WO2014187343A1 - Benzofuran derivative, preparation method therefor, and medical application thereof - Google Patents

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

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WO2014187343A1
WO2014187343A1 PCT/CN2014/078156 CN2014078156W WO2014187343A1 WO 2014187343 A1 WO2014187343 A1 WO 2014187343A1 CN 2014078156 W CN2014078156 W CN 2014078156W WO 2014187343 A1 WO2014187343 A1 WO 2014187343A1
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group
fluorenyl
compound
formula
salt
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PCT/CN2014/078156
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French (fr)
Chinese (zh)
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张晨
王健民
何平
雷鸣
叶飞
魏用刚
邓炳初
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四川海思科制药有限公司
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Priority to CN201480003531.4A priority Critical patent/CN104870429B/en
Publication of WO2014187343A1 publication Critical patent/WO2014187343A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • the present invention relates to a benzofuran derivative, a preparation method thereof and its use in medicine, in particular to a novel benzofuran derivative having a G protein-coupled receptor 40 (GPR40) receptor function regulating function. Or a stereoisomer, hydrate, solvate, co-crystal, pharmaceutically acceptable salt or prodrug thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and its use in medicine.
  • GPR40 G protein-coupled receptor 40
  • Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly characterized by insufficient insulin secretion or insulin resistance (ie, the body tissue cannot respond effectively to endogenous insulin), genetic and environmental factors, etc. Causes insulin resistance.
  • hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolyldione CTZD S ; » a-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP) -IV), sodium-glucose cotransporter 2 GLT-2) inhibitors and the like.
  • these hypoglycemic agents have side effects such as hypoglycemia, weight gain, cardiovascular risk and genitourinary tract infections (Vinod S. Deshmukh et al. (2013). International Journal of Basic & Clinical Pharmacology? 2, 4-11 These side effects further increase the burden on diabetic patients. Therefore, it is necessary to develop a new generation of hypoglycemic agents with a novel mechanism of action.
  • G-protein coupled receptor 40 is a novel target with hypoglycemic potential and is highly expressed in islet beta cells.
  • GPR40 also known as fatty acid receptor 1 (FFAR1), is a membrane receptor belonging to the homologous G protein-coupled receptor superfamily and is highly conserved among many species.
  • FFAR1 fatty acid receptor 1
  • G protein-coupled receptors have seven transmembrane structures that can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses.
  • GPR40 can be activated by medium-long-chain free fatty acid CFFAs (Itoh Y et al. (2003) ). Nature, 422, 173-176).
  • FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40.
  • the interaction of FFAs with GPR40 increases Ca 2+ flux through PLC or L-type Ca 2+ channel signaling pathways in islet beta cells, which in turn leads to cellular responses (Fujiwara et al. (2005). Am J Physiol Endocrinol Metab, 289, E670 -E677).
  • Studies have shown that in animal models, agonistic GPR40 is effective in lowering blood glucose; in clinical trials, short-term and long-term treatment with GPR40 agonists promotes glucose-induced insulin secretion and increases glucose tolerance (K Nagasumi et al.
  • Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical practice and has proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and effectively controls blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Tsujihata Y et al. (2010).
  • GPR40 is a safe and feasible new target for oral hypoglycemic agents.
  • the development of GPR40 agonists has very important research value and application prospects.
  • a number of research literatures related to GPR40 agonists are currently published.
  • US2006258722 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic agent for diabetes, and its structural formula is as follows:
  • the cyclic group of the optionally substituted substituent of Ar the cyclic group of the optional substituent of A, and not substituted by thiazole, oxazole, imidazole and pyrazole, each independently selected from a bond or containing 1 a chain of -5 atoms
  • Xc is selected from 0, S, SO or S0 2
  • Xd is selected from a bond, CH or CH 2
  • D is selected from a benzene ring, a thiophene or a thiazole
  • B is selected from a ring of 5 to 7 members
  • R 1 is selected from a hydroxyl group.
  • CN101616913 describes a fused ring compound which can function as an insulin secretion promoting agent and a GPR40 receptor function regulating effect of a preventive and/or therapeutic drug for diabetes, and has the following structural formula:
  • R 1 is selected from -S0 2 -R 6
  • R 6 is selected from d- 6 fluorenyl or optionally substituted 1,1-dioxotetrahydrothiopyranyl
  • X is selected from a bond or a divalent hydrocarbon group.
  • R 2 and R 3 are selected from H, a halogen atom, a substituted hydroxy group or substituted hydrocarbyl
  • R 4 and R 5 is selected from substituted with hydroxy ⁇ - 6 alkyl with
  • a is selected from a benzene ring
  • B 5 is selected from To a 7-membered ring
  • Y is selected from a bond or CH2, and R is selected from a hydroxyl group.
  • X, Xa is selected from CH or N
  • Y is selected from 0 or CR 6 R 7
  • R 1 and R la are selected from H, halogen, d- 6 fluorenyl or d- 6 methoxy
  • R 2 is selected From H, d- 6 fluorenyl or optionally substituted acyl
  • R 3 and R 4 are selected from H or halogen
  • R 5 is selected from substituted hydroxy or substituted amine groups, and the compounds specifically described in US7786165 are not considered to be the present invention. a part of.
  • WO2010143733 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic drug for diabetes, and its structural formula is as follows:
  • R 1 is selected from halogen, hydroxy, optionally substituted d- 6 fluorenyl or optionally substituted d- 6 fluorenyloxy;
  • R 2 is selected from substituted hydroxy,
  • R 3 is selected from H, halogen or optionally substituted the embankment d_ 6-yl,
  • X is CH 2
  • Y is selected from CH 2
  • Z is selected from CH or N,
  • a is selected from halogen, an optionally substituted amino group or 4-13 membered ring.
  • the present invention provides a novel structure of a compound represented by the formula ⁇ , which has been shown to exhibit excellent pharmacodynamic activity as a GPR40 agonist.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from H, d- 8 fluorenyl or PEG, preferably H or d- 6 fluorenyl, more preferably 11 or -4- mercapto, further preferably H;
  • ring Q is selected from a 5- to 8-membered carbocyclic or heterocyclic group.
  • R 1, R 2, R 3 and R 4 are each independently optionally selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8 or 8 embankment D- Oxy group, preferably H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, more preferably H, F, Cl, Br, I, cyanide Further, H, F, Cl, cyano, hydroxy, d- 3 fluorenyl or d- 3 decyloxy, more preferably H, F, Cl, a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group.
  • any one of R 6 and R 7 , R and R 8 , R and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 8 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, preferably forming a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably R 6 and R 7 , any of R 8 and R 9 may form a 3 to 6 membered carbocyclic ring.
  • each R 12a may be The same or different preferably 0 to 3 in the range is selected from 0 to 3 R 12a , more preferably 0 to 2 R 12a ;
  • R 12a when two R 12a are attached to the same atom, they can form a 3 to 8 together with the atoms to which they are attached.
  • R i2 , R i2b, Ri 3 and R i3a are selected from the group consisting of H , F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy , a carboxyl group, a d- 8 fluorenyl group, a d- 8 methoxy group, a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, Amino group, d- 6 fluorenyl group, d- 6 methoxy group, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, more preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, D- 4 fluorenyl, d- 4 methoxy, 3
  • oxy group is selected from the group consisting of F, Cl, Br, -CF 3 , d- 3 fluorenyl or d- 3 methoxy, preferably 0 to 1 selected from F, d- 2 fluorenyl or this ⁇ —2 methoxy;
  • p is selected from 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
  • q is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
  • t is selected from 0, 1 or 2, preferably 0 or 1, more preferably 1;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • the phrase "as a selection” means that the scheme after "as a selection” is a side-by-side selection relationship with the scheme before “as a selection”, rather than a further selection in the foregoing scheme.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl Or d- 6 methoxy, preferably H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, cyano, hydroxy, d- 3 fluorenyl or d-3 methoxy, further preferably H, d- 2 fluorenyl or d- 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group are each independently optionally further 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 fluorenyl or d- 6 fluorenyl
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl
  • H, F, Cl, Br, I, d- 4 fluorenyl or d- 4 fluorenyloxy more preferably H, F, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H or d - 2 fluorenyl
  • the fluorenyl and decyloxy groups each independently optionally further from 0 to 3 selected from F, Cl, Br, Substituting for a substituent of I, -CH 2 F, -CHF 2 , -CF 3 , 6 fluorenyl or d- 6 methoxy, preferably 0
  • Preferred embodiments of the invention include a compound of the formula (I) or all stereoisomers, hydrates, esters, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 decyloxy, preferably H, F, cyanide a hydroxy group, a d- 3 fluorenyl group or a d- 3 methoxy group, more preferably H, d- 2 fluorenyl or d- 2 methoxy, more preferably H, wherein the fluorenyl or decyloxy group is independently Optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or -4- methoxy, preferably 0-2 is selected from F, Cl, -CF 3, d- 3 ⁇ alkyl with or --3 embankment group, more preferably F, d- 2-yl or embankment
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, d 4 fluorenyl or d 4 methoxy, preferably H, F, 3 decyl or d- 3 decyloxy, More preferably, H, F, d- 2- indenyl or d- 2- nonyloxy, further preferably H or d- 2- indenyl, each independently optionally further selected from 0 to 2 Substituted with a substituent of F, Cl, Br, I, d- 4 fluorenyl or d- 4 methoxy, preferably 0 to 2 are selected from F, d- 3 fluorenyl or -3- decyloxy, more preferably F , or alkyl with d- 2 ⁇ - 2 embankment group, more preferably d- 2 embankment group.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 , R 5 , R 1Q and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, Propyloxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, F, methyl, ethyl, methoxy, B Oxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably H, methyl, ethyl, methoxy or ethoxy, further preferably H or A base.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring or a 3 to 6 membered heterocyclic ring preferably any group of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring.
  • R 12 , R 13 and R 13a are selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 methoxy, (3 to 6-membered carbocyclic) Or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6 membered carbocyclyl or 3 to 6
  • the heterocyclic group is more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl , Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, further preferably
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy,
  • the Cw fluorenyl group is further preferably H, d 2 decyloxy or -d 2 fluorenyl-O-Cw fluorenyl, and the fluorenyl and decyloxy groups are each independently optionally further 0 to 3 selected from -CH 2 Substituted with a substituent of F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy or d
  • any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring.
  • it is a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 selected from N, 0 or a hetero atom of S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 3 substituents of R 12a , preferably 0 to 2 R 12a ;
  • the methoxy group is further optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy, d - 4 ⁇ Substituted with a substituent of a 4- methoxy group, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl, CM ⁇ The oxy group, more preferably 0 to 3, is selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , - -CF 3 , d- 4 fluorenyl, CM ⁇ The oxy group, more preferably 0 to 3, is selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , - -CF 3 , d
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxy Methyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, methyl, methoxy, ethoxy, methoxymethyl, ethoxy Methyl, methoxyethyl or ethoxyethyl, more preferably H, methoxy, ethoxy, methoxymethyl or ethoxymethyl, further preferably H;
  • R 6 and any of R 7 , R 8 and R 9 may form a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring, preferably a 3 membered carbon ring or a 3 membered heterocyclic ring, more preferably a 3 membered carbon.
  • a ring said heterocyclic ring containing 1 to 3 heteroatoms of 0, N or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, and the resulting carbocyclic or heterocyclic ring may optionally be further From 0 to 3 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, A Substituted by a substituent of an oxyethyl group, a methoxypropyl group, an ethoxymethyl group or an ethoxyethyl group, preferably 0 to 2 are selected from the group consisting of F, methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably 0 to 1 selected from F,
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, or a derivative thereof.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolic salt or prodrug thereof, wherein:
  • Ring Q is selected from .
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from H or d 6 fluorenyl, preferably H or d 4 fluorenyl, more preferably H;
  • R 1 is selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, preferably H, F, Cl, Br, cyano, amino a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group, more preferably H, F, Cl, Br, a cyano group, an amino group, a hydroxyl group, a 3 fluorenyl group or a d- 3 methoxy group, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group is each independently optionally further from 0 to 3 selected from F, Cl, Br, I, - Substituted with a substituent of CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy,
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl
  • H, F, Cl, Br, d- 4 fluorenyl or d- 4 decyloxy more preferably H, F, Cl, Br, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, Cl, Br, d- 2 fluorenyl or d- 2- decyloxy, further preferably H, F, d 2 fluorenyl or d-2-decyloxy, the fluorenyl or decyloxy group being independently optional Further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 6 fluorenyl
  • R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy,
  • any one of R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , R 6 and R 8 , R 6 and R 9 may form a 3 to 6 carbon ring or 3 to 6 member.
  • the heterocyclic ring preferably any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring or a 3 to 4 membered heterocyclic ring.
  • the ring is further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, and the heterocyclic ring contains 1 to 3 N, 0 or S atoms, preferably 1 to 2 selected from N, 0 or S. a hetero atom, the carbocyclic or heterocyclic ring optionally further substituted by 0 to 3 substituents of R 12a , preferably 0 to 2
  • a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring may be formed, preferably a 3 to 6 membered heterocyclic ring containing 1 to 3 a hetero atom selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 3 selected from F, Cl, Br , I, CF 3, hydroxy, cyano, or alkyl with 6 ⁇ - 6 embankment group substituents, preferably 0 to 2 groups selected from F, Cl, Br, CF 3 , hydroxy, cyano, d- 4 fluorenyl or -4- yloxy, more preferably 0 to 2 selected from F, d- 3 fluorenyl or d- 3 methoxy, more preferably 0 to 1 selected from F, d 2 fluorenyl or d_ 2 ⁇ oxy;
  • R 12 , R 13 and R 13a are selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 decyloxy, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6-membered carbocyclic or 3 to 6-membered
  • the cyclo group is more preferably H, F, Cl, Br, d_ 4 fluorenyl, d 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl, Br, D- 4 fluorenyl, d- 4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, further preferably d-
  • p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 is selected from H, F, Cl, Br, cyano, amino, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, Cl, Br, cyano, amino, hydroxy, d- 3 fluorenyl or d-3 methoxy, more preferably H, F, d-2 fluorenyl or d-2-decyloxy, further preferably H, wherein the flu
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d- 2- indenyl or d- 2- indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy.
  • Substituted preferably 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, more preferably 0 to 2 selected from F, Cl, Br, d — 3 ⁇ or d— 3 ⁇ oxy, more preferably 0 to 1 selected from F, d— 2 fluorenyl or d ⁇ 2 fluorenyl;
  • any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring.
  • the heterocyclic ring contains 1 to 3 ⁇ , 0 or S atoms, preferably 1 to 2 hetero atoms selected from N, 0 or S, optionally further 0 to 3 R 12a Substituted by a substituent, preferably 0 to 2 R 12a ;
  • R 12 , R 13 and R 13a are selected from H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclyl or 3 to a 6-membered heterocyclic group, preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 5 membered carbocyclic group or 3 to 5 membered heterocyclic group, further preferably d- 3 fluorenyl, d- 3 methoxy, 3 to a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, further preferably a 2 fluorenyl group or a d- 2 fluoren
  • p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 5 , R 1U and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d-2-indenyl or d-2-indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, preferably 0 to 2 selected from F, Cl, Br, d- 3 fluorenyl or -3-decyloxy, more preferably 0 to 1 selected from F, d- 2 fluorenyl or -2- decyloxy;
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably H, F, Cl, Br, D_ 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, more preferably d 3 fluorenyl, 3 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, further preferably d- 2 fluorenyl or d- 2 fluorenyloxy;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 5 , R 1Q and R 11 are each independently selected from H, F, methyl or ethyl.
  • Preferred embodiments of the present invention include a compound represented by the formula (IV) or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutical thereof among them:
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing from 1 to 3 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with from 0 to 3 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula 0V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, preferably d 3 fluorenyl, d 3 ⁇ An oxy group, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, more preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group; m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-O-CM fluorenyl, preferably H, d 3 decyl, 3 decyloxy or -d --3 alkyl with - Od- 3 embankment group, more preferably H, d- 3 embankment group or alkyl with -d- 3 - Od- 3 embankment group, more preferably H, d- 2 embankment group or -d- 2 Mercapto-Od- 2 fluorenyl, further preferably H;
  • R 8 and R 9 are each independently selected from H, d- 4 alkyl with, d- 4 group or -d- 4 embankment embankment embankment -Od- 4-yl group, preferably H, d_ 3 alkyl with, d- 3 embankment Oxy or -d-3indolyl-Od- 3 fluorenyl, more preferably H, d- 2 fluorenyl, d- 2 -nonyloxy or -d-2indolyl-O-Cw fluorenyl, further preferably H, d_ 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
  • R 8 and R 9 may form a 3-membered carbon ring.
  • Preferred embodiments of the invention include a compound of the formula ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from g H, d_ 3 fluorenyl, d 3 methoxy or -d 3 fluorenyl-O-Cw fluorenyl, preferably H, d 3 methoxy or - 3 fluorenyl- Od- 3 embankment group, more preferably H, d- 2 embankment embankment -d- 2-yl group or - Od- 2 embankment group, more preferably H;
  • R 8 and R 9 are each independently selected from H, d. 3 fluorenyl, 3 decyloxy or -d-3indolyl-indole-d- 3 fluorenyl, preferably H, decyl, d 2 decyloxy or -d_ 2 fluorenyl-O-Cw fluorenyl, more preferably H, d 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
  • R 8 and R 9 may form a 3-membered carbon ring.
  • Preferred embodiments of the invention include a compound of the formula ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl, preferably H, Methoxy or ethoxy, more preferably H;
  • R 8 and R 9 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or methoxyethyl, preferably H, methyl, methoxy Methyl or ethoxymethyl, more preferably H, methoxymethyl or ethoxymethyl; alternatively, R 8 and R 9 form a 3-membered carbocyclic ring.
  • Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 8 and R 9 are each independently selected from H, methoxymethyl or ethoxymethyl; or, alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring.
  • R is selected from 11 or - 8 fluorenyl
  • R 6 and R 7 can be formed ( ⁇ ( ⁇ or two ⁇ 12 ! ⁇ 215 ;
  • p is selected from 0, 1, 2 or 3;
  • q is selected from 0, 1, 2, 3 or 4;
  • t is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 and R 4 are each independently selected from F, Cl, Br or d 4 alkyl, preferably F or CI;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br or d 4 fluorenyl, preferably H;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I or d- 4 , preferably H, F or methyl.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-OC ⁇ -(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, " ⁇ O ⁇ , 0, ' ⁇ Q , or
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
  • R 11 or R 12 is selected from ⁇ - 6 alkyl with, preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is of the general formula (II) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from 11 or - 4 fluorenyl groups, preferably H:
  • R 1 is selected from F, C1 or Br, preferably F or C1;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-O-CM ⁇ -(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 3 ⁇ 4 ⁇ C ⁇ , ⁇ 0, ⁇ Q , or
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
  • R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
  • p is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic thereof a compound, a metabolite, a pharmaceutically acceptable salt or a prodrug, which is a compound of the formula (in) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable Accepted salt or prodrug:
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC —(CH 2 ) m —NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, , 0
  • R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from H or d 4 alkyl, preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a compound of the formula ⁇ or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is of the formula (IV) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-0-C -1-4 - (CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 0
  • R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from the group consisting of 11 or 4 - 4, preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a preferred embodiment of the invention a compound of the formula (IV): or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from the group consisting of H, methyl, methoxy, ethoxy, W or N , ⁇ S ⁇ ;
  • R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl, Or 0;
  • R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
  • a compound of the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is a formula a compound represented by (V): or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 4 is selected from H, F or Cl, preferably H or F;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, CI or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-O-CM -(CH 2 ) m - NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, . , , , ⁇ 0 ,
  • R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a preferred embodiment of the invention a compound of the formula (V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 4 is selected from H, F or Cl, preferably H or F;
  • R 5 and R 11 are methyl
  • R 1Q is selected from H or F, preferably H;
  • R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl, ⁇ . ⁇ or ' ⁇ . ⁇ , or R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached, preferably R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached; a preferred embodiment of the invention, formula (V) The compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
  • Suitable pharmaceutically acceptable salts of the compounds of the formula ⁇ include, but are not limited to, sodium salts, potassium salts, aluminum salts, lithium salts, zinc salts, calcium salts, magnesium salts, barium salts, ammonium salts, Trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt , methylpyridine salt, 2,6-lutidine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, hydrazine -ethylpiperidine salt, polyamine resin salt, phenamine penicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate,
  • the present invention also relates to a process for the preparation of the compound of the formula (I), and it is known to those skilled in the art that the compound of the present invention can be synthesized by various preparation methods. Preferred methods include, but are not limited to, the methods described below. Those skilled in the art will appreciate that the functionality exhibited on the molecule should be consistent with the planned transformation. In order to obtain the desired compound of the present invention, a judgment is sometimes required to change the order of the synthetic steps or to select a particular process scheme. Reasonable protecting groups are selected for the protection of reactive functional groups present in the compounds described herein. Specifically, the method for producing the compound of the formula (I) of the present invention is selected from one of the following methods:
  • the compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction.
  • a compound of formula (Ib) is sequentially converted into a compound of formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction.
  • a compound of formula (Ib) is sequentially converted into a compound of the formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction
  • the compound of the formula (I-b) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a reduction reaction;
  • the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction and a hydrolysis reaction; the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction;
  • the compound of the formula (I-e) is converted into a compound of the formula (I-f) by an epoxidation reaction and a ring-opening reaction; or the compound of the formula (I-e) is converted into a compound of the formula (I-f) by a nucleophilic substitution reaction;
  • a compound of the formula (If) is converted to a compound of the formula (lc) by a suzuki coupling reaction; or a compound of the formula (If) is converted into a compound of the formula (lc) by a suzuki coupling reaction and a hydrogenation reduction reaction; a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
  • a compound of the formula (Ig) is converted to a compound of the formula (Ia) by an Adol reaction; or a compound of the formula (Ig) is converted to a compound of the formula (Ia) by a nucleophilic substitution reaction;
  • the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction and a dehydroxylation reaction;
  • the compound of the formula (I-f) is subjected to a suzuki coupling reaction to a compound of the formula (I-c); or the compound of the formula (I-f) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a hydrogenation reduction reaction.
  • a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
  • the compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction and a hydrogenation reduction reaction;
  • the compound of the formula (1-i) is converted into a compound of the formula (I) by a nucleophilic substitution reaction, a Mitsimobu condensation reaction and a hydrolysis reaction, or a compound of the formula (1-i) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction. ; among them:
  • L is selected from F, Cl, Br or I
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention; 16.
  • R 17 and R 18 are selected from H, hydroxy, methyl or ethyl.
  • preparation method of the compound of the general formula (I) of the present invention is selected from one of the following methods:
  • the compound of the formula (Ia) is reacted with diethoxycyanomethyl phosphate under basic conditions using tetrahydrofuran as a solvent, and then the cyano group is reduced to an aldehyde group with diisobutylaluminum hydride, and further with a reducing agent.
  • the reaction is then further reacted with a thiolation reagent under basic conditions to obtain a compound of the formula (Ib); or the compound of the formula (Ia) is reacted with a reducing agent, and further, in the presence of concentrated sulfuric acid, a elimination reaction is carried out to obtain a general formula.
  • the palladium catalyst is selected from the group consisting of [ ⁇ , ⁇ -bis(; diphenyl) Phosphine) ferrocene] palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloromethane ruthenium complex, tetrakis(triphenylphosphine) palladium, two Palladium chloride, palladium acetate or bistriphenylphosphine palladium dichloride, the group consisting of [ ⁇ , ⁇ -bis(; diphenyl) Phosphine) ferrocene] palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloromethane ruthenium complex, tetrakis(triphenylphosphine) palladium, two Palladium chloride, palladium acetate or bistriphenylphosphine palladium dichloride,
  • the compound of the formula (Id) is substituted with 3-bromopropene in the presence of potassium carbonate in the presence of acetonitrile, tetrahydrofuran, toluene or 1,2-dichloroacetic acid as a solvent, and then at 180 ° C, through Clay Reordering to obtain a compound of the formula (Ie);
  • the compound of the formula (Ie) is epoxidized with m-chloroperoxybenzoic acid by using methylene chloride or 1,2-dichloroacetic acid as a solvent, and then heated to reflux with 1,2-dichloroethane as a solvent.
  • the compound of the formula (Ig) is reacted with formaldehyde to obtain a compound of the formula (Ia) in the presence of methanol and water as a solvent in the presence of potassium carbonate; or tetrahydrofuran, hydrazine, hydrazine-dimethylformamide as a solvent, in sodium hydrogen
  • a nucleophilic substitution reaction with iodoformamidine or 1,2-dibromoacetamidine gives a compound of the formula (Ia);
  • the compound of the formula (Ia) is reacted with lithium tetrahydroaluminum to obtain a compound of the formula (If) in the presence of tetrahydrofuran as a solvent in the presence of aluminum trichloride; or the compound of the formula (Ia) is hydrogenated under the action of a reducing agent, and further Dehydroxylation gives a compound of the formula (If) wherein the dehydroxylation agent is selected from the group consisting of triethylsilyl, palladium/carbon, TMSCl/Nal or CS 2 /NaH, and TMSC1 refers to trimethylsilyl silane, wherein The reducing agent is as described above;
  • a compound of the formula (If) undergoes a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then a hydrogenation reduction reaction is carried out under the action of a reducing agent.
  • a compound of (Ic) wherein the palladium catalyst and the reducing agent are as defined above;
  • the Mitsunobu reaction gives a compound of the formula (I); or the compound of the formula (I-c) is converted into a compound of the formula ⁇ by a Mitsimobu condensation reaction and a hydrolysis reaction under the above conditions;
  • the compound of the formula (Ia) is subjected to a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then hydrogenated to reduce the formula under the action of a reducing agent.
  • R, R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention Consistent; R 16 , R 17 , R 18 are selected from H, hydroxy, methyl or ethyl.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a compound of the formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, A pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
  • the composition may further comprise one or more other Therapeutic agent.
  • Other therapeutic agents described therein include:
  • glucagon receptor antagonist or a pharmaceutically acceptable salt
  • a drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter!
  • An agonist a cholesterol absorption inhibitor, an acyl CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or
  • the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof.
  • the DDPIV inhibitor is selected from the group consisting of linagliptin (Lilatripin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vidatripin), alogliptin (alogliptin), saxagliptin (sand Gliptin), denagliptin (digagliptin), Carmegliptin, Melogliptin (Merrolidine), Dutogliptin, Teneligliptin (Teliglitin), Gemigliptin or Trelagliptin.
  • the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin.
  • the PARP inhibitor is selected from the group consisting of bezafibrate, feno fib rate, pioglitazone, azelaic acid ⁇ rosiglitazone or saroglitazar.
  • the biguanide therapeutic agent is selected from the group consisting of metformin or dibiguanidine.
  • the thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone or dapaglitazone.
  • the sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, Tolglybutamide, glibenclamide, glibenclamide, gliclazone, glipizide, or gliclazide.
  • the levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide.
  • Said (X-glucosidase inhibitor is selected from the group consisting of acarbose, Voglibose or miglitol.
  • the GLP-1 analogue is selected from the group consisting of exenatide or liraglutide.
  • the present invention also relates to a compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof as a G protein conjugation
  • a compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof as a G protein conjugation
  • the use of the body 40 agonist in medicine and also relates to the compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of a prodrug for medical use preferably a compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal thereof, pharmaceutically acceptable
  • the salt or prodrug is used as a G protein coupled receptor 40 agonist for the preparation of a pharmaceutical preparation for the treatment and/or prevention of metabolic diseases.
  • the metabolic diseases may include, for example, diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia.
  • high triglycerideemia hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acids Or elevated levels of glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke.
  • the compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof is used as a G protein couple.
  • a conjugated 40 agonist is used to prepare a pharmaceutical preparation for the treatment and/or prevention of type 2 diabetes.
  • the invention also relates to a method of treating and/or preventing the metabolic disease, the method comprising administering to a subject an effective amount of a compound of the formula ⁇ according to the invention or a stereoisomer, hydrate or ester thereof A solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition comprising the same.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention.
  • the nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen), ⁇ (T, also known as super heavy hydrogen; I, oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N,
  • the fluorine isotopes include 17 F and 19 F
  • the chlorine isotopes include 35 C1 and 37 C1
  • the bromine isotopes include 7 3 ⁇ 4r and 81 Br.
  • Mercapto refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further A fluorenyl group of 1 to 4 carbon atoms is preferred.
  • Alkoxy means -0-fluorenyl, non-limiting examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl- 1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy Base, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy.
  • Alkenyl means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexene-3-yl, g Alken-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl.
  • the alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Alkynyl means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecy-3-yl, dodecyn-4-yl.
  • the alkynyl group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
  • the ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, phenyl, 1-cyclopentyl-2 -alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, ring Heptyl, ring Octyl, cyclodecyl, cyclodecyl, cyclodecyl, cyclododedecyl, ⁇ , *w.
  • Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 4 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include an epoxy group, a propylene group, an aziridine group, and an oxygen hetero ring.
  • PEG means a polymer containing ⁇ , wherein n is an integer in the range of from 2 to about 1,000, preferably from 2 to about 500, more preferably from 2 to about 250, still more preferably from 2 to about 125, still more preferably from 2 to about 50. Further, an integer in the range of 2 to about 25 is further preferable.
  • Amino means -NH 2 .
  • Mercaptoalkyl refers to an amino group having one or two mercapto substituents.
  • Neitro means -N0 2 .
  • Carboxy means -COOH.
  • Carboxylic acid ester means COOR 15 wherein R 15 is a fluorenyl group.
  • Haldroxymethane means a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a C1-4 fluorenyl group.
  • Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid.
  • Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethylammonium, Diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, proca
  • Non-limiting examples of the inorganic acid and organic acid choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic acid, propionic acid, 2-hydroxypropionic acid, malonic acid, trifluoroacetic acid, methanesulfonic
  • Carrier means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
  • An "adjuvant” is a non-specific immunopotentiator that, when injected with an antigen or pre-injected into the body, enhances the body's immune response to the antigen or alters the type of immune response.
  • “Diluent” is also called “filler”. When the original drug is processed into a powder, or to facilitate the spraying of the added inert substance to be diluted.
  • a powder or to facilitate the spraying of the added inert substance to be diluted.
  • Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention, which can be removed by conventional procedures or in vivo to give the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, respectively. Amino or free sulfhydryl.
  • Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
  • eutectic refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bonds, wherein the active pharmaceutical ingredient (API) and the eutectic formation (CCF) are in a pure state. They are all solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
  • Non-limiting examples of eutectic formations include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, and half Cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid , nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, Fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid,
  • Stepoisomer refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.
  • heterocyclic group optionally substituted by a thiol group means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group happening.
  • “Pharmaceutical composition” means a combination of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and one or more additional therapeutic agents, and a pharmaceutically acceptable form.
  • the “EC 50 " half effective concentration refers to the concentration at which half of the maximum efficacy is reached. Detailed ways
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ is given in units of 10 - 6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.20 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ⁇ 0.5 mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the optimum reaction temperature at room temperature is 20 ° C ⁇ 30 ° C.
  • Resorcinol 1A (17.62 g, 160.02 mmol) was added in small portions to concentrated sulfuric acid (60 mL) containing ethyl chloroformate (28.00 g 170.12 mmol) at 0 ° C, and the reaction was stirred at room temperature 2 hour. The reaction mixture was poured into ice water, and the mixture was filtered. Step 2: 2-(6-Hydroxybenzofuran-3-yl)acetic acid (1C)
  • Step 5 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1)
  • Step 5 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 2)
  • diethoxycyanomethyl phosphate (1.1 g, 6.22 mmol) was slowly added dropwise to a solution of sodium hydride (149 mg, 6.22 mmol) in tetrahydrofuran (20 mL). After stirring for 10 minutes, a solution of 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (1.0 g, 4.15 mmol) in tetrahydrofuran was slowly added dropwise to the mixture and the mixture was warmed to 35 ° C. The reaction was stirred for 3 hours.
  • Step 7 (3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol (3g)
  • Step 8 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Methyl oxy)-2,3-dihydrobenzofuran-3-yl)acetate (3h) Methyl 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2 -dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate
  • Step 9 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Oxy)) 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 3)
  • Step 6 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl;)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl;) methyl acetate (4f) Methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n-3-yl)acetate
  • Step 7 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzene And furan-3-yl)acetic acid (compound 4)
  • reaction solution was concentrated to remove a solvent, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3), and the organic phase was combined with saturated brine (100 mL x 2) and water (100 mL x 2) )washing. The residue was dried over anhydrous sodium sulfate (MgSO4).
  • Step 5 3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (5e)
  • Tetrakis(triphenylphosphine)palladium (93.6 mg, 0.08 mmol) was added to the reaction system under a nitrogen atmosphere, the temperature was raised to 80 ° C, and the reaction was stirred for 18 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL EtOAc). The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
  • Step 6 (3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol (5f)
  • Step 7 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy) -2,3-dihydrobenzofuran-3-yl;) methyl acetate (5g)
  • Step 7 2-(6-((3-(2-(methoxy))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran Methyl-3-yl;) methyl acetate (6g)
  • Tributylphosphine (0.13 mL, 0.52 mmol) and azodiyldipiperidine (130.9 mg, 0.52 mmol) were added to (3-(2-(methylmethoxy)-4,6-) under a nitrogen atmosphere.
  • EtOAc mjjjjjjjjj
  • Step 8 2-(6-((3-(2-(methoxy))-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 6)
  • Tributylphosphine (0.41 mL, 1.64 mmol) and azodiyldipiperidine (413.8 mg, 1.64 mmol) were added to 5-(3-hydroxymethylphenyl)-4,6-dimethyl Methyl-benzofuran-3(2H)-one 9a (200 mg, 0.75 mmol) and methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (186.1 mg, 0.89 mmol) in dry dichloromethane (15 mL). The reaction solution was stirred at room temperature for 2 hours.
  • the third step 2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 9)
  • Step 4 (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro-[benzofuran-2,1'-cyclopropyl]-5) -yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (1 Od)
  • Tributylphosphine 0.3 mL, 1.20 mmol
  • azodiyldipiperidine 302 mg, 1.20 mmoL
  • 5-(3-hydroxymethylphenyl)-4,6-dimethyl in a nitrogen atmosphere.
  • -3H-spiro [benzofuran-2, fluorenyl-cyclopropyl]-3-one 10c 160 mg, 0.54 mmol
  • S) 2-(6-hydroxy-2,3-dihydrobenzofuran -3-yl)methyl acetate 3D 136 mg, 0.65 mmoL
  • dry dichloromethane 15 mL
  • Step 5 (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro[benzofuran-2,1'-cyclopropyl]-5-) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 10)
  • Second step (S) 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzene) Methyl furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (lib)
  • Tributylphosphine (0.34 mL, 1.36 mmol) and azodiyldipiperidine (343 mg, 1.36 mmol) were added to 5-(3-(hydroxymethyl)phenyl)-2,2- under a nitrogen atmosphere.
  • Bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one 11a (220 mg, 0.62 mmol) and (S) 2-(6-hydroxy-2,3-di Methyl hydrobenzofuran-3-yl)acetate 3D (154 mg, 0.74 mmol) in dry methylene chloride (15 mL). The reaction solution was stirred at room temperature for 1 hour.
  • the third step (S) 2-(6-((3-(2,2-bis(methoxymethyl))-4,6-dimethyl-3-oxo-2,3-dihydrobenzene And furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 11)
  • Tributylphosphine 0.3 mL, 1.23 mmol
  • azodiyldipiperidine 317 mg, 1.23 mmol
  • Dihydrobenzofuran-5-yl)phenylmethanol 13c
  • (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate Ester 3D 129 mg, 0.62 mmol
  • dry methylene chloride 12 mL
  • Step 5 (3S) 2-(6-((3-(2,4,6-Trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 13)
  • Step 6 (S) 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-) Methyl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (14f)
  • Tributylphosphine (0.21 mL, 0.83 mmol) and azodiyldipiperidine (214 mg, 0.83 mmol) were added to 3-(2,2-bis(ethoxymethyl)-4 under nitrogen atmosphere.
  • 6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 14e 140 mg, 0.38 mmol
  • (S) 2-(6-hydroxy-2,3-dihydrobenzofuran Methyl 3-methyl)acetate 3D (94 mg, 0.45 mmoL) in dry dichloromethane (12 mL).
  • the reaction solution was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting product was directly subjected to the next reaction.
  • Step 7 (3S) 2-(6-((3-(2,2-Diethoxymethyl-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 14)
  • Step 3 ( S) 2-(6-((3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]-5-yl)benzyl)oxy)-2, Methyl 3-dihydrobenzofuran-3-yl)acetate (15c)
  • tributylphosphine (0.34 mL, 1.34 mmol) and azodiyldipiperidine (338 mg, 1.34 mmol) were added (3-(4,6-dimethyl-3H-spiro[benzo Furan-2, fluorenyl-cyclopropyl]-5-yl)benzyl alcohol 15b (170 mg, 0.61 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl) Methyl acetate 3D (139 mg, 0.67 mmoL) in dry methylene chloride (12 mL). The reaction mixture was stirred at room temperature for 2 hours.
  • Step 5 (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) - 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 16)
  • Step 8 Methyl 2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropane embankment] -5-yl) phenyl] methoxy] - 2, 3-dihydro-benzofuran-3-yl] acetate (18i)
  • Tributylphosphine (0.39 mL, 1.56 mmol) and hydrazine, hydrazine-(azo-dicarbonyl)dipiperidine (393 mg, 1.56 mmol) were added in vacuo, and stirred at room temperature for 3 hr.
  • Step 9 2-[(3S 6-[[3-(7-Fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl;)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 18)
  • Second step 2,2-bis[tert-butyl(dimethyl)methylsilyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl -benzofuran-3-one (19b) 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-benzofUran -3-one
  • Step 3 Methyl -2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl-3 -oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (19c)
  • Tributylphosphine (1.04 ml, 4.15 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (1.05 g, 4.15 mmol) were added, and then stirred at room temperature for 3 hr.
  • the residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) - bis[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy ]-2,3-Dihydrobenzofuran-3-yl]acetic acid 19c (1.2 g, yield 87%).
  • Step 5 2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl] Phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (Compound 19)
  • the third step 4,6-dimethyl-N-(3-methanesulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3- Dihydrobenzofuran-3-amine (20c)
  • Step 5 Methyl 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran) -5-yl]phenyl] Methyl methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetate (20e)
  • tributylphosphine (0.24 mL, 0.94 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (238 mg, 0.94 mmol) were sequentially added and stirred at room temperature for 2 hr.
  • Step 6 2-[(3S)-6-[[3-[4,6-Dimethyl-3-(3-methanesulfonylpropylamino)-2,3-dihydrobenzofuran-5 -yl]phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (compound 20)
  • Step 5 Methyl 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl)-2-fluoro-phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester (21f)

Abstract

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

Description

苯并呋喃衍生物、 其制备方法及其在医药上的应用 技术领域  Benzofuran derivative, preparation method thereof and application thereof in medicine
本发明涉及一种苯并呋喃衍生物、其制备方法及其在医药上的应用， 具体涉及一种具有 G 蛋白偶联受体 40(GPR40)受体功能调节作用的新颖的苯并呋喃衍生物或其立体异构体、 水合 物、 溶剂化物、 共晶体、 药学上可接受的盐或者前药、 其制备方法及包含其的药物组合物以及 其在医药上的应用。 背景技术  The present invention relates to a benzofuran derivative, a preparation method thereof and its use in medicine, in particular to a novel benzofuran derivative having a G protein-coupled receptor 40 (GPR40) receptor function regulating function. Or a stereoisomer, hydrate, solvate, co-crystal, pharmaceutically acceptable salt or prodrug thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and its use in medicine. Background technique
糖尿病及其并发症严重影响了人们的生活质量， 并成为导致死亡的重要原因之一， 糖尿病 中过高的血糖水平导致患者出现多尿、 多饮和多食的典型症状， 糖尿病的并发症如肾损伤、糖 尿病酮酸中毒和心脏病等可危及生命。 II型糖尿病是最常见的一类糖尿病， 主要发生在成年阶 段，主要表现为胰岛素分泌不足或胰岛素抵抗 (即机体组织不能有效对内源性胰岛素做出反应)， 遗传和环境等诸多因素均可导致胰岛素抵抗。  Diabetes and its complications seriously affect people's quality of life and become one of the important causes of death. Excessive blood sugar levels in diabetes lead to typical symptoms of polyuria, polydipsia and polyphagia. Diabetes complications such as Kidney damage, diabetic ketoacidosis and heart disease can be life threatening. Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly characterized by insufficient insulin secretion or insulin resistance (ie, the body tissue cannot respond effectively to endogenous insulin), genetic and environmental factors, etc. Causes insulin resistance.
糖尿病患者如果通过饮食和锻炼不能有效控制血糖， 则需注射激素类药物或口服降糖药。 目前已批准上市的口服降糖药包括磺酰脲类、 双胍类、 噻唑垸二酮类 CTZDS;»、 a-葡萄糖苷酶抑 制剂、糊精类似物 、 二肽基肽酶抑制剂 (DPP-IV) 、钠-葡萄糖协同转运蛋白 2 GLT-2)抑制剂 等类药物。 然而， 以上这些降糖药均有副作用， 如低血糖、 体重增加、 心血管风险和泌尿生殖 道感染等 (Vinod S. Deshmukh等 (2013). International Journal of Basic & Clinical Pharmacology? 2， 4-11), 这些副作用进一步加重了糖尿病患者的负担， 因此， 需要开发具有新型作用机制的 新一代降糖药。 If diabetics cannot effectively control their blood sugar through diet and exercise, they need to take hormonal drugs or oral hypoglycemic agents. Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolyldione CTZD S ;», a-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP) -IV), sodium-glucose cotransporter 2 GLT-2) inhibitors and the like. However, these hypoglycemic agents have side effects such as hypoglycemia, weight gain, cardiovascular risk and genitourinary tract infections (Vinod S. Deshmukh et al. (2013). International Journal of Basic & Clinical Pharmacology? 2, 4-11 These side effects further increase the burden on diabetic patients. Therefore, it is necessary to develop a new generation of hypoglycemic agents with a novel mechanism of action.
G蛋白偶联受体 40(GPR40)是一个具有降糖尿潜力的新靶点， 在胰岛 β细胞中高表达。 GPR40又称脂肪酸受体 1(FFAR1)， 是一个属于同源 G蛋白偶联受体超家族的膜受体， 在多种 物种中高度保守。 G蛋白偶联受体有 7次跨膜结构，可感受胞外信号，激活胞内信号转导通路， 并最终引起细胞应答， GPR40可被中长链游离脂肪酸 CFFAs)激活 (Itoh Y等 (2003). Nature, 422, 173-176)。 FFAs除了作为能量来源外， 也是一种重要的信号分子， 可促进胰岛素分泌， 该功能 主要是通过 GPR40 实现的。 FFAs与 GPR40相互作用后， 可通过胰岛 β细胞中的 PLC 或 L 型 Ca2+通道信号通路提高 Ca2+流量， 进而引起细胞应答 (Fujiwara等 (2005). Am J Physiol Endocrinol Metab, 289, E670-E677)。 研究表明， 在动物模型中， 激动 GPR40可有效降低血糖； 临床试验中，患者短期和长期使用 GPR40激动剂进行治疗均可促进葡萄糖诱导的胰岛素分泌， 并可提高葡萄糖耐量 (K Nagasumi等 (2009). Diabetes, 58， 1067-1076), 且由于 GPR40只有在 高水平血糖的情况下才可促进胰岛素分泌， 因此产生低血糖的风险低。 Fasiglifam hemihydrate(TAK-875)是目前已进入三期临床并被证明有效的 GPR40激动剂。 研究表明：在糖尿病动物模型中， fasiglifam hemihydrate (TAK-875)可促进胰岛素分泌并可有效 控制血糖， 而在正常大鼠中则不会促进胰岛素分泌 (Tsujihata Y等 (2010). Diabetes, 59， A165); 在临床试验中， fasiglifam hemihydrateCrAK-875)也表现出明显的降糖效果， 同时具有较低的低 血糖风险 (T. Araki等 (2012). Diabetes, Obesity and Metabolisml4, 271—278)。 其它一些 GPR40 激动剂也相继被开发， 如 JTT-851、 LY-2881835等。 G-protein coupled receptor 40 (GPR40) is a novel target with hypoglycemic potential and is highly expressed in islet beta cells. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane receptor belonging to the homologous G protein-coupled receptor superfamily and is highly conserved among many species. G protein-coupled receptors have seven transmembrane structures that can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses. GPR40 can be activated by medium-long-chain free fatty acid CFFAs (Itoh Y et al. (2003) ). Nature, 422, 173-176). In addition to being an energy source, FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40. The interaction of FFAs with GPR40 increases Ca 2+ flux through PLC or L-type Ca 2+ channel signaling pathways in islet beta cells, which in turn leads to cellular responses (Fujiwara et al. (2005). Am J Physiol Endocrinol Metab, 289, E670 -E677). Studies have shown that in animal models, agonistic GPR40 is effective in lowering blood glucose; in clinical trials, short-term and long-term treatment with GPR40 agonists promotes glucose-induced insulin secretion and increases glucose tolerance (K Nagasumi et al. (2009) Diabetes, 58, 1067-1076), and because GPR40 promotes insulin secretion only at high levels of blood glucose, the risk of hypoglycemia is low. Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical practice and has proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and effectively controls blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Tsujihata Y et al. (2010). Diabetes, 59, A165); In clinical trials, fasiglifam hemihydrateCrAK-875) also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml 4, 271-278). Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and the like.
综上所述， GPR40是一个安全可行的口服降糖药新靶点， GPR40激动剂的开发具有十分 重要的研究价值和应用前景。 目前一些关于 GPR40激动剂相关的研究文献相继公开。  In summary, GPR40 is a safe and feasible new target for oral hypoglycemic agents. The development of GPR40 agonists has very important research value and application prospects. A number of research literatures related to GPR40 agonists are currently published.
(1) US2006258722描述了可作为胰岛素分泌促进剂及糖尿病的预防和 /或治疗药的 GPR40 受体调节剂， 其结构式如 ：
Figure imgf000004_0001
(1) US2006258722 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic agent for diabetes, and its structural formula is as follows:
Figure imgf000004_0001
其中， Ar任选取代基的环状基团， A任选取代基的环状基团， 且不被噻唑、 噁唑、 咪唑 和吡唑所取代， Xa和 Xb各自独立选自键或包含 1-5个原子的链， Xc选自 0、 S、 SO或 S02， Xd选自键、 CH或 CH2， D选自苯环、 噻吩或噻唑， B选自 5至 7元的环， R1选自羟基。 不认 为此专利中具体描述是本发明的一部分。 Wherein, the cyclic group of the optionally substituted substituent of Ar, the cyclic group of the optional substituent of A, and not substituted by thiazole, oxazole, imidazole and pyrazole, each independently selected from a bond or containing 1 a chain of -5 atoms, Xc is selected from 0, S, SO or S0 2 , Xd is selected from a bond, CH or CH 2 , D is selected from a benzene ring, a thiophene or a thiazole, and B is selected from a ring of 5 to 7 members, R 1 is selected from a hydroxyl group. The specific description in this patent is not considered to be part of the present invention.
(2) CN101616913描述了可作为胰岛素分泌促进剂及糖尿病的预防和 /或治疗药的 GPR40 受体功能调节作用的稠环化合 其结构式如下：
Figure imgf000004_0002
(2) CN101616913 describes a fused ring compound which can function as an insulin secretion promoting agent and a GPR40 receptor function regulating effect of a preventive and/or therapeutic drug for diabetes, and has the following structural formula:
Figure imgf000004_0002
其中， R1选自 -S02-R6， ， R6选自 d— 6垸基或任选被取代的 1 ,1-二氧代四氢噻喃基， X选 自键或二价烃基； R2和 R3选自 H、 卤原子、被取代的烃基或被取代的羟基； R4和 R5选自被羟 基取代的^— 6垸基； A选自苯环， B选自 5至 7元环， Y选自键或 CH2， R选自羟基。 不认为 此专利中具体描述是本发明的一部分。 Wherein R 1 is selected from -S0 2 -R 6 , and R 6 is selected from d- 6 fluorenyl or optionally substituted 1,1-dioxotetrahydrothiopyranyl, and X is selected from a bond or a divalent hydrocarbon group. ; R 2 and R 3 are selected from H, a halogen atom, a substituted hydroxy group or substituted hydrocarbyl; R 4 and R 5 is selected from substituted with hydroxy ^ - 6 alkyl with; a is selected from a benzene ring, B 5 is selected from To a 7-membered ring, Y is selected from a bond or CH2, and R is selected from a hydroxyl group. The specific description in this patent is not considered to be part of the present invention.
(3) US7786165描述了 GPR40受体功能调节剂， 其结构式如下：  (3) US7786165 describes a GPR40 receptor function regulator with the following structural formula:
Figure imgf000004_0003
Figure imgf000004_0003
其中， Ar任选取代基的环状基团， 且不被 4-哌啶基取代， B任选取代基的环状基团， 且 不被噻唑或噁唑取代， V选自键或含有 1-3个原子的链， 且此链不为 -N=N-基团， W选自键或Wherein, Ar is optionally a cyclic group of a substituent, and is not substituted by a 4-piperidinyl group, and a cyclic group of the optional substituent of B, and Not substituted by thiazole or oxazole, V is selected from a bond or a chain containing 1-3 atoms, and this chain is not a -N=N- group, and W is selected from a bond or
6垸基， X、 Xa选自 CH或 N， Y选自 0或 CR6R7， R1和 Rla选自 H、 卤素、 d— 6垸基或 d— 6 垸氧基， R2选自 H、 d— 6垸基或任选取代的酰基， R3和 R4选自 H或卤素， R5选自取代的羟基 或取代的胺基， 不认为 US7786165中具体描述的化合物是本发明的一部分。 6垸, X, Xa is selected from CH or N, Y is selected from 0 or CR 6 R 7 , and R 1 and R la are selected from H, halogen, d- 6 fluorenyl or d- 6 methoxy, R 2 is selected From H, d- 6 fluorenyl or optionally substituted acyl, R 3 and R 4 are selected from H or halogen, and R 5 is selected from substituted hydroxy or substituted amine groups, and the compounds specifically described in US7786165 are not considered to be the present invention. a part of.
(4) WO2010143733描述了可作为胰岛素分泌促进剂及糖尿病的预防和 /或治疗药的 GPR40 受体调节剂， 其结构式如下：  (4) WO2010143733 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic drug for diabetes, and its structural formula is as follows:
Figure imgf000005_0001
Figure imgf000005_0001
其中， R1选自卤素、 羟基、 任选取代的 d— 6垸基或任选取代的 d— 6垸氧基； R2选自取代 的羟基， R3选自 H、 卤素或任选取代的 d_6垸基， X是 CH2， Y选自 CH2、 NH或 0， Z选自 CH或 N， A选自卤素、任选取代的胺基或 4-13元环。不认为 WO2010143733中具体描述的化 合物是本发明的一部分。 发明内容 Wherein R 1 is selected from halogen, hydroxy, optionally substituted d- 6 fluorenyl or optionally substituted d- 6 fluorenyloxy; R 2 is selected from substituted hydroxy, R 3 is selected from H, halogen or optionally substituted the embankment d_ 6-yl, X is CH 2, Y is selected from CH 2, NH or 0, Z is selected from CH or N, a is selected from halogen, an optionally substituted amino group or 4-13 membered ring. Compounds specifically described in WO2010143733 are not considered to be part of the present invention. Summary of the invention
本发明提供一类结构新颖如通式 ω所示的化合物， 经过研究表明， 本发明化合物作为 GPR40激动剂显示出优异的药效活性。  The present invention provides a novel structure of a compound represented by the formula ω, which has been shown to exhibit excellent pharmacodynamic activity as a GPR40 agonist.
本发明优选方案， 一种通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000005_0002
Figure imgf000005_0002
其中： among them:
R选自 H、 d— 8垸基或 PEG, 优选 H或 d— 6垸基， 更优选 11或 — 4垸基， 进一步优选 H; 环 Q选自 5至 8元碳环基或杂环基， 优选 5至 6元碳环基或杂环基， 更优选 5元碳环基 或杂环基， 进一步优选选 5元杂环基， 所述的杂环基含有 1至 4个 N、 0或 3(=0)11原子或者 基团 (其中当含有多个 N、 0或 S(=0)n原子或者基团时， 各杂原子可相同或不同， 下文中类似 的描述具有相同的含义， 不再赘述 )， 优选 1至 3个^^、 0或 3(=0)11原子或者基团， 更优选 1 至 2个 N、 0或 S(=0)n原子或者基团， 所述的碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 -(CH2)m - 烯基 -R12、 -(CH2)m -炔基 -R12、 -0-C(=0)-0-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-S(=0)n-R12或者 -NR13R13a的取代基所取代 (其中当具有多个取代基时， 各取代基可相同 或不同， 下文中类似的描述具有相同的含义， 不再赘述 )， 优选 0至 3个选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d_6垸基、 d_6垸氧基、 -0-C(=0)-0-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-S(=0)n-R12或者 -NR13R13a， 更优选 0至 3个 选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 6垸基或 d— 6垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 4 垸基或 CM垸氧基， 进一步优选 F、 d— 3垸基或 d— 3垸氧基； R is selected from H, d- 8 fluorenyl or PEG, preferably H or d- 6 fluorenyl, more preferably 11 or -4- mercapto, further preferably H; ring Q is selected from a 5- to 8-membered carbocyclic or heterocyclic group. a 5- to 6-membered carbocyclic group or a heterocyclic group, more preferably a 5-membered carbocyclic group or a heterocyclic group, further preferably a 5-membered heterocyclic group having 1 to 4 N, 0 or 3 (=0) 11 atoms or groups (wherein when a plurality of N, 0 or S(=0) n atoms or groups are present, each hetero atom may be the same or different, and similar descriptions have the same meanings hereinafter, 1), preferably 1 to 3 ^^, 0 or 3 (=0) 11 atoms or groups, more preferably 1 to 2 N, 0 or S (=0) n atoms or groups, Carbocyclyl or heterocyclyl optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, D- 8 methoxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-R 12 , Substituted by a substituent of -(CH 2 ) m -S(=0) n -R 12 or -NR 13 R 13a (wherein, when having a plurality of substituents, each substituent may be the same or different, a similar description hereinafter Having the same meaning, no further details), preferably 0 to 3 selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 6 fluorenyl, d_ 6 methoxy, -0-C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)- R 12 , —(CH 2 ) m —S(=0) n —R 12 or —NR 13 R 13a , more preferably 0 to 3 selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyanide a group, an amino group, a nitro group, a hydroxyl group, a carboxyl group, a d- 6 fluorenyl group or a d- 6 methoxy group, further preferably 0 to 2 members selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, An amino group, a nitro group, a hydroxyl group, a carboxyl group, a d- 4 fluorenyl group or a C M decyloxy group, further preferably F, d- 3 fluorenyl or d- 3 decyloxy;
R1, R2、 R3和 R4各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 8垸基或 d— 8垸氧基， 优选 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 d— 6垸基或 d— 6垸氧基， 更优选 H、 F、 Cl、 Br、 I、 氰基、 羟基、 d— 4垸基或 d— 4垸氧基， 进一步优选 H、 F、 Cl、 氰基、 羟基、 d— 3垸基或 d— 3垸氧基， 进一步优选 H、 F、 Cl、 d— 2垸基或 d— 2垸氧基， 进一步优选 H、 F或 Cl， 其中所述垸基、垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 6垸基或者 d_6垸氧基， 更优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基或者 d_4垸 氧基的取代基所取代， 进一步优选 0至 2个选自 F、 Cl、 -CF3、 d— 3垸基或者^— 3垸氧基， 进 一步优选 F、 d_2垸基或者 d— 2垸氧基； R 1, R 2, R 3 and R 4 are each independently optionally selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8 or 8 embankment D- Oxy group, preferably H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, more preferably H, F, Cl, Br, I, cyanide Further, H, F, Cl, cyano, hydroxy, d- 3 fluorenyl or d- 3 decyloxy, more preferably H, F, Cl, a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group. Or d-2 methoxy, more preferably H, F or Cl, wherein the fluorenyl, decyl or amino groups are each independently optionally further from 0 to 4 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, -(CH 2 m - alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0) -0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)- 0-R 12 or -NR 13 R 13a substituent Substituted, preferably 0 to 3 substituents selected from F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, hydroxy, d- 6 alkyl with or embankment d_ 6 group, More preferably, 0 to 3 substituents selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl or d 4 methoxy are substituted, further preferably 0 to 2 One selected from the group consisting of F, Cl, -CF 3 , d-3 fluorenyl or methoxycarbonyl, further preferably F, d 2 fluorenyl or d 2 fluorenyloxy;
R5、 R6、 R7、 R8、 R9、 R1。和 R11各自独立地选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、异氰基、氨基、硝基、羟基、羧基、 C 垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基、 -(CH2)m- 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基)或者 -0-(CH2)m-(3至 10元杂环基)， 优选 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 6垸基、 6垸氧基、 - — 6垸 基 -O-d— 6垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 更优 选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、氰基、羟基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基 -O-d— 4 垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)，进一 步优选 H、 F、 Cl、 Br、 羟基、 氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基、 -(CH2)m - 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3 至 6元杂环基)，进一步优选 H、 F、 Cl、 Br、羟基、氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基 -O-d— 4 垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 4元碳环基)或 者 -0-(CH2)m-(3至 4元杂环基)， 进一步优选 H、 F、 Cl、 Br、 羟基、 氰基、 d— 4垸基、 d— 4垸氧 基、 -CM垸基 -O-CM垸基或者 -(CH2)mS(=0)nR12，进一步优选 H、 d_4垸基、 d_4垸氧基或者 -d_4 垸基 -O-d— 4垸基， 所述的杂环基含有 1至 4个 N、 0或 3(=0；)11原子或者基团， 优选 1至 3个 选自 N、 0或 S的杂原子， 更优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸 基、 -(CH2)m-烯基 -R12、 -(CH2)m-炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12 、 -(CH2)m-C(=0)-NR13R13a 、 -0-C(=0)-NR13R13a 、 -0-C(=0)-R12 、 -0-C(=0)-0-R12 、 -(CH2)mS(=0)nR12 、 -N(R12b)C(=0)NR13R13a 、 -N(R12b)C(=0)R12 、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基;)或者 -CKCH2)m-(3至 10元杂环基;)的取代基所取代，优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 氨基、 硝基、 羟基、 羧基、 d— 6垸基、 d— 6垸氧基、 -(CH2)m - 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a 或者 -(CH2)mS(=0)nR12， 更优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟 基、 d— 4垸基或者 — 4垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3 垸基或者 3垸氧基， 进一步优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2垸基或者 d— 2垸氧 基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 — 2垸氧基； R 5 , R 6 , R 7 , R 8 , R 9 , R 1 . And R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, C decyl , d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12, - (CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m - C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N(R 12b ) C(=0)OR 12 , -(CH 2 ) m -(3 to 10 membered carbocyclic group), -(CH 2 ) m -(3 to 10 membered heterocyclic group), -0-(CH 2 m - (3 to 10 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 10 membered heterocyclic group), preferably H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d- 6 fluorenyl, 6 methoxy, - 6 fluorenyl-Od- 6 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m - alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0) -0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m -(3 to 6 membered carbocyclic group), -(CH 2 ) m - (3 to 6-membered heterocyclic group), -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered heterocyclic group), preferably F, Cl, Br, -CH 2 F, -CHF 2, -CF 3, cyano, hydroxy, d- 4 alkyl with, d- 4 embankment group, -d- 4 alkyl with alkyl with -Od- 4 -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0 )-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(= 0) n R 12 , -(CH 2 ) m - (3 to 6-membered carbocyclic group), -(CH 2 ) m -(3 to 6-membered heterocyclic group), -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6 membered) a heterocyclic group), more preferably H, F, Cl, Br, hydroxy, cyano, d- 4 alkyl with, d- 4 embankment group, -d- 4 alkyl with - Od- 4 embankment group, - (CH 2 m - alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m -(3 to 6 Or a carbocyclic group) or -0-(CH 2 ) m - (3 to 6 membered heterocyclic group), further preferably H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl, d- 4垸group, -d- 4 alkyl with embankment -Od- 4-yl, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12, - (CH 2) m S ( =0) n R 12 , -0-(CH 2 ) m - (3 to 4 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 4 membered heterocyclic group), further preferably H, F , Cl, Br, hydroxy, cyano, d- 4 fluorenyl, d- 4 methoxy, -CM thiol-O-CM thiol or -(CH 2 ) m S(=0) n R 12 , further Preferred is H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-Od- 4 -yl, said heterocyclic group containing 1 to 4 N, 0 or 3 (=0;) 11 atoms or a group, preferably 1 to 3, selected from N a hetero atom of 0 or S, more preferably 1 to 2 hetero atoms selected from N, 0 or S, said fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclyl or heterocyclic group optionally further From 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 alkyl with, d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12, - (CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0- R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N (R 12b )C(=0)OR 12 , —(CH 2 ) m —(3 to 10 membered carbocyclic group), —(CH 2 ) m —(3 to 10 membered heterocyclic group), —0—( Substituting CH 2 ) m - (3 to 10 membered carbocyclyl;) or -CKCH 2 ) m - (3 to 10 membered heterocyclic;), preferably 0 to 3 selected from F, Cl, Br , I, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy Base, d- 6 fluorenyl, d- 6 methoxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C( =0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a or -(CH 2 ) m S (=0) n R 12 , more preferably 0 to 3 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d-4 fluorenyl or — 4 Further, the methoxy group, more preferably 0 to 2, is selected from the group consisting of F, Cl, Br, -CF 3 , cyano, hydroxy, d- 3 fluorenyl or 3- decyloxy, and further preferably 0 to 1 is selected from F, Cl, a cyano group, a hydroxyl group, a d- 2 fluorenyl group or a d- 2 fluorenyloxy group, further preferably 0 to 1 member selected from the group consisting of F, d- 2 fluorenyl or -2- decyloxy;
作为选择， R6和 R7可以形成 (=0;^=CR12R12b， 优选形成 (=0); Alternatively, R 6 and R 7 may form (=0; ^ = CR 12 R 12b , preferably formed (=0);
作为选择， R8和 R9可以形成 (=0;^=CR12R12b， 优选形成 (=0); Alternatively, R 8 and R 9 may form (=0; ^ = CR 12 R 12b , preferably formed (=0);
作为选择， R6与 R7、 R与 R8、 R与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 8元碳环或 3至 8元杂环， 优选形成一个 3至 6元碳环或 3至 6元杂环， 更优选 R6与 R7、 R8与 R9的任意一组可以形成一个 3至 6元碳环或 3至 6元杂环， 进一步优选 3至 4 元碳环或 3至 4元杂环， 进一步优选 3元碳环或 3元杂环， 进一步优选 3元碳环， 所述的杂环 含有 1至 4个 N、 0或 3(=0)11原子或者基团， 优选 1至 3个选自 N、 0或 S(=0)n原子或者基 团， 更优选 1至 2个选自 N、 0或 3(=0)11原子或者基团， 所述的碳环或杂环任选进一步被 0 至 4个 R 的取代基所取代 (其中当具有多个 Ri^时， 各 R12a可在所述范围内相同或不同 优 选 0至 3个选自 0至 3个 R12a， 更优选 0至 2个 R12a; R12a选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 Ci-8焼基、 Ci-8焼氧基、 Ci-8焼基 -O-Ci— 8焼基、 -(CH2)m-j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基)或者 -0-(CH2)m-(3至 10元杂环基)， 优选 F、 Cl、 Br、 I、 =0、 羟 基、氣基、 Ci— 6焼基、 6焼氧基、 6焼基 -0- 6焼基、 -(C¾)m -稀基 -R12、 -(C¾)m-块基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12 、 -(CH2)m-C(=0)-0-R12 、 -(CH2)mC(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)或 -(CH2)m-(3至 6元杂环基)， 更优选 F、 Cl、 Br、 I、 =0、羟基、氰基、 d— 6垸基、 d— 6垸氧基、 d— 6垸基- 0-d— 6垸基、 -(CH2)m -烯基 -R12、 -(CH2)m- 炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)mC(=0)-NR13R13a 或者 -(CH2)mS(=0)nR12， 进一步优选 F、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基、 d— 4垸基 -O-d— 4垸基或者 -(CH2)mS(=0)nR12， 进一步优选 F、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基 或者 CM垸基 O-d— 4垸基，进一步优选 F、 =0、羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 O-d— 3 垸基， 优选 F、 d— 2垸基、 d— 2垸氧基或者 d— 2垸基 O-d— 2垸基， 所述的杂环含有 1至 4个^^、 0或 3(=0)11原子或者基团， 优选 1至 3个选自 N、 0或 S的杂原子， 更优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步被 0至 4个 选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d_8垸 基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基;)或者 -C CH2)m-(3至 10元杂环基;） 的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 6垸基、 d— 6垸氧 基、 -d— 6垸基- O-d— 6垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12或者 -(CH2)mS(=0)nR12，更优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基、 d_4垸氧基， 进一步优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 CM垸基或 CM垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 优选 0至 1个选自 F、 d— 2垸基或这 — 2垸氧基； Alternatively, any one of R 6 and R 7 , R and R 8 , R and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 8 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, preferably forming a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably R 6 and R 7 , any of R 8 and R 9 may form a 3 to 6 membered carbocyclic ring. Or a 3- to 6-membered heterocyclic ring, further preferably a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, and the heterocyclic ring contains 1 Up to 4 N, 0 or 3 (=0) 11 atoms or groups, preferably 1 to 3 atoms selected from N, 0 or S(=0) n atoms or groups, more preferably 1 to 2 selected from N, 0 or 3 (=0) 11 atoms or groups, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 4 substituents of R (wherein when having a plurality of Ri^, each R 12a may be The same or different preferably 0 to 3 in the range is selected from 0 to 3 R 12a , more preferably 0 to 2 R 12a ; R 12a is selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, Ci-8 fluorenyl, Ci-8 methoxy, Ci-8 fluorenyl-O-Ci-8 fluorenyl, -(CH 2 ) m -j: thiol-R 12 , -(CH 2 ) m -blockyl-R 12 , (CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0- R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N (R 12b )C(=0)OR 12 , —(CH 2 ) m —(3 to 10 membered carbocyclic group), —(CH 2 ) m —(3 to 10 membered heterocyclic group), —0—( CH 2 ) m - (3 to 10 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 10 membered heterocyclic group), preferably F, Cl, Br, I, =0, hydroxyl group, gas group , the CI-6-yl firing, firing group 6, 6 -0-6 firing firing yl group, - (C¾) m - group dilute -R 12, - (C¾) m - block basis -R 12, - (CH 2 m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m C( =0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m - (3 to 6 membered carbocyclic group) or -(CH 2 ) m - (3 to 6 membered heterocyclic group), more preferably F, Cl, Br, I, =0, hydroxy, cyano, d —6 fluorenyl, d- 6 methoxy, d- 6 fluorenyl- 0-d- 6 fluorenyl, —(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -( CH 2 ) m C(=0)-NR 13 R 13a or -(CH 2 ) m S(=0) n R 12 , further preferably F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d --4 embankment group, d- 4 alkyl with -Od- 4 alkyl with or - (CH 2) m S ( = 0) n R 12, more preferably F, Cl, Br, = 0 , hydroxy, d- 4 embankment Further, d- 4 methoxy or CM fluorenyl Od-4 fluorenyl, further preferably F, =0, hydroxy, d-3 fluorenyl, d-3 decyloxy or d- 3 fluorenyl Od- 3 fluorenyl Preferably, F, d- 2 fluorenyl, d- 2- decyloxy or d- 2 fluorenyl Od- 2 fluorenyl, said heterocyclic ring containing 1 to 4 ^, 0 or 3 (=0) 11 atoms Or a group, preferably 1 to 3 hetero atoms selected from N, 0 or S, more preferably 1 to 2 hetero atoms selected from N, 0 or S, said mercapto group Embankment alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is further optionally substituted with 0 to 4 substituents selected from F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, cyano , isocyano, amino, nitro, hydroxy, carboxy, d_ 8 alkyl with, d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl group -R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m - C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0 )-R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N(R 12b )C(=0)OR 12 , -(CH 2 ) m -(3 to 10 membered carbocyclic group), -(CH 2 ) m - (3 to 10 membered heterocyclic group), -0-(CH 2 ) m - (3 to 10 membered carbocyclic group;) or -C CH 2 ) m - (3 to 10 membered heterocyclic group; Substituted by a substituent, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d - 6 alkyl with, d- 6 embankment group, -d- 6 alkyl with - Od- 6 alkyl with, - (CH 2 m - alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 or -(CH 2 ) m S(=0) n R 12 , more preferably 0 to 3 selected from F , Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d_ 4 fluorenyl, d 4 methoxy, more preferably 0 to 3 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , CM thiol or CM methoxy, further preferably 0 to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or D- 4 methoxy, more preferably 0 to 1 selected from F, Cl, Br, -CF 3 , d- 3 fluorenyl or d- 3 methoxy, preferably 0 to 1 selected from F, d-2 Mercapto or this - 2 methoxy group;
作为选择， 当两个 R12a连接在同一个原子上时， 可与它们相连的原子一起形成一个 3至 8 元碳环或 3至 8元杂环， 优选 3至 6元的碳环或 3至 6元的杂环， 更优选 3至 6元的杂环， 所 述的杂环含有 1至 4个^^、 0或 3(=0)11原子或者基团， 优选 1至 3个选自 N、 0或 S的杂原 子， 更优选 1至 2个选自 N、 0或 S的杂原子， 所述的碳环或杂环任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基;)或者 -CKCH2)m-(3至 10元杂环基;)的取代基所取代，优选 0至 3个选自 F、 Cl、 Br、 I、 羟基、 氰基、 d— 6垸基、 d— 6垸氧基或 -C^C -d— 4垸基， 更优选 0至 2个选自 F、 Cl、 Br、 羟基、氰基、 d— 4垸基或者 — 4垸氧基，进一步优选 0至 2个选自 F、 d— 3垸基或者^— 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 — 2垸氧基； Alternatively, when two R 12a are attached to the same atom, they can form a 3 to 8 together with the atoms to which they are attached. a carbocyclic ring or a 3 to 8 membered heterocyclic ring, preferably a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 6 membered heterocyclic ring, said heterocyclic ring having 1 to 4 ^^ , 0 or 3 (=0) 11 atoms or groups, preferably 1 to 3 hetero atoms selected from N, 0 or S, more preferably 1 to 2 hetero atoms selected from N, 0 or S, said The carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 alkyl with, d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(= 0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0) R 12 , -N(R 12b )C(=0)OR 12 , -(CH 2 ) m -(3 to 10 membered carbocyclic group), -(CH 2 ) m - (3 to 10 membered heterocyclic group) , -0- (CH 2) m - (3 to 10-membered carbocyclic;) or -CKCH 2) m - (3 to 10-membered heterocyclic ;) The substituents, preferably 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, cyano, d- 6 alkyl with, d- 6 embankment group or a -C ^ C -d- 4 embankment More preferably 0 to 2 are selected from the group consisting of F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl or -4- decyloxy, further preferably 0 to 2 selected from F, d- 3 fluorenyl or ^ — 3垸 oxy, more preferably 0 to 1 selected from F, d— 2 fluorenyl or — 2 fluorenyloxy;
Ri2、 Ri2b、 Ri3和 Ri3a选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 巯基、 异氰 基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 3至 10元碳环基或 3至 10元杂环基， 优选 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 6垸基、 d— 6垸氧基、 3至 6元碳环基或 3至 6元杂环基， 更优选 H、 F、 Cl、 Br、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 3 至 6元碳环基或 3至 6元杂环基， 进一步优选 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧基、 3至 6 元碳环基或 3至 6元杂环基， 进一步优选 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧基、 3至 5元碳 环基或 3至 5元杂环基， 进一步优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5元杂环 基， 优选 d— 2垸基或 d— 2垸氧基， 所述的杂环基含有 1至 4个^^、 0或 3(=0)11原子或者基团， 优选 1至 3个选自 N、 0或 S(=0)n原子或者基团， 更优选 1至 2个选自 N、 0或 S(=0)n原子 或者基团， 所述的垸基、 垸氧基、 碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 -CLS 垸基 -O-d— 8 垸基、 -(CH2)m-烯基 -R12、 -(CH2)m-炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基;)或者 -CKCH2)m-(3至 10元杂环基;)的取代基所取代，优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 6垸基、 d— 6垸氧基、 -Ci_6 垸基 -O-d— 6 垸基、 -(CH2)m-烯基 -R12、 -(CH2)m-炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12或者 -(CH2)mS(=0)nR12，更优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d— 4垸基、 CM垸氧基， 进一步优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 R i2 , R i2b, Ri 3 and R i3a are selected from the group consisting of H , F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy , a carboxyl group, a d- 8 fluorenyl group, a d- 8 methoxy group, a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, Amino group, d- 6 fluorenyl group, d- 6 methoxy group, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, more preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, D- 4 fluorenyl, d- 4 methoxy, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic group, further preferably H, F, Cl, Br, d 4 fluorenyl, d 4 methoxy, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, further preferably H, F, Cl, Br, d 4 fluorenyl, d 4 fluorenyloxy, 3 to 5 membered carbocyclic group or 3 to 5 membered hetero a cyclo group, further preferably a d- 3 fluorenyl group, a d- 3 methoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group, preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group, The heterocyclic group contains 1 to 4 ^, 0 or 3 (=0) 11 atoms or groups, preferably 1 to 3 selected from N, 0 or S (=0) n More preferably 1 to 2 atoms or groups selected from N, 0 or S(=0) n atoms or groups, said fluorenyl, decyloxy, carbocyclyl or heterocyclic group being optionally further Up to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl , d- 8 methoxy, -CLS fluorenyl-Od- 8 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C( =0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 , - (CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N(R 12b ) C(=0)OR 12 , -(CH 2 ) m -(3 to 10 membered carbocyclic group), -(CH 2 ) m -(3 to 10 membered heterocyclic group), -0-(CH 2 ) m - (3 to 10 membered carbocyclic group;) or -CKCH 2 ) m - (3 to 10 membered heterocyclic group;) substituent, preferably 0 to 3 selected from F, Cl, Br, I, - CH 2 F, -CHF 2, -CF 3, cyano, isocyano, amino, nitro, hydroxy, Base, d- 6 alkyl with, d- 6 embankment group, -Ci_ 6 alkyl with alkyl with -Od- 6, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl - R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , - (CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0 -0-R 12 or -(CH 2 ) m S(=0) n R 12 , more preferably 0 to 3 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d - 4 fluorenyl, CM methoxy, more preferably 0 to 3 selected from F, Cl, Br, -CH 2 F, -CHF 2 ,
-CF3、 d_4垸基或 d_4垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 CM垸基或 d— 4垸氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 优选 0至 1个选自 F、 d— 2垸基或这^— 2垸氧基； -CF 3 , d 4 fluorenyl or d 4 methoxy, more preferably 0 to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , CM thiol or d - 4 fluorene The oxy group, further preferably 0 to 1 is selected from the group consisting of F, Cl, Br, -CF 3 , d- 3 fluorenyl or d- 3 methoxy, preferably 0 to 1 selected from F, d- 2 fluorenyl or this ^ —2 methoxy;
作为选择， R12与 R12b、 R13与 1 1¾可以形成 3至 8元碳环或 3至 8元杂环， 优选 3至 6元 的碳环或 3至 6元的杂环， 更优选 3至 6元的杂环， 所述的杂环含有 1至 4个 N、 0或 S(=C n 原子或者基团， 优选 1至 3个选自 N、 0或 3(=0)11原子或者基团， 更优选 1至 2个选自 N、 0 或 3(=0)11原子或者基团， 所述的碳环或杂环任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、氰基、异氰基、氨基、硝基、羟基、羧基、 d— 8垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8 垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12 、 -(CH2)m-C(=0)-NR13R13a 、 -0-C(=0)-NR13R13a 、 -0-C(=0)-R12 、 -0-C(=0)-0-R12 、 -(CH2)mS(=0)nR12 、 -N(R12b)C(=0)NR13R13a 、 -N(R12b)C(=0)R12 、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基;)或者 -CKCH2)m-(3至 10元杂环基;)的取代基所取代，优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 6垸基、 d— 6垸氧基、 -Ci_6 垸基 -O-d— 6 垸基、 -(CH2)m-烯基 -R12、 -(CH2)m-炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12或者 -(CH2)mS(=0)nR12，更优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基、 d_4垸氧基， 进一步优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 CM垸基或 d_4垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 CM垸基或 d— 4垸氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 优选 0至 1个选自 F、 d— 2垸基或这 — 2垸氧基； Alternatively, R 12 and R 12b , R 13 and 1 13⁄4 may form a 3 to 8 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, preferably a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably 3 a 6-membered heterocyclic ring containing 1 to 4 N, 0 or S (=C n atoms or groups, preferably 1 to 3 atoms selected from N, 0 or 3 (=0) 11 atoms or a group, more preferably 1 to 2, selected from N, 0 or 3 (=0) 11 atoms or groups, optionally further 0 to 4 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, -d- 8 fluorenyl - Od- 8 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0- C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N(R 12b )C(=0)R 12 , -N(R 12b )C(=0)OR 12 , -(CH 2 m - (3 to 10 membered carbocyclic group), -(CH 2 ) m - (3 to 10 membered heterocyclic ring) Substituted with a substituent of -0-(CH 2 ) m -(3 to 10 membered carbocyclic group;) or -CKCH 2 ) m - (3 to 10 membered heterocyclic group;), preferably 0 to 3 Selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 6 fluorenyl, d- 6 oxime , -Ci_ 6 fluorenyl-Od- 6 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 or -(CH 2 ) m S(=0) n R 12 , more preferably 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl, d 4 methoxy, further Preferably, 0 to 3 are selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , CM fluorenyl or d 4 methoxy, and further preferably 0 to 2 are selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , CM fluorenyl or d- 4 methoxy, more preferably 0 to 1 selected from F, Cl, Br, -CF 3 , d- 3 fluorenyl or d- 3 methoxy group, preferably 0 to 1 One selected from the group consisting of F, d-2 fluorenyl or this quinoneoxy;
p选自 0、 1、 2或 3， 优选 0、 1或 2， 更优选 0或 1， 进一步优选 0;  p is selected from 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
q选自 0、 1、 2、 3或 4， 优选 0、 1或 2， 更优选 0或 1， 进一步优选 0;  q is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
t选自 0、 1或 2， 优选 0或 1， 更优选 1 ;  t is selected from 0, 1 or 2, preferably 0 or 1, more preferably 1;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明中， 所述的 "作为选择"是指"作为选择"之后的方案与 "作为选择"之前的方案为并列 选择关系， 而非是在前述方案中的进一步选择。  In the present invention, the phrase "as a selection" means that the scheme after "as a selection" is a side-by-side selection relationship with the scheme before "as a selection", rather than a further selection in the foregoing scheme.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1, R2、 R3和 R4各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 d— 6垸基 或 d— 6垸氧基， 优选 H、 F、 Cl、 Br、 I、 氰基、 羟基、 d— 4垸基或 d— 4垸氧基， 更优选 H、 F、 氰基、 羟基、 d— 3垸基或 d— 3垸氧基， 进一步优选 H、 d— 2垸基或 d— 2垸氧基， 进一步优选 H， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、羟基、 d— 6垸基或者 d— 6垸氧基的取代基所取代， 优选 0至 3个选 自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基或者 d_4垸氧基的取代基所取代， 更优选 0 至 2个选自 F、 Cl、 -CF3、 d— 3垸基或者 d— 3垸氧基， 进一步优选 F、 d— 2垸基或者 d— 2垸氧基， 进一步优选 2垸氧基； R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl Or d- 6 methoxy, preferably H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, cyano, hydroxy, d- 3 fluorenyl or d-3 methoxy, further preferably H, d- 2 fluorenyl or d- 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group are each independently optionally further 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 fluorenyl or d- 6 fluorenyloxy Substituted, preferably 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl or d 4 methoxy, more preferably 0 Up to 2 selected from F, Cl, -CF 3 , d - 3 fluorenyl or d - 3 decyloxy, further preferably F, d - 2 fluorenyl or d - 2 decyloxy, further preferably 2 decyloxy;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 羟基、 d— 6垸基、 d— 6垸氧基或 者 6垸基 -O-d— 6垸基， 优选 H、 F、 Cl、 Br、 I、 d— 4垸基或 d— 4垸氧基， 更优选 H、 F、 d— 3 垸基或 d— 3垸氧基， 进一步优选 H、 F、 d— 2垸基或 d— 2垸氧基， 进一步优选 H或 d— 2垸基， 所述垸基、垸氧基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 6垸基或者 d— 6垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 I、 d— 4垸基或者^— 4 垸氧基的取代基所取代， 更优选 0至 2个选自 F、 d— 3垸基或者 — 3垸氧基， 进一步优选 F、 2垸基或者 — 2垸氧基， 进一步优选 d— 2垸氧基。 R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl Preferably, H, F, Cl, Br, I, d- 4 fluorenyl or d- 4 fluorenyloxy, more preferably H, F, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H or d - 2 fluorenyl, the fluorenyl and decyloxy groups each independently optionally further from 0 to 3 selected from F, Cl, Br, Substituting for a substituent of I, -CH 2 F, -CHF 2 , -CF 3 , 6 fluorenyl or d- 6 methoxy, preferably 0 to 2 are selected from the group consisting of F, Cl, Br, I, d- 4 Substituted with a substituent of a 4- methoxy group, more preferably 0 to 2 is selected from the group consisting of F, d- 3 fluorenyl or -3- decyloxy, further preferably F, 2 fluorenyl or -2- decyloxy, Further preferred is d- 2- nonyloxy.
本发明优选方案， 包括通式（I)所示的化合物或所有其立体异构体、 水合物、 酯、 溶剂化 物、 药学上可接受的盐或者前药， 其中：  Preferred embodiments of the invention include a compound of the formula (I) or all stereoisomers, hydrates, esters, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein:
R1, R2、 R3和 R4各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、羟基、 d— 4垸基或 d— 4垸氧基， 优选 H、 F、 氰基、 羟基、 d— 3垸基或 d— 3垸氧基， 更优选 H、 d— 2垸基或 d— 2垸氧基， 进一步 优选 H， 其中所述垸基或垸氧基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或者^— 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 -CF3、 d— 3 垸基或者^— 3垸氧基， 更优选 F、 d— 2垸基或者^— 2垸氧基， 进一步优选 d— 2垸氧基； R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 decyloxy, preferably H, F, cyanide a hydroxy group, a d- 3 fluorenyl group or a d- 3 methoxy group, more preferably H, d- 2 fluorenyl or d- 2 methoxy, more preferably H, wherein the fluorenyl or decyloxy group is independently Optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or -4- methoxy, preferably 0-2 is selected from F, Cl, -CF 3, d- 3 ^ alkyl with or --3 embankment group, more preferably F, d- 2-yl or embankment ^ - 2 embankment group, more preferably d- 2 embankment Oxylate
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 I、 d_4垸基或 d_4垸氧基， 优选 H、 F、 3垸基或 d— 3垸氧基， 更优选 H、 F、 d— 2垸基或 d— 2垸氧基， 进一步优选 H或 d— 2垸基， 所 述垸基或者垸氧基各自独立地任选进一步被 0至 2个选自 F、 Cl、 Br、 I、 d— 4垸基或者 d— 4垸 氧基的取代基所取代， 优选 0至 2个选自 F、 d— 3垸基或者 — 3垸氧基， 更优选 F、 d— 2垸基或 者^— 2垸氧基， 进一步优选 d— 2垸氧基。 R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, d 4 fluorenyl or d 4 methoxy, preferably H, F, 3 decyl or d- 3 decyloxy, More preferably, H, F, d- 2- indenyl or d- 2- nonyloxy, further preferably H or d- 2- indenyl, each independently optionally further selected from 0 to 2 Substituted with a substituent of F, Cl, Br, I, d- 4 fluorenyl or d- 4 methoxy, preferably 0 to 2 are selected from F, d- 3 fluorenyl or -3- decyloxy, more preferably F , or alkyl with d- 2 ^ - 2 embankment group, more preferably d- 2 embankment group.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中：  Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1, R5、 R1Q和 R11各自独立地选自 H、 F、 Cl、 Br、 I、 甲基、 乙基、 丙基、 异丙基、 丁基、 甲氧基、 乙氧基、 丙氧基、 甲氧基甲基、 甲氧基乙基、 甲氧基丙基、 乙氧基甲基或者乙氧基乙 基， 优选 H、 F、 甲基、 乙基、 甲氧基、 乙氧基、 甲氧基甲基、 甲氧基乙基、 乙氧基甲基或者 乙氧基乙基， 更优选 H、 甲基、 乙基、 甲氧基或乙氧基， 进一步优选 H或甲基。 本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： R 1 , R 5 , R 1Q and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, Propyloxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, F, methyl, ethyl, methoxy, B Oxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably H, methyl, ethyl, methoxy or ethoxy, further preferably H or A base. Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 Ci_6焼基、 Ci_6焼氧基、 -Ci_6焼基 -O-Ci— 6焼基、 -(CH2)m- j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元 碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 优选 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元 碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 更优选 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4 垸氧基、 -d— 4垸基 -O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 进一步优选 H、 F、 Cl、 Br、 羟 基、氣基、 Ci— 4焼基、 Ci— 4焼氧基、 -Ci— 4焼基 -O-Ci— 4焼基、 -(CH2)m-j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 4元碳环基)或者 -0-(CH2)m-(3至 4元杂环基)， 进一步优选 H、 F、 Cl、 Br、羟基、氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基或者 -(CH2)mS(=0)nR12， 进一步优选 H、 d— 4垸基、 d— 4垸氧基或者 -d— 4垸基- O-d— 4垸基， 所述的杂环基含有 1至 3个 选自 N、 0或 S的杂原子， 优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯 基、 炔基、 碳环基或杂环基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、氰基、氨基、硝基、羟基、羧基、 d— 6垸基、 d— 6垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m- 炔基 -R12 、 -(CH2)m-C(=0)-R12 、 -(CH2)m-C(=0)-0-R12 、 -(CH2)m-C(=0)-NR13R13a 或 者 -(CH2)mS(=0)nR12的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基或者^— 4垸氧基， 更优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 3垸基或者 d— 3垸氧基， 进一步优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2垸基或者 d— 2 垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 d— 2垸氧基； R 6 , R 7 , R 8 and R 9 are each independently selected from H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, Ci- 6 fluorenyl, Ci_ 6 methoxy, -Ci_ 6 fluorenyl-O-Ci-6 fluorenyl, -(CH 2 ) m - j: thiol-R 12 , -(CH 2 ) m -blockyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m - C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m -(3 to 6 membered carbocyclic group), -(CH 2 ) m - (3 to 6-membered heterocyclic group), -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered heterocyclic group), preferably H , F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d-4 fluorenyl, d-4 methoxy, -d-4 fluorenyl- Od-4 fluorenyl -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0 )-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(= 0) n R 12 , -(CH 2 ) m - (3 to 6-membered carbocyclic group), -(CH 2 ) m - (3 to 6-membered heterocyclic group), -0-(CH 2 ) m - ( 3 to 6-membered carbocyclic group) or - 0-(CH 2 ) m -(3 to 6 membered heterocyclic group), more preferably H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy, -d- 4 fluorenyl -Od- 4 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0 -(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl group, gas group , Ci-4 fluorenyl, Ci-4 methoxy, -Ci-4 fluorenyl-O-Ci-4 fluorenyl, -(CH 2 ) m -j: thiol-R 12 , -(CH 2 ) m - Block group - R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m - (3 to 4 membered carbocyclic group) or -0-(CH 2 ) m - (3-4 membered heterocyclyl), more preferably H, F, Cl, Br, hydroxy, cyano, d- 4 alkyl with, d- 4 embankment group, -d- 4 alkyl with - Od- 4 alkyl with or - (CH 2) m S ( = 0) n R 12, more preferably H, d- 4 alkyl with, d- 4 embankment embankment -d- 4-yl group or - Od- 4 alkyl with the hybrid The cyclic group contains 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 hetero atoms selected from N, 0 or S, said fluorenyl, decyloxy, alkenyl, alkynyl, Carbocyclyl or heterocyclic groups are each independently optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro , hydroxy, carboxy, d- 6 fluorenyl, d- 6 methoxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m - alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a or -(CH 2 Substituting m S(=0) n R 12 , preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d — 4垸 或者 or — 4垸 oxy, more preferably 0 to 2 selected from F, Cl, Br, —CF 3 , cyano, hydroxy, 3 fluorenyl or d 3 methoxy, more preferably 0 to One selected from the group consisting of F, Cl, cyano, hydroxy, d- 2- indenyl or d- 2- nonyloxy, further preferably 0 to 1 selected from F, d- 2- indenyl or d- 2- indolyloxy;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 6元碳环或 3至 6元杂环， 优选 R6与 R7、 R8与 R9的任意一组可以形成一个 3至 6 元碳环或 3至 6元杂环， 更优选 3至 4元碳环或 3至 4元杂环，进一步优选 3元碳环或 3元杂 环， 进一步优选 3元碳环， 所述的杂环含有 1至 3个^^、 0或 S原子， 优选 1至 2个选自 N、 0或 S的杂原子， 所述的碳环或杂环任选进一步被 0至 3个 R12a的取代基所取代， 优选 0至 2 R12a选自 F、 Cl、 Br、 I、 =0、 羟基、 氰基、 d— 6垸基、 d— 6垸氧基、 d— 6垸基- O- d— 6垸基、 -(CH2)m- 烯 基 -R12 、 -(CH2)m- 炔 基 -R12 、 -(CH2)m-NR13R13a 、 -(CH2)m-C(=0)-R12 、 -(CH2)m-C(=0)-0-R12、 -(CH2)mC(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3 至 6元碳环基) 或 -(CH2)m-(3至 6元杂环基)的取代基所取代； 优选 F、 Cl、 Br、 I、 =0、羟基、氰基、 d_6垸基、 d_6垸氧基、 d— 6垸基- 0- d— 6垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)mC(=0)-NR13R13a或者 -(CH2)mS(=0)nR12， 更优 选！7、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基、 d— 4垸基- 0-d— 4垸基或者 -(CH2)mS(=0)nR12， 进一步优选 F、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基或者 d— 4垸基 0-d— 4垸基， 进一步 优选 F、 =0、羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 0-d— 3垸基， 进一步优选 F、 d— 2垸基、 d_2垸氧基或者 d— 2垸基 Ο-d— 2垸基， 所述的杂环含有 1至 3个^^、 0或 S原子， 优选 1至 2 个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步 被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 6垸基、 d— 6垸氧基、 -d— 6垸基 -0-d— 6垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12或者 -(CH2)mS(=0)nR12的取代基所取代， 优 选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基、 d_4垸氧基， 更优选 0至 3 个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d_4垸基或 d_4垸氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者^— 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或这 d— 2垸氧基； 作为选择， 当两个 R12a连接在同一个原子上时， 可与它们相连的原子一起形成 3至 6元碳 环或 3至 6元的杂环，优选 3至 6元的杂环，所述杂环含有 1至 3个选自 N、 0或 S的杂原子， 优选 1至 2个选自 N、 0或 S的杂原子，所述杂环或者碳环任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 羟基、 氰基、 d— 6垸基、 d— 6垸氧基或 -Q^C -d— 4垸基的取代基所取代， 优选 0至 2个 选自 F、 Cl、 Br、 羟基、 氰基、 d— 4垸基或者 d— 4垸氧基， 更优选 0至 2个选自 F、 d— 3垸基或 者 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 d— 2垸氧基； Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon. a ring or a 3 to 6 membered heterocyclic ring, preferably any group of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring. Or a 3- to 4-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring containing 1 to 3 ^, 0 or S atoms, preferably 1 to 2 a hetero atom selected from N, 0 or S, said carbocyclic or heterocyclic ring optionally being further substituted by 0 to 3 substituents of R 12a , preferably 0 to 2 R 12a is selected from the group consisting of F, Cl, Br, I, =0, hydroxy, cyano, d- 6 fluorenyl, d- 6 methoxy, d- 6 fluorenyl-O-d- 6 fluorenyl, -(CH 2 ) m - alkenyl-R 12 , -(CH 2 ) m - alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 Substituting a substituent of -(CH 2 ) m -(3 to 6-membered carbocyclic group) or -(CH 2 ) m - (3 to 6-membered heterocyclic group); preferably F, Cl, Br, I, = 0, hydroxy, cyano, d- 6 fluorenyl, d 6 methoxy, d- 6 fluorenyl- 0-d- 6 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m - alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0 -R 12 , -(CH 2 ) m C(=0)-NR 13 R 13a or -(CH 2 ) m S(=0) n R 12 , more preferably! 7 , Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4 methoxy, d-4 fluorenyl- 0-d-4 fluorenyl or -(CH 2 ) m S(=0) n R 12 , further preferably F, Cl, Br, =0, hydroxy, d-4 fluorenyl, d-4-decyloxy or d-4 fluorenyl 0-d-4 fluorenyl, further preferably F, =0, hydroxy , d - 3 fluorenyl, d - 3 methoxy or d - 3 fluorenyl 0-d- 3 fluorenyl, further preferably F, d - 2 fluorenyl, d 2 decyloxy or d - 2 fluorenyl hydrazine - a d- 2 fluorenyl group, the heterocyclic ring containing 1 to 3 ^, 0 or S atoms, preferably 1 to 2 hetero atoms selected from N, 0 or S, the fluorenyl group, the decyloxy group, Alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyanato , amino, nitro, hydroxy, carboxy, 6 fluorenyl, d- 6 methoxy, -d- 6 fluorenyl-0-d- 6 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , (CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(= 0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR Substituting 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R 12 or -(CH 2 ) m S(=0) n R 12 , Preferably, 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d_ 4 fluorenyl, d 4 methoxy, more preferably 0 to 3 selected from F, Cl , Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy, more preferably 0 to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl or d 4 methoxy, more preferably 0 to 1 selected from F, Cl, Br, -CF 3 , d-3 fluorenyl or methoxycarbonyl, further preferably 0 to 1 selected from F, d- 2 fluorenyl or d- 2 methoxy; alternatively, when two R 12a are bonded to the same atom, they may form 3 to 6 together with the atoms to which they are attached a carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 6 membered heterocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 selected from N, 0 Or a hetero atom of S, said heterocyclic ring or carbocyclic ring optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, d- 6 fluorenyl, d- 6 methoxy or Q ^ C -d- 4 Group substituents, preferably 0 to 2 groups selected from F, Cl, Br, hydroxy, cyano, d- 4 alkyl with or d- 4 embankment group, more preferably 0 to 2 groups selected from F, d- 3 mercapto or 3 decyloxy, further preferably 0 to 1 selected from F, d - 2 fluorenyl or d - 2 decyloxy;
R12、 R13和 R13a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 6垸基、 d— 6垸氧基、 (3至 6元碳环基)或 3至 6元杂环基， 优选 H、 F、 Cl、 Br、 羟基、 巯基、 氰基、 氨基、 d_4垸 基、 CM垸氧基、 3至 6元碳环基或 3至 6元杂环基， 更优选 H、 F、 Cl、 Br、 d— 4垸基、 d— 4 垸氧基、 3至 6元碳环基或 3至 6元杂环基， 进一步优选 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧 基、 3至 5元碳环基或 3至 5元杂环基， 进一步优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5元杂环基， 进一步优选 d— 2垸基或 d— 2垸氧基； m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2; R 12 , R 13 and R 13a are selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 methoxy, (3 to 6-membered carbocyclic) Or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6 membered carbocyclyl or 3 to 6 The heterocyclic group is more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl , Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, further preferably d- 3 fluorenyl, d- 3 methoxy, 3 to 5 carbon a cyclo group or a 3- to 5-membered heterocyclic group, further preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group; m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 氰基、 d_4垸基、 d_4垸氧基、R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy,
-CM垸基 -O-CM垸基或者 -(CH2)mS(=0)NR12，优选 H、 d_4垸基、 d_4垸氧基或者 -d_4垸基 -O-CM 垸基， 更优选 H、 d— 3垸基、 d— 3垸氧基或者 -d— 3垸基- O-d— 3垸基， 进一步优选 H、 d— 3垸氧基 或者 -Cw垸基 -O-Cw垸基，进一步优选 H、 d_2垸氧基或者 -d_2垸基 -O-Cw垸基，所述的垸基、 垸氧基各自独立任选进一步被 0至 3个选自 -CH2F、 -CHF2、 -CF3、 氰基、 氨基、 硝基、 羟基、 羧基或 d— 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3 垸基或者^— 3垸氧基， 更优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2垸基或者^— 2垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 — 2垸氧基； -CM垸-O-CM thiol or -(CH 2 ) m S(=0) N R 12 , preferably H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-O-CM 垸group, more preferably H, d- 3 alkyl with, d- 3 embankment group or alkyl with -d- 3 - Od- 3 embankment group, more preferably H, d- 3 embankment group or -Cw alkyl with -O- The Cw fluorenyl group is further preferably H, d 2 decyloxy or -d 2 fluorenyl-O-Cw fluorenyl, and the fluorenyl and decyloxy groups are each independently optionally further 0 to 3 selected from -CH 2 Substituted with a substituent of F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy or d- 4 methoxy, preferably 0 to 2 are selected from F, Cl, Br, -CF 3 , cyano, hydroxy, d- 3 ^ alkyl with or --3 embankment group, more preferably 0 to 1 heteroatom selected from F, Cl, cyano, hydroxy, d- 2-yl or embankment ^ - 2 embankment group, further Preferably 0 to 1 is selected from the group consisting of F, d- 2 fluorenyl or -2- decyloxy;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9中任意一组可以形成一个 3至 6元碳环或 3至 6元杂环， 优 选 3至 4元碳环或 3至 4元杂环， 更优选 3元碳环或 3元杂环， 进一步优选 3元碳环， 所述杂 环含有 1至 3个选自 N、 0或者 S的杂原子， 优选 1至 2个选自 N、 0或者 S的杂原子， 并且 所形成的碳环或杂环可以任选进一步被 0至 3个 R12a的取代基所取代， 优选 0至 2个 R12a ; Alternatively, any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring. More preferably, it is a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 selected from N, 0 or a hetero atom of S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 3 substituents of R 12a , preferably 0 to 2 R 12a ;
R12a选自 F、 Cl、 Br、 I、 =0、 羟基、 氰基、 d— 4垸基、 d— 4垸氧基、 d— 4垸氧- 0- d— 4垸基 或者 -(CH2)mS(=0)nR12， 优选 F、 Cl、 Br、 =0、羟基、 d_4垸基、 d_4垸氧基或者 d_4垸基 O-C 垸基， 更优选 F、 =0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 O-d— 3垸基， 进一步优选 F、R 12a is selected from the group consisting of F, Cl, Br, I, =0, hydroxy, cyano, d- 4 fluorenyl, d- 4 methoxy, d- 4 oxo- 0-d- 4 fluorenyl or -CH 2 ) m S(=0) n R 12 , preferably F, Cl, Br, =0, hydroxy, d_ 4 fluorenyl, d 4 methoxy or d 4 fluorenyl OC fluorenyl, more preferably F, =0, a hydroxyl group, d- 3 fluorenyl group, d- 3 methoxy group or d- 3 fluorenyl Od- 3 fluorenyl group, further preferably F,
2垸基、 d— 2垸氧基或者 d— 2垸基 O-d— 2垸基，进一步优选 F、 d— 2垸氧基或者 d— 2垸基 O-d— 2 垸基， 所述的垸基或垸氧基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 氨基、 硝基、 羟基、 羧基、 d— 4垸基或者^— 4垸氧基的取代基所取代， 优选 0至 3个选 自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d— 4垸基、 CM垸氧基， 更优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 CM垸氧基，进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 CM垸氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基 或者 d— 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或这^— 2垸氧基； Alkyl with 2, D- or D- 2 2 embankment group alkyl with alkyl with the OD-2, more preferably F, d- 2 embankment group or alkyl with the OD-D- 2 2 embankment group, or a group of the embankment The methoxy group is further optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy, d - 4垸Substituted with a substituent of a 4- methoxy group, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl, CM垸The oxy group, more preferably 0 to 3, is selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d - 4 fluorenyl or CM decyloxy, further preferably 0 to 2 selected from F , Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or CM methoxy, more preferably 0 to 1 selected from the group consisting of F, Cl, Br, -CF 3 , d- 3 Mercapto or d- 3 methoxy, further preferably 0 to 1 selected from F, d- 2 fluorenyl or oxa- 2- yloxy;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： R6、 R7、 R8和 R9各自独立选自 H、 F、 甲基、 乙基、 丙基、 异丙基、 丁基、 甲氧基、 乙氧 基、 丙氧基、 甲氧基甲基、 甲氧基乙基、 甲氧基丙基、 乙氧基甲基或者乙氧基乙基， 优选 H、 甲基、 甲氧基、 乙氧基、 甲氧基甲基、 乙氧基甲基、 甲氧基乙基或乙氧基乙基， 更优选 H、 甲 氧基、 乙氧基、 甲氧基甲基或乙氧基甲基， 进一步优选 H; Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxy Methyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, methyl, methoxy, ethoxy, methoxymethyl, ethoxy Methyl, methoxyethyl or ethoxyethyl, more preferably H, methoxy, ethoxy, methoxymethyl or ethoxymethyl, further preferably H;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9任一组可形成一个 3至 4元碳环或者 3至 4元杂环， 优选 3 元碳环或 3元杂环， 更优选 3元碳环， 所述的杂环含有 1至 3个 0、 N或者 S的杂原子， 优选 1至 2个选自 N、 0或者 S的杂原子， 并且所形成的碳环或杂环可以任选进一步被 0至 3个选 自 F、 Cl、 Br、 I、 甲基、 乙基、 丙基、 异丙基、 丁基、 甲氧基、 乙氧基、 丙氧基、 甲氧基甲基、 甲氧基乙基、 甲氧基丙基、乙氧基甲基或者乙氧基乙基的取代基所取代，优选 0至 2个选自 F、 甲基、 乙基、 丙基、 异丙基、 甲氧基、 乙氧基、 甲氧基甲基、 甲氧基乙基、 乙氧基甲基或者乙 氧基乙基， 更优选 0至 1个选自 F、 甲基、 乙基、 甲氧基、 乙氧基、 甲氧基甲基、 甲氧基乙基、 乙氧基甲基或者乙氧基乙基， 进一步优选甲氧基、 乙氧基、 甲氧基甲基、 甲氧基乙基或者乙氧 基甲基。 Alternatively, R 6 and any of R 7 , R 8 and R 9 may form a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring, preferably a 3 membered carbon ring or a 3 membered heterocyclic ring, more preferably a 3 membered carbon. a ring, said heterocyclic ring containing 1 to 3 heteroatoms of 0, N or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, and the resulting carbocyclic or heterocyclic ring may optionally be further From 0 to 3 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, A Substituted by a substituent of an oxyethyl group, a methoxypropyl group, an ethoxymethyl group or an ethoxyethyl group, preferably 0 to 2 are selected from the group consisting of F, methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably 0 to 1 selected from F, methyl, ethyl, methoxy Methyl, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, further preferably methoxy, ethoxy, methoxymethyl, methoxy Base or ethoxymethyl.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代  Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, or a derivative thereof.
Figure imgf000015_0001
且 环 Q可以进一步被 0至 3个任选自 F、 Cl、 Br、 I、 =0、 氨基、 羟基、 d— 6垸基或 d— 6垸氧基 的取代基所取代， 优选 0至 3个任选 g F、 Cl、 =0、 d— 4垸基或 d— 4垸氧基， 更优选 0至 2个 任选自 F、 Cl、 =0、 d— 3垸基或 d— 3垸氧基， 进一步优选 0至 2个任选自 F、 Cl、 =0、 d— 2垸 基或 d— 2垸氧基， 进一步优选 0至 2个任选自 F、 =0或 d— 2垸氧基。
Figure imgf000015_0001
And the ring Q may be further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, =0, amino, hydroxy, d- 6 fluorenyl or d- 6 methoxy, preferably 0 to 3. Optionally, g F, Cl, =0, d - 4 fluorenyl or d - 4 decyloxy, more preferably 0 to 2 are selected from F, Cl, =0, d - 3 fluorenyl or d - 3 hydrazine The oxy group, further preferably 0 to 2, is selected from the group consisting of F, Cl, =0, d- 2 fluorenyl or d- 2 methoxy, and further preferably 0 to 2 is selected from F, =0 or d- 2. Oxygen.
本发明优选方案， 包括通式 （I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢 受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolic salt or prodrug thereof, wherein:
环 Q选自
Figure imgf000015_0002
。 Ring Q is selected from
Figure imgf000015_0002
.
本发明优选方案， 一种通式（II)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：
Figure imgf000016_0001
A preferred embodiment of the invention, a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000016_0001
其中-among them-
R选自 H或 d_6垸基， 优选 H或 d_4垸基， 更优选 H; R is selected from H or d 6 fluorenyl, preferably H or d 4 fluorenyl, more preferably H;
l 、 > 。、 Α ,Ν. i -s. > 。、  l , > . , Α , Ν. i -s. > . ,
\ 、 或者 ， 优选 或者 更优选^， 且环 Q可 以进一步被 0至 3个任选自 F、 Cl、 Br、 I、 =0、 氨基、 羟基、 d— 6垸基或 d— 6垸氧基的取代基 所取代， 优选 0至 3个任选 g F、 Cl、 =0、 d_4垸基或 d_4垸氧基， 更优选 0至 2个任选 g F、 Cl、 =0、 d— 3垸基或 d— 3垸氧基， 进一步优选 0至 2个任选自 F、 Cl、 =0、 d— 2垸基或 d— 2垸 氧基， 进一步优选 0至 2个任选自 F、 =0或^— 2垸氧基； Or, preferably or more preferably, and the ring Q may be further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, =0, amino, hydroxy, d- 6 fluorenyl or d- 6 fluorenyloxy. Substituted by a substituent, preferably 0 to 3 optionally g F, Cl, =0, d 4 fluorenyl or d 4 methoxy, more preferably 0 to 2 optionally g F, Cl, =0, d — 3 fluorenyl or d- 3 methoxy, more preferably 0 to 2 are selected from F, Cl, =0, d- 2 fluorenyl or d- 2- decyloxy, further preferably 0 to 2 are selected from F , =0 or ^ - 2 oxime;
R1选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、硝基、羟基、 d— 6垸基或 d— 6垸氧基， 优选 H、 F、 Cl、 Br、 氰基、 氨基、 羟基、 d— 4垸基或 d— 4垸氧基， 更优选 H、 F、 Cl、 Br、 氰基、 氨基、 羟 基、 3垸基或 d— 3垸氧基， 进一步优选 H、 F、 d— 2垸基或 d— 2垸氧基， 进一步优选 H， 其中 所述垸基、垸氧基或氨基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 6垸基或者 d— 6垸氧基的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d_4垸基或者 d_4垸氧基， 更优选 0至 2 个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 3垸基或者 d— 3垸氧基， 进 一步优选 0至 2个选自 F、 -CF3、 d— 2垸基或者 — 2垸氧基； R 1 is selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, preferably H, F, Cl, Br, cyano, amino a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group, more preferably H, F, Cl, Br, a cyano group, an amino group, a hydroxyl group, a 3 fluorenyl group or a d- 3 methoxy group, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group is each independently optionally further from 0 to 3 selected from F, Cl, Br, I, - Substituted with a substituent of CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, preferably 0 to 3 are selected from F, Cl, Br , -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d 4 fluorenyl or d 4 methoxy, more preferably 0 to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d - 3 fluorenyl or d - 3 decyloxy, further preferably 0 to 2 selected from F, -CF 3 , d - 2 fluorenyl Or — 2 methoxy;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 羟基、 d— 6垸基、 d— 6垸氧基或 者 6垸基 -O-d— 6垸基， 优选 H、 F、 Cl、 Br、 d— 4垸基或者 d— 4垸氧基， 更优选 H、 F、 Cl、 Br、 d— 3垸基或 d— 3垸氧基， 进一步优选 H、 F、 Cl、 Br、 d— 2垸基或 d— 2垸氧基， 进一步优选 H、 F、 d_2垸基或 d— 2垸氧基， 所述垸基或垸氧基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d— 6垸基或者 d— 6垸氧基的取代基所取代， 优选 0至 3个选 自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d_4垸基或者 d_4垸氧基， 更优选 0至 2个选自 F、 Cl、 Br、 d— 4垸基或者^— 4垸氧基的取代基所取代， 进一步优选 0至 2个选自 F、 Cl、 Br、 d— 3垸基 或者 d— 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 d— 2垸氧基； R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl Preferably, H, F, Cl, Br, d- 4 fluorenyl or d- 4 decyloxy, more preferably H, F, Cl, Br, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, Cl, Br, d- 2 fluorenyl or d- 2- decyloxy, further preferably H, F, d 2 fluorenyl or d-2-decyloxy, the fluorenyl or decyloxy group being independently optional Further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 6 fluorenyl or d- 6 methoxy, preferably 0 to 3 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl or d 4 methoxy, more preferably 0 to 2 selected from F, Cl, Br, d- Substituted with a substituent of a 4-mercapto or a 4-methoxy group, further preferably 0 to 2 are selected from the group consisting of F, Cl, Br, d- 3 fluorenyl or d- 3 methoxy, more preferably 0 to 1 From F, d- 2 fluorenyl or d- 2- nonyloxy;
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy,
Ci_6焼基、 Ci_6焼氧基、 -Ci_6焼基 -O-Ci— 6焼基、 -(CH2)m- j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元 碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 优选 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 CM垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、Ci_ 6 fluorenyl, Ci 6 methoxy, -Ci_ 6 fluorenyl-O-Ci-6 fluorenyl, -(CH 2 ) m - j: thiol-R 12 , -(CH 2 ) m -blockyl- R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , - (CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m -(3 to 6-membered carbocyclic group), - (CH 2 ) m - (3 to 6-membered heterocyclic group), -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered hetero Ring group), preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano group, Hydroxy, CM fluorenyl, d-4 methoxy, -d-4 fluorenyl-Od-4 fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 ,
-(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元 碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 更优选 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4 垸氧基、 -d— 4垸基 -O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 进一步优选 H、 F、 Cl、 Br、 羟 基、氣基、 Ci— 4焼基、 Ci— 4焼氧基、 -Ci— 4焼基 -O-Ci— 4焼基、 -(CH2)m-j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 4元碳环基)或者 -0-(CH2)m-(3至 4元杂环基)， 进一步优选 H、 F、 Cl、 Br、羟基、氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基或者 -(CH2)mS(=0)nR12， 进一步优选 H、 d— 4垸基、 d— 4垸氧基或者 -d— 4垸基- O-d— 4垸基， 所述的杂环基含有 1至 3个 选自 N、 0或 S的杂原子优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、垸氧基、烯基、 炔基、碳环基或杂环基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 氨基、 硝基、羟基、 羧基、 d— 6垸基、 d— 6垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a或者 -(CH2)mS(=0)nR12的取 代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基 或者 d— 4垸氧基， 更优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3垸基或者 d— 3垸 氧基， 进一步优选 0至 1个选自 F、 Cl、 氰基、羟基、 d— 2垸基或者^ 2垸氧基， 进一步优选 0 至 1个选自 F、 d_2垸基或者 d_2垸氧基； -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m -(3 to 6 membered carbocyclic group), -(CH 2 ) m - (3 to 6 membered heterocyclic group), -0-(CH 2 ) m - (3 to 6 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6 membered heterocyclic group) more preferably H, F, Cl, Br, hydroxy, cyano, d_ 4 alkyl with, d_ 4 embankment group, -d- 4 alkyl with embankment -Od- 4-yl, - (CH 2) m - enyl - R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered heterocyclic group), further preferably H, F, Cl, Br, hydroxyl group, gas group, Ci-4 fluorenyl group, Ci-4 methoxy group, -Ci- 4 fluorenyl-O-Ci-4 fluorenyl, -(CH 2 ) m -j: thiol-R 12 , -(CH 2 ) m -blockyl-R 12 , -(CH 2 ) m S(=0 n R 12 , -0-(CH 2 ) m - (3 to 4 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 4 membered heterocyclic group), further preferably H, F, Cl , Br, hydroxy, cyano, d- 4 alkyl with, d- 4 embankment group, -d- 4 alkyl with - Od- 4 alkyl with or - (CH 2) m S ( = 0) n R 1 2, more preferably H, d- 4 alkyl with, d- 4 embankment embankment -d- 4-yl group or - Od- 4 alkyl with a heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S The hetero atom is preferably 1 to 2 heteroatoms selected from N, 0 or S, and the fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic groups are each independently optionally further 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy, d- 6 fluorenyl, d- 6 methoxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C (=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a or -(CH 2 ) m S(=0) n The substituent of R 12 is substituted, preferably 0 Up to 3 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably 0 to 2 It is selected from the group consisting of F, Cl, Br, -CF 3 , cyano, hydroxy, d - 3 fluorenyl or d - 3 decyloxy, further preferably 0 to 1 selected from the group consisting of F, Cl, cyano, hydroxy, d- 2 Mercapto or ^ 2 methoxy, further preferably 0 to 1 One selected from the group consisting of F, d 2 fluorenyl or d 2 methoxy;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R7与 R8、 R8与 R9、 R6与 R8、 R6与 R9的任意一组可以形成一个 3 至 6元碳环或 3至 6元杂环， 优选 R6与 R7、 R8与 R9的任意一组可以形成一个 3至 6元碳环 或 3至 6元杂环， 更优选 3至 4元碳环或 3至 4元杂环， 进一步优选 3元碳环或 3元杂环， 进 一步优选 3元碳环， 所述的杂环含有 1至 3个 N、 0或 S原子， 优选 1至 2个选自 N、 0或者 S的杂原子， 所述的碳环或杂环任选进一步被 0至 3个 R12a的取代基所取代， 优选 0至 2个Alternatively, any one of R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , R 6 and R 8 , R 6 and R 9 may form a 3 to 6 carbon ring or 3 to 6 member. The heterocyclic ring, preferably any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring or a 3 to 4 membered heterocyclic ring. The ring is further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, and the heterocyclic ring contains 1 to 3 N, 0 or S atoms, preferably 1 to 2 selected from N, 0 or S. a hetero atom, the carbocyclic or heterocyclic ring optionally further substituted by 0 to 3 substituents of R 12a , preferably 0 to 2
R12a; R 12a;
R12a选自 F、 Cl、 Br、 I、 =0、 羟基、 氰基、 d— 6垸基、 d— 6垸氧基、 d— 6垸基- 0- d— 6垸基、 -(CH2)m- 烯 基 -R12 、 -(CH2)m- 炔 基 -R12 、 -(CH2)m-NR13R13a 、 -(CH2)m-C(=0)-R12 、 -(CH2)m-C(=0)-0-R12、 -(CH2)mC(=0)-NR13R13a或者 -(CH2)mS(=0)nR12的取代基所取代； 优选 F、 Cl、 Br、 =0、 羟基、 d_4垸基、 d_4垸氧基、 d_4垸基 -O-CM垸基或者 -(CH2)mS(=0)nR12， 更优 选？、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基或者 d— 4垸基 O-d— 4垸基， 进一步优选 F、R 12a is selected from the group consisting of F, Cl, Br, I, =0, hydroxy, cyano, d- 6 fluorenyl, d- 6 methoxy, d- 6 fluorenyl- 0-d- 6 fluorenyl, -(CH 2 ) m - alkenyl-R 12 , -(CH 2 ) m - alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m C(=0)-NR 13 R 13a or -(CH 2 ) m S(=0) n R 12 Substituted by a substituent; preferably F, Cl, Br, =0, hydroxy, d_ 4 fluorenyl, d 4 methoxy, d 4 fluorenyl-O-CM fluorenyl or -(CH 2 ) m S (=0 ) n R 12 , more preferably? , Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4 decyloxy or d- 4 fluorenyl Od- 4 fluorenyl, further preferably F,
=0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 O-d— 3垸基， 进一步优选 F、 d— 2垸基、 d— 2垸 氧基或者 2垸基 O-d— 2垸基， 进一步优选 F、 d— 2垸氧基或者 d— 2垸基 0-d— 2垸基， 所述的 垸基、 垸氧基、 烯基、 炔基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、异氰基、氨基、硝基、羟基、羧基、 6垸基、 d— 6垸氧基、 -d— 6垸基- O-d— 6垸基、 -(CH2)m- 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a 、 -0-C(=0)-NR13R13a 、 -0-C(=0)-R12 、 -0-C(=0)-0-R12 或 者 -(CH2)mS(=0)nR12的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 CM垸基、 CM垸氧基， 更优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 CM垸氧基， 进一步优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d_4垸基或 d_4垸 氧基， 进一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 进一步优选 0 至 1个选自 F、 d— 2垸基或这^— 2垸氧基； =0, hydroxy, d- 3 fluorenyl, d- 3 decyloxy or d- 3 fluorenyl Od- 3 fluorenyl, further preferably F, d- 2 fluorenyl, d- 2垸 Oxyl or 2 fluorenyl Od- 2 fluorenyl, further preferably F, d- 2- decyloxy or d- 2 fluorenyl 0-d- 2 fluorenyl, said fluorenyl, decyloxy, alkenyl, alkyne Further optionally from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, 6垸base, d- 6 embankment group, -d- 6 alkyl with - Od- 6 alkyl with, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12, - ( CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)-R 12 , -0-C(=0)-0-R Substituting 12 or -(CH 2 ) m S(=0) n R 12 substituents, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , CM thiol, CM methoxy, more preferably 0 to 3 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or CM methoxy, further preferably 0 Up to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d 4 fluorenyl or d 4 methoxy, more preferably 0 to 1 selected from F, Cl, Br, -CF 3 , d - 3 fluorenyl or d - 3 decyloxy, further preferably 0 to 1 selected from F, d - 2 fluorenyl or oxacarbonyl;
作为选择，当两个 R12a连接在同一个原子上时，可以形成 3至 6元碳环或 3至 6元的杂环， 优选 3至 6元的杂环，所述杂环含有 1至 3个选自 N、 0或 S的杂原子，优选 1至 2个选自 N、 0或 S的杂原子， 所述杂环或者碳环任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 CF3、 羟基、 氰基、 6垸基或者^— 6垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 CF3、 羟基、 氰基、 d— 4垸基或者^— 4垸氧基， 更优选 0至 2个选自 F、 d— 3垸基或者 d— 3垸氧基， 进一步优 选 0至 1个选自 F、 d_2垸基或者 d_2垸氧基； Alternatively, when two R 12a are bonded to the same atom, a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring may be formed, preferably a 3 to 6 membered heterocyclic ring containing 1 to 3 a hetero atom selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 3 selected from F, Cl, Br , I, CF 3, hydroxy, cyano, or alkyl with 6 ^ - 6 embankment group substituents, preferably 0 to 2 groups selected from F, Cl, Br, CF 3 , hydroxy, cyano, d- 4 fluorenyl or -4- yloxy, more preferably 0 to 2 selected from F, d- 3 fluorenyl or d- 3 methoxy, more preferably 0 to 1 selected from F, d 2 fluorenyl or d_ 2垸oxy;
R12、 R13和 R13a选自 H、 F、 Cl、 Br、 I、 羟基、 巯基、 氰基、 氨基、 d— 6垸基、 d— 6垸氧基、 3至 6元碳环基或 3至 6元杂环基， 优选 H、 F、 Cl、 Br、羟基、巯基、 氰基、 氨基、 d— 4垸基、 CM垸氧基、 3至 6元碳环基或 3至 6元杂环基， 更优选 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧 基、 3至 6元碳环基或 3至 6元杂环基， 进一步优选 H、 F、 Cl、 Br、 d— 4垸基、 d— 4垸氧基、 3 至 5元碳环基或 3至 5元杂环基， 进一步优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5 元杂环基， 进一步优选 d— 2垸基或 d— 2垸氧基； R 12 , R 13 and R 13a are selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 decyloxy, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6-membered carbocyclic or 3 to 6-membered The cyclo group is more preferably H, F, Cl, Br, d_ 4 fluorenyl, d 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl, Br, D- 4 fluorenyl, d- 4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, further preferably d- 3 fluorenyl, d- 3 methoxy, 3 to 5 membered carbocyclic a base or a 3- to 5-membered heterocyclic group, further preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group;
p选自 0、 1或 2， 优选 0或 1， 更优选 0;  p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 (II)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R选自 11 环 Q选自
Figure imgf000018_0001
0至 3个任选自 F、 Cl、 =0、 d— 4垸基或 d— 4垸氧基的取代基所取代， 优选 0至 2个任选 g F、 Cl、 =0、 d— 3垸基 或^— 3垸氧基， 更优选 0至 2个任选 g F、 Cl、 =0、 d— 2垸基或 d— 2垸氧基， 进一步优选 0至 2个任选 g F、 =0或^— 2垸氧基； R1选自 H、 F、 Cl、 Br、 氰基、 氨基、 羟基、 d— 4垸基或 d— 4垸氧基， 优选 H、 F、 Cl、 Br、 氰基、 氨基、 羟基、 d— 3垸基或 d— 3垸氧基， 更优选 H、 F、 d— 2垸基或 d— 2垸氧基， 进一步优 选 H，其中所述垸基、垸氧基或氨基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、羟基、 d— 4垸基或者^— 4垸氧基的取代基所取代， 优选 0至 2个选 自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 3垸基或者 d— 3垸氧基， 更优选 0至 2个选自 F、 -CF3、 d— 2垸基或者^— 2垸氧基； R is selected from 11 ring Q selected from
Figure imgf000018_0001
0 to 3 substituents selected from the group consisting of F, Cl, =0, d-4 fluorenyl or d-4 methoxy, preferably 0 to 2 optionally g F, Cl, =0, d- 3 alkyl with or ^ --3 embankment group, more preferably optionally 0-2 g F, Cl, = 0, d- 2 alkyl with or embankment d- 2 group, more preferably optionally 0-2 g F, =0 or ^ - 2 oxime; R 1 is selected from H, F, Cl, Br, cyano, amino, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, Cl, Br, cyano, amino, hydroxy, d- 3 fluorenyl or d-3 methoxy, more preferably H, F, d-2 fluorenyl or d-2-decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino groups are each independently optional It is further substituted with 0 to 3 substituents selected from F, Cl, Br, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, hydroxy, alkyl with 4 or D- ^ - substituted 4-yl group embankment Substituted, preferably 0 to 2 are selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 3 decyl or d- 3 decyloxy, More preferably, 0 to 2 are selected from the group consisting of F, -CF 3 , d - 2 fluorenyl or phthalyloxy;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 d_4垸基或者 d_4垸氧基， 优选 H、 F、 Cl、 Br、 d— 3垸基或 d— 3垸氧基， 更优选 H、 F、 Cl、 Br、 d— 2垸基或 d— 2垸氧基， 进一步优选 H、 F、 d— 2垸基或 d— 2垸氧基， 所述垸基或垸氧基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或者 d— 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 d— 4垸基或者^— 4垸氧基的取代基所取代， 更优选 0至 2个选自 F、 Cl、 Br、 d— 3垸基 或者 d— 3垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 d— 2垸氧基； R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d- 2- indenyl or d- 2- indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy. Substituted, preferably 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, more preferably 0 to 2 selected from F, Cl, Br, d — 3垸 or d— 3垸 oxy, more preferably 0 to 1 selected from F, d— 2 fluorenyl or d − 2 fluorenyl;
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 Ci-4焼基、 Ci-4焼氧基、 -Ci-4焼基 -O-Ci— 4焼基、 -(CH2)m- j:希基 -R12、 -(CH2)m-块基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)mS(=0)nR12、 -(CH2)m-(3至 6元碳环基)、 -(CH2)m-(3至 6元杂环基)、 -0-(CH2)m-(3至 6元 碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 优选 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4 垸氧基、 -d— 4垸基 -O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 更优选 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-CM垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 4元碳环基)或者 -0-(CH2)m-(3至 4元杂环基)， 进一步优选 H、 F、 Cl、 Br、羟基、氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基或者 -(CH2)mS(=0)nR12， 进一步优选 H、 d— 4垸基、 d— 4垸氧基或者 -d— 4垸基- O-d— 4垸基， 所述的杂环基含有 1至 3个 选自 N、 0或 S的杂原子， 优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯 基、炔基、碳环基或杂环基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基或者^— 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3垸基或者 — 3垸氧基， 更优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2 垸基或者 — 2垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者^— 2垸氧基； R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, Ci-4 fluorenyl, Ci- 4 methoxy, -Ci-4 fluorenyl-O-Ci-4 fluorenyl, -(CH 2 ) m - j: thiol-R 12 , -(CH 2 ) m -blockyl-R 12 , -( CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m S(=0) n R 12 , -(CH 2 ) m -(3 to 6 membered carbocyclic group), -(CH 2 ) m - (3 to 6-membered heterocyclic group), -0-(CH 2 ) m - (3 to 6-membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6-membered heterocyclic group), preferably H, F, Cl, Br, hydroxy, cyano, d_ 4 alkyl with, d_ 4 embankment group, -d- 4 alkyl with embankment -Od- 4-yl, - (CH 2) m - alkenyl group -R 12, -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m -(3 to 6-membered carbocyclic group) or -0- (CH 2 ) m -(3 to 6 membered heterocyclic group), more preferably H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-O- CM fluorenyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(C H 2 ) m - (3 to 4 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 4 membered heterocyclic group), further preferably H, F, Cl, Br, hydroxy, cyano, d --4 alkyl with, d- 4 embankment group, -d- 4 alkyl with - Od- 4 alkyl with or - (CH 2) m S ( = 0) n R 12, more preferably H, d- 4-yl embankment, d- 4 embankment embankment -d- 4-yl group or - Od- 4 alkyl with a heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S heteroatom, preferably 1 to 2 heteroatoms selected from N a hetero atom of 0 or S, wherein the fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic group is each independently optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I Substituted with a substituent of -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d - 4 fluorenyl or -4- methoxy, preferably 0 to 2 selected from F, Cl, Br, -CF 3, cyano, hydroxy, d- 3 alkyl with or --3 embankment group, more preferably 0 to 1 heteroatom selected from F, Cl, cyano, hydroxy, d- 2-yl or embankment - 2 embankment group, more preferably 0-1 selected from F, d- 2-yl or embankment ^ - 2 embankment group;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9的任意一组可以形成一个 3至 6元碳环或 3至 6元杂环， 优 选 3至 4元碳环或 3至 4元杂环， 更优选 3元碳环或 3元杂环， 进一步优选 3元碳环， 所述的 杂环含有 1至 3个^^、 0或 S原子， 优选 1至 2个选自 N、 0或者 S的杂原子， 所述的碳环或 杂环任选进一步被 0至 3个 R12a的取代基所取代， 优选 0至 2个 R12a ; Alternatively, any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring. More preferably, a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, The heterocyclic ring contains 1 to 3 ^, 0 or S atoms, preferably 1 to 2 hetero atoms selected from N, 0 or S, optionally further 0 to 3 R 12a Substituted by a substituent, preferably 0 to 2 R 12a ;
R12a选自 F、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基、 d— 4垸基- O-d— 4垸基或者 -(CH2)mS(=0)nR12的取代基所取代， 优选 F、 Cl、 Br、 =0、 羟基、 d— 4垸基、 d— 4垸氧基或者R 12a is selected from the group consisting of F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4 methoxy, d- 4 fluorenyl- Od- 4 fluorenyl or -(CH 2 ) m S (=0 Substituted by a substituent of n R 12 , preferably F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4 decyloxy or
4垸基 0-d— 4垸基， 更优选 F、 =0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 0-d— 3垸基， 进一步优选 F、 d— 2垸基、 d— 2垸氧基或者 d— 2垸基 O-d— 2垸基， 进一步优选 F、 d— 2垸氧基或 者 Ci— 2焼基 O-Ci— 2焼基； 4 fluorenyl 0-d-4 fluorenyl, more preferably F, =0, hydroxy, d-3 fluorenyl, d-3 methoxy or d-3 fluorenyl 0-d-3 fluorenyl, further preferably F, d- 2 embankment group, d- 2 group or d- 2 embankment embankment embankment Od- 2-yl group, more preferably F, d- 2 embankment firing Ci- 2-yl group or O-Ci- 2 ware group;
R12、 R13和 R13a选自 H、 F、 Cl、 Br、 羟基、 巯基、 氰基、 氨基、 d— 4垸基、 d— 4垸氧基、 3至 6元碳环基或 3至 6元杂环基， 优选 H、 F、 Cl、 Br、 d— 4垸基、 d— 4垸氧基、 3至 6元碳 环基或 3至 6元杂环基， 更优选 H、 F、 Cl、 Br、 d— 4垸基、 d— 4垸氧基、 3至 5元碳环基或 3 至 5元杂环基， 进一步优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5元杂环基， 进一 步优选 2垸基或 d— 2垸氧基； R 12 , R 13 and R 13a are selected from H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclyl or 3 to a 6-membered heterocyclic group, preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 5 membered carbocyclic group or 3 to 5 membered heterocyclic group, further preferably d- 3 fluorenyl, d- 3 methoxy, 3 to a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, further preferably a 2 fluorenyl group or a d- 2 fluorenyloxy group;
p选自 0、 1或 2， 优选 0或 1， 更优选 0;  p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 (III)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000020_0001
Figure imgf000020_0001
其中-among them-
R5、 R1U和 R11各自独立任选自 H、 F、 Cl、 Br、 d_4垸基或 d_4垸氧基， 优选 H、 F、 Cl、 Br、 d— 3垸基或 d— 3垸氧基， 更优选 H、 F、 Cl、 Br、 d— 2垸基或 d— 2垸氧基， 进一步优选 H、 F、 d— 2垸基或 d— 2垸氧基， 所述垸基或者垸氧基各自独立地任选进一步被 0至 2个选自 F、 Cl、 Br、 d— 4垸基或者^— 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 d— 3垸基或 者 — 3垸氧基， 更优选 0至 1个选自 F、 d— 2垸基或者 — 2垸氧基； R 5 , R 1U and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d-2-indenyl or d-2-indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, preferably 0 to 2 selected from F, Cl, Br, d- 3 fluorenyl or -3-decyloxy, more preferably 0 to 1 selected from F, d- 2 fluorenyl or -2- decyloxy;
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4垸氧基、 -CM垸基 -O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3 至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 优选 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 CM垸氧基、 -d— 4垸基- O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3至 4元碳环基)或者 -0-(CH2)m-(3至 4元杂环基)， 更优选 H、 F、 Cl、 Br、 羟基、 氰基、 CM垸基、 d_4垸氧基、 -d_4垸基 -O-CM垸基或者 -(CH2)mS(=0)nR12， 进一步优选 H、 d.4 垸基、 CM垸氧基或者 -d— 4垸基- O-d— 4垸基， 进一步优选 H、 d— 3垸基、 d— 3垸氧基或者 -d— 3 垸基 -O-d— 3垸基，所述的杂环基含有 1至 3个选自 N、 0或 S的杂原子，优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基或者 d— 4垸氧基的取 代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3垸基或者 d— 3垸氧基， 更优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2垸基或者 d— 2垸氧基， 进一步优选 0至 1个选 自 F、 d— 2垸基或者^— 2垸氧基； R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy, -CM fluorenyl-Od- 4 fluorenyl -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m - (3 to 6 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6 membered heterocyclic group), preferably H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, CM embankment group, -d- 4 alkyl with - Od- 4 embankment group, - (CH 2) m - alkenyl -R 12, - (CH 2) m - alkynyl -R 12, - (CH 2) m S (=0) n R 12 , -0-(CH 2 ) m - (3 to 4 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 4 membered heterocyclic group), more preferably H, F, Cl, Br, hydroxy, cyano, C M decyl, d 4 methoxy, -d 4 fluorenyl-O-CM fluorenyl or -(CH 2 ) m S(=0) n R 12 , further Preferred H, d.4 Alkyl with, the CM embankment group or alkyl with -d- 4 - Od- 4 embankment group, more preferably H, d- 3 alkyl with, d- 3 embankment -d- 3 group or alkyl with alkyl with -Od- 3 Said heterocyclic group contains 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 hetero atoms selected from N, 0 or S, said fluorenyl, decyloxy, olefin The radical, alkynyl, carbocyclyl or heterocyclyl are each independently optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d- Substituted with a substituent of 4 fluorenyl or d- 4 methoxy, preferably 0 to 2 is selected from the group consisting of F, Cl, Br, -CF 3 , cyano, hydroxy, d - 3 fluorenyl or d - 3 decyloxy More preferably, 0 to 1 is selected from the group consisting of F, Cl, cyano, hydroxy, d- 2- indenyl or d- 2- indolyloxy, and further preferably 0 to 1 is selected from F, d- 2- indenyl or ^ -2 Alkoxy group;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9中任意一组可以形成一个 3至 4元碳环或 3至 4元杂环， 优 选 3元碳环或 3元杂环，更优选 3元碳环，所述杂环含有 1至 2个选自 N、 0或者 S的杂原子， 并且所形成的碳环或杂环可以任选进一步被 0至 2个 R12a的取代基所取代； Alternatively, any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan. a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
R12a选自 F、 Cl、 Br、 =0、羟基、 d— 4垸基、 d— 4垸氧基或者 d— 4垸基 O-d— 4垸基， 优选 F、 =0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 O-d— 3垸基， 更优选 F、 d— 2垸基、 d— 2垸氧基 或者 d— 2垸基 O-d— 2垸基， 进一步优选 F、 d— 2垸氧基或者 d— 2垸基 O-d— 2垸基； 所述的垸基 或垸氧基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 d_4垸基或 d_4垸 氧基的取代基所取代， 优选 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4 垸氧基， 更优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧基， 进 一步优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d_3垸基或者 d_3垸氧基， 进一步优选 0至 1个选 自 F、 d_2垸基或这 d_2垸氧基； R 12a is selected from the group consisting of F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4- decyloxy or d- 4 fluorenyl Od- 4 fluorenyl, preferably F, =0, hydroxy, d- 3 Anthracenyl, d- 3 methoxy or d- 3 fluorenyl Od- 3 , more preferably F, d- 2 fluorenyl, d- 2- decyloxy or d- 2 fluorenyl Od- 2 fluorenyl, further Preferably, F, d- 2- decyloxy or d- 2 -indenyl Od- 2 fluorenyl; said fluorenyl or decyloxy optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH Substituted with a substituent of 2 F, -CHF 2 , -CF 3 , d_ 4 fluorenyl or d 4 methoxy, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , CF 3 , d- 4 fluorenyl or d- 4 methoxy, more preferably 0 to 2 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d — 4垸 oxy, more preferably 0 to 1 selected from F, Cl, Br, —CF 3 , d 3 fluorenyl or d 3 methoxy, more preferably 0 to 1 selected from F, d 2 fluorenyl or This d_ 2 methoxy group;
R12选自 H、 F、 Cl、 Br、 d— 4垸基、 d— 4垸氧基、 3至 6元碳环基或 3至 6元杂环基， 优选 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧基、 3至 5元碳环基或 3至 5元杂环基， 更优选 d_3垸基、 3垸氧基、 3至 5元碳环基或 3至 5元杂环基， 进一步优选 d— 2垸基或 d— 2垸氧基； R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably H, F, Cl, Br, D_ 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, more preferably d 3 fluorenyl, 3 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, further preferably d- 2 fluorenyl or d- 2 fluorenyloxy;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 (III)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R5、 R1Q和 R11各自独立选自 H、 F、 甲基或乙基。 R 5 , R 1Q and R 11 are each independently selected from H, F, methyl or ethyl.
本发明优选方案， 包括通式（IV)所示的化合物或其立体异构体、水合物、酯、溶剂化物、 共晶体、 代谢产物、 药学
Figure imgf000021_0001
其中： Preferred embodiments of the present invention include a compound represented by the formula (IV) or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutical thereof
Figure imgf000021_0001
among them:
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4垸氧基、 -CM垸基 -O-d— 4垸基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)mS(=0)nR12、 -0-(CH2)m-(3 至 6元碳环基)或者 -0-(CH2)m-(3至 6元杂环基)， 优选 H、 F、 Cl、 Br、 羟基、 氰基、 d— 4垸基、 d— 4垸氧基、 -d— 4垸基- O-d— 4垸基或者 -(CH2)mS(=0)nR12， 更优选 H、 d— 4垸基、 d— 4垸氧基或 者 -CM垸基 -O-CM垸基， 进一步优选 H、 d_3垸基、 d_3垸氧基或者 -d_3垸基 -O-Cw垸基， 进 一步优选11、 d— 3垸氧基或者 -d— 3垸基- O-d— 3垸基， 所述的杂环基含有 1至 3个选自 N、 0或 S的杂原子， 优选 1至 2个选自 N、 0或 S的杂原子， 所述的垸基、 垸氧基、 烯基、 炔基、 碳 环基或杂环基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4垸基或者 — 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 d— 3垸基或者^— 3垸氧基， 更优选 0至 1个选自 F、 Cl、 氰基、 羟基、 d— 2垸基或者 — 2 垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 d— 2垸氧基； R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy, -CM fluorenyl-Od-4 fluorenyl -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m S(=0) n R 12 , -0-(CH 2 ) m - (3 to 6 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 6 membered heterocyclic group), preferably H, F, Cl, Br, hydroxy, cyano, d- 4 fluorenyl, d- 4 embankment group, -d- 4 alkyl with - Od- 4 alkyl with or - (CH 2) m S ( = 0) n R 12, more preferably H, d- 4 alkyl with, d- 4 oxygen embankment Or a CM fluorenyl-O-CM fluorenyl group, further preferably H, d 3 fluorenyl, d 3 methoxy or -d 3 fluorenyl-O-Cw fluorenyl, further preferably 11, d - 3 fluorenyloxy alkyl with or -d- 3 - Od- 3 embankment group, said heterocyclic group containing 1 to 3 heteroatoms selected from N, 0 or S heteroatom, preferably 1 to 2 heteroatoms selected from N, 0, or S heteroatoms Atom, said fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic group each independently optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2, -CF 3, cyano, hydroxy, d- 4 alkyl with or --4 Group substituents, preferably 0 to 2 groups selected from F, Cl, Br, -CF 3 , cyano, hydroxy, d- 3 ^ alkyl with or --3 embankment group, more preferably 0-1 selected from From F, Cl, cyano, hydroxy, d- 2- indenyl or - 2 decyloxy, further preferably 0 to 1 selected from F, d- 2- indenyl or d- 2- indolyloxy;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9中任意一组可以形成一个 3至 4元碳环或 3至 4元杂环， 优 选 3元碳环或 3元杂环，更优选 3元碳环，所述杂环含有 1至 3个选自 N、 0或者 S的杂原子， 并且所形成的碳环或杂环可以任选进一步被 0至 3个 R12a的取代基所取代； Alternatively, any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan. a carbocyclic ring containing from 1 to 3 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with from 0 to 3 substituents of R 12a ;
R12a选自 F、 Cl、 Br、 =0、羟基、 d— 4垸基、 d— 4垸氧基或者 d— 4垸基 O-d— 4垸基， 优选 F、 =0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基 O-d— 3垸基， 更优选 F、 d— 2垸基、 d— 2垸氧基 或者 d— 2垸基 O-d— 2垸基， 进一步优选 F、 d— 2垸氧基或者 d— 2垸基 O-d— 2垸基； 所述的垸基、 垸氧基任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧基 的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧 基， 更优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 进一步优选 0至 1个 选自 F、 d— 2垸基或这^— 2垸氧基； R 12a is selected from the group consisting of F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4- decyloxy or d- 4 fluorenyl Od- 4 fluorenyl, preferably F, =0, hydroxy, d- 3 Anthracenyl, d- 3 methoxy or d- 3 fluorenyl Od- 3 , more preferably F, d- 2 fluorenyl, d- 2- decyloxy or d- 2 fluorenyl Od- 2 fluorenyl, further Preferably, F, d- 2- decyloxy or d- 2 -indenyl Od- 2 fluorenyl; said fluorenyl, decyloxy optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F Substituted with a substituent of -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy, preferably 0 to 2 are selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , CF 3 , d - 4 fluorenyl or d - 4 decyloxy, more preferably 0 to 1 selected from F, Cl, Br, -CF 3 , d - 3 fluorenyl or d - 3 decyloxy, further preferably 0 to a selected F, d- 2 or alkyl with this ^ - 2 embankment group;
R12选自 H、 F、 Cl、 Br、 d— 4垸基、 d— 4垸氧基、 3至 6元碳环基或 3至 6元杂环基， 优选R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably
H、 F、 Cl、 Br、 CM垸基、 d— 4垸氧基、 3至 5元碳环基或 3至 5元杂环基， 更优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5元杂环基， 进一步优选 d— 2垸基或 d— 2垸氧基； H, F, Cl, Br, CM thiol, d- 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, more preferably d- 3 fluorenyl, d- 3 methoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, further preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group;
m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2;  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 0V)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula 0V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7、 R8和 R9各自独立地选自 H、 F、 Cl、 Br、 羟基、 氰基、 d_4垸基、 d_4垸氧基、 -CM垸基 -O-CM垸基或者 -(CH2)mS(=0)NR12，优选 H、 d_4垸基、 d_4垸氧基或者 -d_4垸基 -O-CM 垸基， 更优选 H、 d— 3垸基、 d— 3垸氧基或者 -d— 3垸基- O-d— 3垸基， 进一步优选 H、 d— 3垸氧基 或者 -Cw垸基 -O-Cw垸基， 进一步优选 H、 d_2垸氧基或者 -d_2垸基 -O-Cw垸基， 所述的垸基 或垸氧基各自独立任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、羟基、 d— 4垸基或者 — 4垸氧基的取代基所取代， 优选 0至 2个选自 F、 Cl、 Br、 -CF3、 氰基、 羟基、 3垸基或者 d— 3垸氧基， 更优选 0至 1个选自 F、 Cl、氰基、羟基、 d— 2垸基或者 d— 2垸氧基， 进一步优选 0至 1个选自 F、 d— 2垸基或者 — 2垸氧基； R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy, -CM垸-O-CM thiol or -(CH 2 ) m S(=0) N R 12 , preferably H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-O-CM 垸More preferably, H, d-3 fluorenyl, d-3 methoxy or -d-3 fluorenyl-Od-3 fluorenyl, further preferably H, d- 3 decyloxy or -Cw fluorenyl-O- Further, preferably, H, d 2 decyloxy or -d 2 fluorenyl-O-Cw fluorenyl, each of the fluorenyl or fluorenyloxy groups is optionally further further selected from 0 to 3 selected from F and Cl. Substituted with a substituent of Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d - 4 fluorenyl or -4-decyloxy, preferably 0 to 2 selected from F, Cl, Br , -CF 3 , cyano, hydroxy, trimethyl or d - 3 methoxy, more preferably 0 to 1 selected from F, Cl, cyano, hydroxy, d - 2 fluorenyl or d - 2 decyloxy Further preferably 0 to 1 is selected from the group consisting of F, d- 2- indenyl or - 2 indenyloxy;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R8与 R9中任意一组可以形成一个 3至 4元碳环或 3至 4元杂环， 优 选 3元碳环或 3元杂环，更优选 3元碳环，所述杂环含有 1至 2个选自 N、 0或者 S的杂原子， 并且所形成的碳环或杂环可以任选进一步被 0至 2个 R12a的取代基所取代； Alternatively, any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan. a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
R12a选自 F、 Cl、 Br、 =0、羟基、 d— 4垸基、 d— 4垸氧基或者 d— 4垸基- O-d— 4垸基， 优选 F、 =0、 羟基、 d— 3垸基、 d— 3垸氧基或者 d— 3垸基- O-d— 3垸基， 更优选 F、 d— 2垸基、 d— 2垸氧基 或者 d— 2垸基- O-d— 2垸基， 进一步优选 F、 d— 2垸氧基或者 d— 2垸基- O-d— 2垸¾ 所述的垸基 或垸氧基任选进一步被 0至 2个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 d— 4垸基或 d— 4垸氧 基的取代基所取代， 优选 0至 1个选自 F、 Cl、 Br、 -CF3、 d— 3垸基或者 d— 3垸氧基， 更优选 0 至 1个选自 F、 d_2垸基或这 d_2垸氧基； R 12a is selected from the group consisting of F, Cl, Br, =0, hydroxy, d- 4 fluorenyl, d- 4- decyloxy or d- 4 fluorenyl-Od- 4 fluorenyl, preferably F, =0, hydroxy, d- 3 fluorenyl, d- 3 methoxy or d- 3 fluorenyl-Od- 3 fluorenyl, more preferably F, d- 2 fluorenyl, d- 2- decyloxy or d- 2 fluorenyl-Od- 2垸Further preferably, the fluorenyl or decyloxy group of the F, d- 2 methoxy or d- 2 fluorenyl-Od- 2垸 3⁄4 is further further selected from 0 to 2 selected from the group consisting of F, Cl, Br, Substituted with a substituent of CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy, preferably 0 to 1 is selected from the group consisting of F, Cl, Br, -CF 3 , d- 3 Anthracenyl or d- 3 methoxy, more preferably 0 to 1 selected from F, d 2 fluorenyl or this d 2 methoxy;
R12选自 H、 F、 Cl、 Br、 d_4垸基、 d_4垸氧基、 3至 5元碳环基或 3至 5元杂环基， 优选 d— 3垸基、 d— 3垸氧基、 3至 5元碳环基或 3至 5元杂环基， 更优选 d— 2垸基或 d— 2垸氧基； m选自 0、 1、 2、 3或 4， 优选 0、 1、 2或 3， 更优选 0、 1或 2; R 12 is selected from the group consisting of H, F, Cl, Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, preferably d 3 fluorenyl, d 3垸An oxy group, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, more preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group; m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 包括通式 (IV)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7各自独立地选自 H、 d_4垸基、 d_4垸氧基或者 -d_4垸基 -O-CM垸基， 优选 H、 d_3 垸基、 3垸氧基或者 -d— 3垸基- O-d— 3垸基， 更优选 H、 d— 3垸氧基或者 -d— 3垸基- O-d— 3垸基， 进一步优选 H、 d— 2垸氧基或者 -d— 2垸基- O-d— 2垸基， 进一步优选 H; R 6 and R 7 are each independently selected from H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-O-CM fluorenyl, preferably H, d 3 decyl, 3 decyloxy or -d --3 alkyl with - Od- 3 embankment group, more preferably H, d- 3 embankment group or alkyl with -d- 3 - Od- 3 embankment group, more preferably H, d- 2 embankment group or -d- 2 Mercapto-Od- 2 fluorenyl, further preferably H;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
R8和 R9各自独立地选自 H、 d— 4垸基、 d— 4垸氧基或者 -d— 4垸基 -O-d— 4垸基， 优选 H、 d_3垸基、 d— 3垸氧基或者 -d— 3垸基 -O-d— 3垸基， 更优选 H、 d_2垸基、 d— 2垸氧基或者 -d— 2 垸基 -O-Cw垸基， 进一步优选 H、 d_2垸氧基或者 -d_2垸基 -O-Cw垸基； R 8 and R 9 are each independently selected from H, d- 4 alkyl with, d- 4 group or -d- 4 embankment embankment embankment -Od- 4-yl group, preferably H, d_ 3 alkyl with, d- 3 embankment Oxy or -d-3indolyl-Od- 3 fluorenyl, more preferably H, d- 2 fluorenyl, d- 2 -nonyloxy or -d-2indolyl-O-Cw fluorenyl, further preferably H, d_ 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
作为选择， R8与 R9可以形成一个 3元碳环。 本发明优选方案， 包括通式 ν)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： Alternatively, R 8 and R 9 may form a 3-membered carbon ring. Preferred embodiments of the invention include a compound of the formula ν) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7各自独立地选 g H、 d_3垸基、 d_3垸氧基或者 -d_3垸基 -O-Cw垸基， 优选 H、 d_3 垸氧基或者 - — 3垸基 -O-d— 3垸基， 更优选 H、 d— 2垸氧基或者 -d— 2垸基- O-d— 2垸基， 进一步优 选 H; R 6 and R 7 are each independently selected from g H, d_ 3 fluorenyl, d 3 methoxy or -d 3 fluorenyl-O-Cw fluorenyl, preferably H, d 3 methoxy or - 3 fluorenyl- Od- 3 embankment group, more preferably H, d- 2 embankment embankment -d- 2-yl group or - Od- 2 embankment group, more preferably H;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
R8和 R9各自独立地选自 H、 d.3垸基、 3垸氧基或者 -d— 3垸基 -Ο-d— 3垸基， 优选 H、 垸基、 d_2垸氧基或者 -d_2垸基 -O-Cw垸基， 更优选 H、 d_2垸氧基或者 -d_2垸基 -O-Cw 焼基； R 8 and R 9 are each independently selected from H, d. 3 fluorenyl, 3 decyloxy or -d-3indolyl-indole-d- 3 fluorenyl, preferably H, decyl, d 2 decyloxy or -d_ 2 fluorenyl-O-Cw fluorenyl, more preferably H, d 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
作为选择， R8与 R9可以形成一个 3元碳环。 Alternatively, R 8 and R 9 may form a 3-membered carbon ring.
本发明优选方案， 包括通式 ν)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula ν) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6和 R7各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 甲氧基甲基、 乙氧基甲基、 甲氧基 乙基或乙氧基乙基， 优选 H、 甲氧基或乙氧基， 更优选 H; R 6 and R 7 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl, preferably H, Methoxy or ethoxy, more preferably H;
作为选择， R6和 R7可形成 (=0); Alternatively, R 6 and R 7 may form (=0);
R8和 R9各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 甲氧基甲基、 乙氧基甲基或甲氧基 乙基， 优选 H、 甲基、 甲氧基甲基或乙氧基甲基， 更优选 H、 甲氧基甲基或乙氧基甲基； 作为选择， R8和 R9可形成一个 3元碳环。 R 8 and R 9 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or methoxyethyl, preferably H, methyl, methoxy Methyl or ethoxymethyl, more preferably H, methoxymethyl or ethoxymethyl; alternatively, R 8 and R 9 form a 3-membered carbocyclic ring.
本发明优选方案， 包括通式 (IV)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R和 R7选自 H; 或者， R6和 R7可形成一个 =0; R and R 7 are selected from H; or, R 6 and R 7 may form an =0;
R8和 R9各自独立任选自 H、 甲氧基甲基或乙氧基甲基； 或者， 作为选择， R8和 R9可形成 一个 3元碳环。 R 8 and R 9 are each independently selected from H, methoxymethyl or ethoxymethyl; or, alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring.
本发明优选方案，提供如通式（I)所示的化合物或其立体异构体、水合物、酯、溶剂化物、 共晶体、 代谢产物、  According to a preferred embodiment of the present invention, there is provided a compound represented by the formula (I) or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite thereof,
Figure imgf000024_0001
Figure imgf000024_0001
其中： among them:
R选自 11或 — 8垸基； R is selected from 11 or - 8 fluorenyl;
环 Q选自 5至 8元碳环基或杂环基， 所述的杂环基含有 1至 4个 Ν、 0或 S(=0)n原子或 者基团， 所述的碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰 基、 氨基、 硝基、 羟基、 羧基、 垸基、 d— 8垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、Ring Q is selected from a 5- to 8-membered carbocyclic or heterocyclic group containing from 1 to 4 fluorene, 0 or S(=0) n atoms or groups, said carbocyclic group or hetero The ring group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyanide Base, amino, nitro, hydroxy, carboxy, decyl, d- 8 decyloxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 ,
-0-C(=0)-0-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-S(=0)n-R12或者 -NR13R13a 的取代基所取代； -0-C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-R 12 , -( Substituting CH 2 ) m -S(=0) n -R 12 or -NR 13 R 13a ;
R1和 R4各自独立任选自 F、 Cl、 Br、 I、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8 垸基或 d— 8垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8 垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代； R2和 R3各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基或 d— 8垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基或 C 垸氧基的取代基所取代； R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl or d- 8 decyloxy, wherein The fluorenyl, decyloxy or amino groups are each independently optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino , nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , - (CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or substituted with a substituent of -NR 13 R 13a ; R 2 and R 3 are each independently optional From H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 decyl or d- 8 decyloxy, wherein said fluorenyl, decyloxy or The amino groups are each independently optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy , d- 8垸 base or C 垸Substituted by a substituent of an oxy group;
R5、 R6、 R7、 R8、 R9、 R1Q和 R11各自独立地选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、异氰基、氨基、硝基、羟基、羧基、 垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基、 -(CH2)m - 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、 -(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基)或者 -0-(CH2)m-(3至 10元杂环基)， 所述的杂环基含有 1至 4个 N、 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 烯基、 炔 基、 碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 垸基、 d— 8垸氧基或 -d— 8垸基 -O-d— 8垸基的取 代基所取代； R 5 , R 6 , R 7 , R 8 , R 9 , R 1Q and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano , isocyano, amino, nitro, hydroxy, carboxy, alkyl with, d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl group -R 12, -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C( =0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)- R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N (R 12b )C(=0)R 12 , -N(R 12b )C(=0)OR 12 , -(CH 2 ) m -(3 to 10 membered carbocyclic group), -(CH 2 ) m - (3 to 10 membered heterocyclic group), -0-(CH 2 ) m - (3 to 10 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 10 membered heterocyclic group), The heterocyclic group contains 1 to 4 N, 0 or 3 (=0) 11 atoms or groups, and the fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, = 0, -CH 2 F, -CHF 2, -CF 3, cyano, isocyanato , Amino, nitro, hydroxy, carboxy, alkyl with, d- 8 -d- 8 embankment group or alkyl with -Od- 8 embankment group substituents;
作为选择， R6和 R7可以形成 (^(^或二^^12!^215; Alternatively, R 6 and R 7 can be formed (^(^ or two ^^ 12 !^ 215 ;
作为选择，
Figure imgf000025_0001
As an option,
Figure imgf000025_0001
作为选择， R6与 R7、 R与 R8、 R与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 8元碳环或 3至 8元杂环， 所述的杂环含有 1至 4个 N、 0或 S(=C n原子或者基 团， 所述的碳环或杂环任选进一步被 0至 4个 R12a的取代基所取代； Alternatively, any one of R 6 and R 7 , R and R 8 , R and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 8 membered carbocyclic ring or a 3- to 8-membered heterocyclic ring containing 1 to 4 N, 0 or S (=C n atoms or groups, optionally further 0 to 4 R 12a Substituted by a substituent;
R12a选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 Ci— 8焼基、 C— 8焼氧基或 C— 8焼基- O-C— 8焼基； R 12a is selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, Ci- 8 fluorenyl, C- 8 methoxy or C- 8 fluorenyl-OC- 8 fluorenyl;
R12和 R12b选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 巯基、 异氰基、 氨基、 硝基、羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 3至 10元碳环基或 3至 10元杂环基， 所述的杂环 基含有 1至 4个 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 碳环基或杂环基任选 进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝 基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基或 -d— 8垸基 -Ο-d— 8垸基的取代基所取代； R 12 and R 12b are selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, 3 to 10 membered carbocyclic group or 3 to 10 membered heterocyclic group, said heterocyclic group having 1 to 4 0 or 3 (=0) 11 atoms or groups , the thiol, decyloxy, carbocyclyl or heterocyclic group is optional Further from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d- alkyl with 8, d- 8 embankment group or a group -D-8 -Ο-d- 8 embankment embankment group substituents;
R13和 R13a选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 巯基、 异氰基、 氨基、 硝基、羟基、 羧基、 垸基、 d— 8垸氧基、 3至 10元碳环基或 3至 10元杂环基， 所述的杂环 基含有 1至 4个 N、 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 碳环基或杂环基任选 进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝 基、羟基、 羧基、 8垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基或 -(CH2)mS(=0)nR12的取代基所 取代； R 13 and R 13a are selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy, carboxy, fluorenyl a d- 8 methoxy group, a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, said heterocyclic group having 1 to 4 N, 0 or 3 (=0) 11 atoms or groups, The fluorenyl, decyloxy, carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8, 8 embankment group D-, -D-8-yl embankment - Od- 8 alkyl with or - (CH 2) m S ( = 0) Substituted by a substituent of n R 12 ;
p选自 0、 1、 2或 3 ;  p is selected from 0, 1, 2 or 3;
q选自 0、 1、 2、 3或 4;  q is selected from 0, 1, 2, 3 or 4;
t选自 0、 1或 2;  t is selected from 0, 1 or 2;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 通式（I)所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶 体、 代谢产物、 药学上可接受的盐或前药， 其中：  A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1和 R4各自独立任选自 F、 Cl、 Br或 d_4垸基， 优选 F或 CI; R 1 and R 4 are each independently selected from F, Cl, Br or d 4 alkyl, preferably F or CI;
R2和 R3各自独立任选自 H、 F、 Cl、 Br或 d_4垸基， 优选 H; R 2 and R 3 are each independently selected from H, F, Cl, Br or d 4 fluorenyl, preferably H;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 I或 d_4垸基， 优选 H、 F或甲基。 R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I or d- 4 , preferably H, F or methyl.
本发明优选方案， 通式（I)所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶 体、 代谢产物、 药学上可接受的盐或前药， 其中：  A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C 垸 -(CH2)m-NR13R13a，优选 H、- CH2OH、甲基、甲氧基、乙氧基、"^O^、 0 、 '\〜Q、 或
Figure imgf000026_0001
R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-OC 垸-(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, "^O^, 0, '\~ Q , or
Figure imgf000026_0001
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 6元碳环， 优选 3至 4元碳环， 更优选 3元碳环； Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon. a ring, preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
R13和 R13a选自 H或 d— 6垸基， 优选 11或^— 4垸基， 所述的垸基可以进一步被 0至 2个选 g -(CH2)mS(=0)nR12的取代基所取代； R 13 and R 13a are selected from H or d- 6 fluorenyl, preferably 11 or 4 fluorenyl, and the fluorenyl group may be further selected from 0 to 2 g -(CH 2 ) m S(=0) n Substituted by a substituent of R 12 ;
R12选自 11或^— 6垸基， 优选 H或甲基； 11 or R 12 is selected from ^ - 6 alkyl with, preferably H or methyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。 本发明优选方案， 通式 ω所述化合物或其立体异构体、水合物、酯、溶剂化物、共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： 环 Q选自^、 ,
Figure imgf000027_0001
〜 、 、 〜、 '"^或者 '^^， 优选 Y 且环 Q可以进一步被 0至 3个任选自 F、 Cl、 Br、 I、 =0、 氨基、 羟基、 d_6垸基或 d_6垸氧 基的取代基所取代。 n is selected from 0, 1, or 2. A preferred embodiment of the invention, a compound of the formula ω or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: the ring Q is selected from the group consisting of ,
Figure imgf000027_0001
~,, ~, '' Or ^ '^^, Y and the ring Q may preferably be further optionally selected from 0-3 F, Cl, Br, I, = 0, amino, hydroxy, alkyl with d_ 6 or d_ 6 Substituted by a substituent of a methoxy group.
本发明优选方案， 通式 （I)所述化合物或其立体异构体、水合物、酯、溶剂化物、共晶体、 代谢产物、 药学上可接受的盐或前药， 其为下述通式 （II) 所示的化合物或其立体异构体、 水 合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is of the general formula (II) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000027_0002
Figure imgf000027_0002
其中-among them-
R选自 11或 — 4垸基， 优选 H: R is selected from 11 or - 4 fluorenyl groups, preferably H:
丫。  Hey.
环 Q为\ , 且环 Q可以进一步被 0至 3个任选自 F、 =0、氨基、羟基、 d— 4垸基或 d_4 垸氧基的取代基所取代； Ring Q is \ , and ring Q may be further substituted with 0 to 3 substituents selected from the group consisting of F, =0, amino, hydroxy, d- 4 fluorenyl or d 4 methoxy;
R1选自 F、 C1或 Br， 优选 F或 C1; R 1 is selected from F, C1 or Br, preferably F or C1;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br或 d_4垸基， 优选 H、 F或甲基；R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-CM 垸 -(CH2)m-NR13R13a，优选 H、- CH2OH、甲基、甲氧基、乙氧基、 ¾^C^、 ^^0 、 〜Q、 或
Figure imgf000027_0003
R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-O-CM 垸-(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 3⁄4^C^, ^^0, 〜Q , or
Figure imgf000027_0003
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 6元碳环， 优选 3至 4元碳环， 更优选 3元碳环； Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon. a ring, preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 11或^— 4垸基， 优选 H或甲基； R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
p选自 0、 1或 2;  p is selected from 0, 1 or 2;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 通式（I)所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶 体、 代谢产物、 药学上可接受的盐或前药， 其为通式 （in)所示的化合物或其立体异构体、 水 合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：
Figure imgf000028_0001
Preferred Embodiments of the Invention, the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic thereof a compound, a metabolite, a pharmaceutically acceptable salt or a prodrug, which is a compound of the formula (in) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable Accepted salt or prodrug:
Figure imgf000028_0001
其中-among them-
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br或 d_4垸基， 优选 H、 F或甲基； R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C -(CH2)m-NR13R13a，优选 H、- CH2OH、甲基、甲氧基、乙氧基、 、0
Figure imgf000028_0002
R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC —(CH 2 ) m —NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, , 0
Figure imgf000028_0002
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成一个 3元碳环； Alternatively, R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 H或 d_4垸基， 优选 H或甲基； R 12 is selected from H or d 4 alkyl, preferably H or methyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 通式 ω所述化合物或其立体异构体、水合物、酯、溶剂化物、共晶体、 代谢产物、药学上可接受的盐或前药，其为通式（IV)所示的化合物或其立体异构体、水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  Preferred Embodiments of the Invention, a compound of the formula ω or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is of the formula (IV) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000028_0003
Figure imgf000028_0003
其中-among them-
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -0-C -1-4 -(CH2)m-NR13R13a，优选 H、- CH2OH、甲基、甲氧基、乙氧基、 、0
Figure imgf000028_0004
R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-0-C -1-4 - (CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 0
Figure imgf000028_0004
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成 水 3元碳环; Alternatively, R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR 的取代基所取代； R12选自 11或^— 4垸基， 优选 H或甲基； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R ; R 12 is selected from the group consisting of 11 or 4 - 4, preferably H or methyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 通式 （IV)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共 晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  A preferred embodiment of the invention, a compound of the formula (IV): or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6和 R7各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 W 或 N、〜S\ ; R 6 and R 7 are each independently selected from the group consisting of H, methyl, methoxy, ethoxy, W or N , ~S\ ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
R8和 R9各自独立任选自 H、 -CH2OH、 甲基、
Figure imgf000029_0001
或 0 ； R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl,
Figure imgf000029_0001
Or 0;
作为选择， R8和 R9可与其相连接的碳原子形成一个 3元碳环。 Alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
本发明优选方案，通式 （I)所述化合物的化合物或其立体异构体、水合物、酯、溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其为通式 （V)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  A preferred embodiment of the invention, a compound of the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is a formula a compound represented by (V): or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000029_0002
Figure imgf000029_0002
(V)  (V)
其中-among them-
R4选自 H、 F或 Cl， 优选 H或 F; R 4 is selected from H, F or Cl, preferably H or F;
R5、 R1Q和 R11各自独立任选自 H、 F、 CI或 d_4垸基， 优选 H、 F或甲基； R 5 , R 1Q and R 11 are each independently selected from H, F, CI or d 4 alkyl, preferably H, F or methyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-CM -(CH2)m-NR13R13a，优选 H、- CH2OH、甲基、甲氧基、乙氧基、 。,、 、 、 〜0、
Figure imgf000029_0003
R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-O-CM -(CH 2 ) m - NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, . , , , , ~ 0 ,
Figure imgf000029_0003
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成 水 3元碳环; Alternatively, R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
12 12
R13和 R13a选自 H或 d— 4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR 的取代基所取代； R 13 and R 13a are selected from H or d- 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R ;
R12选自 11或^— 4垸基， 优选 H或甲基； R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
本发明优选方案， 通式 （V)所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共 晶体、 代谢产物、 药学上可接受的盐或前药， 其中： R4选自 H、 F或 Cl， 优选 H或 F; A preferred embodiment of the invention, a compound of the formula (V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 4 is selected from H, F or Cl, preferably H or F;
R5和 R11为甲基； R 5 and R 11 are methyl;
R1Q选自 H或 F， 优选 H; R 1Q is selected from H or F, preferably H;
R6和 R7各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 \〜"\或 ^~/^5\， 或者 R6 和 R7形成 (=0)， 优选 H或者 R6和 R7形成 (=0)， 更优选 R6和 R7形成 (=0); R 6 and R 7 are each independently selected from H, methyl, methoxy, ethoxy, \~"\ or ^~/^ 5 \, or R 6 and R 7 are formed (=0), preferably H or R 6 and R 7 are formed (=0), more preferably R 6 and R 7 are formed (=0);
R8和 R9各自独立任选自 H、 -CH2OH、 甲基、 ^^。^或'^。^， 或者 R8和 R9与其相 连接的碳原子形成一个 3元碳环， 优选 R8和 R9与其相连接的碳原子形成一个 3元碳环； 本发明优选方案， 通式 （V)所述化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶 体、 代谢产物、 药学上可接受的盐或前药， 其中： R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl, ^^. ^ or '^. ^, or R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached, preferably R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached; a preferred embodiment of the invention, formula (V) The compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R和 R7为 H或者 R6和 R7形成 (=0)， 优选 R6和 R7形成 (=0); R and R 7 are H or R 6 and R 7 are formed (=0), preferably R 6 and R 7 are formed (=0);
R8和 R9可与其相连接的碳原子形成一个 3元碳环。 R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
本发明优选方案， 通式（I)所示的化合物或其立体异构体、 水合物、 溶剂化物、 酯  Preferred embodiments of the invention, the compound of the formula (I) or a stereoisomer, hydrate, solvate or ester thereof
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000030_0001
Figure imgf000031_0001
本发明涉及通式 ω所示化合物的合适的药学上可接受的盐包括， 但不限于钠盐、 钾盐、 铝盐、 锂盐、 锌盐、 钙盐、 镁盐、钡盐、 铵盐、三甲胺盐、 四甲基铵盐、 二乙胺盐、 三乙胺盐、 异丙基胺盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二环己基胺盐、 吡啶盐、 甲基 吡啶盐、 2,6-二甲基吡啶盐、 咖啡碱盐、 普鲁卡因盐、 胆碱盐、 甜菜碱盐、 可可碱盐、 嘌吟盐、 哌嗪盐、 哌啶盐、 Ν-乙基哌啶盐、 聚胺树脂盐、 苯明青霉素盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 甲酸盐、 乙酸盐、 羟乙酸盐、 丙酸盐、 2-羟基丙酸盐、 丙二酸盐、 三氟乙酸 盐、 甲磺酸盐、 乙磺酸盐、三氟甲磺酸盐、 乙烯磺酸盐、 苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、 苯乙酸盐、 褐藻酸盐、 氨茴酸盐、 樟脑酸盐、 马来酸盐、 酒石酸盐、 柠檬酸盐、 琥珀酸盐、 扁 桃酸盐、 富马酸盐、 苹果酸盐、 草酸盐、水杨酸盐、 葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、 天冬氨酸盐、 谷氨酸盐、 肉桂酸盐、 它们的组合。 优选钠盐、 钾盐、 铵盐、 三乙胺盐、 乙醇胺 盐、 二乙醇胺盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 磷酸盐、 三氟乙酸盐、 乙酸盐、 马来酸盐、 天 冬氨酸盐、 谷氨酸盐、 苹果酸盐或它们的组合。  Suitable pharmaceutically acceptable salts of the compounds of the formula ω include, but are not limited to, sodium salts, potassium salts, aluminum salts, lithium salts, zinc salts, calcium salts, magnesium salts, barium salts, ammonium salts, Trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt , methylpyridine salt, 2,6-lutidine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, hydrazine -ethylpiperidine salt, polyamine resin salt, phenamine penicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate, propionic acid Salt, 2-hydroxypropionate, malonate, trifluoroacetate, methanesulfonate, ethanesulfonate, triflate, vinyl sulfonate, besylate, p-toluene Acid salt, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate , citrate, succinate, mandelate, fumarate, malate, oxalate, salicylate, glucuronide, galacturonate, citrate, aspartate Acid salts, glutamate, cinnamate, combinations thereof. Preferred are sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, trifluoroacetate salt, acetate salt, maleic acid Salt, aspartate, glutamate, malate or a combination thereof.
本发明还涉及制备所述的通式 （I)所示化合物的方法，本领域技术人员知道本发明的化合 物可以通过多种制备方法合成。优选的方法包括， 但不限于以下所描述的方法。 本领域的技术 人员能够理解在分子上表现出的功能性应当与所计划的转化一致。为了得到本发明的所需化合 物， 有时需要一种判断以改变合成步骤的顺序或者选择一种特定的工艺方案。为了对本发明所 描述的化合物中存在的反应性功能基团进行保护而选择合理的保护基团。具体而言， 本发明的 通式 (I)化合物的制备方法选自以下方法中的一种：  The present invention also relates to a process for the preparation of the compound of the formula (I), and it is known to those skilled in the art that the compound of the present invention can be synthesized by various preparation methods. Preferred methods include, but are not limited to, the methods described below. Those skilled in the art will appreciate that the functionality exhibited on the molecule should be consistent with the planned transformation. In order to obtain the desired compound of the present invention, a judgment is sometimes required to change the order of the synthetic steps or to select a particular process scheme. Reasonable protecting groups are selected for the protection of reactive functional groups present in the compounds described herein. Specifically, the method for producing the compound of the formula (I) of the present invention is selected from one of the following methods:
方法一：
Figure imgf000031_0002
通式 (I-a)化合物依次通过 Homer-Wadsworth-Emmons反应 (或 wittig反应）、 还原反应以及 垸基化反应转化为通式 (I-b)化合物； 或者通式 (I-a)化合物通过还原消除反应转化为通式 (I-b)化 合物；
Figure imgf000032_0001
method one:
Figure imgf000031_0002
The compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction. a compound of formula (Ib);
Figure imgf000032_0001
l-b l-c  L-b l-c
通式 (I-b)化合物通过 suzuki偶联反应以及加 还原反应转化为通式 (I-c)化合物;  The compound of the formula (I-b) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a reduction reaction;
Figure imgf000032_0002
Figure imgf000032_0002
通式 (I-c)化合物通过 Mitsunobu缩合反应以及水解反应转化为通式 (I)化合物； 通式 (I-c)化 合物通过 Mitsunobu缩合反应转化为通式 (I)化合物；  The compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction and a hydrolysis reaction; the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction;
方法二：
Figure imgf000032_0003
Method Two:
Figure imgf000032_0003
l-d l-e  L-d l-e
通式 (I-d)化合物通过亲核取代反应以及克莱森重排反应转化为通式 (I-e)化合物 t "Compound of formula (Id) by nucleophilic substitution reaction and Claisen rearrangement t converted to compounds of formula (Ie) "
Figure imgf000032_0004
Figure imgf000032_0004
l-f  L-f
通式 (I-e)化合物通过环氧化反应以及开环反应转化为通式 (I-f)化合物；或者通式 (I-e)化合物 通过亲核取代反应转化为通式 (I-f)化合物；  The compound of the formula (I-e) is converted into a compound of the formula (I-f) by an epoxidation reaction and a ring-opening reaction; or the compound of the formula (I-e) is converted into a compound of the formula (I-f) by a nucleophilic substitution reaction;
Figure imgf000032_0005
Figure imgf000032_0005
l-f l-c  L-f l-c
通式 (I-f)化合物通过 suzuki偶联反应通式 (l-c)化合物；或者通式 (I-f)化合物通过 suzuki偶联 反应以及加氢还原反应转化为通式 (l-c)化合物；
Figure imgf000033_0001
通式 (I-c)化合物通过 Mitsimobu缩合反应以及水解反应转化为通式 (I)化合物； 通式 (I-c)化 合物通过 Mitsimobu缩合反应转化为通式 (I)化合物； a compound of the formula (If) is converted to a compound of the formula (lc) by a suzuki coupling reaction; or a compound of the formula (If) is converted into a compound of the formula (lc) by a suzuki coupling reaction and a hydrogenation reduction reaction;
Figure imgf000033_0001
a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
方法三：
Figure imgf000033_0002
Method three:
Figure imgf000033_0002
l-g 1-3  L-g 1-3
通式 (I-g)化合物通过 Adol反应转化为通式 (I-a)化合物；或者通式 (I-g)化合物通过亲核取代 反应转化为通式 (I-a)化合物；
Figure imgf000033_0003
a compound of the formula (Ig) is converted to a compound of the formula (Ia) by an Adol reaction; or a compound of the formula (Ig) is converted to a compound of the formula (Ia) by a nucleophilic substitution reaction;
Figure imgf000033_0003
l-a l-f  L-a l-f
通式 (I-a)化合物通过还原反应转化为通式 (I-f)化合物； 或者通式 (I-a)化合物通过还原反应 以及脱羟基反应转化为通式 (I-f)化合物；  The compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction and a dehydroxylation reaction;
Figure imgf000033_0004
Figure imgf000033_0004
l-f l-c  L-f l-c
通式 (I-f)化合物通过 suzuki偶联反应通式 (I-c)化合物； 或者通式 (I-f)化合物通过 suzuki偶 联反应以及加氢还原反应转化为通式 (I-c)化合物  The compound of the formula (I-f) is subjected to a suzuki coupling reaction to a compound of the formula (I-c); or the compound of the formula (I-f) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a hydrogenation reduction reaction.
Figure imgf000033_0005
通式 (I-c)化合物通过 Mitsimobu缩合反应以及水解反应转化为通式 (I)化合物； 通式 (I-c)化 合物通过 Mitsimobu缩合反应转化为通式 (I)化合物； 方法四：
Figure imgf000033_0005
a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction; Method four:
Figure imgf000034_0001
Figure imgf000034_0001
l-a |-h  L-a |-h
通式 （I-a)化合物通过 suzuki偶联反应转化为通式 (I-h)化合物； 或者通式 (I-a)化合物通过 suzuki偶联反应以及加氢还原反应转化为通式 (I-h)化合物；  The compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction and a hydrogenation reduction reaction;
Figure imgf000034_0002
通式 (I-h)化合物通过还原胺化转化为通式 （1-i) 化合物;
Figure imgf000034_0002
a compound of the formula (Ih) is converted to a compound of the formula (1-i) by reductive amination;
Figure imgf000034_0003
通式 （1-i)化合物通过亲核取代反应、 Mitsimobu缩合反应以及水解反应转化为通式 （I)化 合物， 或者通式 （1-i)化合物通过 Mitsimobu缩合反应转化为通式 (I)化合物； 其中：
Figure imgf000034_0003
The compound of the formula (1-i) is converted into a compound of the formula (I) by a nucleophilic substitution reaction, a Mitsimobu condensation reaction and a hydrolysis reaction, or a compound of the formula (1-i) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction. ; among them:
L选自 F、 Cl、 Br或 I;  L is selected from F, Cl, Br or I;
R、 R1, R2、 R3、 R4、 R5、 R6、 R7、 R8、 R9、 R10、 Ru、 Q、 p、 q和 t如同本发明中所定义; R16、 R17和 R18选自 H、 羟基、 甲基或乙基。 R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention; 16. R 17 and R 18 are selected from H, hydroxy, methyl or ethyl.
更具体而言， 本发明的通式 (I)化合物的制备方法选自以下方法中的一种：  More specifically, the preparation method of the compound of the general formula (I) of the present invention is selected from one of the following methods:
方法一  method one
Figure imgf000034_0004
在碱性条件下， 以四氢呋喃为溶剂， 通式 （I-a)化合物与二乙氧基氰甲基磷酸酯反应， 然 后用二异丁基氢化铝将氰基还原为醛基， 再进一步与还原剂反应， 然后在碱性条件下， 进一步 与垸基化试剂反应得到通式 （I-b)化合物； 或者通式 （I-a)化合物与还原剂反应， 再进一步在 浓硫酸存在下， 发生消除反应得到通式 （I-b)化合物； 其中所述的碱选自钠氢、 氨基钠、 叔丁 醇钾、 丁基锂或者二异丙基胺基锂； 还原剂选自硼氢化钠、 硼氢化钾、 氢化铝锂、 硫代硼氢化 钠或者三仲丁基硼氢化锂； 垸基化试剂选自碘甲垸、 对甲苯磺酸甲酯、 硫酸二甲酯、 溴乙垸、 对甲苯磺酸乙酯或者硫酸二乙酯；
Figure imgf000034_0004
The compound of the formula (Ia) is reacted with diethoxycyanomethyl phosphate under basic conditions using tetrahydrofuran as a solvent, and then the cyano group is reduced to an aldehyde group with diisobutylaluminum hydride, and further with a reducing agent. The reaction is then further reacted with a thiolation reagent under basic conditions to obtain a compound of the formula (Ib); or the compound of the formula (Ia) is reacted with a reducing agent, and further, in the presence of concentrated sulfuric acid, a elimination reaction is carried out to obtain a general formula. (Ib) a compound; wherein the base is selected from the group consisting of sodium hydrogen, sodium amide, potassium t-butoxide, butyl lithium or lithium diisopropylamide; the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium aluminum hydride , sodium thioborohydride or lithium tri-sec-butyl borohydride; the thiolation reagent is selected from the group consisting of methyl iodide, methyl p-toluenesulfonate, dimethyl sulfate, ethyl bromide, ethyl p-toluenesulfonate or sulfuric acid Ethyl ester
以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水为溶剂， 碳酸钾、 碳酸钠或者 磷酸钾存在条件下，钯催化剂作用下， 通式 （I-b)化合物与 3-甲酰基苯硼酸发生 suzuki偶联反 应，然后在还原剂作用下，加氢还原得到通式 (I-c)化合物；其中所述的钯催化剂选自 [Ι ,Γ-双 (；二 苯基膦)二茂铁]二氯化钯、 [Ι ,Γ-双 (二苯基膦)二茂铁]二氯化钯二氯甲垸络合物、 四 (三苯基膦) 钯、 二氯化钯、 醋酸钯或者双三苯基磷二氯化钯， 所述的还原剂如上所述；  In the presence of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or potassium phosphate, palladium catalyst, formula (Ib) The compound is subjected to a suzuki coupling reaction with 3-formylbenzeneboronic acid, and then hydrogenated to obtain a compound of the formula (Ic) by a reducing agent; wherein the palladium catalyst is selected from the group consisting of [Ι, Γ-bis(; diphenyl) Phosphine) ferrocene] palladium dichloride, [Ι, Γ-bis(diphenylphosphino)ferrocene] palladium dichloromethane ruthenium complex, tetrakis(triphenylphosphine) palladium, two Palladium chloride, palladium acetate or bistriphenylphosphine palladium dichloride, the reducing agent as described above;
以二氯甲垸或者四氢呋喃为溶剂，三叔丁基膦条件下，偶氮二甲酸二异丙酯或者 1,1- (偶氮 二羰基；)二哌啶存在下， 通式 （I-c) 化合物与 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基；)乙酸乙酯发生 Mitsunobu反应得到通式 （1)化合物； 或者通式 (I-c)化合物在上述条件下通过 Mitsimobu缩合 反  a compound of the formula (Ic) in the presence of di-tert-butylphosphine or di-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl;)dipiperidine Mitsunobu reaction with ethyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl;) to give a compound of the formula (1); or a compound of the formula (Ic) under the above conditions by Mitsimobu Condensation
Figure imgf000035_0001
以乙腈、 四氢呋喃、 甲苯或者 1,2-二氯乙垸为溶剂， 碳酸钾存在下， 通式 （I-d)化合物与 3-溴丙烯反生亲核取代， 然后在 180°C下， 通过克莱森重排得到通式（I-e)化合物；
Figure imgf000035_0001
The compound of the formula (Id) is substituted with 3-bromopropene in the presence of potassium carbonate in the presence of acetonitrile, tetrahydrofuran, toluene or 1,2-dichloroacetic acid as a solvent, and then at 180 ° C, through Clay Reordering to obtain a compound of the formula (Ie);
以二氯甲垸或者 1,2-二氯乙垸为溶剂， 通式（I-e)化合物与间氯过氧苯甲酸发生环氧化反 应， 然后以 1,2-二氯乙垸为溶剂加热回流得到通式 （I-f)化合物； 或者以二氯甲垸或者 1,2-二 氯乙垸为溶剂， 在三氟甲磺酸存在下， 通式 （I-e)化合物发生亲核取代反应得到通式 （I-f)化 合物；  The compound of the formula (Ie) is epoxidized with m-chloroperoxybenzoic acid by using methylene chloride or 1,2-dichloroacetic acid as a solvent, and then heated to reflux with 1,2-dichloroethane as a solvent. Obtaining a compound of the formula (If); or using a solution of the compound of the formula (Ie) in the presence of trifluoromethanesulfonic acid in the presence of trichloromethane or 1,2-dichloroacetic acid to give a formula If) compound;
以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水为溶剂， 碳酸钾、 碳酸钠或者 磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-f)化合物与 3-羟基甲基苯硼酸发生 suzuki偶联 反应得到通式 （I-c)化合物， 或者以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水 为溶剂， 碳酸钾、 碳酸钠或者磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-f)化合物与 3-甲 酰基苯硼酸发生 suzuki偶联反应， 然后在还原剂作用下， 加氢还原得到通式 (I-c)化合物， 其 中所述的钯催化剂和还原剂如上文定义； Toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or In the presence of potassium phosphate, a compound of the formula (If) is subjected to a suzuki coupling reaction with 3-hydroxymethylbenzeneboronic acid under the action of a palladium catalyst to obtain a compound of the formula (Ic), or toluene/ethanol/water, acetonitrile/water, In the presence of 1,4-dioxane/water or tetrahydrofuran/water as solvent, in the presence of potassium carbonate, sodium carbonate or potassium phosphate, the compound of the formula (If) is suzuki coupled with 3-formylbenzeneboronic acid under the action of a palladium catalyst. And a hydrogenation reduction to obtain a compound of the formula (Ic), wherein the palladium catalyst and the reducing agent are as defined above;
以二氯甲垸或者四氢呋喃为溶剂，三叔丁基膦条件下，偶氮二甲酸二异丙酯或者 1,1- (偶氮 二羰基；)二哌啶存在下， 通式 （I-c) 化合物与 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基；)乙酸乙酯发生 Mitsunobu反应得到通式 （I)化合物； 或者通式 (I-c)化合物在上述条件下通过 Mitsimobu缩合 反应以及水解反应转化为通式 ω化合物；  a compound of the formula (Ic) in the presence of di-tert-butylphosphine or di-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl;)dipiperidine Mitsunobu reaction with ethyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl;) to give a compound of the formula (I); or a compound of the formula (Ic) under the above conditions by Mitsimobu The condensation reaction and the hydrolysis reaction are converted into a compound of the general formula ω;
Figure imgf000036_0001
以甲醇和水为溶剂，碳酸钾存在下，通式 （I-g)化合物与甲醛发生 Add反应得到通式 （I-a) 化合物； 或者以四氢呋喃、 Ν,Ν-二甲基甲酰胺为溶剂， 在钠氢存在下， 通式 (I-g)化合物与碘 甲垸或 1,2-二溴乙垸发生亲核取代反应得到通式（I-a)化合物；
Figure imgf000036_0001
The compound of the formula (Ig) is reacted with formaldehyde to obtain a compound of the formula (Ia) in the presence of methanol and water as a solvent in the presence of potassium carbonate; or tetrahydrofuran, hydrazine, hydrazine-dimethylformamide as a solvent, in sodium hydrogen In the presence of a compound of the formula (Ig), a nucleophilic substitution reaction with iodoformamidine or 1,2-dibromoacetamidine gives a compound of the formula (Ia);
以四氢呋喃为溶剂，三氯化铝存在下，通式 （I-a)化合物与四氢铝锂反应得到通式 （I-f)化 合物； 或者通式 （I-a)化合物在还原剂作用下加氢还原， 再进一步脱去羟基得到通式 （I-f) 化 合物， 其中脱羟基试剂选自三乙基硅垸、 钯 /炭、 TMSCl/Nal或者 CS2/NaH， TMSC1是指三甲 基氯硅垸， 其中所述的还原剂如上所述； The compound of the formula (Ia) is reacted with lithium tetrahydroaluminum to obtain a compound of the formula (If) in the presence of tetrahydrofuran as a solvent in the presence of aluminum trichloride; or the compound of the formula (Ia) is hydrogenated under the action of a reducing agent, and further Dehydroxylation gives a compound of the formula (If) wherein the dehydroxylation agent is selected from the group consisting of triethylsilyl, palladium/carbon, TMSCl/Nal or CS 2 /NaH, and TMSC1 refers to trimethylsilyl silane, wherein The reducing agent is as described above;
以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水为溶剂， 碳酸钾、 碳酸钠或者 磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-f)化合物与 3-羟基甲基苯硼酸发生 suzuki偶联 反应得到通式 （I-c)化合物， 或者以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水 为溶剂， 碳酸钾、 碳酸钠或者磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-f)化合物与 3-甲 酰基苯硼酸发生 suzuki偶联反应， 然后在还原剂作用下， 加氢还原得到通式 (I-c)化合物， 其 中所述的钯催化剂和还原剂如上文定义；  In the presence of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or potassium phosphate, palladium catalyst, general formula (If) The compound is subjected to suzuki coupling reaction with 3-hydroxymethylbenzeneboronic acid to obtain a compound of the formula (Ic), or as a solvent of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water. In the presence of potassium carbonate, sodium carbonate or potassium phosphate, a compound of the formula (If) undergoes a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then a hydrogenation reduction reaction is carried out under the action of a reducing agent. a compound of (Ic), wherein the palladium catalyst and the reducing agent are as defined above;
以二氯甲垸或者四氢呋喃为溶剂，三叔丁基膦条件下，偶氮二甲酸二异丙酯或者 1,1- (偶氮 二羰基；)二哌啶存在下， 通式 （I-c) 化合物与 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基；)乙酸乙酯发生Using dichloromethyl hydrazine or tetrahydrofuran as solvent, di-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1- (azo) The compound of the formula (Ic) and the ethyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate are present in the presence of dicarbonyl;
Mitsunobu反应得到通式 （I)化合物； 或者通式 (I-c)化合物在上述条件下通过 Mitsimobu缩合 反应以及水解反应转化为通式 ω化合物； The Mitsunobu reaction gives a compound of the formula (I); or the compound of the formula (I-c) is converted into a compound of the formula ω by a Mitsimobu condensation reaction and a hydrolysis reaction under the above conditions;
Figure imgf000037_0001
以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水为溶剂， 碳酸钾、 碳酸钠或者 磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-a)化合物与 3-羟基甲基苯硼酸发生 suzuki偶联 反应得到通式 （I-h)化合物， 或者以甲苯 /乙醇 /水、 乙腈 /水、 1,4-二氧六环 /水或者四氢呋喃 /水 为溶剂， 碳酸钾、 碳酸钠或者磷酸钾存在条件下， 钯催化剂作用下， 通式 （I-a)化合物与 3- 甲酰基苯硼酸发生 suzuki偶联反应， 然后在还原剂作用下， 加氢还原得到通式 （I-h)化合物， 其中所述的钯催化剂和还原剂如上文定义；
Figure imgf000037_0001
In the presence of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or potassium phosphate, palladium catalyst, formula (Ia) The compound is subjected to suzuki coupling reaction with 3-hydroxymethylbenzeneboronic acid to obtain a compound of the formula (Ih), or a solvent of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water. In the presence of potassium carbonate, sodium carbonate or potassium phosphate, the compound of the formula (Ia) is subjected to a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then hydrogenated to reduce the formula under the action of a reducing agent. (Ih) a compound wherein the palladium catalyst and reducing agent are as defined above;
以甲醇 /水、 乙醇 /水、异丙醇 /水为溶剂， 氢氧化钠、氢氧化钾或者氢氧化锂存在的条件下， 通式 （I-h) 与盐酸羟胺发生缩合， 然后在还原剂四氢铝锂、 硼垸作用下或者在兰尼镍、 钯碳作 用下加氢还原得到通式（1-i)化合物。  The condensation of the general formula (Ih) with hydroxylamine hydrochloride in the presence of methanol/water, ethanol/water, isopropanol/water as solvent, sodium hydroxide, potassium hydroxide or lithium hydroxide, followed by tetrahydrogen in the reducing agent The compound of the formula (1-i) is obtained by hydrogenation under the action of aluminum lithium or borax or under the action of Raney nickel and palladium carbon.
以乙腈、 Ν,Ν-二甲基甲酰胺为溶剂， 碳酸钾、 碳酸钠、 氢氧化钾、 氢氧化钠、 氢氧化锂、 三乙胺、 Ν,Ν-二异丙基乙胺存在下， 通式 （1-i) 发生亲核取代反应， 然后以二氯甲垸或者四氢 呋喃为溶剂， 三叔丁基膦条件下， 偶氮二甲酸二异丙酯或者 1,1- (偶氮二羰基)二哌啶存在下， 与 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基；)乙酸乙酯发生 Mitsimobu反应得到通式 （I)化合物； 或者 通式 （I-i)化合物在上述条件下再进一步水解转化为通式 （I)化合物。 其中， L选自 F、 Cl、 Br或者 I;  In the presence of acetonitrile, hydrazine, hydrazine-dimethylformamide as solvent, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, hydrazine, hydrazine-diisopropylethylamine, A nucleophilic substitution reaction of the formula (1-i) followed by dichloromethane or tetrahydrofuran as a solvent, tri-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl) In the presence of dipiperidine, a Mitsimobu reaction with ethyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl;) gives a compound of the formula (I); or a formula (Ii) The compound is further hydrolyzed to the compound of formula (I) under the conditions described above. Wherein L is selected from the group consisting of F, Cl, Br or I;
R、 R\ R2、 R3、 R4、 R5、 R6、 R7、 R8、 R9、 R10、 Ru、 Q、 p、 q和 t的定义与本发明中所 述定义一致； R16、 R17、 R18选自 H、 羟基、 甲基或者乙基。 Definitions of R, R\R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention Consistent; R 16 , R 17 , R 18 are selected from H, hydroxy, methyl or ethyl.
本发明还涉及一种药物组合物， 所述的组合物包括： 有效剂量的通式 （I)所示化合物或其 所有立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前药， 及 药学上可接受的载体、稀释剂、 佐剂或赋形剂。所述的组合物还可进一步包括一种或多种其他 治疗剂。 其中所述的其他治疗剂包括： The present invention also relates to a pharmaceutical composition comprising: an effective amount of a compound of the formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, A pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient. The composition may further comprise one or more other Therapeutic agent. Other therapeutic agents described therein include:
(a) GPR40激动剂或药学上可接受的盐， 和 /或  (a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or
(b) DPP-IV抑制剂或药学上可接受的盐， 和 /或  (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or
(c) SGLT-2抑制剂或药学上可接受的盐， 和 /或  (c) an SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or
((1) ?? 1^激动剂和部分激动剂或药学上可接受的盐， 和 /或  ((1) ?? 1 ^ agonist and partial agonist or pharmaceutically acceptable salt, and / or
(e) PPAR^双重激动剂或药学上可接受的盐， 和 /或  (e) a PPAR^ dual agonist or pharmaceutically acceptable salt, and/or
(； f) PPARs激动剂或药学上可接受的盐， 和 /或 (; f) a PPAR s agonist or pharmaceutically acceptable salt, and/or
(g)胰岛素或拟胰岛素或药学上可接受的盐， 和 /或  (g) insulin or pseudo-insulin or a pharmaceutically acceptable salt, and / or
(h) 蛋白酪氨酸磷酸酶 -1BCPTP-1B)抑制剂或药学上可接受的盐， 和 /或  (h) a protein tyrosine phosphatase-1BCPTP-1B) inhibitor or a pharmaceutically acceptable salt, and/or
(i)磺酰脲类抑制剂或药学上可接受的盐， 和 /或  (i) a sulfonylurea inhibitor or a pharmaceutically acceptable salt, and/or
(D a-葡糖苷酶抑制剂或药学上可接受的盐， 和 /或  (D a-glucosidase inhibitor or pharmaceutically acceptable salt, and/or
(k) GLP-K GLP-1类似物、 GIP-1、 HSD-1或药学上可接受的盐， 和 /或  (k) a GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or
(1)胰高血糖素受体拮抗剂或药学上可接受的盐， 和 /或  (1) a glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or
(m)抗炎药， 和 /或  (m) anti-inflammatory drugs, and / or
(n) 回肠胆汁酸转运蛋白抑制剂或药学上可接受的盐， 和 /或  (n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or
(0)减肥药， 和 /或  (0) diet pills, and / or
(p) 改善患者脂质分布的药物， 所述药物选自 HMG-CoA还原酶抑制剂、 胆汁酸螯合剂、 烟碱、烟酸或其盐、？？入！^激动剂、胆固醇吸收抑制剂、酰基 CoA (胆固醇酰基转移酶 (ACAT)) 抑制剂、 CETP抑制剂或酚类抗氧剂或药学上可接受的盐， 和 /或  (p) A drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter! An agonist, a cholesterol absorption inhibitor, an acyl CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or
(q)双胍类、 噻唑垸二酮类、 列奈类或其药学上可接受的盐或前药， 和 /或  (q) biguanides, thiazolidinediones, linoles or pharmaceutically acceptable salts or prodrugs thereof, and/or
(r) PARP抑制剂。  (r) PARP inhibitors.
本发明优选方案， 所述的 GPR40激动剂选自 fasiglifam hemihydrate或其药学上可接受的 盐或前药。 所述的 DDPIV 抑制剂选自 linagliptin (利拉列汀）、 omarigliptin (MK-3102) , sitagliptin (西他列汀）、 vildagliptin (维达列汀）、 alogliptin (阿格列汀）、 saxagliptin (沙格列汀）、 denagliptin (地格列汀）、 Carmegliptin, Melogliptin (美罗利汀）、 Dutogliptin, Teneligliptin (特力利 汀)、 Gemigliptin或者 Trelagliptin。 所述的 SGLT-2抑制剂选自 dapagliflozin、 propanediol, empagliflozin、 ertugliflozin、 ipragliflozin、 tofogliflozin、 canagliflozinlus或 eogliflozin。 所述的 PARP抑制剂选自 bezafibrate、feno fib rate 、pioglitazone、azelaic acid^ rosiglitazone或 saroglitazar。 所述的双胍类治疗剂选自二甲双胍或者二乙双胍。 所述的噻唑垸二酮类治疗剂选自环格列酮、 吡咯列酮、 罗格列酮、 曲格列酮、 法格列酮或者达格列酮。 所述的磺酰脲类治疗剂选自格列美 脲、 Tolglybutamide、 格列波脲、 格列苯脲、 格列喹酮、 格列吡嗪、 或格列齐特。 所述的列奈 类治疗剂选自那格列奈、 瑞格列奈或者米格列奈。 所述的 (X-葡萄糖苷酶抑制剂选自阿卡波糖、 伏格列波糖或者米格列醇。 所述的 GLP-1类似物选自艾赛那肽或者利拉鲁肽。 In a preferred embodiment of the invention, the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof. The DDPIV inhibitor is selected from the group consisting of linagliptin (Lilatripin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vidatripin), alogliptin (alogliptin), saxagliptin (sand Gliptin), denagliptin (digagliptin), Carmegliptin, Melogliptin (Merrolidine), Dutogliptin, Teneligliptin (Teliglitin), Gemigliptin or Trelagliptin. The SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin. The PARP inhibitor is selected from the group consisting of bezafibrate, feno fib rate, pioglitazone, azelaic acid^ rosiglitazone or saroglitazar. The biguanide therapeutic agent is selected from the group consisting of metformin or dibiguanidine. The thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone or dapaglitazone. The sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, Tolglybutamide, glibenclamide, glibenclamide, gliclazone, glipizide, or gliclazide. The levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide. Said (X-glucosidase inhibitor is selected from the group consisting of acarbose, Voglibose or miglitol. The GLP-1 analogue is selected from the group consisting of exenatide or liraglutide.
本发明还涉及通式 （I)所示化合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前药作为一种 G蛋白偶联受体 40激动剂在医学上的用途， 还涉 及所述包括通式 （I)所示化合物或其立体异构体、水合物、溶剂化物、酯、代谢产物、共晶体、 药学上可接受的盐或前药的药物组合物在医学上的用途，优选本发明的通式 （I)所示化合物或 其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前药是作为 一种 G蛋白偶联受体 40激动剂用于制备用于治疗和 /或预防代谢性疾病的药物制剂。所述的代 谢性疾病例如可以是包括糖尿病、 II型糖尿病、 糖尿病性视网膜病、 糖尿病性神经病、 糖尿病 性肾病、 糖尿病并发症、 高胆固醇血症、 高血糖、 高胰岛素血症、 高脂血症、 高甘油三酸脂血 症、 高血压、 高脂蛋白血症、 高 LDL胆固醇、 低 HDL胆固醇、 低血糖症、 血脂异常、 血栓性 疾病、 心血管疾病、 肾脏疾病、 酮症酸中毒、 脂肪酸或甘油的升高的水平、 脂肪萎缩、 脂肪毒 性、肥胖症、代谢综合症、 X综合症、胰岛素抗性、胰岛素过敏症、葡萄糖耐受不良、 皮肤病、 动脉粥样硬化及其后遗症心绞痛、跛行、 心脏病发作或中风中的一种或多种。进一步优选本发 明的通式 （I)所示化合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学 上可接受的盐或前药是作为一种 G蛋白偶联受体 40激动剂用于制备用于治疗和 /或预防 II型糖 尿病的药物制剂。  The present invention also relates to a compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof as a G protein conjugation The use of the body 40 agonist in medicine, and also relates to the compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt thereof. Or a pharmaceutical composition of a prodrug for medical use, preferably a compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal thereof, pharmaceutically acceptable The salt or prodrug is used as a G protein coupled receptor 40 agonist for the preparation of a pharmaceutical preparation for the treatment and/or prevention of metabolic diseases. The metabolic diseases may include, for example, diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia. , high triglycerideemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acids Or elevated levels of glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke. Further preferably, the compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof is used as a G protein couple. A conjugated 40 agonist is used to prepare a pharmaceutical preparation for the treatment and/or prevention of type 2 diabetes.
本发明还涉及一种治疗和 /或预防所述代谢疾病的方法， 该方法包括给予受试者有效量的 本发明所述的通式 ω所示化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产 物、 药学上可接受的盐或前药， 或者所述的包括其的药物组合物。  The invention also relates to a method of treating and/or preventing the metabolic disease, the method comprising administering to a subject an effective amount of a compound of the formula ω according to the invention or a stereoisomer, hydrate or ester thereof A solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition comprising the same.
除非有相反的陈述， 在本发明中使用的术语具有下述含义。  Unless otherwise stated, the terms used in the present invention have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素情况， 及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应 的同位素所替代， 其中碳的同位素包括 12C、 13C和 14C， 氢的同位素包括氕（H)、 氘 （D， 又叫 重氢 )、 氚 （T， 又叫超重氢； I， 氧的同位素包括160、 170和180， 硫的同位素包括 32S、 33S、 34S 和 36S， 氮的同位素包括 14N和 15N， 氟的同位素包括 17F和 19F， 氯的同位素包括 35C1和 37C1， 溴的同位素包括 7¾r和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention. Or the nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen),氚 (T, also known as super heavy hydrogen; I, oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, The fluorine isotopes include 17 F and 19 F, the chlorine isotopes include 35 C1 and 37 C1, and the bromine isotopes include 7 3⁄4r and 81 Br.
"垸基"是指含 1至 20个碳原子的直链或支链饱和脂肪族烃基， 优选为 1至 8个碳原子的 垸基， 更优选为 1至 6个碳原子的垸基， 进一步优选为 1至 4个碳原子的垸基。非限制性实施 例包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 叔丁基、 正戊基、 2-戊基、 3-戊基、 2-甲基 -2-戊基、 3-甲基 -2-戊基、 4-甲基 -2-戊基、 3-甲基 -3-戊基、 2-甲基 -3-戊基、 2,3-二甲基 -2- 丁基、 3,3-二甲基 -2-丁基、 正庚基、 正辛基及其各种支链异构体； 所述的垸基可以任选进一步 被 0至 5个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 -SR14、 -S(=0)R14、 -S(=0)2R14, 硝基、 氰基、 异氰基、 醛基、 羧基、 氨基、 垸基胺基、 酰胺基、 烯基、 炔基、 垸 基、羟基垸基、垸氧基、碳环基、杂环基、羧酸酯、羧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代， 其中 R14选自 1至 8个碳原子的垸基、 3至 10 个碳原子的碳环基或者 3至 10个碳原子的杂环基， R12、 R13和 1 1¾如同与权利要求 1所定义， 本文中出现的垸基， 其定义如上所述。 "Mercapto" refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further A fluorenyl group of 1 to 4 carbon atoms is preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl -2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- Dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl and various branched isomers thereof; the thiol group may optionally be further Up to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxyl, thiol, -SR 14 , -S(=0)R 14 , -S(=0) 2 R 14 , nitro, cyano, isocyano, aldehyde, carboxyl, amino, decylamino, amide, alkenyl, alkynyl, decyl, hydroxy fluorenyl, hydrazine , carbocyclyl, heterocyclic, carboxylic acid ester, carboxyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C (=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or substituted by a substituent of -NR 13 R 13a wherein R 14 is selected from a fluorenyl group of 1 to 8 carbon atoms a carbocyclic group of 3 to 10 carbon atoms or a heterocyclic group of 3 to 10 carbon atoms, R 12 , R 13 and 1 13⁄4 as defined in claim 1, the fluorenyl group appearing herein, as defined above Said.
"垸氧基"是指 -0-垸基， 非限制性实施例包括甲氧基、 乙氧基、 1-丙氧基、 2-丙氧基、 1-丁 氧基、 2-甲基 -1-丙氧基、 2-丁氧基、 2-甲基 -2-丙氧基、 1-戊氧基、 2-戊氧基、 3-戊氧基、 2-甲基 -2-丁氧基、 3-甲基 -2-丁氧基、 3-甲基 -1-丁氧基和 2-甲基 -1-丁氧基。 所述的垸基可以任选进一 步被 0至 5个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 -SR14、 -S(=0)R14、 -S(=0)2R14, 硝基、 氰基、 异氰基、 醛基、 羧基、 氨基、 垸基胺基、 酰胺基、 烯基、 炔基、 垸 基、羟基垸基、垸氧基、碳环基、杂环基、羧酸酯、羧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代， 其中 R14如上文定义， R12、 R13和 R13a如同与 权利要求 1所定义。 "Alkoxy" means -0-fluorenyl, non-limiting examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl- 1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy Base, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy. The thiol group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, thiol, -SR 14 , -S (=0)R 14 , -S(=0) 2 R 14 , nitro, cyano, isocyano, aldehyde, carboxyl, amino, decylamino, amide, alkenyl, alkynyl, fluorenyl , hydroxyindenyl, oximeoxy, carbocyclyl, heterocyclyl, carboxylic acid ester, carboxyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , (CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a Substituted by a substituent of -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or -NR 13 R 13a , wherein R 14 is as defined above, R 12 , R 13 and R 13a are as defined in claim 1.
"烯基 "是指含有 1至 3个碳-碳双键， 由 2-20个碳原子组成的直链或者支链不饱和脂肪族 烃基， 优选 2-12个碳原子的烯基， 更优选 2-8个碳原子的烯基。 非限制性实施例包括乙烯基、 丙烯 -2-基、 丁烯 -2-基、 戊烯 -2-基、 戊烯 -4-基、 己烯 -2-基、 己烯 -3基、 庚烯 -2-基、 庚烯 -3-基、 庚烯 -4-基、 辛烯 -3-基、 壬烯 -3-基、 癸烯 -4-基和十一烯 -3-基。 所述的烯基可以任选进一步被 0 至 4个选自 F、 Cl、 Br、 I、 垸基、 垸氧基、 直链烯基、 直链炔基、 氨基、 硝基、 氰基、 巯基、 酰胺基、 碳环基或者杂环基的取代基所取代。  "Alkenyl" means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexene-3-yl, g Alken-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl. The alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
"炔基 "是指含有 1至 3个碳-碳叁键， 由 2-20个碳原子组成的直链或者支链不饱和脂肪族 烃基， 优选 2-12个碳原子的炔基， 更优选 2-8个碳原子的炔基。 非限制性实施例包括乙炔基、 丙炔 -1-基、 丙炔 -2-基、 丁炔 -1-基、 丁炔 -2-基、 丁炔 -3-基、 3,3-二甲基丁炔 -2-基、 戊炔 -1-基、 戊炔 -2-基、 己炔 -1-基、 1-庚炔 -1-基、 庚炔 -3-基、 庚炔 -4-基、 辛炔 -3-基、 壬炔 -3-基、 癸炔 -4- 基、 十一炔 -3-基、 十二炔 -4-基。 所述的炔基可以任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 垸基、 垸氧基、 直链烯基、 直链炔基、 氨基、 硝基、 氰基、 巯基、 酰胺基、 碳环基或者杂环基 的取代基所取代。  "Alkynyl" means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecy-3-yl, dodecyn-4-yl. The alkynyl group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
"碳环基"是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是 3至 10 元的单环、 4至 12元双环或者 10至 15元三环体系， 碳环基可以连接有桥环或者螺环， 非限 制性实施例包括环丙基、 环丁基、 环戊基、 1-环戊基 -1-烯基、 苯基、 1-环戊基 -2-烯基、 1-环戊 基 -3-烯基、 环己基、 1-环己基 -2-烯基、 1-环己基 -3-烯基、 环己烯基、 环己二烯基、 环庚基、环 辛基、 环壬基、 环癸基、 环十一垸基、 环十二垸基、 ^、 *w。 所述的碳环基可 以任选进一步被 0至 8个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 -SR14、 -S(=0)R14, -S(=0)2R14, 硝基、 氰基、 异氰基、 醛基、 羧基、 氨基、 垸基胺基、 酰胺基、 烯基、 炔基、垸基、羟基垸基、垸氧基、碳环基、杂环基、羧酸酯、羧基、 -(CH2)m -烯基 -R12、 -(CH2)m - 炔 基 -R12 、 -(CH2)m-C(=0)-R12 、 -(CH2)m-C(=0)-0-R12 、 -(CH2)m-C(=0)-NR13R13a 、 -(CH2)m-S(=0)n-R12, -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代，其中 R14如上文定义， R12、 R13和 1 1¾如同与权利要求 1所定义。 "Carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system. The ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, phenyl, 1-cyclopentyl-2 -alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, ring Heptyl, ring Octyl, cyclodecyl, cyclodecyl, cyclodecyl, cyclododedecyl, ^, *w. The carbocyclic group may be further optionally further selected from 0 to 8 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, -SR 14 , S(=0)R 14 , -S(=0) 2 R 14 , nitro, cyano, isocyano, aldehyde, carboxyl, amino, decylamino, amide, alkenyl, alkynyl, anthracene , hydroxy fluorenyl, decyloxy, carbocyclic, heterocyclic, carboxylic acid ester, carboxyl, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R Substituted by a substituent of 13a , -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or -NR 13 R 13a wherein R 14 is as defined above R 12 , R 13 and 1 13⁄4 are as defined in claim 1.
"杂环基"是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香 环可以是 3至 10元的单环、 4至 12元双环或者 10至 15元三环体系，且包含 1至 4个选自 N、 0或 S的杂原子， 优选 3至 8元杂环基， 杂环基的环中选择性取代的 N、 S可被氧化成各种氧 化态。杂环基可以连接在杂原子或者碳原子上， 杂环基可以连接有桥环或者螺环， 非限制性实 施例包括环氧乙基、 环氧丙基、 氮杂环丙基、 氧杂环丁基、 氮杂环丁基、 硫杂环丁基、 1,3-二 氧戊环基、 1,4-二氧戊环基、 1,3-二氧六环基、氮杂环庚基、 氧杂环庚基、硫杂环庚基、 氧氮杂 卓基、 二氮杂卓基、 硫氮杂卓基、 吡啶基、 哌啶基、 高哌啶基、 呋喃基、 噻吩基、 吡喃基、 N-垸基吡咯基、 嘧啶基、 吡嗪基、 哒嗪基、 哌嗪基、 高哌嗪基、 咪唑基、 哌啶基、 哌叮基、 吗 啉基、 硫代吗啉基、 、 噻噁垸基、 1,3-二噻基、 二氢呋喃基、 二氢吡喃基、 二噻戊环基、 四氢 呋喃基、 四氢噻吩基、 四氢吡喃基、 四氢噻喃基、 四氢吡咯基、 四氢咪唑基、 四氢噻唑基、 四 氢吡喃基、 苯并咪唑基、 苯并吡啶基、 吡咯并吡啶基、 苯并二氢呋喃基、 2-吡咯啉基、 3-吡咯 啉基、 二氢吲哚基、 2H-吡喃基、 4H-吡喃基、 二氧杂环己基、 1,3-二氧戊基、 吡唑啉基、 二噻 垸基、 二噻茂垸基、 二氢噻吩基、 吡唑垸基咪唑啉基、 咪唑垸基、 1,2,3,4-四氢异喹啉基、 3- 氮杂双环 [3丄 0]己基、 3-氮杂双环 [4.1.0]庚基、 氮杂双环 [2.2.2]己基、 3H-吲哚基喹嗪基、 N-吡 啶基尿素、 1,1-二氧硫代吗啉基、 氮杂二环 [3.2.1]辛垸基、 氮杂二环 [5.2.0]壬垸基、 氧杂三环 [5.3.1.1]十二垸基、氮杂金刚垸基和氧杂螺 [3.3]庚垸基。所述的杂环基可以任选进一步被 0至 8 个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、羟基、 巯基、 -SR14、 -S(=0)R14、 -S(=0)2R14、 硝基、 氰基、 异氰基、 醛基、 羧基、 氨基、垸基胺基、 酰胺基、烯基、 炔基、垸基、羟基垸基、 垸氧基、碳环基、杂环基、羧酸酯、羧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12, -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12 或者 -NR13R13a的取代基所取代， 其中 R14如上文定义。 "Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 4 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state. The heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include an epoxy group, a propylene group, an aziridine group, and an oxygen hetero ring. Butyl, azetidinyl, thiaridolyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azepanyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyridyl Cyclol, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl , thiaxanthyl, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyran , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrroline , 3-pyrrolyl, indanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiazinyl , dithiadecyl, dihydrothienyl, pyrazolyl imidazolinyl, imidazolium, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3丄0]hexyl , 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl , azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]fluorenyl, oxatricyclo[5.3.1.1]t-decyl, aza-gold fluorenyl and oxaspiro[3.3 ] Geng Jiji. The heterocyclic group may be further optionally 0 to 8 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, -SR 14 , - S(=0)R 14 , -S(=0) 2 R 14 , nitro, cyano, isocyano, aldehyde, carboxyl, amino, mercaptoamine, amide, alkenyl, alkynyl, anthracene a group, a hydroxy fluorenyl group, a decyloxy group, a carbocyclic group, a heterocyclic group, a carboxylic acid ester, a carboxyl group, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R Substituted by a substituent of 13a , -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or -NR 13 R 13a , wherein R 14 is as defined above .
"PEG"是指含有^^ 的聚合物， 其中 n是 2〜大约 1000范围内的整数， 优选 2〜大 约 500， 更优选 2〜大约 250， 更优选 2〜大约 125， 更优选 2〜大约 50， 进一步优选 2〜大约 25范围内的整数。 "氨基 "是指 -NH2。 "PEG" means a polymer containing ^^, wherein n is an integer in the range of from 2 to about 1,000, preferably from 2 to about 500, more preferably from 2 to about 250, still more preferably from 2 to about 125, still more preferably from 2 to about 50. Further, an integer in the range of 2 to about 25 is further preferable. "Amino" means -NH 2 .
"垸基胺基"是指具有一个或者两个垸基取代基的氨基基团。  "Mercaptoalkyl" refers to an amino group having one or two mercapto substituents.
"氰基 "是指^ N。 "Cyano" means ^ N .
"异氰基"是指 ≡e_。 " Isocyano " means ≡e_ .
"硝基 "是指 -N02。 "Nitro" means -N0 2 .
"羟基 "是指 -OH。  "Hydroxy" means -OH.
"巯基 "是指 -SH。  "巯基" means -SH.
"酸基 "是指 -C(=0)H。  "Acid group" means -C(=0)H.
"羧基 "是指 -COOH。  "Carboxy" means -COOH.
"羧酸酯"是指 COOR15， 其中 R15为垸基。 "Carboxylic acid ester" means COOR 15 wherein R 15 is a fluorenyl group.
"酰胺基"是指 -CONR13R13a， R13和 1 1¾如同与权利要求 1所定义。 "Amido" means -CONR 13 R 13a , R 13 and 1 13⁄4 as defined in claim 1.
"=0"为本领域通常习惯用法，是指以双键相连的氧原子，譬如羰基中与碳原子相连的双键 氧原子。  "=0" is a commonly used practice in the art and refers to an oxygen atom bonded by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.
"羟基垸基"是指被 1、 2或者 3个羟基取代的垸基， 所述的垸基优选为 C1-4垸基。 非限制 性实施例包括羟基甲基、 1-羟基乙基、 2-羟基乙基、 1,2-二羟基丙基、 1,3-二羟基丙基和 2,3-二 羟基丙基。  "Hydroxymethane" means a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a C1-4 fluorenyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl.
"药学上可接受的盐 "或者 "其药学上可接受的盐"是指本发明化合物保持游离酸或者游离 碱的生物有效性和特性， 且所述的游离酸通过与无毒的无机碱或者有机碱， 所述的游离碱通过 与无毒的无机酸或者有机酸反应获得的盐。 所述的无机碱的非限制性实施例包括钠、 钾、 铝、 锂、 锌、 钙、 镁、 钡； 所述的有机碱的非限制性实施例包括氨、 三甲胺、 四甲基铵、 二乙胺、 三乙胺、 异丙基胺、 乙醇胺、 二乙醇胺、 三乙醇胺、 环己胺、 二环己基胺、 吡啶、 甲基吡啶、 2,6-二甲基吡啶、 咖啡碱、 普鲁卡因、 胆碱、 甜菜碱、 可可碱、 嘌吟、 哌嗪、 哌啶、 N-乙基哌 啶、聚胺树脂、苯明青霉素盐； 所述的无机酸和有机酸的非限制性实施例盐酸、氢溴酸、硫酸、 硝酸、 磷酸、 甲酸、 乙酸、 羟乙酸、 丙酸、 2-羟基丙酸、 丙二酸、 三氟乙酸、 甲磺酸、 乙磺酸、 三氟甲磺酸、 乙烯磺酸、 苯磺酸、 对甲苯磺酸、 苯甲酸、 苯乙酸、 褐藻酸、 氨茴酸、 樟脑酸、 马来酸、 酒石酸、 柠檬酸、 琥珀酸、 扁桃酸、 富马酸、 苹果酸、 草酸、 水杨酸、 葡萄糖醛酸、 半乳糖醛酸、 枸橼酸、 天冬氨酸、 谷氨酸、 肉桂酸、  "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid. Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethylammonium, Diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, proca Non-limiting examples of the inorganic acid and organic acid; choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic acid, propionic acid, 2-hydroxypropionic acid, malonic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, Ethylene sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, phenylacetic acid, alginic acid, anthranilic acid, camphoric acid, maleic acid, tartaric acid, citric acid, succinic acid, mandelic acid, fumaric acid, malic acid , oxalic acid, salicylic acid, glucuronic acid, galactose Aldehyde acid, citric acid, aspartic acid, glutamic acid, cinnamic acid,
"载体 "是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材 料。  "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
"赋形剂"是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳 酸钙、 磷酸钙、 糖、 淀粉、 纤维素衍生物 （包括微晶纤维素)、 明胶、 植物油、 聚乙二醇类、 稀 释剂、 成粒剂、 润滑剂、 粘合剂和崩解剂。 "佐剂 "是非特异性免疫增强剂， 当与抗原一起注射或预先注入机体时， 可增强机体对抗原 的免疫应答或改变免疫应答类型。 "Excipient" means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant. An "adjuvant" is a non-specific immunopotentiator that, when injected with an antigen or pre-injected into the body, enhances the body's immune response to the antigen or alters the type of immune response.
"稀释剂"也叫"填充剂"。 把原药加工成粉剂时， 或为了使其便于喷施所加入的进行稀释的 惰性物质。 如： 粘土、 高岭土、 陶土、 滑石粉等。  "Diluent" is also called "filler". When the original drug is processed into a powder, or to facilitate the spraying of the added inert substance to be diluted. Such as: clay, kaolin, clay, talcum powder, etc.
"前药 "是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本 发明化合物中的功能基团来制备， 该修饰可以通过常规的操作或者在体内被除去， 而得到母体 化合物。前药包括本发明化合物中的一个羟基、氨基或者巯基连接在任何集团上所形成的化合 物， 当本发明的前药被施予哺乳动物个体时， 前药被割裂而分别形成游离的羟基、游离的氨基 或者游离的巯基。 前药的例子包括但不限于， 本发明化合物中的羟基或氨基功能基团与甲酸、 乙酸或苯甲酸所形成的化合物。  "Prodrug" means a compound of the invention that can be converted to biological activity by metabolism in vivo. The prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention, which can be removed by conventional procedures or in vivo to give the parent compound. A prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, respectively. Amino or free sulfhydryl. Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
"共晶"是指活性药物成分和共晶形成物在氢键或其他非共价键的作用下结合而成的晶体， 其中活性药物成分（API)和共晶形成物 （CCF) 的纯态在室温下均为固体， 并且各组分间存在 固定的化学计量比。共晶是一种多组分晶体， 既包含两种中性固体之间形成的二元共晶， 也包 含中性固体与盐或溶剂化物形成的多元共晶。 非限定性实例共晶形成物包括丙氨酸、 缬氨酸、 亮氨酸、 异亮氨酸、 脯氨酸、 苯丙氨酸、 色氨酸、 蛋氨酸、 甘氨酸、 丝氨酸、 苏氨酸、 半胱氨 酸、 酪氨酸、 天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、 组氨酸、天冬氨酸、 门冬氨酸、谷氨酸、 焦谷氨酸、硫酸、 磷酸、 硝酸、 氢溴酸、 盐酸、 甲酸、 乙酸、 丙酸、 苯磺酸、 苯甲酸、 苯乙酸、 水杨酸、 褐藻酸、 氨茴酸、 樟脑酸、 柠檬酸、 乙烯磺酸、 蚁酸、 富马酸、 糠酸、 葡萄糖酸、 葡 萄糖醛酸、谷氨酸、 乙醇酸、羟乙磺酸、 乳酸、 马来酸、 苹果酸、 扁桃酸、粘液酸、双羟萘酸、 泛酸、 硬脂酸、 琥珀酸、 磺胺酸、 酒石酸、 对甲苯磺酸、 丙二酸、 2-羟基丙酸、 草酸、羟乙酸、 葡萄糖醛酸、半乳糖醛酸、枸橼酸、 肉桂酸、对甲苯磺酸、 甲磺酸、 乙磺酸或三氟甲磺酸、氨、 异丙基胺、 三甲基胺、 二乙胺、 三乙胺、 三丙基胺、 二乙醇胺、 乙醇胺、 二甲基乙醇胺、 2-二 甲基氨基乙醇、 2-二乙基氨基乙醇、 二环己基胺、 咖啡碱、 普鲁卡因、 胆碱、 甜菜碱、 苯明青 霉素、 乙二胺、 葡萄糖胺、 甲基葡糖胺、 可可碱、 三乙醇胺、 氨丁三醇、 嘌吟、 哌嗪、 哌啶和 N-乙基哌啶。  "eutectic" refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bonds, wherein the active pharmaceutical ingredient (API) and the eutectic formation (CCF) are in a pure state. They are all solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate. Non-limiting examples of eutectic formations include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, and half Cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid , nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, Fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid Acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid, p-toluenesulfonic acid , methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, different Amine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl Amine, caffeine, procaine, choline, betaine, phenylephrine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperazine Pyridine and N-ethylpiperidine.
"立体异构体 "是指由分子中原子在空间上排列方式不同所产生的异构体， 包括顺反异构 体、 对映异构体和构象异构体。  "Stereoisomer" refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.
"任选 "或"任选地 "或"选择性的"或"选择性地"是指随后所述的事件或状况可以但未必发 生， 该描述包括其中发生该事件或状况的情况及其中未发生的情况。 例如， "选择性地被垸基 取代的杂环基 "是指该垸基可以但未必存在， 该描述包括其中杂环基被垸基取代的情况， 及其 中杂环基未被垸基取代的情况。"药物组合物"表示一种或多种本文所述化合物或其生理学 /药学 上可接受的盐或前体药物的组合或 /和一种或多种其它治疗剂以及药学上可接受的赋形剂、 佐 剂、 稀释剂和载体。 "Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "heterocyclic group optionally substituted by a thiol group" means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group Happening. "Pharmaceutical composition" means a combination of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and one or more additional therapeutic agents, and a pharmaceutically acceptable form. Agent Agent, diluent and carrier.
"EC50"半数有效浓度， 指达到最大药效一半时的浓度。 具体实施方式 The "EC 50 " half effective concentration refers to the concentration at which half of the maximum efficacy is reached. Detailed ways
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好 地理解本发明的实质和特点， 不作为对本案可实施范围的限定。  The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.
本发明中，化合物的结构是通过核磁共振（NMR) 或 （和）质谱（MS)来确定的。 NMR位 移 （δ) 以 10- 6 (ppm) 的单位给出。 NMR的测定是用 （Bruker Avance III 400和 Bruker Avance 300) 核磁仪， 测定溶剂为氘代二甲基亚砜 （DMSO-d6)， 氘代氯仿 （CDC13)， 氘代甲醇 (CD3OD), 内标为四甲基硅垸 (TMS)。 In the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 - 6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
MS的测定用 (Agilent 6120B(ESI)和 Agilent 6120B(APCI))。  The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦 1260DAD高压液相色谱仪（Zorbax SB-C18 100x4.6 mm)。  The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
薄层层析硅胶板使用烟台黄海 HSGF254 或青岛 GF254硅胶板，薄层色谱法（TLC)使用 的硅胶板采用的规格是 0.15 mm~0.20 mm, 薄层层析分离纯化产品采用的规格是 0.4 mm~0.5 mm。  The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm~0.20 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ~0.5 mm.
柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。  Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成， 或可购买于泰坦科 技、 安耐吉化学、 上海德默、 成都科龙化工、 韶远化学科技、 百灵威科技等公司。  The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
氮气氛是指反应瓶连接一个约 1L容积的氮气气球。  The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
氢化反应通常抽真空， 充入氢气， 反复操作 3次。  The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
实施例中无特殊说明， 反应在氮气氛下进行。  Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
实施例中无特殊说明， 溶液是指水溶液。  There is no particular description in the examples, and the solution means an aqueous solution.
实施例中无特殊说明， 反应的温度为室温。  There is no particular description in the examples, and the reaction temperature is room temperature.
室温为最适宜的反应温度， 为 20°C ~ 30°C。  The optimum reaction temperature at room temperature is 20 ° C ~ 30 ° C.
本文所用的其他符号具有下列意义：  Other symbols used in this article have the following meanings:
s:单峰  s: single peak
d: 二重峰  d: doublet
t: 三重峰  t: triple peak
q: 四重峰  q: Quadruple peak
m: 多重峰  m: multiple peak
br: 宽峰  Br: wide peak
J: 耦合常数 Hz: 赫兹 J: coupling constant Hz: Hertz
Bn: 苄基  Bn: benzyl
Me: 甲基  Me: methyl
Et: 乙基  Et: ethyl
TBS : 叔丁基二甲基硅基  TBS : tert-butyldimethylsilyl
中间体 1 : 2-(6-羟基 -2，3-二氢苯并呋喃 -3-基)乙酸甲酯（IE) Intermediate 1 : methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (IE)
methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000045_0001
第一步： 4- (氯甲基) -7-羟基 -2H-苯并吡喃 -2-酮 （1B)
Figure imgf000045_0001
First step: 4-(Chloromethyl)-7-hydroxy-2H-benzopyran-2-one (1B)
4-(chloromethyl)-7-hydroxy-2H-chromen-2-one
Figure imgf000045_0002
4-(chloromethyl)-7-hydroxy-2H-chromen-2-one
Figure imgf000045_0002
0°C下，将间苯二酚 1A (17.62 g, 160.02 mmol)分小份地加入溶有氯甲酰乙酸乙酯 （28.00 g 170.12 mmol) 的浓硫酸（60 mL) 中， 室温搅拌反应 2小时。 将反应液倒入冰水中， 将混合物 过滤， 滤饼用水（100 mL x 3)洗涤并干燥， 得到米色固体状的粗品， 直接用于下一步反应。 第二步： 2-(6-羟基苯并呋喃 -3-基)乙酸 （1C)  Resorcinol 1A (17.62 g, 160.02 mmol) was added in small portions to concentrated sulfuric acid (60 mL) containing ethyl chloroformate (28.00 g 170.12 mmol) at 0 ° C, and the reaction was stirred at room temperature 2 hour. The reaction mixture was poured into ice water, and the mixture was filtered. Step 2: 2-(6-Hydroxybenzofuran-3-yl)acetic acid (1C)
2-(6-hydroxybenzofuran-3-yl)acetic aci 2-(6-hydroxybenzofuran-3-yl)acetic aci
Figure imgf000045_0003
Figure imgf000045_0003
将 4- (氯甲基;) -7-羟基 -2H-苯并吡喃 -2-酮 IB粗品溶于氢氧化钠水溶液 (1000 mL, 1M) 中， 加热回流反应 2小时。 反应结束， 用浓硫酸酸化反应液， 乙酸乙酯（250 mL x 3)萃取， 无水 硫酸镁干燥， 过滤减压浓缩， 得到棕色固体状的化合物 1C (16.00 g,产率 52%)。  The crude 4-(chloromethyl;)-7-hydroxy-2H-benzopyran-2-one IB was dissolved in aqueous sodium hydroxide (1000 mL, 1M). After the reaction was completed, the reaction mixture was evaporated to mjjjjjlililililililililililililili
第三步： 2-(6-羟基苯并呋喃 -3-基；)乙酸甲酯（ID) The third step: 2-(6-hydroxybenzofuran-3-yl;) methyl acetate (ID)
methyl 2-(6-hydroxybenzofuran-3-yl)acetate
Figure imgf000046_0001
Methyl 2-(6-hydroxybenzofuran-3-yl)acetate
Figure imgf000046_0001
将 2-(6-羟基苯并呋喃 -3-基)乙酸 1C (16.00 g, 83.26 mmol)溶于甲醇 （75 mL) 中， 滴加浓 硫酸 （8 mL;i， 将混合物加热回流反应 4小时。反应结束， 将反应液浓缩旋干， 用二氯甲垸（30 mL)溶解，依次用水（100 mL x 3)和饱和食盐水（100 mL >< 3)洗涤，无水硫酸镁干燥，过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 4/1)，得到淡黄色固体状 的化合物 1D (8.37 g,产率 48%)。  2-(6-Hydroxybenzofuran-3-yl)acetic acid 1C (16.00 g, 83.26 mmol) was dissolved in methanol (75 mL), concentrated sulfuric acid (8 mL; i, the mixture was heated and refluxed for 4 hours) After the reaction was completed, the reaction solution was concentrated to dryness, dried with methylene chloride (30 mL), washed successively with water (100 mL x 3) and brine (100 mL > < 3), dried over anhydrous magnesium sulfate, filtered The filtrate was concentrated under reduced pressure. EtOAc EtOAc m.
第四步： 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 （1E) Step 4: Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (1E)
methyl 2-(6-hydroxy-2,3-dihydrobenzo Methyl 2-(6-hydroxy-2,3-dihydrobenzo
Figure imgf000046_0002
Figure imgf000046_0002
将钯碳 (1.38 g, 3.60 mmol, 10%)加入 2-(6-羟基苯并呋喃 -3-基)乙酸甲酯 1D (7.38 g, 35.79 mmol) 的甲醇 （65 mL)溶液中， 用氢气置换反应体系 3次， 通入氢气， 搅拌反应 18小时。 将 反应液过滤， 减压旋干。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到白色固 体状的化合物 1E (4.50 g,产率 60.4%)。  Palladium carbon (1.38 g, 3.60 mmol, 10%) was added to a solution of methyl 2-(6-hydroxybenzofuran-3-yl)acetate 1D (7.38 g, 35.79 mmol) in methanol (65 mL). The reaction system was replaced three times, hydrogen gas was introduced, and the reaction was stirred for 18 hours. The reaction solution was filtered, and dried under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
中间体 2: 5-溴 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -3-醇（2G) Intermediate 2: 5-Bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol (2G)
5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol  5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol
Figure imgf000046_0003
第一步： 4-溴 -3,5-二甲基苯基乙酸酯 （2B)
Figure imgf000046_0003
First step: 4-bromo-3,5-dimethylphenyl acetate (2B)
4-bromo-3 ,5-dimethylphenyl acetate
Figure imgf000046_0004
4-bromo-3 ,5-dimethylphenyl acetate
Figure imgf000046_0004
将醋酸酐 (12.10 g,l 19 mmol), 三乙胺（12.00 g,l 19 mmol)加入 4-溴 -3,5-二甲酚 2A (20.00 g,99 mmol) 的二氯甲垸（50 mL)溶液中， 室温下搅拌反应 2小时。 向反应液中加入冰水（100 mL) 淬灭反应，用二氯甲垸（100 mL x 3)萃取，合并有机相，饱和氯化钠溶液（100 mL x 3)洗 涤， 用无水硫酸钠干燥有机相， 过滤， 浓缩滤液得到棕色液体状的粗产品， 直接用于下一步反 第二步： 1-(3-溴 -6-羟基 -2,4-二甲基苯)乙酮 （2C) Acetic anhydride (12.10 g, l 19 mmol), triethylamine (12.00 g, 19 mmol) was added to 4-bromo-3,5-xylenol 2A (20.00 g, 99 mmol) of dichloromethane. In a solution of mL), the reaction was stirred at room temperature for 2 hours. Add ice water to the reaction solution (100 The reaction was quenched and extracted with chloroform (100 mL×3). The organic phase was combined and washed with saturated sodium chloride (100 mL×3). Crude product in brown liquid, used directly in the next step. Step 2: 1-(3-Bromo-6-hydroxy-2,4-dimethylphenyl)ethanone (2C)
l-(3-bromo-6-hydroxy-2,4-dimethylphenyl)
Figure imgf000047_0001
L-(3-bromo-6-hydroxy-2,4-dimethylphenyl)
Figure imgf000047_0001
将 4-溴 -3,5-二甲基苯基乙酸酯粗产品 2B和三氯化铝 （19.7 g,148.1 mmol)加入到 1,2-二氯 乙垸（200 mL) 中， 升温至回流， 搅拌反应 2.5小时， 反应体系颜色变深。 将混合物用冰水浴 冷却至 0°C，缓慢滴加 1M HC1终止反应，加入水（100 mL)稀释，用二氯甲垸（100 mL x 3)萃 取， 合并有机相， 饱和氯化钠水溶液（200 mL x 3)洗涤， 无水硫酸钠干燥， 过滤浓缩。 残留 物用石油醚 /二氯甲垸重结晶， 得到白色絮状物 2C C16.0 g, 两步产率 66%)。  Add 4-bromo-3,5-dimethylphenylacetate crude product 2B and aluminum trichloride (19.7 g, 148.1 mmol) to 1,2-dichloroethane (200 mL) and warm to After refluxing, the reaction was stirred for 2.5 hours, and the color of the reaction system became dark. The mixture was cooled to 0 ° C with an ice water bath, and the reaction was quenched slowly by dropwise addition of 1M HCl. Water (100 mL) was diluted and extracted with dichloromethane (100 mL x 3). Wash with 200 mL x 3), dry over anhydrous sodium sulfate and concentrate. The residue was recrystallized from petroleum ether / methylene chloride to afford white crystals (yield: 2 C C16.0 g, yield of 66%).
MS m/z(ESI):241.0,243.0[M-l]  MS m/z (ESI): 241.0, 243.0 [M-l]
^ NMR (300 MHz, CDC13) δ 10.99 (s, 1H), 6.77 (s, 1H), 2.61 (s, 6H), 2.40 (s, 3H).  ^ NMR (300 MHz, CDC13) δ 10.99 (s, 1H), 6.77 (s, 1H), 2.61 (s, 6H), 2.40 (s, 3H).
第三步： 2-溴 -(3-溴 -6-羟基 -2,4-二甲基苯)乙酮 （2D) Step: 2-Bromo - (3 - bromo - 6 - hydroxy - 2, 4 - dimethylphenoxy) ethanone (2 D)
2-bromo- 1 -(3-bromo-6-hydroxy-2,4-dimethylphenyl)ethanone
Figure imgf000047_0002
2-bromo-1 -(3-bromo-6-hydroxy-2,4-dimethylphenyl)ethanone
Figure imgf000047_0002
将 1-(3-溴 -6-羟基 -2,4-二甲基苯)乙酮 2C (10.0 g, 41.14 mmol), 溴化铜 (15.6 g,69.85 mmol) 溶于氯仿 （100 mL)和乙酸乙酯 （50 mL) 混合溶剂中， 加热回流搅拌反应 4小时。 反应结束， 将反应液用冰水浴冷却至室温， 过滤。 滤液中加水（100 mL)稀释， 用乙酸乙酯（100 mL x 3;» 萃取， 合并有机相， 用饱和氯化钠水溶液（200 mL x l)洗涤， 无水硫酸钠干燥有机相， 过滤， 滤液减压浓缩， 得到粗品， 直接用于下一步反应。  1-(3-Bromo-6-hydroxy-2,4-dimethylphenyl)ethanone 2C (10.0 g, 41.14 mmol), copper bromide (15.6 g, 69.85 mmol) dissolved in chloroform (100 mL) Ethyl acetate (50 mL) was mixed and stirred under reflux with stirring for 4 hr. After completion of the reaction, the reaction solution was cooled to room temperature with an ice water bath and filtered. The filtrate was diluted with water (100 mL), extracted with ethyl acetate (100 mL EtOAc), EtOAc (EtOAc) Concentration under reduced pressure gave a crude material which was used directly for the next step.
第四步： 5-溴 -4,6-二甲基苯并呋喃 -3(2H)-酮 （2E) Step 4: 5-Bromo-4,6-dimethylbenzofuran-3(2H)-one (2E)
5-bromo-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000047_0003
5-bromo-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000047_0003
将醋酸钠 （10.1 g,123.3 mmol)加入上步产物 2-溴 -(3-溴 -6-羟基 -2,4-二甲基苯)乙酮粗品 2D 的甲醇 （150 mL)溶液中， 室温下搅拌反应 2小时。反应结束， 向反应液中加水（50 mL) 淬灭 反应，将混合物减压浓缩除去部分甲醇，加水稀释至 lOO mL,用乙酸乙酯 （100 mL x 3)萃取， 合并有机相， 用饱和氯化钠水溶液（200 mL x 1)洗涤， 无水硫酸镁干燥， 过滤， 将滤液减压 浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1), 得到淡黄色固体状化合物 2E (5.4 g, 两步产率 55%)。 Ή NMR (300 MHz, DMSO) δ 7.22 (s, 1H), 4.83 (s, 2H), 2.61 (s, 6H). Add sodium acetate (10.1 g, 123.3 mmol) to a solution of the crude 2-bromo-(3-bromo-6-hydroxy-2,4-dimethylphenyl)ethanone 2D in methanol (150 mL). The reaction was stirred for 2 hours. At the end of the reaction, water (50 mL) was added to the reaction mixture to quench the mixture. The mixture was concentrated under reduced pressure to remove a portion of methanol, diluted with water to 100 mL, and extracted with ethyl acetate (100 mL x 3). The aqueous sodium chloride solution (200 mL x 1) was washed, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified with EtOAc EtOAcjjjj( NMR NMR (300 MHz, DMSO) δ 7.22 (s, 1H), 4.83 (s, 2H), 2.61 (s, 6H).
13C NMR (75 MHz, CDC13) δ 199.31, 172.98, 148.75, 139.18, 121.13, 118.19, 112.51, 75.11 25.54, 17.64. 13 C NMR (75 MHz, CDC1 3 ) δ 199.31, 172.98, 148.75, 139.18, 121.13, 118.19, 112.51, 75.11 25.54, 17.64.
第五步： 5-溴 -2,2,4,6-四甲基苯并呋喃 -3(2H)-酮 （2F) Step 5: 5-Bromo-2,2,4,6-tetramethylbenzofuran-3(2H)-one (2F)
5-bromo-2,2,4,6-tetramethylbenzofuran-3( -one
Figure imgf000048_0001
5-bromo-2,2,4,6-tetramethylbenzofuran-3 ( -one
Figure imgf000048_0001
无水无氧氛围， 在 -30°C下， 将氢化钠 （125 mg, 5.21 mmol)加入到 5-溴 -4,6-二甲基苯并呋 喃 -3(2H)-酮 2E (500 mg, 2.07 mmol) 的干燥四氢呋喃 （20 mL)溶液中， 搅拌 20分钟。 向混合 物中加入碘甲垸（1.5 g, 10.57 mmol), 升至室温反应 3小时。 向反应体系中加入饱和氯化铵水 溶液（50 mL) 淬灭反应， 加水（10 mL)稀释， 用乙酸乙酯 （100 mL x 3)萃取， 合并有机相， 用无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到淡黄色固体状化合物 2F (482 mg,产率 85%)。  Anhydrous anaerobic atmosphere, sodium hydride (125 mg, 5.21 mmol) was added to 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (500 mg at -30 °C) , 2.07 mmol) in dry tetrahydrofuran (20 mL), stirred for 20 min. Iodoformamidine (1.5 g, 10.57 mmol) was added to the mixture, and the mixture was allowed to react to room temperature for 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) Concentrate under reduced pressure. The residue was purified with EtOAc EtOAcjjjj(
¾ NMR (300 MHz, CDC13) δ 6.83 (s, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 1.43 (s, 6H).  3⁄4 NMR (300 MHz, CDC13) δ 6.83 (s, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 1.43 (s, 6H).
第六步： 5-溴 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -3-醇 （2G) Step 6: 5-Bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol (2G)
5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobe
Figure imgf000048_0002
5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobe
Figure imgf000048_0002
将 5-溴 -2,2,4,6-四甲基苯并呋喃 -3(2H)-酮 2F (482 mg, 1.79 mmol)溶于甲醇（4 mL)和四 氢呋喃 （16 mL) 混合溶剂中， 冰浴下， 分小份加入硼氢化钠 （339 mg, 8.96 mmol), 室温下搅 拌反应 0.5小时。反应结束， 向混合物中加水（15 mL) 淬灭反应， 浓缩除去部分反应液， 加入 盐酸 （10 mL, 1M)酸化，用乙酸乙酯（50 mL x 3)萃取，合并有机相，无水硫酸钠干燥，过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /二氯甲垸 = 2/1)，得到白色固体状化 合物 2G (450 mg,产率 92%)。  5-Bromo-2,2,4,6-tetramethylbenzofuran-3(2H)-one 2F (482 mg, 1.79 mmol) was dissolved in methanol (4 mL) and tetrahydrofuran (16 mL) Under ice cooling, sodium borohydride (339 mg, 8.96 mmol) was added in small portions, and the mixture was stirred at room temperature for 0.5 hour. At the end of the reaction, water was added to the mixture (15 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
中间体 3: (S) 2-(6-羟基 -2，3-二氢苯并呋喃 -3-基)乙酸甲酯 （3D) Intermediate 3: (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester (3D)
(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate  (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000048_0003
第一步:
Figure imgf000048_0003
first step:
(S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸（ R)苯乙胺盐 (3B)  (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid (R)phenylethylamine salt (3B)
(R)- 1 -phenylethanaminium (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000049_0001
(R)- 1 -phenylethanaminium (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000049_0001
将 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸 3A (9.32 g, 48 mmol)溶于丙酮 (80 mL)中， 加热 至回流状态下， 将 R-苯乙胺的丙酮溶液 (2.91 g, 24 mmol, 13 mL), 缓慢的滴入反应溶液中。滴 加结束后， 关闭加热， 使其缓慢降至室温， 搅拌过夜。 过滤， 沉淀用少量丙酮洗涤。 再向其中 加入 1N稀盐酸， 调 PH < 2， 加乙酸乙酯萃取， 浓缩。 再将浓缩物溶于丙酮 (35 mL)中， 加热至 回流状态下， 将 R-苯乙胺的丙酮溶液 (1.53 g, 12.7 mmol), 缓慢的滴入反应溶液中。 滴加结束 后， 关闭加热， 使其缓慢降至室温， 搅拌过夜。 过滤， 沉淀用少量丙酮洗涤， 并将此沉淀溶于 丙酮 (25 mL), 重结晶得化合物 3B (600 mg, 60%)。  2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid 3A (9.32 g, 48 mmol) was dissolved in acetone (80 mL) and heated to reflux to give R-benzene An acetone solution of ethylamine (2.91 g, 24 mmol, 13 mL) was slowly added dropwise to the reaction solution. After the completion of the dropwise addition, the heating was turned off, allowed to slowly cool to room temperature, and stirred overnight. After filtration, the precipitate was washed with a small amount of acetone. Further, 1 N of dilute hydrochloric acid was added thereto, and the pH was adjusted to <2, extracted with ethyl acetate and concentrated. The concentrate was dissolved in acetone (35 mL), and heated to reflux. A solution of R-phenylethylamine in acetone (1.53 g, 12.7 mmol) was slowly dropped into the reaction solution. At the end of the addition, the heat was turned off, allowed to slowly cool to room temperature, and stirred overnight. After filtration, the precipitate was washed with a small amount of acetone, and this precipitate was dissolved in acetone (25 mL) and then recrystallized to give Compound 3B (600 mg, 60%).
第二步： （S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸 (3C) Step 2: (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid (3C)
(S)-2-(6-hydroxy-2,3-dihydrobenzofuran- -yl)acetic acid
Figure imgf000049_0002
(S)-2-(6-hydroxy-2,3-dihydrobenzofuran- -yl)acetic acid
Figure imgf000049_0002
将 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基;)乙酸（ R)苯乙胺盐 3B溶于 1M盐酸水溶液中，加入 乙酸乙酯 (50mLx3)萃取， 合并有机层， 无水硫酸钠干燥， 浓缩得化合物 3C (370 mg, 99%;»， 第三步： （S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 (3D)  (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl;)acetic acid (R) phenethylamine salt 3B was dissolved in 1M aqueous hydrochloric acid and extracted with ethyl acetate (50 mL×3) The organic layer was combined, dried over anhydrous sodium sulfate and evaporated and evaporated to afford compound 3C (370 mg, 99%;», Step 3: (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3- Methyl acetate (3D)
(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzo
Figure imgf000049_0003
(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzo
Figure imgf000049_0003
室温下，将 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基；)乙酸 3C溶于甲醇中，滴加浓硫酸 0.2 mL, 升温至 50°C反应 2小时后， 加饱和碳酸氢钠水溶液终止反应， 加乙酸乙酯 (50mLx3)萃取， 合 并有机层， 无水硫酸钠干燥， 浓缩， 柱层析分离纯化 (硅胶 6.0 g， 石油醚 /乙酸乙酯 = 5/1)洗脱， 得白色固体化合物 3D(317 mg, 80%， ee% = 99%)。  (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl;)acetic acid 3C was dissolved in methanol at room temperature, 0.2 mL of concentrated sulfuric acid was added dropwise, and the temperature was raised to 50 ° C. After a few hours, the reaction was quenched with EtOAc EtOAc EtOAc (EtOAc) 5/1) Elution afforded compound 3D (317 mg, 80%, ee% = 99%).
产品的绝对构型根据文献 (ACS Med. Chem. Lett. 2010, 1, 290-294)以及保留时间确定。  The absolute configuration of the product is determined according to the literature (ACS Med. Chem. Lett. 2010, 1, 290-294) and retention time.
实施例 1 Example 1
2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 酸 （化合物 1) 2- (6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2 ,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1)
2-(6-((3-(3-methoxy-2,2,4,6 etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzof uran-3-yl)acetic acid 2-(6-((3-(3-methoxy-2,2,4,6 etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzof uran-3-yl)acetic Acid
Figure imgf000050_0001
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0002
无水无氧氛围， 在冰水浴下， 将氢化钠 （48 mg, 1.99 mmol)加入 5-溴 -2,2,4,6-四甲基 -2,3- 二氢苯并呋喃 -3-醇 2G (450 mg, 1.66 mmol) 的干燥四氢呋喃 （15 mL)溶液中， 搅拌 20分钟。 将碘甲垸（471 mg,3.32 mmol)加入混合物中， 升至室温反应 1小时。 反应结束， 加入饱和氯 化铵水溶液（15 mL) 淬灭反应， 加水（25 mL)， 用乙酸乙酯 （30 mL x 3)萃取。 合并有机相， 用饱和食盐水（30 mL x l)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱 层析分离纯化 (石油醚 /乙酸乙酯 = 4/1), 得到淡黄色油状液体状的化合物 la (360 mg,产率 77%)。  Anhydrous anhydrous atmosphere, sodium hydride (48 mg, 1.99 mmol) was added to 5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3- under ice-water bath A solution of the alcohol 2G (450 mg, 1.66 mmol) in dry THF (15 mL) Iodomethyl hydrazine (471 mg, 3.32 mmol) was added to the mixture, and the mixture was allowed to react to room temperature for 1 hour. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The combined organic layers were washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut
¾ NMR (300 MHz, CDC13) δ 6.56 (s, 1Η), 4.44 (s, 1H), 3.38 (s, 3H), 2.38 (d, 6H), 1.53 (s, 3H): 1.33 (s, 3H). 3⁄4 NMR (300 MHz, CDC1 3 ) δ 6.56 (s, 1Η), 4.44 (s, 1H), 3.38 (s, 3H), 2.38 (d, 6H), 1.53 (s, 3H) : 1.33 (s, 3H) ).
第二步： 3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛（lb) Second step: 3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (lb)
3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000050_0003
3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000050_0003
将 5-溴 -3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 la (350 mg, 1.30 mmol)和 3-甲酰基苯 硼酸 （210 mg, 1.40 mmol)溶于碳酸钠水溶液（10 mL, 1M) 中， 加入甲苯（15 mL)及乙醇 （5 mL)。 用氮气置换反应体系， 加入四 (三苯基膦；)钯（81 mg, 0.07 mmol)。 保持氮气氛围， 升温至 80°C反应 15小时。 反应结束， 向反应液中加水（5 mL)和乙酸乙酯 （40 mL)， 用硅藻土过滤。 滤液用饱和食盐水溶液（20 mL X 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物 用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 =14/1)，得到淡黄色油状液体的化合物 lb (335 mg,产 率 83%)。 第三步： （3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 （lc) 5-Bromo-3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran la (350 mg, 1.30 mmol) and 3-formylphenylboronic acid (210 mg 1.40 mmol) was dissolved in aqueous sodium carbonate (10 mL, 1M). Toluene (15 mL) and ethanol (5 mL). The reaction system was replaced with nitrogen, and tetrakis(triphenylphosphine;)palladium (81 mg, 0.07 mmol) was added. The atmosphere was kept under nitrogen, and the mixture was heated to 80 ° C for 15 hours. After the reaction was completed, water (5 mL) and ethyl acetate (40 mL) were evaporated. The filtrate was washed with aq. EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAcjjjjjjjj Step 3: (3-(3-Methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol (lc)
(3-(3-methoxy-2,2,4,6-tetramethyl-2, -dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000051_0001
(3-(3-methoxy-2,2,4,6-tetramethyl-2, -dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000051_0001
将 3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛 lb (335 mg, 1.08 mmol)溶于 甲醇 (4mL)和四氢呋喃 (16 mL)混合溶液中，冰浴下，分小份将硼氢化钠 （204 mg, 5.40 mmol)加 入混合物中， 升至室温反应 1小时。 反应结束， 向反应液中加水（10 mL) 淬灭反应， 减压浓 缩除去部分反应液。向混合物中加盐酸 (6 mL, 1M),用乙酸乙酯 pO mL )萃取，合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 5/1), 得到淡黄色粘稠状固体 lc (322 mg,产率 95%)。  3-(3-Methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde lb (335 mg, 1.08 mmol) was dissolved in methanol ( In a mixed solution of 4 mL) and tetrahydrofuran (16 mL), sodium borohydride (204 mg, 5.40 mmol) was added to the mixture in small portions, and the mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction mixture to quench the reaction, and a portion of the reaction mixture was concentrated under reduced pressure. Hydrochloric acid (6 mL, 1 M) was added toEtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc)
¾ NMR (400 MHz, CDC13) δ 7.41 (t, 1Η), 7.34 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 1H), 6.54 (s,3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.41 (t, 1Η), 7.34 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 1H), 6.54 (s,
1H), 4.73 (d, 2H), 4.45 (d, 1H), 3.49 (s, 1H), 3.41 (d, 3H), 1.98 (d, 6H), 1.57 (s, 3H), 1.39 (s, 3H). 第四步：2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基;)乙酸甲酯 （Id) 1H), 4.73 (d, 2H), 4.45 (d, 1H), 3.49 (s, 1H), 3.41 (d, 3H), 1.98 (d, 6H), 1.57 (s, 3H), 1.39 (s, 3H) The fourth step: 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (Id)
methyl 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)-2,3 -dihydrobenzofuran-3-yl)acetat Methyl 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)-2,3 -dihydrobenzofuran-3-yl) Acetat
Figure imgf000051_0002
Figure imgf000051_0002
将 (3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 lc (130 mg, 0.4 mmol)和 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 1E (100 mg, 0.48 mmol)溶于二氯甲垸 （15 mL) 中。氮气置换反应体系，将三丁基膦（178 mg, 0.88 mmol)和 Ι,Γ- (偶氮二羰基)二哌啶 （222 mg, 0.88 mmol)加入混合物中， 室温下搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤， 将滤 液浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 8/1), 得到淡黄色粘稠状固体 Id (165 mg,产率 82.1%)。  (3-(3-Methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol lc (130 mg, 0.4 mmol) Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (100 mg, 0.48 mmol) was dissolved in dichloromethane (15 mL). The reaction system was replaced with nitrogen, and tributylphosphine (178 mg, 0.88 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (222 mg, 0.88 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction solution, which was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
第五步：2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 （化合物 1) Step 5: 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1)
2-(6-((3-(3-methoxy-2,2,4,6 etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzof uran-3-yl)acetic acid 2-(6-((3-(3-methoxy-2,2,4,6 etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzof uran-3-yl)acetic Acid
Figure imgf000051_0003
将氢氧化钠溶液 (1 mL, 2M)加入 2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基；) 苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 Id (200 mg,0.40 mmol)在甲醇 (2 mL)和四氢呋喃 ( 4 mL) 混合溶剂中， 室温下搅拌反应 2小时。 反应结束， 加水（20 mL)稀释反应， 用 1M的 盐酸水溶液酸化至 PH为 1， 乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过 滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 =2/1)， 得到白色固体状 的化合物 1 (178 mg,产率 91.3%)。
Figure imgf000051_0003
Add sodium hydroxide solution (1 mL, 2M) to 2-(6-(3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran)- 5-Base;) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester Id (200 mg, 0.40 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) The solvent was stirred at room temperature for 2 hours in a solvent. After the reaction was completed, the mixture was diluted with water (20 mL), EtOAc EtOAc (EtOAc m. . The residue was purified with EtOAc EtOAcjjjjjjjj
MS m/z(ESI):487.0[M-l]  MS m/z (ESI): 487.0 [M-l]
^ NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 7.44 (td, 1H), 7.38 (d, 1H), 7.14 (s, 1H), 7.08 (dd, 2H), 6.52 (s, 1H), 6.50 - 6.41 (m, 2H), 5.10 (d, 2H), 4.68 (t, 1H), 4.47 (s, 1H), 4.23 - 4.10 (m, 1H), 3.75― 3.55 (m, 1H), 3.36 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.90 (dd, 6H), 1.46 (s, 3H), 1.31 (s, 3H).  ^ NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 7.44 (td, 1H), 7.38 (d, 1H), 7.14 (s, 1H), 7.08 (dd, 2H), 6.52 (s, 1H) , 6.50 - 6.41 (m, 2H), 5.10 (d, 2H), 4.68 (t, 1H), 4.47 (s, 1H), 4.23 - 4.10 (m, 1H), 3.75 - 3.55 (m, 1H), 3.36 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.90 (dd, 6H), 1.46 (s, 3H), 1.31 (s, 3H).
实施例 2 Example 2
2-(6-((3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 酸 （化合物 2)  2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2 ,3-dihydrobenzofuran-3-yl)acetic acid (Compound 2)
2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofur an-3-yl)acetic acid  2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofur an-3-yl) Acetic acid
Figure imgf000052_0001
Figure imgf000052_0001
第一步： 5-溴 -3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 （2a) First step: 5-bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (2a)
5-bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran
Figure imgf000052_0002
5-bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran
Figure imgf000052_0002
无水无氧氛围， 冰浴下， 将氢化钠 （80 mg, 3.32 mmol)加入 5-溴 -2,2,4,6-四甲基 -2,3-二氢 苯并呋喃 -3-醇 2G (750 mg, 2.76 mmol) 的干燥四氢呋喃 （20 mL)溶液中， 搅拌反应 20分钟。 向混合物中加入碘乙垸（0.45 mL, 3.52 mmol), 升至室温反应 5小时， 加热回流继续反应 2小 时，反应结束。加水（20 mL)稀释反应液，加饱和氯化铵水溶液（10 mL)，用乙酸乙酯 （30 mL x 3)萃取。 合并有机相， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分 离纯化（石油醚 /乙酸乙酯 = 3/1)， 得到淡黄色液体状的化合物 2a (532 mg,产率 64.4%)。 Anhydrous anaerobic atmosphere, sodium hydride (80 mg, 3.32 mmol) was added to 5-bromo-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-3-ol under ice bath 2G (750 mg, 2.76 mmol) in dry tetrahydrofuran (20 mL) was stirred for 20 min. Iodoethyl hydrazine (0.45 mL, 3.52 mmol) was added to the mixture, and the mixture was allowed to react to room temperature for 5 hours, and the mixture was heated under reflux to continue the reaction for 2 hours. Add the water (20 mL) to dilute the reaction solution, add saturated aqueous ammonium chloride (10 mL), ethyl acetate (30 mL) x 3) Extraction. The combined organic layers were dried with anhydrous sodium The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
¾ NMR (400 MHz, CDC13) δ 6.55 (s, IH), 4.51 (s, IH), 3.56 (q, 2H), 2.37 (d, 6H), 1.52 (s, 3H) 1.34 (s, 3H), 1.22 (t, 3H). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.55 (s, IH), 4.51 (s, IH), 3.56 (q, 2H), 2.37 (d, 6H), 1.52 (s, 3H) 1.34 (s, 3H) , 1.22 (t, 3H).
第二步： 3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛（2b) Step 2: 3-(3-Ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (2b)
3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000053_0001
3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000053_0001
将 5-溴 -3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 2a (500 mg, 1.67 mmol)和 3-甲酰基苯 硼酸 （334 mg, 2.23 mmol)溶于碳酸钠溶液（11 mL, 1M)、 甲苯（15 mL) 及乙醇（4 mL) 混合 溶剂中。 用氮气置换反应体系， 将四 (三苯基膦)钯（127 mg, 0.11 mmol)加入混合物中， 保持 氮气氛围，升温至 80°C搅拌反应 21小时。反应结束，向反应液中加水（10 mL)和乙酸乙酯 （50 mL), 用硅藻土过滤。 滤液用饱和食盐水溶液（30 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 20/1)， 得到淡黄色粘稠固 体状化合物 2b (435 mg,产率 80.1%)。  5-Bromo-3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran 2a (500 mg, 1.67 mmol) and 3-formylbenzeneboronic acid (334 mg) , 2.23 mmol) was dissolved in a mixed solvent of sodium carbonate solution (11 mL, 1 M), toluene (15 mL) and ethanol (4 mL). The reaction system was replaced with nitrogen, and tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol) was added to the mixture to maintain a nitrogen atmosphere, and the mixture was heated to 80 ° C and stirred for 21 hours. After the reaction was completed, water (10 mL) and ethyl acetate (50 mL) were evaporated. The filtrate was washed with aq. aq. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
第三步： 3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇（2c) Step 3: 3-(3-Ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol (2c)
(3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000053_0002
(3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000053_0002
冰水下，分批将硼氢化钠 （254 mg, 6.70 mmol)加入 3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯 并呋喃 -5-基)苯甲醛 2b (435 mg, 1.34 mmol)在甲醇 （5 mL)和四氢呋喃 （10 mL) 混合溶剂中， 升至室温搅拌反应 0.5小时。反应结束， 向反应液中加水（10 mL)淬灭反应， 减压浓缩除去部 分反应液， 加入饱和氯化铵溶液（10 mL)。混合物用乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 8/1), 得到白色粘稠状固体 2c (400 mg,产率 91.5%)。  Sodium borohydride (254 mg, 6.70 mmol) was added in portions to 3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5). To a solution of benzaldehyde 2b (435 mg, 1.34 mmol) in a mixed solvent of methanol (5 mL) and tetrahydrofuran (10 mL). After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was evaporated. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc)
^ NMR (400 MHz, DMSO) δ 7.38 (td, IH), 7.28 (d, IH), 7.04 (d, IH), 7.00― 6.93 (m, IH), 6.51 (s, IH), 5.21 (dd, IH), 4.55 (d, 2H), 4.53 (s, IH), 3.59 (tt, 2H), 1.91 (d, 6H), 1.45 (s, 3H), 1.31 (s: 3H), 1.12 (t, 3H). ^ NMR (400 MHz, DMSO) δ 7.38 (td, IH), 7.28 (d, IH), 7.04 (d, IH), 7.00 - 6.93 (m, IH), 6.51 (s, IH), 5.21 (dd, IH), 4.55 (d, 2H), 4.53 (s, IH), 3.59 (tt, 2H), 1.91 (d, 6H), 1.45 (s, 3H), 1.31 (s : 3H), 1.12 (t, 3H) ).
第四步：2-(6-((3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 （2d) The fourth step: 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) Methyl 2-(3,3-dihydrobenzofuran-3-yl)acetate (2d)
methyl 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3- dihydrobenzofuran-3-yl)acetate
Figure imgf000054_0001
Methyl 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl) Aclate
Figure imgf000054_0001
将 3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 2c (150 mg, 0.46 mmol)和 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 1E (1 15 mg, 0.55 mmol)溶于二氯甲垸 （15 mL) 中。氮气置换反应体系，将三丁基膦（202 mg, 1.00 mmol)和 Ι ,Γ- (偶氮二羰基)二哌啶 （252 mg, 1.00 mmol)加入混合物中， 室温下搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤， 将滤 液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 8/1)，得到无色透明油状液体 2d (185 mg,产率 77.9%)。  3-(3-Ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 2c (150 mg, 0.46 mmol) and 2- ( Methyl 6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (1 15 mg, 0.55 mmol) was dissolved in dichloromethane (15 mL). The reaction system was replaced with nitrogen, and tributylphosphine (202 mg, 1.00 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (252 mg, 1.00 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, which was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAcEtOAcEtOAcEtOAc
第五步：2-(6-((3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 （化合物 2) Step 5: 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 2)
2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofur an-3-yl)acetic acid  2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofur an-3-yl) Acetic acid
Figure imgf000054_0002
Figure imgf000054_0002
将氢氧化钠水溶液 (0.9 mL, 2M)加入 2-(6-((3-(3-乙氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 2d (185 mg,0.36 mmoL)在甲醇 (2 mL)和四 氢呋喃 (4 mL)混合溶剂中， 室温下搅拌反应 1.5小时。 反应结束， 向反应液中加水（20 mL) 淬 灭反应， 用 1M盐酸水溶液酸化至 pH为 1， 用乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 无 水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 （石油醚 /乙酸乙酯 = 1.5/1), 得到白色固体状的化合物 2 (150 mg,产率 83.4%)。  Aqueous sodium hydroxide (0.9 mL, 2M) was added to 2-(6-(3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran)- Methyl 5-(yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 2d (185 mg, 0.36 mmoL) in methanol (2 mL) and tetrahydrofuran (4 mL) The reaction was stirred at room temperature for 1.5 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjj(
MS m/z(ESI):501.2[M-l]  MS m/z (ESI): 501.2 [M-l]
^ NMR (400 MHz, CDC13) δ 7.40 (dt, 2H), 7.18 (s, 1H), 7.08 (dd, 2H), 6.55― 6.41 (m, 3H),^ NMR (400 MHz, CDC1 3 ) δ 7.40 (dt, 2H), 7.18 (s, 1H), 7.08 (dd, 2H), 6.55- 6.41 (m, 3H),
5.06 (s, 2H), 4.76 (t, 1H), 4.53 (d, 1H), 4.29 (dd, 1H), 3.91― 3.74 (m, 1H), 3.67― 3.48 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 1.97 (dd, 6H), 1.55 (s, 3H), 1.39 (s, 3H), 1.24 (t, 3H). 5.06 (s, 2H), 4.76 (t, 1H), 4.53 (d, 1H), 4.29 (dd, 1H), 3.91- 3.74 (m, 1H), 3.67- 3.48 (m, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 1.97 (dd, 6H), 1.55 (s, 3H), 1.39 (s, 3H), 1.24 (t, 3H).
实施例 3 Example 3
2-(6-((3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸 (；化合物 3)  2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) - 2,3-dihydrobenzofuran-3-yl)acetic acid (; compound 3)
2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydroben zofuran-3 -yl)acetic acid 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydroben zofuran-3 -yl) Acetic acid
Figure imgf000055_0001
Figure imgf000055_0001
第一步： 2-(5-溴 -4,6-二甲基苯并呋喃 -3-基)乙腈（3a) First step: 2-(5-Bromo-4,6-dimethylbenzofuran-3-yl)acetonitrile (3a)
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)
Figure imgf000055_0002
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)
Figure imgf000055_0002
无水无氧氛围， 0°C下， 将二乙氧基氰甲基磷酸酯 （1.1 g, 6.22 mmol) 缓慢滴加至氢化钠 (149 mg, 6.22 mmol) 的四氢呋喃 （20 mL)溶液中， 搅拌 10分钟， 将 5-溴 -4,6-二甲基苯并呋喃 -3(2H)-酮 2E (1.0 g, 4.15 mmol) 的四氢呋喃溶液缓慢滴加到混合物中，升至 35°C继续搅拌反应 3小时。 向反应液中加入饱和氯化铵溶液（20 mL)和水（20 mL)， 用乙酸乙酯（20 mL x 3)萃 取， 合并有机相， 用饱和食盐水（50 mL x l)洗涤， 无水硫酸钠干燥有机相， 过滤， 将滤液减 压浓缩， 用石油醚洗涤。 残余物用乙酸乙酯重结晶， 得到淡黄色固体状化合物 3a (870 mg,产 率 82.9%)。  Oxygen-free anaerobic atmosphere, diethoxycyanomethyl phosphate (1.1 g, 6.22 mmol) was slowly added dropwise to a solution of sodium hydride (149 mg, 6.22 mmol) in tetrahydrofuran (20 mL). After stirring for 10 minutes, a solution of 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (1.0 g, 4.15 mmol) in tetrahydrofuran was slowly added dropwise to the mixture and the mixture was warmed to 35 ° C. The reaction was stirred for 3 hours. Saturated ammonium chloride solution (20 mL) and water (20 mL) were added to ethyl acetate (20 mL×3), and the organic phase was combined and washed with brine (50 mL×l) The organic phase was dried over Na2SO4, filtered and evaporated. The residue was recrystallized from ethyl acetate to afford Compound 3a (yield: 870 mg, yield: 82.9%).
¾ NMR (300 MHz, DMSO) δ 7.95 (s, 1H), 7.52 (s, 1H), 4.26 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3⁄4 NMR (300 MHz, DMSO) δ 7.95 (s, 1H), 7.52 (s, 1H), 4.26 (s, 2H), 2.68 (s, 3H), 2.46 (s,
3H). 3H).
第二步： 2-(5-溴 -4,6-二甲基苯并呋喃 -3-基)乙醛（3b) Step 2: 2-(5-Bromo-4,6-dimethylbenzofuran-3-yl)acetaldehyde (3b)
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)acetaldehyde
Figure imgf000055_0003
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)acetaldehyde
Figure imgf000055_0003
氮气氛围， 0°C下， 将二异丁基氢化铝 （434 mg, 3.05 mmol) 缓慢滴加至 2-(5-溴 -4,6-二甲 基苯并呋喃 -3-基)乙腈 3a (0.73 g, 2.78 mmol) 的甲苯（30 mL)溶液中， 搅拌反应 1.5小时。 反 应结束，向反应液中加入乙醚（10 mL)和水（0.12 mL)，再加入氢氧化钠溶液（0.12 mL, 15%)， 继续搅拌 15分钟。 再次加水（3 mL), 继续搅拌 15分钟。 混合物用无水硫酸镁干燥， 抽滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /二氯甲垸 = 2/1)，得到淡红色粘稠状 物 3b (400 mg,产率 52.6%)。 Nitrogen diisobutylaluminum hydride (434 mg, 3.05 mmol) was slowly added dropwise to 2-(5-bromo-4,6-dimethylbenzofuran-3-yl)acetonitrile 3a at 0 ° C. (0.73 g, 2.78 mmol) in toluene (30 mL) was stirred for 1.5 h. At the end of the reaction, diethyl ether (10 mL) and water (0.12 mL) were added to the reaction mixture, and then sodium hydroxide solution (0.12 mL, 15%) was added. Stirring was continued for 15 minutes. Add water (3 mL) again and continue stirring for 15 minutes. The mixture was dried over anhydrous MgSO.sub. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) elute
¾ NMR (300 MHz, DMSO) δ 9.79 (s, 1Η), 7.86 (s, 1H), 7.49 (s, 1H), 4.06 (s, 2H), 2.50 (s, 3⁄4 NMR (300 MHz, DMSO) δ 9.79 (s, 1Η), 7.86 (s, 1H), 7.49 (s, 1H), 4.06 (s, 2H), 2.50 (s,
6H). 6H).
第三步： 2-(5-溴 -4,6-二甲基苯并呋喃 -3-基)乙醇 （3c) Step 3: 2-(5-Bromo-4,6-dimethylbenzofuran-3-yl)ethanol (3c)
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)ethanol
Figure imgf000056_0001
2-(5-bromo-4,6-dimethylbenzofuran-3-yl)ethanol
Figure imgf000056_0001
2-(5-溴 -4,6-二甲基苯并呋喃 -3-基)乙醛 2b溶于甲醇 （3 mL)和四氢呋喃 （10 mL) 的混合 溶剂中， 0°C下， 将硼氢化钠 （124 mg, 3.28 mmol)加入混合物中， 搅拌反应 0.5小时。 反应结 束， 向反应液中加水（5 mL) 淬灭反应， 浓缩反应液除去部分有机溶剂。 加水（10 mL)稀释， 用乙酸乙酯 （10 mL x 3)萃取， 合并有机相， 用饱和食盐水（30 mL x l) 洗涤， 无水硫酸钠干 燥有机相， 硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 9/1), 得到淡黄色固体 3c (251 mg,产率 71.3%)。  2-(5-Bromo-4,6-dimethylbenzofuran-3-yl)acetaldehyde 2b was dissolved in a mixed solvent of methanol (3 mL) and tetrahydrofuran (10 mL), boron at 0 ° C Sodium hydride (124 mg, 3.28 mmol) was added to the mixture, and the mixture was stirred for 0.5 hr. After completion of the reaction, water (5 mL) was added to the reaction mixture to quench the reaction, and the reaction mixture was concentrated to remove a portion of organic solvent. Diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), EtOAc (EtOAc)EtOAc. Ether/ethyl acetate = 9/1) gave a pale yellow solid 3c (251 mg, yield 71.3%).
第四步： 5-溴 -3-甲氧乙基 -4,6-二甲基苯并呋喃 （3d) Step 4: 5-Bromo-3-methoxyethyl-4,6-dimethylbenzofuran (3d)
5-bromo-3-(2-methoxyethyl)-4,6-dimethylbenzofuran
Figure imgf000056_0002
氮气氛围中，将碘甲垸（198mg, 1.40mmol) 加入 2-(5-溴 -4,6-二甲基苯并呋喃 -3-基)乙醇 3c (251 mg, 0.93 mmol) 的四氢呋喃 （10 mL)溶液中，搅拌 20分钟。将氢化钠 （34 mg, 1.40 mmol) 加入混合溶液中， 升温至 40°C搅拌反应 5小时， 加热至回流继续反应 2小时。 反应结束， 向 反应液中加入饱和氯化铵溶液 mL)和水（10 mL 用石油醚（30 mL x 3)萃取， 合并有机 相， 用饱和食盐水（30 mL x l)洗涤， 无水硫酸钠干燥有机相， 过滤， 将滤液减压浓缩。 残留 物用硅胶柱层析分离纯化（石油醚 /二氯甲垸 = 3/1)， 得到淡黄色固体状化合物 3d (260 mg,产 率 98%)。 5-bromo-3-(2-methoxyethyl)-4,6-dimethylbenzofuran
Figure imgf000056_0002
Iodomethyl hydrazine (198 mg, 1.40 mmol) was added to 2-(5-bromo-4,6-dimethylbenzofuran-3-yl)ethanol 3c (251 mg, 0.93 mmol) in tetrahydrofuran (10). In a solution of mL), stir for 20 minutes. Sodium hydride (34 mg, 1.40 mmol) was added to the mixed solution, and the mixture was heated to 40 ° C, and the mixture was stirred for 5 hours, and heated to reflux to continue the reaction for 2 hours. At the end of the reaction, a saturated ammonium chloride solution (mL) and water (10 mL of petroleum ether (30 mL x 3) were added to the reaction mixture, and the organic phase was combined, washed with saturated brine (30 mL×l), anhydrous sodium sulfate The organic phase was dried, filtered, and the filtrate was evaporated to dryness crystals crystals crystalssssssssssssssssssss ).
¾ NMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.43 (s, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 3.00 (t, 2H), 3⁄4 NMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.43 (s, 1H), 3.60 (t, 2H), 3.28 (s, 3H), 3.00 (t, 2H),
2.64 (s, 3H), 2.44 (s, 3H). 2.64 (s, 3H), 2.44 (s, 3H).
第五步： 3-(3-(2-甲氧乙基) -4,6-二甲基苯并呋喃 -5-基；)苯甲醛（3e) Step 5: 3-(3-(2-methoxyethyl)-4,6-dimethylbenzofuran-5-yl;)benzaldehyde (3e)
3-(3-(2-methoxyethyl)-4,6-dimethylb
Figure imgf000056_0003
3-(3-(2-methoxyethyl)-4,6-dimethylb
Figure imgf000056_0003
^ 5-溴 -3-甲氧乙基 -4,6- mg, l.Olmmol)溶于碳酸钠水溶液（2.8 mL, 1M) 中， 加入甲苯（5 mL)及乙醇（5 mL)。 用氮 气置换反应体系， 将四 (三苯基膦)钯（53 mg, 0.045 mmol)加入混合物中。 保持氮气氛围， 升 温至 80°C搅拌反应 24小时。反应结束，向反应液中加入饱和氯化铵溶液（20 mL)和水（5 mL)， 用乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 饱和食盐水（30 mL x l)洗涤， 无水硫酸钠干燥 有机相， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 14/1), 得到无色粘稠状物状化合物 3e (170 mg,产率 60%)。 ^ 5-Bromo-3-methoxyethyl-4,6- M, l.Olmmol) was dissolved in aqueous sodium carbonate (2.8 mL, 1M), toluene (5 mL) and ethanol (5 mL). The reaction system was replaced with nitrogen, and tetrakis(triphenylphosphine)palladium (53 mg, 0.045 mmol) was added to the mixture. The atmosphere was kept under nitrogen, and the mixture was heated to 80 ° C to stir the reaction for 24 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) and water (5 mL) were added, and ethyl acetate (30 mL x 3) was extracted, and the organic phase was washed with saturated brine (30 mL xl). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
¾ NMR (400 MHz, DMSO) δ 10.07 (s, 1Η), 7.94 (d, 1H), 7.74― 7.68 (m, 3H), 7.52 (dd, 1H), 7.35 (s, 1H), 3.62 (t, 2H), 3.29 (s, 3H), 3.02 (t, 2H), 2.23 (s, 3H), 2.01 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 10.07 (s, 1Η), 7.94 (d, 1H), 7.74- 7.68 (m, 3H), 7.52 (dd, 1H), 7.35 (s, 1H), 3.62 (t, 2H), 3.29 (s, 3H), 3.02 (t, 2H), 2.23 (s, 3H), 2.01 (s, 3H).
第六步： （3-(3-(2-甲氧乙基) -4,6-二甲基苯并呋喃 -5-基)苯基)甲醇 （3f) Step 6: (3-(3-(2-methoxyethyl)-4,6-dimethylbenzofuran-5-yl)phenyl)methanol (3f)
(3-(3-(2-methoxyethyl)-4,6- ethanol
Figure imgf000057_0001
(3-(3-(2-methoxyethyl)-4,6-ethanol
Figure imgf000057_0001
冰浴条件下， 将硼氢化钠 （42 mg, 1.10 mmol)加入 3-(3-(2-甲氧乙基) -4,6-二甲基苯并呋喃 -5- 基)苯甲醛 3e (170 mg, 0.55 mmol)在四氢呋喃 （5 mL)和甲醇 （2 mL) 的混合溶剂中的溶液 中， 搅拌反应 0.5小时。 向反应液中加水（13 mL)终止淬灭反应， 用乙酸乙酯 （10 mL x 3)萃 取， 有机层用饱和食盐水（30 mL x l)洗涤， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残 留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到无色粘稠状化合物 3f (151 mg,产 率 88%)。 Sodium borohydride (42 mg, 1.10 mmol) was added to 3-(3-(2-methoxyethyl)-4,6-dimethylbenzofuran-5-yl)benzaldehyde 3e under ice bath. 170 mg, 0.55 mmol) In a mixed solvent of tetrahydrofuran (5 mL) and methanol (2 mL), the mixture was stirred for 0.5 hour. The reaction mixture was quenched with water (3 mL), EtOAc (EtOAc)EtOAc. Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
第七步： （3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 （3g) Step 7: (3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol (3g)
(3-(3-(2-methoxyethyl)-4,6-dimethyl- -dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000057_0002
(3-(3-(2-methoxyethyl)-4,6-dimethyl- -dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000057_0002
将 (3-(3-(2-甲氧乙基) -4,6-二甲基苯并呋喃 -5-基)苯基)甲醇 3f (151 mg, 0.49 mmol)溶于甲 醇 （6 mL)和四氢呋喃 （3 mL) 混合溶剂中，将钯碳（30 mg,钯含量 w/w=10%)加入到混合物 中。 氢气置换反应体系， 在室温下搅拌反应 1小时， 升温至 55°C继续反应 7小时。 用乙酸乙 酯 （15 mL)稀释反应液， 硅藻土过滤， 滤液中加水（10 mL)。 用乙酸乙酯 （10 mL x 3)萃取， 有机层用饱和食盐水（30 mL x l)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用 硅胶柱层析分离纯化（石油醚 /二氯甲垸 = 1/1)， 得到无色油状化合物 3g (91 mg,产率 59%)。  (3-(3-(2-Methoxyethyl)-4,6-dimethylbenzofuran-5-yl)phenyl)methanol 3f (151 mg, 0.49 mmol) dissolved in methanol (6 mL) Palladium carbon (30 mg, palladium content w/w = 10%) was added to the mixture in a mixed solvent of tetrahydrofuran (3 mL). The reaction system was replaced with hydrogen, and the reaction was stirred at room temperature for 1 hour, and the temperature was raised to 55 ° C to continue the reaction for 7 hours. The reaction mixture was diluted with ethyl acetate (15 mL), filtered and evaporated. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
¾ NMR (400 MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.08― 6.91 (m, 2H), 6.55 (s, 1H), 5.20 (t, 1H), 4.53 (dd, 2H), 4.42 (d, 2H), 3.47― 3.36 (m, 4H), 3.24 (s, 3H), 1.89 (s, 6H).  3⁄4 NMR (400 MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.08 - 6.91 (m, 2H), 6.55 (s, 1H), 5.20 (t, 1H), 4.53 (dd, 2H), 4.42 (d, 2H), 3.47― 3.36 (m, 4H), 3.24 (s, 3H), 1.89 (s, 6H).
第八步：2-(6-((3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸甲酯（3h) methyl 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2 -dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate Step 8: 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Methyl oxy)-2,3-dihydrobenzofuran-3-yl)acetate (3h) Methyl 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2 -dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000058_0001
Figure imgf000058_0001
氮气氛围， 在（TC下， （3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 3g (82 mg, 0.26 mmoL), 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 1E (66 mg, 0.32 mmoL)溶于干 燥的二氯甲垸（10 mL)溶液中， 将三丁基膦（115 mg, 0.57 mmoL)、 Ι,Γ- (偶氮二羰基)二哌啶 (144 mg, 0.57 mmoL)加入混合物中， 升至室温搅拌反应 6小时， TLC板跟踪反应结束。 将反 应液减压浓缩， 残留物用硅胶柱层析法分析纯化 (石油醚 /乙酸乙酯 = 6/1)， 得到无色油状物 3h (92 mg,产率 70.2%)。  Under nitrogen atmosphere, (3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol 3g (82 mg, 0.26 mmoL), methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (66 mg, 0.32 mmol) dissolved in dry methylene chloride (10) In a solution of mL), tributylphosphine (115 mg, 0.57 mmoL), hydrazine, hydrazine-(azodicarbonyl)dipiperidine (144 mg, 0.57 mmoL) was added to the mixture, and the mixture was stirred at room temperature for 6 hours. The TLC plate was used to complete the reaction. The reaction mixture was evaporated to dryness crystals crystals crystals crystals ).
第九步：2-(6-((3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸 （化合物 3) Step 9: 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Oxy)) 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 3)
2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydroben zofuran-3 -yl)acetic acid  2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydroben zofuran-3 -yl) Acetic acid
Figure imgf000058_0002
Figure imgf000058_0002
将氢氧化钠水溶液（1 mL, 1M)加入 2-(6-((3-(3-(2-甲氧乙基) -4,6-二甲基 -2,3-二氢苯并呋 喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3h (92 mg, 0.18 mmoL) 的四氢呋喃 （5 mL)溶液中，室温下搅拌反应 1小时。将反应液浓缩除去部分溶剂，用 1M盐酸溶液调节 pH≤ 3， 用乙酸乙酯 （10 mL x 2)萃取， 合并有机相， 饱和食盐水（10 mL x 1)洗涤， 用无水硫酸 钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析法分离纯化（二氯甲垸 /甲醇 = 10/1), 得到白色固体状化合物 3 (71 mg,产率 79%)。  Add aqueous sodium hydroxide (1 mL, 1 M) to 2-(6-((3-(3-(2-methoxyethyl))-4,6-dimethyl-2,3-dihydrobenzofuran Methyl 5-amino)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate in 3h (92 mg, 0.18 mmol) in tetrahydrofuran (5 mL) 1 hour. The reaction solution was concentrated to remove a portion of the solvent, and the mixture was adjusted to pH ≤ 3 with a 1M hydrochloric acid solution, and extracted with ethyl acetate (10 mL x 2). The organic phase was combined, washed with saturated brine (10 mL×1) and dried over anhydrous sodium sulfate Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut
ESIMS [M+H]+: 489.0. ESIMS [M+H] + : 489.0.
¾ NMR (400 MHz, DMSO) δ 12.36 (s, 1Η), 7.44 (t, 1H), 7.37 (d, 1H), 7.08 (dt, 3H), 6.55 (s, 1H), 6.46 (t, 2H), 5.09 (s, 2H), 4.68 (t, 1H), 4.42 (d, 2H), 4.18 (dd, 1H), 3.71 - 3.60 (m, 1H), 3.48 - 3.36 (m, 3H), 3.24 (s, 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.86 (s, 6H), 1.90― 1.78 (m, 1H), 1.63 (m, 1H).  3⁄4 NMR (400 MHz, DMSO) δ 12.36 (s, 1 Η), 7.44 (t, 1H), 7.37 (d, 1H), 7.08 (dt, 3H), 6.55 (s, 1H), 6.46 (t, 2H) , 5.09 (s, 2H), 4.68 (t, 1H), 4.42 (d, 2H), 4.18 (dd, 1H), 3.71 - 3.60 (m, 1H), 3.48 - 3.36 (m, 3H), 3.24 (s , 3H), 2.70 (dd, 1H), 2.46 (d, 1H), 1.86 (s, 6H), 1.90- 1.78 (m, 1H), 1.63 (m, 1H).
实施例 4 Example 4
2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 (；化合物 4) 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3 -yl)acetic acid (; compound 4)
2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000059_0001
Figure imgf000059_0001
第一步： 5-溴 -4,6-二甲基 -2,3-二氢苯并呋喃 -3-醇（4a) First step: 5-bromo-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol (4a)
5-bromo-4,6-dimethyl-2,3-dihydrobenzofur -3-ol
Figure imgf000059_0002
5-bromo-4,6-dimethyl-2,3-dihydrobenzofur -3-ol
Figure imgf000059_0002
冰浴下，将硼氢化钠 （0.24g, 6.22 mmol)分批次加入 5-溴 -4,6-二甲基苯并呋喃 -3(2H)-酮 2E (0.50 g, 2.07 mmol)在四氢呋喃 （10 mL)和甲醇 （2 mL) 混合溶剂中的混合溶液中， 升至室温 搅拌反应 0.5小时。 向反应液中加水（15 mL)稀释， 用乙酸乙酯 （20 mL x 3)萃取， 有机层用 饱和食盐水（50 mL x 1)洗涤， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱 层析分离纯化（石油醚 /乙酸乙酯 = 6/1)， 得到白色固体状化合物 4a (400 mg,产率 79%)。 第二步： 5-溴 -4,6-二甲基苯并呋喃 （4b)  Sodium borohydride (0.24 g, 6.22 mmol) was added in portions to 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (0.50 g, 2.07 mmol) in tetrahydrofuran. In a mixed solution of (10 mL) and methanol (2 mL) in a mixed solvent, the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with water (15 mL), EtOAc (EtOAc)EtOAc. concentrate. The residue was purified with EtOAc EtOAcjjjjjjjj Second step: 5-bromo-4,6-dimethylbenzofuran (4b)
5-bromo-4,6-dimethylbenzofuran
Figure imgf000059_0003
5-bromo-4,6-dimethylbenzofuran
Figure imgf000059_0003
将对甲苯磺酸（568 mg, 3.30 mmol)加入 5-溴 -4,6-二甲基 -2,3-二氢苯并呋喃 -3-醇 4a (400 mg, 1.65 mmol) 的甲苯 (20 mL)溶液中， 加热回流搅拌反应 15分钟， 反应结束。 将反应液冷 却至室温， 加水（15 mL)稀释， 用石油醚（10 mL x 3)萃取， 饱和食盐水（30 mL x 1)洗涤， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚)， 得到无 色液体状化合物 4b (363 mg,产率 97%)。  Add p-toluenesulfonic acid (568 mg, 3.30 mmol) to 5-bromo-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol 4a (400 mg, 1.65 mmol) in toluene (20) In the mL) solution, the reaction was stirred under reflux with heating for 15 minutes, and the reaction was completed. The reaction mixture was cooled to room temperature, diluted with water (15 mL), EtOAc (EtOAc)EtOAc. . The residue was purified by silica gel column chromatography (EtOAc) eluting
¾ NMR (400 MHz, DMSO) δ 7.96 (d, 1Η), 7.49 (s, 1H), 7.07 (d, 1H), 2.54 (s, 3H), 2.46 (s, 3⁄4 NMR (400 MHz, DMSO) δ 7.96 (d, 1 Η), 7.49 (s, 1H), 7.07 (d, 1H), 2.54 (s, 3H), 2.46 (s,
3H). 3H).
第三步： 3-(4,6-二甲基苯并呋喃 -5-基)苯甲醛（4c) The third step: 3-(4,6-dimethylbenzofuran-5-yl)benzaldehyde (4c)
3-(4,6-dimethylbenzofuran-5-yl)benzaldehyde
Figure imgf000060_0001
3-(4,6-dimethylbenzofuran-5-yl)benzaldehyde
Figure imgf000060_0001
将甲苯 (10 mL)及乙醇 (5 mL)加入 5-溴 -4,6-二甲基苯并呋喃 4b (363 mg, 1.61 mmol)和 3-甲酰基苯硼酸 （266 mg, 1.77 mmol) 的碳酸钠溶液（4.8mL, 1M) 中。 用氮气置换反应体系， 将四 (三苯基膦)钯（93 mg, 0.08 mmol)加入混合物中。 保持氮气氛围， 升温至 80°C搅拌反应 24小时。 反应结束， 将混合物过滤， 滤液加水（10 mL)稀释， 用乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 用饱和食盐水（50 mL x l)洗涤， 无水硫酸钠干燥有机相， 过滤， 将滤液减压浓 缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 8/1), 得到无色油状物 4c (249mg,产 率 61.8%)。  Add toluene (10 mL) and ethanol (5 mL) to 5-bromo-4,6-dimethylbenzofuran 4b (363 mg, 1.61 mmol) and 3-formylbenzeneboronic acid (266 mg, 1.77 mmol) Sodium carbonate solution (4.8 mL, 1 M). The reaction system was replaced with nitrogen, and tetrakis(triphenylphosphine)palladium (93 mg, 0.08 mmol) was added to the mixture. The nitrogen atmosphere was maintained, and the mixture was heated to 80 ° C to stir the reaction for 24 hours. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,, It was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut
¾ NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 7.94 (t, 2H), 7.74― 7.69 (m, 2H), 7.54 (d, 1H), 7.40 (s, 1H), 7.02 (d, 1H), 2.13 (s, 3H), 2.05 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 7.94 (t, 2H), 7.74 - 7.69 (m, 2H), 7.54 (d, 1H), 7.40 (s, 1H), 7.02 (d, 1H), 2.13 (s, 3H), 2.05 (s, 3H).
第四步： （3-(4,6-二甲基苯并呋喃 -5-基；)苯基;)甲醇（4d) Fourth step: (3-(4,6-dimethylbenzofuran-5-yl;)phenyl;)methanol (4d)
(3-(4,6-dimethylbenzofuran-5-yl)phenyl)methanol
Figure imgf000060_0002
(3-(4,6-dimethylbenzofuran-5-yl)phenyl)methanol
Figure imgf000060_0002
冰浴条件下， 将硼氢化钠 （112 mg, 2.96 mmol)加入 3-(4,6-二甲基苯并呋喃 -5-基)苯甲醛 4c (247 mg, 0.99 mmol)在四氢呋喃 （10 mL)和甲醇 （3 mL) 的混合溶剂中， 搅拌反应 0.5小 时。 向反应液中加水（15 mL) 淬灭反应， 用乙酸乙酯 （10 mL x 3)萃取， 有机层用饱和食盐 水（30 mL x 1)洗涤，用无水硫酸钠干燥，过滤，将滤液减压浓缩，得到无色油状物 4d (241 mg, 产率 96%)。  Sodium borohydride (112 mg, 2.96 mmol) was added to 3-(4,6-dimethylbenzofuran-5-yl)benzaldehyde 4c (247 mg, 0.99 mmol) in tetrahydrofuran (10 mL). The reaction was stirred for 0.5 hour in a mixed solvent of methanol (3 mL). The reaction mixture was diluted with water (15 mL), EtOAc (EtOAc m. Concentration under reduced pressure gave 4d (yield: 241 mg, yield: 96%).
ESIMS [M+H]+: 255.1. ESIMS [M+H] + : 255.1.
第五步： （3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 （4e) Step 5: (3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol (4e)
(3-(4,6-dimethyl-2,3-dihydrobenzofura -5-yl)phenyl)methanol
Figure imgf000060_0003
(3-(4,6-dimethyl-2,3-dihydrobenzofura -5-yl)phenyl)methanol
Figure imgf000060_0003
(3-(4,6-二甲基苯并呋喃 -5-基)苯基)甲醇 4d (241 mg, 0.96 mmol)溶于甲醇 （10 mL)和四氢 呋喃 （5 mL) 混合溶剂中，将钯碳（48 mg, 10%)加入混合物中。用氢气置换反应体系，在 35°C 下搅拌反应 24小时， 升温至 55°C继续反应 48小时。 用乙酸乙酯 （15 mL)稀释反应液， 硅藻 土过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到无色 油状物 4e (190 mg,产率 78%)。  (3-(4,6-Dimethylbenzofuran-5-yl)phenyl)methanol 4d (241 mg, 0.96 mmol) dissolved in methanol (10 mL) and tetrahydrofuran (5 mL) Carbon (48 mg, 10%) was added to the mixture. The reaction system was replaced with hydrogen, and the reaction was stirred at 35 ° C for 24 hours, and the temperature was raised to 55 ° C to continue the reaction for 48 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc
第六步： 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基;)苄基)氧基) -2,3-二氢苯并呋喃 -3-基;)乙酸甲 酯 （4f) Methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n-3-yl)acetate Step 6: 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl;)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl;) methyl acetate (4f) Methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n-3-yl)acetate
Figure imgf000061_0001
Figure imgf000061_0001
氮气氛围， 在 0°C下， （3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 4e (130 mg, 0.51 mmoL), 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 lE (128 mg， 0.61 mmoL)溶于干燥的二氯 甲垸（10 mL) 中， 将三丁基膦（227 mg, 1.12 mmoL), Ι ,Γ- (偶氮二羰基)二哌啶 （283 mg, 1.12 mmoL)加入混合物中， 升至室温反应 2小时。 将反应液过滤除去不溶物， 将滤液减压浓缩， 残留物用硅胶柱层析法分析纯化（石油醚 /乙酸乙酯 = 7/1)， 得到淡黄色油状物 4f (190 mg,产 率 84%)。  Nitrogen atmosphere, (3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol 4e (130 mg, 0.51 mmoL) at 0 ° C, 2- Methyl (6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (128 mg, 0.61 mmol) dissolved in dry methylene chloride (10 mL). 227 mg, 1.12 mmoL), hydrazine, hydrazine-(azodicarbonyl)dipiperidine (283 mg, 1.12 mmoL) was added to the mixture and allowed to react to room temperature for 2 hours. The reaction mixture was filtered to remove the residue, and the filtrate was evaporated. mjjjjjjjjjjjj %).
第七步： 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 (化合物 4) Step 7: 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzene And furan-3-yl)acetic acid (compound 4)
2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid  2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000061_0002
Figure imgf000061_0002
将氢氧化钠水溶液（5 mL, 2M)加入 2-(6-((；3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基；)苄基；)氧 基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 4f (190 mg， 0.43 mmoL) 的四氢呋喃 （5 mL)溶液中， 室 温搅拌反应过夜。用稀盐酸调节反应液的 pH≤ 2，用乙酸乙酯 （10 mL x 3)萃取，合并有机相， 饱和食盐水（50 mL x l)洗涤， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱 层析法分离纯化（石油醚 /乙酸乙酯 = 1.5/1)， 得到白色固体状化合物 4 (170 mg,产率 92.4%)。  Aqueous sodium hydroxide (5 mL, 2M) was added to 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)) benzyl;) A solution of methyl oxy)-2,3-dihydrobenzofuran-3-yl)acetate 4f (190 mg, 0.43 mmol) in THF (5 mL). The pH of the reaction mixture was adjusted to ≤ 2 with dilute hydrochloric acid, and extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated brine (50 mL×l), dried over anhydrous sodium sulfate and filtered concentrate. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut
ESIMS [M-H]": 429.1.  ESIMS [M-H]": 429.1.
¾ NMR (400 MHz, DMSO) δ 12.35 (s, IH), 7.44 (t, IH), 7.37 (d, IH), 7.16― 7.01 (m, 3H), 6.53 (s, IH), 6.47 (m, 2H), 5.09 (s, 2H), 4.68 (t, IH), 4.52 (t, 2H), 3.66 (m, IH), 3.34 (s, 2H), 3.09 (t, 2H), 2.69 (dd, IH), 1.87 (s, 3H), 1.83 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 12.35 (s, IH), 7.44 (t, IH), 7.37 (d, IH), 7.16 - 7.01 (m, 3H), 6.53 (s, IH), 6.47 (m, 2H), 5.09 (s, 2H), 4.68 (t, IH), 4.52 (t, 2H), 3.66 (m, IH), 3.34 (s, 2H), 3.09 (t, 2H), 2.69 (dd, IH ), 1.87 (s, 3H), 1.83 (s, 3H).
实施例 5 Example 5
2-(6-((3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3- 基)乙酸 （化合物 5) 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 5)
2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3 -yl)acetic acid 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3 -yl )acetic acid
Figure imgf000062_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0002
将碳酸钾 （1.2 g, 8.69 mmol)、 甲醇 （20 mL)和水（20 mL)加入到 5-溴 -4,6-二甲基苯并呋 喃 -3(2H)-酮 2E (1.0 g, 4.16 mmol) 的四氢呋喃 (40 mL)溶液中， 再将甲醛溶液 (0.85 g, 10.41 mmol, 37.6%)加入混合物中，室温下搅拌反应 0.5小时。将反应液浓缩除去部分溶剂，加水（50 mL)稀释，用乙酸乙酯（60 mL x 3)萃取，合并有机相，并依次用饱和食盐水（100 mL x 2)和 水（100 mL x 2)洗涤。 无水硫酸钠干燥， 过滤， 将滤液减压浓缩旋干， 得到白色固体状化合 物 5a (1.18g,产率 94%)。  Potassium carbonate (1.2 g, 8.69 mmol), methanol (20 mL) and water (20 mL) were added to 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (1.0 g, 4.16 mmol) in tetrahydrofuran (40 mL), a solution of formaldehyde (0.85 g, 10.41 mmol, 37.6%) was added to the mixture, and the mixture was stirred at room temperature for 0.5 hour. The reaction solution was concentrated to remove a solvent, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3), and the organic phase was combined with saturated brine (100 mL x 2) and water (100 mL x 2) )washing. The residue was dried over anhydrous sodium sulfate (MgSO4).
MS m/z(ESI):252.9,255.0[M-31]  MS m/z (ESI): 252.9, 255.0 [M-31]
¾ NMR (300 MHz, DMSO) δ 7.15 (s, 1H), 5.08 (t, 2H), 3.67 (d, 4H), 2.57 (s, 3H), 2.45 (s, 3⁄4 NMR (300 MHz, DMSO) δ 7.15 (s, 1H), 5.08 (t, 2H), 3.67 (d, 4H), 2.57 (s, 3H), 2.45 (s,
3H). 3H).
Tetra A .,2008,19,2497-2507 Tetra A., 2008, 19, 2497-2507
第二步： 5-溴 -2,2-二 (甲氧甲基) -4,6-二甲基-苯并呋喃 -3(2H)-酮 （5b) Step 2: 5-Bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-benzofuran-3(2H)-one (5b)
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000062_0003
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000062_0003
无水无氧氛围， 冰浴下， 将氢化钠 （0.5 g, 12.45 mmol, 60%)分批次加入 5-溴 -2,2-二 (羟甲 基) - 4,6-二甲基苯并呋喃 -3(2H)-酮 5a (1.59 g, 4.98 mmol) 的干燥四氢呋喃 （38 mL)溶液中， 搅 拌反应 20分钟， 再将碘甲垸（1.5 mL, 24.90 mmol)加入混合物中。 升至室温继续搅拌反应 3 小时，反应结束。向反应液中加入水（25 mL)和饱和氯化铵溶液（25 mL)，用乙酸乙酯 （50 mL x 3)萃取， 合并有机相并用饱和食盐水（100 mL x 2)洗涤。 无水硫酸钠干燥， 过滤， 将滤液 减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 14/1), 得到白色固体状化合物 5b (734 mg,产率 46%)。 Anhydrous anaerobic atmosphere, sodium hydride (0.5 g, 12.45 mmol, 60%) was added in batches to 5-bromo-2,2-bis(hydroxymethyl)-4,6-dimethylbenzene. To a solution of furan-3(2H)-one 5a (1.59 g, 4.98 mmol) in dry THF (38 mL), the mixture was stirred for 20 min. The reaction was stirred for 3 hours while the temperature was raised to room temperature, and the reaction was completed. Add water (25 mL) and saturated ammonium chloride solution (25 mL) to ethyl acetate (50 mL) x 3) Extraction, the organic phases were combined and washed with saturated brine (100 mL×2). Dry over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified with EtOAc EtOAcjjjjjjjj
MS m/z(ESI):329.0,330.9[M+l]  MS m/z (ESI): 329.0, 330.9 [M+l]
¾ NMR (400 MHz, DMSO) δ 7.18 (s, 1H), 3.65 (s, 4H), 3.17 (s, 6H), 2.57 (s, 3H), 2.44 (s, 3⁄4 NMR (400 MHz, DMSO) δ 7.18 (s, 1H), 3.65 (s, 4H), 3.17 (s, 6H), 2.57 (s, 3H), 2.44 (s,
3H). 3H).
第三步： 5-溴 -2,2-二 (甲氧甲基)—4,6-二甲基 -2,3-二氢苯并呋喃 -3-醇（5c) The third step: 5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol (5c)
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-3-ol
Figure imgf000063_0001
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-3-ol
Figure imgf000063_0001
冰浴下， 将硼氢化钠 （328 mg, 8.66 mmol) 分小份加入 5-溴 -2,2-二 (甲氧甲基) -4,6-二甲基- 苯并呋喃-3(2¾-酮513 (570 1^, 1.73 1^^1) 的甲醇 (5 mL)和四氢呋喃 (10 mL) 混合溶液中， 升至室温反应 0.5小时。向反应体系中加水（10 mL) 淬灭反应，加入饱和氯化铵溶液（15 mL)， 用乙酸乙酯 （20 mL x 3)萃取， 合并有机相并用水（50 mL x 2)洗涤，无水硫酸钠干燥， 过滤， 将反应液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 10/1), 得到无色透明 状液体 5c (572 mg,产率 99%)。  Sodium borohydride (328 mg, 8.66 mmol) was added in small portions to 5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-benzofuran-3 (23⁄4). - Ketone 513 (570 1^, 1.73 1^^1) in a mixed solution of methanol (5 mL) and tetrahydrofuran (10 mL), and allowed to react to room temperature for 0.5 hour. Add water (10 mL) to the reaction system to quench the reaction. Add a saturated solution of ammonium chloride (15 mL), EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
第四步： 5-溴 -2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 （5d) Step 4: 5-Bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran (5d)
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2 -dihydrobenzofuran
Figure imgf000063_0002
5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2 -dihydrobenzofuran
Figure imgf000063_0002
无水无氧氛围， 冰浴下， 将三乙基氢硅垸（16.3 mL, 102.10 mmol)加入 5-溴 -2,2-二 (甲氧 甲基)—4,6-二甲基 -2,3-二氢苯并呋喃 -3-醇 5c (573 mg, 1.73 mmol) 的干燥二氯甲垸 （20 mL) 中， 再缓慢滴加三氟乙酸 （1.03 mL, 13.80 mmol), 搅拌反应 2小时。 向反应液中加入二氯甲垸 (20 mL)和饱和碳酸氢钠溶液（20 mL)， 搅拌 10分钟， 加入水（10 mL)， 分液。 水层用乙酸乙 酯 （30 mL x 2)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶 柱层析分离纯化（石油醚 /乙酸乙酯 = 30/1)， 得到白色固体 5d (480 mg,产率 88%)。  Anhydrous anaerobic atmosphere, triethylhydrogen silane (16.3 mL, 102.10 mmol) was added to 5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2 under ice bath. , 3-dihydrobenzofuran-3-ol 5c (573 mg, 1.73 mmol) in dry dichloromethane (20 mL), then trifluoroacetic acid (1.03 mL, 13.80 mmol). hour. To the reaction mixture were added dichloromethane (20 mL) and a saturated sodium hydrogen carbonate solution (20 mL), and stirred for 10 min. The aqueous layer was extracted with ethyl acetate (30 mL EtOAc). The residue was purified with EtOAc EtOAcjjjjjjjjj
^ NMR (400 MHz, DMSO) δ 6.61 (s, 1Η), 3.46 (d, 4H), 3.28 (s, 6H), 3.01 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H)  ^ NMR (400 MHz, DMSO) δ 6.61 (s, 1 Η), 3.46 (d, 4H), 3.28 (s, 6H), 3.01 (s, 2H), 2.27 (s, 3H), 2.22 (s, 3H)
第五步： 3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛（5e) Step 5: 3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (5e)
3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000063_0003
将 3-甲酰基苯硼酸 （247.4 mg, 1.65 mmol)和碳酸钠溶液（6.5 mL, 1M)加入 5-溴 -2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 5d (510 mg, 1.62 mmol) 的甲苯（15 mL)溶液中， 再 加入乙醇 （3 mL)。 氮气氛围下， 将四 (三苯基膦)钯（93.6 mg, 0.08 mmol)加入反应体系中， 升 温至 80°C，搅拌反应 18小时。反应结束，向反应液中加水（10 mL)稀释，加乙酸乙酯 （50 mL) 稀释。 用硅藻土过滤， 有机层用饱和食盐水（20 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤 液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 12/1), 得到无色透明油状液 体 5e (410 mg,产率 74%)。 3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000063_0003
Add 3-formylbenzeneboronic acid (247.4 mg, 1.65 mmol) and sodium carbonate solution (6.5 mL, 1 M) to 5-bromo-2,2-bis(methoxymethyl)-4,6-dimethyl-2 A solution of 3-dihydrobenzofuran 5d (510 mg, 1.62 mmol) in toluene (15 mL). Tetrakis(triphenylphosphine)palladium (93.6 mg, 0.08 mmol) was added to the reaction system under a nitrogen atmosphere, the temperature was raised to 80 ° C, and the reaction was stirred for 18 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL EtOAc). The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
第六步： （3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 （5f) Step 6: (3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol (5f)
(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000064_0001
(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000064_0001
冰浴条件下， 将硼氢化钠 （228 mg, 6.03 mmol)分批加入 3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛 5e (410 mg, 1.20 mmol) 的四氢呋喃 （8 mL)和甲醇 （4 mL) 混 合溶剂中。 室温搅拌反应 15分钟。 向反应液中加水（10 mL) 淬灭反应， 除去部分溶剂， 加入 饱和氯化铵溶液（15 mL)， 用乙酸乙酯 （25 mL x 3)萃取， 合并有机相并用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到无色透 明油状液体 5f (380 mg,产率 92%)。  Sodium borohydride (228 mg, 6.03 mmol) was added portionwise to 3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzoate under ice-cooling. Furan-5-yl)benzaldehyde 5e (410 mg, 1.20 mmol) in tetrahydrofuran (8 mL) and methanol (4 mL). The reaction was stirred at room temperature for 15 minutes. The reaction mixture was quenched with water (10 mL), EtOAc (EtOAc)EtOAc. It was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
¾ NMR (400 MHz, DMSO) δ 7.37 (t, 1H), 7.27 (d, 1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.49 (s, 1H), 5.19 (t, 1H), 4.53 (d, 2H), 3.57― 3.42 (m, 4H), 3.31 (s, 6H), 2.95 (s, 2H), 1.88 (s, 3H), 1.81 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 7.37 (t, 1H), 7.27 (d, 1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.49 (s, 1H), 5.19 (t, 1H) , 4.53 (d, 2H), 3.57 - 3.42 (m, 4H), 3.31 (s, 6H), 2.95 (s, 2H), 1.88 (s, 3H), 1.81 (s, 3H).
第七步：2-(6-((3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并 呋喃 -3-基；)乙酸甲酯（5g) Step 7: 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy) -2,3-dihydrobenzofuran-3-yl;) methyl acetate (5g)
Methyl2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)2,3-^ ihydrobenzofuran-3-yl)acetate
Figure imgf000064_0002
Methyl2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)2,3-^ ihydrobenzofuran-3-yl) Aclate
Figure imgf000064_0002
将 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 1E (110 mg, 0.53 mmol)加入 (3-(2,2-二 (甲氧 甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 5f (150 mg, 0.44 mmol) 的干燥二氯甲垸（15 mL)溶液中， 氮气氛围下， 将三丁基膦（0.24 mL, 0.97 mmol)和偶氮二甲酰二哌啶 （245 mg, 0.97 mmol)加入混合液中。室温下搅拌反应 2小时， 向反应液中加入少量正己垸， 将混合物过 滤， 滤液减压浓缩。快速柱层析 (石油醚 /乙酸乙酯 = 6/1)得到得到粗品且直接用于下一步反应。 Med.Chem.lett.,2010,1 ,290-294 第八步：2-(6-((3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并 呋喃 -3-基)乙酸 （化合物 5) Add methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (110 mg, 0.53 mmol) to (3-(2,2-bis(methoxymethyl)) 4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 5f (150 mg, 0.44 mmol) in dry methylene chloride (15 mL) Tributylphosphine (0.24 mL, 0.97 mmol) and azodiyldipiperidine (245 mg, 0.97 mmol) were added to the mixture. The reaction was stirred at room temperature for 2 hours, and a small amount of n-hexane was added to the reaction mixture. Filtration and concentration of the filtrate under reduced pressure. flash column chromatography ( petroleum ether / ethyl acetate = 6/1) afforded crude product which was used directly in the next step. Med. Chem.lett., 2010,1,290-294 Step 8: 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 5)
2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3- dihydrobenzofuran-3-yl)acetic acid  2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl) Acetic acid
Figure imgf000065_0001
Figure imgf000065_0001
将氢氧化钠水溶液 Cl. l mL, 2M)加入上步反应粗产物的甲醇 （2 mL)和四氢呋喃 （4 mL) 混合溶剂中， 室温下搅拌反应 1.5小时。 将反应液减压浓缩， 加水（20 mL)稀释， 用 1M盐酸 酸化至 pH为 1， 用乙酸乙酯 （30 mL x 3)萃取， 合并有机相并用无水硫酸钠干燥， 过滤， 将 滤液减压浓缩。 残留物用硅胶柱层析分离纯化（二氯甲垸 /甲醇 = 40/1)， 得到白色固体化合物 5 (168 mg, 两步产率 73%)。  Aqueous sodium hydroxide (1.5 mL, 2M) was added to a mixture of methanol (2 mL) and tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentrated by pressure. The residue was purified by silica gel column chromatography (jjjjjjjjjjjjj
MS m/z(ESI):517.2[M-l]  MS m/z (ESI): 517.2 [M-l]
¾ NMR (400 MHz, CDC13) δ 7.45― 7.33 (m, 2H), 7.16 (s, 1H), 7.06 (t, 2H), 6.57 (s, 1H), 6.53 ― 6.42 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.81 (dt, 1H), 3.68― 3.51 (m, 4H), 3.44 (s, 6H), 3.00 (s, 2H), 2.89― 2.74 (m, 1H), 2.61 (dd, 1H), 1.91 (d, 6H). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.45 - 7.33 (m, 2H), 7.16 (s, 1H), 7.06 (t, 2H), 6.57 (s, 1H), 6.53 ― 6.42 (m, 2H), 5.05 (s, 2H), 4.76 (t, 1H), 4.28 (dd, 1H), 3.81 (dt, 1H), 3.68-3.51 (m, 4H), 3.44 (s, 6H), 3.00 (s, 2H), 2.89― 2.74 (m, 1H), 2.61 (dd, 1H), 1.91 (d, 6H).
实施例 6  Example 6
2-(6-(3-(2- (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 酸 （化合物 6)  2-(6-(3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3 -dihydrobenzofuran-3-yl)acetic acid (compound 6)
2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz  2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz
Figure imgf000065_0002
第一步： 5-烯丙氧基 -2-溴 -1,3-二甲基苯（6a)
Figure imgf000065_0002
First step: 5-allyloxy-2-bromo-1,3-dimethylbenzene (6a)
-(allyloxy)-2-bromo- 1 ,3-dimethylbenzen
Figure imgf000066_0001
-(allyloxy)-2-bromo- 1 ,3-dimethylbenzen
Figure imgf000066_0001
将碳酸钾 (20.6 g, 0.15 mol)和 3-溴丙烯 (8.6 mL, 0.10 mol)加入 4-溴 -3,5-二甲酚 2A (10.0 g, 0.05 mol) 的乙腈（200 mL)溶液中， 加热回流搅拌反应 6小时。 反应结束， 将反应混合物 过滤， 滤液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 50/1), 得到淡黄色 油状液体 6a (10.9 g,产率 90%)。  Potassium carbonate (20.6 g, 0.15 mol) and 3-bromopropene (8.6 mL, 0.10 mol) were added to a solution of 4-bromo-3,5-xylenol 2A (10.0 g, 0.05 mol) in acetonitrile (200 mL) The reaction was stirred under reflux with heating for 6 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
¾ NMR (400 MHz, CDC13) δ 6.66 (s, 2Η), 6.03 (ddd, 1H), 5.33 (dd, 2H), 4.48 (d, 2H), 2.37 (s,3⁄4 NMR (400 MHz, CDC1 3 ) δ 6.66 (s, 2Η), 6.03 (ddd, 1H), 5.33 (dd, 2H), 4.48 (d, 2H), 2.37 (s,
6H). 6H).
第二步： 2-烯丙基 -4-溴 -3,5-二甲基苯酚（6b) Second step: 2-allyl-4-bromo-3,5-dimethylphenol (6b)
2-allyl-4-bromo-3,5-dimethylphenol
Figure imgf000066_0002
2-allyl-4-bromo-3,5-dimethylphenol
Figure imgf000066_0002
无水无氧氛围， 将 5-烯丙氧基 -2-溴 -1,3-二甲基苯 6a (7.5 g, 0.03 mol)加热至 180°C反应 6 小时。 将反应体系冷却至室温， 加入二氯甲垸（50 mL)， 将溶液减压浓缩， 残留物用硅胶柱层 析分离纯化（石油醚 /乙酸乙酯 = 20/1)， 得到灰黄色固体状化合物 6b (1.94 g,产率 25%)。  In an anhydrous anoxic atmosphere, 5-allyloxy-2-bromo-1,3-dimethylbenzene 6a (7.5 g, 0.03 mol) was heated to 180 ° C for 6 hours. The reaction system was cooled to room temperature, and dichloromethane (50 mL) was added. The residue was evaporated to dryness. Compound 6b (1.94 g, yield 25%).
¾ NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 6.68 (s, 1H), 5.82 (dt, 1H), 5.00― 4.79 (m, 2H), 3.38 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 6.68 (s, 1H), 5.82 (dt, 1H), 5.00 - 4.79 (m, 2H), 3.38 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H).
第三步： （5-溴 -4,6-二甲基 -2,3二氢苯并呋喃 -2-基)甲醇 （6c) Step 3: (5-Bromo-4,6-dimethyl-2,3dihydrobenzofuran-2-yl)methanol (6c)
(5-bromo-4,6-dimethyl-2,3-dihydrobenzo l
Figure imgf000066_0003
(5-bromo-4,6-dimethyl-2,3-dihydrobenzo l
Figure imgf000066_0003
将间氯过氧苯甲酸 (538 mg, 3.11 mol)加入 2-烯丙基 -4-溴 -3,5-二甲基苯酚 6b (500 mg, 2.07 mol) 的 1,2-二氯乙垸（20 mL)溶液中， 加热至 70°C搅拌反应 4小时。 反应结束， 将反应 液冷却至室温， 加入饱和硫代硫酸钠溶液（10 mL)， 搅拌 15分钟。 向混合液中加入饱和碳酸 钠溶液（30 mL), 继续搅拌 30分钟。 用乙酸乙酯（40 mL x 3)萃取， 合并有机相， 饱和碳酸 钠溶液（30 mL x 2)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分 离纯化（石油醚 /乙酸乙酯 = 10/1-6/1)， 得到白色固体状化合物 6c (286 mg,产率 53%)。  Addition of m-chloroperoxybenzoic acid (538 mg, 3.11 mol) to 2-allyl-4-bromo-3,5-dimethylphenol 6b (500 mg, 2.07 mol) of 1,2-dichloroacetamidine (20 mL) The solution was heated to 70 ° C and stirred for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and a saturated sodium thiosulfate solution (10 mL) was added and stirred for 15 minutes. Saturated sodium carbonate solution (30 mL) was added to the mixture and stirring was continued for 30 minutes. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAcjjjjjjjjj
¾ NMR (400 MHz, DMSO) δ 6.61 (s, 1H), 4.99 (t, 1H), 4.84― 4.73 (m, 1H), 3.60― 3.48 (m, 2H), 3.16 (dd, 1H), 2.93 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 6.61 (s, 1H), 4.99 (t, 1H), 4.84 - 4.73 (m, 1H), 3.60 - 3.48 (m, 2H), 3.16 (dd, 1H), 2.93 ( Dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).
第四步： 5-溴 -2- (甲氧甲基) -4,6-二甲基 -2,3二氢苯并呋喃 （6d) Fourth step: 5-bromo-2-(methoxymethyl)-4,6-dimethyl-2,3 dihydrobenzofuran (6d)
5-bromo-2-(methoxymethyl)-4,6-dimethyl-2 -dihydrobenzofuran 无水无氧氛围， 冰浴下， 将氢化钠 （40 mg, 1.67 mmol)分批加入 (5-溴 -4,6-二甲基 -2,3二氢 苯并呋喃 -2-基)甲醇 6c (286 mg, 1.11 mmol) 的干燥四氢呋喃 （20 mL) 溶液中， 搅拌 20分钟。 将碘甲垸（788 mg, 5.55 mmol)加入混合液中，升至室温搅拌反应 2小时。向反应液中加水（10 mL) 淬灭反应， 加饱和氯化铵溶液（15 mL)， 用乙酸乙酯 （25 mL x 3) 萃取， 有机相用无水硫 酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 10/1)， 得到无色透明油状液体 6d (270 mg,产率 89%)。 5-bromo-2-(methoxymethyl)-4,6-dimethyl-2 -dihydrobenzofuran Anhydrous anaerobic atmosphere, sodium hydride (40 mg, 1.67 mmol) was added portionwise (5-bromo-4,6-dimethyl-2,3 dihydrobenzofuran-2-yl)methanol under ice bath 6c (286 mg, 1.11 mmol) in dry tetrahydrofuran (20 mL). Iodomethyl hydrazine (788 mg, 5.55 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (10 mL). EtOAc (EtOAc) (EtOAc) Concentrated by pressure. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
¾ NMR (400 MHz, DMSO) δ 6.62 (s, 1Η), 4.93 (ddt, 1H), 3.50 (dd, 2H), 3.29 (s, 3H), 3.21 (dd, 1H), 2.90 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 6.62 (s, 1 Η), 4.93 (ddt, 1H), 3.50 (dd, 2H), 3.29 (s, 3H), 3.21 (dd, 1H), 2.90 (dd, 1H) , 2.27 (s, 3H), 2.23 (s, 3H).
第五步： 3-(2- (甲基甲氧基 )-4,6-二甲基 -2,3二氢苯并呋喃 -5-基;)苯甲醛（6e) Step 5: 3-(2-(methylmethoxy)-4,6-dimethyl-2,3dihydrobenzofuran-5-yl;)benzaldehyde (6e)
3-(2-(methoxymethyl)-4,6-dimethyl- -dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000067_0001
3-(2-(methoxymethyl)-4,6-dimethyl--dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000067_0001
将碳酸钠溶液（4.8 mL, 1M)和乙醇 （2.5 mL)加入 5-溴 -2- (甲氧甲基) -4,6-二甲基 -2,3二氢 苯并呋喃 6d (260 mg, 0.96 mmol)和 3-甲酰基苯硼酸 （159 mg, 1.06 mmol) 的甲苯（10 mL)溶 液中， 用氮气在混合液中鼓泡 30分钟并保持氮气氛围， 将四 (三苯基膦)钯（58 mg, 0.05 mmol) 加入混合物中。将反应液加热至 80°C，搅拌反应 18小时，冷却至室温。向混合物中加水（8 mL) 和乙酸乙酯 （40 mL)， 用硅藻土过滤， 滤液分层， 有机层用饱和食盐水（30 mL x 2)洗涤， 无 水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析法分离纯化（石油醚 /乙酸乙酯为 = 14/1), 得到淡黄色油状液体 6e (260 mg,产率 91%)。  Add sodium carbonate solution (4.8 mL, 1 M) and ethanol (2.5 mL) to 5-bromo-2-(methoxymethyl)-4,6-dimethyl-2,3 dihydrobenzofuran 6d (260 mg , 0.96 mmol) and a solution of 3-formylbenzeneboronic acid (159 mg, 1.06 mmol) in toluene (10 mL), which was bubbled with nitrogen for 30 minutes and kept under nitrogen atmosphere, tetrakis(triphenylphosphine) Palladium (58 mg, 0.05 mmol) was added to the mixture. The reaction solution was heated to 80 ° C, and the reaction was stirred for 18 hours and cooled to room temperature. Water (8 mL) and ethyl acetate (40 mL) were added to the mixture, which was filtered over Celite, and the organic layer was washed with brine (30 mL? The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
第六步： （3-(2- (甲基甲氧基 )-4,6-二甲基 -2,3二氢苯并呋喃 -5-基)苯甲醇 （6f) Step 6: (3-(2-(methylmethoxy)-4,6-dimethyl-2,3dihydrobenzofuran-5-yl)benzyl alcohol (6f)
(3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-5-yl)phenyl)methanol
Figure imgf000067_0002
(3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofumn-5-yl)phenyl)methanol
Figure imgf000067_0002
冰浴条件下，将硼氢化钠 （134 mg, 3.55 mmol)分批加入 3-(2- (甲基甲氧基 )-4,6-二甲基 -2,3 二氢苯并呋喃 -5-基)苯甲醛 6e (260 mg, 0.71 mmol) 的四氢呋喃 （6 mL)和甲醇 （3 mL) 混合溶 剂中， 升至室温搅拌反应 0.5小时。 向反应液中加水（5 mL) 淬灭反应， 除去部分溶剂， 加入 饱和氯化铵溶液（15 mL)。 用乙酸乙酯 （20 mL x 3)萃取， 无水硫酸钠干燥， 过滤， 将滤液减 压浓缩。残留物用硅胶柱层析法分离纯化（石油醚 /乙酸乙酯为 = 5/1)，得到无色透明油状液体 6f (255 mg,产率 97%)。  Sodium borohydride (134 mg, 3.55 mmol) was added portionwise to 3-(2-(methylmethoxy)-4,6-dimethyl-2,3 dihydrobenzofuran-5 under ice bath. To a solution of benzaldehyde 6e (260 mg, 0.71 mmol) in tetrahydrofuran (6 mL) and methanol (3 mL). Water (5 mL) was added to the reaction mixture to quench the mixture, and a portion of solvent was removed, and a saturated ammonium chloride solution (15 mL) was added. Extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
第七步： 2-(6-((3-(2- (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基；)乙酸甲酯（6g) Step 7: 2-(6-((3-(2-(methoxy))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran Methyl-3-yl;) methyl acetate (6g)
methyl 2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate Methyl 2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000068_0001
Figure imgf000068_0001
氮气氛围， 将三丁基膦（0.13 mL, 0.52 mmol)和偶氮二甲酰二哌啶 （130.9 mg, 0.52 mmol) 加入 (3-(2- (甲基甲氧基 )-4,6-二甲基 -2,3二氢苯并呋喃 -5-基)苯甲醇 6f (70.0 mg, 0.23 mmol)和 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 IE (58.9 mg, 0.28 mmol) 的干燥二氯甲垸（8 mL) 溶液中。 将反应液升至室温， 搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤除去混合物 中不溶物， 减压浓缩滤液。残留物用硅胶柱层析法分析纯化（石油醚 /乙酸乙酯 = 6/1)， 得到白 色固体状化合物 6g (90mg,产率 78%)。  Tributylphosphine (0.13 mL, 0.52 mmol) and azodiyldipiperidine (130.9 mg, 0.52 mmol) were added to (3-(2-(methylmethoxy)-4,6-) under a nitrogen atmosphere. Dimethyl-2,3 dihydrobenzofuran-5-yl)benzyl alcohol 6f (70.0 mg, 0.23 mmol) and 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid Methyl ester IE (58.9 mg, 0.28 mmol) in dry dichloromethane (8 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the mixture was filtered to remove insolubles. The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjj
¾ NMR (400 MHz, DMSO) δ 7.44 (t, IH), 7.37 (d, IH), 7.16― 6.99 (m, 3H), 6.51 (s, IH), 6.47 (d, 2H), 5.09 (s, 2H), 4.98― 4.89 (m, IH), 4.67 (t, IH), 4.20 (dd, IH), 3.77― 3.66 (m, IH), 3.63 (s, 3H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, IH), 2.84 (dd, IH), 2.77 (dd, IH), 2.59 (dd, IH), 1.86 (s, 3H), 1.80 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 7.44 (t, IH), 7.37 (d, IH), 7.16 - 6.99 (m, 3H), 6.51 (s, IH), 6.47 (d, 2H), 5.09 (s, (H, IH) (s, 3H), 3.16 (dd, IH), 2.84 (dd, IH), 2.77 (dd, IH), 2.59 (dd, IH), 1.86 (s, 3H), 1.80 (s, 3H).
第八步： 2-(6-((3-(2- (甲氧甲基) - (4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸 （化合物 6) Step 8: 2-(6-((3-(2-(methoxy))-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 6)
2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3-yl)acetic acid  2-(6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3-yl)acetic acid
Figure imgf000068_0002
Figure imgf000068_0002
将氢氧化钠溶液（0.87mL, 2M)加入 2-(6-((3-(2- (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 Add sodium hydroxide solution (0.87 mL, 2M) to 2-(6-((3-(2-(methoxymethyl))-4,6-dimethyl-2,3-dihydrobenzofuran)
-5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 6g (170 mg, 0.35 mmol) 的甲醇 （2 mL)和 四氢呋喃 （4 mL)混合溶剂中。 室温下搅拌反应 1.5小时， 向反应液中加水（20 mL), 用 1M 盐酸调 pH为 1。 用乙酸乙酯 （30 mL x 3)萃取， 有机相用无水硫酸钠干燥， 过滤， 将滤液减 压浓缩旋干。 残留物用硅胶柱层析分离纯化（二氯甲垸 /甲醇 = 50/1)， 得到白色固体状化合物 6 (155 mg,产率 93%)。 Methyl 5-amino)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 6g (170 mg, 0.35 mmol) in methanol (2 mL) and THF (4 mL) In the solvent. The reaction was stirred at room temperature for 1.5 hours, water (20 mL) was added and the mixture was adjusted to pH 1 with 1M hydrochloric acid. It was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified with EtOAc EtOAcjjjjjjjjj
MS m/z(ESI):473.2[M-l]  MS m/z (ESI): 473.2 [M-l]
¾ NMR (400 MHz, CDC13) δ 7.40 (dd, 2H), 7.16 (d, IH), 7.06 (dd, 2H), 6.59 (s, IH), 6.53― 6.43 (m, 2H), 5.05 (s, 2H), 5.02― 4.91 (m, IH), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (td, IH), 3.63 (ddd, 2H), 3.46 (s, 3H), 3.19 (dd, IH), 2.89 (dd, IH), 2.81 (dd, IH), 2.62 (dd, IH), 1.95 (s, 3H), 1.88 (s, 3H). 实施例 7 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.40 (dd, 2H), 7.16 (d, IH), 7.06 (dd, 2H), 6.59 (s, IH), 6.53― 6.43 (m, 2H), 5.05 (s , 2H), 5.02 - 4.91 (m, IH), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (td, IH), 3.63 (ddd, 2H), 3.46 (s, 3H), 3.19 ( Dd, IH), 2.89 (dd, IH), 2.81 (dd, IH), 2.62 (dd, IH), 1.95 (s, 3H), 1.88 (s, 3H). Example 7
(3S) 2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3- 基)乙酸 （化合物 7) (3S) 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) ) -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 7)
-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-  -(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-
Figure imgf000069_0001
Figure imgf000069_0001
第一步： (3S) 2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并 呋喃 -3-基；)乙酸甲酯 First step: (3S) 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Methyl)oxy)-2,3-dihydrobenzofuran-3-yl;
(3S) methyl 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetate(7a)  (3S) methyl 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran- 3-yl)acetate(7a)
Figure imgf000069_0002
Figure imgf000069_0002
将（3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 lc (100 mg, 0.32 mmol) 和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(80 mg, 0.38 mmol)溶于二氯甲垸（10 mL) 中。氮气置换反应体系，将三丁基膦（142 mg, 0.70 mmol)和 1,Γ-(偶氮二羰基)二哌啶 （178 mg, 0.70 mmol)加入混合物中， 室温下搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤， 将滤 液减压浓缩。残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 8/1),得到无色透明油状液体粗品。 第二步： (3S) 2-(6-((3-(3-甲氧基 -2,2,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并 呋喃 -3-基)乙酸 （化合物 7)  (3-(3-Methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol lc (100 mg, 0.32 mmol) (S) Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 3D (80 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL). The reaction system was replaced with nitrogen, and tributylphosphine (142 mg, 0.70 mmol) and 1, Γ-(azodicarbonyl)dipiperidine (178 mg, 0.70 mmol) were added to the mixture, and the mixture was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, which was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to flash column chromatography (EtOAc /EtOAcEtOAc Second step: (3S) 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl) (yl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 7)
(3S) 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran -5-yl)benzyl)oxy)- 2,3- dihydrobenzofuran-3 -yl)acetic acid (3S) 2-(-6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran -5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3 -yl)acetic acid
Figure imgf000069_0003
将氢氧化钠溶液 (0.8mL, 2M)加入上步反应的粗品的甲醇 (2 mL)和四氢呋喃（ 4 mL) 混合 溶剂中， 室温下搅拌反应 2小时。 反应结束， 加水（20 mL)稀释反应， 用 1M的盐酸水溶液 酸化至 PH为 1， 乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液 减压浓缩。 残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 70/1)， 得到白色固体状的化合物 7 (130 mg, 两步产率 83.3%)。
Figure imgf000069_0003
A sodium hydroxide solution (0.8 mL, 2 M) was added to a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) of the above reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (20 mL), EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography (jjjjjjjjjjj
MS m/z(ESI):487.2[M-l]  MS m/z (ESI): 487.2 [M-l]
¾ NMR (400 MHz, CDC13) δ 7.47― 7.33 (m, 2H), 7.17 (d, 1H), 7.08 (dd, 2H), 6.54 (s, 1H), 6.51 - 6.40 (m, 2H), 5.06 (s, 2H), 4.76 (t, 1H), 4.46 (d, 1H), 4.29 (dd, 1H), 3.86 - 3.75 (m, 1H), 3.42 (s, 3H), 2.81 (dd, 1H), 2.61 (dd, 1H), 1.96 (dt, 6H), 1.56 (s, 3H), 1.39 (s, 3H). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.47 - 7.33 (m, 2H), 7.17 (d, 1H), 7.08 (dd, 2H), 6.54 (s, 1H), 6.51 - 6.40 (m, 2H), 5.06 (s, 2H), 4.76 (t, 1H), 4.46 (d, 1H), 4.29 (dd, 1H), 3.86 - 3.75 (m, 1H), 3.42 (s, 3H), 2.81 (dd, 1H), 2.61 (dd, 1H), 1.96 (dt, 6H), 1.56 (s, 3H), 1.39 (s, 3H).
实施例 8 Example 8
(S) 2-(6-(3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯乙基 )-2,3-二氢苯并呋喃 -3- 基；)乙酸 (；化合物 8)  (S) 2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenethyl) -2,3-dihydrobenzofuran-3-yl;)acetic acid (;compound 8)
(S)-2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)phenethyl)-2,3-dihyd robenzofuran-3-yl)acetic acid  (S)-2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)phenethyl)-2,3-dihyd robenzofuran-3- Yl)acetic acid
Figure imgf000070_0001
Figure imgf000070_0001
第一步： （S) 2-(6-(3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯乙基 )-2,3-二氢苯并 呋喃 -3-基；)乙酸甲酯 8a First step: (S) 2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Phenylethyl)-2,3-dihydrobenzofuran-3-yl;)methyl acetate 8a
(S)-methyl 2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenet hyl)-2,3-dihydrobenzofuran-3-yl)acetate  (S)-methyl 2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenet hyl)-2,3-dihydrobenzofuran-3 -yl)acetate
Figure imgf000070_0002
Figure imgf000070_0002
将 (3-(2,2-二（甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 5f (120 mg, 0.35 mmol) 和 （S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(87 mg, 0.42 mmol)溶于二氯甲垸 （10 mL) 中。 氮气置换反应体系， 将三丁基膦 （156 mg, 0.77 mmol)和 Ι,Γ- (偶氮二羰基)二哌啶(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 5f (120 mg, 0.35 mmol) and (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 3D (87 mg, 0.42 mmol) dissolved in dichloromethane (10) In mL). Nitrogen displacement reaction system, tributylphosphine (156 mg, 0.77 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine
(192 mg, 0.77 mmol)加入混合物中， 室温下搅拌反应 2小时。 向反应液中加入少量正己垸， 过 滤， 将滤液减压浓缩。残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 6/1)， 得到无色透明油状 液体粗品， 直接用于下一步。 (192 mg, 0.77 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hr. A small amount of n-hexane was added to the reaction mixture, which was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (EtOAcEtOAcEtOAcEtOAc
第二步： （S) 2-(6-(3-(2,2-二 (甲氧甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯乙基 )-2,3-二氢苯并 呋喃 -3-基；)乙酸 (；化合物 8) Second step: (S) 2-(6-(3-(2,2-bis(methoxy))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) Phenylethyl)-2,3-dihydrobenzofuran-3-yl;)acetic acid (;compound 8)
(S)-2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)phenethyl)-2,3-dihyd robenzofuran-3-yl)acetic acid  (S)-2-(6-(3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofUran-5-yl)phenethyl)-2,3-dihyd robenzofuran-3- Yl)acetic acid
Figure imgf000071_0001
Figure imgf000071_0001
将氢氧化钠溶液 (0.9 mL, 2M)加入上步粗品的甲醇 (2 mL)和四氢呋喃（ 4 mL) 混合溶剂 中， 室温下搅拌反应 1.5小时。 反应结束， 加水（20 mL) 淬灭反应， 用 1M的盐酸水溶液酸化 至 PH为 1， 乙酸乙酯 （25 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压 浓缩。 残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 60/1), 得到白色泡状固体的化合物 8 (140 mg, 两步产率 77.6%)。  A sodium hydroxide solution (0.9 mL, 2 M) was added to a mixture of methanol (2 mL) and tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction was quenched with water (20 mL), EtOAc (EtOAc)EtOAc. concentrate. The residue was purified by silica gel column chromatography (jjjjjjjjjjj)
MS m/z(ESI):5172[M-l]  MS m/z (ESI): 5172 [M-l]
¾ NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.16 - 7.01 (m, 3H), 6.54― 6.42 (m, 3H), 5.09 (s, 2H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.76― 3.59 (m, 1H), 3.54― 3.43 (m, 4H), 3.30 (s, 6H), 2.95 (s, 2H), 2.69 (dd, 1H), 2.49― 2.41 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.16 - 7.01 (m, 3H), 6.54 - 6.42 (m, 3H), 5.09 ( s, 2H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.76 - 3.59 (m, 1H), 3.54 - 3.43 (m, 4H), 3.30 (s, 6H), 2.95 (s, 2H) , 2.69 (dd, 1H), 2.49― 2.41 (m, 1H), 1.86 (s, 3H), 1.79 (s, 3H).
实施例 9 Example 9
2-(6-((3-(4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基）乙酸 (；化合物 9) 2-(6-((3-(4,6-Dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl)acetic acid (compound 9)
2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a cetic acid  2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a cetic acid
Figure imgf000071_0002
Figure imgf000071_0002
第一步： 5-(3-羟基甲基苯基 )-4,6-二甲基-苯并呋喃 -3(2H)-酮 (9a) First step: 5-(3-hydroxymethylphenyl)-4,6-dimethyl-benzofuran-3(2H)-one (9a)
5-(3-(hydroxymethyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000072_0001
5-(3-(hydroxymethyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000072_0001
将 3-羟甲基苯硼酸 （2.8 g, 18.3 mmol)和碳酸钠溶液（83.0 mL, 1M)加入 5-溴 -4,6-二甲基 苯并呋喃 -3(2H)-酮 2E (4.0 g, 16.6 mmol) 的甲苯 (100 mL)溶液中， 再加入乙醇 (40 mL)。 氮 气氛围下， 将四 (三苯基膦)钯（1.0 g, 0.8 mmol)加入反应体系中， 升温至 80。C， 搅拌反应 24 小时。反应结束， 向反应液中加水（30 mL)稀释反应， 加乙酸乙酯 （200 mL)稀释。用硅藻土 过滤， 有机层用饱和食盐水（50 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残 留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 6/1-4/1), 得到淡黄色油状液体 9a (3.3 g,产 率 74%)。  Add 3-hydroxymethylbenzeneboronic acid (2.8 g, 18.3 mmol) and sodium carbonate solution (83.0 mL, 1 M) to 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (4.0 g, 16.6 mmol) in toluene (100 mL), then ethanol (40 mL). Tetrakis(triphenylphosphine)palladium (1.0 g, 0.8 mmol) was added to the reaction system under nitrogen atmosphere, and the temperature was raised to 80. C, stir the reaction for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL EtOAc). The residue was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 6 / 1-4 / 1) to afford a pale yellow oily liquid 9a (3.3 g, yield 74%).
^ NMR (400 MHz, CDC13) δ 7.44 (t, 1Η), 7.38 (d, 1H), 7.11 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H): 4.75 (s, 2H), 4.61 (s, 2H), 2.28 (s, 3H), 2.07 (s, 3H) ^ NMR (400 MHz, CDC1 3 ) δ 7.44 (t, 1Η), 7.38 (d, 1H), 7.11 (s, 1H), 7.03 (d, 1H), 6.87 (s, 1H) : 4.75 (s, 2H) ), 4.61 (s, 2H), 2.28 (s, 3H), 2.07 (s, 3H)
第二步：2-(6-((3-(4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸甲酯 (9b) Second step: 2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)methyl acetate (9b)
Methyl 2-(6-((3 -(4,6-dimethyl-3 -oxo-2,3 -dihydrobenzofuran-5-yl)benzyl)oxy)-2 ,3 - dihydrobenzofuran-3-yl)acetate  Methyl 2-(6-((3 -(4,6-dimethyl-3 -oxo-2,3 -dihydrobenzofuran-5-yl)benzyl)oxy)-2 ,3 - dihydrobenzofuran-3-yl)acetate
Figure imgf000072_0002
Figure imgf000072_0002
氮气氛围， 将三丁基膦（0.41 mL, 1.64 mmol)和偶氮二甲酰二哌啶 （413.8 mg, 1.64 mmol) 加入 5-(3-羟基甲基苯基 )-4,6-二甲基-苯并呋喃 -3(2H)-酮 9a (200 mg, 0.75 mmol)和 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 1E (186.1 mg, 0.89 mmol) 的干燥二氯甲垸（15 mL)溶液中。 将反应液在室温搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤除去混合物中不溶物， 减 压浓缩滤液。残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 6/1)，得到淡黄色透明油状液体粗 品 9b。  Tributylphosphine (0.41 mL, 1.64 mmol) and azodiyldipiperidine (413.8 mg, 1.64 mmol) were added to 5-(3-hydroxymethylphenyl)-4,6-dimethyl Methyl-benzofuran-3(2H)-one 9a (200 mg, 0.75 mmol) and methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (186.1 mg, 0.89 mmol) in dry dichloromethane (15 mL). The reaction solution was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction liquid, and the insoluble matter in the mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to flash column chromatography (EtOAc (EtOAc)
第三步：2-(6-((3-(4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸 （化合物 9) The third step: 2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 9)
2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a  2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)a
Figure imgf000072_0003
Figure imgf000072_0003
将氢氧化钠溶液 (1.9 mL, 2M)加入 2-(6-((3-(4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基；)苄基；) 氧基; 1-2,3-二氢苯并呋喃 -3-基;)乙酸甲酯 9b的甲醇 (2 mL)和四氢呋喃（ 4 mL) 混合溶剂中，室温 下搅拌反应 1.5小时。 反应结束， 加水（20 mL)稀释反应， 用 1M的盐酸水溶液酸化至 PH为 1， 乙酸乙酯 （30 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残 留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 60/1)，得到淡黄色固体状的化合物 9(140 mg, 两 步产率 36.4%)。 Add sodium hydroxide solution (1.9 mL, 2M) to 2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl;) Benzyl;) oxy; 1-2,3-dihydrobenzofuran-3-yl;) methyl acetate 9b in methanol (2 mL) and tetrahydrofuran (4 mL) in a solvent mixture, room temperature The reaction was stirred for 1.5 hours. After the reaction was completed, the mixture was diluted with water (20 mL), EtOAc EtOAc (EtOAc m. . The residue was purified with EtOAc EtOAcjjjjjjjjj
MS m/z(ESI):443.1 [M-l]  MS m/z (ESI): 443.1 [M-l]
¾ NMR (400 MHz, CDC13) δ 7.49― 7.39 (m, 2H), 7.13 (s, 1H), 7.05 (d, 2H), 6.86 (s, 1H), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.61 (s, 2H), 4.29 (dd, 1H), 3.81 (td, 1H), 2.80 (dd, 1H), 2.62 (dd, 1H), 2.26 (s, 3H), 2.06 (s, 3H). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.49 - 7.39 (m, 2H), 7.13 (s, 1H), 7.05 (d, 2H), 6.86 (s, 1H), 6.47 (ddd, 2H), 5.07 (s , 2H), 4.76 (t, 1H), 4.61 (s, 2H), 4.29 (dd, 1H), 3.81 (td, 1H), 2.80 (dd, 1H), 2.62 (dd, 1H), 2.26 (s, 3H), 2.06 (s, 3H).
实施例 10 Example 10
(S) 2-(6-((3-(4,6-二甲基 -3-氧代 -3-氢 -2,1'-环丙基苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 （化合物 10)  (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3-hydro-2,1'-cyclopropylbenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 10)
(S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3-diliyd robenzofuran-3-yl)acetic acid  (S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3 -diliyd robenzofuran-3-yl)acetic acid
Figure imgf000073_0001
Figure imgf000073_0001
第一步： 5-(3-( ((叔丁基二甲基硅基)氧基)甲基)苯基) -4,6-二甲基 -2-氢苯并呋喃 -3-酮 (10a)First step: 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethyl-2-hydrobenzofuran-3-one ( 10a)
-(3-(((tert-bu1yldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000073_0002
-(3-(((tert-bu1yldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000073_0002
单口瓶中加入 5-(3-羟基甲基苯基 )-4,6-二甲基-苯并呋喃 -3(2H)-酮 9a(3.3 g, 12.3 mmol)、 叔 丁基二甲基氯硅垸（3.71 g, 24.6 mmol)、 咪唑 (2.51 g, 36.9 mmol)和二氯甲垸 (40 mL), 在室温下 搅拌 40分钟。 反应结束后， 加入 70 mL水淬灭反应。 加入 250 mL乙酸乙酯后分层， 取有机 层。 有机层用水洗 (100 mLx2)， 无水硫酸钠干燥， 浓缩， 柱层析 (石油醚 /二氯甲垸 = 2/1),得到 淡黄色油状液体 10a(4.68 g, 产率 99%)。 第二步： 5-(3-(((叔丁基二甲基硅基)氧基）甲基)苯基 )-4,6-二甲基 -3H-螺- [苯并呋喃 -2,1'-环丙 基] -3-酮 (10b) Add 5-(3-hydroxymethylphenyl)-4,6-dimethyl-benzofuran-3(2H)-one 9a (3.3 g, 12.3 mmol), tert-butyldimethyl chloride to a vial Silicon germanium (3.71 g, 24.6 mmol), imidazole (2.51 g, 36.9 mmol) and dichloromethane (40 mL) were stirred at room temperature for 40 min. After the reaction was over, the reaction was quenched by the addition of 70 mL of water. After adding 250 mL of ethyl acetate, the layers were separated and the organic layer was taken. The organic layer was washed with water (100 mL EtOAc). Second step: 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethyl-3H-spiro-[benzofuran-2, 1'-cyclopropyl]-3-one (10b)
-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethyl-3H-spiro[benzofuran-2,r-cycloprop  -(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4,6-dimethyl-3H-spiro[benzofuran-2,r-cycloprop
Figure imgf000074_0001
Figure imgf000074_0001
无水无氧氛围， -30'C下， 将 5-(3-W叔丁基二甲基硅基；)氧基；)甲基；)苯基; 1-4,6-二甲基 -2-氢苯 并呋喃 -3-酮 10a(2.5g,6.54 mmol)加入到 lOOmL干燥的四氢呋喃中。加入 60%氢化钠 (1.31 g,32.68 mmol), 搅拌 20分钟。 缓慢滴加 1,2-二溴乙垸 (3.68 g, 19.6 mmol),加完后升温至 50°C下反应 16小时。 反应结束后， 冷却至 0°C， 缓慢加入 25 mL水淬灭反应， 再加入 75 mL饱和氯化铵 水溶液， 用乙酸乙酯萃取 (100 mLx3;»。 合并有机层， 用无水硫酸钠干燥， 浓缩。硅胶柱层析 (石 油醚 /二氯甲垸 = 1/1)得到褐色油状液体 10b(1.08 g, 产率 40%)。  Anhydrous anaerobic atmosphere, at -30 ° C, 5-(3-W-tert-butyldimethylsilyl;)oxy;)methyl;)phenyl; 1-4,6-dimethyl- 2-Hydroxybenzofuran-3-one 10a (2.5 g, 6.54 mmol) was added to 100 mL of dry THF. 60% sodium hydride (1.31 g, 32.68 mmol) was added and stirred for 20 minutes. 1,2-Dibromoacetamidine (3.68 g, 19.6 mmol) was slowly added dropwise, and the mixture was heated to 50 ° C for 16 hours after the addition. After the reaction was completed, it was cooled to 0 ° C, and the reaction was quenched with EtOAc (EtOAc) (EtOAc). Concentration. Silica gel column chromatography (petrole ether / methylene chloride = 1 / 1) afforded a brown oily liquid 10b (1.08 g, yield 40%).
^ NMR (400 MHz, DMSO) δ 7.49 (t, 1H), 7.38 (d, 1H), 7.13 (d, 2H), 7.07 (d, 1H), 4.81 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H), 1.78 (dd, 2H), 1.44 (dd, 2H), 0.91 (s, 9H), 0.10 (s, 6H).  ^ NMR (400 MHz, DMSO) δ 7.49 (t, 1H), 7.38 (d, 1H), 7.13 (d, 2H), 7.07 (d, 1H), 4.81 (s, 2H), 2.26 (s, 3H) , 2.08 (s, 3H), 1.78 (dd, 2H), 1.44 (dd, 2H), 0.91 (s, 9H), 0.10 (s, 6H).
第三步： 5-(3-羟基甲基苯基 )-4,6-二甲基 -3H-螺 [苯并呋喃 -2,1'-环丙基 ]-3-酮 (10c) The third step: 5-(3-hydroxymethylphenyl)-4,6-dimethyl-3H-spiro [benzofuran-2,1'-cyclopropyl]-3-one (10c)
5-(3-(hydroxymethyl)phenyl)-4,6-dimethyl-3H-spiro[benzoftiran-2,r-cyclopropan|-3-one
Figure imgf000074_0002
5-(3-(hydroxymethyl)phenyl)-4,6-dimethyl-3H-spiro[benzoftiran-2,r-cyclopropan|-3-one
Figure imgf000074_0002
单口瓶中加入 5-(3-W叔丁基二甲基硅基)氧基）甲基)苯基; 1-4,6-二甲基 -3H-螺- [苯并呋喃 -2,Γ-环丙基 ]-3-酮 10b (449 mg, 1.1 mmol), 四氢呋喃溶剂 10 mL和四丁基氟化铵 (863 mg, 3.3 mmol),室温下搅拌 30分钟。加入水 10 mL搅拌 10分钟淬灭反应，用乙酸乙酯萃取 (15 mLx3), 合并有机层， 无水硫酸钠干燥， 浓缩。 硅胶柱层析 (石油醚 /乙酸乙酯 = 3/1)得到白色泡状固体 10c(270 mg, 产率 84%)。  Add 5-(3-W-tert-butyldimethylsilyl)oxy)methyl)phenyl to a single-mouth bottle; 1-4,6-dimethyl-3H-spiro-[benzofuran-2,Γ -cyclopropyl]-3-one 10b (449 mg, 1.1 mmol), 10 mL of tetrahydrofuran solvent and tetrabutylammonium fluoride (863 mg, 3.3 mmol), stirred at room temperature for 30 min. After adding 10 mL of water and stirring for 10 minutes, the mixture was evaporated. Silica gel column chromatography (petrole ether / ethyl acetate = 3/1) afforded white crystals of solid 10c (270 mg, yield 84%).
第四步：（S) 2-(6-((3-(4,6-二甲基 -3-氧代 -3H-螺- [苯并呋喃 -2,1'-环丙基 ]-5-基)苄基)氧基) -2,3-二氢 苯并呋喃 -3-基；)乙酸甲酯 (1 Od) Step 4: (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro-[benzofuran-2,1'-cyclopropyl]-5) -yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (1 Od)
(S)-methyl 2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl) benzyl )oxy)-2,3-dihydrobenzofuran-3-yl)acetate  (S)-methyl 2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl) benzyl )oxy)-2, 3-dihydrobenzofuran-3-yl)acetate
Figure imgf000074_0003
Figure imgf000074_0003
氮气氛围， 将三丁基膦（0.3 mL, 1.20 mmol)和偶氮二甲酰二哌啶 （302 mg, 1.20 mmoL)加 入 5-(3-羟基甲基苯基 )-4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]-3-酮 10c (160 mg, 0.54 mmol) 和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(136 mg, 0.65 mmoL) 的干燥二氯甲垸（15 mL)溶液中。 将反应液在室温搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤除去混合 物中不溶物， 减压浓缩滤液。残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 6/1)， 得到淡黄色 透明油状液体粗品 10d。 Tributylphosphine (0.3 mL, 1.20 mmol) and azodiyldipiperidine (302 mg, 1.20 mmoL) were added to 5-(3-hydroxymethylphenyl)-4,6-dimethyl in a nitrogen atmosphere. -3H-spiro [benzofuran-2, fluorenyl-cyclopropyl]-3-one 10c (160 mg, 0.54 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran -3-yl)methyl acetate 3D (136 mg, 0.65 mmoL) of dry dichloromethane (15 mL) in solution. The reaction solution was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction liquid, and the insoluble material in the mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting elut elut
第五步： （S) 2-(6-((3-(4,6-二甲基 -3-氧代 -3H-螺 [苯并呋喃 -2,1'-环丙基 ]-5-基)苄基)氧基) -2,3-二氢 苯并呋喃 -3-基)乙酸（化合物 10) Step 5: (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro[benzofuran-2,1'-cyclopropyl]-5-) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 10)
(S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3-dihy- drobenzofuran-3 -yl)acetic acid  (S)-2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)-2,3 -dihy- drobenzofuran-3 -yl)acetic acid
Figure imgf000075_0001
Figure imgf000075_0001
将氢氧化钠溶液 (1.4 mL, 2M)加入 (S) 2-(6-((3-(4,6-二甲基 -3-氧代 -3H-螺- [苯并呋喃 -2,Γ-环 丙基] -5-基;)苄基;)氧基; 1-2,3-二氢苯并呋喃 -3-基；)乙酸甲酯 10d的甲醇 (3 mL)和四氢呋喃（ 6 mL) 混合溶剂中， 室温下搅拌反应 2小时。 反应结束， 加水（20 mL)稀释反应， 用 1M的盐酸水 溶液酸化至 PH为 1， 乙酸乙酯 （25 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩。残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 70/1)，得到白色泡状固体化合 物 10(215 mg, 两步产率 84%)。  Add sodium hydroxide solution (1.4 mL, 2M) to (S) 2-(6-((3-(4,6-dimethyl-3-oxo-3H-spiro-[benzofuran-2, oxime] -cyclopropyl]-5-yl;)benzyl;)oxy; 1-2,3-dihydrobenzofuran-3-yl;)methyl acetate 10d in methanol (3 mL) and tetrahydrofuran (6 mL The reaction was stirred for 2 hours at room temperature. After the reaction was completed, the reaction was diluted with water (20 mL), acidified with 1M aqueous hydrochloric acid to pH 1 and ethyl acetate (25 mL x 3). The mixture was dried over anhydrous sodium sulfate (MgSO4). 84%).
MS m/z(ESI):469.1 [M-l]  MS m/z (ESI): 469.1 [M-l]
¾ NMR (400 MHz, DMSO) δ 12.35 (s, 1Η), 7.55― 7.40 (m, 2H), 7.18 (d, 1H), 7.11 (d, 3H), 3⁄4 NMR (400 MHz, DMSO) δ 12.35 (s, 1 Η), 7.55- 7.40 (m, 2H), 7.18 (d, 1H), 7.11 (d, 3H),
6.47 (d, 2H), 5.06 (s, 2H), 4.68 (t, 1H), 4.23― 4.11 (m, 1H), 3.74― 3.61 (m, 1H), 2.70 (dd, 1H), 2.506.47 (d, 2H), 5.06 (s, 2H), 4.68 (t, 1H), 4.23 - 4.11 (m, 1H), 3.74 - 3.61 (m, 1H), 2.70 (dd, 1H), 2.50
― 2.41 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H), 1.75 (dd, 2H), 1.41 (q, 2H). ― 2.41 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H), 1.75 (dd, 2H), 1.41 (q, 2H).
实施例 11 Example 11
(S) 2-(6-((3-(2,2-二 (甲氧基甲基 )-4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢 苯并呋喃 -3-基)乙酸（化合物 11) (S) 2-(6-((3-(2,2-bis(methoxymethyl))-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5 -yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 11)
(S)-2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetic acid  (S)-2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2, 3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000075_0002
第一步： 5-(3- (羟基甲基)苯基) -2,2-二 (甲氧基甲基 )-4,6-二甲基苯并呋喃 -3(2H)-酮 (11a)
Figure imgf000075_0002
First step: 5-(3-(hydroxymethyl)phenyl)-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one (11a )
-(3-(hydroxymethyl)phenyl)-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000076_0001
-(3-(hydroxymethyl)phenyl)-2,2-bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000076_0001
将 3-羟甲基苯硼酸 （150 mg, 0.97 mmol)和碳酸钠溶液（8.1 mL, 1M)加入 4,6-二甲基 -2,2- 二 (甲氧甲基) -5-溴-苯并呋喃 -3(2H)-酮 5b (265 mg, 0.81mmol) 的甲苯（10 mL)溶液中， 再加入 乙醇 （4 mL 氮气氛围下， 将四 (三苯基膦)钯（46 mg, 0.04 mmol)加入反应体系中， 升温至 80 °C ,搅拌反应 42小时。反应结束， 向反应液中加水（10 mL)稀释反应，加乙酸乙酯 （50 mL) 稀释。 用硅藻土过滤， 有机层用饱和食盐水（10 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤 液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 6/1-5/1)， 得到淡黄色油状液 体 11a (240 mg,产率 83%)。  Add 3-hydroxymethylbenzeneboronic acid (150 mg, 0.97 mmol) and sodium carbonate solution (8.1 mL, 1 M) to 4,6-dimethyl-2,2-bis(methoxymethyl)-5-bromo- To a solution of benzofuran-3(2H)-one 5b (265 mg, 0.81 mmol) in toluene (10 mL), and then ethanol (4 mL of tetraphenylphosphine) palladium (46 mg, 0.04 mmol) was added to the reaction system, the temperature was raised to 80 ° C, and the reaction was stirred for 42 hours. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with brine (10 mL EtOAc), dried over anhydrous sodium sulfate. /1), a pale yellow oily liquid 11a (240 mg, yield 83%) was obtained.
^ NMR (400 MHz, DMSO) δ 7.43 (t, 1H), 7.34 (d, 1H), 7.08 (s, 1H), 7.02 (d, 2H), 5.23 (t, 1H), 4.55 (d, 2H), 3.66 (s, 4H), 3.21 (s, 6H), 2.03 (s, 3H), 1.99 (s, 2H).  ^ NMR (400 MHz, DMSO) δ 7.43 (t, 1H), 7.34 (d, 1H), 7.08 (s, 1H), 7.02 (d, 2H), 5.23 (t, 1H), 4.55 (d, 2H) , 3.66 (s, 4H), 3.21 (s, 6H), 2.03 (s, 3H), 1.99 (s, 2H).
第二步： （S) 2-(6-((3-(2,2-二 (甲氧基甲基 )-4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧 基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 （l i b) Second step: (S) 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzene) Methyl furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (lib)
(S)-methyl 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5- yl)benzyl)oxy)-2,3-dihy (S)-methyl 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2 , 3-dihy
Figure imgf000076_0002
Figure imgf000076_0002
氮气氛围， 将三丁基膦（0.34 mL, 1.36 mmol)和偶氮二甲酰二哌啶 （343 mg, 1.36 mmol)加 入 5-(3- (羟基甲基)苯基) -2,2-二（甲氧基甲基 )-4,6-二甲基苯并呋喃 -3(2H)-酮 11a (220 mg, 0.62 mmol)和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D (154 mg, 0.74 mmol) 的干燥二氯 甲垸（15 mL)溶液中。 将反应液在室温搅拌反应 1小时。 向反应液中加入少量正己垸， 过滤 除去混合物中不溶物，减压浓缩滤液。残留物用硅胶快速柱层析 （二氯甲垸 /乙酸乙酯 = 60/1)， 得到无色透明油状液体粗品 l lb。  Tributylphosphine (0.34 mL, 1.36 mmol) and azodiyldipiperidine (343 mg, 1.36 mmol) were added to 5-(3-(hydroxymethyl)phenyl)-2,2- under a nitrogen atmosphere. Bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one 11a (220 mg, 0.62 mmol) and (S) 2-(6-hydroxy-2,3-di Methyl hydrobenzofuran-3-yl)acetate 3D (154 mg, 0.74 mmol) in dry methylene chloride (15 mL). The reaction solution was stirred at room temperature for 1 hour. A small amount of n-hexane was added to the reaction mixture, and the insoluble material in the mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was flash chromatographed on silica gel (dichloromethane / ethyl acetate = 60/1).
第三步： （S) 2-(6-((3-(2,2-二（甲氧基甲基) -4,6-二甲基 -3-氧代 -2,3-二氢苯并呋喃 -5-基)苄基)氧 基) -2,3-二氢苯并呋喃 -3-基)乙酸 （化合物 11) The third step: (S) 2-(6-((3-(2,2-bis(methoxymethyl))-4,6-dimethyl-3-oxo-2,3-dihydrobenzene And furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 11)
(S)-2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000077_0001
(S)-2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2, 3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000077_0001
将氢氧化钠溶液 (1.5 mL, 2M)加入 (S) 2-(6-((3-(2,2-二 (甲氧基甲基 )-4,6-二甲基 -3-氧代 -2,3- 二氢苯并呋喃 -5-基；)苄基；)氧基; 1-2,3-二氢苯并呋喃 -3-基；)乙酸甲酯 l ib在甲醇 (4 mL)和四氢呋喃 ( 8 mL) 混合溶剂中， 室温下搅拌反应 1.5小时。 反应结束， 加水（20 mL) 淬灭反应， 用 1M 的盐酸水溶液酸化至 pH为 1， 乙酸乙酯 （25 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 80/1)， 得到白色泡状 固体化合物 11(160 mg, 两步产率 49%)。  Add sodium hydroxide solution (1.5 mL, 2M) to (S) 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo) -2,3-dihydrobenzofuran-5-yl;)benzyl;)oxy; 1-2,3-dihydrobenzofuran-3-yl;)methyl acetate l ib in methanol (4 mL The reaction was stirred at room temperature for 1.5 hours in a mixed solvent of tetrahydrofuran (8 mL). After completion of the reaction, water was added (20 mL) to quench the reaction and acidified with 1M aqueous hydrochloric acid to pH 1 and ethyl acetate (25 mL x 3) The organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 80/1) 160 mg, two-step yield 49%).
MS m/z(ESI):533.2[M+l]  MS m/z (ESI): 533.2 [M+l]
¾ NMR (400 MHz, CDC13) δ 7.48― 7.37 (m, 2H), 7.14 (s, IH), 7.08― 7.03 (m, 2H), 6.91 (s, IH), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (dd, 3H), 3.70 (dd, 2H), 3.36 (s, 6H), 2.81 (dd, IH), 2.62 (dd, IH), 2.24 (s, 3H), 2.05 (s, 3H). 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.48 - 7.37 (m, 2H), 7.14 (s, IH), 7.08 - 7.03 (m, 2H), 6.91 (s, IH), 6.47 (ddd, 2H), 5.07 (s, 2H), 4.76 (t, IH), 4.29 (dd, IH), 3.81 (dd, 3H), 3.70 (dd, 2H), 3.36 (s, 6H), 2.81 (dd, IH), 2.62 ( Dd, IH), 2.24 (s, 3H), 2.05 (s, 3H).
实施例 12 Example 12
(S) 2-(6-((3-(2- (甲氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 (化合物 12)  (S) 2-(6-((3-(2-(Methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 12)
(3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2, 3-dihydrobenzofuran-3- l acetic acid (3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2, 3-dihydrobenzofuran-3- l Acetic acid
Figure imgf000077_0002
Figure imgf000077_0002
第一步： （S) 2-(6-((3-(2- (甲氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯 并呋喃 -3-基)乙酸甲酯 (12a) First step: (S) 2-(6-((3-(2-(methoxymethyl))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl Methyl)oxy)methyl-2,3-dihydrobenzofuran-3-yl)acetate (12a)
(3S) methyl 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy)- 2,3-dihydrobenzofuran-3-yl)acetate 氮气氛围， 将三丁基膦（0.33 mL, 1.33 mmol)和偶氮二甲酰二哌啶 （336 mg, 1.33 mmol)加 入 (3-(2- (甲基甲氧基 )-4,6-二甲基 -2,3二氢苯并呋喃 -5-基)苯甲醇 6f (180 mg, 0.60 mmol)和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D (150 mg, 0.72 mmol) 的干燥二氯甲垸（15 mL) 溶液中。将反应液在室温搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤除去混合物中不 溶物， 减压浓缩滤液。残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 6/1)， 得到淡黄色透明油 状液体粗品 12a。 (3S) methyl 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl) benzyl) oxy)- 2,3-dihydrobenzofuran-3- Yl)acetate Tributylphosphine (0.33 mL, 1.33 mmol) and azodiyldipiperidine (336 mg, 1.33 mmol) were added to (3-(2-(methylmethoxy)-4,6-) under a nitrogen atmosphere. Dimethyl-2,3 dihydrobenzofuran-5-yl)benzyl alcohol 6f (180 mg, 0.60 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3- A solution of methyl acetate 3D (150 mg, 0.72 mmol) in dry dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the mixture was filtered to remove insolubles. The filtrate was concentrated under reduced pressure. EtOAc EtOAc m.
第二步： （S) 2-(6-((3-(2- (甲氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯 并呋喃 -3-基)乙酸 (化合物 12) Second step: (S) 2-(6-((3-(2-(methoxymethyl))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl ()oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 12)
(3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3 (3S) 2-(-6-((3-(2-(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3
-dihydrobenzofuran-3 -yl)acetic acid -dihydrobenzofuran-3 -yl)acetic acid
Figure imgf000078_0001
Figure imgf000078_0001
将氢氧化钠溶液 (1.5 mL, 2M)加入 (S) 2-(6-((3-(2- (甲氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋 喃 -5-基；)苄基)氧基; 1-2,3-二氢苯并呋喃 -3-基;)乙酸甲酯 12a的甲醇 (3 mL)和四氢呋喃（ 6 mL) 混 合溶剂中， 室温下搅拌反应 1.5小时。 反应结束， 加水（20 mL)淬灭反应， 用 1M的盐酸水溶 液酸化至 PH为 1， 乙酸乙酯 （25 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤 液减压浓缩。残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 60/1)，得到白色泡状固体化合物 1 1(215 mg, 两步产率 75.4%)。  Add sodium hydroxide solution (1.5 mL, 2M) to (S) 2-(6-((3-(2-(methoxymethyl))-4,6-dimethyl-2,3-dihydrobenzene And furan-5-yl;) benzyl)oxy; 1-2,3-dihydrobenzofuran-3-yl;) methyl acetate 12a in methanol (3 mL) and tetrahydrofuran (6 mL) in a mixed solvent The reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with water (20 mL) EtOAc (EtOAc)EtOAc. The mixture was dried, filtered, and the filtrate was evaporated to dryness crystals crystals crystals crystalssssssssssssssssssssss ).
MS m/z(ESI):473.1 [M-l]  MS m/z (ESI): 473.1 [M-l]
¾ NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.1 1 (t, 2H), 7.04 (t, 1H): 3⁄4 NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.1 1 (t, 2H), 7.04 (t, 1H) :
6.51 (s, 1H), 6.47 (d, 2H), 5.09 (s, 2H), 5.00― 4.87 (m, 1H), 4.68 (t, 1H), 4.28― 4.12 (m, 1H), 3.76― 3.60 (m, 1H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, 1H), 2.84 (dd, 1H), 2.69 (dd, 1H), 2.49 - 2.41 (m, 1H), 1.83 (d, 6H). 6.51 (s, 1H), 6.47 (d, 2H), 5.09 (s, 2H), 5.00 - 4.87 (m, 1H), 4.68 (t, 1H), 4.28 - 4.12 (m, 1H), 3.76 - 3.60 ( m, 1H), 3.53 (d, 2H), 3.32 (s, 3H), 3.16 (dd, 1H), 2.84 (dd, 1H), 2.69 (dd, 1H), 2.49 - 2.41 (m, 1H), 1.83 (d, 6H).
实施例 13 Example 13
(3S) 2-(6-((3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 (化 合物 13) (3S) 2-(6-((3-(2,4,6-Trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl)acetic acid (compound 13)
(3S) 2-(-6-((3-(2,4,64rimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n -3-yl)acetic acid (3S) 2-(-6-((3-(2,4,64rimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n -3-yl)acetic acid
Figure imgf000079_0001
Figure imgf000079_0001
第一步： 2,4,5,6-四甲基 -2,3-二氢苯并呋喃 (13a) First step: 2,4,5,6-tetramethyl-2,3-dihydrobenzofuran (13a)
2,4,5,6-tetramethyl-2,3-dihydrobenzofura
Figure imgf000079_0002
2,4,5,6-tetramethyl-2,3-dihydrobenzofura
Figure imgf000079_0002
将三氟甲磺酸 C32mg， 0.2 mmol)溶解到 5 mL二氯甲垸中， 然后缓慢滴加到溶解有 2-烯丙 基 -4-溴 -3,5-二甲基苯酚 6b (480 mg,2.0 mmol)的 15 mL二氯甲垸溶液中， 加完后升温至 60°C下 反应 3小时。 反应结束后降至室温， 加入 15 mL饱和碳酸氢钠水溶液和 5 mL水， 用二氯甲垸 萃取 (20 mLx2),合并有机相，无水硫酸钠干燥，浓缩。残留物硅胶柱层析 (石油醚 /二氯甲垸 = 4/1) 得到淡黄色透明油状液体 13a(360 mg,产率 75%)。  Dissolve C32mg, 0.2 mmol) of trifluoromethanesulfonic acid in 5 mL of dichloromethane, and slowly add dropwise 2-allyl-4-bromo-3,5-dimethylphenol 6b (480 mg) , 2.0 mmol) of 15 mL of dichloromethane solution, after the addition, the temperature was raised to 60 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc (EtOAc m. The residue was subjected to silica gel column chromatography (ethyl ether / methylene chloride = 4/1) to give a pale yellow transparent oily liquid 13a (360 mg, yield 75%).
^ NMR (400 MHz, DMSO) δ 6.60 (s, 1Η), 5.02― 4.80 (m, 1H), 3.28 (dd, 1H), 2.73 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.36 (d, 3H).  ^ NMR (400 MHz, DMSO) δ 6.60 (s, 1 Η), 5.02 - 4.80 (m, 1H), 3.28 (dd, 1H), 2.73 (dd, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 1.36 (d, 3H).
第二步： 3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛 (13b) Second step: 3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (13b)
3-(2,4,6-trimethyl-2,3-dihydrobenzofur -5-yl)benzaldehyde
Figure imgf000079_0003
3-(2,4,6-trimethyl-2,3-dihydrobenzofur -5-yl)benzaldehyde
Figure imgf000079_0003
将甲苯（20 mL)及乙醇 （5 mL)加入 2,4,5,6-四甲基 -2,3-二氢苯并呋喃 13a (350 mg, 1.45 mmol)和 3-甲酰基苯硼酸 （253 mg, 1.60 mmol) 的碳酸钠溶液（14.5mL, 1M) 中。 用氮气置换 反应体系，将四 (三苯基膦；)钯（173 mg, 0.10 mmol)加入混合物中。保持氮气氛围，升温至 80°C 搅拌反应 15小时。反应结束，将混合物过滤， 滤液加水（10 mL)稀释，加入 50 mL乙酸乙酯， 用饱和食盐水（20 mL x 3)洗涤， 无水硫酸钠干燥有机相， 过滤， 将滤液减压浓缩。 残留物用 硅胶快速柱层析 (石油醚 /乙酸乙酯 = 20/1)， 得到黄色油状物粗品 13b。  Add toluene (20 mL) and ethanol (5 mL) to 2,4,5,6-tetramethyl-2,3-dihydrobenzofuran 13a (350 mg, 1.45 mmol) and 3-formylbenzeneboronic acid ( 253 mg, 1.60 mmol) in sodium carbonate solution (14.5 mL, 1 M). The reaction system was replaced with nitrogen, and tetrakis(triphenylphosphine;)palladium (173 mg, 0.10 mmol) was added to the mixture. The atmosphere was kept under nitrogen, and the temperature was raised to 80 ° C. The reaction was stirred for 15 hours. After the reaction was completed, the mixture was filtered. EtOAc EtOAc m. The residue was purified by flash chromatography eluting elut elut elut elut
第三步： （3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苯基甲醇 (13c) Third step: (3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)phenylmethanol (13c)
(3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000080_0001
(3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000080_0001
冰浴条件下， 将硼氢化钠 （275 mg, 7.25 mmol)加入 3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5- 基)苯甲醛 13b粗品在四氢呋喃 （12 mL)和甲醇（3 mL) 的混合溶剂中， 升温至室温搅拌反应 0.5小时。 向反应液中加水（10 mL) 淬灭反应， 加入饱和氯化铵水溶液 20 mL和乙酸乙酯 35 mL。 分层后， 水相用乙酸乙酯萃取 （30 mL x 2)， 合并有机相， 用无水硫酸钠干燥， 过滤， 将 滤液减压浓缩， 残留物用硅胶柱层析 (石油醚 /乙酸乙酯 = 10/1)得到淡黄色油状物 13c (315 mg, 两步产率 81%)。  Sodium borohydride (275 mg, 7.25 mmol) was added to the crude 3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde 13b in tetrahydrofuran under ice-bath In a mixed solvent of (12 mL) and methanol (3 mL), the mixture was warmed to room temperature and stirred for 0.5 hour. Water (10 mL) was added to the reaction mixture to quench the mixture, and then 20 mL of saturated aqueous ammonium chloride and ethyl acetate (35 mL). After stratification, the aqueous phase was extracted with ethyl acetate (30 mL EtOAc)EtOAc. Ester = 10/1) gave a pale yellow oil, 13c (315 mg, mp.
MS m/z(ESI):269.1 [M+l]  MS m/z (ESI): 269.1 [M+l]
第四步： （3S) 2-(6-((3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸甲酯 (化合物 13d) The fourth step: (3S) 2-(6-((3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-Dihydrobenzofuran-3-yl)methyl acetate (compound 13d)
(3S) methyl 2-(6-((3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobe nzo- furan-3-yl)acetate
Figure imgf000080_0002
(3S) methyl 2-(6-((3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- 2,3-dihydrobe nzo-furan-3-yl) Aclate
Figure imgf000080_0002
氮气氛围，将三丁基膦（0.3 mL, 1.23 mmol)和偶氮二甲酰二哌啶 （317 mg, 1.23 mmol)加入 (3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苯基甲醇 (13c)(150 mg, 0.56 mmol) 和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(129 mg, 0.62 mmol) 的干燥二氯甲垸（12 mL)溶液中。 将反应液在室温搅拌反应 1.5小时。 向反应液中加入少量正己垸， 过滤除去混合物中不溶物， 减压浓缩滤液。 所得产物直接进行下一步反应。  Tributylphosphine (0.3 mL, 1.23 mmol) and azodiyldipiperidine (317 mg, 1.23 mmol) were added to (3-(2,4,6-trimethyl-2,3-) under a nitrogen atmosphere. Dihydrobenzofuran-5-yl)phenylmethanol (13c) (150 mg, 0.56 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate Ester 3D (129 mg, 0.62 mmol) in dry methylene chloride (12 mL). The reaction mixture was stirred at room temperature for 1.5 hours. A small amount of n-hexane was added to the reaction mixture, and the mixture was filtered to remove insolubles. The filtrate was concentrated. The obtained product was directly subjected to the next reaction.
第五步： （3S) 2-(6-((3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸 (化合物 13) Step 5: (3S) 2-(6-((3-(2,4,6-Trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 13)
(3S) 2-(-6-((3-(2,4,64rimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n -3-yl)acetic acid
Figure imgf000080_0003
(3S) 2-(-6-((3-(2,4,64rimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n -3-yl)acetic acid
Figure imgf000080_0003
将氢氧化钠溶液 (1.4 mL, 2M)加入 (3S) 2-(6-((3-(2,4,6-三甲基 -2,3-二氢苯并呋喃 -5-基)苄基） 氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 13d(235 mg,0.51mmol)在甲醇 (3 mL)和四氢呋喃（ 6 mL) 混合溶剂中， 室温下搅拌反应 1.5小时。 反应结束， 加水（25 mL) 淬灭反应， 用 1M的盐酸水 溶液酸化至 PH为 1， 乙酸乙酯（25 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩。残留物用硅胶柱层析分离纯化 (二氯甲垸 /甲醇 = 60/1)，得到白色泡状固体化合 物 13(190 mg,产率 84%)。 Add sodium hydroxide solution (1.4 mL, 2M) to (3S) 2-(6-((3-(2,4,6-trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Methyl) 2,3-dihydrobenzofuran-3-yl)acetate 13d (235 mg, 0.51 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (6 mL) Reaction for 1.5 hours. After the reaction was completed, the reaction was quenched with EtOAc (EtOAc) (EtOAc) concentrate. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 60/1) to afford white solid. 13 (190 mg, yield 84%).
MS m/z(ESI):443.1 [M-l]  MS m/z (ESI): 443.1 [M-l]
¾ NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.11 (t, 2H), 7.04 (t, 1H): 6.47 (dd, 3H), 5.09 (s, 2H), 4.91 (dd, 1H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.74― 3.60 (m, 1H), 3.24 (dd, 1H), 2.71 (t, 1H), 2.68― 2.63 (m, 1H), 2.46 (dd, 1H), 1.83 (d, 6H), 1.39 (d, 3H). 3⁄4 NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 7.44 (t, 1H), 7.37 (d, 1H), 7.11 (t, 2H), 7.04 (t, 1H) : 6.47 (dd, 3H) , 5.09 (s, 2H), 4.91 (dd, 1H), 4.68 (t, 1H), 4.18 (dd, 1H), 3.74- 3.60 (m, 1H), 3.24 (dd, 1H), 2.71 (t, 1H ), 2.68― 2.63 (m, 1H), 2.46 (dd, 1H), 1.83 (d, 6H), 1.39 (d, 3H).
实施例 14 Example 14
(3S) 2-(6-((3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并 呋喃 -3-基)乙酸 (化合物 14)  (3S) 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 14)
(S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robe  (S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robe
Figure imgf000081_0001
Figure imgf000081_0001
第一步： 5-溴 -2,2-二 (乙氧基甲基 )-4,6-二甲基二氢苯并呋喃 -3(2H)-酮 (14a) First step: 5-bromo-2,2-di(ethoxymethyl)-4,6-dimethyldihydrobenzofuran-3(2H)-one (14a)
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000081_0002
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one
Figure imgf000081_0002
无水无氧氛围， 冰浴下， 将氢化钠 （700 mg, 17.5 mmol,氢化钠含量 w/w=60%)分批次加 入 5-溴 -2,2-二 (羟甲基)- 4,6-二甲基苯并呋喃 -3(2H)-酮 5a (2.11 g, 7.0 mmol) 的干燥 Ν,Ν-二甲基 甲酰胺 （50 mL) 中， 搅拌反应 20分钟， 再将碘乙垸（2.8 mL, 25.0 mmol)加入混合物中。 0°C 搅拌反应 0.5小时， 反应结束。 向反应液中加入水（50 mL)和饱和氯化铵溶液（25 mL)， 用乙 酸乙酯 （80 mL x 3)萃取， 合并有机相并用饱和食盐水（100 mL x 2)洗涤。 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 16/1), 得到油状 液体 14a (450 mg,产率 18%)。 Anhydrous anaerobic atmosphere, sodium hydride (700 mg, 17.5 mmol, sodium hydride content w/w = 60%) was added in batches to 5-bromo-2,2-bis(hydroxymethyl)-4 ,6-dimethylbenzofuran-3(2H)-one 5a (2.11 g, 7.0 mmol) in dry hydrazine, hydrazine-dimethylformamide (50 mL), stirred for 20 min, then iodine Rhodium (2.8 mL, 25.0 mmol) was added to the mixture. The reaction was stirred at 0 ° C for 0.5 hour, and the reaction was completed. Water (50 mL) and a saturated aqueous solution of ammonium chloride (25 mL) were added to the mixture, and the mixture was combined with ethyl acetate (80 mL), and the organic phase was combined and washed with brine (100 mL x 2). Dry over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 16/1) Liquid 14a (450 mg, yield 18%).
^ NMR (400 MHz, DMSO) δ 7.17 (s, 1H), 3.69 (s, 4H), 3.38 (q, 4H), 2.57 (s, 3H), 2.44 (s, 3H) 0.96 (t, 6H).  ^ NMR (400 MHz, DMSO) δ 7.17 (s, 1H), 3.69 (s, 4H), 3.38 (q, 4H), 2.57 (s, 3H), 2.44 (s, 3H) 0.96 (t, 6H).
第二步： 5-溴 -2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -3-醇 (14b) Step 2: 5-Bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol (14b)
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol
Figure imgf000082_0001
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-3-ol
Figure imgf000082_0001
冰浴下， 将硼氢化钠 （238 mg, 6.30 mmol)分批加入 5-溴 -2,2-二 (乙氧基甲基 )-4,6-二甲基 二氢苯并呋喃 -3(2H)-酮 14a (450 mg, 1.26 mmol) 的甲醇 （3 mL)和四氢呋喃 （6 mL) 混合溶 液中，升至室温反应 1.5小时。向反应体系中加水（5 mL) 淬灭反应，加入饱和氯化铵溶液（15 mL), 用乙酸乙酯（20 mL x 3)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将反应液减压浓 缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 15/1)， 得到无色透明状液体 14b (315 mg,产率 70%)。  Sodium borohydride (238 mg, 6.30 mmol) was added portionwise to 5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyldihydrobenzofuran-3 under ice bath. 2H)-ketone 14a (450 mg, 1.26 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (6 mL). The reaction was quenched with water (5 mL). EtOAc (EtOAc) (EtOAc) The liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
第三步： 5-溴 -2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 (14c) Step 3: 5-Bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran (14c)
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran
Figure imgf000082_0002
5-bromo-2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran
Figure imgf000082_0002
无水无氧氛围，冰浴下，将氢硅垸（7.7 mL, 48.2 mmol)加入 4,6-二甲基 -2,2-二乙氧基甲基 -3-羟基 -5-溴 -2,3-二氢苯并呋喃 14b (315 mg, 0.88 mmol) 的干燥二氯甲垸（10 mL) 中， 再缓慢 滴加三氟乙酸 （0.52 mL, 7.0 mmol), 搅拌反应 2.5小时。 向反应液中加入二氯甲垸（10 mL)和 饱和碳酸氢钠溶液（10 mL)， 搅拌 10分钟， 加入水（10 mL)，分液。水层用二氯甲垸（20 mL x 2)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离 纯化（石油醚 /乙酸乙酯 = 40/1)， 得到无色透明液体状的 14c (210 mg,产率 70%)。  Anhydrous anaerobic atmosphere was added to a solution of 4,6-dimethyl-2,2-diethoxymethyl-3-hydroxy-5-bromo-2 under ice bath with hydrazine hydride (7.7 mL, 48.2 mmol). To a solution of 3-dihydrobenzofuran 14b (315 mg, 0.88 mmol) in dry dichloromethane (10 mL), trifluoroacetic acid (0.52 mL, 7.0 mmol) was slowly added dropwise, and the reaction was stirred for 2.5 hours. To the reaction mixture were added dichloromethane (10 mL) and a saturated sodium hydrogen carbonate solution (10 mL), and stirred for 10 min, and water (10 mL) was added. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
第四步： 3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛 (14d) Fourth step: 3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (14d)
3-(2,2-bis(ethoxymethyl)-4,6-dimeth -2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000082_0003
3-(2,2-bis(ethoxymethyl)-4,6-dimeth-2,3-dihydrobenzofuran-5-yl)benzaldehyde
Figure imgf000082_0003
将 3-甲酰基苯硼酸 （106 mg, 0.67 mmol)和碳酸钠溶液（6.1 mL, 1M)加入 5-溴 -2,2-二 (乙 氧基甲基) -4,6-二甲基 -2,3-二氢苯并呋喃 14c (210 mg, 061 mmol) 的甲苯（15 mL)溶液中， 再 加入乙醇 （3 mL)。 氮气氛围下， 将四 (三苯基膦；)钯（70 mg, 0.1 mmol)加入反应体系中， 升温 至 80°C， 搅拌反应 18小时。 反应结束， 向反应液中加水（10 mL) 淬灭反应， 加乙酸乙酯 （50 mL)稀释。 用硅藻土过滤， 有机层用饱和食盐水（20 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 20/1)， 得到淡黄色油状 液体 14d (150 mg,产率 68%)。 Add 3-formylbenzeneboronic acid (106 mg, 0.67 mmol) and sodium carbonate solution (6.1 mL, 1 M) to 5-bromo-2,2-di(ethoxymethyl)-4,6-dimethyl- A solution of 2,3-dihydrobenzofuran 14c (210 mg, 061 mmol) in toluene (15 mL). Tetrakis(triphenylphosphine) palladium (70 mg, 0.1 mmol) was added to the reaction system under a nitrogen atmosphere, and the mixture was heated to 80 ° C, and the mixture was stirred for 18 hours. At the end of the reaction, water (10 mL) was added to the reaction mixture to quench the reaction. MmL) diluted. The organic layer was washed with brine (20 mL EtOAc). The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc
第五步： 3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 (14e) Step 5: 3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol (14e)
(3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000083_0001
(3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol
Figure imgf000083_0001
冰浴条件下， 将硼氢化钠 （78 mg, 2.05 mmol)分批加入 3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醛 14d (150 mg, 0.4 mmol) 的四氢呋喃 （4 mL)和甲醇 （2 mL) 混 合溶剂中。 室温搅拌反应 30分钟。 向反应液中加水（5 mL)稀释反应， 除去部分溶剂， 加入 饱和氯化铵溶液（15 mL)， 用乙酸乙酯 （20 mL x 3)萃取， 合并有机相并用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。残留物用硅胶柱层析分离纯化（石油醚 /乙酸乙酯 = 5/1)， 得到无色透 明油状液体 14e (140 mg,产率 93%)。  Sodium borohydride (78 mg, 2.05 mmol) was added portionwise to 3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzene under ice-bath And furan-5-yl)benzaldehyde 14d (150 mg, 0.4 mmol) in tetrahydrofuran (4 mL) and methanol (2 mL). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (5 mL). EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
MS m/z(ESI):371.3[M+l]  MS m/z (ESI): 371.3 [M+l]
第六步： （S) 2-(6-((3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二 氢苯并呋喃 -3-基；)乙酸甲酯 (14f) Step 6: (S) 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-) Methyl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (14f)
(S)-methyl 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) oxy)- 2,3-dihydrobenzofuran- -yl)acetate  (S)-methyl 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) oxy)- 2,3-dihydrobenzofuran - -yl)acetate
Figure imgf000083_0002
Figure imgf000083_0002
氮气氛围， 将三丁基膦（0.21 mL, 0.83 mmol)和偶氮二甲酰二哌啶 （214 mg, 0.83 mmol)加 入 3-(2,2-二 (乙氧基甲基 )-4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苯甲醇 14e (140 mg, 0.38 mmol) 和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(94 mg, 0.45 mmoL) 的干燥二氯甲垸（12 mL)溶液中。 将反应液在室温搅拌反应 2小时。 向反应液中加入少量正己垸， 过滤除去混合 物中不溶物， 减压浓缩滤液。 所得产物直接进行下一步反应。  Tributylphosphine (0.21 mL, 0.83 mmol) and azodiyldipiperidine (214 mg, 0.83 mmol) were added to 3-(2,2-bis(ethoxymethyl)-4 under nitrogen atmosphere. 6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 14e (140 mg, 0.38 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran Methyl 3-methyl)acetate 3D (94 mg, 0.45 mmoL) in dry dichloromethane (12 mL). The reaction solution was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting product was directly subjected to the next reaction.
第七步： （3S) 2-(6-((3-(2,2-二乙氧基甲基 -4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二 氢苯并呋喃 -3-基)乙酸 (化合物 14) Step 7: (3S) 2-(6-((3-(2,2-Diethoxymethyl-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 14)
(S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robenzofuran-3-yl)acetic acid
Figure imgf000084_0001
(S)-2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihyd robenzofuran -3-yl)acetic acid
Figure imgf000084_0001
将氢氧化钠溶液 (0.8 mL, 2M)加入 (S) 2-(6-((3-(2,2-二乙氧基甲基 -4,6-二甲基 -2,3-二氢苯并 呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 14f (180 mg, 0.32mmol)在甲醇 (3 mL) 和四氢呋喃（6 mL) 混合溶剂中， 室温下搅拌反应 1.5小时。 反应结束， 加水（20 mL) 淬灭反 应， 用 1M的盐酸水溶液酸化至 PH为 1， 乙酸乙酯 （25 mL x 3)萃取， 合并有机相， 无水硫 酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 1/1), 得到白色泡状固体化合物 14 (138 mg, 产率 79%)。  Add sodium hydroxide solution (0.8 mL, 2M) to (S) 2-(6-((3-(2,2-diethoxymethyl-4,6-dimethyl-2,3-dihydro) Methyl benzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 14f (180 mg, 0.32 mmol) in methanol (3 mL) and THF (6) In a mixed solvent, the reaction was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction was quenched with water (20 mL), EtOAc (EtOAc)EtOAc. concentrate. The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
MS m/z(ESI):545.3[M-l]  MS m/z (ESI): 545.3 [M-l]
¾ NMR (400 MHz, CDC13) δ 7.44― 7.32 (m, 2H), 7.16 (s, 1H), 7.06 (dd, 2H), 6.56 (s, 1H), 6.51― 6.43 (m, 2H), 5.05 (s, 2H), 4.75 (t, 1H), 4.28 (dd, 1H), 3.80 (ddd, 1H), 3.69 (d, 2H), 3.66― 3.48 (m, 6H), 2.99 (s, 2H), 2.80 (dd, 1H), 2.61 (dd, 1H), 1.94 (s, 3H), 1.87 (s, 3H), 1.21 (t, 6H). 实施例 15 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.44 - 7.32 (m, 2H), 7.16 (s, 1H), 7.06 (dd, 2H), 6.56 (s, 1H), 6.51 - 6.43 (m, 2H), 5.05 (s, 2H), 4.75 (t, 1H), 4.28 (dd, 1H), 3.80 (ddd, 1H), 3.69 (d, 2H), 3.66- 3.48 (m, 6H), 2.99 (s, 2H), 2.80 (dd, 1H), 2.61 (dd, 1H), 1.94 (s, 3H), 1.87 (s, 3H), 1.21 (t, 6H). Example 15
(S)2-(6-((3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 酸 （化合物 15)  (S) 2-(6-((3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 15)
(S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz o  (S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz o
Figure imgf000084_0002
Figure imgf000084_0002
第一步： 叔丁基 (3-(4,6-二甲基 -3Η-螺 [苯并呋喃 -2,1'-环丙基 ]-5-基)苯基)氧基)二甲基硅醚（15a) tert-bu1yl((3-(4,6-dimethyl-3H-spiro -5-yl)benzyl)oxy)dimethylsilane
Figure imgf000084_0003
First step: tert-butyl (3-(4,6-dimethyl-3-indole-spiro[benzofuran-2,1'-cyclopropyl]-5-yl)phenyl)oxy) dimethyl Silyl ether (15a) tert-bu1yl((3-(4,6-dimethyl-3H-spiro -5-yl)benzyl)oxy)dimethylsilane
Figure imgf000084_0003
无水无氧氛围， 冰水浴下， 将三氯化铝 (420 mg,3.15 mmol)加入到 20 mL干燥四氢呋喃中， 往其中加入四氢铝锂 (114 mg, 3.0 mmol),搅拌 15分钟。将 4,6-二甲基 -5-(3-(((；叔丁基二甲基硅基) 氧基)甲基)苯基） -2-氢 -2,1'-环丙基苯并呋喃 -3-酮 10b (625 mg, 1.53 mmol)配制成干燥的四氢 呋喃 （10 mL)溶液， 滴加到反应液中， 然后升温至室温下反应 1小时。 反应结束后， 冰水浴 冷却， 缓慢滴加 0.5 N氢氧化钠水溶液 15 mL， 搅拌 10分钟， 加入水 15 mL。 用乙酸乙酯萃取 (30 mLx3), 合并有机相， 用饱和食盐水洗 (30 mLx3;»。 有机相有无水硫酸钠干燥， 浓缩。 残留 物硅胶柱层析 (石油醚 /二氯甲垸 = 7/1)得到无色透明油状液体 15a(450 mg,产率 76%)。 Anhydrous anaerobic atmosphere, aluminum trichloride (420 mg, 3.15 mmol) was added to 20 mL of dry tetrahydrofuran under ice-water bath. Lithium aluminum hydride (114 mg, 3.0 mmol) was added thereto and stirred for 15 minutes. 4,6-Dimethyl-5-(3-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-2-hydro-2,1'-cyclopropylbenzene A solution of furan-3-one 10b (625 mg, 1.53 mmol) in dry tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, which was then warmed to room temperature for 1 hour. After completion of the reaction, the ice water bath was cooled, and 15 mL of a 0.5 N aqueous sodium hydroxide solution was slowly added dropwise, stirred for 10 minutes, and 15 mL of water was added. It was extracted with ethyl acetate (30 mL×3), EtOAc (EtOAc m. 7/1) A colorless transparent oily liquid 15a (450 mg, yield 76%) was obtained.
^ NMR (400 MHz, DMSO) δ 7.40 (t, 1H), 7.27 (d, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.52 (s, 1H) 4.75 (s, 2H), 3.23 (s, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.08 (q, 2H), 0.88 (s, 9H), 0.77 (q, 2H), 0.06 (s, 6H).  ^ NMR (400 MHz, DMSO) δ 7.40 (t, 1H), 7.27 (d, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.52 (s, 1H) 4.75 (s, 2H), 3.23 (s, 2H), 1.89 (s, 3H), 1.84 (s, 3H), 1.08 (q, 2H), 0.88 (s, 9H), 0.77 (q, 2H), 0.06 (s, 6H).
第二步： （3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]-5-基)苯甲醇（15b) Step 2: (3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]-5-yl)benzyl alcohol (15b)
(3-(4,6-dimethyl-3H-spiro[benzofuran- -cyclopropan]-5-yl)phenyl)methanol
Figure imgf000085_0001
(3-(4,6-dimethyl-3H-spiro[benzofuran- -cyclopropan]-5-yl)phenyl)methanol
Figure imgf000085_0001
单口瓶中加入叔丁基 (3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,1'-环丙基 ]-5-基;)苯基)氧基)二甲基 硅醚 15a (500 mg,1.3mmol)、 四氢呋喃溶剂 12 mL和四丁基氟化铵 (994 mg, 3.8 mmol), 室温下 搅拌 30分钟。加入水 20 mL搅拌 10分钟淬灭反应， 用乙酸乙酯萃取 (20 mLx4), 合并有机层， 无水硫酸钠干燥，浓缩。硅胶柱层析 (石油醚 /乙酸乙酯 = 4/1)得到淡黄色油状液体 15b(353 mg， 产率 99%)。  Add tert-butyl (3-(4,6-dimethyl-3H-spiro[benzofuran-2,1'-cyclopropyl]-5-yl))phenyl)oxy) dimethyl to a one-neck bottle The silyl ether 15a (500 mg, 1.3 mmol), tetrahydrofuran solvent 12 mL and tetrabutylammonium fluoride (994 mg, 3.8 mmol) were stirred at room temperature for 30 min. After adding 20 mL of water and stirring for 10 minutes, the mixture was evaporated. Silica gel column chromatography (petroleum ether / ethyl acetate = 4/1) afforded pale yellow oily liquid 15b (353 mg, yield 99%).
¾ NMR (400 MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 6.51 (s, 1H), 5.17 (t, 1H), 4.54 (d, 2H), 3.22 (s, 2H), 1.90 (s, 3H), 1.84 (s, 3H), 1.08 (t, 2H), 0.80 - 0.74 (m, 2H). 第三步： （S) 2-(6-((3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]-5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸甲酯（15c)  3⁄4 NMR (400 MHz, DMSO) δ 7.38 (t, 1H), 7.28 (d, 1H), 7.04 (s, 1H), 6.96 (d, 1H), 6.51 (s, 1H), 5.17 (t, 1H) , 4.54 (d, 2H), 3.22 (s, 2H), 1.90 (s, 3H), 1.84 (s, 3H), 1.08 (t, 2H), 0.80 - 0.74 (m, 2H). Step 3: ( S) 2-(6-((3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]-5-yl)benzyl)oxy)-2, Methyl 3-dihydrobenzofuran-3-yl)acetate (15c)
(S)-methyl 2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)- 2,3- dihydrobenzofuran-3 -yl)acetate  (S)-methyl 2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-5-yl)benzyl)oxy)- 2,3-dihydrobenzofuran- 3 -yl)acetate
Figure imgf000085_0002
Figure imgf000085_0002
氮气氛围， 将三丁基膦（0.34 mL, 1.34 mmol)和偶氮二甲酰二哌啶 （338 mg, 1.34 mmol)加 入 (3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]-5-基)苯甲醇 15b (170 mg, 0.61 mmol)和 (S) 2-(6- 羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(139 mg, 0.67 mmoL) 的干燥二氯甲垸（12 mL)溶液 中。将反应液在室温搅拌反应 2小时。向反应液中加入少量正己垸，过滤除去混合物中不溶物， 减压浓缩滤液。 残留物用硅胶快速柱层析 （石油醚 /乙酸乙酯 = 9/1) , 得无色透明油状液体 15c(230 mg, 80%)。 第四步： （S) 2-(6-((3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙基 ]-5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸 （化合物 15) In a nitrogen atmosphere, tributylphosphine (0.34 mL, 1.34 mmol) and azodiyldipiperidine (338 mg, 1.34 mmol) were added (3-(4,6-dimethyl-3H-spiro[benzo Furan-2, fluorenyl-cyclopropyl]-5-yl)benzyl alcohol 15b (170 mg, 0.61 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl) Methyl acetate 3D (139 mg, 0.67 mmoL) in dry methylene chloride (12 mL). The reaction mixture was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the mixture was filtered to remove insolubles. The filtrate was concentrated under reduced pressure. EtOAc EtOAc m. Step 4: (S) 2-(6-((3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 15)
(S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3-yl)acetic acid  (S)-2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2, -cyclopropan]-5-yl)benzyl)oxy)-2,3-dihydrobenz ofuran-3- Yl)acetic acid
Figure imgf000086_0001
Figure imgf000086_0001
将氢氧化钠溶液 (1.2 mL, 2M)加入 (S) 2-(6-((3-(4,6-二甲基 -3H-螺 [苯并呋喃 -2,1'-环丙基 ]-5- 基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 15c (230 mg,0.49 mmol)在甲醇 (3 mL)和四氢 呋喃（6 mL) 混合溶剂中， 室温下搅拌反应 1.0小时。 反应结束， 加水（20 mL)稀释反应， 用 1M的盐酸水溶液酸化至 PH为 3， 乙酸乙酯 （20 mL x 3)萃取， 合并有机相， 无水硫酸钠干 燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 2/1)， 得到白 色泡状固体化合物 15(200 mg, 产率 90%)。  Add sodium hydroxide solution (1.2 mL, 2M) to (S) 2-(6-((3-(4,6-dimethyl-3H-spiro[benzofuran-2,1'-cyclopropyl]] Methyl 5-amino)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 15c (230 mg, 0.49 mmol) eluted in methanol (3 mL) and THF (6 mL) The solvent was stirred at room temperature for 1.0 hour in a solvent. After the reaction was completed, the mixture was diluted with water (20 mL), evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. . The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
MS m/z(ESI):455.2[M-l]  MS m/z (ESI): 455.2 [M-l]
^ NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 7.44 (t, 1H), 7.38 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 2H), 6.52 (s, 1H), 6.50― 6.44 (m, 2H), 5.10 (s, 2H), 4.67 (t, 1H), 4.18 (dd, 1H), 3.71― 3.63 (m, 1H), 3.22 (s, 2H), 2.68 (dd, 1H), 2.46 (d, 1H), 1.88 (s, 3H), 1.82 (s, 3H), 1.08 (t, 2H), 0.77 (t, 2H).  ^ NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 7.44 (t, 1H), 7.38 (d, 1H), 7.13 (s, 1H), 7.07 (dd, 2H), 6.52 (s, 1H) , 6.50― 6.44 (m, 2H), 5.10 (s, 2H), 4.67 (t, 1H), 4.18 (dd, 1H), 3.71- 3.63 (m, 1H), 3.22 (s, 2H), 2.68 (dd , 1H), 2.46 (d, 1H), 1.88 (s, 3H), 1.82 (s, 3H), 1.08 (t, 2H), 0.77 (t, 2H).
实施例 16 Example 16
(S) 2-(6-((3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 (化合物 16)  (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3- Dihydrobenzofuran-3-yl)acetic acid (Compound 16)
(S)-2-(6-((3-(3,3,4,64etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3- yl)acetic acid (S)-2-(6-((3-(3,3,4,64etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000086_0002
Figure imgf000086_0002
16e 化合物 16 2-溴- 1 ,3-二甲基 -5-((2-甲基烯丙基)氧基苯 ( 16b) 16e compound 16 2-bromo-1,3-dimethyl-5-((2-methylallyl)oxybenzene (16b)
2-bromo- 1 ,3-dimethyl-5-((2-methylallyl)oxy)benzene
Figure imgf000087_0001
2-bromo-1,3-dimethyl-5-((2-methylallyl)oxy)benzene
Figure imgf000087_0001
室温下， 将 4-溴 -3,5-二甲基苯酚 16a(8.04 g, 40 mmol), 2-甲基 -3-氯 -丙烯 (3.62 g, 40 mmol) 和无水碳酸钾 (1 1.06 g, 80 mmol)加入到乙腈 (80 mL)中， 升温至 95°C回流反应 15 小时， TLC 显示反应完全。 向反应体系中加入乙酸乙酯 (200 mL)、 水 (200 mL)， 搅拌 10分钟， 分液， 有机 相用无水硫酸钠 (10 g)干燥， 浓缩， 硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 30/1)得到棕色液 体 16b (8.0 g， 产率 80%)。  4-Bromo-3,5-dimethylphenol 16a (8.04 g, 40 mmol), 2-methyl-3-chloro-propene (3.62 g, 40 mmol) and anhydrous potassium carbonate (1 1.06) g, 80 mmol) was added to acetonitrile (80 mL), and the mixture was warmed to reflux at 95 ° C for 15 hours, and TLC showed the reaction was completed. Ethyl acetate (200 mL) and water (200 mL) were added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic phase was dried over anhydrous sodium sulfate (10 g), concentrated, and purified by silica gel column chromatography /ethyl acetate = 30/1) gave a brown liquid 16b (8.0 g, yield 80%).
第二步： 5-溴 -3,3,4,6-四甲基 -2,3-二氢苯并呋喃 (16c) Second step: 5-bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran (16c)
5-bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran
Figure imgf000087_0002
5-bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran
Figure imgf000087_0002
室温下， 将 2-溴 -1 ,3-二甲基 -5-((2-甲基烯丙基)氧基苯 16b (18.0 g, 31 mmol)加入到二氯甲 垸 (lOO mL)中， 降温至 0°C， 加入无水三氯化铝 (208 mg, 1.57 mmol), 升至室温反应， 30分钟 后反应完全。 向反应体系中加入水 (10 mL), 搅拌 5分钟， 分液， 有机相浓缩， 硅胶柱层析分 离纯化 (石油醚 /乙酸乙酯 = 30/1)， 得棕色液体 16c (3.2 g， 收率 40%)。  2-Bromo-1,3-dimethyl-5-((2-methylallyl)oxybenzene 16b (18.0 g, 31 mmol) was added to dichloromethane (100 mL) at room temperature The temperature was lowered to 0 ° C, anhydrous aluminum trichloride (208 mg, 1.57 mmol) was added, and the reaction was allowed to rise to room temperature, and the reaction was completed after 30 minutes. Water (10 mL) was added to the reaction system, and the mixture was stirred for 5 minutes. The organic phase was concentrated and purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 30/1) to afford brown liquid 16c (3.2 g, yield 40%).
第三步： （3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)甲醇 (16d) Step 3: (3-(3,3,4,6-Tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)methanol (16d)
(3-(3,3,4,6-tetramethyl-2,3-dihydrobenzo methanol
Figure imgf000087_0003
(3-(3,3,4,6-tetramethyl-2,3-dihydrobenzo methanol
Figure imgf000087_0003
室温下， 将 5-溴 -3,3,4,6-四甲基 -2,3-二氢苯并呋喃 16c (2.55 g, 10 mmol)、 3-羟甲基苯硼酸 (1.52 g, 10 mmol), 四三苯基膦钯 (578 mg, 0.5 mmol)和无水碳酸钠 (3.18 g, 30 mmol)加入到甲苯 (50 mL)中， 升温至 100°C反应， 22 小时后反应完全。 向反应体系中加入乙酸乙酯 (100 mL)和 水 (lOO mL), 分液， 有机相用水洗 (50 mL x 3)， 无水硫酸钠 (10 g)干燥， 浓缩， 硅胶柱层析分离 纯化 (石油醚 /乙酸乙酯 = 5/1)， 得白色固体 16d (565 mg， 产率 20%)。  5-Bromo-3,3,4,6-tetramethyl-2,3-dihydrobenzofuran 16c (2.55 g, 10 mmol), 3-hydroxymethylphenylboronic acid (1.52 g, 10 at room temperature) Methyl), tetrakistriphenylphosphine palladium (578 mg, 0.5 mmol) and anhydrous sodium carbonate (3.18 g, 30 mmol) were added to toluene (50 mL), warmed to 100 ° C, and the reaction was completed after 22 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction mixture, and the organic phase was washed with water (50 mL×3), dried over anhydrous sodium sulfate (10 g), and concentrated. Purification (petroleum ether / ethyl acetate = 5/1) gave white solid 16d (565 mg, yield 20%).
¾ NMR (400 MHz, CDC13) δ 7.39 (t, 1H), 7.33 (d, 1H), 7.12 (s, 1H), 7.08 (d, 1H), 6.51 (s, 1H), 4.71 (s, 2H), 2.94 (s, 2H), 1.97 (s, 3H), 1.87 (s, 3H), 1.50 (s, 6H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.39 (t, 1H), 7.33 (d, 1H), 7.12 (s, 1H), 7.08 (d, 1H), 6.51 (s, 1H), 4.71 (s, 2H ), 2.94 (s, 2H), 1.97 (s, 3H), 1.87 (s, 3H), 1.50 (s, 6H).
第四步： (S) 2-(6-((3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸甲酯 （16e) Fourth step: (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) - 2,3-dihydrobenzofuran-3-yl)methyl acetate (16e)
(S)-methyl 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3-yl)acetate
Figure imgf000088_0001
(S)-methyl 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro benzofuran-3-yl Acetate
Figure imgf000088_0001
室温下， 将 (3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)甲醇 16d (565 mg, 2 mmol)、 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3C(416 mg, 2 mmol)和偶氮二甲酰二哌啶 (1.05 g, 4 mmol)加入到二氯甲垸 (30 mL)中， 滴入三丁基膦 (809 mg, 4 mmol)。 滴完后， 2 小时反应完全。 将反应体系浓缩至干，硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 = 1/1)。得白色固体 16e (472 mg, 产率 50%)。  (3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)methanol 16d (565 mg, 2 mmol), (S) Methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 3C (416 mg, 2 mmol) and azodiyldipiperidine (1.05 g, 4 mmol) Tributylphosphine (809 mg, 4 mmol) was added dropwise to dichloromethane (30 mL). After the completion of the dropwise addition, the reaction was completed in 2 hours. The reaction system was concentrated to dryness and purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 1/1). A white solid 16e (472 mg, yield 50%) was obtained.
第五步： (S) 2-(6-((3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基) 乙酸 （化合物 16) Step 5: (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) - 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 16)
(S)-2-(6-((3-(3,3,4,64etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3- yl)acetic acid
Figure imgf000088_0002
(S)-2-(6-((3-(3,3,4,64etramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000088_0002
室温下， 将 (S) 2-(6-((3-(3,3,4,6-四甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸甲酯 16e (472 mg, 1 mmol)混悬于甲醇 (10 mL)中，加入氢氧化钠 (800 mg, 20 mmol) 的水 (l mL)溶液， 室温反应 15小时。将反应液浓缩至 2mL， 加入水 (10 mL)， 用盐酸调 PH<4， 用乙酸乙酯萃取 (10 mLx 3)， 合并有机相， 用水洗 (10 mL)， 无水硫酸钠 (1 g)干燥， 浓缩， 硅胶 柱层析分离纯化 (石油醚 /乙酸乙酯 = 1/2)。得白色固体化合物 16 (220 mg,产率 48%， HPLC纯 度 97.96%)。  (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)- Methyl 2,3-dihydrobenzofuran-3-yl)acetate 16e (472 mg, 1 mmol) was suspended in methanol (10 mL), then sodium hydroxide (800 mg, 20 mmol) The solution was stirred at room temperature for 15 hours. The reaction solution was concentrated to 2 mL, water (10 mL) was added, EtOAc (EtOAc) (EtOAc) Dry, concentrated, and purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 1/2). White solid compound 16 (220 mg, yield 48%, HPLC purity 97.96%).
MS m/z(ESI):459.3[M+l]  MS m/z (ESI): 459.3 [M+l]
¾ NMR (400 MHz, CDC13) δ 7.37 (m, 2H), 7.18 (s, IH), 7.06(m, 2H), 6.50(m, 3H), 5.06(s, 2H), 4.76 (t, IH), 4.28 (dd, IH), 3.80 (m, IH), 2.94 (s, 2H), 2.83 (dd, IH), 2.63 (dd, IH), 1.96 (s, 3H): 1.86 (s, 3H), 1.50 (s, 6H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.37 (m, 2H), 7.18 (s, IH), 7.06 (m, 2H), 6.50 (m, 3H), 5.06 (s, 2H), 4.76 (t, IH ), 4.28 (dd, IH), 3.80 (m, IH), 2.94 (s, 2H), 2.83 (dd, IH), 2.63 (dd, IH), 1.96 (s, 3H) : 1.86 (s, 3H) , 1.50 (s, 6H).
实施例 17 Example 17
(S) 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙酸 （化合 物 17)  (S) 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzo Furan-3-yl)acetic acid (compound 17)
(S)-2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acet ic acid
Figure imgf000088_0003
Figure imgf000089_0001
(S)-2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000088_0003
Figure imgf000089_0001
一步： （S) 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 甲酯 （17a)  One step: (S) 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl)methyl ester (17a)
(S)-methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzo furan-3-yl)acetate
Figure imgf000089_0002
(S)-methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate
Figure imgf000089_0002
氮气氛围， 在 O'C下， 将 (3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基；)苯基)甲醇 4e(180 mg， 0.71 mmol)和 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D(162 mg, 0.78 mmol)溶于干燥的二氯 甲垸（10 mL)中， 将三丁基膦（315 mg, 1.56 mmol), Ι,Γ- (偶氮二羰基)二哌啶 （393 mg, 1.56 mmol)加入混合物中， 升至室温反应 2小时。 将反应液过滤除去不溶物， 将滤液减压浓缩， 残 留物用硅胶柱层析法分析纯化（石油醚 /乙酸乙酯 = 7/1)，得到淡黄色油状物 17a (231 mg,产率 73%)  Under a nitrogen atmosphere, (3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl;)phenyl)methanol 4e (180 mg, 0.71 mmol) and (S) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 3D (162 mg, 0.78 mmol) dissolved in dry methylene chloride (10 mL) Tributylphosphine (315 mg, 1.56 mmol), hydrazine, hydrazine-(azodicarbonyl)dipiperidine (393 mg, 1.56 mmol) was added to the mixture and allowed to react to room temperature for 2 hours. The reaction mixture was filtered to remove the residue, and the filtrate was evaporated. mjjjjjjjjjjj %)
第二步： （S) 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基)苄基)氧基) -2,3-二氢苯并呋喃 -3-基)乙 酸 （化合物 17) Second step: (S) 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3- Dihydrobenzofuran-3-yl)acetic acid (Compound 17)
(S)-2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acet ic acid (S)-2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000089_0003
Figure imgf000089_0003
将氢氧化钠水溶液（5 mL, 2M)加入 (S) 2-(6-((3-(4,6-二甲基 -2,3-二氢苯并呋喃 -5-基；)苄基；) 氧基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 17a (231 mg, 0.52 mmol) 的四氢呋喃 （5 mL)溶液中， 室温搅拌反应过夜。 用稀盐酸调节反应液的 pH≤2， 用乙酸乙酯（10 mL x 3)萃取， 合并有机 相， 饱和食盐水（50 mL x l)洗涤， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅 胶柱层析法分离纯化（石油醚 /乙酸乙酯 = 1.5/1)，得到白色固体化合物 17 (175 mg,产率 78%)。  Add sodium hydroxide aqueous solution (5 mL, 2M) to (S) 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)) benzyl ;) A solution of methyl oxy)- 2,3-dihydrobenzofuran-3-yl)acetate 17a (231 mg, 0.52 mmol) in THF (5 mL). The pH of the reaction mixture was adjusted to ≤2 with dilute hydrochloric acid, and extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated brine (50 mL×l), dried over anhydrous sodium sulfate concentrate. The residue was purified by silica gel column chromatography (EtOAc (EtOAc)
MS m/z(ESI):[M-l]": 429.3. ^ NMR (400 MHz, CDC13) δ 12.22 (s, IH), 7.35 (t, IH), 7.29 (d, IH), 7.06― 6.98 (m, 2H), 6.95 (d, IH), 6.44 (s, IH), 6.41― 6.34 (m, 2H), 5.01 (s, 2H), 4.59 (t, IH), 4.44 (t, 2H), 4.10 (dd, IH), 3.59 (td, IH), 3.00 (t, 2H), 2.60 (dd, IH), 2.37 (d, IH), 1.79 (s, 3H), 1.74 (s, 3H). MS m/z (ESI): [Ml]": 429.3. ^ NMR (400 MHz, CDC1 3 ) δ 12.22 (s, IH), 7.35 (t, IH), 7.29 (d, IH), 7.06 - 6.98 (m, 2H), 6.95 (d, IH), 6.44 (s , IH), 6.41― 6.34 (m, 2H), 5.01 (s, 2H), 4.59 (t, IH), 4.44 (t, 2H), 4.10 (dd, IH), 3.59 (td, IH), 3.00 ( t, 2H), 2.60 (dd, IH), 2.37 (d, IH), 1.79 (s, 3H), 1.74 (s, 3H).
实施例 18 Example 18
2-[(3S)-6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基;)苯基]甲氧基 ]-2,3-二氢苯 并呋喃 -3-基]乙酸（化合物 18)  2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropanthene]-5-yl) ;)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 18)
2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y] - -dihydrobenzofuran-3-yl] acetic acid  2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y] - -dihydrobenzofuran-3-yl] acetic acid
Figure imgf000090_0001
Figure imgf000090_0001
第一步： 4-溴 -2-氟 -3,5-二甲基苯酚（18b) First step: 4-bromo-2-fluoro-3,5-dimethylphenol (18b)
4-bromo-2-fluoro-3,5-dimethylphenol
Figure imgf000090_0002
4-bromo-2-fluoro-3,5-dimethylphenol
Figure imgf000090_0002
将 4-溴 -3,5-二甲基苯酚 2A (5.0 g,24.8 mmol) 和三氟甲磺酸 N-吡啶鑰 (15.3 g, 62.0 mmol)加 入到 1 ,2-二氯乙垸（50 mL) 中， 氮气氛围下回流反应 24小时。 反应结束后加入饱和硫代硫酸 钠水溶液（50 mL)， 搅拌 5分钟。 用二氯甲垸萃取水层 （50 mi x 2)， 合并有机相， 无水硫酸钠 干燥， 过滤， 将滤液减压浓缩， 残留物硅胶柱层析分离纯化（石油醚 /二氯甲垸（v/v) =l/l)， 得 到黄色固体状的 4-溴 -2-氟 -3,5-二甲基苯酚 18b (2.1 g, 产率 38.7%)。 第二步： 4-溴 -2-氟 -3,5-二甲基苯酚乙酸酯 （18c) 4-Bromo-3,5-dimethylphenol 2A (5.0 g, 24.8 mmol) and N-pyridyl trifluoromethanesulfonate (15.3 g, 62.0 mmol) were added to 1,2-dichloroethane (50) In mL), the reaction was refluxed for 24 hours under a nitrogen atmosphere. After completion of the reaction, a saturated aqueous solution of sodium thiosulfate (50 mL) was added and stirred for 5 min. The aqueous layer was extracted with methylene chloride (50 mi x 2), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. v/v) = l/l) gave 4-bromo-2-fluoro-3,5-dimethylphenol 18b (2.1 g, yield 38.7%) as a yellow solid. Second step: 4-bromo-2-fluoro-3,5-dimethylphenol acetate (18c)
4-bromo-2-fluoro-3,5-dimethylphenyl ac
Figure imgf000091_0001
4-bromo-2-fluoro-3,5-dimethylphenyl ac
Figure imgf000091_0001
向反应瓶中依次加入 4-溴 -2-氟 -3,5-二甲基苯酚 (2.0 g, 9.1 mmol)、 乙酸酐 (1.4 g, 1.37 mmol)、 三乙胺 (1.39 g,1.37 mmol)和二氯甲垸（30 mL) 中， 室温搅拌 2小时。 反应结束后加 入水（50 mL)， 用二氯甲垸萃取水层 （30 mL x 2)， 合并有机相， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩，残留物硅胶柱层析分离纯化（石油醚 /二氯甲垸（v/v) =10/l)得到淡黄色油状的 4-溴 -2-氟 -3,5-二甲基苯酚乙酸酯 18c (2.4 g， 产率 100%)。  To the reaction flask were added 4-bromo-2-fluoro-3,5-dimethylphenol (2.0 g, 9.1 mmol), acetic anhydride (1.4 g, 1.37 mmol), triethylamine (1.39 g, 1.37 mmol). It was stirred at room temperature for 2 hours with dichloromethane (30 mL). After the reaction, water (50 mL) was added, and the aqueous layer was extracted with dichloromethane (30 mL EtOAc). Purification (petroleum ether/dichloromethane (v/v) = 10/l) afforded 4-bromo-2-fluoro-3,5-dimethylphenol acetate 18c (2.4 g, yield 100%).
第三步： 1-(3-溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮（18d) Step: 1- (3-bromo-5-fluoro - 6 - hydroxy - 2, 4 - dimethylphenyl) ethanone (18 d)
l-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone L-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone
Figure imgf000091_0002
Figure imgf000091_0002
向反应瓶中依次加入 4-溴 -2-氟 -3,5-二甲基苯酚乙酸酯 （2.35 g, 9.0 mmol), 三氯化铝 (3.6 g, 27.0 mmol)和 1,2二氯乙垸（25 mL)， 回流反应 2小时。 反应结束后， 冷却至室温， 将反应液 倒入冰水（200 mL) 中， 用 6N盐酸酸化 pH为 3， 用二氯甲垸萃取水层（200 mL >< 3)。 合并有 机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯化（石油醚 /二氯 甲垸（v/v) =1/1)得到黄色固体状的 1-(3-溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮 18d (0.91 g,产率 38%)  To the reaction flask were added 4-bromo-2-fluoro-3,5-dimethylphenol acetate (2.35 g, 9.0 mmol), aluminum trichloride (3.6 g, 27.0 mmol) and 1,2 dichlorochloride. Acetate (25 mL) was refluxed for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water (200 mL), acidified to pH 3 with 6N hydrochloric acid, and the aqueous layer was extracted with dichloromethane (200 mL > < 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 1-(3-Bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone 18d (0.91 g, yield 38%)
¾ NMR (400 MHz, DMSO) δ 10.23 (t, 1Η), 2.45 (s, 3H), 2.29 (d, 3H), 2.14 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 10.23 (t, 1 Η), 2.45 (s, 3H), 2.29 (d, 3H), 2.14 (s, 3H).
第四步： 2-溴 -l-(3-溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮 （18e) Step 4: 2-Bromo-l-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone (18e)
2-bromo-l-(3-bromo-5-fluoro-6-hydroxy-2, -dimethylphenyl)ethanone  2-bromo-l-(3-bromo-5-fluoro-6-hydroxy-2, -dimethylphenyl)ethanone
Figure imgf000091_0003
Figure imgf000091_0003
向反应瓶中依次加入 1-(3-溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮 18d (900 mg, 3.45 mmol), 溴化铜 (1.15 g,5.17 mmol), 氯仿 (15 mL)和乙酸乙酯 (10 mL), 回流反应 18小时。 反应结束 后， 冷却至室温， 过滤， 用水洗涤 （15 mL 1), 收集滤液， 无水硫酸钠干燥， 将滤液减压浓 缩。残留物硅胶柱层析分离纯化（石油醚 /二氯甲垸（v/v) =l/l)得到棕红色固体状的 2-溴 -1-(3- 溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮 18e粗品 （1.17 g)， 直接投入下步反应。 第五步： 5-溴 -7-氟 -4,6-二甲基-苯并呋喃 -3-酮 （18f) To the reaction flask was added 1-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone 18d (900 mg, 3.45 mmol), copper bromide (1.15 g, 5.17). Methyl acetate (15 mL) and ethyl acetate (10 mL). After completion of the reaction, the mixture was cooled to room temperature, filtered, washed with water (15 mL 1). Separation and purification of the residue by silica gel column chromatography ( petroleum ether / methylene chloride (v/v) = l / l) to give 2-bromo-1-(3-bromo-5-fluoro-6-hydroxyl as a brown solid The crude product of -2,4-dimethylphenyl)ethanone 18e (1.17 g) was directly charged to the next step. Step 5: 5-Bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one (18f)
5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one  5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one
Figure imgf000092_0001
Figure imgf000092_0001
向反应瓶中依次加入 2-溴 -1-(3-溴 -5-氟 -6-羟基 -2,4-二甲基苯基)乙酮 18e粗品 （1.17 g, 3.45 mmol),醋酸钠 （848 mg, 10.34 mmol)和甲醇 （15 mL)，室温搅拌 3天。反应结束后，加入水（15 mL), 用乙酸乙酯萃取 （15 mL x 3)， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯化（石油醚 /二氯甲垸（v/v) =2/l)得到黄色固体状的 5-溴 -7-氟 -4,6- 二甲基-苯并呋喃 -3-酮 18f (530 mg, 第四步和第五步总产率 59%)。  To the reaction flask were successively added 2-bromo-1-(3-bromo-5-fluoro-6-hydroxy-2,4-dimethylphenyl)ethanone 18e crude (1.17 g, 3.45 mmol), sodium acetate ( 848 mg, 10.34 mmol) and methanol (15 mL) were stirred at room temperature for 3 days. After the reaction was completed, water (15 mL), EtOAc (EtOAc)EtOAc. (petroleum ether/dichloromethane (v/v) = 2/l) afforded 5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one 18f (530 mg as a yellow solid) , the fourth and fifth steps total yield 59%).
第六步： 5-溴 -7-氟 -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 （18g) Step 6: 5-Bromo-7-fluoro-4,6-dimethyl-spiro [benzofuran-2,1'-cyclopropanthone]-3-one (18g)
5-bromo-7-fluoro-4,6-dimethyl-spiro[b ropane]-3-one  5-bromo-7-fluoro-4,6-dimethyl-spiro[b ropane]-3-one
Figure imgf000092_0002
Figure imgf000092_0002
无水无氧氮气保护下， 向反应瓶中依次加入 5-溴 -7-氟 -4,6-二甲基-苯并呋喃 -3-酮 18f (530 mg, 2.0 mmol)和无水四氢呋喃 (15 mL), -30°C， 加入氢化钠 (410 mg, 10.2 mmol), 搅拌 20 分钟。 升至室温搅拌 20分钟， 再升温至 35°C， 缓慢滴加 1,2,-二溴乙垸（0.53 ml， 6.1 mmol), 加完后， 搅拌 10分钟。 升温至 45°C下反应 30小时。 反应结束， 冷却至 0°C， 缓慢加入饱和 氯化铵水溶液（15 mL)， 用乙酸乙酯萃取水层 （15 mi x 4)， 合并有机相， 无水硫酸钠干燥， 过 滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯化（石油醚 /二氯甲垸（v/v) =2/1)得到粉红 色固体状的 5-溴 -7-氟 -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 18g (260 mg, 产率 45%)。 第七步： 7-氟 -5-[3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 （18h)  Under the protection of anhydrous oxygen-free nitrogen, 5-bromo-7-fluoro-4,6-dimethyl-benzofuran-3-one 18f (530 mg, 2.0 mmol) and anhydrous tetrahydrofuran were sequentially added to the reaction flask. 15 mL), -30 ° C, sodium hydride (410 mg, 10.2 mmol) was added and stirred for 20 min. After stirring to room temperature for 20 minutes, the temperature was raised to 35 ° C, and 1,2,-dibromoacetamidine (0.53 ml, 6.1 mmol) was slowly added dropwise. After the addition, the mixture was stirred for 10 minutes. The temperature was raised to 45 ° C for 30 hours. At the end of the reaction, the mixture was cooled to 0 ° C, and aq. EtOAc (EtOAc) Concentration by pressure, the residue was purified by silica gel column chromatography ( petroleum ether / methylene chloride (v/v) = 2 / 1) to give 5-bromo-7-fluoro-4,6-dimethyl Base-spiro [benzofuran-2,1'-cyclopropanthene]-3-one 18 g (260 mg, yield 45%). Step 7: 7-Fluoro-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-spiro[benzofuran-2,1'-cyclopropanthene]-3-one ( 18h)
-fluoro-5-[3-(hydroxymethyl)phenyl]- -dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one
Figure imgf000092_0003
-fluoro-5-[3-(hydroxymethyl)phenyl]- -dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one
Figure imgf000092_0003
将 5-溴 -7-氟 -4,6-二甲基-螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 18g (250 mg,0.88 mmol), 3-羟甲基 苯硼酸 （160 mg,1.05 mmol)加入到 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入 2M碳酸钾水溶液 (1.75 mL),氮气置换反应，加入 [Ι,Γ-双 (二苯基膦基)二茂铁]二氯化钯（32 mg, 0.04 mmol), 90°C 反应 1小时。 反应结束， 冷却至室温， 加入乙酸乙酯 （30 mL)， 过滤， 用水洗涤（10 mi x 3)， 无水硫酸钠干燥有机层， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 /乙酸 乙酯 （v/v) =4/l)得到黄色油状液体的 7-氟 -5-[3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,1'-环 丙垸] -3-酮 18h (220 mg, 产率 81%)。 5-Bromo-7-fluoro-4,6-dimethyl-spiro[benzofuran-2,indole-cyclopropane]-3-one 18g (250 mg, 0.88 mmol), 3-hydroxymethylbenzene Boric acid (160 mg, 1.05 mmol) was added to hydrazine, hydrazine-dimethylformamide (5 mL), 2M aqueous potassium carbonate solution (1.75 mL) was added, and the reaction was carried out under nitrogen, and [Ι,Γ-bis(diphenyl) was added. Phosphyl)ferrocene]palladium dichloride (32 mg, 0.04 mmol) was reacted at 90 ° C for 1 hour. After the reaction was completed, the mixture was cooled to EtOAc EtOAc EtOAc (EtOAc) Separation and purification (petroleum ether / acetic acid Ethyl ester ( v / v) = 4 / l) to give a yellow oily liquid of 7-fluoro-5-[3-(hydroxymethyl)phenyl] -4,6-dimethyl-spiro[benzofuran-2 , 1'-Cyclopropanoid]-3-one 18h (220 mg, yield 81%).
第八步： 甲基 2-[(3S)-6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基)苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 （18i) Step 8: Methyl 2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropane embankment] -5-yl) phenyl] methoxy] - 2, 3-dihydro-benzofuran-3-yl] acetate (18i)
methyl2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl] methoxy] -2,3-dihydrobenzofura -3-yl] acetate Methyl2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl] methoxy] -2,3 -dihydrobenzofura -3-yl] acetate
Figure imgf000093_0001
Figure imgf000093_0001
将 7-氟 -5-[3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 18h (220 rag, 0.71 raraol) 加入到二氯甲垸 （15mL) 中， 加入 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 3D (162.4 mg, 0.78 mmol),氮气置换。 0。C下依次加入三丁基膦（0.39mL， 1.56 mmol)和 Ι,Γ- (偶 氮二羰基） 二哌啶 （393 mg， 1.56 mmol), 室温搅拌 3小时。 过滤， 将滤液减压浓缩得到淡黄 色油状的甲基 2-[(3S)-6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基)苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 18i粗品， 直接用于下步反应。  7-Fluoro-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-spiro[benzofuran-2, fluorene-cyclopropanthene]-3-one 18h (220 rag, 0.71 raraol) was added to dichloromethane (15 mL), and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 3D (162.4 mg, 0.78 mmol) , nitrogen replacement. 0. Tributylphosphine (0.39 mL, 1.56 mmol) and hydrazine, hydrazine-(azo-dicarbonyl)dipiperidine (393 mg, 1.56 mmol) were added in vacuo, and stirred at room temperature for 3 hr. Filtration and concentration of the filtrate under reduced pressure afforded methyl 2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran] -2,1'-Cyclopropenyl]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester 18i crude, used directly in the next step.
第九步： 2-[(3S 6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基;)苯基]甲氧基] -2,3-二氢苯并呋喃 -3-基]乙酸 (化合物 18) Step 9: 2-[(3S 6-[[3-(7-Fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl;)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 18)
2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y] -2,3-dihydrobenzofuran-3-yl] acetic acid  2-[(3 S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro [benzofuran-2, 1 '-cyclopropane]-5-yl)phenyl]methox y] -2,3-dihydrobenzofuran-3-yl] acetic acid
Figure imgf000093_0002
Figure imgf000093_0002
将上步粗产品甲基 2-[(3S)-6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基) 苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸甲酯 18i溶于甲醇 （2 mL)和四氢呋喃 （5 mL) 的混 合溶液中， 加入 2M的氢氧化钠溶液（1.7 mL;i， 室温搅拌 2小时， 减压浓缩， 向反应液中加入 水（10 mL)， 滴加 1M稀盐酸至反应液 pH为 3， 用乙酸乙酯 （15 mL x 3)萃取， 合并有机相并 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱色谱分离提纯 （二氯甲垸 /甲醇 (v/v) =100/1)得到白色泡状固体状的 2-[(3S)-6-[[3-(7-氟 -4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环 丙垸] -5-基)苯基]甲氧基 ]-2-2,3-二氢苯并呋喃 -3-基]乙酸 化合物 18 (225 rag,第八歩和第九歩总 收率为 65%， HPLC: 97.39%)  The crude product methyl 2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-) a mixed solution of methyl propyl]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 18i in methanol (2 mL) and tetrahydrofuran (5 mL) Add 2M sodium hydroxide solution (1.7 mL; i, stir at room temperature for 2 hours, concentrate under reduced pressure, add water (10 mL) to the reaction mixture, add 1 M dilute hydrochloric acid to pH 3, with acetic acid The ester was extracted (15 mL×3), EtOAc (EtOAc m. 1) 2-[(3S)-6-[[3-(7-Fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1') as a white foamy solid - Cyclopropanoid] -5-yl)phenyl]methoxy]-2-2,3-dihydrobenzofuran-3-yl]acetic acid compound 18 (225 rag, eighth and ninth total) The rate is 65%, HPLC: 97.39%)
MS: 487.2[M-1] MS: 487.2 [M-1]
¾ NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 7.50 (m, 2H), 7.21 (s, 1H), 7.11 (m, 2H), 6.47 (dt, 2H), 5.12 (s, 2H), 4.68 (t, IH), 4.18 (dd, IH), 3.67 (m, IH), 2.69 (dd, IH), 2.46 (m, IH), 2.18 (s, 3H), 1.97 (d, 3H), 1.86 (dd, , 2H), 1.47 (q, 2H). 3⁄4 NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 7.50 (m, 2H), 7.21 (s, 1H), 7.11 (m, 2H), 6.47 (dt, 2H), 5.12 (s, 2H), 4.68 (t, IH), 4.18 (dd, IH), 3.67 (m, IH), 2.69 (dd, IH), 2.46 (m, IH), 2.18 (s, 3H), 1.97 (d, 3H), 1.86 (dd, , 2H), 1.47 (q, 2H).
实施例 19 Example 19
2-[(3S)-6-[[3-[2,2-双 (羟甲基) -4,6-二甲基 -3-氧代-苯并呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢苯并呋喃 吡啶 -3-基]乙酸 （化合物 I9) 2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]- Oxy]-2,3-dihydrobenzofuranpyridine- 3 -yl]acetic acid (compound I 9 )
2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydr  2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydr
Figure imgf000094_0001
Figure imgf000094_0001
第一步： 5-溴 -2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基-苯并呋喃 -3-酮 (19a) 5-bromo-2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-benzofuran-3-one
Figure imgf000094_0002
First step: 5-bromo-2,2-bis[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-4,6-dimethyl-benzofuran-3-one ( 19a) 5-bromo-2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-benzofuran-3-one
Figure imgf000094_0002
向反应瓶中依次加入 5-溴 -2,2-二 (羟甲基) -4,6-二甲基苯并呋喃 -3(2H)-酮 5a (603 mg,2.0 mmol), 甲基叔丁基氯硅垸（1.2 g， 8.0 mmol)、 咪唑（816 mg， 12.0 mmol)和 Ν,Ν-二甲基甲酰 胺 （8 mL) 中， 室温下搅拌 30分钟。 反应结束后， 加入水（10 mL)和乙酸乙酯 (50 mL)， 分层 后， 用水洗有机层 p0 mL x 2)， 有机层用无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物 用硅胶柱层析分离纯化 （石油醚）得到淡黄色油状的 5-溴 -2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧 基甲基 ]-4,6-二甲基-苯并呋喃 -3-酮 19a (1.05 g， 产率 99%)。  Add 5-bromo-2,2-bis(hydroxymethyl)-4,6-dimethylbenzofuran-3(2H)-one 5a (603 mg, 2.0 mmol) to the reaction flask. Butyl chlorosilane (1.2 g, 8.0 mmol), imidazole (816 mg, 12.0 mmol) and hydrazine, hydrazine-dimethylformamide (8 mL) were stirred at room temperature for 30 min. After the reaction, water (10 mL) and ethyl acetate (50 mL) were evaporated. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) 6-Dimethyl-benzofuran-3-one 19a (1.05 g, yield 99%).
第二步：2,2-双 [叔丁基 (二甲基)甲硅垸基]氧基甲基] -5-[3- (羟甲基)苯基] -4,6-二甲基-苯并呋喃 -3- 酮 (19b) 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-benzofUran -3-one Second step: 2,2-bis[tert-butyl(dimethyl)methylsilyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl -benzofuran-3-one (19b) 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-benzofUran -3-one
Figure imgf000095_0001
Figure imgf000095_0001
将 5-溴 -2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基-苯并呋喃 -3-酮 19a(1.0 g， 1.89 mmol), 3-羟甲基苯硼酸 （344 mg， 2.27 mmol)加入到 Ν,Ν-二甲基甲酰胺 (15 ml) 中， 加 入 2M碳酸钾水溶液（3.78 mL)，氮气置换反应，加入 [Ι,Γ-双 (；二苯基膦基)二茂铁]二氯化钯（69 mg,0.05 mmol), 90°C下反应 1小时。 反应结束， 冷却至室温， 加入乙酸乙酯（50 mL)， 过滤， 滤液用水洗涤 （20 mL X 3)， 无水硫酸钠干燥有机层， 过滤， 将滤液减压浓缩， 残留物用硅胶 柱层析分离提纯 （石油醚 /乙酸乙酯 （v/v) =10/1)得到黄色油状的 2,2-双 [叔丁基 (二甲基；)甲硅 垸基]氧基甲基] -5-[3- (羟甲基;)苯基] -4,6- 二甲基-苯并呋喃 -3-酮 19b (1.03 g， 产率 99%)。  5-Bromo-2,2-bis[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-4,6-dimethyl-benzofuran-3-one 19a (1.0 g , 1.89 mmol), 3-hydroxymethylbenzeneboronic acid (344 mg, 2.27 mmol) was added to hydrazine, hydrazine-dimethylformamide (15 ml), and 2M aqueous potassium carbonate solution (3.78 mL) was added. [Ι,Γ-bis(;diphenylphosphino)ferrocene]palladium dichloride (69 mg, 0.05 mmol) was added, and the reaction was carried out at 90 ° C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (50 mL) was evaporated, evaporated, evaporated, evaporated, evaporated. Separation and purification (petroleum ether/ethyl acetate (v/v) = 10/1) gave 2,2-bis[tert-butyl(dimethyl(methyl))methylsilyl]oxymethyl] in the form of a yellow oil. 5-[3-(Hydroxymethyl;)phenyl]-4,6-dimethyl-benzofuran-3-one 19b (1.03 g, yield 99%).
¾ NMR (400 MHz, DMSO) δ 7.45 (d, IH), 7.34 (s, IH), 7.03 (s, IH), 7.02 (s, IH), 6.92 (d, IH), 5.22 (t, IH), 4.57 (d, 2H), 3.92 (d, 4H), 2.16 (s, 3H), 2.04 (s, 3H), 0.72 (d, 18H), -0.00 (t, 12H). 第三步： 甲基 -2-[(3S)-6-[[3-[2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基 -3-氧代-苯 并呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸 （19c)  3⁄4 NMR (400 MHz, DMSO) δ 7.45 (d, IH), 7.34 (s, IH), 7.03 (s, IH), 7.02 (s, IH), 6.92 (d, IH), 5.22 (t, IH) , 4.57 (d, 2H), 3.92 (d, 4H), 2.16 (s, 3H), 2.04 (s, 3H), 0.72 (d, 18H), -0.00 (t, 12H). Step 3: Methyl -2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl-3 -oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (19c)
Methyl 2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofumnMethyl 2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofumn
-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate -yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate
Figure imgf000095_0002
Figure imgf000095_0002
将 2,2-双 [叔丁基(二甲基)甲硅垸基]氧基甲基] -5-[3- (羟甲基)苯基] -4,6- 二甲基-苯并呋喃 -3-酮 19b (1 05 g?1.88 mmol)加入到二氯甲垸 (20 mL) 中， 加入 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3- 基)乙酸甲酯 3D (396.4 mg,1.9 mmol),氮气置换， 0。C下依次加入三丁基膦（1.04 ml, 4.15 mmol) 和 Ι,Γ- (偶氮二羰基） 二哌啶 （1.05 g， 4.15 mmol), 室温搅拌 3小时， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 /乙酸乙酯 （v/v) =10/1) 得到黄色油状的甲基 -2-[(3S)-6-[[3-[2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6- 二甲基 -3-氧代-苯并呋喃 -5-基] 苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸 19c (1.2 g， 产率 87%)。 2,2-bis[tert-butyl(dimethyl)methylsilyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-benzo Furan-3-one 19b (1 05 g ? 1.88 mmol) was added to dichloromethane (20 mL), and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl was added. ) Methyl acetate 3D (396.4 mg, 1.9 mmol), nitrogen displacement, 0. Tributylphosphine (1.04 ml, 4.15 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (1.05 g, 4.15 mmol) were added, and then stirred at room temperature for 3 hr. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) - bis[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy ]-2,3-Dihydrobenzofuran-3-yl]acetic acid 19c (1.2 g, yield 87%).
第四步： 2-[(3S)-6-[[3-[2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基 -3-氧代-苯并呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸（19d) Fourth step: 2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl 3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (19d)
2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzoftiran-5-yl]phe nyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid
Figure imgf000096_0001
2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-4,6-dimethyl-3-oxo-benzoftiran-5-yl]phe nyl ]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid
Figure imgf000096_0001
将甲基 -2-[(3S)-6-[[3-[2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6- 二甲基 -3-氧代-苯 并呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸 19c (1.2 g， 1.6 mmol)溶于甲醇 （3 mL) 和四氢呋喃 （9 mL) 的混合溶液中， 加入 2M氢氧化钠溶液（2.2 mL)， 室温搅拌 2小时， 减压 浓缩， 向反应液中加入水（10 mL)， 滴加 1M稀盐酸 （5 mL)， 用乙酸乙酯 （15 mL x 3)萃取， 合并有机相并用无水硫酸钠干燥， 过滤， 将滤液减压浓缩得到淡黄色油状的 2-[pS)-6-[[3-[2,2- 双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基 -3-氧代-苯并呋喃 -5-基]苯基]甲氧基 ]-2,3-二 氢苯并呋喃 -3-基]乙酸 19d (1.08 g)。  Methyl-2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl 3-Oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid 19c (1.2 g, 1.6 mmol) dissolved in methanol ( 2 mL) and tetrahydrofuran (9 mL) were mixed with 2M sodium hydroxide solution (2.2 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, water (10 mL) was added to the reaction mixture, and 1 M diluted hydrochloric acid was added dropwise. (5 mL), EtOAc (EtOAc EtOAc (EtOAc) -[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl-3-oxo-benzofuran-5-yl]benzene Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid 19d (1.08 g).
第五步： 2-[(3S)-6-[[3-[2,2-双 (羟甲基) -4,6-二甲基 -3-氧代-苯并呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢 苯并呋喃吡啶 -3-基]乙酸（化合物 19) Step 5: 2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl] Phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (Compound 19)
2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydrobenzofuran-3-yl] acetic acid  2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-di hydrobenzofuran -3-yl] acetic acid
Figure imgf000096_0002
Figure imgf000096_0002
将上步 2-[(3S)-6-[[3-[2,2-双 [[叔丁基 (二甲基)甲硅垸基]氧基甲基] -4,6-二甲基 -3-氧代 -苯并 呋喃 -5-基]苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸 19d的粗产品 （1.08 g, 1.47 mmol)溶解到 四氢呋喃 （10 mL)， 加入四丁基氟化铵三水化合物 （2.32 g， 7.35 mmol),室温下搅拌 45分钟。 反应结束， 加入水（20 mL) 淬灭反应， 用乙酸乙酯萃取水层 （20 mL x 3)， 合并有机相， 无水 硫酸钠干燥， 减压浓缩。 残留物用硅胶柱层析分离提纯 （石油醚 /乙酸乙酯 （v/v) =1/1)得到淡 黄色泡状的 2-[(3S)-6-[[3-[2,2-双 (羟甲基) -4,6-二甲基 -3-氧代-苯并呋喃 -5-基]苯基]甲氧基 ]-2,3- 二氢苯并呋喃吡啶 -3-基]乙酸化合物 19 (470 mg,第四步和第五步总产率为 63.4%， HPLC: 96.33%)  The above step 2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl The crude product (1.08 g, 1.47 mmol) of -3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid 19d was dissolved Tetrahydrofuran (10 mL), tetrabutylammonium fluoride trihydrate (2.32 g, 7.35 mmol) was added and stirred at room temperature for 45 min. After the reaction was completed, water (20 mL) was evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 1 / 1) to give 2-[(3S)-6-[[3-[2,2- Bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl Acetic acid compound 19 (470 mg, total yield of the fourth and fifth steps was 63.4%, HPLC: 96.33%)
MS m/z(ESI): 527.3[M+23];503.2[M-1].  MS m/z (ESI): 527.3 [M+23]; 503.2 [M-1].
¾ NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.19 (s, 1H), 7.09 (m, 2H), 7.01 (d, 1H), 6.47 (dt, 2H), 5.10 (s, 2H), 5.03 (s, 2H), 4.67 (d, 1H), 4.18 (dd, 1H), 3.68 (m, 5H), 2.69 (dd, 1H), 2.46 (d, 1H), 2.14 (s, 3H), 2.01 (s, 3H).  3⁄4 NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.49 (d, 1H), 7.43 (d, 1H), 7.19 (s, 1H), 7.09 (m, 2H), 7.01 (d, 1H) , 6.47 (dt, 2H), 5.10 (s, 2H), 5.03 (s, 2H), 4.67 (d, 1H), 4.18 (dd, 1H), 3.68 (m, 5H), 2.69 (dd, 1H), 2.46 (d, 1H), 2.14 (s, 3H), 2.01 (s, 3H).
实施例 20 Example 20
2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基) -2,3-二氢苯并呋喃 -5-基]苯基]甲氧基 ]-2,3-二 氢苯并呋喃吡啶 -3-基]乙酸 （化合物 20) 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]phenyl]m ethoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid 2-[(3S)-6-[[3-[4,6-Dimethyl-3-(3-methanesulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]benzene Methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (compound 20) 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]phenyl]m ethoxy]-2,3-dihydrobenzofuran- 3-yl]acetic acid
Figure imgf000097_0001
Figure imgf000097_0001
第一步： 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基)苯基]苯并呋喃 -3-酮（20a) First step: 4,6-Dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]benzofuran-3-one (20a)
4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]benzofuran-3-one
Figure imgf000097_0002
4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]benzofuran-3-one
Figure imgf000097_0002
将 4,6-二甲基 -5-(3-羟基甲基苯基)苯并呋喃 -3-酮 9a (1.30 g,4.8 mmol)溶于二氯甲垸（20 mL) 中， 加入 3,4-二氢吡喃 （0.5 mL， 5.8 mmol)和对甲基苯磺酸吡啶盐（125 mg， 0.5 mmol), 室 温下搅拌 30分钟。反应结束后， 加入饱和碳酸氢钠水溶液（20 mL)， 用二氯甲垸萃取水层 （20 mL X 3), 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物硅胶柱层析分离提 纯 （石油醚 /乙酸乙酯 （v/v) =5/1)得到淡黄色油状的 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基；)苯 基]苯并呋喃 -3-酮 20a (1.59 g, 产率 94%)。  4,6-Dimethyl-5-(3-hydroxymethylphenyl)benzofuran-3-one 9a (1.30 g, 4.8 mmol) was dissolved in dichloromethane (20 mL). 4-Dihydropyran (0.5 mL, 5.8 mmol) and p-toluenesulfonic acid pyridinium salt (125 mg, 0.5 mmol) were stirred at room temperature for 30 min. After the reaction was completed, aq. EtOAc EtOAc (EtOAc m. Separation and purification by silica gel column chromatography (EtOAc/EtOAc (v/v) = 5/1) to give 4,6-dimethyl-5-[3- (tetrahydropyran-2-yl) as a pale yellow oil. Oxymethyl; phenyl]benzofuran-3-one 20a (1.59 g, yield 94%).
第二步： 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基)苯基] -2,3-二氢苯并呋喃 -3-胺 （20b) Second step: 4,6-Dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzofuran-3-amine (20b)
4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzofuran-3-amine
Figure imgf000097_0003
4,6-dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzofuran-3-amine
Figure imgf000097_0003
将 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基)苯基]苯并呋喃 -3-酮 20a (563 mg, 1.6 mmol)和 盐酸羟胺 （333 mg， 4.8 mmol)加入到甲醇 （10 mL) 中， 向反应瓶中加入氢氧化钠 （211 mg， 5.28 mmol) 的水（3 mL)溶液， 80°C下反应 4小时，减压浓缩，向残留物中加入水（20 mL)和 二氯甲垸（50 mL)， 有机层用水洗涤 （10 mL x 2)， 收集有机相， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩， 残留物再次溶解到甲醇中 （10 mL), 加入镍（120 mg)， 氢气氛下室温搅拌 24 小时。 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （二氯甲垸 /甲醇 （v/v) =50/l)得 到淡黄色油状的 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基;)苯基] -2,3-二氢苯并呋喃 -3-胺 20b (240 mg, 产率 68%)。 4,6-Dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]benzofuran-3-one 20a (563 mg, 1.6 mmol) and Hydroxylamine hydrochloride (333 mg, 4.8 mmol) was added to methanol (10 mL), and a solution of sodium hydroxide (211 mg, 5.28 mmol) in water (3 mL) was added to the reaction flask, and the reaction was carried out at 80 ° C for 4 hours. Concentration by pressure, water (20 mL) and dichloromethane (50 mL) were added, and the organic layer was washed with water (10 mL x 2), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, After concentration, the residue was dissolved again in methanol (10 mL). Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjjjjjjj 3-(Tetrahydropyran-2-yloxymethyl;)phenyl]-2,3-dihydrobenzofuran-3-amine 20b (240 mg, yield 68%).
第三步： 4,6-二甲基 -N-(3-甲磺酰基丙基 )-5-[3- (四氢吡喃 -2-基氧甲基)苯基] -2,3-二氢苯并呋喃 -3-胺 （20c) The third step: 4,6-dimethyl-N-(3-methanesulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3- Dihydrobenzofuran-3-amine (20c)
4,6-dimethyl-N-(3-methylsulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydro benzofuran-3 -amine  4,6-dimethyl-N-(3-methylsulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydro benzofuran-3 -amine
Figure imgf000098_0001
Figure imgf000098_0001
将 4,6-二甲基 -5-[3- (四氢吡喃 -2-基氧甲基)苯基] -2,3-二氢苯并呋喃 -3-胺 20b (240 mg, 0.68 mmol), 3- (甲基磺酰基)丙基 4-甲基苯磺酸 （226 mg,0.82 mmol),碳酸钾 （188 mg,1.36 mmol)加 入到乙腈（10 mL) 中， 90°C下反应 48小时。反应结束后， 过滤， 将滤液减压浓缩得到淡黄色 油状的 4,6-二甲基 -N-P-甲磺酰基丙基 )-5-[3- (四氢吡喃 -2-基氧甲基)苯基] -2,3-二氢苯并呋喃 -3- 胺 20c粗品， 直接用于下步反应。  4,6-Dimethyl-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzofuran-3-amine 20b (240 mg, 0.68 Methyl) 3-(methylsulfonyl)propyl 4-methylbenzenesulfonic acid (226 mg, 0.82 mmol), potassium carbonate (188 mg, 1.36 mmol) in acetonitrile (10 mL) at 90 ° C Reaction for 48 hours. After completion of the reaction, the mixture was filtered, and then evaporated tolulululululululululululululululululululu The crude phenyl]-2,3-dihydrobenzofuran-3-amine 20c was used directly in the next step.
第四步： （3-(4,6-二甲基 -3-((3-(甲基磺酰基)丙基)氨基) -2,3-二氢苯并呋喃 -5-基;)苯基)甲醇 (20d)The fourth step: (3-(4,6-dimethyl-3-((3-(methylsulfonyl)propyl)amino)-2,3-dihydrobenzofuran-5-yl;) benzene Base) methanol (20d)
[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofumn-5-yl]phenyl]methanol [3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofumn-5-yl]phenyl]methanol
Figure imgf000098_0002
Figure imgf000098_0002
将上步 4,6-二甲基 -N-P-甲磺酰基丙基 )-5-[3- (四氢吡喃 -2-基氧甲基)苯基] -2,3-二氢苯并呋 喃 -3-胺 20c粗品溶解于四氢呋喃 （5 mL)和甲醇（3 mL) 的混合溶剂中， 加入 12N的盐酸 （1 mL), 室温搅拌 30分钟。 加入饱和碳酸氢钠溶液（15 mL)， 用乙酸乙酯萃取 （15 mL x 3)， 合 并有机相， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （二氯甲 垸 /甲醇 （v/v) =60/l)得到淡黄色油状的 （3-(4,6-二甲基 -3-((3- (甲基磺酰基)丙基)氨基) -2,3-二氢 苯并呋喃 -5-基；)苯基)甲醇 20d (175 mg, 第三步和第四步总产率 66%)。  The above step 4,6-dimethyl-NP-methanesulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3-dihydrobenzo The crude furan-3-amine 20c was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (3 mL). Add a saturated solution of sodium hydrogencarbonate (15 mL), EtOAc (EtOAc)EtOAc. (Dichloromethane/methanol (v/v) = 60/l) gave (3-(4,6-dimethyl-3-((3-(methylsulfonyl))propyl)amino) - 2,3-dihydrobenzofuran-5-yl;)phenyl)methanol 20d (175 mg, total yield of 66% in the third and fourth steps).
第五步： 甲基 2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基) -2,3-二氢苯并呋喃 -5-基]苯基] 甲氧基 ]-2,3-二氢苯并呋喃吡啶 -3-基]乙酸甲酯 （20e) Step 5: Methyl 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran) -5-yl]phenyl] Methyl methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetate (20e)
methyl2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]ph enyljmethoxy] -2,3-dihydrobe Methyl2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]ph enyljmethoxy] -2,3-dihydrobe
Figure imgf000099_0001
Figure imgf000099_0001
将 (3-(4,6-二甲基 -3-((3- (甲基磺酰基)丙基)氨基) -2,3-二氢苯并呋喃 -5-基)苯基)甲醇 20d (167 rag, 43 mrnol)加入到二氯甲垸（10 mL) 中， 加入 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲 酯 3D (98.3 mg， 0.47 mmol), 氮气置换， 0。C下， 依次加入三丁基膦 (0.24mL, 0.94 mmol)和 Ι,Γ- (偶氮二羰基）二哌啶 （238 mg， 0.94 mmol), 室温搅拌 2小时。 过滤， 将滤液减压浓缩得 到淡黄色油状的甲基 2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基) -2,3-二氢苯并呋喃 -5-基: 苯基]甲氧基 ]-2,3-二氢苯并呋喃吡啶 -3-基]乙酸甲酯 20e粗品， 直接用于下步反应。  (3-(4,6-Dimethyl-3-((3-(methylsulfonyl)propyl)amino)-2,3-dihydrobenzofuran-5-yl)phenyl)methanol 20d (167 rag, 43 mrnol) was added to dichloromethane (10 mL) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 3D (98.3) Mg, 0.47 mmol), nitrogen replacement, 0. Under C, tributylphosphine (0.24 mL, 0.94 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (238 mg, 0.94 mmol) were sequentially added and stirred at room temperature for 2 hr. Filtration and concentration of the filtrate under reduced pressure afforded methyl 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2 , 3-Dihydrobenzofuran-5-yl: phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid methyl ester 20e crude, used directly in the next step.
第六步： 2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基) -2,3-二氢苯并呋喃 -5-基]苯基]甲氧 基] -2,3-二氢苯并呋喃吡啶 -3-基]乙酸 （化合物 20) Step 6: 2-[(3S)-6-[[3-[4,6-Dimethyl-3-(3-methanesulfonylpropylamino)-2,3-dihydrobenzofuran-5 -yl]phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (compound 20)
2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]phenyl]m ethoxy]-2,3-dihydrobenzofura -3-yl]acetic acid  2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran-5-yl]phenyl]m ethoxy]-2,3-dihydrobenzofura - 3-yl]acetic acid
Figure imgf000099_0002
Figure imgf000099_0002
将上步粗品甲基 2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基) -2,3-二氢苯并呋喃 -5-基] 苯基]甲氧基 ]-2,3-二氢苯并呋喃吡啶 -3-基]乙酸甲酯 20e加入到四氢呋喃 （6 mL)和甲醇 （3 mL) 中， 加入 2M氢氧化钠溶液（1.05 mL)， 室温搅拌 2小时， 反应结束， 加入 2M盐酸 （1.5 mL)， 加入磷酸钾调 pH至 6-7， 加入水（10 mL)， 用乙酸乙酯萃取 （15 mL x 3)， 合并有机相， 无水 硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯 （二氯甲垸 /甲醇 （v/v) =50/1) 得到黄色固体状的 2-[(3S)-6-[[3-[4,6-二甲基 -3-(3-甲磺酰基丙基氨基; 1-2,3-二氢苯并呋喃 -5-基] 苯基]甲氧基 ]-2,3-二氢苯并呋喃吡啶 -3-基]乙酸化合物 20 (170 mg， 第五步和第六步总产率 70%, HPLC:99.75  The crude methyl 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methanesulfonylpropylamino)-2,3-dihydrobenzofuran) -5-yl] phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetate methyl ester 20e was added to tetrahydrofuran (6 mL) and methanol (3 mL), and 2M hydrogen was added. Sodium oxide solution (1.05 mL), stirred at room temperature for 2 hours, the reaction was completed, 2M hydrochloric acid (1.5 mL) was added, pH was adjusted to 6-7 by adding potassium phosphate, water (10 mL) was added, and extracted with ethyl acetate (15 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated. 2-[(3S)-6-[[3-[4,6-Dimethyl-3-(3-methanesulfonylpropylamino; 1-2,3-dihydrobenzofuran-5-) Phenyl] methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid compound 20 (170 mg, fifth step and sixth step total yield 70%, HPLC: 99.75
MS m/z(ESI):564.3[M-l].  MS m/z (ESI): 564.3 [M-l].
¾ NMR (400MHz, DMSO) 57.44 (td,lH), 7.38 (d, IH), 7.08 (m,3H), 6.57 (s, IH), 6.47 (ddd, 3⁄4 NMR (400MHz, DMSO) 57.44 (td,lH), 7.38 (d, IH), 7.08 (m,3H), 6.57 (s, IH), 6.47 (ddd,
2H), 5.09 (s, 2H), 4.67 (t, 1H),4.38 (m,3H), 4.18 (t, IH), 3.67 (m, IH), 3.13(dd, 2H), 2.92 (s, 3H), 2.69 (dd, IH), 2.59 (m, 2H), 2.46 (d, IH), 1.95 (d, 3H), 1.88 (s, 3H), 1.80 (m, 2H). 实施例 21 2H), 5.09 (s, 2H), 4.67 (t, 1H), 4.38 (m, 3H), 4.18 (t, IH), 3.67 (m, IH), 3.13 (dd, 2H), 2.92 (s, 3H) ), 2.69 (dd, IH), 2.59 (m, 2H), 2.46 (d, IH), 1.95 (d, 3H), 1.88 (s, 3H), 1.80 (m, 2H). Example 21
2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基) -2-氟-苯基]甲氧基]- 2,3-二氢苯 并呋喃 -3-基]乙酸（化合物 21)  2-[(3S)-6-[[5-(4,6-Dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropanindole]-5-yl)-2- Fluoro-phenyl]methoxy]- 2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 21)
2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho -2,3-dihydrobenzofuran-3-yl] acetic acid  2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho -2,3 -dihydrobenzofuran-3-yl] acetic acid
Figure imgf000100_0001
Figure imgf000100_0001
无水无氧氮气保护下， 将 5-溴 -4,6-二甲基苯并呋喃 -3(2H)-酮 2E (12.05 g， 50 mmol)加入 到四氢呋喃 （150 mL) 中， -30°C下， 加入氢化钠 （10 g， 60% wt, 250 mmol), 搅拌 30分钟， 缓慢升温至 35°C下搅拌 30分钟， 滴加 1,2-二溴乙垸（13 mL， 150 mmol), 加完后升温至 45°C 下反应 24小时。 反应结束后冷却至 -20°C， 缓慢加入水淬灭反应（50 mL)。 加入饱和氯化铵水 溶液（50 mL)， 用乙酸乙酯萃取 （80 mL x 3)， 合并有机相， 无水硫酸钠干燥， 过滤， 将滤液 减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 /二氯甲垸（v/v) =1/1)得到粉红色固体状的 5-溴 -4,6-二甲基-螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 21a (8.78g, 产率 65.8%)。  5-Bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (12.05 g, 50 mmol) was added to tetrahydrofuran (150 mL), -30° under anhydrous oxygen-free nitrogen. Under C, sodium hydride (10 g, 60% wt, 250 mmol) was added, stirred for 30 minutes, slowly warmed to 35 ° C and stirred for 30 minutes, and 1,2-dibromoacetamidine (13 mL, 150 mmol) was added dropwise. After the addition, the temperature was raised to 45 ° C for 24 hours. After completion of the reaction, the mixture was cooled to -20 ° C, and the reaction was quenched slowly (50 mL). After adding a saturated aqueous solution of ammonium chloride (50 mL), EtOAc (EtOAc) (petroleum ether/dichloromethane (v/v) = 1/1) gives 5-bromo-4,6-dimethyl-spiro [benzofuran-2, fluorene-cyclopropene] as a pink solid. 3-ketone 21a (8.78 g, yield 65.8%).
¾ NMR (400 MHz, DMSO) δ 7.23 (s, 1Η), 2.62 (s, 3H), 2.46 (s, 3H), 1.77 (q, 2H), 1.43 (q, 2H). 第二步： 4,6-二甲基 -5-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 (21b) 3⁄4 NMR (400 MHz, DMSO) δ 7.23 (s, 1Η), 2.62 (s, 3H), 2.46 (s, 3H), 1.77 (q, 2H), 1.43 (q, 2H). Step 2: 4, 6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) snail [benzofuran-2,1'-cyclopropane垸]-3-one (21b)
4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[benzofuran-2,l'-cyclopropane]-3- one
Figure imgf000101_0001
4,6-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[benzofuran-2,l'-cyclopropane]-3-one
Figure imgf000101_0001
将 5-溴 -4,6-二甲基-螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 21a (5.34 g,20 mmol), 联硼酸频那醇酯 (5.59 g, 22 mmol), [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯二氯甲垸络合物 （818 mg， 1 mmol), 乙 酸钾 （5.89 g， 60 mmol), 加入到乙醇溶液（100 mL) 中， 氮气置换， 回流反应 16小时。 反应 结束后， 稍微浓缩反应液， 加入水（100mL)， 用二氯甲垸萃取 （100 mL x 3;»， 合并有机相， 无 水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱层析分离提纯 （石油醚 /二氯甲垸（v/v) =1/1) 得到淡黄色固体状的 4,6-二甲基 -5-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基;)螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 21b (3.7 g， 产率 59%)。  5-Bromo-4,6-dimethyl-spiro[benzofuran-2, fluorenyl-cyclopropane-3-one 21a (5.34 g, 20 mmol), benzoic acid pinacol ester (5.59 g, 22 mmol), [Ι,Γ-bis(diphenylphosphino)ferrocene]palladium dichloromethane ruthenium complex (818 mg, 1 mmol), potassium acetate (5.89 g, 60 mmol), In an ethanol solution (100 mL), the mixture was replaced with nitrogen and refluxed for 16 hours. After the reaction was completed, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (petroleum ether / methylene chloride (v/v) = 1 / 1) to give 4,6-dimethyl-5- (4,4,5,5- Methyl-1,3,2-dioxaborolan-2-yl;) spiro[benzofuran-2,1'-cyclopropanthene]-3-one 21b (3.7 g, yield 59%).
¾ NMR (400 MHz, DMSO) δ 6.94 (s, 1Η), 2.60 (s, 3H), 2.42 (s, 3H), 1.71 (q, 2H), 1.37 (dd, 2H), 1.34 (s, 12H).  3⁄4 NMR (400 MHz, DMSO) δ 6.94 (s, 1 Η), 2.60 (s, 3H), 2.42 (s, 3H), 1.71 (q, 2H), 1.37 (dd, 2H), 1.34 (s, 12H) .
第三步 5-溴 -2-氟苯甲醇（2 Id) The third step 5-bromo-2-fluorobenzyl alcohol (2 Id)
(5-bromo-2-fluorophenyl)methanol
Figure imgf000101_0002
(5-bromo-2-fluorophenyl)methanol
Figure imgf000101_0002
将 5-溴 -2-氟苯甲醛 21c (1.015 g， 5.0 mmol)溶于甲醇 (5 mL)和四氢呋喃 （10 mL)的混合 溶液中， 0°C下加入硼氢化钠 （378 mg， 10 mmol), 加完后继续搅拌 15分钟。 加入水（10 mL) 淬灭反应。 稍微浓缩反应液， 加入饱和氯化铵水溶液（10 mL)， 用乙酸乙酯萃取（20 mL x3;»， 合并有机相， 依次用饱和氯化铵溶液洗涤 （50 mL x l)、 水洗涤（50 mL x l)， 合并有机相， 减 压浓缩得到白色固体状的 5-溴 -2-氟苯甲醇 21d (1.1 g， 产率 99%)。 第四步 5-[4-氟 -3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 (21e)  5-Bromo-2-fluorobenzaldehyde 21c (1.015 g, 5.0 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (10 mL), and sodium borohydride (378 mg, 10 mmol) ), continue to stir for 15 minutes after the addition. The reaction was quenched by the addition of water (10 mL). The reaction mixture was concentrated slightly, EtOAc EtOAc (EtOAc (EtOAc) The combined organic phase was concentrated under reduced pressure to give 5-bromo-2-fluorobenzyl alcohol as a white solid 21d (1.1 g, yield 99%). Step 4 5-[4-fluoro-3- (hydroxy) Methyl)phenyl] -4,6-dimethyl-spiro[benzofuran-2,1'-cyclopropanthene]-3-one (21e)
-[4-fluoro-3-(hydroxymethyl)pheny -4,6-dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one
Figure imgf000101_0003
-[4-fluoro-3-(hydroxymethyl)pheny -4,6-dimethyl-spiro[benzofuran-2, -cyclopropane]-3-one
Figure imgf000101_0003
将 4,6-二甲基 -5-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 21b (628 mg, 2.0 mmol)和 5-溴 -2-氟苯甲醇 21d (615 mg， 3.0 mmol)加入到 Ν,Ν-二甲基甲酰胺 （5 mL) 中， 加入 2M碳酸钾溶液（5 mL)， 氮气置换反应， 加入 [Ι,Γ-双 (；二苯基膦；)二茂铁]二氯化 钯（73 mg， 0.1 mmol), 90°C下反应 1小时，加入乙酸乙酯，过滤，滤液用水洗涤（10 mL x 3)， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 /乙酸乙酯 (v/v) =5/1)得到黄色油状的 5-[4-氟 -3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 21e (462 mg, 产率 74%)。 4,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) snail [benzofuran-2, hydrazine- Cyclopropyl hydrazin-3-one 21b (628 mg, 2.0 mmol) and 5-bromo-2-fluorobenzyl alcohol 21d (615 mg, 3.0 mmol) were added to hydrazine, hydrazine-dimethylformamide (5 mL) Add 2M potassium carbonate solution (5 mL), replace the reaction with nitrogen, and add [Ι,Γ-bis(;diphenylphosphine;)ferrocene]palladium dichloride (73 mg, 0.1 mmol) at 90 °C After the reaction was carried out for 1 hour, ethyl acetate was added, and the filtrate was filtered, washed with water (10 mL EtOAc) Ester (v/v) = 5/1) to give 5-[4-fluoro-3-(hydroxymethyl)phenyl]-4,6-dimethyl-spiro[benzofuran-2,1 as a yellow oil. '-Cyclopropanol-3-one 21e (462 mg, yield 74%).
¾ NMR (400 MHz, DMSO) δ 7.23 (ddd , 2H), 7.11 (s, 1H), 7.10― 7.05 (m, 1H), 5.28 (t, 1H), 4.60 (d, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.74 (q, 2H), 1.41 (q, 2H).  3⁄4 NMR (400 MHz, DMSO) δ 7.23 (ddd, 2H), 7.11 (s, 1H), 7.10 - 7.05 (m, 1H), 5.28 (t, 1H), 4.60 (d, 2H), 2.24 (s, 3H), 2.06 (s, 3H), 1.74 (q, 2H), 1.41 (q, 2H).
第五步： 甲基 2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基) -2-氟-苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 （21f) Step 5: Methyl 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl)-2-fluoro-phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester (21f)
Methyl  Methyl
2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy] -2,3-dihydrobenzofuran-3-yl] acetate  2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy] -2 ,3-dihydrobenzofuran-3-yl] acetate
Figure imgf000102_0001
Figure imgf000102_0001
向反应瓶中依次加入 5-[4-氟 -3- (羟甲基)苯基] -4,6-二甲基-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 Add 5-[4-fluoro-3-(hydroxymethyl)phenyl]-4,6-dimethyl-spiro[benzofuran-2,1'-cyclopropene]-3- to the reaction flask ketone
21e (300 rag, 0.96 ramoI)、 二氯甲垸（15 mL)和 （S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基)乙酸甲 酯 3D (210 mg, 1.01 mmol), 氮气保护下， 0。C下依次加入三丁基膦 (0.53 mL, 2.11 mmol)和 Ι,Γ- (偶氮二羰基）二哌啶 （532 mg， 2.11 mmol), 室温搅拌 3小时， 过滤， 将滤液减压浓缩得 到淡黄色油状的甲基 2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基；) -2-氟-苯 基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸甲酯 21f粗品， 直接用于下步反应。 21e (300 rag, 0.96 ramoI), methylene chloride (15 mL) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate methyl ester 3D (210 mg, 1.01 mmol), under nitrogen protection, 0. Tributylphosphine (0.53 mL, 2.11 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (532 mg, 2.11 mmol) were added, and then stirred at room temperature for 3 hr. Methyl 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5) -Base;) -2-fluoro-phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 21f crude, used directly in the next step.
第六步 2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃- 2,1'-环丙垸 ]-5-基;) -2-氟-苯基]甲氧基] - 2,3-二氢苯并呋喃 -3-基]乙酸 （化合物 21) Step 6 2-[(3S)-6-[[5-(4,6-Dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropanindole]-5-yl; -2-fluoro-phenyl]methoxy] - 2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 21)
2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy]-2,3-dihydrobenzofuran-3-yl]acetic acid  2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)-2-fluoro-phenyl]metho xy]-2 ,3-dihydrobenzofuran-3-yl]acetic acid
Figure imgf000102_0002
Figure imgf000102_0002
将上步的甲基 2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基) -2-氟-苯基]甲 氧基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 21f粗品溶于甲醇 （5 mL)和四氢呋喃 （10 mL) 的混合 溶液中，加入 2M氢氧化钠溶液 C2.4 mL)，室温搅拌 2小时，减压浓缩，向反应液中加入水（10 mL), 滴加 1M稀盐酸至反应液 pH为 1， 用乙酸乙酯 （15 mL x 3)萃取， 合并有机相并用无水 硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) =4: 1—二氯甲垸 /甲醇 ( hi、 =70: 1)得到黄色泡状的 2-[(3S)-6-[[5-(4,6-二甲基 -3-氧代-螺 [苯并呋 喃- 2,1'-环丙垸 ]-5-基;) -2-氟-苯基]甲氧基]- 2,3-二氢苯并呋喃 -3-基]乙酸 化合物 21 (366 mg, 第 五步和第六步总收率 78%)。 MS m/z(ESI):487.1 M-lj. The methyl 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5) a mixture of methyl 2-bromo-phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 21f in methanol (5 mL) and tetrahydrofuran (10 mL) Add 2M sodium hydroxide solution C2.4 mL) to the solution, stir at room temperature for 2 hours, concentrate under reduced pressure, add water (10 mL) to the reaction solution, add 1 M dilute hydrochloric acid to pH 1 and use acetic acid The ester was extracted (15 mL×3), EtOAc (EtOAc m. 1-Chloromethylhydrazine/methanol (hi, =70:1) gave 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[ Benzofuran-2,1'-cyclopropanyl]-5-yl;)-2-fluoro-phenyl]methoxy]- 2,3-dihydrobenzofuran-3-yl]acetic acid compound 21 ( 366 mg, the total yield of the fifth and sixth steps is 78%). MS m/z (ESI): 487.1 M-lj.
¾ NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 7.39― 7.27 (m, 2H), 7.23― 7.15 (m, 1H), 7.11 (t, 2H), 6.49 (dd, 2H), 5.14 (s, 2H), 4.68 (t, 1H), 4.19 (dd, 1H), 3.73― 3.61 (m, 1H), 2.69 (dd, 1H), 2.47 (dd, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.74 (dd, 2H), 1.41 (q, 2H). 实施例 22  3⁄4 NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 7.39 - 7.27 (m, 2H), 7.23 - 7.15 (m, 1H), 7.11 (t, 2H), 6.49 (dd, 2H), 5.14 ( s, 2H), 4.68 (t, 1H), 4.19 (dd, 1H), 3.73- 3.61 (m, 1H), 2.69 (dd, 1H), 2.47 (dd, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.74 (dd, 2H), 1.41 (q, 2H). Example 22
2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基)苯基]甲氧基 ]-2-2,3-二氢 苯并呋喃 -3-基]乙酸（化合物 22)  2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropanindole]-5-yl) Phenyl]methoxy]-2-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 22)
2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho -2,3-dihydrobenzofuran-3-yl] acetic acid  2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho -2,3- Dihydrobenzofuran-3-yl] acetic acid
Figure imgf000103_0001
Figure imgf000103_0001
22b 22c  22b 22c
Figure imgf000103_0002
Figure imgf000103_0002
第一步： （5-溴 -2-氯苯基)甲醇 （22b)  First step: (5-bromo-2-chlorophenyl)methanol (22b)
(5-bromo-2-chlorophenyl)methanol
Figure imgf000103_0003
(5-bromo-2-chlorophenyl)methanol
Figure imgf000103_0003
将 5-氯 -2-氟苯甲醛（1.10 g, 5.0 mmol)溶于甲醇（5 mL)和四氢呋喃 （10 mL) 中， 0°C下 加入硼氢化钠 （378 mg， 10 mmol), 加完后继续搅拌 15分钟。 加入水（10 mL)淬灭反应， 稍 微浓缩反应液， 加入饱和氯化铵溶液（10 mL)， 用乙酸乙酯萃取 （20 mL x 3)， 合并有机相， 依次用饱和氯化铵溶液洗涤 （50 mL x l)、 水洗涤（50 mL x l)， 有机相减压浓缩得到白色固体 状的 (5-溴 -2-氯苯基)甲醇 22b (1.15 g, 产率 99%)。  5-Chloro-2-fluorobenzaldehyde (1.10 g, 5.0 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL), and sodium borohydride (378 mg, 10 mmol) was added at 0 ° C. Stirring was continued for 15 minutes. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) (50 mL x 1 ), EtOAc (EtOAc) (EtOAc)
第二步： 5-(4-氯 -3- (羟甲基)苯基) -4,6-二甲基 -3H-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 （22c)  Step 2: 5-(4-Chloro-3-(hydroxymethyl)phenyl)-4,6-dimethyl-3H-spiro[benzofuran-2,1'-cyclopropene]-3- Ketone (22c)
5-(4-chloro-3-(hydroxymethyl)phenyl)- -dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-3-one
Figure imgf000103_0004
5-(4-chloro-3-(hydroxymethyl)phenyl)- -dimethyl-3H-spiro[benzofuran-2,l'-cyclopropan]-3-one
Figure imgf000103_0004
将 4,6-二甲基 -5-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 21b (628 mg, 2.0 mmol)和 （5-溴 -2-氯苯基）甲醇 22b (615 mg， 3.0 mmol)加入到 Ν,Ν-二甲基甲酰 胺 （5 mL)中， 加入 2M碳酸钾溶液 (5 mL)， 氮气置换反应， 加入 [Ι,Γ-双 (；二苯基膦；)二茂铁]二氯 化钯（73 mg， 0.1 mmol), 90°C下反应 2小时， 加入乙酸乙酯， 过滤， 滤液用水洗涤 （lO mL x 3), 无水硫酸钠干燥有机层， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 / 乙酸乙酯 i N、 =5/1) 得到黄色油状的 5-(4-氯 -3- (羟甲基；)苯基； 1-4,6-二甲基 -3H-螺 [苯并呋喃 -2,1'-环丙垸 ]-3-酮 22c (500 mg, 产率 76%)。 4,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) snail [benzofuran-2, hydrazine- Cyclopropanol-3-one 21b (628 mg, 2.0 mmol) and (5-bromo-2-chlorophenyl)methanol 22b (615 mg, 3.0 mmol) were added to hydrazine, hydrazine-dimethylformamide (5 mL), and 2M potassium carbonate solution was added. (5 mL), Nitrogen displacement reaction, adding [Ι,Γ-bis(;diphenylphosphine;)ferrocene]palladium dichloride (73 mg, 0.1 mmol), reacting at 90 ° C for 2 hours, adding acetic acid Ethyl acetate, filtered, and the filtrate was washed with water (10 mL EtOAc). =5/1) 5-(4-chloro-3-(hydroxymethyl)phenyl) as a yellow oil; 1-4,6-dimethyl-3H-spiro[benzofuran-2,1'- Cyclopropyl hydrazin-3-one 22c (500 mg, yield 76%).
MS m/z(ESI):331.1 [M+] ]. MS m/z (ESI): 331.1 [M+]].
第三步： 甲基 2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基)苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 （22d) Step 3: Methyl 2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropane Methyl]]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (22d)
methyl2-[(3S)-6-[ [2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,l'-cyclopropane]-5-yl)phenyl jmethoxy] -2,3-dihydro benzo Methyl2-[(3S)-6-[ [2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,l'-cyclopropane]-5-yl)phenyl jmethoxy] -2, 3-dihydro benzo
Figure imgf000104_0001
Figure imgf000104_0001
将 5-(4-氯 -3- (羟甲基)苯基) -4,6-二甲基 -3H-螺 [苯并呋喃 -2,Γ-环丙垸 ]-3-酮 22c(49() mg,1.49 raraol)二氯甲垸 （15mL) 中， 加入 (S) 2-(6-羟基 -2,3-二氢苯并呋喃 -3-基）乙酸甲酯 3D(326 mg, 1.57 mmol,中间体)， 氮气保护下， 0度下， 依次加入三丁基膦（0.82ml， 3.28 mmol)和 Ι,Γ- (偶氮二羰基） 二哌啶 （828 mg， 3.28 mmol), 室温搅拌 3小时， 过滤， 将滤液减压浓缩得到淡 黄色油状的甲基 2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基)苯基]甲 氧基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 22d粗品， 直接用于下步反应。  5-(4-Chloro-3-(hydroxymethyl)phenyl)-4,6-dimethyl-3H-spiro[benzofuran-2,indole-cyclopropanthene]-3-one 22c (49 () mg, 1.49 raraol) dichloromethane (15 mL), added (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 3D (326 mg, 1.57 Methylene, intermediate), under nitrogen, at 0 °, tributylphosphine (0.82 ml, 3.28 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (828 mg, 3.28 mmol), room temperature Stir for 3 hours, filter, and concentrate the filtrate under reduced pressure to give m-[2-[(3)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo- snail) as a pale yellow oil. [benzofuran-2,1'-cyclopropane]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 22d crude, used directly The next step is the reaction.
第六步： 2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸 ]-5-基）苯基]甲氧 基] -2-2,3-二氢苯并呋喃 -3-基]乙酸 （化合物 22) Step 6: 2-[(3S)-6-[[2-Chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]] -5-yl)phenyl]methoxy]-2-2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 22)
2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho xy]-2,3-dihydrobenzofuran-3-yl]acetic acid  2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2, -cyclopropane]-5-yl)phenyl]metho xy]-2, 3-dihydrobenzofuran-3-yl]acetic acid
Figure imgf000104_0002
Figure imgf000104_0002
将上步 (甲基 2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯并呋喃 -2,1'-环丙垸] -5-基)苯基]甲 氧基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 22d粗品溶于甲醇 （5 mL)和四氢呋喃 （10 mL) 的混合 溶液中，加入 2M氢氧化钠溶液 C3.7 mL)，室温搅拌 2小时，减压浓缩，向反应液中加入水（10 mL), 滴加 1M稀盐酸至反应液 pH为 1， 用乙酸乙酯 （15 mL x 3)萃取， 合并有机相并用无水 硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) =4: 1—二氯甲垸 /甲醇 （v/v) =70: 1)得到黄色泡状的 2-[(3S)-6-[[2-氯 -5-(4,6-二甲基 -3-氧代-螺 [苯 并呋喃 -2,1 '-环丙垸 ]-5-基)苯基]甲氧基 ]-2-2,3-二氢苯并呋喃 -3-基]乙酸化合物 22 (595 mg,第五 步和第六步总收率为 79%). The above step (methyl 2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropane垸]-5-yl)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 22d crude solution in methanol (5 mL) and tetrahydrofuran (10 mL) Add 2M sodium hydroxide solution C3.7 mL), stir at room temperature for 2 hours, concentrate under reduced pressure, add water (10 mL) to the reaction solution, add 1 M dilute hydrochloric acid to the reaction solution pH 1 and use ethyl acetate (15 mL x 3), EtOAc (EtOAc/EtOAc) =4: 1 -Dichloromethane/methanol (v/v) = 70: 1) 2-[(3S)-6-[[2-chloro-5-(4,6-dimethyl) Benzyl-3-oxo-spiro[benzofuran-2,1 '-cyclopropanyl]-5-yl)phenyl]methoxy]-2-2,3-dihydrobenzofuran-3-yl ] acetic acid compound 22 (595 mg, total yield of the fifth and sixth steps is 79%).
MS m/z(ESI): 506,0! M+1],  MS m/z (ESI): 506,0! M+1],
^ NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.60 (d, 1H), 7.33 (s, 1H), 7.18 (dd, 1H), 7.11 (t, ^ NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.60 (d, 1H), 7.33 (s, 1H), 7.18 (dd, 1H), 7.11 (t,
2H), 6.47 (d, 2H), 5.16 (s, 2H), 4.68 (t, 1H), 4.24― 4.16 (m, 1H), 3.75― 3.60 (m, 1H), 2.69 (dd, 1H), 2.50 - 2.42 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.74 (dd, 2H), 1.41 (dd, 2H). 生物测试例 2H), 6.47 (d, 2H), 5.16 (s, 2H), 4.68 (t, 1H), 4.24 - 4.16 (m, 1H), 3.75 - 3.60 (m, 1H), 2.69 (dd, 1H), 2.50 - 2.42 (m, 1H), 2.19 (s, 3H), 2.00 (s, 3H), 1.74 (dd, 2H), 1.41 (dd, 2H). Biological test cases
1.GPR40 荧光素酶报告基因试验 1.GPR40 luciferase reporter gene assay
利用 GPR40荧光素酶报告基因试验测试本发明化合物的活性， 试验过程如下： 用 DMSO 将化合物配制成 10mM 的储存液， 再按 3 倍梯度稀释待用。 将稳定表达株 The activity of the compound of the present invention was tested using the GPR40 luciferase reporter gene assay as follows: The compound was formulated into a 10 mM stock solution in DMSO and diluted for a 3-fold gradient. Stable expression strain
HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl以适当密度接种于 96孔板。第二天， 待细胞汇合 度达到 70%左右， 更换为无血清培养基，饥饿过夜。 第三天， 加入含有不同浓度受试化合物的 DMEM培养基， 每孔 200μ1， 放入细胞培养箱孵育 5小时。 利用 Luciferase Assay System试剂 盒检测荧光素酶活性。使用 Origin 7软件对荧光数据进行拟合分析， 计算各化合物的 EC5Q， 试 验结果见表 1。 HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl was seeded at a suitable density in 96-well plates. On the second day, the cell confluence reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, DMEM medium containing different concentrations of the test compound was added, 200 μl per well, and incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. The fluorescence data was fitted and analyzed using Origin 7 software, and the EC 5Q of each compound was calculated. The test results are shown in Table 1.
表 1荧光素酶报告基因试验结果  Table 1 luciferase reporter gene test results
Figure imgf000105_0001
Figure imgf000105_0001
结论： 本发明化合物对人 GPR40有明显激动活性。 2.口服葡萄糖耐量试验 Conclusion: The compounds of the invention have significant agonistic activity on human GPR40. 2. Oral glucose tolerance test
利用口服葡萄糖耐量试验 (OGTT)评价本发明化合物在糖负荷小鼠中的降糖效果。 试验过 程如下：  The hypoglycemic effect of the compounds of the present invention in sugar-loaded mice was evaluated using an oral glucose tolerance test (OGTT). The test process is as follows:
使用的动物为 SPF级 ICR小鼠， 18-22g， 雌性， 购自北京华阜康生物科技股份有限公司， 动物生产合格证号： SCXK (；京 )2009-0004。 将购买的小鼠用高脂饲料诱导 25天， 禁食过夜。 根据禁食后的基础血糖值分组，每组 10只。受试化合物以 5% DMSO-15% solutol-80% 生理盐 水配制成 2mg/ml的混悬液。 灌胃给药， 给药量为 20mg/kg。 空白对照组给予 5% DMSO-15% solutol-80%生理盐水。给药 15 min后给予 20 %的葡萄糖水溶液 (lg/kg)， 并在 0、 15、 30、 45、 60、 120 min时使用强生稳豪血糖测定仪测定各小鼠的血糖值， 计算药-时曲线下面积 (AUC)降 低比例。 试验结果见表 2。  The animals used were SPF grade ICR mice, 18-22 g, female, purchased from Beijing Huakangkang Biotechnology Co., Ltd., Animal Production Certificate No.: SCXK (; Jing) 2009-0004. The purchased mice were induced with high fat diet for 25 days and fasted overnight. According to the basic blood glucose values after fasting, 10 groups in each group. The test compound was formulated into a 2 mg/ml suspension in 5% DMSO-15% solutol-80% physiological saline. The drug was administered by intragastric administration at a dose of 20 mg/kg. The blank control group was given 5% DMSO-15% solutol-80% saline. After 15 minutes of administration, 20% glucose solution (lg/kg) was administered, and the blood glucose level of each mouse was measured at 0, 15, 30, 45, 60, 120 min using a Johnson & Johnson blood glucose meter. The area under the curve (AUC) is reduced by the ratio. The test results are shown in Table 2.
表 2口服葡萄糖耐量试验结果  Table 2 oral glucose tolerance test results
Figure imgf000106_0001
Figure imgf000106_0001
结论： 本发明化合物有良好的降糖效果。  Conclusion: The compounds of the invention have good hypoglycemic effects.

Claims

权利要求书 Claim
1. 一种通式（I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢 产物、 药学上可接 A compound represented by the formula (I) or a stereoisomer, a hydrate, an ester, a solvate, a cocrystal, a metabolite, or a pharmaceutically acceptable compound
Figure imgf000107_0001
Figure imgf000107_0001
其中： among them:
R选自 11或 — 8垸基； R is selected from 11 or - 8 fluorenyl;
环 Q选自 5至 8元碳环基或杂环基， 所述的杂环基含有 1至 4个 Ν、 0或 S(=0)n原子或 者基团， 所述的碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 氰基、 异氰 基、 氨基、 硝基、 羟基、 羧基、 垸基、 d— 8垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -0-C(=0)-0-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-S(=0)n-R12或者 -NR13R13a 的取代基所取代； Ring Q is selected from a 5- to 8-membered carbocyclic or heterocyclic group containing from 1 to 4 fluorene, 0 or S(=0) n atoms or groups, said carbocyclic group or hetero The cyclic group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, cyano, isocyano, amino, nitro, hydroxy, carboxy, decyl, d- 8 methoxy, (CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m -C(=0 -0-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -S(=0) n -R 12 or substituted by a substituent of -NR 13 R 13a ;
R1和 R4各自独立任选自 F、 Cl、 Br、 I、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8 垸基或 C 垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基、 d— 8 垸氧基、 -(CH2)m -烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -(CH2)m-S(=0)n-R12、 -0-C(=0)-0-R12或者 -NR13R13a的取代基所取代； R2和 R3各自独立任选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基或 d— 8垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 d— 8垸基或 d_8垸氧基的取代基所取代； R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 decyl or C decyl, wherein the fluorenyl group And the methoxy or amino groups are each independently optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, and nitrate. Base, hydroxy, carboxyl, d- 8 fluorenyl, d- 8 decyloxy, -(CH 2 ) m -alkenyl-R 12 , -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C(=0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -(CH 2 ) m -S(=0) n -R 12 , -0-C(=0)-0-R 12 or -NR 13 R 13a substituted; R 2 and R 3 are each independently selected from H , F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, d- 8 decyl or d- 8 decyloxy, wherein each of the fluorenyl, decyl or amino groups Optionally optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, d - 8 alkyl with or d_ 8 embankment Group substituents;
R5、 R6、 R7、 R8、 R9、 R1Q和 R11各自独立地选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、异氰基、氨基、硝基、羟基、羧基、 垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基、 -(CH2)m- 烯基 -R12、 -(CH2)m -炔基 -R12、 -(CH2)m-NR13R13a、 -(CH2)m-C(=0)-R12、 -(CH2)m-C(=0)-0-R12、 -(CH2)m-C(=0)-NR13R13a、 -0-C(=0)-NR13R13a、 -0-C(=0)-R12、 -0-C(=0)-0-R12、 -(CH2)mS(=0)nR12、 -N(R12b)C(=0)NR13R13a、 -N(R12b)C(=0)R12、 -N(R12b)C(=0)OR12、 -(CH2)m-(3至 10元碳环基)、R 5 , R 6 , R 7 , R 8 , R 9 , R 1Q and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano , isocyano, amino, nitro, hydroxy, carboxy, alkyl with, d- 8 embankment group, -d- 8 alkyl with - Od- 8 embankment group, - (CH 2) m - alkenyl group -R 12, -(CH 2 ) m -alkynyl-R 12 , -(CH 2 ) m -NR 13 R 13a , -(CH 2 ) m -C(=0)-R 12 , -(CH 2 ) m -C( =0)-0-R 12 , -(CH 2 ) m -C(=0)-NR 13 R 13a , -0-C(=0)-NR 13 R 13a , -0-C(=0)- R 12 , -0-C(=0)-0-R 12 , -(CH 2 ) m S(=0) n R 12 , -N(R 12b )C(=0)NR 13 R 13a , -N (R 12b )C(=0)R 12 , —N(R 12b )C(=0)OR 12 , —(CH 2 ) m —(3 to 10 membered carbocyclic group),
-(CH2)m-(3至 10元杂环基)、 -0-(CH2)m-(3至 10元碳环基)或者 -0-(CH2)m-(3至 10元杂环基)， 所述的杂环基含有 1至 4个 N、 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 烯基、 炔 基、 碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 垸基、 d— 8垸氧基或 -d— 8垸基 -O-d— 8垸基的取 代基所取代； -(CH 2 ) m -(3 to 10 membered heterocyclic group), -0-(CH 2 ) m - (3 to 10 membered carbocyclic group) or -0-(CH 2 ) m - (3 to 10 membered) a heterocyclic group having 1 to 4 N, 0 or 3 (=0) 11 atoms or a group, said fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic group Or a heterocyclic group optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with, d- 8 -d- 8 embankment group or alkyl with alkyl with -Od- 8 taken Substituted by Daiji;
作为选择， R6和 R7可以形成 (^(^或二^^12!^215; Alternatively, R 6 and R 7 can be formed (^(^ or two ^^ 12 !^ 215 ;
作为选择，
Figure imgf000108_0001
As an option,
Figure imgf000108_0001
作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 8元碳环或 3至 8元杂环， 所述的杂环含有 1至 4个 N、 0或 S(=0)n原子或者基 团， 所述的碳环或杂环任选进一步被 0至 4个 R12a的取代基所取代； Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 8 membered carbon. a ring or a 3 to 8 membered heterocyclic ring having 1 to 4 N, 0 or S(=0) n atoms or a group, and the carbocyclic or heterocyclic ring is optionally further further 0 to 4 Substituted by a substituent of R 12a ;
R12a选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝基、 羟基、 羧基、 Ci— 8焼基、 Ci— 8焼氧基或 Ci— 8焼基- O-Ci— 8焼基； R 12a is selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , cyano, isocyano, amino, nitro, hydroxy, carboxy, Ci- 8 fluorenyl, Ci- 8 methoxy or Ci- 8 fluorenyl-O-Ci- 8 fluorenyl;
R12和 R12b选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 巯基、 异氰基、 氨基、 硝基、羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 3至 10元碳环基或 3至 10元杂环基， 所述的杂环 基含有 1至 4个 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 碳环基或杂环基任选 进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝 基、 羟基、 羧基、 d— 8垸基、 d— 8垸氧基或 -d— 8垸基 -O-d— 8垸基的取代基所取代； R 12 and R 12b are selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, 3 to 10 membered carbocyclic group or 3 to 10 membered heterocyclic group, said heterocyclic group having 1 to 4 0 or 3 (=0) 11 atoms or groups The thiol, decyloxy, carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8 D-, -D-D- group or embankment 8 8 8 substituted alkyl with -Od- substituted alkyl with the group;
R13和 R13a选自 H、 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 巯基、 异氰基、 氨基、 硝基、羟基、 羧基、 d— 8垸基、 d— 8垸氧基、 3至 10元碳环基或 3至 10元杂环基， 所述的杂环 基含有 1至 4个 0或 3(=0)11原子或者基团， 所述的垸基、 垸氧基、 碳环基或杂环基任选 进一步被 0至 4个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 氰基、 异氰基、 氨基、 硝 基、羟基、 羧基、 8垸基、 d— 8垸氧基、 -d— 8垸基- O-d— 8垸基或 -(CH2)mS(=0)nR12的取代基所 取代； R 13 and R 13a are selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy, carboxy, d- 8 fluorenyl, d- 8 decyloxy, 3 to 10 membered carbocyclic group or 3 to 10 membered heterocyclic group, said heterocyclic group having 1 to 4 0 or 3 (=0) 11 atoms or groups The thiol, decyloxy, carbocyclyl or heterocyclic group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8, 8 embankment group D-, -D-8-yl embankment - Od- 8 alkyl with or - (CH 2) m S ( =0) substituted with a substituent of n R 12 ;
p选自 0、 1、 2或 3 ;  p is selected from 0, 1, 2 or 3;
q选自 0、 1、 2、 3或 4;  q is selected from 0, 1, 2, 3 or 4;
t选自 0、 1或 2;  t is selected from 0, 1 or 2;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
2. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其中：  2. A compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1和 R4各自独立任选自 F、 Cl、 Br或 d_4垸基； R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br or d 4 fluorenyl;
R2和 R3各自独立任选自 H、 F、 Cl、 Br或 d_4垸基； R 2 and R 3 are each independently selected from H, F, Cl, Br or d 4 fluorenyl;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br、 I或 d_4垸基。 R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I or d- 4 .
3. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其中：  3. A compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C 垸基或 -(CH2)m-NR13R13a ; R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC. Mercapto or -(CH 2 ) m -NR 13 R 13a ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8和 R9可以形成 (=0); Alternatively, R 8 and R 9 can be formed (=0);
作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 6元碳环； Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon. ring;
R13和 R13a选自 H或 d— 6垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d- 6 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 11或 — 6垸基； R 12 is selected from 11 or 6 fluorenyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
4. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其中： 环 Q选自 、 ^、
Figure imgf000109_0001
The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: ring Q is selected from, ^,
Figure imgf000109_0001
且环 Q可以进一步被 0至 3个任选自 F、 Cl、 Br、 I、 =0、 氨基、 羟基、 d— 6垸基或 d— 6垸氧 基的取代基所取代。 And the ring Q may be further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, =0, amino, hydroxy, d- 6 fluorenyl or d- 6 methoxy.
5. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其为下述通式 （II)所示的化合物或其立体异构体、 水合 物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is represented by the following formula (II) a compound shown or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000109_0002
Figure imgf000109_0002
其中-among them-
R选自 11或^— 4垸基： 环 Q为\^， 且环 Q可以进一步被 0至 3个任选自 F、 =0、 氨基、 羟基、 d— 4垸基或 CM垸氧基的取代基所取代； R is selected from 11 or 4 - 4 fluorenyl: ring Q is \^, and ring Q may be further selected from 0 to 3 selected from F, =0, amino, hydroxy, d- 4 fluorenyl or CM methoxy. Substituted by a substituent;
R1选自 F、 C1或 Br; R 1 is selected from F, C1 or Br;
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br或 d_4垸基； R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 fluorenyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH20H、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C 垸基或 -(CH2)m-NR13R13a; R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 0H, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC fluorenyl or —(CH 2 ) m -NR 13 R 13a ;
作为选择， R6和 R7可以形成 (=0); 作为选择， R6与 R7、 R6与 R8、 R6与 R9、 R7与 R8、 R7与 R9、 R8与 R9的任意一组可以形 成一个 3至 6元碳环； Alternatively, R 6 and R 7 may form (=0); Alternatively, any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon. ring;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 11或 — 4垸基； R 12 is selected from 11 or - 4 fluorenyl;
p选自 0、 1或 2;  p is selected from 0, 1 or 2;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
6. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其为通式 （in)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶  The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is represented by the formula (in) Compound or stereoisomer, hydrate, ester, solvate, eutectic
Figure imgf000110_0001
Figure imgf000110_0001
其中： among them:
R5、 R1Q和 R11各自独立任选自 H、 F、 Cl、 Br或 d_4垸基； R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 fluorenyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C 垸基或 -(CH2)m-NR13R13a; R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC fluorenyl or —(CH 2 ) m -NR 13 R 13a ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成一个 3元碳环； Alternatively, R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 11或 — 4垸基； R 12 is selected from 11 or - 4 fluorenyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
7. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其为通式 （IV)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体 代谢产物、 药学上可接受的盐或前药：  The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is represented by the formula (IV) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000110_0002
Figure imgf000110_0002
其中- R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-C 垸基或 -(CH2)m-NR13R13a; among them- R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC fluorenyl or —(CH 2 ) m -NR 13 R 13a ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成一个 3元碳环； Alternatively, R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR12 的取代基所取代； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R 12 ;
R12选自 11或^— 4垸基； R 12 is selected from the group consisting of 11 or 4 - 4 fluorenyl;
m选自 0、 1、 2、 3或 4;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
8. 根据权利要求 7所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其中：  8. A compound according to claim 7 or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R6和 R7各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 〜υ、 或 N 〜S\ ; R 6 and R 7 are each independently selected from the group consisting of H, methyl, methoxy, ethoxy, ~ υ , or N 〜 S \ ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
R8和 R9各自独立任选自 H、 -CH2OH、 甲基、 或 0 ； R 8 and R 9 are each independently selected from H, -CH 2 OH, methyl, or 0;
作为选择， R8和 R9可与其相连接的碳原子形成一个 3元碳环。 Alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
9. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其为通式 （V)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, which is represented by the formula (V) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000111_0001
Figure imgf000111_0001
(V)  (V)
其中： among them:
R4选自 H、 F或 C1; R 4 is selected from H, F or C1;
R5、 R1Q和 R11各自独立任选自 H、 F、 CI或 d_4垸基； R 5 , R 1Q and R 11 are each independently selected from H, F, CI or d 4 fluorenyl;
R6、 R7、 R8和 R9各自独立地选自 H、 -CH2OH、 d_4垸基、 d_4垸氧基、 -d_4垸基 -O-d 垸基或 -(CH2)m-NR13R13a; R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-Od fluorenyl or —(CH 2 ) m -NR 13 R 13a ;
作为选择， R6和 R7可以形成 (=0); Alternatively, R 6 and R 7 may form (=0);
作为选择， R8与 R9可与其相连接的碳原子形成一个 3元碳环； Alternatively, R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
R13和 R13a选自 H或 d_4垸基， 所述的垸基可以进一步被 0至 2个选自 -(CH2)mS(=0)nR 的取代基所取代； R12选自 11或^— 4垸基； R 13 and R 13a are selected from H or d 4 fluorenyl, and the fluorenyl group may be further substituted by 0 to 2 substituents selected from -(CH 2 ) m S(=0) n R ; R 12 is selected from the group consisting of 11 or 4 - 4 fluorenyl;
m选自 0、 1、 2、 3或 4 ;  m is selected from 0, 1, 2, 3 or 4;
n选自 0、 1或 2。  n is selected from 0, 1, or 2.
10. 根据权利要求 9所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药， 其中：  10. A compound according to claim 9 or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R4选自 H、 F或 C1 ; R 4 is selected from H, F or C1;
R5和 R11为甲基； R 5 and R 11 are methyl;
R1Q选自 H或 F; R 1Q is selected from H or F;
R6和 R7各自独立任选自 H、 甲基、 甲氧基、 乙氧基、 〜"\或?^^^5\， 或者 R6 和 R7形成 (=0) ; R 6 and R 7 are each independently selected from H, methyl, methoxy, ethoxy, ~"\ or ?^^^ 5 \, or R 6 and R 7 are formed (=0);
R8和 R9各自独立任选自 H、 -CH2OH、 甲基、
Figure imgf000112_0001
或 0 ； R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl,
Figure imgf000112_0001
Or 0;
作为选择， R8和 R9可与其相连接的碳原子形成一个 3元碳环。 Alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
1 1. 根据权利要求 10所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中：  A compound according to claim 10, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R和 R7为 H或者 R6和 R7形成 (=0) ; R and R 7 are H or R 6 and R 7 are formed (=0);
R8和 R9与其相连接的碳原子形成一个 3元碳环。 R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
12. 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代  12. The compound according to claim 1 or a stereoisomer, hydrate, ester, solvate, co-crystal, or generation thereof
Figure imgf000112_0002
Figure imgf000112_0002
Figure imgf000113_0001
Figure imgf000113_0001
13. 根据权利要求 1~12中任一项所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中所述的盐选自钠盐、 钾盐、 铝盐、 锂盐、 锌盐、钙盐、 镁盐、 钡盐、 铵盐、三甲胺盐、 四甲基铵盐、 二乙胺盐、三乙胺盐、 异丙基胺盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二环己基胺盐、 吡啶盐、 甲基吡啶盐、 2,6- 二甲基吡啶盐、 咖啡碱盐、 普鲁卡因盐、 胆碱盐、 甜菜碱盐、 可可碱盐、 嘌吟盐、 哌嗪盐、 哌 啶盐、 N-乙基哌啶盐、 聚胺树脂盐、 苯明青霉素盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷 酸盐、 甲酸盐、 乙酸盐、 羟乙酸盐、 丙酸盐、 2-羟基丙酸盐、 丙二酸盐、 三氟乙酸盐、 甲磺酸 盐、 乙磺酸盐、三氟甲磺酸盐、 乙烯磺酸盐、苯磺酸盐、对甲苯磺酸盐、 苯甲酸盐、苯乙酸盐、 褐藻酸盐、 氨茴酸盐、 樟脑酸盐、 马来酸盐、 酒石酸盐、 柠檬酸盐、 琥珀酸盐、 扁桃酸盐、 富 马酸盐、 苹果酸盐、 草酸盐、 水杨酸盐、 葡萄糖醛酸盐、 半乳糖醛酸盐、 枸橼酸盐、 天冬氨酸 盐、 谷氨酸盐、 肉桂酸盐或者它们的组合。  The compound according to any one of claims 1 to 12, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein The salt is selected from the group consisting of sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt. , isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt, methylpyridine salt, 2,6-lutidine salt, caffeine salt, Procaine salt, choline salt, betaine salt, theobromine salt, guanidinium salt, piperazine salt, piperidine salt, N-ethylpiperidine salt, polyamine resin salt, phenicillin salt, hydrochloric acid Salt, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate, propionate, 2-hydroxypropionate, malonate, trifluoroacetate , methanesulfonate, ethanesulfonate, triflate, vinyl sulfonate, besylate, p-toluenesulfonate Benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, fumarate, malic acid Salt, oxalate, salicylate, glucuronide, galacturonate, citrate, aspartate, glutamate, cinnamate or a combination thereof.
14. 根据权利要求 13所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中所述的盐选自钠盐、 钾盐、 铵盐、 三乙胺盐、 乙醇 胺盐、 二乙醇胺盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 磷酸盐、 三氟乙酸盐、 乙酸盐、 马来酸盐、 天冬氨酸盐、 谷氨酸盐、 苹果酸盐或它们的组合。  The compound according to claim 13 or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein the salt is selected from the group consisting of sodium salt , potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, acetate, maleate, day Aspartate, glutamate, malate or a combination thereof.
15. 制备根据权利要求 1~14任一项中所述化合物的方法， 该方法可选自包括以下步骤的 方法一、 方法二、 方法三或方法四：  15. A process for the preparation of a compound according to any one of claims 1 to 14, which may be selected from process 1, process 2, process 3 or process 4 comprising the following steps:
方法一:
Figure imgf000113_0002
通式 (I-a)化合物依次通过 Horner-Wadsworth-Emmons反应或 wittig反应、还原反应以及垸 基化反应转化为通式 (I-b)化合物； 或者通式 (I-a)化合物通过还原消除反应转化为通式 (I-b)化合 物； method one:
Figure imgf000113_0002
The compound of the formula (Ia) is subsequently converted into a compound of the formula (Ib) by a Horner-Wadsworth-Emmons reaction or a wittig reaction, a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a formula by a reduction elimination reaction ( Ib) a compound;
Figure imgf000114_0001
Figure imgf000114_0001
l-b l-c  L-b l-c
通式 (I-b)化合物通过 suzuki偶联反应以及加 还原反应转化为通式 (I-c)化合物;  The compound of the formula (I-b) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a reduction reaction;
Figure imgf000114_0002
通式 (I-c)化合物通过 Mitsunobu反应以及水解反应转化为通式 (I)化合物； 或者通式 (I-c)化 合物通过 Mitsunobu反应转化为通式 (I)化合物；
Figure imgf000114_0002
a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsunobu reaction and a hydrolysis reaction; or a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsunobu reaction;
方法二：  Method Two:
Figure imgf000114_0003
Figure imgf000114_0003
l-d l-e  L-d l-e
通式 (I-d)化合物通过亲核取代反应以及克莱森重排反应转化为通式 (I-e)化合物;  The compound of the formula (I-d) is converted into a compound of the formula (I-e) by a nucleophilic substitution reaction and a Claisen rearrangement reaction;
Figure imgf000114_0004
Figure imgf000114_0004
l-e l-f  L-e l-f
通式 (I-e)化合物通过环氧化反应以及开环反应转化为通式 (I-f)化合物；或者通式 (l-e)化合物 通过亲核取代反 I-f)化合物；  The compound of the formula (I-e) is converted into a compound of the formula (I-f) by an epoxidation reaction and a ring-opening reaction; or the compound of the formula (1-e) is substituted by a nucleophilic compound of the anti-I-f);
Figure imgf000114_0005
Figure imgf000114_0005
l-f 通式 (I-f)化合物通过 suzuki偶联反应通式 (I-c)化合物；或者通式 (I-f)化合物通过 suzuki偶联 反应以及加氢还原反应转化为通式 (I-c)化合物； Lf a compound of the formula (If) is suzuki coupled to a compound of the formula (Ic); or a compound of the formula (If) is converted to a compound of the formula (Ic) by a suzuki coupling reaction and a hydrogenation reduction reaction;
Figure imgf000115_0001
Figure imgf000115_0001
通式 (I-c)化合物通过 Mitsimobu缩合反应以及水解反应转化为通式 (I)化合物；或者通式 (I-c) 化合物通过 Mitsimobu缩合反应转化为通式 (I)化合物；  The compound of the formula (I-c) is converted to the compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; or the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
方法三：  Method three:
Figure imgf000115_0002
Figure imgf000115_0002
1-9 l-a  1-9 l-a
通式 (I-g)化合物通过 Adol反应转化为通式 (I-a)化合物；或者通式 (I-g)化合物通过亲核取代 反应转化为通式 (I-a)化合物;
Figure imgf000115_0003
a compound of the formula (Ig) is converted to a compound of the formula (Ia) by an Adol reaction; or a compound of the formula (Ig) is converted to a compound of the formula (Ia) by a nucleophilic substitution reaction;
Figure imgf000115_0003
卜 a l-f  Bu a l-f
通式 (I-a)化合物通过还原反应转化为通式 (I-f)化合物； 或者通式 (I-a)化合物通过还原反应 以及脱羟基反应转化为通式 (I-f)化合物；  The compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction and a dehydroxylation reaction;
Figure imgf000115_0004
Figure imgf000115_0004
l-f l-c  L-f l-c
通式 (I-f)化合物通过 suzuki偶联反应通式 (I-c)化合物； 或者通式 (I-f)化合物通过 suzuki偶 联反应以及加氢还原反应转化为通式 (I-c)化合物  The compound of the formula (I-f) is subjected to a suzuki coupling reaction to a compound of the formula (I-c); or the compound of the formula (I-f) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a hydrogenation reduction reaction.
Figure imgf000115_0005
通式 (I-c)化合物通过 Mitsimobu缩合反应以及水解反应转化为通式 (I)化合物；或者通式 (I-c) 化合物通过 Mitsimobu缩合反应转化为通式 (I)化合物；
Figure imgf000115_0005
a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; or a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction;
方法四：  Method four:
Figure imgf000116_0001
Figure imgf000116_0001
l-a  L-a
通式 （I-a)化合物通过 suzuki偶联反应转化为通式 (I-h)化合物； 或者通式 (I-a)化合物通过 suzuki偶联反应以及加氢还原反应转化为通式I-h)化合物；  The compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction; or the compound of the formula (I-a) is converted into a compound of the formula I-h) by a suzuki coupling reaction and a hydrogenation reduction reaction;
Figure imgf000116_0002
通式 (I-h)化合物通过还原胺化转化为通式 （1-i) 化合物;
Figure imgf000116_0002
a compound of the formula (Ih) is converted to a compound of the formula (1-i) by reductive amination;
Figure imgf000116_0003
通式 （1-i)化合物通过亲核取代反应、 Mitsimobu缩合反应以及水解反应转化为通式 (I)化 合物， 或者通式 (I-i)化合物通过 Mitsimobu缩合反应转化为通式 (I)化合物； 其中：
Figure imgf000116_0003
The compound of the formula (1-i) is converted to the compound of the formula (I) by a nucleophilic substitution reaction, a Mitsimobu condensation reaction and a hydrolysis reaction, or the compound of the formula (Ii) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction; :
L选自 F、 Cl、 Br或 I;  L is selected from F, Cl, Br or I;
R、 R1, R2、 R3、 R4、 R5、 R6、 R7、 R8、 R9、 R10、 Ru、 Q、 p、 q和 t如同与权利要求 1~14 中任一项所定义； R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as in claims 1 to 14 Defined by any one of them;
R16、 R17和 R18选自 H、 OH、 甲基或乙基。 R 16 , R 17 and R 18 are selected from H, OH, methyl or ethyl.
16. 一种药物组合物， 所述的组合物包括： 有效剂量的根据权利要求 1~14中任一项所述 的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或 前药， 以及药学上可接受的载体、 稀释剂、 佐剂或赋形剂； 还可进一步包括一种或多种其他治 疗剂。  A pharmaceutical composition, comprising: an effective amount of a compound according to any one of claims 1 to 14, or a stereoisomer, hydrate, ester, solvate, co-crystal thereof, A metabolite, a pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; may further comprise one or more additional therapeutic agents.
17. 根据权利要求 16所述的药物组合物， 其中所述的其他治疗剂包括： (a) GPR40激动剂或药学上可接受的盐， 和 /或 17. The pharmaceutical composition according to claim 16, wherein said other therapeutic agent comprises: (a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or
(b) DPP-IV抑制剂或药学上可接受的盐， 和 /或  (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or
(c) SGLT-2抑制剂或药学上可接受的盐， 和 /或  (c) an SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or
(d)？？ ！^激动剂和部分激动剂或药学上可接受的盐， 和 /或  (d)? ? ! An agonist and a partial agonist or a pharmaceutically acceptable salt, and/or
(e PPAR^双重激动剂或药学上可接受的盐， 和 /或  (e PPAR^ dual agonist or pharmaceutically acceptable salt, and/or
(； f) PPARs激动剂或药学上可接受的盐， 和 /或 (; f) a PPAR s agonist or pharmaceutically acceptable salt, and/or
(g)胰岛素或拟胰岛素或药学上可接受的盐， 和 /或  (g) insulin or pseudo-insulin or a pharmaceutically acceptable salt, and / or
(h) 蛋白酪氨酸磷酸酶 -1BCPTP-1B)抑制剂或药学上可接受的盐， 和 /或  (h) a protein tyrosine phosphatase-1BCPTP-1B) inhibitor or a pharmaceutically acceptable salt, and/or
(i)磺酰脲类抑制剂或药学上可接受的盐， 和 /或  (i) a sulfonylurea inhibitor or a pharmaceutically acceptable salt, and/or
G) a-葡糖苷酶抑制剂或药学上可接受的盐， 和 /或  G) an a-glucosidase inhibitor or a pharmaceutically acceptable salt, and/or
(k) GLP-K GLP-1类似物、 GIP-1、 HSD-1或药学上可接受的盐， 和 /或  (k) a GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or
(1)胰高血糖素受体拮抗剂或药学上可接受的盐， 和 /或  (1) a glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or
(m)抗炎药， 和 /或  (m) anti-inflammatory drugs, and / or
(n) 回肠胆汁酸转运蛋白抑制剂或药学上可接受的盐， 和 /或  (n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or
(0)减肥药， 和 /或  (0) diet pills, and / or
(p) 改善患者脂质分布的药物， 所述药物选自 HMG-CoA还原酶抑制剂、 胆汁酸螯合剂、 烟碱、烟酸或其盐、？？入！^激动剂、胆固醇吸收抑制剂、酰基 CoA (胆固醇酰基转移酶 (ACAT)) 抑制剂、 CETP抑制剂或酚类抗氧剂或药学上可接受的盐， 和 /或  (p) A drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter! An agonist, a cholesterol absorption inhibitor, an acyl CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or
(q)双胍类、 噻唑垸二酮类、 列奈类或其药学上可接受的盐或前药， 和 /或  (q) biguanides, thiazolidinediones, linoles or pharmaceutically acceptable salts or prodrugs thereof, and/or
(r) PARP抑制剂。  (r) PARP inhibitors.
18. 权利要求 17 所述的药物组合物， 其中， 所述 GPR40 激动剂选自 fasiglifam hemihydrate(TAK-875)或其药学上可接受的盐或前药。  The pharmaceutical composition according to claim 17, wherein the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate (TAK-875) or a pharmaceutically acceptable salt or prodrug thereof.
19. 权利要求 17所述的药物组合物，其中，所述 DDP-IV抑制剂选自 linagliptin (；利拉列汀 )、 omarigliptin (MK-3102), sitagliptin (西他列汀）、 vildagliptin (维达列汀）、 alogliptin (阿格列汀）、 saxagliptin (沙格列汀）、 denagliptin (地格列汀）、 Carmegliptin, Melogliptin (美罗利汀）、 Dutogliptin, Teneligliptin (特力利汀）、 Gemigliptin 或者 Trelagliptin; SGLT-2 抑制剂选自 dapagliflozin、 propanedioK empagliflozin、 ertugliflozin、 ipragliflozin、 tofogliflozin、 canagliflozinluseogliflozin； PARP抑制剂选自 bezafibrate、feno fib rate 、pioglitazone、azelaic acid、 rosiglitazone或 saroglitazar。  The pharmaceutical composition according to claim 17, wherein the DDP-IV inhibitor is selected from the group consisting of linagliptin (; linagliptin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (dimensional) Dalectin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin, Melogliptin (Merolidine), Dutogliptin, Teneligliptin (Teliglitin), Gemigliptin or Trelagliptin; The SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, propanedioK empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinluseogliflozin; the PARP inhibitor is selected from the group consisting of bezafibrate, feno fib rate, pioglitazone, azelaic acid, rosiglitazone or saroglitazar.
20. 根据权利要求 17所述的药物组合物， 其中， 所述双胍类治疗剂选自二甲双胍或者二 乙双胍； 噻唑垸二酮类治疗剂选自 Ciglitazone (环格列酮）、 Pioglitazone (吡咯列酮）、 The pharmaceutical composition according to claim 17, wherein the biguanide therapeutic agent is selected from metformin or diethylbiguanide; the thiazolidinedione therapeutic agent is selected from the group consisting of Ciglitazone (cycloglitazone) and Pioglitazone (pyrrole) ketone),
Rosiglitazone (罗格列酮)、 Troglitazone (曲格列酮)、 Farglitazar (法格列酮)或者 Darglitazoan (达格 列酮 )； 磺酰脲类治疗剂选自 Glimepiride (格列美脲)、 Tolglybutamide, Glibomuride (格列波脲 )、 Glibenclamide (格列苯脲)、 Gliquidone (格列喹酮)、 Glipizide (格列吡嗪)或 Gliclazipe (格列齐特)； 列奈类治疗剂选自 Nateglinide (那格列奈)、 Repaglinide (瑞格列奈)或者 Mitiglinid 米格列奈)； α- 葡萄糖苷酶抑制剂选自 Acarbose (阿卡波糖)、 MiglitolC伏格列波糖)或者米格列醇； GLP-1类似 物选自 Exenatide (艾赛那肽)或者 Liraglutide (利拉鲁肽 )。 Rosiglitazone, Roglitazone, Farglitazar or Darglitazonan; sulfonylurea therapeutics selected from Glimepiride, Tolglybutamide, Glibomuride, Glibenclamide, Gliquidone, Glipizide or Gliclazipe; Lenina therapeutics are selected from Nateglinide, Repaglinide Glinide) or Mitiglinid mitiglinide); α-glucosidase inhibitors are selected from Acarbose, MiglitolC voglibose or miglitol; GLP-1 analogues are selected from Exenatide (Essinide) or Liraglutide (Lilaglutide).
21. 权利要求 1-14中任一项所述的化合物或其立体异构体、水合物、 酯、溶剂化物、共晶 体、 代谢产物、 药学上可接受的盐或前药或者权利要求 16-20中任一项所述的药物组合物在制 备 G蛋白偶联受体 40激动剂中的用途，特别是在制备用于治疗和 /或预防代谢疾病的药物制剂 中的用途。  21. The compound of any one of claims 1 to 14, or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, or claim 16- Use of the pharmaceutical composition according to any of the preceding claims for the preparation of a G protein coupled receptor 40 agonist, in particular for the preparation of a pharmaceutical preparation for the treatment and/or prevention of a metabolic disease.
22. 根据权利要求 21所述的用途， 其中， 所述代谢疾病包括糖尿病、 II型糖尿病、 糖尿 病性视网膜病、 糖尿病性神经病、 糖尿病性肾病、 糖尿病并发症、 高胆固醇血症、 高血糖、 高 胰岛素血症、高脂血症、高甘油三酸脂血症、高血压、高脂蛋白血症、高 LDL胆固醇、低 HDL 胆固醇、 低血糖症、 血脂异常、 血栓性疾病、 心血管疾病、 肾脏疾病、 酮症酸中毒、 脂肪酸或 甘油的升高的水平、 脂肪萎缩、 脂肪毒性、 肥胖症、 代谢综合征、 X综合症、 胰岛素抗性、 胰 岛素过敏症、 葡萄糖耐受不良、 皮肤病、 动脉粥样硬化及其后遗症心绞痛、 跛行、 心脏病发作 或中风中的一种或多种。  The use according to claim 21, wherein the metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, high Insulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney Disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, arteries A atherosclerosis and its sequelae one or more of angina, limp, heart attack or stroke.
23. 根据权利要求 22所述的用途， 其中， 所述代谢疾病包括 II型糖尿病。  23. The use according to claim 22, wherein the metabolic disease comprises type II diabetes.
24. —种治疗和 /或预防代谢疾病的方法， 该方法包括给予受试者有效量的权利要求 1-14 中任一项所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上 可接受的盐或前药或者权利要求 16-20中任一项所述的药物组合物。  24. A method of treating and/or preventing a metabolic disease, the method comprising administering to a subject an effective amount of a compound of any one of claims 1-14, or a stereoisomer, hydrate, ester, solvent thereof A compound, a co-crystal, a metabolite, a pharmaceutically acceptable salt or prodrug or a pharmaceutical composition according to any one of claims 16-20.
25. 根据权利要求 24所述的方法， 其中， 所述代谢疾病包括糖尿病、 II型糖尿病、 糖尿 病性视网膜病、 糖尿病性神经病、 糖尿病性肾病、 糖尿病并发症、 高胆固醇血症、 高血糖、 高 胰岛素血症、高脂血症、高甘油三酸脂血症、高血压、高脂蛋白血症、高 LDL胆固醇、低 HDL 胆固醇、 低血糖症、 血脂异常、 血栓性疾病、 心血管疾病、 肾脏疾病、 酮症酸中毒、 脂肪酸或 甘油的升高的水平、 脂肪萎缩、 脂肪毒性、 肥胖症、 代谢综合征、 X综合症、 胰岛素抗性、 胰 岛素过敏症、 葡萄糖耐受不良、 皮肤病、 动脉粥样硬化及其后遗症心绞痛、 跛行、 心脏病发作 或中风中的一种或多种。  25. The method according to claim 24, wherein the metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, high Insulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney Disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, arteries A atherosclerosis and its sequelae one or more of angina, limp, heart attack or stroke.
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