stereoisomer that indicate can effective excitement FXR receptor, so as to complete the present invention.
Specifically, the present invention relates to following technical proposals:
Scheme 1, logical formula (I) compound represented, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6 alkyl aminos, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8Alkynyl；
R3Selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, or the C optionally replaced by one or more substituent group P1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, carboxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, carboxyl C1-6Alkoxy, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, 3-8 member naphthenic base, 3-8 member naphthenic base C1-6Alkyl, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base C1-6Alkyl；
P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C2-8Alkenyl or C2-8Alkynyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, carboxyl C1-6Alkyl, carboxyl oxygroup C1-6Alkyl, carboxyamino C1-6Alkyl, amino C1-6Alkyl, amino carbonyl C1-6Alkyl, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, carboxyl C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkylsulphonylaminocarbonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino, 5-8 unit's heteroaryl or 3-8 circle heterocyclic ring base；
W is selected from CH2、NH、O、S、SO、SO2Or CO；
A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted aryl, 5-8 unit's heteroaryl, 3-8 member naphthenic base or 3-8 circle heterocyclic ring base by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl or C2-8Alkynyl；
E is selected from CH2、NH、O、S、SO、SO2Or CO；
F be selected from be not present, CH2、NH、O、S、SO、SO2Or CO；
X is selected from CH or N；
Y is selected from CH2、NH、O、S、SO、SO2Or CO；
E, the connection type between X, Y, F is separately selected from singly-bound；
M is selected from the integer of 0-3；
N is selected from the integer of 0-4.
Scheme 2, compound as described in scheme 1, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino sulfonyl, C2-6Alkenyl or C2-6Alkynyl；
R3Selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, or the C optionally replaced by one or more substituent group P1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, 3-6 member naphthenic base, 3-6 member naphthenic base C1-4Alkyl, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base C1-4Alkyl；
P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl, halogenated C1-4Alkane Oxygroup, C1-4Alkoxy C1-4Alkyl, C1-4Alkyl-carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C2-6Alkenyl or C2-6Alkynyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxygroup C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino, 5-6 unit's heteroaryl or 4-7 circle heterocyclic ring base；
W is selected from CH2、NH、O、S、SO、SO2Or CO；
A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted aryl, 5-6 unit's heteroaryl, 3-6 member naphthenic base or 4-7 circle heterocyclic ring base by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C2-6Alkenyl or C2-6Alkynyl；
E is selected from CH2, NH, O, S or CO；
F be selected from be not present, CH2, NH, O or S；
X is selected from CH or N；
Y is selected from CH2, NH, O or S；
E, the connection type between X, Y, F is separately selected from singly-bound；
M is selected from the integer of 0-2；
N is selected from the integer of 0-3.
Scheme 3, the compound as described in scheme 2, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy or C1-4Alkoxy C1-4Alkyl；
R3Selected from cyano, the C that is optionally replaced by one or more substituent group P1-4It is alkyl, halogenated C1-4Alkyl, 3-6 member naphthenic base, 3-6 member naphthenic base C1-4Alkyl, 3-6 circle heterocyclic ring base or 3-6 circle heterocyclic ring base C1-4Alkyl；
P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxygroup C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino, 5-6 unit's heteroaryl or 5-6 circle heterocyclic ring base；
W is selected from CH2、NH、O、S、SO、SO2Or CO；
A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl, the 5-6 unit's heteroaryl containing 1-2 N, O and/or S atom, 5-6 member naphthenic base, or the 5-6 circle heterocyclic ring base containing 1-2 N, O and/or S atom by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E is selected from CH2, NH, O or CO；
F be selected from be not present, CH2, NH or O；
X is selected from CH or N；
Y is selected from CH2, NH or O；
E, the connection type between X, Y, F is separately selected from singly-bound；
M is selected from the integer of 0-2；
N is selected from the integer of 0-3.
Scheme 4, the compound as described in scheme 3, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R3Selected from cyano, the C that is optionally replaced by one or more substituent group P1-4It is alkyl, halogenated C1-4Alkyl or C3-6Naphthenic base C1-4Alkyl；
P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
W is selected from NH, O or S；
A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl by one or more substituent group Q, or the 5-6 unit's heteroaryl containing 1-2 N, O and/or S atom；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
Benzo pyrrolin base, coumaran base, chromanyl, benzo 1,3- dioxa cyclopentenyl, benzo 1,4- dioxine base, benzo 1,3- dioxine base, benzotetrahydropyridand base, benzo dihydro oxazines base, benzo tetrahydro pyrazinyl, 1,2,3,4- tetrahydro quinazoline base, 1,2,3,4- tetrahydro cinnoline bases, dihydro indenyl, tetralyl, tetralone；
N is selected from the integer of 0-3.
Scheme 5, compound as described in scheme 4, its pharmaceutically acceptable salt, its ester or its stereoisomer:
R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, bromine atom, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl, trifluoroethyl or trifluoromethoxy；
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, trifluoro propyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl, dimethylamino, sulfonyloxy methyl amido carbonyl, ethyl sulfonamide base carbonyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
Z be selected from by one or more substituent group Q replace or unsubstituted phenyl, pyrrole radicals, Pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furyl, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
N is selected from the integer of 0-2.
Scheme 6, compound as described in scheme 5, its pharmaceutically acceptable salt, its ester or its stereoisomer:
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
N is selected from 1 or 2.
Scheme 7, the compound as described in scheme 6, its pharmaceutically acceptable salt, its ester or its stereoisomer:
R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, Cvclopropvlmethvl or cyclobutylmethyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group, acetylamino, sulfonyloxy methyl amido carbonyl, ethyl sulfonamide base carbonyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl, pyrrole radicals, pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furyl, pyridyl group, pyrimidine radicals, pyrazinyl or pyridazinyl by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, propyl, butyl, methoxyl group, ethylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
N is selected from 1.
Scheme 8, compound as described in scheme 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, the structure with following formula (I-1):
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy or C1-4Alkoxy C1-4Alkyl；
R3Selected from cyano, the C that is optionally replaced by one or more substituent group P1-4Alkyl, halogenated C1-4Alkyl, 3-6 member naphthenic base or 3-6 member naphthenic base C1-4Alkyl；
P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino or 5-6 unit's heteroaryl；
W is selected from CH2, NH, O, S, SO or SO2；
A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl or 5-6 unit's heteroaryl by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E is selected from CH2, NH, O or CO；
F be selected from be not present, CH2, NH or O；
X is selected from CH or N；
Y is selected from CH2, NH or O；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from the integer of 0-3.
Scheme 9, the compound as described in scheme 8, its pharmaceutically acceptable salt, its ester or its stereoisomer,
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, bromine atom, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl, trifluoroethyl or trifluoromethoxy；
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, trifluoro propyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl-methyl or cyclohexyl methyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl, sulfonyloxy methyl amido carbonyl, ethyl sulfonamide base carbonyl, dimethylamino, pyrazoles, imidazoles, oxazole, isoxazole, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
W is selected from CH2, NH, O or S；A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl or 5-6 unit's heteroaryl by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E is selected from CH2, NH, O or CO；F be selected from be not present, CH2, NH or O；
X is selected from CH or N；Y is selected from CH2, NH or O；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1 or 2.
Scheme 10, the compound as described in scheme 9, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, Cvclopropvlmethvl or cyclobutylmethyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group, acetylamino, sulfonyloxy methyl amino carbonyl, ethyl sulfonyl-amino-carbnyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl or pyridyl group by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E is selected from CH2, NH, O or CO；F is selected from CH2, NH or O；
X is selected from CH or N；Y is selected from CH2, NH or O；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1 or 2.
Scheme 11, the compound as described in scheme 10, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, the cyclic group and phenyl ring that E, X, Y, F are collectively formed are formed together structure below:
Chromanyl, benzo Isosorbide-5-Nitrae-dioxine base, benzo 1,3- dioxine base, benzotetrahydropyridand base, benzo dihydro oxazines base, benzo tetrahydro pyrazinyl, 1,2,3,4- tetrahydro quinazoline bases, 1,2,3,4- tetrahydro cinnoline bases, tetralyl, tetralone.
Scheme 12, the compound as described in scheme 11, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, Z is selected from is replaced or unsubstituted phenyl by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4 Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
Scheme 13, the compound as described in scheme 12, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, W is selected from O；
A is selected from O；
Z is selected to be replaced or unsubstituted phenyl by 1-2 substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, methoxyl group, ethyoxyl, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
N is selected from 1.
Scheme 14, the compound as described in scheme 9, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, Cvclopropvlmethvl or cyclobutylmethyl；
R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group, acetylamino, sulfonyloxy methyl amido carbonyl, ethyl sulfonamide base carbonyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected to be replaced or unsubstituted phenyl or pyridyl group by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E is selected from CH2, NH or O；F is selected from and is not present；
X is selected from CH or N；Y is selected from CH2Or O；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1 or 2.
Scheme 15, the compound as described in scheme 14, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, the cyclic group and phenyl ring that E, X, Y are collectively formed are formed together structure below:
Benzo pyrrolin base, coumaran base, benzo 1,3- dioxa cyclopentenyl or dihydro indenyl.
Scheme 16, the compound as described in scheme 15, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, W is selected from O；A is selected from O；
Z is selected to be replaced or unsubstituted phenyl by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
Scheme 17, the compound as described in scheme 9, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein,
Z is selected to be replaced or unsubstituted phenyl by one or more substituent group Q；
Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, methyl, ethyl, propyl, methoxyl group, ethyoxyl, methylamino, ethylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
E is selected from CH2, O or CO；F be selected from be not present, CH2Or O；
X is selected from CH or N；Y is selected from CH2；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1 or 2.
Scheme 18, the compound as described in scheme 17, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, E is selected from O or CH2；F be selected from be not present, CH2Or O；
X is selected from CH；Y is selected from CH2；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1.
Scheme 19, the compound as described in scheme 18, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, E is selected from O；F is selected from and is not present or CH2；
X is selected from CH；Y is selected from CH2；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1.
Scheme 20, the compound as described in scheme 19, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, the cyclic group and phenyl ring that E, X, Y, F are collectively formed are formed together structure below:
Scheme 21, the compound as described in scheme 17, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, E is selected from CH2；F is selected from and is not present or CH2；
X is selected from N；Y is selected from CH2；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1.
Scheme 22, the compound as described in scheme 17, its pharmaceutically acceptable salt, its ester or its stereoisomer:
Wherein, E, X, Y, F are separately selected from CH2；
E, the connection type between X, Y, F is separately selected from singly-bound；
N is selected from 1.
Group between above scheme can in any combination, and obtained technical solution is recorded in this article.
Part of compounds of the invention
Detailed description of the invention
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom etc..
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, including such as " C1-4Alkyl ", " C1-3Alkyl " etc., specific example includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyl, 1- methyl-propyl, 1, 1- dimethyl ethyl, n-pentyl, 3- methyl butyl, 2- methyl butyl, 1- methyl butyl, 1- ethyl propyl, n-hexyl, 4- methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3, 3- dimethylbutyl, 2, 2- dimethylbutyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2, 3- dimethylbutyl, 2- ethyl-butyl, or 1, 2- dimethyl propyl etc..
" C of the present invention1-4Alkyl " indicates the alkyl containing 1-4 carbon atom of linear chain or branched chain, including such as " C1-4Alkyl ", " C1-3Alkyl " etc., specific example include but is not limited to: methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- methyl-propyl, 1- methyl-propyl or 1,1- dimethyl ethyl etc..
" C of the present invention2-8Alkenyl " refers to that the carbon atom number containing at least one double bond is the alkenyl of the linear chain or branched chain of 2-8, including such as " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl " etc.; specific example includes but is not limited to: vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyl, 3- cyclobutenyl, 2- methyl-1-propylene base, 1- methyl-2- acrylic, 1- pentenyl, 2- pentenyl, 3- pentenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl-3- cyclobutenyl, 1,1- dimethyl-2- acrylic, 1- ethyl-2- acrylic, 2- hexenyl, 3- hexenyl, 2- methyl-1- Pentenyl, 3- methyl-1-pentene alkenyl, 1- methyl -2- pentenyl, 3- methyl -2- pentenyl, 2- methyl-3-pentenyl, 1- methyl -4- pentenyl, 3- methyl -4- pentenyl, 1, 1- dimethyl -3- cyclobutenyl, 1, 2- dimethyl -3- cyclobutenyl, 1, 3- dimethyl -2- cyclobutenyl, 2, 2- dimethyl -3- cyclobutenyl, 2, 3- dimethyl -2- cyclobutenyl, 2, 3- dimethyl -1- cyclobutenyl, 2- ethyl -1- cyclobutenyl, 2- ethyl -3- cyclobutenyl, 2- heptenyl, 3- heptenyl, 4- heptenyl, 1- octenyl, 3- octenyl, 4- octenyl, 1, 3- butadienyl, 2, 4- pentadienyl, 1, 4- hexadienyl, 2, 4- hexadienyl, 1, 5- heptadiene base , 2,5- heptadiene base or 2,6- octadienyl etc..
" C of the present invention2-8Alkynyl " refers to that the carbon atom number containing three keys is the alkynyl of the linear chain or branched chain of 2-8, including such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., specific example includes but is not limited to: acetenyl, 1- propinyl, 2- butynyl, 1- methyl -2-propynyl, valerylene base, 3- pentynyl, 1- methyl -2- butynyl, 2- methyl -3- butynyl, 1, 1- dimethyl -2-propynyl, 1- ethyl -2-propynyl, 2- hexin base, 3- hexin base, 1- methyl-valerylene base, 1- methyl -3- pentynyl, 2- methyl -3- pentynyl, 1, 1- dimethyl -3- butynyl, 2- ethyl -3- butynyl, 2- heptynyl, 3- heptynyl, 4- methyl -2- hexin base, 5- methyl -2- hexin base, 2- methyl -3- hexin base, 5- methyl -3- hexin base, 2- methyl -4- hexin base, 4- methyl -5- hexin base, 2- octynyl, 3- octynyl, 4- octynyl, 4- methyl -2- heptynyl, 5- methyl -3- heptynyl, 6- methyl -3- heptynyl, 2- methyl -4- heptynyl, 2- methyl -5- heptynyl or 3- methyl -6- heptynyl etc..
" C of the present invention1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C1-6Alkylsulphonylaminocarbonyl " refers to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6Alkyl-S-, C1-6Alkyl-C (O)-, C1-6Alkyl-C (O)-O-, C1-6Alkyl-SO2-、C1-6Alkyl-NH-SO2-、(C1-6Alkyl)2-N-SO2-、C1-6Alkyl-SO2-NH-、C1-6Alkyl-SO2-O-、C1-6Alkyl-SO2The group that-NH-C (O)-mode is formed, wherein " C1-6Described in alkyl " text as defined above.
" C of the present invention1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino sulfonyl, C1-4Alkyl sulfonyl amino, C1-4Alkylsulfonyloxy, C1-4Alkylsulphonylaminocarbonyl " refers to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4Alkyl-C (O)-, C1-4Alkyl-C (O)-O-, C1-4Alkyl-SO2-、C1-4Alkyl-NH-SO2-、(C1-4Alkyl)2-N-SO2-、C1-4Alkyl -SO2-NH-、C1-4Alkyl-SO2-O-、C1-4Alkyl-SO2The group that-NH-C (O)-mode is formed, wherein " C1-4Described in alkyl " text as defined above.
" halogenated C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, carboxyl C1-6Alkoxy, carboxyl oxygroup C1-6Alkyl, carboxyamino C1-6Alkyl, amino carbonyl C1-6Alkyl " refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, amino, C1-6Alkoxy, carboxyl, carboxyl oxygroup, carboxyamino, amino carbonyl replace C respectively1-6Alkyl, C1-6Hydrogen atom in alkoxy is formed by group.
" halogenated C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, carboxyl C1-4Alkyl, amino C1-4Alkyl, C1-4Alkoxy C1-4Alkyl, halogenated C1-4Alkoxy, hydroxyl C1-4Alkoxy, carboxyl C1-4Alkoxy, carboxyl oxygroup C1-4Alkyl, carboxyamino C1-4Alkyl, amino carbonyl C1-4Alkyl " refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, amino, C1-4Alkoxy, carboxyl, carboxyl oxygroup, carboxyamino, amino carbonyl replace C respectively1-4Alkyl, C1-4Hydrogen atom in alkoxy is formed by group.
" 3-8 member naphthenic base C of the present invention1-6Alkyl, 3-8 circle heterocyclic ring base C1-6Alkyl " refers to 3-8 member naphthenic base, 3-8 circle heterocyclic ring base " replace C1-6Hydrogen atom in alkyl is formed by group.
" 3-6 member naphthenic base C of the present invention1-4Alkyl, 3-6 circle heterocyclic ring base C1-4Alkyl " refers to 3-6 member naphthenic base, 3-6 circle heterocyclic ring base " replace C1-4Hydrogen atom in alkyl is formed by group.
" aryl " of the present invention refers to aromatic ring, such as phenyl, naphthalene, anthryl etc..
The cyclic group that it is 5~8 containing at least one heteroatomic unsaturated annular atom number that " 5-8 unit's heteroaryl " of the present invention, which refers to, the hetero atom has nitrogen, oxygen and sulphur etc., while including the case where carbon atom, nitrogen-atoms and sulphur atom by oxo.Including such as " 5-7 unit's heteroaryl ", " 5-6 unit's heteroaryl ", " 7-8 unit's heteroaryl ", it is specifically as follows " the 5-8 unit's heteroaryl containing 1~3 O, S and/or N ", " the 5-8 unit's heteroaryl containing 1~2 O, S and/or N ", " the 5-8 unit's heteroaryl containing 2~3 O, S and/or N ", " the 5-6 unit's heteroaryl containing 1-2 N, O and/or S atom ", " 6 unit's heteroaryls containing 1-2 N, O and/or S atom ".Specific example includes but are not limited to furyl, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazoles base, imidazole radicals, pyrazolyl, 1,2,3-triazoles base, 1,2,4- triazolyl, tetrazole radical, 1,2,3-oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles bases, 1,3,4- oxadiazoles bases, pyridyl group, 2- pyridone, 4- pyridone, pyrimidine radicals, Pyridazinyl, pyrazinyl, 1,2,3- triazine radicals, 1,3,5-triazines base or 1,2,4,5- tetrazine bases etc..
" 3-8 member naphthenic base ", refer to that the paraffin section of 3-8 carbon atom removes the monocycle cyclic alkyl of fractional saturation derived from a hydrogen atom or saturation, including such as " 3-6 member naphthenic base ", " 4-7 member naphthenic base ", " 4-6 member naphthenic base ", " 5-6 member naphthenic base " etc..It is specifically as follows " 3-8 member saturated cyclic alkyls ", " 3-8 member fractional saturation naphthenic base ", " 5-6 member saturated cyclic alkyls ", " 5-6 member fractional saturation naphthenic base ".3-8 member saturated cyclic alkyls include but is not limited to: cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc.；3-8 member fractional saturation naphthenic base includes but is not limited to: cyclopentenyl, 1,3- cyclopentadienyl group, cyclohexenyl group, Isosorbide-5-Nitrae-cyclohexadienyl, cycloheptenyl, Isosorbide-5-Nitrae-cycloheptadiene base or cyclo-octene base.
" 3-8 circle heterocyclic ring base " refers to that the monocyclic heterocyclic compound of the saturation containing 3-8 annular atom and containing at least one hetero atom (such as 1,2,3,4 or 5 hetero atom) or fractional saturation removes the group that a hydrogen atom obtains.Including such as " 3-7 circle heterocyclic ring base ", " 3-6 circle heterocyclic ring base ", " 3-5 circle heterocyclic ring base ", " 4-7 circle heterocyclic ring base ", " 4-6 circle heterocyclic ring base ", " 5-6 circle heterocyclic ring base ", 6-7 circle heterocyclic ring base ", " 6-8 circle heterocyclic ring base " etc..It is specifically as follows: " the 3-8 circle heterocyclic ring base containing 1-2 N, O and/or S atom ", " the 3-8 member saturated heterocyclyl containing 1-2 N, O and/or S atom ", " 5-6 member saturated heterocyclyl ", " the 5-6 circle heterocyclic ring base containing 1-2 N, O and/or S atom ", " the 5-6 member saturated heterocyclyl containing 1-2 N, O and/or S atom ".3-8 member fractional saturation list heterocycle, refers to containing double bond, heteroatomic cyclic group.3-8 member is saturated single heterocycle, and refer to all saturated bonds contains heteroatomic cyclic group.Example includes but are not limited to: aziridine base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclo acrylic, azetidinyl, 1, 4- dioxane base, 1, 3- dioxane base, 1, 3- dioxolane base, 1, 4- Dioxin base, tetrahydrofuran base, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4, 5- glyoxalidine base, pyrazolidinyl, 4, 5- pyrazoline base, 2, 5- dihydrothiophene, tetrahydro-thienyl, 4, 5- dihydro-thiazolyl, piperidyl, piperazinyl, morpholinyl, 4, 5- dihydro-oxazole base, 4, 5- dihydro-isoxazole base, 2, 3- dihydro-isoxazole base, 2H-1, 2- oxazines base, 6H-1, 3- oxazines base, 4H-1, 3- thiazinyl, 6H-1 , 3- thiazinyl, 2H- pyranose, 2H- pyran-2-one base, 3,4- dihydro -2H- pyranose, 2,5- dihydrothiophene, 3,4- dihydro -2H- pyranose, 5,6- dihydro -4H-1,3- oxazines base, 1,2,3,6- tetrahydro pyridyl, 1,2,3,4- tetrahydro pyridyl or 2,3,4,5- tetrahydro pyridyls etc..
" hetero atom " of the present invention refers to N, O, S, SO and/or SO2Deng, preferably N, O、S。
" fractional saturation " of the present invention is that ring portion includes at least one double or triple bonds.
" F is selected from and is not present " of the present invention, refers to that Y is directly connect with phenyl.
E, the cyclic group and phenyl ring that X, Y, F are collectively formed can be formed together structure below:
Wherein, preferably Further preferably
In addition, the present invention also provides the preparation methods of the compound of above-mentioned logical formula (I) expression, its pharmaceutically acceptable salt, its ester and their stereoisomer.
Specifically, the preparation method comprising but be not limited to following process routes and (wherein, be defined as follows representated by each abbreviation: DCM: methylene chloride；DMF:N, N-dimethylformamide；DMSO: dimethyl sulfoxide；EA: ethyl acetate；MeOH: methanol；NBS:N- bromo-succinimide；NCS:N- chlorosuccinimide；PE: petroleum ether；THF: tetrahydrofuran；DIBAL-H: diisobutyl aluminium hydride；Pd(dppf)C12: [1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride)；PPTS: para-methylbenzenepyridinsulfonate sulfonate；DHP:3,4-2H- dihydropyran；TFAA: trifluoroacetic anhydride；LiHMDS: two (trimethyl silicon substrate) lithium amides；TBSCl: tert-butyl chloro-silicane；TBAF: 4-butyl ammonium fluoride trihydrate；DEAD: diethyl azodiformate):
R1、R2、R3、R4, m, n, W, A, Z, E, F, X, Y be as it was noted above, A ' represents fluorine atom, chlorine atom, bromine atom, iodine atom.
Specific illustrative steps are as follows:
1, the preparation of intermediate 1
Starting material 1 is dissolved in organic solvent (such as lower alcohols such as ethyl alcohol etc.), starting material 2 is slowly added in batches, finishes, is added alkaline solution (such as NaOH solution etc.), is heated to 60 DEG C of -90 DEG C of reactions 5-48 hours.Solvent is removed under reduced pressure in end of reaction, reaction solution, and solid is washed with water, dry, obtains intermediate 1.
2, the preparation of intermediate 2
Intermediate 1 is dissolved in organic solvent (such as DMF etc.), is slowly added to parental materials reagent (such as N- chlorosuccinimide etc.) in batches, after adding, stirs 0.2-5 hours, reaction solution is poured into water.It being extracted with organic solvent (such as ethyl acetate etc.), organic phase is washed with water and saturated sodium chloride solution, and it is dry, it removes solvent and obtains intermediate 2.
3, the preparation of intermediate 3
Intermediate 2 is dissolved in organic solvent (such as triethylamine etc.), starting material 3 is added, is reacted 5-20 hours.End of reaction, removed under reduced pressure solvent, pillar layer separation (such as PE: EA=10: 1) obtain intermediate 3.
4, the preparation of intermediate 4
Intermediate 3 is dissolved in organic solvent (such as tetrahydrofuran etc.), ice bath is cooling, the toluene solution of diisobutyl aluminium hydride (DIBAL-H) is added, addition, which finishes, is warming up to 20-30 DEG C of reaction 5-20 hours, end of reaction, ice bath, halogenating agent (such as ammonium chloride solution etc.) quenching reaction of saturation is added, it is extracted with organic solvent (such as ethyl acetate etc.), the halogenating agent (such as ammonium chloride solution and sodium chloride solution etc.) of organic phase saturation washs, it is dry, it removes solvent and obtains intermediate 4.
5, the preparation of intermediate 5
Intermediate 4 is dissolved in organic solvent (such as methylene chloride etc.), be added triethylamine, then be added halide (such as phosphorus trichloride, phosphorus tribromide etc.), 20-40 DEG C reaction 0.5-5 hours.Solvent is removed after completion of the reaction, and pillar layer separation (such as PE: EA=10: 1) obtains intermediate 5.
6, the preparation of intermediate 6
Preparation or purchase intermediate 6.
7, the preparation of intermediate 7
Intermediate 6 is dissolved in organic solvent (such as N, dinethylformamide, acetonitrile, toluene etc.) in, add alkaline reagent (such as potassium carbonate, cesium carbonate, sodium iodide etc.) and intermediate 5, in 0-100 DEG C of stirring (0.5-24 hours).Organic solvent (such as ethyl acetate etc.) dilution is added, halogenating agent (such as sodium chloride solution etc.) or washing with saturation, dry, concentration, Through silica gel column chromatography, (such as ethyl acetate: petroleum ether=1: methylene chloride: methanol=15: 1) 1-10 purifies to obtain intermediate 7.
8, the preparation of formula (I) compound
Intermediate 7 is dissolved in organic solvent (such as methanol/water, tetrahydrofuran, methanol, tetrahydrofuran/methanol, methanol/tetrahydrofuran/water etc.) in, addition alkali compounds (such as a hydronium(ion) lithia, sodium hydroxide etc.), 15-60 DEG C stirring 8-72 hours.Water dilution is added in reaction solution, acid solution (such as citric acid, hydrochloric acid etc.) pH value is adjusted to 2-7, it is added organic solvent (such as ethyl acetate etc.), liquid separation, the halogenating agent (such as sodium chloride solution etc.) of organic phase saturation is washed, it is dry, concentration, purified (way of purification is preferred are as follows: preparative high-performance liquid chromatographic, silica gel column chromatography etc.) obtain formula (I) compound.
" pharmaceutically acceptable salt " of compound shown in formula (I) of the present invention refers to the salt that acidic functionality present in formula (I) compound and appropriate inorganic or organic cation (alkali) are formed, including salt, the ammonium salt formed with alkali or alkaline earth metal, and the salt formed with nitrogenous organic base；And basic functionality present in formula (I) compound (such as-NH2Deng) with appropriate inorganic or organic anion (acid) formation salt, including with inorganic acid and organic carboxyl acid.
" ester " of compound shown in formula (I) of the present invention refers to, when there are when carboxyl for formula (I) compound, the ester that esterification can occurs with alcohol and be formed, when formula (I) compound is there are when hydroxyl, esterification can occur with organic acid, inorganic acid, acylate etc. and the ester that is formed.Under the conditions of ester is existing for the acid or alkali, hydrolysis can occur and generate corresponding acid or alcohol.
" alloisomerism " of the compounds of this invention is divided into conformation and configuration isomery, and configuration isomery is also divided into cis-trans isomerism and optical isomerism.Conformational isomerism refers to a kind of stereo-isomerism that the organic molecule with certain configuration makes each atom of molecule or atomic group generate different arrangement modes in space due to carbon, the rotation of carbon single bond or distortion, the structure that common are alkane and naphthene-based compounds, such as the chair conformation and boat conformation occurred in cyclohexane structure." stereoisomer " refers to when the compounds of this invention contains one or more asymmetric centers, thus can be used as racemic modification and racemic mixture, single enantiomter, non-enantiomer mixture and single diastereoisomer.The compounds of this invention has asymmetric center, and this kind of asymmetric center respectively will independently generate two optical isomers, and the scope of the present invention includes all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.If compound of the present invention contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer and transisomer.Compound of the present invention can exist with tautomeric forms, have the tie point of different hydrogen by one or more double-bond shifts.
The present invention also provides a kind of pharmaceutical compositions, contain above-mentioned formula (I) compound represented, its pharmaceutically acceptable salt, its ester and their stereoisomer.In particular, the present invention provide it is a kind of for treat and/or prevent FXR mediation disease pharmaceutical composition, contain above-mentioned formula (I) compound represented, its pharmaceutically acceptable salt, its ester and their stereoisomer.
The present invention further provides the pharmaceutical preparations for including above-mentioned formula (I) compound represented, its pharmaceutically acceptable salt, its ester and their stereoisomer and one or more pharmaceutical carriers and/or diluent, and pharmaceutically acceptable any dosage form can be made.The patient for needing this treatment is applied in a manner of oral, parenteral, rectum or transpulmonary administration etc..When for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；It may be made as oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, suitable filler, adhesive, disintegrating agent, lubricant etc. can be added.When for parenteral administration, injection, including injection, injection sterile powder and concentrated solution for injection can be made into.When injection is made, the conventional method production that can be used in existing pharmaceutical field can be added without additives when preparing injection, and suitable additives can also be added according to the property of drug.When for rectally, suppository etc. can be made into.When for transpulmonary administration, inhalant or spray etc. can be made into.
The present invention also provides formula (I) compound represented of the present invention, its pharmaceutically acceptable salt, its ester and their stereoisomer in preparation for treating and/or preventing the application in the disease of FXR mediation and the drug of related disease.The disease includes: in (1) Chronic Liver or some form of extrahepatic cholestasis illness, or chronic bile smoulders liver fibrosis caused by illness or acute intrahepatic cholestasis illness, cirrhosis, the obstructive or chronic inflammatory disorders of liver, fatty liver and its complication, fatty liver related with alcohol and its complication, acute hepatic failure, cholelithiasis and/or inflammatory bowel disease, primary biliary cirrhosis；Due to forcing lipid, especially triglycerides to accumulate, illness and disease caused by then promoting liver fibrosis that caused chronic fatty and fibroid is activated to be denaturalized, such as non-alcoholic fatty liver disease or nonalcoholic steatohepatitis；Lipid or lipoprotein disorders, such as atherosclerosis, dyslipidemia, thrombus.(2) clinical complication of I type or type-2 diabetes mellitus, other results observed including nephrosis, diabetic neuropathy, diabetic retinopathy and its clinical dominant long-term diabetes.(3) non-malignant excess proliferative disease or excess proliferative disease, are selected from: hepatocellular carcinoma, colonic adenoma and polyposis, adenocarcinoma of colon, breast cancer, cancer of pancreas, the cancer of the esophagus and other forms gastrointestinal tract and liver neoplasm disease.(4) Dyslipidemia disease includes Atherosclerosis Change, bile acid disorder, benign intrahepatic cholestasis, progressive familial intrahepatic cholestasis, primary biliary cirrhosis, primary sclerotic cholangitis, cholesterol stone, dyslipidemia, fibrillation related disease, chronic hepatitis, non-viral hepatitis, inflammatory bowel disease, intestinal bacilli illness, liver transplant, fatty liver, cirrhosis, hepatitis, liver failure, cholestasia, cholelithiasis, non-alcohol fatty liver, alcohol fatty liver, diabetes, myocardial infarction, apoplexy, thrombus, cancer etc..
The present invention also provides the method for treating and/or preventing the disease that FXR is mediated, include the steps that giving above-mentioned formula (I) compound represented, its pharmaceutically acceptable salt, its ester and their stereoisomer into the mammal for needing this treatment.
The compounds of this invention has the advantage that
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester and their stereoisomer have excellent FXR receptor agonist activity, can be by safety for treating and/or preventing the related diseases such as nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumour；
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester and their stereoisomer show good biological stability, act on more longlasting, bioavilability height；
(3) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester and their stereoisomer are shown low toxicity, and drug resistance is good, highly-safe.
Below by way of biological experiment the present invention is further explained compound advantageous effect, but this should not be interpreted as to the compounds of this invention only there is following beneficial effect.
Experimental example 1: the external biochemical analysis of the compounds of this invention
(1) tester: the compounds of this invention, chemical name and preparation method are shown in the preparation embodiment of each compound.
(2) experimental method:
Detection compound is dissolved in 100%DMSO, after 1000 times of dilution, takes 160nL, and 3.84 μ L detection buffer is then added；Target/Antibody mixture adds 8 μ L solution after 2 times of dilution；The co-activation peptide that 4.0 μ L dilute 4 times is added；In incubation at room temperature 60 minutes；It is detected after incubation in fluorescence microplate reader and analyzes data.
(3) experimental result and conclusion:
The biochemical analysis of 1 the compounds of this invention of table
Seen from table 1, the compounds of this invention has different degrees of agonism to FXR, have great importance for related diseases such as treatment nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumours, especially compound 1, compound 2, compound 4, compound 5, compound 6, compound 7, compound 9.
Experimental example 2: the detection of the compounds of this invention cell in vitro level
(1) tester: the compounds of this invention, chemical name and preparation method are shown in the preparation embodiment of each compound.
(2) experimental method:
This experiment be polystyrene-TC processing micro reaction plate (healthy and free from worry Cat.#3712).
The analysis medium of 1000 × compound 40nL and 4 μ L are added on experimental plate together；Analysis medium in be added 32 μ L cell be diluted to suitable cell density after be added on experimental plate；It is 40 μ L that 4 μ L analysis medium, which is added to analysis volume final in all holes,；Experimental plate is placed on 37 DEG C/5%CO216-24h is incubated in the incubator of humidification；8 μ L substrates are added on experimental plate later；Experimental plate is protected from light in incubation at room temperature 2h；(Tecan Safire is detected in fluorescence microplate reader after incubation2) and analyze data.
(3) experimental result and conclusion:
The FXR agonist activity of 2. the compounds of this invention of table
From table 2, the compounds of this invention has different degrees of agonism to UAS-bla HEK 293T cell, have great importance for related diseases such as treatment nonalcoholic fatty liver, primary biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumours, especially compound 2, compound 4 and compound 9.
Experimental example 3: the compounds of this invention to HepG2 cell and source of people liver cell BSEP, The influence of CYP7A1 and SHP mRNA relative expression quantity
(1) tester: the compounds of this invention, chemical name and preparation method are shown in the preparation embodiment of each compound.
PBS represents phosphate buffer.
Comparison medicine: PX-104, specific structure are shown in background technique；PX-102, for disappearing for PX-104 Revolve body.
(2) experimental method:
1. spreading cell, adding compound and collecting cell
Using pancreatin digestion, cell is collected, measures cell concentration；According to count results, cell is resuspended to 7.5e5cell/mL density；6 porocyte culture plates, every hole are inoculated with 2mL cell；By culture plate as in incubator, in 37 DEG C, 5%CO2CMC model 24 hours.
Using DMSO dilution untested compound to 12150,4050,1350,450,150,50,16.67,5.56 and 1.85 μM；The 5 μ L of liquid storage for taking previous step to dilute is added separately in 5mL culture medium.Obtained working solution concentration is respectively 12150,4050,1350,450,150,50,16.67,5.56,1.85nM.Control group culture medium is prepared using isometric DMSO instead of liquid storage；Tissue culture plate is taken out from incubator, removes culture medium, and working solution and control medium is added；Culture plate is put back into incubator, in 37 DEG C, 5%CO2CMC model 24 hours.
After processing 24 hours, tissue culture plate is taken out from incubator, culture medium is removed, with PBS rinse cell 3 times of pre-cooling (4 DEG C)；200 μ L pancreatin (being preheated to 37 DEG C) are added in every hole, shake gently so that pancreatin uniform fold board bottom.Culture plate is put back to incubator to incubate until cell detachment board bottom.1mL culture medium is added and terminates digestion.After gently being blown and beaten several times with pipettor, all substances in hole are drawn into the centrifuge tube of the Rnase-free of 1.5mL, 200 × g is centrifuged 5 minutes；Supernatant is removed, cell sample is collected.
2. extraction and purifying RNA from cell sample
Cell cracking: prepare fresh RNA lysate (1mL lysate adds 10 μ L 2 mercapto ethanols)；600 μ L lysates are added to cell sample；Violent vortex 1-2 minutes, crack cell completely；Cell pyrolysis liquid is centrifuged 5 minutes in 12,000 × g；Supernatant is taken to be transferred in the 1.5mL centrifuge tube of RNase-free.
RNA extraction purification: 70% ethyl alcohol of equivalent is added into cell pyrolysis liquid；Acutely concussion centrifuge tube, is sufficiently mixed, and the particulate deposits being likely to form after ethyl alcohol are added in dispersion as far as possible；Adsorption column is placed on collecting pipe, shifts mixture into adsorption column.At most 700 μ L of transfer every time；12,000 × g of room temperature is centrifuged 15 seconds.The solution in collecting pipe is discarded, and adsorption column is reapposed on collecting pipe；Remaining mixture is transferred completely into adsorption column.Add 700 μ L eluent I into adsorption column；12,000 × g of room temperature is centrifuged 15 seconds.Adsorption column is placed on new collecting pipe；Add 500 μ L eluent II into adsorption column；12,000 × g of room temperature is centrifuged 15 seconds.The solution in collecting pipe is discarded, and adsorption column is reapposed on collecting pipe；500 μ L are added to wash De- liquid II is into adsorption column；Room temperature 12,000 × g are centrifuged 1-2 minutes, adsorption column are placed on RNA collecting pipe；50 μ L RNase-free water are added to the center of adsorption column, are incubated at room temperature 1 minute；Room temperature 14,000 × g are centrifuged 2 minutes, RNA are eluted in collecting pipe.
Measure the concentration and quality of the RNA extracted.RNA is stored in -80 DEG C.
3. RNA reverse transcription is cDNA
The RNA extracted in second step is incubated for 5 minutes at 70 DEG C is denaturalized RNA.Sample is placed on ice after processing；
RNA sample is diluted to 200ng/ μ L using RNAse-free water；The reverse transcription solution of 10 μ L is prepared according to following table, and is mixed with 10 μ L denaturation RNA.The total amount of RNA is 2 μ g in reverse transcription reaction.In experimentation, all reagents are placed on ice.
Reverse transcription carries out on G-Storm GS1 thermal cycler PCR thermal cycler.Process of reverse-transcription is provided that 25 DEG C 10 minutes → 37 DEG C 120 minutes → 85 DEG C 5 minutes → 4 DEG C ∞.Reverse transcription product (cDNA) is stored in -20 DEG C.
4. sample qPCR is tested
According to qPCR amplification efficiency, suitable cDNA concentration is selected to carry out the qPCR experiment of sample.The cDNA sample that third step reverse transcription obtains takes 10 μ L that 60 μ L Rnase-free water is added to dilute 7 times.
The reaction mixture for preparing 80 μ L according to following table, takes 20 μ L into 96 hole PCR reaction plates, 3 repetition (each reacting hole adds 7 μ L 100ng) cDNA samples with pipettor.
QPCR is carried out on ABI7500 real-time PCR, and program is provided that 50 DEG C 2 minutes → 95 DEG C 10 minutes → 95 DEG C 15 seconds → 60 DEG C 60 seconds, wherein 95 DEG C of 15 seconds and 60 DEG C of settings between 60 seconds, 40 circulations.
(3) experimental result and conclusion:
The BSEP of 3. various concentration of table, SHP, CYP7A1mRNA testing result
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 4. the compounds of this invention of table processing
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 5. the compounds of this invention of table processing
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 6. the compounds of this invention of table processing
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 7. the compounds of this invention of table processing
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 8. the compounds of this invention of table processing
The testing result of BSEP mRNA relative expression quantity in the HepG2 cell of 9. the compounds of this invention of table processing
Remarks: the relative expression quantity %=100* [mRNA (tester)/mRNA (PX-102 or PX-104)] of mRNA
As shown in Table 3, the compounds of this invention 1 has preferable agonism to BSEP (EC50nM) and SHP (EC50nM), has good inhibiting effect to CYP7A1；By table 4- table 9 it is found that the compounds of this invention has preferable expressional function to BSEP mRNA in HepG2 cell, have great importance for treatment nonalcoholic fatty liver.
Experimental example 4: the Beagle dog pharmacokinetic studies of the compounds of this invention
Test sample: compound of the embodiment of the present invention, self-control, chemical name and preparation method are shown in the preparation embodiment of each compound.
The preparation of compound test solution of the embodiment of the present invention:
Compound intravenous injection of the embodiment of the present invention (iv) is 5%DMSO+10%PEG400+85% (28%HP- β-CD) to effective prescription.
The preparation of 28%HP- β-CD: weighing HP- β-CD (hydroxypropyl beta cyclodextrin) 2.8g, a small amount of sterilized water for injection ultrasonic dissolution is added, then be settled to 10ml with sterilized water for injection, vortex mixes to obtain the final product.
Compound 18.10mg of the embodiment of the present invention is weighed, 1.65ml DMSO is added, be vortexed dissolution, 3.3ml PEG400 is added, vortex mixed adds 28.05ml 28%HP- β-CD, it is vortexed and mixes, 50 DEG C are injected intravenously for 0.5mg/mL to drug solns for heat preservation 20 minutes to get concentration.
It is 0.1% Tween 80+2%HPC that (po) prescription, which is administered orally, in compound of the embodiment of the present invention.
The preparation of 0.1% Tween 80+2%HPC: weighing HPC (hydroxypropyl cellulose) 2g, and purified water is added to 100ml, is persistently stirred to dissolve, and adds 0.1ml Tween 80, after stirring and dissolving, shakes up to get the blank solvent of 0.1% Tween 80+2%HPC.
The above-mentioned solvent of 64ml is added in accurately weighed compound of embodiment of the present invention 35.04mg, and tissue grinder, which grinds 5 minutes, to be made to be uniformly dispersed, and being ground to fine and smooth uniform suspension to get concentration is 0.5mg/mL gastric infusion suspension solution.
Experimental method
Test sample medical fluid is administered according to following table method:
Blood sampling time point:
Iv: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h after medicine, for 24 hours, 48h.
Po: 0.167h, 0.5h, 1h, 2h, 4h, 6h, 8h after medicine, for 24 hours, 48h, 72h.
Sampled plasma: fixed animal, each time point are acquired the blood of 400 μ l or so by foreleg vein, are placed into containing EDTA-K2In anticoagulant tube, mixing uniform blood 8000 revs/min of centrifugations, 6 minutes separated plasmas under the conditions of 4 DEG C freeze in -80 DEG C of refrigerators.
Plasma sample analysis:
Plasma sample analysis uses precipitation of protein: drawing 20 μ l blood plasma, the acetonitrile solution that 200 μ l internal standards contain Tolbutamide (orinase) 50ng/ml is added), 1000 revs/min are vortexed 10 minutes, 4000 revs/min are centrifuged 20 minutes, 100 μ l of Aspirate supernatant, 100 μ l water are added, is vortexed and mixes, LC-MS/MS analysis.
Experimental result:
Compound exposure of the embodiment of the present invention is high, half-life period is longer, and bioavilability is 50% or more.
Specific embodiment
The specific embodiment of form by the following examples is described in further detail above content of the invention.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.The techniques implemented on the basis of the foregoing are all within the scope of the present invention.
Preparation example 1:(E) -2,6- dichloro benzaldoxime preparation
By 2,6- dichlorobenzaldehyde (25g, it 0.14mol) is dissolved in ethyl alcohol (200mL), it is slowly added to hydroxylamine hydrochloride (11g, 0.16mol) in batches, addition finishes, NaOH solution (6.4g is added, 0.16mol is dissolved in 100mL water), it is heated to 90 DEG C and reacts 24 hours.Solvent is removed under reduced pressure in end of reaction, reaction solution, and solid is washed with water (200mL), dry, obtains title compound 25.9g, yield 97%.
Preparation example 2:(Z) -2,6- bis- chloro- N- hydroxyl benzimidoyl chlorine preparation
By (E) -2,6- dichloro benzaldoxime (25.9g, 0.136mol) it is added to DMF (300mL), it is slowly added to N- chlorosuccinimide (18.2g in batches, 0.136mol), after adding, 25 DEG C are stirred one hour, and reaction solution is poured into water (500mL).It is extracted with ethyl acetate (500mL), organic phase is washed with water (200mL) and saturated sodium chloride solution (200mL), and anhydrous sodium sulfate is dry, is removed solvent and is obtained title compound 28g, and crude product does not purify, and carries out in next step.
The preparation of preparation example 3:5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- Ethyl formate
By (Z) -2, the chloro- N- hydroxyl benzimidoyl chlorine (28g, 0.125mol) of 6- bis- is dissolved in triethylamine (100mL), is added 3- cyclopropyl -3- ethyl 3-oxopropanoate (19.5g, 0.125mol), and 25 DEG C are reacted 12 hours.End of reaction, removed under reduced pressure solvent, pillar layer separation (PE: EA=10: 1) obtain title compound 24.4g, two step yields 55.1%.
Preparation example 4:(5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol preparation
By 5- cyclopropyl -3- (2, 6- dichlorophenyl) isoxazole -4- Ethyl formate (20g, it 61.3mmol) is dissolved in tetrahydrofuran (300mL), ice bath is cooling, toluene solution (the 1.5mol/L of diisobutyl aluminium hydride (DIBAL-H) is added, 123mL, 0.184mol), addition finishes, 25 DEG C are warming up to react 12 hours, end of reaction, ice bath, saturated ammonium chloride solution (200mL) quenching reaction is added, it is extracted with ethyl acetate (500mL), organic phase is washed with saturated ammonium chloride solution (200mL) and saturated sodium chloride solution (200mL), anhydrous sodium sulfate is dry, it removes solvent and obtains title compound 16g, yield 92.0%.
The preparation of preparation example 5-1:4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol (5.0g, it 17.6mmol) is added in methylene chloride (30mL), triethylamine (1.78g is added, 17.6mmol), then phosphorus tribromide (4.77g, 17.6mmol) is added, 30 DEG C are reacted 2 hours.Solvent is removed after completion of the reaction, and pillar layer separation (PE: EA=10: 1) obtains title compound 4.3g, yield 70.4%.
The preparation of preparation example 5-2:4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol (5.0g, it 17.6mmol) is added in methylene chloride (30mL), triethylamine (1.78g is added, 17.6mmol), then phosphorus trichloride (2.42g, 17.6mmol) is added, 30 DEG C are reacted 2 hours.Solvent is removed after completion of the reaction, and pillar layer separation (PE: EA=10: 1) obtains title compound 3.60g, yield 67.7%.
1 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) first Oxygroup) phenyl) benzodihydropyran -6- formic acid preparation (compound 1)
(1) preparation of (E) -1- (the bromo- 2- hydroxy phenyl of 5-) -3- (2- chloro-4-hydroxyl phenyl) propane -2- alkene -1- ketone
By 1- (the bromo- 2- hydroxy phenyl of 5-) ethyl ketone (40.7g, 189.26mmol) and 2- chloro-4-hydroxyl benzaldehyde (30g, it 191.61mmol) is dissolved in ethyl alcohol (1000mL), is added potassium hydroxide (42.56g, 760mmol).Reaction solution is stirred at room temperature 24 hours, ice water is added, (5L) is quenched, and with 2mol/L salt acid for adjusting pH value to 2, solid filtering is precipitated, obtains title compound (42g crude product).
(2) preparation of the bromo- 2- of 6- (2- chloro-4-hydroxyl phenyl) 4-chromanone
(E) -1- (the bromo- 2- hydroxy phenyl of 5-) -3- (2- chloro-4-hydroxyl phenyl) propane -2- alkene -1- ketone (42g crude product) is dissolved in acetic acid (500mL), it is added concentrated hydrochloric acid (100mL), is heated to back flow reaction 4 days.It is cooled to room temperature, ethyl acetate (2L) dilution is added, is washed (500mL × 4) with saturated sodium chloride solution, anhydrous sodium sulfate is dry, is concentrated in vacuo to obtain title compound (34g crude product).
(3) preparation of 4- (the bromo- benzodihydropyran -2- base of 6-) -3- chlorophenol
By mercuric chloride (39.4g, it 0.1449mol) is dissolved in 5mol/L hydrochloric acid (500mL), zinc powder (92.7g is added portionwise, 1.449mol), control temperature is stirred at room temperature 30 minutes less than 20 DEG C after adding, outwell liquid, 5mol/L hydrochloric acid (500mL) is added in solid, stirs 5 minutes at room temperature, outwells liquid.The toluene solution (500mL) of 5mol/L hydrochloric acid (1000mL) and the bromo- 2- of 6- (2- chloro-4-hydroxyl phenyl) 4-chromanone (34g crude product) are added into residual solid, 80 DEG C are heated to after adding to react 4 hours, it is cooled to room temperature, ethyl acetate extracts (400mL × 2), organic phase merges, anhydrous sodium sulfate is dry, concentration, crude product is through silica gel column chromatography (ethyl acetate: petroleum ether=1: 5) purifying, obtain title compound 11g, 3 step yields 16.9%.
(4) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- formonitrile HCN
By 4- (the bromo- benzodihydropyran -2- base of 6-) -3- chlorophenol (11g; it 32.5mmol) is dissolved in N-Methyl pyrrolidone (200mL); zinc cyanide (2g is added; 17mmol) and tetrakis triphenylphosphine palladium (1.87g; 1.62mmol), 110 DEG C of reactions are heated under nitrogen protection overnight.It is cooled to room temperature, ethyl acetate (500mL) dilution is added, (200mL × 3) are washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, concentration, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 5) purifying obtains title compound 3.1g, yield 33% to crude product.
(5) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester
By 2- (2- chloro-4-hydroxyl phenyl)-benzodihydropyran -6- formonitrile HCN (3.1g, it 10.85mmol) is dissolved in methanol (100mL), the lower dropwise addition concentrated sulfuric acid (10mL) is stirred at room temperature, back flow reaction is heated to after adding 4 days.Ethyl acetate (500mL) dilution is added after cooling to room temperature, it is washed (200mL × 3) with saturated sodium chloride solution, anhydrous sodium sulfate is dry, vacuum concentration, crude product is purified through silica gel column chromatography (EA: PE=1: 5), obtains title compound (2g crude product).
(6) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- methyl formate
2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester (2g crude product) is dissolved in N, in dinethylformamide (30mL), sodium iodide (1.89g is added, 12.60mmol), potassium carbonate (2.61g, 18.90mmol) and 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (2.27g, N 7.50mmol), dinethylformamide solution (20mL) is warming up to 60 DEG C and is stirred overnight.Ethyl acetate (200mL) dilution is added, it is washed (50mL × 3) with saturated sodium chloride solution, anhydrous sodium sulfate is dry, vacuum concentration, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 5) purifying obtains product (1.2g crude product) to crude product.
(7) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formic acid
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- methyl formate (1.2g, 2.00mmol) is dissolved in methanol/water (100mL/20 ML), a hydronium(ion) lithia (252mg, 6.00mmol) is added, is stirred overnight at room temperature.Water (100mL) dilution is added in reaction solution, aqueous citric acid solution adjusts pH value to 3, it is added ethyl acetate (500mL), liquid separation, organic phase are washed (100mL × 2) with saturated sodium chloride solution, and anhydrous sodium sulfate is dry, vacuum concentration, crude product is purified through preparative high-performance liquid chromatographic, obtains title compound 45mg, 3 step yields 0.73%.
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85 LC-MS (negative, m/z): 570 (M+H)+
1H-NMR (300MHz, CD3OD) δ: 7.82-7.77 (m, 2H), 7.54-7.38 (m, 4H), 6.90-6.79 (m, 3H), 4.94-4.85 (m, 2H), 3.09-2.98 (m, 1H), 2.86-2.81 (m, 2H), 2.37-2.25 (m, 2H), 1.97-1.90 (m, 1H), 1.30-1.19 (m, 4H)
2 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) -2,3- Dihydrobenzofuranes -5- formic acid (compound 2)
(1) preparation of the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) benzaldehyde
2- chloro-4-hydroxyl benzaldehyde (1.0g, 6.38mmol), 3,4- dihydropyran (1.1g, 13.1mmol) and para-methylbenzenepyridinsulfonate sulfonate (0.8g, 3.18mmol) be added sequentially to methylene chloride (100mL), 25 DEG C react 4 hours, after completion of the reaction, concentration, residue (petroleum ether: ethyl acetate=10: 1), obtains title compound 1.2g, yield 78.1% through silica gel column chromatography.
(2) preparation of 2- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -2,3- Dihydrobenzofuranes -5- methyl formate
By the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) benzaldehyde (1.1g, 4.57mmol), 3- Methyl -4- nitrobenzene methyl (1.07g, 5.48mmol), n,N-diisopropylethylamine (1.24g, 9.6mmol) and tetrabutyl ammonium fluoride (8.2mL, 8.2mmol, 1M tetrahydrofuran solution) it is added sequentially in tetrahydrofuran (10mL), 80 DEG C are reacted 16 hours, solvent is removed after completion of the reaction, residue (petroleum ether: ethyl acetate=20: 1), obtains title compound 1.1g, yield 61.9% through silica gel column chromatography.
(3) 2- (2- chloro-4-hydroxyl phenyl) -2,3- Dihydrobenzofuranes -5- methyl formate preparation
By 2- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygen) phenyl) -2,3- Dihydrobenzofuranes -5- methyl formate (1.1g, 2.83mmol) and p-methyl benzenesulfonic acid (0.2g, 1.16mmol) be added in methanol (20mL), 25 DEG C react 2 hours, after completion of the reaction, remove solvent, residue (petroleum ether: ethyl acetate=5: 1), obtains title compound 0.54g, yield 62.6% through silica gel column chromatography.
(4) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2,3- Dihydrobenzofuranes -5- methyl formate
Preparation process is referring to embodiment 1, reaction step (6).
(5) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2,3- Dihydrobenzofuranes -5- formic acid
Preparation process is referring to embodiment 1, reaction step (7).
Molecular formula: C28H20Cl3NO5Molecular weight: 556.8 LC-MS (m/z): 556.2 (M+H)+
1H-NMR (400MHz, MeOD) δ: 7.90 (d, J=4.4Hz, 1H), 7.86 (s, 1H), 7.42-7.51 (m, 3H), 7.27 (d, J=8.8Hz, 1H), 6.89 (d, J=4.4Hz, 1H), 6.86 (s 1H), 6.73 (d, J=8.8Hz, 1H), 6.06 (t, J=8.8Hz, 1H), 4.90 (s, 2H), 3.74-3.81 (m, 1H), 3.01-3.07 (m, 1H), 2.32 (t, J=6.0Hz, 1H), 1.18-1.21 (m, 4H)
3 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) -2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin -6- formic acid preparation (compound 3)
(1) preparation of the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) benzaldehyde
By 2- chloro-4-hydroxyl benzaldehyde (2g, 12.77mmol) and 3,4-2H- dihydropyran (1.5g, it 17.83mmol) adds in methylene chloride (50mL), it is added para-methylbenzenepyridinsulfonate sulfonate (0.3g, 1.19mmol), 25 DEG C are stirred to react 6 hours.Reaction solution is concentrated, (petroleum ether: ethyl acetate=50: 1) purifying is to get title compound 2.6g, yield 83.9% with silica gel column chromatography for gained crude product.
(2) preparation of 2- (the chloro- 4- vinyl benzene oxygroup of 3-) tetrahydro -2H- pyrans
By methyltriphenylphosphonium bromide (4g; 11.17mmol) and potassium tert-butoxide (1.5g; it 13.37mmol) adds in tetrahydrofuran (80mL); 0 DEG C is cooled under nitrogen protection; the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) benzaldehyde (2.5g is added; tetrahydrofuran (20mL) solution 10.4mmol), 25 DEG C are stirred to react 3 hours.Water (100mL) and ethyl acetate (100mL) is added, liquid separation, water phase is extracted with ethyl acetate (100mL × 3), merge organic phase, is dried, filtered with anhydrous sodium sulfate, concentration, (petroleum ether: ethyl acetate=50: 1) purifying is to get title compound 2g, yield 80.6% with silica gel column chromatography for gained crude product.
(3) preparation of 1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethane -1,2- glycol
By 2- (the chloro- 4- vinyl benzene oxygroup of 3-) tetrahydro -2H- pyrans (1.6g, 6.7mmol) it is dissolved in the tert-butyl alcohol (20mL) and water (20mL) in the mixed solvent, it is cooled to 0 DEG C, it is added AD-mix-beta (2g), 25 DEG C are stirred to react 6 hours.Water (50mL) and ethyl acetate (50mL) is added, liquid separation, water phase is extracted with ethyl acetate (50mL × 3), merge organic phase, is dried, filtered with anhydrous sodium sulfate, concentration, (petroleum ether: ethyl acetate=3: 1) purifying is to get title compound 1.2g, yield 65.7% with silica gel column chromatography for gained crude product.
(4) preparation of 2- ((t-Butyldimethylsilyl) oxygroup) -1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethyl alcohol
By 1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethane -1,2- glycol (1g, 3.67mmol) and imidazoles (0.5g, it 7.34mmol) is dissolved in methylene chloride (20mL), tert-butyl chloro-silicane (0.7g is added, 4.64mmol), it is stirred to react 16 hours for 25 DEG C.Reaction solution is concentrated, (petroleum ether: ethyl acetate=10: 1) purifying is to get title compound 1.2g, yield 84.7% with silica gel column chromatography for gained crude product.
(5) preparation of 4- (2- ((t-Butyldimethylsilyl) oxygroup) -1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethyoxyl) -3- iodo-benzoic acid methyl esters
By 2- ((t-Butyldimethylsilyl) oxygroup) -1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethyl alcohol (1g, 2.58mmol), 4- hydroxyl -3- iodo-benzoic acid methyl esters (0.7g, 2.52mmol) and triphenyl phosphorus (0.8g, it 3.05mmol) is dissolved in tetrahydrofuran (20mL), it is cooled to 0 DEG C Diethyl azodiformate (0.6g, 3.44mmol) is added under nitrogen protection, 25 DEG C are stirred to react 16 hours.Reaction solution is concentrated, (petroleum ether: ethyl acetate=5: 1) purifying is to get title compound 0.9g, yield 55.2% with silica gel column chromatography for gained crude product.
(6) preparation of 4- (1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -2- hydroxyl-oxethyl) -3- iodo-benzoic acid methyl esters
By 4- (2- ((t-Butyldimethylsilyl) oxygroup) -1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) ethyoxyl) -3- iodo-benzoic acid ester (0.9g, it 1.39mmol) is dissolved in tetrahydrofuran (20mL), 4-butyl ammonium fluoride trihydrate (0.44g is added, 1.39mmol), it is stirred to react 2 hours for 25 DEG C.Reaction solution is concentrated, (petroleum ether: ethyl acetate=5: 1) purifying is to get title compound 0.7g, yield 94.6% with silica gel column chromatography for gained crude product.
(7) preparation of 2- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin -6- methyl formate
By 4- (1- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -2- hydroxyl-oxethyl) -3- iodo-benzoic acid methyl esters (0.6g; 1.13mmol) it is dissolved in 1; in 4- dioxane (10mL); sodium tert-butoxide (0.11g is added; 1.14mmol); 1; 10- phenanthrene vomits quinoline (25mg; 0.13mmol); cuprous iodide (24mg; 0.13mmol), 100 DEG C are heated under nitrogen protection to be stirred to react 16 hours.Reaction solution is concentrated, gained crude product silica gel column chromatography purify (petroleum ether: ethyl acetate=5: 1) up to title compound 0.25g, yield 54.4%.
(8) 2- (2- chloro-4-hydroxyl phenyl) -2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin -6- methyl formate preparation
By 2- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -2,3- dihydrobenzo [b] [1,4] dioxin -6- formic acid esters (0.25g, it 0.62mmol) is dissolved in dehydrated alcohol (5mL), para-methylbenzenepyridinsulfonate sulfonate (20mg is added, 0.08mmol), 80 DEG C are heated to be stirred to react 2 hours.Reaction solution is concentrated, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=2: 1) to get title compound 0.16g, yield 80.0%.
(9) preparation of 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol (0.5g, 1.76mmol) and triphenyl phosphorus (0.6g, it 2.29mmol) is dissolved in tetrahydrofuran (5mL), it is cooled to 0 DEG C, it is added carbon tetrabromide (0.76g, 2.29mmol), 25 DEG C are stirred to react 2 hours.Reaction solution is concentrated, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=5: 1) to get title compound 0.5g, yield 81.9%.
(10) 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2, the preparation of 3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxane -6- methyl formate
By 2- (2- chloro-4-hydroxyl phenyl) -2,3- dihydrobenzo [b] [1,4] dioxin -6- methyl formate (0.12g, 0.37mmol) and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (0.13g, 0.37mmol) is dissolved in N, in dinethylformamide (5mL), it is added potassium carbonate (0.1g, 0.72mmol), is heated to 80 DEG C and is stirred to react 16 hours.Reaction solution is concentrated, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=2: 1) to get title compound 0.15g, yield 68.2%.
(11) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2,3- dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin -6- formic acid
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2,3- dihydrobenzo [b] [1,4] dioxin -6- methyl formate (0.12g, it 0.2mmol) is dissolved in tetrahydrofuran (3mL) and methanol (3mL), Lithium hydroxide monohydrate (12mg, 0.28mmol) water (1mL) solution is added, 25 DEG C are stirred to react 16 hours.Reaction solution is concentrated, (methylene chloride: methanol=20: 1) and Combiflash (acetonitrile/water 10%-35%-80%) purifying is to get title compound 20mg, yield 17.1% with silica gel column chromatography for gained crude product.
Molecular formula: C28H20Cl3NO6Molecular weight: 572.8 LC-MS (m/z): 572.1,574.1 (M+H)+
1H-NMR (400MHz, MeOD) δ: 7.41-7.61 (m, 6H), 6.95 (d, J=8.4Hz, 1H), 6.89 (s, 1H), 6.85 (dd, J1=8.8Hz, J=2.6Hz, 1H), 5.42 (dd, J1=8.4Hz, J=2.0Hz, 1H), 4.96 (s, 2H), 4.45 (dd, J1=11.6Hz, J=2.4Hz, 1H), 3.90-3.95 (m, 1H), 2.32-2.42 (m, 1H), 1.22-1.24 (m, 4H)
4 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- formic acid preparation (compound 4)
(1) preparation of 4- ((the bromo- 3- chlorophenoxy of 4-) methyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole
The bromo- 3- chlorophenol (11g, 53.02mmol) of 4- is dissolved in n,N-Dimethylformamide (150 ML in), sodium iodide (16g is added, 106.74mmol), potassium carbonate (44g, 318.36mmol) and 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (17.6g, n,N-Dimethylformamide solution (50mL) 58.17mmol), is warming up to 60 DEG C and is stirred overnight.It is cooled to room temperature, ethyl acetate (1L) dilution is added, (200mL × 3) are washed with saturated sodium chloride solution, anhydrous sodium sulfate is dry, vacuum concentration, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 10) purifying obtains title compound (19.6g, 2 step yields 78.5%) to crude product.
(2) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- methyl formates
By 4- ((the bromo- 3- chlorophenoxy of 4-) methyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (2.1g, 4.43mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (60mL), it is added 1,2,3,4- tetrahydroisoquinoline -6- methyl formate hydrochloride (1g, 4.39mmol), cesium carbonate (4.3g, 13.20mmol) with Brettphos-Pd (100mg, 0.11mmol), it is heated to back flow reaction 3 days.Water (20mL) and ethyl acetate (300mL) is added in reaction solution, (50mL × 3) are washed with saturated sodium chloride solution, organic phase is dry with anhydrous sodium sulfate, vacuum concentration, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 5) purifying obtains title compound (180mg crude product) to residue.
(3) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- formic acid
The preparation method of 1 step of reference implementation example (7), 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2 is added, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -6- methyl formate (180mg crude product) obtains title compound (8mg, 2 step yields 0.3%).
Molecular formula: C29H23Cl3N2O4Molecular weight: 569.86 LC-MS (positive, m/z): 571 (M+H)+
1H-NMR (300MHz, CD3OCD3) δ: 7.86-7.81 (m, 2H), 7.60-7.52 (m, 3H), 7.28-7.25 (m, 1H), 7.16 (d, J=8.7Hz, 1H), 6.95 (d, J=2.7Hz, 1H), 6.82 (dd, J1=3Hz, J2=8.7Hz, 1H), 4.96 (s, 2H), 4.21 (s, 2H), 3.30-3.26 (m, 2H), 3.08-2.95 (m, 2H), 2.47-2.38 (m, 1H), 1.23-1.17 (m, 4H)
5 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) first Oxygroup) phenyl) -1,2,3,4- tetrahydroisoquinoline -7- formic acid preparation (compound 5)
(1) preparation of 4- (2- amino-ethyl) methyl benzoate
By 4- (cyano methyl) methyl benzoate (6.0g, it 34.2mmol) is dissolved in the hydrogen chloride saturated solution (10mL) of dioxane, it is added methanol (10mL), palladium carbon (10%) (0.6g), after replacing hydrogen, it is reacted 24 hours at 25 DEG C, filtering, filter cake is rinsed with methanol (20mL), after filtrate concentration, (methylene chloride: methanol=10: 1), title compound (1.5g, yield 24.6%) is obtained through column chromatography.
(2) preparation of 4- (2- (2,2,2- trifluoroacetamido) ethyl) methyl benzoate
By 4- (2- amino-ethyl) methyl benzoate (1.5g, it 8.4mmol) is added in trifluoroacetic anhydride (10mL), it is stirred to react at 25 DEG C 3 hours, then reaction solution is poured into 20mL ice water, continue stirring 30 minutes, the solid of precipitation is filtered, is washed with n-hexane (10mL), dry title compound (1.5g, yield 65.2%).
(3) preparation of -1,2,3,4- tetrahydroisoquinoline -7- methyl formate of 2- (2,2,2- trifluoroacetyl group)
Under ice bath, to addition 4- (2- (2 in the mixed solution of glacial acetic acid (6mL) and the concentrated sulfuric acid (9mL), 2,2- trifluoroacetamido) ethyl) methyl benzoate (1.5g, 5.5mmol), paraformaldehyde (250mg, 8.3mmol), after being stirred 16 hours at 25 DEG C, reaction solution is poured into 150mL ice water, ethyl acetate extracts (100mL × 3), merge organic phase, (petroleum ether: ethyl acetate=5: 1), title compound (1.3g, yield 82.3%) is obtained through column chromatography.
The preparation of (4) 1,2,3,4- tetrahydroisoquinoline -7- methyl formates
By 2- (2; 2; 2- trifluoroacetyl group) -1; 2; 3,4- tetrahydroisoquinoline -7- methyl formates (1.2g, 4.2mmol) are dissolved in the mixed solution of methanol (10mL) and water (4mL); potassium carbonate (0.9g is added; 6.5mmol), it is stirred to react 3 hours, after removing methanol under reduced pressure at 25 DEG C; it is added water (50mL); ethyl acetate extracts (30mL × 3), merges organic phase, chromatographs (petroleum ether: ethyl acetate=5: 1) through column; it obtains title compound (0.6g, yield 75%).
(5) preparation of the bromo- 2- chloro-4-methoxy benzene of 1-
By the bromo- 3- chlorophenol (0.3g of 4-, 1.4mol) it is dissolved in N, in dinethylformamide (20mL), potassium carbonate (0.3g is added, 2.2mol), iodomethane (0.3g, 2.1mmol), it is stirred to react 2 hours at 25 DEG C, is added ethyl acetate (50mL), water (50mL) is added to wash, saturated sodium chloride solution (50mL) washing, organic phase is dry with anhydrous sodium sulfate, chromatographs (petroleum ether: ethyl acetate=10: 1) through column, it obtains title compound (0.3g, yield 93.7%).
(6) preparation of -1,2,3,4- tetrahydroisoquinoline -7- formic acid of 2- (2- chloro-4-methoxy phenyl)
By the bromo- 2- chloro-4-methoxy benzene (0.3g, 1.4mmol) of 1-, 1,2,3,4- tetrahydroisoquinoline -7- methyl formate (0.3g, it 1.6mmol) is dissolved in toluene (10mL), 1,1 '-dinaphthalene -2 is added, 2 '-bis- diphenylphosphines (87mg, 0.14mmol), tris(dibenzylideneacetone) dipalladium (130mg, 0.14mmol), sodium tert-butoxide (270mg, 2.8mmol), it is warming up to 100 DEG C to react 8 hours, end of reaction will Reaction solution concentration, residue chromatograph through column and (petroleum ether: ethyl acetate=2: 1), obtain title compound (80mg, yield 18%).
(7) preparation of -1,2,3,4- tetrahydroisoquinoline -7- formic acid of 2- (2- chloro-4-hydroxyl phenyl)
Under ice bath, by 2- (2- chloro-4-methoxy phenyl) -1,2,3,4- tetrahydroisoquinoline -7- formic acid (80mg, 0.26mmol) are dissolved in methylene chloride (5mL), it is added Boron tribromide (125mg, 0.5mmol), rises to 25 DEG C and be stirred to react 6 hours, it is cooled to 0 DEG C, saturated sodium bicarbonate solution 2mL is added into reaction solution, separates to obtain organic phase, is evaporated solution after anhydrous sodium sulfate is dry, it obtains title compound (75mg, yield 98.8%).
(8) preparation of -1,2,3,4- tetrahydroisoquinoline -7- methyl formate of 2- (2- chloro-4-hydroxyl phenyl)
By 2- (2- chloro-4-hydroxyl phenyl) -1,2,3,4- tetrahydroisoquinoline -7- formic acid (75mg, it 0.24mmol) is dissolved in methanol (5mL), it is added dropwise thionyl chloride (60mg, 0.50mmol), is warming up to 90 DEG C and reacts 2 hours, reaction solution is concentrated, (methylene chloride: methanol=20: 1), title compound (60mg, yield 78.6%) is obtained through column chromatography.
(9) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -7- methyl formates
By 4- (bromomethyl) -5- cyclopropyl -3- (2, 6- dichlorophenyl) isoxazole (66mg, 0.19mmol), 2- (2- chloro-4-hydroxyl phenyl) -1, 2, 3, 4- tetrahydroisoquinoline -7- methyl formate (60mg, 0.19mmol) it is dissolved in N, in dinethylformamide (5mL), cesium carbonate (130mg is added, 0.4mmol), be warming up to 40 DEG C be stirred to react 3 hours after, it is added water (20mL), ethyl acetate extracts (15mL × 3), merge organic phase, (methylene chloride: methanol=15: 1) is chromatographed through column, obtain title compound (70mg, yield 63.1%).
(10) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -7- formic acid
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -7- methyl formate (70mg, 0.12mmol), it is dissolved in tetrahydrofuran (5mL), is added sodium hydroxide (10mg, 0.25mmol), after being stirred to react 12 hours at 25 DEG C, 1N HCl solution is added and adjusts pH to 6, solution is evaporated, residue chromatographs (methylene chloride: methanol=10: 1) through column, it obtains title compound (40mg, yield 58.5%).
Molecular formula: C29H23Cl3N2O4Molecular weight: 569.9 LC-MS (m/z): 571.1 (M+H)+
1H-NMR (400MHz, DMSO-d6) δ: 7.90 (d, J=8.8Hz, 1H), 7.85 (s, 1H), 7.42 (d, J=7.2Hz, 1H), 7.32-7.36 (m, 1H), 7.28 (s, 1H), 7.00 (d, J=8.8Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 6.71 (dd, J1=8.8Hz, J2=6.0Hz, 1H), 4.79 (s, 2H), 4.23 (s, 2H), 3.30-3.33 (m, 2H), 3.02-3.09 (m, 2H), 2.11-2.19 (m, 1H), 1.27-1.32 (m, 2H), 1.14-1.16 (m, 2H)
6 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) first Oxygroup) phenyl) -1,2,3,4- tetrahydroisoquinoline -5- formic acid preparation (compound 6)
(1) preparation of 5- Cyanoisoquinoline
By 5- bromo-isoquinoline (2.0g; 9.6mmol); zinc cyanide (0.68g; it 5.8mmol) is added in n,N-Dimethylformamide (100mL), tetrakis triphenylphosphine palladium (0.45g is added under nitrogen protection; 0.39mmol); it is warming up to 100 DEG C to react 16 hours, TLC detects fully reacting, is cooled to It 25 DEG C, is added water (200mL), filters, filter cake is washed with water (100mL), is dried in vacuo to obtain title compound (0.9g, yield 60.8%).
(2) preparation of isoquinolin -5- carboxylic acid
By 5- Cyanoisoquinoline (0.9g, it 5.8mmol) is added in 50% sulfuric acid solution (30mL), it is warming up to 100 DEG C to react 16 hours, is cooled to 25 DEG C, pours into ice water (100mL), stirring, white precipitate is precipitated, filters, filter cake vacuum drying, it obtains title compound (0.8g, yield 80%).
(3) preparation of isoquinolin -5- carboxylate methyl ester
Isoquinolin -5- carboxylic acid (0.8g, 4.62mmol) is added in methanol (30mL), the concentrated sulfuric acid (0.5mL) is added with stirring, 83 DEG C are warming up to react 24 hours, TLC detects fully reacting, is concentrated under reduced pressure, and crude product is directly used in next step.
The preparation of (4) 1,2,3,4- tetrahydroisoquinoline -5- carboxylate methyl esters
Isoquinolin -5- carboxylate methyl ester (crude product) is added in glacial acetic acid (30mL), is added with stirring platinum dioxide (86mg), replacing hydrogen, is reacted 4 hours at 25 DEG C.TLC detects fully reacting, filters, and saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (100mL) is added in filtrate concentration, liquid separation, organic phase is dry with anhydrous sodium sulfate, filters, filtrate concentration, obtains title compound (0.87g, yield 98.9%).
(5) preparation of -1,2,3,4- tetrahydroisoquinoline -5- carboxylate methyl ester of 2- (2- chloro-4 nitrophenyl)
1,2,3,4- tetrahydroisoquinoline -5- carboxylate methyl ester (0.84g, 4.4mmol), the fluoro- 4- nitrobenzene (0.85g, 4.8mmol) of the chloro- 1- of 2- and cesium carbonate (2.87g, 8.8mmol) are added to N, N- dimethyl In acetamide (50mL), 70 DEG C are warming up to react 16 hours, TLC detects fully reacting, adds water (150mL) and ethyl acetate (150mL), liquid separation, organic phase is dry with anhydrous sodium sulfate, it filters, vacuum concentration, crude product is through silica gel column chromatography (petroleum ether: ethyl acetate=2: 1), it obtains title compound (860mg, yield 56.2%).
(6) preparation of 2- (4- amino -2- chlorphenyl) -1,2,3,4- tetrahydroisoquinoline -5- carboxylate methyl esters
By 2- (2- chloro-4 nitrophenyl) -1; 2; 3; 4- tetrahydroisoquinoline -5- carboxylate methyl ester (0.86g; it 2.5mmol) is added in tetrahydrofuran (20mL), Raney's nickel (86mg, mass ratio 10%) is added under nitrogen protection; replacing hydrogen, 25 DEG C are reacted 1.5 hours.TLC detects fully reacting, filters, and filtrate is concentrated to give title compound (730mg, yield 92.2%).
(7) preparation of -1,2,3,4- tetrahydroisoquinoline -5- carboxylate methyl ester of 2- (2- chloro-4-hydroxyl phenyl)
By 2- (4- amino -2- chlorphenyl) -1, 2, 3, 4- tetrahydroisoquinoline -5- carboxylate methyl ester (700mg, 2.2mmol) it is added to the in the mixed solvent of 1mol/L sulfuric acid (10mL) and methanol (2mL), it is cooled to 0 DEG C, sodium nitrite (167mg is added, 2.42mmol), 50% sulfuric acid (10mL) is added after 1 hour in reaction, 100 DEG C are warming up to react 2 hours, adjusting pH with 1mol/L sodium hydrate aqueous solution is 7, ethyl acetate (200mL) extraction is added, organic phase vacuum concentration, crude product is through silica gel column chromatography (petroleum ether: ethyl acetate=1: 3), obtain title compound (130mg, yield 18.6%).
(8) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -5- methyl formates
Preparation process is referring to embodiment 5, reaction step (9).
(9) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -1,2,3,4- tetrahydroisoquinoline -5- formic acid
Preparation process is referring to embodiment 5, reaction step (10).
Molecular formula: C29H23Cl3N2O4Molecular weight: 569.9 LC-MS (m/z): 569.1 (M+H)+
1H-NMR (400MHz, DMSO-d6) δ: 7.99-7.96 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.29 (m, 3H), 7.00 (d, J=8.8Hz, 1H), 6.90 (d, J=2.8Hz, 1H), 6.72-6.69 (m, 1H), 4.78 (s, 2H), 4.22 (s, 2H), 3.43-3.41 (m, 2H), 3.30-3.27 (m, 2H), 2.19-2.15 (m, 1H), 1.19-1.14 (m, 4H)
7 6- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) -5,6,7,8- naphthane -2- formic acid preparation (compound 7)
(1) bromo- 3, the 4- dihydronaphthalene -2- base triflate of 6-
Under nitrogen protection; 6- bromo- 3 is added in there-necked flask; (1H) -one of 4- dihydronaphthalene -2 (10g; 44.43mmol) and tetrahydrofuran (250mL); it is cooled to -78 DEG C; then two (trimethyl silicon substrate) lithium amides (89.2mL, 89.2mmol) are added dropwise.- 78 DEG C are stirred 1 hour, are added dropwise 1,1, fluoro- N- phenyl-N- (trifluoromethyl) sulphonyl of 1- tri-) Methanesulfonamide (19.1g, tetrahydrofuran solution (50mL) 53.46mmol) stirs 30 minutes, restores to being stirred at room temperature 30 minutes.The water quenching reaction of 30mL is added, is extracted with ethyl acetate (3 × 200mL), merges organic phase, wash with water (3 × 50mL), anhydrous magnesium sulfate is dry to be concentrated, residue through silica gel column purification (ethyl acetate: petroleum ether= 1: 100-1: 50), obtaining 4.6g title compound, yield 29%.
(2) 2- (2- chloro-4-methoxy phenyl) -4,4,5,5- tetramethyls -1,3, the preparation of 2- dioxaborolanes
The bromo- 2- chloro-4-methoxy benzene (10g of 1- is added in there-necked flask, 45.15mmol), 1,4- dioxane (200mL), connection boric acid pinacol ester (12g, 47.24mmol), potassium acetate (13.4g, 136.54mmol), Pd (dppf) Cl2Chloride dichloromethane complex (1.86g, 2.28mmol).Nitrogen is replaced three times, is then heated to 90 DEG C of reactions overnight.Reaction mixture is cooling, is diluted with ethyl acetate (50mL), and water (3 × 100mL) washing is added.Anhydrous magnesium sulfate is dry to be concentrated to give residue, crosses silica gel column purification and (ethyl acetate: petroleum ether=1: 100-1: 20), obtains the title compound of 7g, yield 58%.
(3) synthesis of the bromo- 3- of 7- (2- chloro-4-methoxy phenyl) -1,2- dihydronaphthalene
2- (2- chloro-4-methoxy phenyl) -4 is added in there-necked flask, 4,5,5- tetramethyls -1,3,2- dioxaborolanes (3g, 11.17mmol), bromo- 3, the 4- dihydronaphthalene -2- base trifluoromethayl sulfonic acid ester (4.39g of Isosorbide-5-Nitrae-dioxane (40mL), 6-, 12.29mmol) and the aqueous solution (5mL) of sodium carbonate (2.97g, 27.76mmol), Pd (dppf) Cl2DCM (89.9mg), displacement nitrogen three times, are heated to 80 DEG C of reactions overnight.It is cooling, ethyl acetate (50mL) dilution is added.Mixture is washed with water (3 × 20mL).Organic phase is dry with anhydrous sodium sulfate, concentration, and residue crosses silica gel column purification and (ethyl acetate: petroleum ether=1: 100-1: 30) obtains the title compound of 1.5g, yield 38%.
(4) 6- (2- chloro-4-methoxy phenyl) -7,8- dihydronaphthalene -2- formonitrile HCN preparation
The bromo- 3- of 7- (2- chloro-4-methoxy phenyl) -1 is added in single port bottle, 2- dihydronaphthalene (1.5g, 4.29mmol), DMF (30mL), dicyano zinc (748mg, 6.37mmol) and tetrakis triphenylphosphine palladium (497mg, 0.43mmol), substitute nitrogen three times, 125 DEG C of reactions are overnight.It is cooling, it filters out not Ethyl acetate (50mL) dilution is added in molten solid.Mixture is washed with water (3 × 20mL).Organic phase is dry with anhydrous sodium sulfate, and concentration, residue crosses silica gel column purification (ethyl acetate: petroleum ether=1: 50-1: 20).Obtain the title compound of 0.9g, yield 71%.
(5) 6- (2- chloro-4-methoxy phenyl) -7,8- dihydronaphthalene -2- methyl formate preparation
6- (2- chloro-4-methoxy phenyl) -7,8- dihydronaphthalene -2- formonitrile HCN (900mg, 3.04mmol) and methanol (15mL) are added in single port bottle, then 0 DEG C of dropwise addition H2SO4(5mL), is added dropwise, and 80 DEG C of reactions are overnight, cooling, and ethyl acetate (50mL) dilution is added.Mixture is washed with water (3 × 20mL).Organic phase is dry with anhydrous sodium sulfate, concentration, and residue crosses silica gel column purification and (ethyl acetate: petroleum ether=1: 50-1: 30) obtains the title compound of 0.7g, yield 70%.
(6) preparation of -5,6,7,8- naphthane -2- methyl formate of 6- (2- chloro-4-methoxy phenyl)
6- (2- chloro-4-methoxy phenyl) -7,8- dihydronaphthalene -2- methyl formate (700mg, 2.13mmol), ethyl acetate (20mL), PtO is added in 50mL single port bottle2(96mg) is hydrogenated 1 hour in 0 DEG C.Insoluble solid is filtered out, filtrate is concentrated to get 690mg product, yield 98%.
(7) preparation of -5,6,7,8- naphthane -2- methyl formate of 6- (2- chloro-4-hydroxyl phenyl)
6- (2- chloro-4-methoxy phenyl) -5,6,7,8- naphthane -2- methyl formate (680mg, 2.06mmol), methylene chloride (30mL) are added in 50mL single port bottle, is then cooled to 0 DEG C of dropwise addition BF3(Me2S)(2.68g).0 DEG C of reaction solution is stirred 5 hours.Then methylene chloride (50mL) dilution is added, is washed with water (3 × 30mL).It is dry to separate organic layer, concentration, residue crosses column purification and (ethyl acetate: petroleum ether=1: 20-1: 5), obtains the product of 390mg, yield 60%.
(8) preparation of (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5,6,7,8- naphthane -2- methyl formates
(5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol (524mg, 1.84mmol) and methylene chloride (10mL) are added in the single port bottle of 50mL, is then added dropwise to SOCl for 0 DEG C2(871mg, 7.32mmol) and n,N-Dimethylformamide (2 drop), kept for 0 DEG C stir 30 minutes, 6- (2- chloro-4-hydroxyl phenyl) -5,6,7 is added in concentration, 8- naphthane -2- methyl formate (390mg, 1.23mmol), n,N-Dimethylformamide (10mL), sodium iodide (55mg, 0.369mmol) and K2CO3(1.02g, 7.33mmol).60 DEG C of mixture are stirred overnight.Reaction mixture is cooling, and ethyl acetate (30mL) dilution is added, is then washed with water (3 × 30mL).It is dry to separate organic layer, is concentrated to get the title compound of 750mg.
(9) preparation of 6- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5,6,7,8- naphthane -2- formic acid
6- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2 is added in the single port bottle of 50mL, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5,6,7,8- naphthane -2- methyl formate (750mg, 1.29mmol), methanol (20mL) and sodium hydroxide (103mg, aqueous solution (1mL) 2.58mmol), 60 DEG C are heated to be stirred overnight, cooling concentration, residue is purified with prep-HPLC, obtains title compound 100mg.
Molecular formula: C30H24Cl3NO4, molecular weight: 568.87 LC-MS (ES, m/z): 566 (M+H)+
1H-NMR (DMSO, ppm): δ: 7.5-7.7 (m, 5H), 7.25-7.3 (m, 3H), 6.91 (s, 1H), 6.7-6.8 (m, 1H), 4.9 (s, 2H), 2.8-2.99 (m, 5H), 1.8-1.9 (m, 2H), (1.11-1.29 m, 5H)
8 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) xylylenimine -5- formic acid prepares (compound 8)
The preparation of (1) 3,4- dimethylbenzoate methyl ester
3,4- mesitylenic acid (5.0g, 33.3mmol) is dissolved in methanol (50mL), thionyl chloride (7.9g, 66.4mmol) is added dropwise under ice-water bath, rises to 25 DEG C, continue stirring 6 hours, remove solvent, residue continues in next step.
The preparation of (2) 3,4- bis- (bromomethyl) methyl benzoate
By 3,4- dimethylbenzoate methyl ester (5.4g, 32.9mmol), N- bromo-succinimide (12.8g, 71.9mmol) and the benzoyl peroxide (100mg of catalytic amount, it 0.4mmol) is dissolved in carbon tetrachloride (50mL), is heated to 80 DEG C, react 12 hours.25 DEG C are cooled to, filtering, filtrate is washed with saturated sodium bicarbonate solution (20mL), and anhydrous sodium sulfate dries, filters, and filtrate concentration obtains title compound 10.6g, yield 100.0%.
(3) preparation of 2- (4- methoxy-benzyl) iso-indoles -5- methyl formate
By 3, (bromomethyl) methyl benzoate of 4- bis- (10.6g, it 32.9mmol) is dissolved in tetrahydrofuran (50mL), 4-Methoxybenzylamine (4.5g is added, 32.8mmol) and triethylamine (6.6g, 65.3mmol), it is stirred 16 hours at 25 DEG C, solvent is removed, ethyl acetate (100mL) and water (30mL), liquid separation is added, remove organic phase, residue (petroleum ether: ethyl acetate=2: 1), obtains title compound 4.5g, yield 46% through column chromatography for separation.
(4) preparation of xylylenimine quinoline -5- methyl formate
By 2- (4- methoxy-benzyl) iso-indoles -5- methyl formate (1.7g, it 5.7mmol) is dissolved in methylene chloride (50mL), 1- chloroethylchloroformate ester (5.7g is added, 39.9mmol), it is stirred to react at 25 DEG C 30 hours, it is added methanol (5mL), continues stirring 1 hour.Solvent is removed, ethyl acetate (100mL) and saturated sodium bicarbonate solution (20mL) is added, liquid separation is concentrated, and residue (methylene chloride: methanol=20: 1), obtains title compound 0.7g, yield 70% through column chromatography for separation.
(5) preparation of the bromo- 2- chloro-4-methoxy benzene of 1-
By the bromo- 3- chlorophenol (2.0g of 4-, it 9.6mmol) is dissolved in n,N-Dimethylformamide (20mL), potassium carbonate (2.0g is added, 14.5mol), iodomethane (1.6g, 11.3mmol) is stirred to react 2 hours at 25 DEG C, ethyl acetate (50mL) and water (50mL) is added, liquid separation, organic phase are dried, filtered with anhydrous sodium sulfate.Concentration, residue chromatograph through column and (petroleum ether: ethyl acetate=10: 1), obtain title compound 1.7g, yield 80%.
(6) preparation of 2- (2- chloro-4-methoxy phenyl) xylylenimine -5- methyl formate
By the bromo- 2- chloro-4-methoxy benzene (0.62g of 1-, 2.8mmol), xylylenimine -5- methyl formate (0.5g, it 2.8mmol) is dissolved in toluene (10mL), 1,1 '-dinaphthalene -2,2 '-bis- diphenyl phosphine (0.35g are added, 0.56mmol), tris(dibenzylideneacetone) dipalladium (0.26g, 0.28mmol), sodium tert-butoxide (0.82g, 8.5mmol), it is warming up to 100 DEG C to react 8 hours, reaction solution is concentrated, residue chromatographs (petroleum ether: ethyl acetate=2: 1) through column, obtain product 0.15g, yield 16.9%.
(7) preparation of 2- (2- chloro-4-hydroxyl phenyl) xylylenimine -5- formic acid
Under ice bath, by 2- (2- chloro-4-methoxy phenyl) xylylenimine -5- methyl formate (0.15g, 0.47mmol) it is dissolved in methylene chloride (5mL), Boron tribromide (1.9mL is added, 1.9mmol), it rises to 25 DEG C to be stirred to react 6 hours, is cooled to 0 DEG C, unsaturated carbonate hydrogen is added into reaction solution Sodium solution (2mL), concentration, residue chromatograph through column and (methylene chloride: methanol=30: 1), obtain title compound 0.07g, yield 50%.
(8) preparation of 2- (2- chloro-4-hydroxyl phenyl) xylylenimine -5- methyl formate
By 2- (2- chloro-4-hydroxyl phenyl) xylylenimine -5- formic acid (0.07g, it 0.24mmol) is dissolved in methanol (5mL), thionyl chloride (0.06g is added dropwise, 0.50mmol), it is warming up to 90 DEG C to react 2 hours, reaction solution is concentrated, residue chromatographs (methylene chloride: methanol=30: 1) through column, obtain title compound 0.05g, yield 68.5%.
(9) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) xylylenimine -5- methyl formate
Preparation method in 5 step of reference implementation example (9), it is added 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (0.055g, 0.16mmol), 2- (2- chloro-4-hydroxyl phenyl) xylylenimine -5- methyl formate (0.05g, 0.16mmol) obtain product 0.03g, yield 33.0%.
(10) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) xylylenimine -5- formic acid
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) xylylenimine -5- methyl formate (0.03g, 0.05mmol), it is dissolved in methanol (5mL), Lithium hydroxide monohydrate (21mg is added, 0.5mmol), it is stirred to react at 25 DEG C 48 hours, concentration is added water (5mL), and 1N HCl solution tune pH to 6 is added, concentration, residue chromatographs through column and (methylene chloride: methanol=15: 1), obtains title compound 15mg, yield 53.9%.
Molecular formula: C28H21Cl3N2O4Molecular weight: 555.8LC-MS (m/z): 555.1 (M+H)+
1H-NMR (400MHz, MeOD) δ: 7.94 (s, 2H), 7.48-7.53 (m, 3H), 7.37 (d, J=8.4Hz, 1H), 7.12 (d, J=9.2Hz, 1H), 6.81 (d, J=2.8Hz, 1H), 6.72 (dd, J=9.2Hz, 2.8Hz, 1H), 4.67 (s, 2H), 4.58 (s, 4H), 2.31-2.37 (m, 1H), 0.88-0.92 (m, 4H)
Embodiment 9 (R) -2- (chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid preparation (compound 9)
(1) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester
The preparation of specific 1 step (1)-(5) of preparation method reference implementation example.
(2) fractionation of (R) -2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester and (S) -2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester
The crude product (4.5g) of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester is separated by chiral preparatory column (Chiral-Prep-HPLC): chiral column, DAICEL CHIRALPAK AD-H；Mobile phase, mobile phase A: n-hexane (0.1%TFA), Mobile phase B: isopropanol, A: B=80: 20.Obtain (R) -2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester (2.3g, crude product) and (S) -2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester (1.2g).
(3) preparation of (R) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylate methyl ester
By (5- cyclopropyl alkyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methanol (1.066g, dichloromethane solution (10mL) 3.75mmol) is added in the round-bottomed flask of a 50mL, then sulphinyl chlorine (10mL) is slowly added dropwise under conditions of being stirred at room temperature into solution, after charging completely, it is stirred at room temperature 2.5 hours, is concentrated under reduced pressure to give crude product.Separately take the three-necked flask of a 100mL, sequentially add (R) -2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- carboxylate methyl ester (1g, DMF solution (40mL) 3.14mmol), potassium carbonate (2.167g), sodium iodide (1.4g).It is stirred at room temperature down, the DMF solution of crude product obtained above is slowly added dropwise thereto, after charging completely, 60 DEG C of stirring 18h.Ethyl acetate (200mL) is added into reaction solution, is then washed with saturated salt solution (50mL × 3), separates the drying of organic phase anhydrous sodium sulfate, is concentrated under reduced pressure, obtains product (crude product, 1.6g).
(4) preparation of (R) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid
By (R) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylate methyl ester (1.6g, crude product) methanol/water (20/5mL) solution be added in the round-bottomed flask of a 50mL, under the conditions of 0 DEG C, lithium hydroxide (328.8mg) is added portionwise thereto, after charging completely, it is stirred at room temperature 2 days.The pH value of reaction solution is adjusted to 4-5 with citric acid, ethyl acetate (100mL) then is added, is washed with saturated salt solution (50mL × 2), organic phase is dry with anhydrous magnesium sulfate, is concentrated under reduced pressure.Residue passes through quick separating (acetonitrile, water, 1% ammonium hydroxide), obtains title compound 270mg, and two step yields are 15.1%.
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85LC-MS:(ES, m/z): 568.1 (M-1)-
1H-NMR (300MHz, DMSO, ppm): δ 12.5 (brs, 1H), 7.52-7.75 (m, 5H), (7.37-7.40 d, J=8.7Hz, 1H), (6.97-6.97 d, J=2.4Hz, 1H), 6.82-6.89 (m, 2H), 5.32-5.36 (m, 1H), 4.94 (s, 2H), 2.98-3.02 (m, 1H), 2.79-2.84 (m, 1H), 2.44 (m, 1H), 2.14-2.19 (m, 1H), 1.95-2.07 (m, 1H), 1.10-1.23 (m, 4H)
Embodiment 10 (S) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- Base) methoxyl group) phenyl) and benzodihydropyran -6- carboxylic acid preparation (compound 10)
(1) preparation of (S) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylate methyl ester
9 step (3) of preparation method reference implementation example, obtains crude title compound.
(2) preparation of (S) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid
9 step (4) of preparation method reference implementation example, obtains title compound (150mg), and two step yields are 16.7%.
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85LC-MS:568.1 (M-1)-
1H NMR (300MHz, DMSO-d6, ppm): δ 7.52-7.73 (m, 5H), 7.37-7.40 (d, J=8.4Hz, 1H), 6.96-6.97 (d, J=2.4Hz, 1H), 6.82-6.87 (m, 2H), 5.31-5.35 (m, 1H), 4.94 (s, 2H), 2.97-3.01 (m, 1H), 2.73-2.83 (m, 1H), 2.43 (m, 1H), 2.18-2.27 (m, 1H), 1.94-1.99 (m, 1H), 1.12-1.21 (m, 4H)
Embodiment 11 (S) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- Base) methoxyl group) phenyl) and -2,3- Dihydrobenzofuranes -5- formic acid preparation (compound 11)
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -2, 3- Dihydrobenzofuranes -5- formic acid (291mg, 0.52mmol, preparation method is shown in embodiment 2, step 1-5) it is split, splitting condition: chromatographic column DAICEL CHIRALPAK AD-3 (4.6mm × 50mm, 3.0 μm), column temp:25 DEG C, phase A:n-Hexane (0.1%TFA), phase B:Ethanlol, total flow:1.0mL/min, Wavelength:from 190nm to 500nm , product 60mg, yield 20.6% are obtained, ee value is 99.66%.
Molecular formula: C28H20Cl3NO5Molecular weight: 556.8LC-MS (m/z): 554 (M-H+)
1H-NMR (300MHz, DMSO) δ: 7.80 (d, J=5.1Hz, 2H), 7.59-7.63 (m, 2H), 7.52-7.56 (m, 1H), 7.27 (d, J=9.0Hz, 1H), 7.01 (d, J=2.7Hz, 1H), 6.96 (d, J=3.9Hz, 1H), 6.78 (dd, J1=2.7Hz, J2=5.7Hz, 1H), 6.03-6.09 (m, 1H), 4.93 (s, 2H), 3.71-3.80 (m, 1H), 3.04-3.13 (m, 1H), 2.43-2.45 (m, 1H), 1.10-1.22 (m, 4H)
Embodiment 12 (R) -2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- Base) methoxyl group) phenyl) and -2,3- Dihydrobenzofuranes -5- formic acid preparation (compound 12)
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) benzene Base) -2,3- Dihydrobenzofuranes -5- formic acid (291mg, 0.52mmol, preparation method is shown in embodiment 2, step 1-5) it is split, splitting condition is identical as the splitting condition in embodiment 11, product 90mg, yield 30.9% are obtained, ee value is 90.48%.
Molecular formula: C28H20Cl3NO5Molecular weight: 556.8LC-MS (m/z): 556 (M+H+)
1H-NMR (300MHz, DMSO) δ: 7.80 (d, J=5.7Hz, 2H), 7.59-7.63 (m, 2H), 7.52-7.56 (m, 1H), 7.27 (d, J=9.0Hz, 1H), 7.01 (d, J=2.7Hz, 1H), 6.96 (d, J=3.6Hz, 1H), 6.78 (dd, J1=2.7Hz, J2=5.7Hz, 1H), 6.03-6.09 (m, 1H), 4.93 (s, 2H), 3.71-3.80 (m, 1H), 3.04-3.13 (m, 1H), 2.43-2.45 (m, 1H), 1.10-1.22 (m, 4H)
13 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -5- carboxylic acid preparation (compound 13)
(1) preparation of 2- formoxyl -3- methyl hydroxybenzoate
By 3- methyl hydroxybenzoate (30.00g, 197.2mmol), it is added in trifluoroacetic acid (500mL), it is slowly added into HMTA (33.20g, 236.8mmol), it adds, it is warming up at 80 DEG C and reacts 6 hours, reaction solution is poured into 1.5L ice water, the extraction of 1L ethyl acetate is added, organic phase washed with water and each 800mL of saturated salt solution are washed, anhydrous sodium sulfate is dry, concentration, residue obtain title compound 20.30g, yield 57.1% through column chromatography (PE: EA=8: 1).
(2) preparation of 1- (2- chloro-4-methoxy phenyl) second -1- ketone
By m-chloroanisole (30.00g at 0 DEG C, it 210.4mmol) is added drop-wise in DCM (200mL) solution containing chloroacetic chloride (19.80g, 252.2mmol) and anhydrous aluminum chloride (36.45g, 273.4mmol), drop finishes, and the reaction was continued 2 hours.Reaction solution is poured into ice water (500mL), HCl (300mL) and DCM (800mL) extraction of 1M is added, organic phase is dry with anhydrous sodium sulfate, concentration, residue obtains title compound 13.7g, yield 35.3% through column chromatography (PE: EA=10: 1).
(3) preparation of the bromo- 1- of 2- (2- chloro-4-methoxy phenyl) second -1- ketone
1- (2- chloro-4-methoxy phenyl) second -1- ketone (8.01g, 43.4mmol) is dissolved in methylene chloride (200mL), bromine (6.94g, 43.4mmol) is added dropwise under ice-water bath, drop finishes, and the reaction was continued 2 hours.Reaction solution, which is directly concentrated, obtains product 8.34g, yield 73.0% through column chromatography (PE: EA=8: 1).
(4) preparation of (2- (2- chloro-4-methoxy phenyl) -2- oxoethyl) diethyl phosphonate
The bromo- 1- of 2- (2- chloro-4-methoxy phenyl) second -1- ketone (8.34g, 31.7mmol) and triethyl phosphite (7.89g, 47.6mmol) are added in toluene (100mL), 110 DEG C is warming up to and reacts 24 hours.Reaction solution, which is directly concentrated, obtains product 4.40g, yield 43.3% through column chromatography (PE: EA=5: 1).
(5) preparation of 2- (3- (2- chloro-4-methoxy phenyl) -3- oxo propyl- 1- alkene -1- base) -3- methyl hydroxybenzoate
By (2- (2- chloro-4-methoxy phenyl) -2- oxoethyl) diethyl phosphonate (4.40g; 13.7mmol); 2- formoxyl -3- methyl hydroxybenzoate (4.90g; 27.4mmol) and DBU (4.20g; 27.4mmol); it is added in THF (100mL), reacts 3 hours.Addition water and each 200mL extraction of ethyl acetate, organic phase is dry with anhydrous sodium sulfate, and concentration, residue obtains title compound 2.08g, yield 43.7% through column chromatography (PE: EA=5: 1).
(6) system of 2- (3- (2- chloro-4-methoxy phenyl) -3- oxopropyl) -3- methyl hydroxybenzoate It is standby
By 2- (3- (2- chloro-4-methoxy phenyl) -3- oxo propyl- 1- alkene -1- base) -3- methyl hydroxybenzoate (1.50g, 4.3mmol), it is added in THF (50mL), is added Pt/C (150mg), reacted 2 hours under nitrogen atmosphere.It filters, filter cake is washed with THF (10mL), and filtrate is directly used in be reacted in next step.
(7) preparation of 2- (3- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -3- methyl hydroxybenzoate
Filtrate (60mL) obtained by upper step is placed in 250mL flask, is added sodium borohydride (197mg, 5.2mmol), stirring 1 hour is added.Addition water and each 100mL extraction of ethyl acetate, organic phase is dry with anhydrous sodium sulfate, concentration, obtains title compound 1.45g, two step yields 95.6% through column chromatography (PE: EA=1: 1).
(8) preparation of 2- (2- chloro-4-methoxy phenyl) benzodihydropyran -5- carboxylate methyl ester
By 2- (3- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -3- methyl hydroxybenzoate (1.45g, 4.1mmol), triphenylphosphine (5.37g, 20.5mmol) and DEAD (3.57g, 20.5mmol) is added to reaction 2 hours in THF (50mL).Reaction solution is directly spin-dried for, and residue obtains title compound 800mg, yield 58.1% through column chromatography (PE: EA=25: 1).
(9) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -5- carboxylate methyl ester
2- (2- chloro-4-methoxy phenyl) benzodihydropyran -5- carboxylate methyl ester (800mg, it 2.4mmol) is dissolved in DCM (20ml), the DCM solution (7.2mL) of the Boron tribromide of 1M is added dropwise at -10 DEG C, drop finishes, and the reaction was continued 2 hours.5mL water quenching is added to go out.Water (50mL) and DCM (80mL) extraction is added, organic phase is washed with saturated salt solution (60mL), and anhydrous sodium sulfate is dry, concentration, residue obtains title compound 90mg, yield 11.7% through column chromatography (PE: EA=10: 1).
(10) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -5- carboxylate methyl ester
By 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -5- carboxylate methyl ester (90mg, 0.28mmol), 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (145mg, 0.42mmol) and potassium carbonate (77mg, it 0.56mmol) is added in DMF (5mL), reacts 2 hours.Addition water and each 80mL extraction of ethyl acetate, organic phase are washed with saturated salt solution (60mL), and anhydrous sodium sulfate is dry, and concentration, residue obtains title compound 120mg, yield 72.7% through column chromatography (PE: EA=3: 1).
(11) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -5- carboxylic acid
By methyl 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -5- carboxylate methyl ester (120mg, it 0.2mmol) is added in THF (2mL), it is added methanol (2mL), water (2mL), a hydronium(ion) lithia (51mg, 1.2mmol) is added, is reacted 6 hours.PH to 2 is adjusted with the HCl of 1M, water (30mL) and ethyl acetate (60mL) extraction is added, organic phase is washed with saturated salt solution (30mL), anhydrous sodium sulfate is dry, concentration, residue obtains title compound 28mg, yield 23.9% through column chromatography (DCM: MeOH=20: 1).
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85LC-MS (M/e): 570.1 (M+H+)
1H-NMR (400MHz, DMSO) δ: 7.65-7.60 (m, 2H), 7.59-7.51 (m, 1H), 7.48-7.39 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d, J=1.2Hz, 1H), 7.01 (d, J=1.2Hz, 1H), 6.90-6.80 (m, 1H), 5.30-5.25 (m, 1H), 4.94 (s, 2H), 3.20-3.10 (m, 2H), 2.49-2.40 (m, 1H), 2.22-2.10 (m, 1H), 1.89-1.80 (m, 1H), 1.23-1.17 (m, 2H), 1.17-1.11 (m , 2H) and
14 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid preparation (compound 14)
(1) preparation of (E) -1- (the bromo- 2- hydroxy phenyl of 4-) -3- (2- chloro-4-hydroxyl phenyl) propyl- 2- alkene -1- ketone
Preparation method preparation in 1 step of reference implementation example (1), 1- (the bromo- 2- hydroxy phenyl of 4-) second -1- ketone (27.4g is added, 127.42mmol), 2- chloro-4-hydroxyl benzaldehyde (20g, 127.74mmol), product 36g (yield 80%) is obtained.
(2) preparation of the bromo- 2- of 7- (2- chloro-4-hydroxyl phenyl) 4-chromanone
In the four-hole boiling flask of 3L, by (E) -1- (the bromo- 2- hydroxy phenyl of 4-) -3- (2- chloro-4-hydroxyl phenyl) propyl- 2- alkene -1- ketone (36g, 101.81mmol) it is dissolved in methanol (720mL) and hydrochloric acid (12N, 720mL) in the mixed solvent is warming up to 73 DEG C and reacts 72 hours.Reaction solution is poured into stirring in 3L ice water and a large amount of precipitatings occurs, is filtered, filtration cakes torrefaction obtains product 21g (yield 58%).
(3) preparation of 4- (7- bromine chroman -2- base) -3- chlorophenol
The preparation method of 1 step of reference implementation example (3) is added the bromo- 2- of 7- (2- chloro-4-hydroxyl phenyl) 4-chromanone (21g, 59.39mmol) and obtains product 13g (yield 64%).
(4) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- formonitrile HCN
4- (7- bromine chroman -2- base) -3- chlorophenol (13g, 38.28mmol) is added in tri- mouthfuls of round-bottomed bottles of 250mL, the preparation method of 1 step of reference implementation example (4) obtains product 6.0g (yield 55%).
(5) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- methyl formate
The preparation method of 1 step of reference implementation example (5) is added 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- formonitrile HCN (6g, 21.00mmol), obtains product 2.5g (yield 37%).
(6) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylate methyl ester
The preparation method of 1 step of reference implementation example (6), 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- methyl formate (2.5g is added, 7.84mmol), 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (2.84g, 9.39mmol), product 1.2g (yield 26%) is obtained.
(7) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid
2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2 is added into 100mL there-necked flask, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylate methyl ester (1.2g, the mixed solvent of first alcohol and water 2.05mmol), it is cooled to 0 DEG C, lithium hydroxide monohydrate (260mg is added portionwise, 6.19mmol), 30 DEG C are warming up to react 2 days.PH=4 is adjusted with hydrochloric acid (1mol/L), ethyl acetate (500mL) and saturated salt solution (500mL) is added, separate organic phase saturated common salt water washing (2 × 500mL), anhydrous sodium sulfate is dry, concentration, residue through column chromatograph (petroleum ether: ethyl acetate=4: 1~1: 1) product 0.28g (yield 24%).
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85LC-MS:(ES, m/z): 570 (M+1)+
1H NMR:(300MHz, DMSO-d6, ppm): δ 12.82 (brs, 1H), 7.64-7.39 (m, 5H), 7.32-7.31 (d, J=1.2Hz, 1H), 7.26-7.23 (m, 1H), 6.70-6.69 (d, J=2.4Hz, 1H), 6.86-6.85 (m, 1H), (5.31-5.28 d, J=9.0Hz, 1H), 4.93 (s, 2H), 3.07-2.73 (m, 2H), 2.47-2.45 (m, 1H), 2.19-2.14 (m, 1H), 1.99-1.90 (m, 1H), 1.23-1.134 (m, 4H)
15 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -8- formic acid preparation (compound 15)
(1) preparation of gaultherolin
By salicylic acid (20.0g, it 0.14mol) is added in methanol (100ml), thionyl chloride (20.7g, 0.17mol) is added dropwise in batches to the system at 25 DEG C, 50 DEG C are risen to be stirred to react 12 hours, reaction solution is spin-dried for, methylene chloride (500ml) is added into the reaction system, adjusts pH value to 7 with sodium bicarbonate, separate organic phase, organic phase is dry with anhydrous sodium sulfate, is concentrated to get title compound (20.0g, yield 90.9%).
(2) 3- aldehyde radical -2 hydroxybenzoic acid methyl esters preparation
By gaultherolin (20.0g, it 0.13mol) is added in trifluoroacetic acid (200mL), methenamine (28.0g is added into this system, 0.2mol), cuprous oxide (14.8g, 0.13mol), 60 DEG C are heated to be stirred to react 24 hours, reaction solution pours into water (1000ml), is added methylene chloride (500ml), separates organic phase, rotary evaporation removes solvent, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 10) purifying obtains title compound (7.0g, yield 29.5%) to residue.
(3) preparation of diethyl (2- (2- chloro-4-methoxy phenyl) -2- oxygen ethyl) phosphonate ester
By m-chloroanisole (15.0g, 0.11mol) it is added to trifluoroacetic anhydride (115.5g, in 0.55mol), add diethyl phosphorus acetic acid (25.5g, 0.13mol), phosphoric acid (15.0g) is added dropwise at 25 DEG C, 25 DEG C are stirred to react 24 hours, reaction solution pours into ice water (500ml), is extracted with methylene chloride (500ml), separates organic phase, reaction solution is concentrated, through column chromatography, (methylene chloride: methanol=50: 1) purifying obtains title compound (18.0g, crude product) to residue.
(4) preparation of (E, Z) -3- (3- (2- chloro-4-methoxy phenyl) -3- oxo propyl- 1- alkene -1- base) -2 hydroxybenzoic acid methyl esters
By diethyl (2- (2- chloro-4-methoxy phenyl)-2- oxygen ethyl) phosphonate ester (5.9g, 18.5mmol), 3- aldehyde radical-2 hydroxybenzoic acid methyl esters (3.0g, 16.6mmol), 1,11-5- alkene (3.4g of 5- diazabicylo [5.4.0], it 22.2mmol) is added in tetrahydrofuran (50ml), it is stirred to react at 25 DEG C 24 hours, reaction solution is concentrated, through silica gel column chromatography, (ethyl acetate: petroleum ether=1: 10) purifying obtains title compound (2.0g, yield 34.7%) to residue.
(5) preparation of 3- (3- (2- chloro-4-methoxy phenyl) -3- oxopropyl) -2 hydroxybenzoic acid methyl esters
By (Z) -3- (3- (2- chloro-4-methoxy phenyl) -3- oxo propyl- 1- alkene -1- base) -2 hydroxybenzoic acid methyl esters (1.0g, 2.9mmol), it is added in tetrahydrofuran (20ml), it is replaced 3 times with hydrogen, hydrogenation reaction 12 hours at 25 DEG C, reaction solution filtering, filtrate concentration, obtain title compound (900mg, yield 90%).
(6) preparation of 3- (3- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -2 hydroxybenzoic acid methyl esters
By 3- (3- (2- chloro-4-methoxy phenyl) -3- oxopropyl) -2 hydroxybenzoic acid methyl esters (900mg, it 2.6mmol) is added in tetrahydrofuran (20ml), sodium borohydride (97.5mg is added, 2.6mmol), it is stirred to react at 25 DEG C 2 hours, water (50ml), ethyl acetate (30ml) is added in reaction solution, separate organic phase, it is dry with anhydrous sodium sulfate, concentration, obtain product (900mg, crude product).
(7) preparation of 2- (2- chloro-4-methoxy phenyl) benzodihydropyran -8- methyl formate
By 3- (3- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -2 hydroxybenzoic acid methyl esters (900mg, it 2.6mmol) is added in tetrahydrofuran (20ml), triphenylphosphine (1.3g is added, 5.0mmol), diethyl azodiformate (0.89g, 5.13mmol), 12 hours are stirred to react for 25 DEG C, reaction solution Concentration, column chromatography (petroleum ether: ethyl acetate=20: 1) obtain product (300mg, yield 35.0%).
(8) preparation of 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -8- methyl formate
By -8 methyl formate (300.0mg of 2- (2- chloro-4-methoxy phenyl) benzodihydropyran, it 0.9mmol) is added in methylene chloride (20ml), it is cooled to -25 DEG C, Boron tribromide (1.1g is added dropwise, 4.5mmol), reaction 1 hour, methanol (10ml) will be added dropwise in reaction solution, pH to 7 is adjusted with sodium bicarbonate aqueous solution, organic phase is separated (petroleum ether: ethyl acetate=20: 1) to obtain title compound (120mg, yield 41.8%) through column chromatography.
(9) preparation of 2- (the chloro- 4- of 2- (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- methoxyl group) phenyl) benzodihydropyran -8- methyl formate
By 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -8- methyl formate (120.0mg, 0.38mmol), 4- bromomethyl -5- cyclopropyl -3- (2, 6- dichlorophenyl) isoxazole (131.9mg, 0.38mmol), it is added to N, dinethylformamide (10ml) and cesium carbonate (245.3mg, in 0.75mmol), it is heated to 50 DEG C, reaction 1 hour, reaction solution is poured into water (50ml), it is extracted with ethyl acetate (100ml), separate organic phase, it is dry with anhydrous sodium sulfate, rotary evaporation removes solvent and obtains title compound (100mg, yield 45.5%).
(10) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -8- formic acid
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) Benzodihydropyran -8- methyl formate (100mg, 0.17mmol), lithium hydroxide (20.5mg, 0.85mmol) is added, tetrahydrofuran (1ml), water (1ml) stirs 12 hours at 25 DEG C, and ethyl acetate (100ml) is added and separates organic phase, anhydrous sodium sulfate is dry, rotary evaporation removes solvent, obtains title compound (60.8mg, yield 62.0%).
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85 LC-MS (M/e): 569.8,571.7 (M+H+)
1H NMR(CDCl3) δ: 8.05-8.06 (d, J=6.4Hz, 1H), 7.32-7.43 (m, 5H), 7.05-7.09 (m, 1H), 6.88 (s, 1H), 6.77-6.80 (m, 1H), 5.59-5.62 (d, J=10.4Hz, 1H), 4.84 (s, 2H), 2.87-3.15 (m, 2H), 2.05-2.17 (m, 3H), 1.16-1.33 (m, 5H).
16 3- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid preparation (compound 16)
(1) preparation of 3- hydroxy-4-methyl ethyl benzoate
Weigh 3- hydroxy-4-methyl benzoic acid (5.0g, it 32.8mmol) is added in 100mL ethyl alcohol, the 0.5mL concentrated sulfuric acid is added dropwise, is warming up to 81 DEG C and reacts 24 hours, concentration, water and each 100mL of ethyl acetate is added, it is layered to obtain organic phase, anhydrous sodium sulfate dries, filters, filtrate is concentrated to give product (5.17g, yield 87.5%).
(2) preparation of 1- (bromomethyl) -2- chloro-4-methoxy benzene
By 2- chloro-4-methoxy -1- methylbenzene (4.46g, it 28.5mmol) is added in 60mL carbon tetrachloride, NBS (5.06g, 28.4mmol) and AIBN (468mg, 2.85mmol) is added, 80 DEG C are warming up to react 2.0 hours, 25 DEG C are cooled to, is filtered, filtrate concentration, residue obtains product (5.52g, yield 82.3%) through column chromatography (PE: EA=10: 1).
(3) preparation of 2- (2- chloro-4-methoxy phenyl) acetonitrile
1- (bromomethyl) -2- chloro-4-methoxy benzene (5.52g, 23.4mmol) and potassium carbonate (6.46g, 46.8mmol) are added in 100mL acetonitrile, TMSCN (2.78g, 28.0mmol) is added with stirring.It is warming up to 60 DEG C to react 8.0 hours, TLC detects fully reacting, concentration, water (100mL) and ethyl acetate (150mL) is added, is layered to obtain organic phase, is concentrated, residue obtains product (4.1g, yield 96.5%) through column chromatography (PE: EA=5: 1).
(4) preparation of 3- (methoxymethoxy) -4- methylbenzoic acid ethyl ester
By 3- hydroxy-4-methyl ethyl benzoate (5.17g, 28.7mmol) it is dissolved in DCM (100mL), it is cooled to 0 DEG C, DIPEA (8.14g is added, 63.1mmol) with chloromethyl methyl ether (4.62g, 57.4mmol), it is warming up to 25 DEG C and reacts 24 hours, TLC detects fully reacting, concentration is added water and each 150mL of ethyl acetate, is layered to obtain ethyl acetate phase, EA phase is washed with water, saturated sodium-chloride water solution is washed, and anhydrous sodium sulfate dries, filters, filtrate is concentrated to give product (5.8g, yield 90.1%).
(5) preparation of 2- (2- chloro-4-methoxy phenyl) acetic acid
By 2- (2- chloro-4-methoxy phenyl) acetonitrile (4.1g, 22.6mmol) it is added to the in the mixed solvent of HAc (60mL) and water (60mL), stirring is lower to be added dropwise the concentrated sulfuric acid (20mL), 100 DEG C are warming up to react 8.0 hours, reaction solution is poured into ice water, white precipitate occurs in stirring, filters, filtration cakes torrefaction obtains product (3.84g, yield 84.8%).
(6) preparation of 2- (2- chloro-4-methoxy phenyl) ethyl acetate
By 2- (2- chloro-4-methoxy phenyl) acetic acid (3.84g, 19.1mmol) and ethyl alcohol (2.64g, it 57.4mmol) is added in 60mL methylene chloride, triethylamine (1.93g is added, 19.1mmol) and EDCi (3.67g, 19.1mmol), it is added with stirring DMAP (93mg, 0.76mmol), 25 DEG C are reacted 4.0 hours, TLC detects fully reacting, concentration, adds water and each 100mL of ethyl acetate, is layered to obtain ethyl acetate phase, ethyl acetate phase is washed with 1N HCl (50mL), and saturated sodium-chloride is water-soluble Liquid is washed, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give product (4.1g, yield 93.8%).
(7) preparation of 4- (bromomethyl) -3- (methoxymethoxy) ethyl benzoate
By 3- (methoxymethoxy) -4- methylbenzoic acid ethyl ester (2.24g, it 10mmol) is added in 40mL carbon tetrachloride, NBS (1.78g, 10mmol) and AIBN (164mg, 1.0mmol) is added, 80 DEG C are warming up to react 2.0 hours, 25 DEG C are cooled to, is filtered, filtrate concentration, residue obtains product (2.7g, yield 89.1%) through column chromatography (PE: EA=5: 1).
(8) preparation of 4- (2- (the chloro- 4- aminomethyl phenyl of 2-) -3- ethyoxyl -3- oxopropyl) -3- (methoxymethoxy) ethyl benzoate
By 2- (2- chloro-4-methoxy phenyl) ethyl acetate (1.1g, it 4.81mmol) is dissolved in 20mL tetrahydrofuran, it is cooled to 0 DEG C, NaHMDS (2.0M is added, 4.8mL, 9.6mmol), 4- (bromomethyl) -3- (methoxymethoxy) ethyl benzoate (1.46g is added after stirring 1.0 hours at 0 DEG C, 4.82mmol), 25 DEG C are warming up to react 18 hours, water (50mL) and EA (100mL) is added, it is layered to obtain EA phase, concentration, residue obtain product (1.5g, yield 69.1%) through column chromatography (PE: EA=2: 1).
(9) preparation of 4- (2- (2- chloro-4-methoxy phenyl) -3- ethyoxyl -3- oxopropyl) -3- nipagin A
By 4- (2- (the chloro- 4- aminomethyl phenyl of 2-) -3- ethyoxyl -3- oxopropyl) -3- (methoxymethoxy) ethyl benzoate (1.5g, 3.33mmol) it is added to 10mL TFA and DCM (20mL) in the mixed solvent, it is reacted 4.0 hours at 25 DEG C, LC-MS detects fully reacting, concentration, residue obtains product (620mg, yield 45.9%) through column chromatography (PE: DCM=1: 3).
(10) 4- (2- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -3- nipagin A Preparation
By 4- (2- (2- chloro-4-methoxy phenyl) -3- ethyoxyl -3- oxopropyl) -3- nipagin A (620mg, it 1.52mmol) is added in 20mL tetrahydrofuran, it is cooled to 0 DEG C, is slowly added to Lithium Aluminium Hydride (58mg, 1.53mmol).1ml water quenching reaction is added after 0 DEG C of reaction 40min, filters, filtrate concentration, residue obtains product (130mg, yield 23.5%) through column chromatography (EA: DCM=1: 4).
(11) preparation of 3- (2- chloro-4-methoxy phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester
By 4- (2- (2- chloro-4-methoxy phenyl) -3- hydroxypropyl) -3- nipagin A (130mg, it 0.36mmol) is added in 20mL tetrahydrofuran, it is cooled to 0 DEG C, triphenylphosphine (283mg is added, 1.08mmol) and DEAD (188mg, 1.08mmol), it is reacted 18 hours at 25 DEG C, LC-MS detects fully reacting, concentration, residue obtains product (120mg, yield 96.0%) through column chromatography (PE: EA=25: 1).
(12) preparation of 3- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester
3- (2- chloro-4-methoxy phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester (120mg, 0.35mmol) is added in 5mL DCM, is cooled to 0 DEG C, 1M BBr is added3Dichloromethane solution (1.4mL, 1.4mmol), be warming up to 10 DEG C react 1.5 hours, LC-MS detects fully reacting, and 1mL methanol, concentration is added, residue obtains product (100mg, yield 85.8%) through column chromatography (PE: EA=9: 1).
(13) preparation of 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester
By 3- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester (100mg, 0.30mmol) and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (114mg, it 0.33mmol) is added in 10mL DMF, it is added with stirring potassium carbonate (83mg, 0.60mmol), 50 DEG C are warming up to react 2.0 hours, LC-MS detection has product generation, is cooled to 25 DEG C, and 30mL water is added, ultrasound precipitates, it filters, filtration cakes torrefaction obtains product (130mg, yield 72.2%).
(14) preparation of 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid
By 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -7- carboxylic acid, ethyl ester (130mg, 0.22mmol) it is dissolved in THF (4mL), the in the mixed solvent of MeOH (2mL) and water (1mL), a hydronium(ion) lithia (37mg is added at 25 DEG C, 0.88mmol), reaction 18 hours, LC-MS detects fully reacting, ethyl acetate (50mL) and water (50mL) is added, it is layered to obtain ethyl acetate phase, concentration, residue obtains product (80mg through silica gel column chromatography (DCM: MeOH=10: 1), yield 63.7%).
Molecular formula: C29H22Cl3NO5Molecular weight: 570.85 LC-MS (M/e): 570.1 (M+H+)
1H-NMR (400MHz, MeOD) δ: 7.52-7.42 (m, 5H), 7.20 (d, J=8.0Hz, 1H), 7.13 (d, J=8.8Hz, 1H), 6.86 (d, J=2.8Hz, 1H), 6.72 (dd, J1=2.8Hz, J2=8.8HZ, 1H), 4.90 (s, 2H), 4.30 (dd, J1=3.2Hz, J2=10.4HZ, 1H), 4.06 (t, 1H), 3.63-3.61 (m, 1H), 3.05 (d, J=7.6Hz, 2H), 2.34-2.30 (m, 1H), 1.21-1.19 (m, 4H).
17 2- of embodiment (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy Base) phenyl) benzodihydropyran -6- formic acid preparation (compound 17)
(1) preparation of 4- hydroxyl -3- iodo-benzoic acid methyl esters
4-HBA methyl esters (3.55g, 23.3mmol) is dissolved in acetic acid (20mL), acetic acid (5mL) solution of lodine chloride (3.78g, 23.3mmol) is added dropwise to, is heated to 65 DEG C and is stirred to react 16 hours.Reaction solution is filtered, filter cake is washed with water (20mL), is drying to obtain title compound (4.0g, yield 61.7%).
(2) preparation of 1- (4- methoxyphenyl) ethane -1- ketone
By 1- (4- hydroxy phenyl) ethane -1- ketone (5g, it 36.8mmol) is dissolved in acetonitrile (50mL), potassium carbonate (10g is added, 72.3mmol), it is cooled to 0 DEG C, it is added iodomethane (6.3g, 44.4mmol), is warming up to 25 DEG C and is stirred to react 3 hours.Reaction solution is filtered, filtrate is concentrated up to title compound (5.2g, yield 94.5%).
(3) preparation of 1- (4- methoxyphenyl) -2- acrylic -1- ketone
By 1- (4- methoxyphenyl) ethane -1- ketone (5g, 33.3mmol), N- methyl trifluoro aniline acetate (11g, 49.7mmol) and paraformaldehyde (10g, it 333.3mmol) adds in tetrahydrofuran (100mL), is heated to 80 DEG C and is stirred to react 24 hours.Reaction solution is filtered, ethyl acetate (100mL) and water (150mL), liquid separation are added in filtrate, organic phase is dry with anhydrous sodium sulfate, filtering, filtrate are concentrated up to crude title compound (3.9g), are directly used in and react in next step.
(4) methyl 4- hydroxyl -3- (3- (4- methoxyphenyl) -3- oxopropyl -1- alkene -1- base) benzene first The preparation of acid esters
By 1- (4- methoxyphenyl) -2- acrylic -1- ketone (3.5g, crude product), 4- hydroxyl -3- iodo-benzoic acid methyl esters (6g, 21.6mmol), triethylamine (7g, 69.2mmol), triphenylphosphine (0.3g, 1.14mmol), acid chloride (0.4g, it 1.78mmol) adds in acetonitrile (100mL), is heated to 90 DEG C and is stirred to react 16 hours.Reaction solution is concentrated, gained crude product (petroleum ether: ethyl acetate=5: 1) is purified with silica gel column chromatography up to title compound (0.9g, two step yields 8.6%).
(5) preparation of methyl 4- hydroxyl -3- (3- (4- methoxyphenyl) -3- oxopropyl) benzoic ether
By methyl 4- hydroxyl -3- (3- (4- methoxyphenyl) -3- oxopropyl -1- alkene -1- base) benzoic ether (0.9g, it 2.88mmol) is dissolved in methanol (10mL), it is added palladium carbon (0.1g), is stirred to react 16 hours under 25 DEG C of pressurized with hydrogen.Reaction solution is filtered, filtrate is concentrated up to title compound (0.85g, yield 94.4%).
(6) preparation of methyl 4- hydroxyl -3- (3- hydroxyl -3- (4- methoxyphenyl) propyl) benzoic ether
By methyl 4- hydroxyl -3- (3- (4- methoxyphenyl) -3- oxopropyl) benzoic ether (0.85g, it 2.7mmol) is dissolved in dehydrated alcohol (10mL), it is added sodium borohydride (0.2g, 5.3mmol), 25 DEG C are stirred to react 16 hours.Dilute hydrochloric acid (20mL is added, 1M) quenching reaction, it is extracted with ethyl acetate (30mL × 3), merge organic phase, it is dried, filtered with anhydrous sodium sulfate, filtrate concentration, gained crude product (petroleum ether: ethyl acetate=2: 1) purifies to obtain title compound (0.5g, yield 58.1%) with silica gel column chromatography.
(7) preparation of methyl 2- (4- methoxyphenyl) benzodihydropyran -6- formic acid esters
By methyl 4- hydroxyl -3- (3- hydroxyl -3- (4- methoxyphenyl) propyl) benzoic ether (0.5g; 1.58mmol) and triphenylphosphine (0.5g; it 1.91mmol) is dissolved in tetrahydrofuran (10mL); it is cooled to 0 DEG C; diethyl azodiformate (0.4g is added; 2.3mmol), it is stirred to react 16 hours for lower 25 DEG C of nitrogen protection.Water (20mL) and ethyl acetate (20mL) liquid separation is added, water phase is extracted with ethyl acetate (30mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, filtering, filtrate concentration, gained crude product (petroleum ether: ethyl acetate=20: 1) are purified with silica gel column chromatography up to title compound (0.37g, yield 78.7%).
(8) preparation of 2- (4- hydroxy phenyl) benzodihydropyran -6- formic acid
By methyl 2- (4- methoxyphenyl) benzodihydropyran -6- formic acid esters (0.37g, it 1.24mmol) is dissolved in methylene chloride (10mL), it is cooled to -60 DEG C, Boron tribromide (0.93g is added, 3.71mmol), 25 DEG C are warming up to be stirred to react 6 hours.Reaction solution is quenched with water (20mL), ethyl acetate (30mL × 3) extraction is added, merges organic phase, is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated up to title compound (0.3g, yield 89.5%).
(9) preparation of methyl 2- (4- hydroxy phenyl) benzodihydropyran -6- formic acid esters
By 2- (4- hydroxy phenyl) benzodihydropyran -6- formic acid (0.3g, it 1.11mmol) is dissolved in anhydrous methanol (10mL), it is added dropwise to thionyl chloride (0.13g, 1.1mmol), 60 DEG C is heated to and is stirred to react 16 hours.Reaction solution is concentrated, it is added ethyl acetate (50mL), it is washed with saturated sodium bicarbonate aqueous solution (20mL), it is dry that anhydrous sodium sulfate is added, filtering, filtrate concentration, gained crude product silica gel column chromatography purify (petroleum ether: ethyl acetate=5: 1) to obtain the final product title compound (0.2g, yield 63.4%).
(10) preparation of methyl 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formic acid esters
By methyl 2- (4- hydroxy phenyl) benzodihydropyran -6- formic acid esters (0.15g, 0.53mmol) and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (0.2g, it 0.58mmol) is dissolved in acetonitrile (10mL), potassium carbonate (0.15g is added, 1.1mmol), 80 DEG C are heated to be stirred to react 6 hours.Reaction solution is concentrated, gained crude product silica gel column chromatography purifies (petroleum ether: ethyl acetate=1: 1) up to title compound (0.1g, yield 34.5%).
(11) preparation of 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formic acid
By methyl 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formic acid esters (0.1g, it 0.18mmol) is dissolved in tetrahydrofuran (3mL) and methanol (3mL), a hydronium(ion) lithia (15mg is added, 0.36mmol) water (1mL) solution, 25 DEG C are stirred to react 16 hours.Reaction solution is concentrated, gained crude product (methylene chloride: methanol=20: 1) is purified with silica gel column chromatography up to title compound (50mg, yield 51.5%).
Molecular formula: C29H23Cl2NO5Molecular weight: 536.41 LC-MS (M/e): 536.2 (M+H+)
1H-NMR (400MHz, DMSO) δ: 7.71 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 7.61 (d, J=8Hz, 2H), 7.53-7.58 (m, 1H), 7.27 (d, J=8.8Hz, 2H), 6.80-6.85 (m, 3H), 5.08 (d, J=10Hz, 1H), 4.86 (s, 1H), 2.91-3.00 (m, 1H), 2.73-2.80 (m, 1H), 2.42-2.50 (m, 1H), 2.08-2.15 (m, 1H), 1.95-2.02 (m, 1H), 1.10-1.23 (m, 4H)
18 2- of embodiment (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy Base) pyridin-3-yl) benzodihydropyran -6- formic acid preparation (compound 18)
(1) preparation of 1- (6- (benzyl oxygroup) pyridin-3-yl) ethyl ketone
By 1- (6- pyridone -3- base) ethyl ketone (3.0g, it 21.9mmol) is dissolved in toluene (30mL), is added silver carbonate (9.1g, 33.3mmol), cylite (3.8g is slowly added dropwise, 22.2mmol), it is added dropwise, is warming up to 100 DEG C, it is stirred to react 12 hours, reaction solution is filtered, filtrate is concentrated to give title compound (3.9g, yield 78.3%).
(2) preparation of 1- (6- (benzyl oxygroup) pyridin-3-yl) propyl- 2- alkene -1- ketone
By 1- (6- (benzyl oxygroup) pyridin-3-yl) ethyl ketone (3.8g, 16.7mmol), N- methyl trifluoro aniline acetate (5.5g, 24.9mmol) and paraformaldehyde (5.0g, it 166.7mmol) adds in tetrahydrofuran (50mL), is warming up to 80 DEG C and is stirred to react 24 hours.Reaction solution is filtered, ethyl acetate (100mL) and water (150mL) are added in filtrate, liquid separation is concentrated after organic phase anhydrous sodium sulfate drying, obtains crude title compound (2.0g), be directly used in and react in next step.
(3) preparation of (E) -3- (3- (6- (benzyl oxygroup) pyridin-3-yl) -3- oxo propyl- 1- alkene -1- base) -4-HBA methyl esters
By 1- (6- (benzyl oxygroup) pyridin-3-yl) propyl- 2- alkene -1- ketone crude product (2.0g), 4- hydroxyl -3- iodine Methyl benzoate (2.3g, 8.4mmol), triethylamine (2.6g, 25.7mmol), triphenylphosphine (100mg, 0.38mmol), acid chloride (128mg, it 0.57mmol) adds in acetonitrile (30mL), is warming up to 90 DEG C and is stirred to react 12 hours.Reaction solution is concentrated, through silica gel column chromatography, (petroleum ether: ethyl acetate=5: 1) purifying obtains title compound (0.5g, two step yields 7.7%).
(4) preparation of 4- hydroxyl -3- (3- (6- pyridone -3- base) -3- oxopropyl) methyl benzoate
By (E) -3- (3- (6- (benzyl oxygroup) pyridin-3-yl) -3- oxo propyl- 1- alkene -1- base) -4- hydroxy benzenes (0.5g, it 1.3mmol) is dissolved in methanol (5mL), it is added palladium carbon 10% (50mg), is stirred to react 12 hours under 25 DEG C of pressurized with hydrogen.Filtering, filtrate are concentrated to give product (0.3g, yield 77.5%).
(5) preparation of 4- hydroxyl -3- (3- hydroxyl -3- (6- pyridone -3- base) propyl) methyl benzoate
By 4- hydroxyl -3- (3- (6- pyridone -3- base) -3- oxopropyl) methyl benzoate (0.3g, it 1.0mmol) is dissolved in anhydrous methanol (5mL), sodium borohydride (115mg is added, 3.0mmol), after 25 DEG C are stirred to react 1 hour, it is cooled to 0 DEG C of addition dilute hydrochloric acid (1M) and adjusts pH=7, it is extracted with ethyl acetate (20mL × 3), merge organic phase, it is dry with anhydrous sodium sulfate, concentration, through silica gel column chromatography (methylene chloride: methanol=10: 1) title compound (290mg, yield 96.7%).
(6) preparation of 2- (6- pyridone -3- base) benzodihydropyran -6- methyl formate
By 4- hydroxyl -3- (3- hydroxyl -3- (6- pyridone -3- base) propyl) methyl benzoate (290mg; 0.96mmol) and triphenylphosphine (0.76g; it 2.9mmol) is dissolved in tetrahydrofuran (10mL); it is cooled to 0 DEG C; diethyl azodiformate (0.5g is added; 2.9mmol), it is stirred to react 12 hours for lower 25 DEG C of nitrogen protection.Water (10mL) and ethyl acetate (20mL) liquid separation is added, water phase is extracted with ethyl acetate (20mL × 3), merges organic phase, concentration dry with anhydrous sodium sulfate, crude product warp Silica gel column chromatography (methylene chloride: methanol=40: 1) obtains title compound (112mg, yield 41.0%).
(7) preparation of 2- (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) pyridin-3-yl) benzodihydropyran -6- methyl formate
By 2- (6- pyridone -3- base) benzodihydropyran -6- methyl formate (100mg, 0.35mmol), 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (122mg, 0.35mmol), silver carbonate (193mg, 0.7mmol), it is dissolved in toluene (5mL), 100 DEG C are warming up to, is stirred to react 12 hours, reaction solution is filtered, crude product through silica gel column chromatography (petroleum ether: ethyl acetate=3: 1) title compound (127mg, yield 65.8%).
(8) preparation of 2- (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) pyridin-3-yl) benzodihydropyran -6- formic acid
By 2- (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) pyridin-3-yl) benzodihydropyran -6- methyl formate (120mg, it 0.22mmol) is dissolved in tetrahydrofuran (3mL) and methanol (3mL), a hydronium(ion) lithia (47mg is added, aqueous solution (1mL) 1.1mmol), 25 DEG C are stirred to react 16 hours.Dilute hydrochloric acid (1M) is added and adjusts pH=7, reaction solution is concentrated, (methylene chloride: methanol=20: 1), obtains title compound (40mg, yield 33.8%) through silica gel column chromatography.
Molecular formula: C28H22C12N2O5Molecular weight: 537.39 LC-MS (M/e): 537.1 (M+H+)
1H-NMR (400MHz, CDCl3) δ: 8.08 (s, 1H), 7.89 (d, J=7.2Hz, 2H), 7.61 (dd, J1=8.8Hz, J2=6.4Hz, 1H), 7.38-7.41 (m, 2H), 7.28-7.34 (m, 1H), 6.91 (d, J=8.8Hz, 1H), 6.67 (d, J=8.8Hz, 1H), 5.31 (s, 2H), 5.09 (dd, J1=10.0Hz, J2=2.0Hz, 1H), 3.01-3.04 (m, 1H), 2.86-2.90 (m, 1H), 2.32-2.36 (m, 1H), 2.20-2.25 (m, 1H), 2.09-2.12 (m, 1H), 1.28-1.31 (m, 2H), 1.13-1.18 (m, 2H)
(2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) of embodiment 19 Methoxyl group) phenyl) benzodihydropyran -6- base) and methanol preparation (compound 19)
By 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2; 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid (220mg; it 0.39mmol) is added in 50mL three neck round bottom flask; 20mL tetrahydrofuran is dissolved under nitrogen protection; it is cooled to 0 DEG C, rises to 25 DEG C of stirrings 1.0 hours after borine (THF solution of 1mol/L) (1.94mL) is added dropwise.Reaction solution is cooled to 0 DEG C, hydrochloric acid (2N) quenching reaction is added.The dilution of 100mL ethyl acetate is added, saturated common salt water washing (2 × 30mL) is layered to obtain ethyl acetate phase, and anhydrous sodium sulfate is dry, and concentration, high pressure preparative separation obtains product (203mg, yield 93.5%).
Molecular formula: C29H24Cl3NO4Molecular weight: 556.86 LC-MS:(ES, m/z): 578 (M+Na)
1H NMR:(CD3OD, ppm) δ: 7.38-7.54 (m, 4H), 7.09-7.11 (m, 2H), 6.77-6.85 (m, 3H), 5.27-5.31 (dd, J1=2.1Hz, J2=10.2Hz, 1H), 4.93 (s, 2H), 4.51 (s, 2H), 2.76-3.00 (m, 2H), 2.21-2.37 (m, 2H), 1.86-1.89 (m, 1H), 1.20-1.23 (m, 4H)
20 2- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl)-N- (methyl sulphonyl) benzodihydropyran -6- formamide preparation (compound 20)
2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2 is added in the there-necked flask of a 100-mL, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl)-benzodihydropyran -6- formic acid (200mg, 0.35mmol), it is dissolved in methylene chloride (50mL), EDCI (134mg is added, 0.70mmol), 4- bis- Dimethylaminopyridine (128mg, 1.05mmol), Methanesulfomide (66.5mg, 0.70mmol).It is stirred overnight at room temperature under nitrogen protection.Methylene chloride (100mL) is added in reaction mixture, and saturated salt solution (3 × 50mL) washing is then added, separates organic layer, dry with anhydrous sodium sulfate, and concentration obtains product 168mg, yield 74% through column chromatographic purifying.
Molecular formula: C30H25Cl3N2O6S molecular weight: 647.95 LC-MS:(ES, m/z): 647 (M+1)+
1HNMR (DMSO, ppm): δ 11.89 (brs, 1H), 7.82 (s, 1H), 7.71-7.74 (dd, J1=2.1Hz, J2=8.4Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.57 (m, 1H), (7.38-7.40 d, J=8.7Hz, 1H), (6.98-6.99 d, J=2.7Hz, 1H), 6.85-6.92 (m, 1H), 6.82-6.83 (m, 1H), 5.35-5.38 (m, 1H), 4.94 (s, 2H), 3.32-3.34 (d, J=6.6Hz, 3H), 2.71-3.06 (m, 2H), 1.93-2.49 (m, 3H), (1.13-1.21 m, 4H)
21 4- of embodiment ((4- (6- (2H- tetrazolium -5- base) benzodihydropyran -2- base) -3- chlorobenzene Oxygroup) methyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole preparation (compound 21)
(1) preparation of 2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formonitrile HCN
The preparation method of 1 step of reference implementation example (6), 2- (2- chloro-4-hydroxyl phenyl) benzodihydropyran -6- formonitrile HCN (3g is added, 10.50mmol), 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (3.802g, 12.57mmol).Obtain product 2.8g, yield 48.4%.
(2) preparation of 4- ((4- (6- (2H- tetrazolium -5- base) benzodihydropyran -2- base) -3- chlorophenoxy) methyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole
2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2 is added in the round-bottomed bottle of a 50mL, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- formonitrile HCN (500mg, 0.91mmol), ammonium chloride (975mg, 18.23mmol), n,N-Dimethylformamide (15mL), NaN3(900mg, 13.84mmol).Reaction mixture is heated to 120 DEG C and reacts 12 hours, and NaHSO is added in system3(30mL) quenching reaction.Ethyl acetate (3 × 50mL) extraction is added.Merge organic phase and is concentrated to get title compound 261mg, yield 48.4%.
Molecular formula: C29H22Cl3N5O3Molecular weight: 594.88 LC-MS (ES, m/z): 594 (M+1)+
1HNMR(DMSO-d6, ppm): 7.79 (s of δ, 1H), 7.75 (d, J=8.4Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.57 (m, 1H), 7.43 (d, J=8.7Hz, 1H), 6.97 (d, J=2.4Hz, 1H), 6.82-6.88 (m, 2H), 5.32 (d, J=8.4Hz, 1H), 4.94 (s, 2H), 3.03-3.10 (m, 1H), 2.80-2.88 (m, 1H), 2.45 (d, J=3.3Hz, 1H), 2.14-2.19 (m, 1H), 1.92-2.00 (m, 1H), 1.10-1.22 (m, 4H)
22 2- of embodiment (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy Base) -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylic acid preparation (compound 23)
(1) 6- oxo -2- (trifluoromethyl) -1,6- dihydropyridine -3- Ethyl formate preparation
6- oxo -2- (trifluoromethyl)-Isosorbide-5-Nitrae, 5,6- tetrahydropyridine -3- Ethyl formates (90g, 379.5mmol), CCl are added in the there-necked flask of a 2000mL4(900mL), NBS (81.88g, 460.05mmol).Reaction mixture is warming up to 80 DEG C and reacts 24 hours, is down to room temperature, filters out solid, and filtrate is added methylene chloride (1000mL), is washed with saturated salt solution (3 × 2000mL). It is dry to separate organic layer anhydrous sodium sulfate, is concentrated under reduced pressure, residue chromatographs through column and (ethyl acetate/petroleum ether=1: 10) purifies to obtain title compound 50g, yield 56%.
(2) preparation of 6- (benzyloxy) -2- (trifluoromethyl) ethyl nicotinate
6- oxo -2- (trifluoromethyl) -1,6- dihydropyridine -3- carboxylic acid, ethyl ester (50g, 212.6mmol), toluene (500mL), Ag are added in the there-necked flask of a 1000mL2CO3(76g, 276.7mmol) and BnBr (43.7g, 255.5mmol).Reaction mixture is heated to 50 DEG C and reacts 12 hours, it is cooled to room temperature, ethyl acetate (1000mL) dilution is added, saturated salt solution (3 × 1000mL) washing, it is dry to separate organic layer anhydrous sodium sulfate, it is concentrated under reduced pressure, residue chromatographs through column and (ethyl acetate/petroleum ether=1: 20~1: 10) purifies to obtain title compound 37.5g, yield 54%.
(3) preparation of (6- (benzyloxy) -2- (trifluoromethyl) pyridin-3-yl) methanol
6- (benzyloxy) -2- (trifluoromethyl) ethyl nicotinate (30g is added in the there-necked flask of a 2000mL; tetrahydrofuran (300mL) solution 92.23mmol); under nitrogen protection; temperature is down to -78 DEG C; then DIBAL-H (1M in toluene is added dropwise; 277mL), it is added dropwise and continues to keep -78 DEG C of stirrings 3 hours.Methanol (140mL) quenching reaction is added dropwise, it is warming up to room temperature reaction 5 minutes, is added dropwise potassium sodium tartrate (280mL aqueous solution), filters out solid, ethyl acetate (2000mL) dilution is added in filtrate, and saturated salt solution (3 × 2000mL) washing is added.It is dry to separate organic layer anhydrous sodium sulfate, is concentrated under reduced pressure, residue chromatographs through column and (ethyl acetate/petroleum ether=1: 6~1: 4) purifies to obtain title compound 24g, yield 92%.
(4) preparation of 6- (benzyloxy) -2- (trifluoromethyl) cigarette aldehyde
Methylene chloride (500mL) solution of (6- (benzyloxy) -2- (trifluoromethyl) pyridin-3-yl) methanol (24g, 84.73mmol) is added in the there-necked flask of a 1000mL.Temperature is down to 0 DEG C, and Dess-Martin periodinane (43.1g, 101.6mmol) is added portionwise.Reaction mixture is stirred at room temperature 18 hours.Solid is filtered out, methylene chloride (500mL) dilution is added in filtrate, and saturation food is added Salt water (3 × 1000mL) washing.It is dry to separate organic layer anhydrous sodium sulfate, is concentrated under reduced pressure, residue chromatographs through column and (ethyl acetate/petroleum ether=1: 8~1: 6) purifies to obtain product 23g, yield 97%.
(5) preparation of (E) -3- (6- (benzyloxy) -2- (trifluoromethyl) pyridin-3-yl) -1- (the bromo- 2- hydroxy phenyl of 5-) propyl- 2- alkene -1- ketone
6- (benzyloxy) -2- (trifluoromethyl) cigarette aldehyde (23g is added in the there-necked flask of a 2000mL, ethanol solution (460mL) and 1- (the bromo- 2- hydroxy phenyl of 5-) second -1- ketone (17.5g, 81.38mmol) 81.78mmol).Then be added portionwise KOH (32.1g, 572.2mmol) solution, 60 DEG C heating stirring 48 hours, ice/water (1000mL) quenching reaction is added in reaction solution.It is 7 with the pH value that hydrochloric acid (6mol/L) adjusts solution.The solid was filtered, is dried under reduced pressure to obtain 36g product, yield 92%.
(6) preparation of the bromo- 2- of 6- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) 4-chromanone
(E) -3- (6- (benzyloxy) -2- (trifluoromethyl) pyridin-3-yl) -1- (the bromo- 2- hydroxy phenyl of 5-) propyl- 2- alkene -1- ketone (36g is added in the there-necked flask of a 2000mL, 75.27mmol), acetic acid (360mL), hydrochloric acid (12N, 360mL), sulfuric acid (1mL).88 DEG C of reaction solution are reacted 16 hours, are cooled to room temperature, are poured into ice water (2000mL), are filtered, are obtained solid, decompression drying obtains 23.6g title compound, yield 81%.
(7) preparation of 5- (6- bromine chromene -2- base) -6- (trifluoromethyl) pyridine -2- alcohol
HgCl is added in the there-necked flask of a 250-mL2(6.96g) and hydrochloric acid (5N) (150 ML), then temperature is down to 0 DEG C, and Zn (16.4g) is added portionwise.System is stirred at room temperature 30 minutes, divide and goes liquid phase, hydrochloric acid (5N is added in solid under to She, 100mL), be stirred at room temperature 10 minutes, point go liquid phase, to She under solid hydrochloric acid (5N is added, 150mL) and toluene (100mL) solution of the bromo- 2- of 6- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) 4-chromanone (6.6g, 17.00mmol).80 DEG C of reaction mixture are stirred 16 hours, cooling, are added ethyl acetate (500mL), and organic layer is washed with saturated salt solution (3 × 500mL).Organic phase is separated, anhydrous sodium sulfate drying is added, is concentrated under reduced pressure, residue is chromatographed through column and (ethyl acetate/petroleum ether=1: 10~1: 5) purified, isolated 3g product, yield 47%.
(8) preparation of 2- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- formonitrile HCN
5- (6- bromine benzodihydropyran -2- base) -6- (trifluoromethyl) pyridine -2- alcohol (3g, 8.02mmol), NMP (30mL), ZnCN are added in the there-necked flask of a 100mL2(1.12g, 9.5mmol), Pd (PPh3)4(930mg, 0.81mmol).Under nitrogen protection, it reacts 16 hours for 120 DEG C.Reaction solution is cooled to room temperature, ethyl acetate (200mL) dilution is added, filter out solid, filtrate is washed with saturated salt solution (3 × 200mL), organic phase is separated, anhydrous sodium sulfate drying is added, is concentrated under reduced pressure, residue (ethyl acetate/petroleum ether=1: 10~1: 6) obtains 1.7g product, yield 66% through column chromatographic purifying.
(9) preparation of 2- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylate methyl ester
2- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- formonitrile HCN (1.7g is added in the there-necked flask of a 100mL, 5.31mmol), methanol (30mL), then the concentrated sulfuric acid (3mL) is added dropwise in room temperature.Reaction solution is heated to reflux three days, is cooled to room temperature, is poured into ice water (200mL), is collected solid, is washed, solid decompression drying with water (3 × 50mL), obtain title compound 1.3g, yield 69%.
(10) preparation of 2- (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylate methyl ester
The n,N-Dimethylformamide (30mL) of 2- (6- hydroxyl -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylate methyl ester (1.3g, 3.68mmol), K are added in the there-necked flask of a 100mL2CO3(2.55g, 18.45mmol), NaI (1.66g, 11.07mmol), 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl 1)-isoxazole (1.33g, 4.40mmol).60 DEG C of reaction solution are reacted 16 hours, and room temperature is cooled to, and ethyl acetate (200mL) dilution is added, is washed with saturated salt solution (3 × 200mL).Organic phase is separated, anhydrous sodium sulfate drying is added, is concentrated under reduced pressure to give 0.7g product, yield 31%.
(11) preparation of 2- (6- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylic acid
2- (6- ((5- cyclopropyl -3- (2 is added in the there-necked flask of a 250mL, 6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) pyridin-3-yl) benzodihydropyran -6- carboxylate methyl ester (700mg, methanol (100mL) solution 1.13mmol), water (10mL) and LiOH.H2O (143mg, 3.40mmol).Reaction solution is stirred at room temperature 3 days.It is concentrated under reduced pressure, ice water (100mL) is added in residue, adjusts pH to 7 with hydrochloric acid (1mol/L).The solid was filtered, and solid water (3 × 100mL) and n-hexane (3 × 100mL) wash to obtain 210mg title compound, yield 31%.
Molecular formula: C29H21Cl2F3N2O5Molecular weight: 605.39LC-MS:(ES, m/z): 605.1 (M+1)+
1HNMR (300MHz, DMSO-d6, ppm): δ 12.60 (brs, 1H), (8.08-8.05 d, J=9.0Hz, 1H), 7.77 (s, 1H), 7.71-7.68 (m, 1H), 7.57-7.46 (m, 3H), (7.00-6.98 d, J=8.7Hz, 1H), (6.90-6.87 d, J=8.7Hz, 1H), 5.40-5.27 (m, 3H), 3.11-3.00 (m, 1H), 2.90-2.85 (m, 1H), 2.57-2.55 (m, 1H), 2.09-2.00 (m, 2H), 1.23-1.14 (m, 4H)
23 2- of embodiment (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy Base) -2- fluorophenyl) benzodihydropyran -6- formic acid preparation (compound 24)
(1) preparation of 1- (the fluoro- 4- methoxyphenyl of 2-) propyl- 2- alkene -1- ketone
Preparation method in 17 step of reference implementation example (3) is added 1- (the fluoro- 4- methoxyphenyl of 2-) second -1- ketone (1.7g, 10.1mmol), obtains product 2.0g (crude product).
(2) preparation of (E) -3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- oxo propyl- 1- alkene -1- base) -4-HBA methyl esters
Preparation method in 17 step of reference implementation example (4) obtains product (0.9g, two step yields 27.0%).
(3) preparation of 3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- oxopropyl) -4-HBA methyl esters
The preparation method of 17 step of reference implementation example (5), (E) -3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- oxo propyl- 1- alkene -1- base) -4-HBA methyl esters (0.83g is added, 2.51mmol), obtain product 0.8g, yield 95.8%.
(4) preparation of 3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- hydroxypropyl) -4-HBA methyl esters
3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- oxopropyl) -4-HBA methyl esters (800mg, 2.41mmol) is dissolved in methanol (20mL), is down to 0 DEG C, NaBH is then added4(146mg, 3.86mmol), 0 DEG C is reacted 2 hours.Reaction solution is poured into water (50mL), is extracted with ethyl acetate (100mL × 3), organic layer is merged, anhydrous sodium sulfate dries, filters, and is concentrated, obtains product 1.1g (crude product).
(5) preparation of 2- (the fluoro- 4- methoxyphenyl of 2-) benzodihydropyran -6- methyl formate
3- (3- (the fluoro- 4- methoxyphenyl of 2-) -3- hydroxypropyl) -4-HBA methyl esters (1.1g, crude product) is added in phosphoric acid (10mL), 90 DEG C is heated to and reacts 30 minutes.It is subsequently poured into water (50mL), neutrality is neutralized to sodium carbonate, then it is extracted with ethyl acetate (100mL × 3), merge organic layer, concentration, residue (petroleum ether: ethyl acetate=10: 1) obtains product 700mg, two step yields 91.9% through silica gel column chromatography.
(6) preparation of 2- (the fluoro- 4- hydroxy phenyl of 2-) benzodihydropyran -6- methyl formate
2- (the fluoro- 4- methoxyphenyl of 2-) benzodihydropyran -6- methyl formate (700mg, 2.21mmol) is dissolved in DCM (30mL), is down to -20 DEG C, N2BBr is slowly added under protection3(2.7g, 10.77mmol) reacts 4 hours.After completion of the reaction, it is slowly added to water (20mL), then is extracted with DCM (50mL × 3), merge organic layer, concentration, residue (petroleum ether: ethyl acetate=3: 1) obtains product 350mg, yield 52.3% through silica gel column chromatography.
(7) preparation of 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- fluorophenyl) benzodihydropyran -6- methyl formate
By 2- (the fluoro- 4- hydroxy phenyl of 2-) benzodihydropyran -6- methyl formate (0.3g, 0.99mmol) and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (0.35g, 1.0mmol) and carbon Sour potassium (0.28g, it 2.02mmol) is added sequentially in DMF (20mL), 60 DEG C are heated to react 4.6 hours, it is subsequently poured into water (100mL), solid is precipitated, filtering, filter cake through silica gel column chromatography (petroleum ether: ethyl acetate=10: 1) product 0.43g, yield 76.2%.
(8) preparation of 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- fluorophenyl) benzodihydropyran -6- formic acid
By 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- fluorophenyl) benzodihydropyran -6- methyl formate (0.3g, it 0.528mmol) is dissolved in THF (10mL), add water (10mL) and lithium hydroxide monohydrate (110mg, 2.62mmol), 50 DEG C are heated to stir 24 hours.THF is boiled off, (10mL) is added water, is down to 0 DEG C, adjusts pH=2-3 with dilute hydrochloric acid (1M), solid, filtering is precipitated, filter cake successively uses water (20mL), acetonitrile (20mL) washing, dry product (200mg, yield 68.4%).
Molecular formula: C29H22Cl2FNO5Molecular weight: 554.40 LC-MS (M/e): 555.2 (M+)
1H-NMR (400MHz, DMSO) δ: 12.55 (s, 1H), 7.73 (s, 1H), 7.67 (d, J=8.4Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.55 (m, 1H), 7.34 (t, J=8.4Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.76 (d, J=10.8Hz, 1H), 6.68 (d, J=8.4Hz, 1H), 5.29 (d, J=10.0Hz, 1H), 4.86 (s, 2H), 2.96-3.05 (m, 1H), 2.78-2.82 (m, 1H), (2.33-2.42 m 1H), 1.95-2 .10 (m 1H), 1.11-1.21 (m, 4H).
24 2- of embodiment (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy Base) -2- (trifluoromethyl) phenyl) benzodihydropyran -6- formic acid preparation (compound 26)
(1) preparation of 4- methoxyl group -2- trifluoromethylated benzaldehyde
The bromo- 4- methoxyl group -2- benzotrifluoride (12.7g, 49.8mmol) of compound 1- is placed in 250ml three-necked flask, 150ml THF dissolution, N after sealing is added2Ventilation 3 times.Reaction flask stirs under the conditions of being placed in -78 DEG C of dry ice.22ml n-BuLi (2.5M) is added to above-mentioned reaction flask, is slowly added thereto 4g DMF after stirring 30min at -78 DEG C, the reaction was continued, and about 15min is moved back to reacting at room temperature, and TLC monitors reaction process.It is poured into the end of reacting, after solvent concentration in 150ml saturation NaCl aqueous solution, ethyl acetate extracts 3 times (150ml × 3), organic phase is dry with anhydrous sodium sulfate, through silica gel column chromatography (EA: PE=1: 30) after concentration, product (4.8g, yield 47.1%) is obtained.
(2) preparation of 1- (4- methoxyl group -2- (trifluoromethyl) phenyl) propyl- 2- alkene -1- alcohol
Compound 4- methoxyl group -2- trifluoromethylated benzaldehyde (4.7g, 23.0mmol) is placed in 250ml there-necked flask, 100ml THF dissolution, N after sealing is added2Ventilation 3 times.27.6ml vinyl magnesium bromide (1M) is slowly added into above-mentioned reaction flask under condition of ice bath, reaction about 15min moves back that about 2h reaction terminates to the reaction was continued at room temperature.Reaction solution saturation NH4Cl solution is quenched, and ethyl acetate extracts 3 times (150ml × 3), and organic phase is dry with anhydrous sodium sulfate, obtains crude product (5.75g) after solvent concentration, not purified to continue on for reacting in next step.
(3) preparation of 1- (4- methoxyl group -2- (trifluoromethyl) phenyl) propyl- 2- alkene -1- ketone
Compound 1- (4- methoxyl group -2- (trifluoromethyl) phenyl) propyl- 2- alkene -1- alcohol crude product obtained by upper step is dissolved in methylene chloride, lower addition is stirred at room temperature and wears this Martin's oxidant (12.7g, 30.0mmol), it is stirred at room temperature 12 hours.To the end of reacting, reaction solution concentration, residue chromatographs to obtain product (2.7g, two step yields 51.0%) through column.
(4) preparation of 4- hydroxyl -3- iodo-benzoic acid methyl esters
The preparation method of 17 step of reference implementation example (1) is added 4-HBA methyl esters (11.8g, 77.6mmol), obtains product (7.6g, yield 35.2%).
(5) preparation of (E) -4- hydroxyl -3- (3- (4- methoxyl group -2- (trifluoromethyl) phenyl) -3- oxo propyl- 1- alkene -1- base)-methyl benzoate
By 1- (4- methoxyl group -2- (trifluoromethyl) phenyl) propyl- 2- alkene -1- ketone (2.7g, 11.7mmol) and 4- hydroxyl -3- iodo-benzoic acid methyl esters (3.3g, 11.7mmol) (4) are reacted referring to the step of embodiment 17, obtain product (3.8g, yield 85.4%).
(6) preparation of 4- hydroxyl -3- (3- (4- methoxyl group -2- (trifluoromethyl) phenyl) -3- oxopropyl)-methyl benzoate
The step of reference implementation example 17, the preparation method of (5) obtained crude product, is directly used in and reacts in next step.
(7) preparation of 4- hydroxyl -3- (3- hydroxyl -3- (4- methoxyl group -2- (trifluoromethyl) phenyl)-propyl)-methyl benzoate
The preparation method of 23 step of reference implementation example (4) obtains product (3.50g, two step yields 91.1%).
(8) preparation of 2- (4- methoxyl group -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate
By compound 4-hydroxy base -3- (3- hydroxyl -3- (4- methoxyl group -2- (trifluoromethyl) phenyl) propyl)-methyl benzoate (1.92g, 5mmol), triphenylphosphine (1.57g, 6mmol), diethyl azodiformate (1.04g, it 6mmol) is dissolved in tetrahydrofuran (30mL), mixture stirs at 0 DEG C.To Reaction terminates, solvent concentration, is extracted with ethyl acetate 3 times (100mL × 3) after 100ml clear water is added, and merges organic layer, and anhydrous sodium sulfate dries, filters, and is concentrated, and residue obtains product (1.29g, yield 70.5%) through silica gel column chromatography.
(9) preparation of 2- (4- hydroxyl -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate
By compound 2- (4- methoxyl group -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate (550mg, it 1.5mmol) is dissolved in methylene chloride (10mL), dichloromethane solution (the 1M of Boron tribromide is slowly added dropwise, 7.5mL), it is reacted 3 hours wait be added dropwise to continue at -78 DEG C.Reaction solution is moved into room temperature to the end of reacting, and reaction solution is poured into ice water, ethyl acetate extracts three times (50ml × 3), saturated sodium-chloride water solution washs organic phase, merge organic phase, chromatographs to obtain product (200mg, yield 37.9%) through column after concentration.
(10) preparation of 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate
By 2- (4- hydroxyl -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate (100mg, it 0.28mmol) is dissolved in DMF (5mL), potassium carbonate (58mg is added, 0.42mmol), 25 DEG C are stirred 10 minutes, and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (97mg is then added, 0.28mmol), it reacts 6 hours at 25 DEG C.After completion of the reaction, it is poured slowly into ice water, solid is precipitated, filtering, filter cake wash with water (20mL), collects filter cake, and dry product crude product (154mg) is directly used in reaction in next step.
(11) preparation of 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) phenyl) benzodihydropyran -6- formic acid
By 2- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) -2- (trifluoromethyl) phenyl) benzodihydropyran -6- methyl formate (154mg) is dissolved in THF (2mL), methanol (2mL) and water (1mL) is added, add lithium hydroxide monohydrate (32mg, 0.75mmol), 30 DEG C are placed in react 2 hours.After completion of the reaction, reaction solution is poured into 50mL clear water, ethyl acetate extracts three times (50ml × 3), saturated sodium chloride solution washs organic phase, and anhydrous sodium sulfate is dry, organic phase concentration, final product (50mg, two step yields 30%) are obtained through silica gel column chromatography.
Molecular formula: C30H22Cl2F3NO5Molecular weight: 604.40LC-MS (M/e): 604.1 (M+H)+
1H-NMR (400MHz, CDCl3) δ: 7.91 (s, 1H), 7.88 (d, J=2.0Hz, 1H), 7.59 (d, J=8.8,1H), 7.41-7.43 (m, 2H), 7.32-7.36 (m, 1H), 7.23 (s, 1H), 7.09 (d, J=2.0Hz, 1H), 7.04 (dd, J1=2.4Hz, J2=8.4Hz, 1H), 5.38 (d, J=10.4Hz, 1H), 4.89 (s, 2H), 2.91-3.08 (m, 1H), 2.85-2.87 (m, 1H), 2.15-2.19 (m, 1H), 1.90-1.99 (m, 1H), 1.16-1.24 (m, 4H).
25 2- of embodiment (2,6- bis- chloro- 4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) Methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid preparation (compound 27)
(1) preparation of 4- hydroxyl -3- iodo-benzoic acid methyl esters
The preparation method of 17 step of reference implementation example (1) is added 4-HBA methyl esters (10.1g, 66.4mol), obtains product (15.0g, yield 81.3%).
(2) preparation of (3,5- dichlorophenoxy) tri isopropyl silane
By 3,5- chlorophenesic acid (11.5g, 70.6mmol), DIPEA (13.7g, 106.2mmol), DMAP (861mg, it 7.06mmol) is added in DCM (200mL), TIPSCl (16.33g, 84.7mmol) is added in batches under ice bath, is then raised to 25 DEG C of sustained responses 8 hours.1N HCl (126mL) is added in system, extracts liquid separation, successively uses NaHCO3(120mL) and NaCl are molten Liquid (150mL) washing, organic phase is dry with anhydrous sodium sulfate, and rotary evaporation removes solvent and obtains product (20.0g, yield 88.8%).
The preparation of the chloro- 4- hydroxy benzaldehyde of (3) 2,6- bis-
(3,5- dichlorophenoxy) tri isopropyl silane (20.0g, 62.7mmol) is added in anhydrous THF (200mL), nBuLi (2.4mol/L is added dropwise at -78 DEG C, 28.7mL, 68.9mmol), persistently stir 1 hour.It is added dropwise again DMF (6.87g, 94.1mmol), sustained response 1 hour at -78 DEG C.It returns at 25 DEG C and reacts 6 hours.System is added 1N HCl 100mL and EA (200mL) and extracts liquid separation, and organic phase is dry with anhydrous sodium sulfate, and concentration, rotary evaporation removes solvent.DCM (100mL) is added, solid is precipitated, decompression filters, and obtains product (9.5g, yield 79.3%).
The preparation of the chloro- 4-methoxybenzaldehyde of (4) 2,6- bis-
By 2, the chloro- 4- hydroxy benzaldehyde (9.5g of 6- bis-, it 49.7mmol) is added in DMF (200mL), potassium carbonate (20.6g is added into the system, 149.3mmol), then iodomethane (14.1g, 99.3mmol) is added dropwise under ice bath, system, which returns at 25 DEG C, reacts 12 hours.System is poured into 400mL water, and decompression filters, and filter cake is washed with water (10mL), and drying obtains product (8.0g, yield 78.5%).
(5) preparation of 1- (2,6- bis- chloro- 4- methoxyphenyl) propyl- 2- alkene -1- alcohol
2,6-, bis- chloro- 4-methoxybenzaldehyde (8.0g, 39.0mmol) is added in 100ml THF, vinyl magnesium bromide (1M/L, 46.8mL, 46.8mmol) is added dropwise under ice bath, is added dropwise and returns at 25 DEG C that the reaction was continued about 6 hours.Then saturation NH is added4(30mL) is quenched in Cl solution, extracts liquid separation with ethyl acetate (200mL) and water (100mL), organic phase is dry with anhydrous sodium sulfate, and rotary evaporation removes solvent and obtains product (7.5g, yield 82.5%).
(6) preparation of 1- (2,6- bis- chloro- 4- methoxyphenyl) propyl- 2- alkene -1- ketone
By 1- (2, the chloro- 4- methoxyphenyl of 6- bis-) propyl- 2- alkene -1- alcohol (7.5g, it 32.2mmol) is dissolved in methylene chloride (200mL), it is added in batches under ice bath and wears this Martin's oxidant (16.4g, 38.7mmol), sustained response 12 hours at 25 DEG C.System decompression filters, and filtrate is spin-dried for, and residue chromatographs (PE: EA=10: 1) through column, obtains product (3.6g, yield 48.4%).
(7) preparation of (E) -3- (3- (2,6- bis- chloro- 4- methoxyphenyl) -3- oxo propyl- 1- alkene -1- base) -4-HBA methyl esters
By 1- (2,6- bis- chloro- 4- methoxyphenyl) propyl- 2- alkene -1- ketone (3.6g, 15.6mmol); 4- hydroxyl -3- iodo-benzoic acid methyl esters (4.77g; 17.2mmol), triethylamine (3.15g, 31.2mmol); triphenylphosphine (409mg; 1.56mmol), acid chloride (175mg, 0.78mmol) is added sequentially in acetonitrile (150mL); nitrogen protection is heated to 90 DEG C and reacts 12 hours.After completion of the reaction, it is concentrated, residue obtains product (3.0g, yield 50.5%) through silica gel column chromatography (PE: EA=3: 1).
(8) preparation of 3- (3- (2,6- bis- chloro- 4- methoxyphenyl) -3- oxopropyl) -4-HBA methyl esters
By (E) -3- (3- (2,6- bis- chloro- 4- methoxyphenyl) -3- oxo propyl- 1- alkene -1- base) -4-HBA methyl esters (3.0g, 7.9mmol), PtO2(300mg) is added in methanol (100mL), and lower 25 DEG C of hydrogen environment are reacted 4 hours.After completion of the reaction, it filters, rotary evaporation removes solvent, and residue obtains product (2.2g, yield 72.7%) through silica gel column chromatography (PE: EA=4: 1).
(9) prepared by 3- (3- (2,6- bis- chloro- 4- methoxyphenyl) -3- hydroxypropyl) -4-HBA methyl esters
By 3- (3- (2,6- bis- chloro- 4- methoxyphenyl) -3- oxopropyl) -4-HBA methyl esters (1.0g, 2.6mmol) is dissolved in THF (20mL), is slowly added to NaBH under ice bath4(290mg, 7.8mmol), 25 DEG C are reacted about 6 hours.1mL water quenching reaction is added in system, obtains product (850mg, yield 84.9%) through silica gel column chromatography (PE: EA=5: 1).
(10) preparation of 2- (2,6- bis- chloro- 4- methoxyphenyl) benzodihydropyran -6- carboxylate methyl ester
By 3- (3- (2, the chloro- 4- methoxyphenyl of 6- bis-) -3- hydroxypropyl) -4-HBA methyl esters (850mg, 2.2mmol), diethyl azodiformate (957mg, it 5.5mmol) is dissolved in tetrahydrofuran (40mL), triphenylphosphine (1.44g is added under ice bath, 5.5mmol), it is raised at 25 DEG C and reacts 12 hours, rotary evaporation removes solvent, residue obtains product (600mg, yield 74.3%) through silica gel column chromatography (PE: EA=20: 1).
(11) preparation of 2- (2,6- bis- chloro- 4- hydroxy phenyl) benzodihydropyran -6- carboxylate methyl ester
By 2- (2, the chloro- 4- methoxyphenyl of 6- bis-) benzodihydropyran -6- carboxylate methyl ester (600mg, it 1.6mmol) is dissolved in methylene chloride (20mL), dichloromethane solution (the 1M/L of Boron tribromide is slowly added dropwise at -78 DEG C, 8.2mL, DCM solution 8.2mmol) is then slowly increased to 25 DEG C, reacts 2 hours.1mL methanol quenching reaction is added in system, obtains product (60mg, yield 10.6%) through silica gel column chromatography (PE: EA=3: 1).
(12) preparation of 2- (2,6- bis- chloro- 4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) chromene -6- carboxylate methyl ester
By 2- (2, the chloro- 4- hydroxy phenyl of 6- bis-) benzodihydropyran -6- carboxylate methyl ester (60mg, 0.17mmol), 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (59mg, 0.17mmol), cesium carbonate (111mg, it 0.34mmol) is added in DMF (10mL), is reacted 2 hours at 50 DEG C.Ethyl acetate (50mL) is added in system and water (30mL) extracts liquid separation, and rotary evaporation removes organic phase, and residue chromatographs (PE: EA=3: 1) through column, obtains product (70mg, yield 66.5%).
(13) preparation of 2- (2,6- bis- chloro- 4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylic acid
By 2- (2, the chloro- 4- of 6- bis- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) benzodihydropyran -6- carboxylate methyl ester (70mg, it 0.11mmol) is added in methanol (4mL) and THF (4mL), add lithium hydroxide monohydrate (24mg, 2mL aqueous solution 0.57mmol), 50 DEG C are reacted 12 hours, system is down to 25 DEG C, adjusts pH to 3-4 with 1M HCl.Ethyl acetate (50mL) is added in system and water (30mL) extracts liquid separation, and rotary evaporation removes organic phase, and residue obtains product (15mg, yield 22.5%) through column chromatography (DCM: MeOH=40: 1).
Molecular formula: C29H21Cl4NO5Molecular weight: 605.29LC-MS (M/e): 606.1 (M+H+)
1H-NMR (400MHz, CDCl3) δ: 7.95-7.70 (m, 2H), 7.50-7.25 (m, 3H), 6.90-6.62 (m, 3H), 5.85-5.65 (m, 1H), 4.80 (s, 2H), 3.55-3.45 (m, 1H), 3.16-2.45 (m, 3H), 2.20-1.83 (m, 2H), 1.38-1.02 (m, 4H)
26 6- of embodiment (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) first Oxygroup) phenyl) -5- oxo -5,6, the preparation (compound 28) of 7,8- naphthane -2- formic acid
(1) preparation of 2- (the bromo- 3- chlorophenoxy of 4-) tetrahydro -2H- pyrans
Preparation method in 2 step of reference implementation example (1), is added the bromo- 3- chlorophenol (10.0g, 48.2mmol) of 4-, and 3,4- dihydropyran (10.5g, 124.8mmol) obtain product 12g, yield 85.4%.
(2) 5- oxo -5,6, the preparation of 7,8- naphthane -2- base triflates
6- hydroxyl -3,4- dihydronaphthalene -1 (2H) -one (11g, 67.8mmol) is dissolved in methylene chloride (150mL), -5 DEG C are down to, is instilled triethylamine (10.3g, 101.8mmol), it is slow added into trifluoromethanesulfonic acid (23g, 153.3mmol), addition finishes, and 25 DEG C are reacted 4 hours, after completion of the reaction, concentration, residue through silica gel column chromatography (petroleum ether: ethyl acetate=20: 1) product 13g, yield: 65.2%.
(3) 5- oxo -5,6, the preparation of 7,8- naphthane -2- methyl formates
By 5- oxo -5,6,7,8- naphthane -2- base triflate (10g, 34mmol) is dissolved in DMF (70mL) and methanol (20mL), sequentially adds triethylamine (7g, 69.2mmol), DPPP (450mg, 1.09mmol), acid chloride (450mg, 2.0mmol), carbon monoxide balloon, 70 DEG C react 16 hours, after completion of the reaction, reaction solution is poured into water, filtering, filter cake through silica gel column chromatography (petroleum ether: ethyl acetate=5: 1) product 6.2g, yield: 89.3%.
(4) 6- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -5- oxo -5,6, the preparation of 7,8- naphthane -2- methyl formates
By 5- oxo -5,6,7,8- naphthane -2- methyl formates (0.6g, 2.94mmol), 2- (the bromo- 3- chlorophenoxy of 4-) tetrahydro -2H- pyrans (1.17g, 4.0mmol), Pd2(dba)3(270mg; 0.29mmol), Xantphos (340mg, 0.58mmol); cesium carbonate (1.9g; 5.8mmol), it is added sequentially in toluene (30mL), nitrogen protection; 120 DEG C are reacted 20 hours; concentration, residue through silica gel column chromatography (petroleum ether: ethyl acetate=10: 1) product 200mg, yield: 16.4%.
(5) 6- (2- chloro-4-hydroxyl phenyl) -5- oxo -5,6, the preparation of 7,8- naphthane -2- methyl formates
By 6- (the chloro- 4- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -5- oxo -5,6,7,8- naphthane -2- methyl formate (0.2g, it 0.48mmol) is dissolved in methylene chloride (10mL), it is added trifluoroacetic acid (2mL), 25 DEG C, reacts 2 hours.Concentration, residue through silica gel column chromatography (petroleum ether: ethyl acetate=5: 1) product 100mg, yield: 63.0%.
(6) 6- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5- oxo -5,6, the preparation of 7,8- naphthane -2- methyl formates
By 6- (2- chloro-4-hydroxyl phenyl) -5- oxo -5,6,7,8- naphthane -2- methyl formate (0.1g, 0.3mmol) and 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole (0.125g, it 0.36mmol) is added sequentially in DMF (10mL) with potassium carbonate (83mg, 0.6mmol), 60 DEG C are reacted 4 hours, after completion of the reaction, it is poured into water, filters, filter cake is through silica gel column chromatography (petroleum ether: ethyl acetate=5: 1-2: 1), obtain product 145mg, yield 81.0%.
(7) 6- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5- oxo -5,6, the preparation of 7,8- naphthane -2- formic acid
By 6- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxyl group) phenyl) -5- oxo -5,6,7,8- naphthane -2- methyl formate (140mg, 0.23mmol) it is dissolved in methanol (4mL), lithium hydroxide monohydrate (50mg is added in tetrahydrofuran (8mL), water (8mL), 1.19mmol), it stirs 16 hours for 25 DEG C.Decompression boils off methanol and tetrahydrofuran after completion of the reaction, then water (10mL) is added to residue, pH=2 is adjusted with dilute hydrochloric acid (1M), with ethyl acetate (20mL × 3) extract, merge organic layer, concentration, residue through silica gel column chromatography (petroleum ether: ethyl acetate=1: 1) product (40mg, yield: 29.8%).
Molecular formula: C30H22Cl3NO5Molecular weight: 582.86LC-MS (M/e): 582.2 (M+H+)
1H-NMR (400MHz, CDCl3) δ: 8.16 (s, 1H), 8.04 (d, J=8.8Hz, 2H), 7.42 (d, J=7.6Hz, 2H), 7.32-7.37 (m, 1H), 7.03 (d, J=8.8Hz, 1H), 6.90 (d, J=2.0Hz, 1H), 6.73 (dd, J=2.0Hz, J=8.8Hz, 1H), 4.79 (s, 2H), 4.21 (dd, J=4.0Hz, J=12.8Hz, 1H), 3.12-3.26 (m, 2H), 2.31-2.42 (m, 2H), 2.10-2.21 (m, 1H), 1.21-1.32 (m, 2H), (1.16-1.19 m, 2H)

Claims (17)

  1. Logical formula (I) compound represented, its pharmaceutically acceptable salt, its ester or its stereoisomer:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8Alkynyl；
    R3Selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, or the C optionally replaced by one or more substituent group P1-6Alkyl, halogenated C1-6Alkyl, hydroxyl C1-6Alkyl, carboxyl C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, carboxyl C1-6Alkoxy, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, 3-8 member naphthenic base, 3-8 member naphthenic base C1-6Alkyl, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base C1-6Alkyl；
    P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C2-8Alkenyl or C2-8Alkynyl；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, carboxyl C1-6Alkyl, carboxyl oxygroup C1-6Alkyl, carboxyamino C1-6Alkyl, amino C1-6Alkyl, amino carbonyl C1-6Alkyl, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, carboxyl C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl-amino, C1-6Alkyl Sulfonyl, C1-6Alkylsulphonylaminocarbonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino, 5-8 unit's heteroaryl or 3-8 circle heterocyclic ring base；
    W is selected from CH2、NH、O、S、SO、SO2Or CO；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted aryl, 5-8 unit's heteroaryl, 3-8 member naphthenic base or 3-8 circle heterocyclic ring base by one or more substituent group Q；
    Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl or C2-8Alkynyl；
    E is selected from CH2、NH、O、S、SO、SO2Or CO；
    F be selected from be not present, CH2、NH、O、S、SO、SO2Or CO；
    X is selected from CH or N；
    Y is selected from CH2、NH、O、S、SO、SO2Or CO；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    M is selected from the integer of 0-3；
    N is selected from the integer of 0-4.
  2. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as described in claim 1:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino sulfonyl, C2-6Alkenyl or C2-6Alkynyl；
    R3Selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, or the C optionally replaced by one or more substituent group P1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy, 3-6 member naphthenic base, 3-6 member naphthenic base C1-4Alkyl, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base C1-4Alkyl；
    P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C1-4Alkyl-carbonyl, C1-4Alkyl carbonyl epoxide, C1-4 Alkyl sulphonyl, C2-6Alkenyl or C2-6Alkynyl；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxygroup C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino, 5-6 unit's heteroaryl or 4-7 circle heterocyclic ring base；
    W is selected from CH2、NH、O、S、SO、SO2Or CO；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted aryl, 5-6 unit's heteroaryl, 3-6 member naphthenic base or 4-7 circle heterocyclic ring base by one or more substituent group Q；
    Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C2-6Alkenyl or C2-6Alkynyl；
    E is selected from CH2, NH, O, S or CO；
    F be selected from be not present, CH2, NH, O or S；
    X is selected from CH or N；
    Y is selected from CH2, NH, O or S；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    M is selected from the integer of 0-2；
    N is selected from the integer of 0-3.
  3. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 2:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy or C1-4Alkoxy C1-4Alkyl；
    R3Selected from cyano, the C that is optionally replaced by one or more substituent group P1-4Alkyl, halogenated C1-4Alkyl, 3-6 member naphthenic base, 3-6 member naphthenic base C1-4Alkyl, 3-6 circle heterocyclic ring base or 3-6 Circle heterocyclic ring base C1-4Alkyl；
    P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl oxygroup C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino, 5-6 unit's heteroaryl or 5-6 circle heterocyclic ring base；
    W is selected from CH2、NH、O、S、SO、SO2Or CO；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted phenyl, the 5-6 unit's heteroaryl containing 1-2 N, O and/or S atom, 5-6 member naphthenic base, or the 5-6 circle heterocyclic ring base containing 1-2 N, O and/or S atom by one or more substituent group Q；
    Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E is selected from CH2, NH, O or CO；
    F be selected from be not present, CH2, NH or O；
    X is selected from CH or N；
    Y is selected from CH2, NH or O；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    M is selected from the integer of 0-2；
    N is selected from the integer of 0-3.
  4. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as described in claim 1, the structure with following formula (I-1):
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halogenated C1-4Alkyl, halogenated C1-4Alkoxy or C1-4Alkoxy C1-4Alkyl；
    R3Selected from cyano, the C that is optionally replaced by one or more substituent group P1-4Alkyl, halogenated C1-4Alkyl, 3-6 member naphthenic base or 3-6 member naphthenic base C1-4Alkyl；
    P is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkyl, carboxyl C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkylsulphonylaminocarbonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino or 5-6 unit's heteroaryl；
    W is selected from CH2, NH, O, S, SO or SO2；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted phenyl or 5-6 unit's heteroaryl by one or more substituent group Q；
    Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E is selected from CH2, NH, O or CO；
    F be selected from be not present, CH2, NH or O；
    X is selected from CH or N；
    Y is selected from CH2, NH or O；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    N is selected from the integer of 0-3.
  5. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 4:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, bromine atom, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl, trifluoroethyl or trifluoromethoxy；
    R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, trifluoro propyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl-methyl or cyclohexyl methyl；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl, sulfonyloxy methyl amino carbonyl, ethyl sulfonyl-amino-carbnyl, dimethylamino, pyrazoles, imidazoles, oxazole, isoxazole, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
    W is selected from CH2, NH, O or S；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted phenyl or 5-6 unit's heteroaryl by one or more substituent group Q；
    Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E is selected from CH2, NH, O or CO；
    F be selected from be not present, CH2, NH or O；
    X is selected from CH or N；
    Y is selected from CH2, NH or O；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    N is selected from 1 or 2.
  6. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 5:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
    R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, Cvclopropvlmethvl or cyclobutylmethyl；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group, acetylamino, sulfonyloxy methyl amino carbonyl, ethyl sulfonyl-amino-carbnyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
    W is selected from NH, O or S；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted phenyl or pyridyl group by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E is selected from CH2, NH, O or CO；
    F is selected from CH2, NH or O；
    X is selected from CH or N；
    Y is selected from CH2, NH or O；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    N is selected from 1 or 2.
  7. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 6:
    Wherein, the cyclic group and phenyl ring that E, X, Y, F are collectively formed are formed together structure below:
    Chromanyl, benzo Isosorbide-5-Nitrae-dioxine base, benzo 1,3- dioxine base, benzotetrahydropyridand base, benzo dihydro oxazines base, benzo tetrahydro pyrazinyl, 1,2,3,4- tetrahydro quinazoline bases, 1,2,3,4- tetrahydro cinnoline bases, tetralyl, tetralone.
  8. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 7:
    Wherein, Z is selected from is replaced or unsubstituted phenyl by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
  9. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 8:
    Wherein,
    W is selected from O；
    A is selected from O；
    Z is selected to be replaced or unsubstituted phenyl by 1-2 substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, methoxyl group, ethyoxyl, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
    E, the cyclic group and phenyl ring that X, Y, F are collectively formed are formed together structure below:
    N is selected from 1.
  10. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 5:
    Wherein,
    R1、R2Separately it is selected from hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, ethyl, propyl, butyl, methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
    R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopenta, Cvclopropvlmethvl or cyclobutylmethyl；
    R4Selected from hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group, acetylamino, sulfonyloxy methyl amino carbonyl, ethyl sulfonyl-amino-carbnyl, oxadiazoles, thiazole, isothiazole, thiadiazoles, triazole or tetrazole；
    W is selected from NH, O or S；
    A is selected from NH, O or S；
    Z is selected to be replaced or unsubstituted phenyl or pyridyl group by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E is selected from CH2, NH or O；
    F is selected from and is not present；
    X is selected from CH or N；
    Y is selected from CH2Or O；
    E, the connection type between X, Y, F is separately selected from singly-bound；
    N is selected from 1 or 2.
  11. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 10:
    Wherein, the cyclic group and phenyl ring that E, X, Y are collectively formed are formed together structure below:
    Benzo pyrrolin base, coumaran base, benzo 1,3- dioxa cyclopentenyl or dihydro indenyl.
  12. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 11:
    Wherein,
    W is selected from O；
    A is selected from O；
    Z is selected to be replaced or unsubstituted phenyl by one or more substituent group Q, and the substituent group Q is selected from cyano, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halogenated C1-4Alkyl or halogenated C1-4Alkoxy；
    E, the cyclic group and phenyl ring that X, Y are collectively formed are formed together structure below:
  13. Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as described in claim 1, wherein the compound is selected from:
  14. A kind of pharmaceutical composition, containing the described in any item compounds of claim 1~13, its pharmaceutically acceptable salt, its ester or its stereoisomer, with one or more pharmaceutical carriers and/or diluent.
  15. Such as the described in any item compounds of claim 1~13, its pharmaceutically acceptable salt, its ester or its stereoisomer are in the purposes for preparing disease and related disease for treating and/or preventing FXR mediation, the disease includes in Chronic Liver or some form of extrahepatic cholestasis illness, or chronic bile smoulders liver fibrosis caused by illness or acute intrahepatic cholestasis illness, cirrhosis, the obstructive or chronic inflammatory disorders of liver, fatty liver and its complication, fatty liver related with alcohol and its complication, acute hepatic failure, cholelithiasis, and/or inflammatory bowel disease, primary biliary cirrhosis, illness and disease caused by chronic fatty and fibroid are denaturalized, lipid or lipoprotein disorders, the clinical complication of I type or type-2 diabetes mellitus, non-malignant excess proliferative disease or excess proliferative disease.
  16. Purposes as claimed in claim 15, wherein chronic fatty and fibroid are denaturalized caused illness and disease selected from non-alcoholic fatty liver disease or nonalcoholic steatohepatitis；Lipid or lipoprotein disorders are selected from atherosclerosis, dyslipidemia, thrombus, and the clinical complication of I type or type-2 diabetes mellitus is selected from nephrosis, diabetic neuropathy, diabetic keratopathy view Other results observed of film disease and its clinical dominant long-term diabetes；Non-malignant excess proliferative disease or excess proliferative disease are selected from the gastrointestinal tract and liver neoplasm disease of hepatocellular carcinoma, colonic adenoma and polyposis, adenocarcinoma of colon, breast cancer, cancer of pancreas, the cancer of the esophagus and other forms.
  17. Intermediate during compound shown in the logical formula (I) of preparation as follows, wherein R4, m, n, A, Z, E, F, X, Y as recited in claim 6,
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