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WO2014187365A1 - Oxabicyclo derivatives, preparation method and use thereof - Google Patents

Oxabicyclo derivatives, preparation method and use thereof Download PDF

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Publication number
WO2014187365A1
WO2014187365A1 PCT/CN2014/078325 CN2014078325W WO2014187365A1 WO 2014187365 A1 WO2014187365 A1 WO 2014187365A1 CN 2014078325 W CN2014078325 W CN 2014078325W WO 2014187365 A1 WO2014187365 A1 WO 2014187365A1
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Prior art keywords
group
membered
alkyl
cycloalkyl
alkoxy
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PCT/CN2014/078325
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French (fr)
Chinese (zh)
Inventor
李瑶
石宗军
陈雷
徐波
叶飞
魏用刚
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN201480000530.4A priority Critical patent/CN104619713B/en
Publication of WO2014187365A1 publication Critical patent/WO2014187365A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P3/04—Anorexiants; Antiobesity 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Definitions

  • the present invention relates to an oxabicyclo derivative, a preparation method and use thereof, and in particular to an oxabicyclic derivative represented by the formula ⁇ or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a process for the preparation thereof, and the like
  • SGLT sodium-dependent glucose transporter
  • Type II diabetes is the most common type of diabetes, and worldwide type II diabetes accounts for about 90% of all diabetes. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high calorie diets. In patients with type II diabetes, high blood sugar is caused by the body's inability to respond effectively to insulin. Hyperglycemia is the leading cause of diabetic complications such as cardiovascular disease, stroke and kidney failure, and these complications further aggravate the condition of diabetic patients.
  • the currently approved drugs for the treatment of type 2 diabetes are mainly insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (CTZDs), ex-glucosidase inhibitors, dextrin analogues, Incretin hormone analog, dipeptidyl peptidase inhibitor (DPP-IV) and the like.
  • CTZDs thiazolidinediones
  • ex-glucosidase inhibitors ex-glucosidase inhibitors
  • dextrin analogues Incretin hormone analog
  • DPP-IV dipeptidyl peptidase inhibitor
  • long-term use of these hypoglycemic agents does not achieve the expected reduction in glycated hemoglobin (HbAlc), and these hypoglycemic agents have side effects such as hypoglycemia, weight gain, and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop new hypogly
  • SGLT-2 is currently considered a promising new target for the treatment of type 2 diabetes (Clinical Diabetes,
  • SGLT-2 is a member of the transmembrane family of sodium-dependent glucose co-transporters (SGLTs), encoded by the SLC5 gene, expressed primarily in the renal proximal convoluted tubules, and approximately 90% of renal glucose reabsorption occurs in the renal cortical proximal tubule S1 In epithelial cells of the segment, SGLT-2 is the primary transporter responsible for this process.
  • SGLT-2 is a low-affinity, high-capacity transporter that allows SGLT-2 to efficiently transport glucose and sodium ions from the lumen to the tubular epithelial cytoplasm (in a molar ratio of 1:2) (Nephrol Dial Transplant, 2010) , 25, 2041-2043).
  • SGLT-2 is a low-affinity, high-capacity transporter that allows SGLT-2 to efficiently transport glucose and sodium ions from the lumen to the tubular epithelial cytoplasm (in a molar ratio of 1:2) (Nephrol
  • SGLT-2 inhibitors have been developed and shown good activity and selectivity, among which canagliflozin and dapagliflozin Already on the market, Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, and Ertugliflozin are in clinical research.
  • SGLT-2 inhibitors are a safe and effective new drug against type II diabetes.
  • a number of literatures on SGLT-2 inhibitor related studies have been reported.
  • WO2012019496 discloses a compound of the following structure as a SGLT-2 protein inhibitor
  • - ring A is selected from aryl or heteroaryl, wherein each aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl Substituents such as aryl, heteroaryl are substituted; R 5 and R 6 are each independently selected from H or a ruthenium atom, and the specific description in this patent is not considered to be part of the present invention.
  • WO2010023594 discloses the use of a compound of the following structure as a sodium-dependent glucose transporter (SGLT) inhibitor for the treatment and prevention of type 2 diabetes,
  • R 2 is CM alkyl, CM alkoxy, C 2 - 4 alkynyl, 0 -,, Cl, F , acyl, F substituting d- 2 alkyl, -S0 2 -Ci_ 4 alkyl, C 3 - 6 carbon ring containing 1 or 2 0, C S heteroatom 5--6 heterocycloalkyl; not specifically described in this patent that are part of the invention.
  • WO2012165914 discloses a compound having a structure having the action of an SGLT-2 inhibitor as an insulin secretion promoting/or therapeutic agent
  • X is selected from 0, S;
  • Y is selected from d- 7 alkyl, C 2 - 7 alkenyl group, C 2 - 7 alkynyl, d- 7 alkoxy, d- 7 -d- 7 alkoxyalkyl group, D- 7 alkylsulfinyl, d- 7 alkylsulfonyl, d- 7 alkylthio; This invention differs greatly from the structure of the compound of the present invention.
  • SGLT-2 inhibitors have compounds of the following structure for the treatment of diabetes
  • X is selected from a chemical single bond, NH, 0, S, S0, S0 2 or an alkylene group;
  • R 3 is selected from the group consisting of 0R 8 , a 5-12 membered spiro group, a 5-12 membered bridged ring group, and 6 to 14 members. a 5-12 membered spiro group, a 5-12 membered bridged ring group, a 6-14 membered ring ring of one or more carbon atoms substituted by a hetero atom of N, 0, S, SO and/or S0 2
  • the compounds of the oxygen-containing bridged ring on the sugar ring are not suggested or referred to in the present invention, and the specific description in this patent is not considered to be part of the present invention.
  • the object of the present invention is to introduce a novel class of SGLT-2 inhibitors, in particular having the compounds of the formula (I), which have been shown to have good SGLT-2 inhibitory activity and selectivity, Has the prospect of treating or relieving diabetes and similar diseases.
  • the present invention relates to an oxabicyclic derivative represented by the formula (I-A) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:
  • ⁇ cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m - (6 to 14 yuan) Heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14) a bridged ring) or -(CH 2 ) m -S( 0) n -R 9 , said alkyl, alkenyl, alkynyl, aryl, heteroaryl, spiro group, bridged ring group, And a cycloalkyl, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I,
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, C alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C 3 - 8 cycloalkyl Alkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 .14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl) ), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo
  • R 6 'and R 7 ' are each independently selected from H, hydroxy d_ 3 alkoxy or d 3 alkyl;
  • G is selected from a 6 to 14 membered aryl group or a 5 to 14 membered heteroaryl group, and the aryl or heteroaryl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 - 8 cycloalkyl, -(CH 2 ) m - (3 to 8-membered hetero Cycloalkyl), -(CH 2 ) m -C 6 - 14 aryl, -(CH 2 ) m -(6 to 14-membere
  • R 8, R 1Q and R 11 are each independently selected from H, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heteroaryl
  • R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic ring
  • n is selected from 0, 1 or 2;
  • p is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H.
  • R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, e
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d — 8 alkoxy, —(CH 2 ) m —C 2 —8 alkenyl- R 12 , —(CH 2 ) m —C 2 —8 alkynyl—R 12 , —(CH 2 ) m —C 3 — 8 -cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 .
  • G is selected from a 6 to 14 membered aryl group or a 5 to 14 membered heteroaryl group, and the aryl or heteroaryl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, C alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C 3 - 8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 - 14 aryl, -(CH 2 ) m -( 6 to 14 membered heteroaryl),
  • R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic ring
  • n is selected from 0, 1 or 2;
  • p is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R is selected from H, d- 6 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - C 6 . 10 aryl, —(CH 2 ) m —(6 to 10 membered heteroaryl), —(CH 2 ) m —(5 to 12 membered spiro group), —(CH 2 ) m —(4 Up to 12-membered and cyclic group), -(CH 2 ) m -(5 to 12-membered bridged ring group), -(CH 2 ) m -C 2 .
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • X is selected from -0- or -S-, preferably -0-.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula ⁇ or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, d- 6 alkyl, d — 6 alkoxy, —(CH 2 ) m —C 2 —6 alkenyl-R 12 , —(CH 2 ) m —C 2 —6 alkynyl-R 12 , —(CH 2 ) m —C 3 — 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14-membered hetero Aryl), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy , ethoxy, propoxy, isopropoxy, butoxy, cyclopropyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -0-cyclohexyl, - 0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, -0-oxetanyl, cyclobutyl, cyclopenty
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, —CH 2 F, —CHF 2 , —CF 3 , methyl, ethyl, methoxy. , ethoxy, cyano, hydroxy, ethynyl or propynyl.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 5 is selected from the group consisting of F, Cl, methyl, ethyl, methoxy, -CHF 2 or -CF 3 , preferably Cl.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • G is selected from a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, preferably a 6 to 10 membered aryl group or a 5 to 6 membered heteroaryl group, further preferably a benzene ring, a thiophene or a thiazole; wherein the benzene ring, The aryl, thiophene, thiazole or heteroaryl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, carboxy , d 6 alkyl, d 6 alkoxy, - 33 ⁇ 4)
  • -(CH 2 ) m -0-(CH 2 ) m -0-R 12 -(CH 2 ) m -(3 to 6-membered heterocycloalkyl)
  • R 12 is selected from a 3- to 6-membered cycloalkyl group
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • G is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, preferably 6 to 10 membered aryl or 5 to 6 membered heteroaryl, further preferably benzene ring, thiophene or thiophene; said benzene ring, Thiophene, thiazole, aryl or heteroaryl optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 Alkyl, d- 6 alkoxy, -( ! ⁇ cycloalkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 )
  • n is selected from 0 1 or 2;
  • n is selected from 0 1 or 2
  • Preferred embodiments of the invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or cocrystal:
  • R is selected from H d 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C .
  • G is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, preferably selected from 6 to 10 membered aryl or 5 to 6 membered heteroaryl, the aryl or heteroaryl group of which is independently optionally further Up to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, aldehyde, carboxyl, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -(3 to 6-membered heterocycloalkane (), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2
  • n is selected from 0, 1 or 2;
  • p is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, wherein:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl, d- 4 alkoxy, -(CH 2 ) m -C 2 _ 4 alkenyl group -R 12 or - (CH 2) m -C 2 _ 4 -R 12 alkynyl group, preferably H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyl Alkyn-1-yl, methoxy, ethoxy, propoxy, isopropoxy or butoxy; wherein the alkyl, alkoxy, alkeny
  • G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein the benzene ring, thiazole or thiophene is further optionally 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, and nitrate group, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-alkyl), -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 6 _ 10 aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl) , -(CH 2 ) m -(5 to 12-membered spiro group), -(
  • R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring
  • n is selected from 0, 1 or 2;
  • p is selected from 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, wherein:
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy, B Oxyl, propoxy, isopropoxy or butoxy, when substituted, are each independently optionally from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3, hydroxy, methyl, ethyl, methoxy or ethoxy substituents; W is selected from -CH 2 - or, and -CH 2 - or are each independently optionally further substituted by 0-2 selected
  • G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein each of the benzene ring, the thiazole or the thiophene is optionally further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano , nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-group ), -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 yuan heteroaryl) Base), -(CH 2 ) m -(5 to 12 membered spiro
  • R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer thereof, a hydrate thereof, a solvent Compound, pharmaceutically acceptable salt,
  • R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 3 -6 cycloalkyl, -( CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 - 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), -(CH 2 ) m -
  • two adjacent groups of R 2 ', R 3 ', R 4 ' and R 5 ' may form a 4- to 8-membered ring, preferably a 4- to 6-membered ring, further preferably a 4-membered ring;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, 6 alkyl, D- 6 alkoxy, - (CH 2) m- 0- (CH 2) m-0-R 12, - (CH 2) m -C 3 - 6 cycloalkyl, - ( CH 2 ) m -(3 to 6-membered heterocycloalkyl), CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), -( CH 2 ) m - (4 to 12 membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0- (5 to 12 membered spir
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, cyano, and . ⁇ . ,, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, uncle butoxy, cyclopropyl, cyclobutyl, -0- cyclopropyl, cyclobutyl -0-, -0- propyl oxetane, oxetanyl -0-, - -CH 2 - ring Propyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, furyl, thienyl,
  • R l R 2 'and R 5 ' are further preferably H or F, and R 3 'and R 4 ' are further preferably F, ethoxy, methoxy or-0-oxocyclopentyl;
  • R 3 'and R 4 ' are further preferably F, ethoxy, methoxy or-0-oxocyclopentyl;
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 10 and R 11 are each independently selected from H or d- 4 alkyl
  • R 12 is selected from H
  • R 13 is each independently selected from H, amino, hydroxy or d- 3- alkyl
  • n is selected from 0;
  • n is selected from 0.
  • Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl , -0-oxetanyl, -(CH 2 )m-0-(CH 2 )m-0-R 12 or -0-oxocyclopentyl.
  • Preferred embodiments of the invention include oxabicyclic derivatives of the formula (I-B) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts thereof, eutectics thereof:
  • the alkyl group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2
  • R 3 'and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 alkyl, alkoxy, -(CH 2 )mC 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m - (6 to 10 membered heteroaryl), -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.
  • Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 3 'and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 4 alkyl, d- 4 alkoxy , -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, - (CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -(5 to 12 membered spiro ring) (), -(CH 2 ) m - (4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered
  • Aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring group), -0- (4 to 12 yuan) Bridged ring), -(CH 2 ) m -S( 0) n -R 9 or -NR 1Q R U , further preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d 4 alkyl, d 4 alkoxy, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkane) a group, -0-C 3 - 6 cycloalkyl or -0-(3 to 6-membered heterocycloalkyl), more preferably 1 ⁇ or - 4 alkoxy; said alkyl, aryl,
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0;
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.
  • Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R 3 'and R 4 ' are each independently selected from H, F, d- 4 alkoxy or ⁇ ° ⁇ 7, preferably H, F, ethoxy or. ⁇ .
  • Preferred embodiments of the invention include a compound of the formula (IB): or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R 3 ' is selected from an ethoxy group Or ⁇ ° ⁇ .
  • Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • Is R 4 ' selected from 11 or? .
  • alkoxy group is further Up to 5 selected from F, Cl, Br, I, hydroxy, d- 4 alkyl or d- 4 alkoxy;
  • X is selected from -0- or -S-;
  • Ring G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein the benzene ring, thiazole or thiophene is further optionally 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, Nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -( !! ⁇ cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), - (CH 2 ) m - (4 to 12 membered bridged ring group), -0 3 -6
  • p is selected from 1, 2 or 3;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • R is selected from H, methyl, ethyl, cyclopropyl, oxetanyl, oxetanyl, oxetanyl, azacyclopentyl or pyridyl, and these groups may optionally be further From 0 to 4 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, amino, cyano or hydroxy Substituted by a substituent;
  • X is selected from -0- or -S-;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, methyl, ethyl, methoxy, ethoxy, cyano, hydroxy, ethynyl or propynyl;
  • W is selected from -CH 2 - or , and -CH 2 - or ⁇ are each independently optionally further 0 to 2 selected from the group consisting of F, Cl, Br, -CF 3 , methyl, ethyl, n-propyl, methoxy Substituted by a substituent of a ethoxy group or an ethoxy group;
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof including oxygen represented by the formula ( ⁇ ) a heterobicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof:
  • X is selected from -0- or -S-;
  • R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy;
  • W is selected from d-3 alkylene or ⁇ >P, and each of the alkylene or "' oxime is further further selected from 0 to 4 selected from the group consisting of F, Cl, -CF 3 , hydroxy, d - 3 alkyl Or substituted with a substituent of a d-3 alkoxy group;
  • n is selected from 0, 1 or 2;
  • p is selected from 1 or 2;
  • n is selected from 0, 1 or 2.
  • the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof which comprises the formula (III) Oxybibicyclic derivatives or stereoisomers, hydrates, solvates, acceptable salts, co-crystals or prodrugs thereof:
  • R 12 is selected from a 3- to 6-membered cycloalkyl group
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the invention include oxabicyclic derivatives of the formula (1), (II) or (III) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts thereof, co-crystals or Prodrug, where:
  • R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, CM alkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 or d_ 4 alkoxy;
  • R 12 is selected from a 3- to 6-membered cycloalkyl group
  • n is selected from 0, 1 or 2;
  • n is selected from 0, 1 or 2.
  • Preferred embodiments of the invention include the oxabicyclic derivatives of the formula 1, (II) or (III) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, co-crystals thereof or Medicine, where:
  • R is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 C ⁇ N, cyclopropyl, cyclobutyl, oxopropyl, pyridyl, oxetanyl or
  • R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, methoxy, ethoxy, cyclopropyl, ',. ⁇ . , -0-oxetanyl or -0-oxocyclopentyl.
  • the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof which comprises the formula (IV) Oxybibicyclic derivatives or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, co-crystals or prodrugs thereof:
  • X is selected from -0- or -S-;
  • X is selected from -0- or -S-;
  • R is selected from the group consisting of methyl, ethyl, isopropyl, ⁇ , 0- C HF 2 , "- ⁇ , cyclopropyl or pyridyl;
  • the invention relates to a compound selected from, but not limited to:
  • the present invention also relates to a compound of the formula 0V) or a stereoisomer thereof, which is an intermediate for the synthesis of an oxabicyclic derivative of the formula (I) :
  • RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W and ring G are identical to the definitions of the compounds of formula (I).
  • G is selected from a 6 to 10 membered aryl group or a 5 to 6 membered heteroaryl group, preferably a benzene ring, thiophene or thiazole; wherein the benzene ring, thiophene, thiazole, aryl or heteroaryl group is optionally further 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, carboxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -0-(CH 2 ) m -0- R 12 , -(CH 2 ) m -C 6 .
  • R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, or preferably 11 ⁇ --4 alkyl, or more preferably 11 - 2 alkyl;
  • R 1Q and R 11 are each independently selected from H, d- 4-alkyl, amino, hydroxy, C 3 - 6 cycloalkyl, 3 to 6-membered heterocyclic group or CM alkoxy, preferably preferably 11, d- 4 alkyl, amino, hydroxy or d- 4 alkoxy, further preferably 11 or -2- alkyl; n is selected from 0, 1 or 2, preferably 0 or 1, Further preferably 0;
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy , ethoxy, propoxy, isopropoxy, butoxy, cyclopropyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -0-cyclohexyl, - 0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, -0-oxetanyl, cyclobutyl, cyclopenty
  • G is selected from phenyl, optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, vinyl, propenyl, allyl, 2-buten-1-yl, ethynyl, propynyl, propargyl , 2-butyn-1-yl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -
  • a substituent preferably selected from 0 to 3, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-Butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropyl, -0- Cyclobutyl, -0-cyclopentyl, -0-oxopropyl,
  • a heterocyclic butyl group, an oxolyl group, a furyl group, a thienyl group or a pyrrolyl group is further preferably F, Cl, or . ⁇ .
  • R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, Propynyl, propargyl, 2-butyn-1-yl, methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy, when substituted, are each independently optional Substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, methyl, ethyl, methoxy or ethoxy;
  • Ring G is selected from phenyl, optionally further selected from 0 to 3 F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropyl, -0-cyclobutyl Base, -0-cyclopentyl, -0-oxopropyl, -0-oxygen
  • the present invention also relates to a process for the preparation of an oxabicyclic derivative of the formula 1, which comprises:
  • the compound of the formula (VI-a) is subjected to elimination reaction under strong base conditions to obtain a compound of the formula (VI-b);
  • the compound (VI-a) undergoes a elimination reaction under a strong base condition under a nitrogen atmosphere to obtain a compound (VI-b);
  • the strong base may be selected from (but not limited to; I: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide , sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide;
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the preferred conditions are as follows: under a nitrogen atmosphere, using hydrazine, hydrazine-dimethylformamide as a solvent, and the compound (VI-a) at 30-40 ° C is Sodium hydride is a strip of alkali for 2 to 8 hours;
  • the compound (VI-b) is epoxidized under an oxidizing agent at a suitable temperature to obtain a compound (VI-c);
  • the polar aprotic solvent may be selected from, but not limited to: dichloromethane, chloroform or 1,2-dichloroethane; wherein the oxidizing agent may be selected from (but not limited to; I: osmium tetroxide, potassium citrate, Hydrogen peroxide, oxygen, peroxybutanol, potassium peroxymonosulfate, peroxyacetone, trifluoroperoxyacetone or m-chloroperoxybenzoic acid;
  • the compound (VI-b) is epoxidized under the condition of using m-chloroperoxybenzoic acid as an oxidizing agent in a solvent of dichloromethane at a temperature of 10 to 35 ° C, and the reaction is stirred for 2 to 8 hours;
  • the compound (VI-b) is treated with m-chloroperoxybenzoic acid as an oxidizing agent at a temperature of 10 to 35 ° C for 2 to 8 hours under a nitrogen atmosphere using dichloromethane as a solvent;
  • the compound (VI-c) undergoes a ring-opening reaction under acidic conditions at a suitable temperature to obtain a compound (VI-d) ;
  • the compound (VI-c) undergoes a ring-opening reaction under acidic conditions at a suitable temperature to obtain a compound (VI-d) ;
  • the acid may be selected from, but not limited to, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, hydrochloric acid, sulfuric acid or acetic acid;
  • the compound (VI-d) undergoes a ring closure reaction under a strong base at a suitable temperature to obtain a compound (VI-e);
  • the compound (VI-d) undergoes a ring-closing reaction under a strong base in a protic solvent at a suitable temperature under a nitrogen atmosphere to obtain a compound (VI-e);
  • the protic solvent is selected from, but not limited to: methanol, ethanol, tert-butanol or isopropanol;
  • the strong base is selected from, but not limited to: DBU, sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, tert-butyl Potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide;
  • the preferred conditions are as follows: using methanol as a solvent, sodium methoxide as a base, and stirring the compound CVI-d at 10 to 35 ° C for 1 to 5 hours; further preferred conditions are: under a nitrogen atmosphere, methanol as a solvent, sodium methoxide as a base , the compound (VI-d) is stirred at 10 ⁇ 35'C for 1 ⁇ 5 hours;
  • the compound of the formula (VI-e) is electrophilically substituted under a strong base to give a compound of the formula (VI);
  • the compound (VI-e) undergoes an electrophilic substitution reaction under a strong base to obtain a compound CVI);
  • the compound (VI-e) undergoes an electrophilic substitution reaction under a strong base to obtain a compound (VI);
  • the strong base may be selected from, but not limited to: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, ethanol Sodium, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide;
  • the preferred conditions are as follows: using hydrazine, hydrazine-dimethylformamide as a solvent, and stirring the compound (; VI-e) at 10 to 35 ° C for 1 to 6 hours; further preferred conditions are: under nitrogen atmosphere, ⁇ , ⁇ -Dimethylformamide is the solvent, and the compound (VI-e) is stirred at 10 ⁇ 35'C.
  • the compound (I) is preferably removed in a protic or aprotic solvent at a suitable temperature and a catalyst to obtain the compound (I);
  • the protic or aprotic solvent may be selected from, but not limited to: methanol, ethanol, isopropanol, formic acid, glacial acetic acid, tetrahydrofuran or acetonitrile;
  • the catalyst can be selected from: palladium/carbon, palladium hydroxide/carbon, ammonium formate and palladium/carbon, boron trichloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, lithium hydroxide, potassium carbonate-methanol, methanol-sodium methoxide. , palladium chloride, tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine or hydrogen fluoride-triethylamine;
  • the preferred conditions are as follows: using methanol as a solvent, 10% palladium/carbon as a catalyst, and reacting at room temperature under normal pressure for 1 to 10 hours in the presence of hydrogen;
  • X is 0;
  • W, R, G, R 4 , R 5 , R 6 and R 7 are as defined in formula (I) or (II);
  • P is a hydroxy protecting group, and P is preferably selected from d-4 alkyl, -C ⁇ C-d- 6 alkyl, benzyl, p-methoxybenzyl, benzoyl, allyl, trimethylsilyl, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, further preferably a benzyl group, an acetyl group or an allyl group;
  • Y is selected from H, d- 4 alkyl, trifluoromethanesulfonate, methylsulfonyl, p-toluenesulfonyl or acetyl, preferably H, d- 4 alkyl, methylsulfonyl or acetyl, more preferably methyl.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of an oxabicyclic derivative of the formula ⁇ or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, A crystal or prodrug and/or one or more additional therapeutic agents and a pharmaceutically acceptable carrier, excipient or diluent.
  • therapeutic agents preferred in the present invention include:
  • the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, Atigliflozin, Empagliflozin, and Ipragliflozin. ), Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin;
  • the DPP-IV inhibitor is selected from the group consisting of Linagliptin, sitagliptin, Vildagliptin, Alogliptin, and Saxagliptin. ), Denagliptin, Carmegliptin, MK-3102 (Omarigliptin), Melogliptin, MK-3102 (Omarigliptin), Dugtogliptin, Tigri Teneligliptin, Geigliptin Or treglifleurin (Trelagliptin);
  • the therapeutic agent biguanide therapeutic agent is selected from the group consisting of metformin or phenformin
  • the thiazolidinedione therapeutic agent is selected from the group consisting of Ciglitazone, Pioglitazone, and Rosiglitazone.
  • Troglitazone, Farglitazar or Darglitazoan sulfonylurea therapeutic agent selected from Glimepiride, Tolglybutamide, Grid Glibomuride, Glibenclamide, Gliquidone, Glipizide or Gliclazipe.
  • the therapeutic agent of Lenna is selected from nateglinide.
  • the ⁇ -glucosidase inhibitor is selected from the group consisting of Acarbose, Voglibose or Miglitol.
  • the glucagon-like peptide-1 analogue is selected from Exenatide or Liraglutide (Limgl U tide;».
  • the pharmaceutical composition of the present invention can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like.
  • Oral directly includes tablets, dispersible tablets, dragees, granules, dry powders, capsules and solutions, and injections include small needles, large infusions, and lyophilized powders.
  • the present invention relates to a compound of the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof thereof as a sodium-dependent glucose transporter inhibitor the use of;
  • the use of the sodium-dependent glucose transporter inhibitor is selected from the group consisting of metabolic diseases;
  • the metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity Symptoms, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension;
  • diabetes is preferably type II diabetes.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen 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 ), ⁇ ( ⁇ , also known as super heavy hydrogen), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 C1 and 37 C1, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably Further, 1 to 6 carbon atoms, still more preferably a linear or branched group of 1 to 4 carbon atoms, and most preferably 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl Base, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3 -hexyl, 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, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethyl Pentyl, 2,3
  • R a and R d are each independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro, and cyclylene.
  • Alkylene means a straight or branched chain alkane derived from the removal of two hydrogen atoms from the above alkyl group, including -(CH 2 ) V - ( V is 1 to
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, and the like.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.
  • Alkoxy means a-0-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, undertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.
  • Alkoxyalkyl means an alkyl group attached to an alkoxy group.
  • the alkoxyalkyl group can be substituted or unsubstituted, non-limiting examples of which include, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy , propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropyloxymethyl, cyclopropane Oxyethyl, cyclopropyloxypropyl and cyclohexyloxymethyl; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkane Oxyl, haloalkyl, thiol, hydroxy, nitro, fluorenyl, amino, cyano, iso
  • Alkenyl means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 in the main chain. Up to 8 carbon atoms, the alkenyl group may be substituted or unsubstituted.
  • Non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1- Decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.
  • Alkynyl means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl group up to 4 carbon atoms.
  • An alkynyl group can be substituted or unsubstituted.
  • Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl , 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups , independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano,
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.
  • Alkylthio means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine.
  • Cyano means -C ⁇ N.
  • Isocyano means -N ⁇ C.
  • Neitro means -N0 2 .
  • Haloalkyl means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo.
  • Mercaptan means a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a mercapto group, and non-limiting examples include methyl mercaptan, ethyl mercaptan, 1,2-dithiol.
  • Hydroxyalkyl means that the alkyl group is substituted by one or more hydroxyl groups, preferably by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a lower alkyl group.
  • Non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl, and the like.
  • Cycloalkyl means a saturated or unsaturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene A group, a cycloheptenyl group, a 1,5-cyclooctadienyl group, a 1,4-cyclohexadienyl group, a cycloheptatrienyl group, and the like.
  • a heteroatom or group non-aromatic ring system the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms.
  • the selectively substituted N, S in the heterocyclyl ring can be oxidized to various oxidation states.
  • Non-limiting examples include oxiranyl, oxetanyl, oxolane, oxetan, oxetan, oxetanyl, aziridine, azetidin Base, azacyclopentyl, nitrogen heterocycle Hexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3- Dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, Pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran
  • R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option
  • R b and R e may form a five- or six-membered cycloalkyl or heterocyclic group.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.
  • one step is preferably 6 to 12 yuan, more preferably 6 to 10 yuan, non-limiting examples of which include
  • R b and R e are independently selected Including H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Acyl, Alternatively, R b and R e may form a five or six membered cycloalkyl or heterocyclic group.
  • R a and R d are each independently selected from aryl, heteroaryl, al
  • Non-limiting examples include
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further Excellent 5 to 12, in further 5 to 10.
  • Non-limiting examples include
  • R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option
  • R b and R e may form a five- or six-membered cycloalkyl or heterocyclic group.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.
  • Benzyl refers to -CH 2 - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH 2 - phenyl, -CH 2 - p-methylphenyl and the like.
  • Aryl means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups.
  • a 6 to 14 membered aromatic ring is preferred, and a 6 to 10 membered aromatic ring is further preferred, and non-limiting examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.
  • the ring is further preferably 5 to 6 yuan.
  • heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include with'
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.
  • Arylthio means an -S-aryl or -S-heteroaryl group as defined herein.
  • arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, pyrimidinylthio, and the like.
  • silica refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.
  • single bond refers to a chemical single bond, such as "a single bond between A and B" means that there is an chemical single bond between A and B, namely: A-B.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or a salt obtained by reacting the free acid with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • metal salts such as iron salts, copper salts, cobalt salts, etc.
  • organic base salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-lutidine salts, ethanolamine salts, Diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, phosphonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, Dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt , tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine , N-ethylpiperidine salt, tetramethylamine salt, di
  • An aryl sulfonate such as besylate, p-toluenesulfonate, etc.; an organic acid salt such as formic acid salt, fumarate, formate, trifluoroethyl Acid salt, citrate, gluconate, glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, dihydroxynaphthalene Acid salt, pantothenate, stearate, succinate, sulfonate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, hydroxyethyl Acid salts, glucuronates, galacturonates, citrates, lysine salts, arginine salts, aspartates, cinnamate salts, and the like.
  • an organic acid salt such as formic acid salt, fumarate, formate, trifluoroethyl Acid salt, citrate, gluconate, gluta
  • “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 a clinically used drug for the treatment, prevention of diabetes or/and SGLT - 2 Inhibitors or/and mixtures of DPP-IV inhibitors with other ingredients, wherein the other components comprise physiological/pharmaceutically acceptable carriers and excipients.
  • Drugs for clinical use and for the prevention of diabetes include biguanide, thiazolidinedione, sulfonylurea, linoleide, (X-glucosidase inhibitor, GLP-1 analogue or a pharmaceutically acceptable salt thereof, For example, metformin, phenformin, Ciglitazone, Pioglitazone, Rosiglitazone, Troglitazone, Farglitazar, Daglitazone (Darglitazoan), Glimepiride, Tolglybutamide, Glibornuride, Glibenclamide, Gliquidone, Glipizide ), gliclazipe, Nateglinide, Repaglinide, mitiglinide, Acarbose, Voglibose , Miglitol, Exenatide or Liraglutide, SGLT-2 inhibitors such as dapagliflozin, Canagliflozin , Empagliflozin, Ipragliflozin,
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, etc.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to provide the parent compound.
  • a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, respectively.
  • Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphorus of the compounds of the invention The acid forms a sodium salt derivative.
  • Co-crystal or “eutectic” refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF cocrystal former
  • the pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • a eutectic is a multicomponent crystal that contains both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed by a neutral solid with a salt or solvate.
  • the "eutectic former” includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols, or other solvents, non-limiting examples of which include alanine CAla), hydrazine Acid (; Val), leucine (; Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), Serine (Ser), Threonine (Thi, Cysteine (Cys Tyrosine (Tyr ⁇ N Asparagine (Asn), Glutamine (Gin), Lysine (Lys), Fine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, C Acid, benzene
  • X Syndrome refers to the conditions, diseases, and conditions of metabolic syndrome.
  • X Syndrome refers to the conditions, diseases, and conditions of metabolic syndrome.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • IC 5Q refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the preparation method of the compound of the formula ⁇ of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof comprises the following steps:
  • X is O
  • W, R, G, R 4 , R 5 , R 6 and R 7 are as defined in the general formula (I);
  • P is a hydroxy protecting group, and P is preferably selected from CM alkyl, -C ⁇ C-d- 6 alkyl, benzyl, p-methoxybenzyl, benzoyl, allyl, trimethylsilyl, triethyl a silyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, further preferably a benzyl group, an acetyl group or an allyl group;
  • Y is selected from H, d- 4 alkyl, trifluoromethanesulfonate, methylsulfonyl, p-toluenesulfonyl or acetyl, preferably H, d- 4 alkyl, methylsulfonyl or acetyl, further preferably methyl;
  • the strong base can be selected from, but not Limited to: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide , lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: ⁇ , ⁇ -dimethyl under nitrogen atmosphere
  • the base formamide is a solvent, and the compound (VI-a) at 30-40 ° C is eliminated under the condition of sodium hydride as a base, and the reaction is stirred for 2
  • the compound (VI-b) Under a nitrogen atmosphere, in a polar aprotic solvent, at a suitable temperature, the compound (VI-b) is under oxidizing conditions.
  • the epoxidation reaction occurs to obtain the compound (VI-c);
  • the polar aprotic solvent may be selected from, but not limited to: dichloromethane, chloroform or 1,2-dichloroethane
  • the oxidizing agent may be selected from, but Not limited to: osmium tetroxide, potassium citrate, hydrogen peroxide, oxygen, peroxybutanol, potassium peroxymonosulfate, peroxyacetone, trifluoroperoxyacetone or m-chloroperoxybenzoic acid; preferred conditions are: nitrogen atmosphere
  • dichloromethane as a solvent
  • the compound (VI-b) at 10 ⁇ 35'C is epoxidized under the condition of m-chloroperoxybenzoic acid as an oxidizing agent, and the reaction is stirred for 2
  • the compound (VI-d) undergoes a ring-closing reaction under a strong base to obtain a compound (VI-e) ;
  • the protic solvent is selected from, but not limited to, : methanol, ethanol, tert-butanol or isopropanol, strong base selected from, but not limited to: DBU, sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide , lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: under nitrogen atmosphere, methanol as solvent, sodium methoxide as alkali, 10 The compound CVI-d) is stirred at ⁇ 35 ° C for 1 to 5 hours;
  • the strong base may be selected from, but not limited to : 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, Lithium hydroxide, lithium aluminum hydride, t-butyl lithium, potassium t-butylate, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: ⁇ , ⁇ -dimethyl under nitrogen atmosphere The formamide is used as a solvent, and the compound (VI-e) is stirred at 10 to 35 ° C for 1 to 6 hours;
  • a protic or aprotic solvent the compound (VI) is removed from the protecting group P at a suitable temperature and a catalyst to obtain a compound proton or an aprotic solvent, which may be selected from, but not limited to: methanol, ethanol, and different Propanol, formic acid, glacial acetic acid, tetrahydrofuran or acetonitrile, catalysts can be used: palladium / carbon, palladium hydroxide / carbon, ammonium formate and palladium / carbon, boron trichloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydroxide Lithium, potassium carbonate-methanol, methanol-methanol sodium, palladium chloride, tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine or hydrogen fluoride-triethylamine; preferred conditions are: methanol as solvent, 10% palladium/carbon as catalyst ,
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10 - 6 (ppm).
  • NMR tetramethylsilane
  • DMSO-d 6 dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the ⁇ MR information is listed in the following format: Chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) , the number of protons).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x 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 a specification of 0.4 mm. ⁇ 0.5 mm.
  • sodium hydride, triphenylphosphine, sodium thiosulfate, sodium methoxide, iodine, trifluoroacetic acid, dicyclohexylcarbodiimide, o-dichlorobenzene were purchased from Chengdu Kelon Chemical Reagent Factory; Benzoic acid was purchased from Ester (Chengdu) Pharmaceutical Technology Co., Ltd.; ethyl iodide, 4-dimethylaminopyridine, boron chloride, 2-mercaptopyridine-N-oxide, diethylaminosulfur trifluoride purchased from An Naiji Chemical; Palladium Carbon purchased from Chengdu Juhui Chemical Technology Co., Ltd.; Lithium tetrahydroborate, Days Martin purchased from Shanghai Titan Technology Co., Ltd.; 2-Iodopropane purchased from Shanghai Bied Pharmaceutical Technology Co., Ltd.; Ethyl ester was purchased from Sinopharm Chemical Reagent Co., Ltd.; i
  • 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 2 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is the optimum reaction temperature, which is 20 ° C ⁇ 30 ° C.
  • reaction solution was diluted with saturated ammonium chloride solution (60 mL), and extracted (100 mL X 3), the organic phase washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and ethyl acetate.
  • Step 5 (lS, 2S, 3S, 4R, 5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6 ,8-Dioxabicyclo[3.2.1]octane-1-ol (Intermediate 1)
  • reaction solution was diluted with a saturated aqueous solution of ammonium chloride (100 mL) and ethyl acetate (100 mL?
  • the organic phase was washed with water (80 mL EtOAc)EtOAc.
  • Step 5 (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6,8-dioxabicyclo[3.2.1]octane-1-ol (intermediate 2)
  • reaction solution was added to ice water, extracted with dichloromethane (200 mL ⁇ 3), and the organic phase was saturated sodium bicarbonate (250 mL x 2), water (200 mL x 2), brine (200 mL x 2) Wash Dry, dry anhydrous sodium sulfate, filtered, concentrated to give a black liquid (2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-( 4-(2-cyclopropyloxyethoxy;)benzyl;)phenyl;)hexane-1,2,6-triyltriacetate 3H crude (15.3 g), directly into the next reaction .
  • Step 6 (3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)) Benzyl)phenyl)hexane-1,2,6-triol (31)
  • Step 7 (2S,3R,4R)-2,3,4-Tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-l-(4-chloro- 3-(4-(2-cyclopropyloxyethoxy;)benzyl;)phenyl;)hexane-1,5-diol (3 J)
  • Step 8 (2R,3R,4S)-2,3,4-Tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-1-(4-chloro- 3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane- 1 ,5-dione (3K)
  • Step 9 (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxy) Ethoxy)benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 3)
  • the mixture was adjusted to neutral with ammonium chloride under ice bath, and the aqueous phase was combined with ethyl acetate (20 mL ⁇ 3).
  • the organic phase was combined and washed with water (20 mL ⁇ 2), brine (20 mL ⁇ l) Dry over sodium sulfate, filter and concentrate under reduced pressure.
  • the reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 1 hour under a hydrogen atmosphere.
  • the reaction solution was filtered, and the palladium carbon was removed.
  • reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 3 hours under a hydrogen atmosphere.
  • reaction solution was diluted with ethyl acetate (100 mL), and aqueous sodium thiosulfate solution was added dropwise to an ice-water bath until the color of the reaction mixture disappeared, and water (100 mL) was added to separate layers.
  • the mixture was extracted with EtOAc (EtOAc)EtOAc.
  • the first step product (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-carbaldehyde 15b was added to a mixed solution of water (27 mL) and acetonitrile (108 mL).
  • Sodium hydrogen phosphate (0.78 g, 5 mmol
  • hydrogen peroxide (30%, 4.2 g, 37 mmol
  • sodium chlorite (5.0 g, 55.5 mol to room temperature for 2 hours.
  • Step 5 (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(pyridin-2-ylthio)- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 15)
  • the activity of the compounds of the invention was evaluated using the SGLT-2 in vitro inhibition assay.
  • the test method is as follows: The test compound is dissolved in DMSOC dimethyl sulfoxide;) to prepare a stock solution, which is then diluted to the desired concentration.
  • hSGLT-2 cells were plated in 96-well plates and cultured in F12 complete medium. After 48 hours of culture, each well was washed 3 times with a buffer of pH 7.4. A buffer containing different test compounds and [14C]-cx-methyl-glucoside (10 ⁇ /ml) was added to each well. After incubation at 37 ° C for 2 hours, stop the reaction and wash with buffer 5 times. The cells were fully lysed by the addition of 20 ⁇ l of pre-cooled 100 mM NaOH per well. Finally, 80 ⁇ M Microscint 40 was added to each well and examined with a MicroBeta Trilux (PerkinElmer) liquid scintillation test. The test results are shown in Table 1.
  • the test method is as follows: The test compound is dissolved in DMSOC dimethyl sulfoxide;) to prepare a stock solution, which is then diluted to the desired concentration.
  • hSGLT1 cells were plated in 96-well plates and cultured in F12 complete medium. After 48 hours of culture, each well was washed 3 times with a buffer of pH 7.4. A buffer containing different test compounds and [14C]-cx-methyl-glucoside ( ⁇ ⁇ /ml) was added to each well. After incubation at 37 ° C for 2 hours, the reaction was stopped and washed 5 times with buffer. The cells were fully lysed by the addition of 20 ⁇ l of pre-cooled 100 mM NaOH per well. Finally, 80 ⁇ M Microscint 40 was added to each well and examined with a MicroBeta Trilux (PerkinElmer) liquid scintillation test. The test results are shown in Table 2.
  • test compound was weighed and dissolved in 0.05 ml of dimethyl sulfoxide, and then 0.05 ml of Solutol was added. After dissolution, 0.95 ml of physiological saline was added to prepare a 1.0 mg/ml solution. The glucose was weighed and dissolved in ultrapure water to prepare a 50% glucose solution for use. After the SD rats were fasted for 18 hours, the body weight of each animal was measured, and the animals were grouped according to the body weight, and 3 rats in each group. The rats were then individually loaded into metabolic cages, and the test compounds were administered to each animal at doses of 3 mg/kg and 10 mg/kg, and the control group was administered with physiological saline.
  • Compound 1 1 2693 Conclusion: The compounds of the invention significantly increase the amount of urine glucose in rats.
  • the activity of the compounds of the invention in monkeys was evaluated using a urine glucose assay.
  • the monkeys were divided into 4 groups, namely blank group, Canagliflozin group, compound 2 group, and compound 8 group, each group consisting of 2 animals, 1 female and 1 male. Fasting alone in the metabolic cage for 18 hours, can not help but water.
  • each animal was given 50% glucose solution at a dose of 2 g/kg ; after 1 hour, the animals were given a feed.
  • the compounds of the present invention are more effective in promoting urinary glucose than the marketed drug cangliflozin.

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Abstract

The present invention relates to a oxabicyclo derivative, preparation method and use thereof, specifically to oxabicyclo derivatives shown by general formula (I) or hydrates, solvates, stereoisomers thereof, pharmaceutically acceptable salts, co-crystals, prodrugs, preparation methods, pharmaceutical compositions comprising the derivatives and pharmaceutical uses for preparing sodium-dependent glucose transporter (SGLT) inhibitors, and the definition of each substituent in general formula (I) is the same as that in description.

Description

氧杂双环衍生物、 制备方法及其应用 技术领域  Oxabicyclo derivative, preparation method and application thereof

本发明涉及一种氧杂双环衍生物、 制备方法及其应用， 具体说涉及通式 ω所示氧杂双 环衍生物或其可用药用的盐或其立体异构体， 其制备方法以及含有该衍生物的药物组合物 ， 以及其作为治疗剂特别是作为钠依赖性葡糖转运蛋白 (SGLT)抑制剂的用途。 背景技术  The present invention relates to an oxabicyclo derivative, a preparation method and use thereof, and in particular to an oxabicyclic derivative represented by the formula ω or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a process for the preparation thereof, and the like Pharmaceutical compositions of derivatives, and their use as therapeutic agents, particularly as sodium-dependent glucose transporter (SGLT) inhibitors. Background technique

II型糖尿病是最常见的糖尿病类型， 在世界范围内， II型糖尿病约占所有糖尿病的 90%。 由于现代不健康的生活方式， 如锻炼减少和高热量饮食等原因， II型糖尿病的发病率 呈逐渐增加的趋势。 在 II型糖尿患者中， 由于机体不能有效对胰岛素做出反应， 因此引起 高血糖。 高血糖是心血管疾病、 中风和肾功能衰竭等糖尿病并发症的主要原因， 这些并发 症进一步加重了糖尿病患者的病情。  Type II diabetes is the most common type of diabetes, and worldwide type II diabetes accounts for about 90% of all diabetes. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high calorie diets. In patients with type II diabetes, high blood sugar is caused by the body's inability to respond effectively to insulin. Hyperglycemia is the leading cause of diabetic complications such as cardiovascular disease, stroke and kidney failure, and these complications further aggravate the condition of diabetic patients.

目前已批准的用于治疗 II型糖尿病上市的药物主要有胰岛素及其类似物、 磺酰脲类、 双胍类、噻唑烷二酮类 CTZDs)、 ex-葡萄糖苷酶抑制剂、糊精类似物、肠促胰岛素激素类似物、 二肽基肽酶抑制剂 (DPP-IV)等。然而，患者长期服用这些降糖药仍不能达到预期的糖化血红 蛋白 (HbAlc)降低指标，而且这些降糖药均有副作用，如低血糖、体重增加和心血管风险等。 这些副作用加重了糖尿病患者的负担。 因此， 迫切需要针对 II型糖尿病开发具有高效、 副 作用少的新型降糖药。  The currently approved drugs for the treatment of type 2 diabetes are mainly insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (CTZDs), ex-glucosidase inhibitors, dextrin analogues, Incretin hormone analog, dipeptidyl peptidase inhibitor (DPP-IV) and the like. However, long-term use of these hypoglycemic agents does not achieve the expected reduction in glycated hemoglobin (HbAlc), and these hypoglycemic agents have side effects such as hypoglycemia, weight gain, and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop new hypoglycemic agents with high efficacy and few side effects for type II diabetes.

SGLT-2 是目前被认为颇具前景的用于治疗 II型糖尿病的新靶点 （Clinical Diabetes, SGLT-2 is currently considered a promising new target for the treatment of type 2 diabetes (Clinical Diabetes,

2010, 28, 5-10)。 SGLT-2 是钠依赖性葡萄糖协同转运体 (SGLTs)跨膜蛋白家族的成员， 由 SLC5基因编码， 主要在肾近曲小管表达，约 90%的肾脏葡萄糖重吸收发生在肾皮质近端小 管 S1段的上皮细胞中， SGLT-2是负责该过程的主要转运体。 SGLT-2是低亲和力、 高容量 的转运体，这使得 SGLT-2可从管腔到肾小管上皮细胞胞浆高效运输葡萄糖和钠离子 (以 1:2 的摩尔比） (Nephrol Dial Transplant, 2010, 25, 2041-2043)。事实上， 肾小管对葡萄糖的再吸收 非常高效， 在肾脏中过滤的葡萄糖负荷约为 180克 /天， 但只有很少量最终被排出体外。 2010, 28, 5-10). SGLT-2 is a member of the transmembrane family of sodium-dependent glucose co-transporters (SGLTs), encoded by the SLC5 gene, expressed primarily in the renal proximal convoluted tubules, and approximately 90% of renal glucose reabsorption occurs in the renal cortical proximal tubule S1 In epithelial cells of the segment, SGLT-2 is the primary transporter responsible for this process. SGLT-2 is a low-affinity, high-capacity transporter that allows SGLT-2 to efficiently transport glucose and sodium ions from the lumen to the tubular epithelial cytoplasm (in a molar ratio of 1:2) (Nephrol Dial Transplant, 2010) , 25, 2041-2043). In fact, renal tubular re-absorption of glucose is very efficient, with a glucose load of approximately 180 g/day in the kidney, but only a small amount is eventually excreted.

研究表明，抑制 SGLT-2可减少机体通过肾脏重吸收葡萄糖的能力， 因此使机体通过尿 液清除体内葡萄糖， 从而达到降低血糖的目的 (Endocrine Reviews, 2011, 32, 515-531)。 在 SGLT-2基因突变的某些家族成员中， 除了尿糖排泄外， 没有明显的肾功能不全、 低血糖或 其它疾病 (J. Am. Soc. Nephrol, 2003, 14, 2873-82)。 一些 SGLT-2抑制剂已经被相继开发， 并 显示了良好的活性和选择性， 其中坎格列净 （Canagliflozin) 和达格列净 （Dapagliflozin) 已上市， 恩帕列净 (Empagliflozin)、依帕列净 ( Ipragliflozin)、托伏列净 ( Tofogliflozin) 、 卢斯列净 （Luseogliflozin) 、 依托列净 （Ertugliflozin) 等则处于临床研究阶段。 Studies have shown that inhibition of SGLT-2 reduces the body's ability to reabsorb glucose through the kidneys, thus allowing the body to clear glucose from the body through the urine, thereby reducing blood sugar (Endocrine Reviews, 2011, 32, 515-531). In some family members of the SGLT-2 gene mutation, there is no significant renal insufficiency, hypoglycemia or other diseases other than urinary glucose excretion (J. Am. Soc. Nephrol, 2003, 14, 2873-82). Some SGLT-2 inhibitors have been developed and shown good activity and selectivity, among which canagliflozin and dapagliflozin Already on the market, Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, and Ertugliflozin are in clinical research.

综上所述， SGLT-2抑制剂是一类安全有效的抗 II型糖尿病的新型药物。 目前已有一些 SGLT-2抑制剂相关研究的文献被相继报道。  In summary, SGLT-2 inhibitors are a safe and effective new drug against type II diabetes. A number of literatures on SGLT-2 inhibitor related studies have been reported.

(l) WO2012019496公布了如下结构的化合物作为 SGLT-2蛋白抑制剂，  (l) WO2012019496 discloses a compound of the following structure as a SGLT-2 protein inhibitor,

Figure imgf000004_0001
Figure imgf000004_0001

其中- 环 A选自芳基或杂芳基， 其中芳基或杂芳基各自独立任选进一步被一个多多个选自卤 素、 烷基、 烯基、 炔基、 环烷基、 杂环烷基、 芳基、 杂芳基等取代基所取代； R5、 R6各自 独立地选自 H或氘原子， 不认为此专利中具体描述是本发明的一部分。 Wherein - ring A is selected from aryl or heteroaryl, wherein each aryl or heteroaryl is independently further optionally further selected from one or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl Substituents such as aryl, heteroaryl are substituted; R 5 and R 6 are each independently selected from H or a ruthenium atom, and the specific description in this patent is not considered to be part of the present invention.

(2) WO2010023594 公布了如下结构的化合物作为钠依赖性葡糖转运蛋白 (SGLT)抑制 剂， 在治疗、 预防 II型糖尿病的用途，  (2) WO2010023594 discloses the use of a compound of the following structure as a sodium-dependent glucose transporter (SGLT) inhibitor for the treatment and prevention of type 2 diabetes,

Figure imgf000004_0002
Figure imgf000004_0002

R2是 CM烷基、 CM烷氧基、 C2— 4炔基、 0 -、 、 Cl、 F、酰基、 F代 d— 2烷基、 -S02-Ci_4 烷基、 C3— 6碳环、 含 1或 2个 0、 S杂原子的 C5— 6杂环烷基； 不认为此专利中具体描述 是本发明的一部分。 R 2 is CM alkyl, CM alkoxy, C 2 - 4 alkynyl, 0 -,, Cl, F , acyl, F substituting d- 2 alkyl, -S0 2 -Ci_ 4 alkyl, C 3 - 6 carbon ring containing 1 or 2 0, C S heteroatom 5--6 heterocycloalkyl; not specifically described in this patent that are part of the invention.

(3) WO2012165914公开了如下结构的化合物具有 SGLT-2抑制剂作用， 作为胰岛素分 泌促 /或治疗药的用途，  (3) WO2012165914 discloses a compound having a structure having the action of an SGLT-2 inhibitor as an insulin secretion promoting/or therapeutic agent,

Figure imgf000004_0003
X选自 0、 S; Y选自 d— 7烷基、 C2— 7烯基、 C2— 7炔基、 d— 7烷氧基、 d— 7烷氧基 -d— 7烷 基、 d— 7烷基亚磺酰基、 d— 7烷基磺酰基、 d— 7烷基硫基； 该发明与本发明的化合物结构差 异较大。
Figure imgf000004_0003
X is selected from 0, S; Y is selected from d- 7 alkyl, C 2 - 7 alkenyl group, C 2 - 7 alkynyl, d- 7 alkoxy, d- 7 -d- 7 alkoxyalkyl group, D- 7 alkylsulfinyl, d- 7 alkylsulfonyl, d- 7 alkylthio; This invention differs greatly from the structure of the compound of the present invention.

(4) WO2013000275公布 SGLT-2抑制剂如下结构的化合物用于治疗糖尿病，  (4) WO2013000275 discloses that SGLT-2 inhibitors have compounds of the following structure for the treatment of diabetes,

Figure imgf000005_0001
Figure imgf000005_0001

其中- among them-

X选自化学单键、 NH、 0、 S、 S0、 S02或亚烷基； R3选自 0R8、 5-12元螺环基、 5-12 元桥环基、 6-14元并环基或被 N、 0、 S、 SO和 /或 S02的杂原子替代的一个或多个碳原子 的 5-12元螺环基、 5-12元桥环基、 6-14元并环基； 但是， 该发明中并未暗示或提及糖环上 含氧杂桥环的化合物， 不认为此专利中具体描述是本发明的一部分。 X is selected from a chemical single bond, NH, 0, S, S0, S0 2 or an alkylene group; R 3 is selected from the group consisting of 0R 8 , a 5-12 membered spiro group, a 5-12 membered bridged ring group, and 6 to 14 members. a 5-12 membered spiro group, a 5-12 membered bridged ring group, a 6-14 membered ring ring of one or more carbon atoms substituted by a hetero atom of N, 0, S, SO and/or S0 2 However, the compounds of the oxygen-containing bridged ring on the sugar ring are not suggested or referred to in the present invention, and the specific description in this patent is not considered to be part of the present invention.

本发明的目的是介绍一类新型 SGLT-2抑制剂，具体而言具有通式 (I)所示的化合物，经 研究表明，此类结构的化合物具有良好的 SGLT-2抑制活性和选择性，具有用于治疗或缓解 糖尿病及类似疾病的前景。 发明内容  The object of the present invention is to introduce a novel class of SGLT-2 inhibitors, in particular having the compounds of the formula (I), which have been shown to have good SGLT-2 inhibitory activity and selectivity, Has the prospect of treating or relieving diabetes and similar diseases. Summary of the invention

本发明涉及一种通式 (I-A)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药：  The present invention relates to an oxabicyclic derivative represented by the formula (I-A) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

Figure imgf000005_0002
其中-
Figure imgf000005_0002
among them-

X选自 -0-、 -S(=0)n-或 -NR8-; X is selected from -0-, -S(=0) n - or -NR 8 -;

R选自 H、 d— 8烷基、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -^！！^ ^环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4 至 14元桥环基)或 -(CH2)m-S(=0)n-R9， 所述的烷基、 烯基、 炔基、 芳基、 杂芳基、 螺环基、 桥环基、并环基、环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2— 8 烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； R is selected from H, d- 8 alkyl, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -^! ! ^^cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m - (6 to 14 yuan) Heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14) a bridged ring) or -(CH 2 ) m -S(=0) n -R 9 , said alkyl, alkenyl, alkynyl, aryl, heteroaryl, spiro group, bridged ring group, And a cycloalkyl, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3, = 0, a cyano group, a nitro, cyano, hydroxyl, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl, -R 12 , -(CH 2 ) m -C 2 .8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocyclic ring Alkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m - (5 to 14 membered spiro group) ), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring), -0-C 3 -8 cycloalkyl, -0- (3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0- (4 to 14 members and ring groups), -0-(4 to 14 members of bridged ring groups), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0 )-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m -S(=0) n -R Substituted by a substituent of 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 atoms selected from N, 0 or S(=0) n Or group;

R R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 d_8烷氧基、 -0-C(=0)-R13、RR 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 8 alkoxy, -0-C(=0)-R 13 ,

-0-C(=0)-0-R13、 -0-C(=0)-(CH2)m-C6— 14芳基、 -0-C(=0)-0-C6— 14芳基、 -0-(CH2)m-C6— 14芳基、 -O-硅烷基或 -0-C2— 8烯基， 其中所述的烷氧基、芳基或烯基可任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 羟基、 d— 8烷基、 d— 8烷氧基、 C3—8环烷基或 3至 8元杂环烷基的取代基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； -0-C(=0)-0-R 13 , -0-C(=0)-(CH 2 ) m -C 6 - 14 aryl, -0-C(=0)-0-C 6 — 14 aryl group, -0- (CH 2) m -C 6 - 14 aryl group, -O- or silane group -0-C 2 - 8 alkenyl group, wherein the alkoxy group, an aryl group or alkenyl group may be is optionally further selected from 0-5 F, Cl, Br, I, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group Substituted by a substituent, the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 硝基、 羟基、 醛 基、羧基、 C 烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -(CH2)m-C3-8 环烷基、 -(CH2)m-(3 至 8元杂环烷基)、 -(CH2)m-C6.14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8 环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环 基)、 -0-(4至 14元桥环基)、 -0-(4至 14元并环基)、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-S(=0)n-R9、 -(CH2)m-C(=O)-NR10Ru、 -(CH2)m-NHC(=0)-R13或 -NR1QRU， 所述的烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 螺 环基、 桥环基、 并环基、 环烷基或杂环烷基各自独立地任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -(CH2)m-C3— 8环烷基、 -(CH2)m-(3 至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环 基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8环烷基、 -0-(3至 8 元杂环烷基)、 -0-C6_14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元 并环基）、 -0-(4 至 14 元桥环基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-NHC(=0)-R13 、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； 作为选择， R5与 R6、 R6与 R7任一组可以形成一个 3至 10元环， 所形成的环选自环烷 基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 3个选自 N、 0或 3(=0)11杂原子或 基团， 且所述的环烷基、 杂环基、 芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧 基、 -(CH2)m-C2_8烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3至 8元杂 环烷基)、 -(CH2)m-C6_i4芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4 至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、-0-(3至 8元杂环烷基)、-0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, C alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C 3 - 8 cycloalkyl Alkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 .14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl) ), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring) (), -0-C 3 - 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl) , -0-(5 to 14 membered spiro group), -0-(4 to 14 membered bridged ring group), -0-(4 to 14 membered and cyclic group), -(CH 2 ) m -C(= 0) -R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0 -C(=0)-0-R 13 , -(CH 2 ) m -S(=0) n -R 9 , -(CH 2 ) m -C(=O)-NR 10 R u , -(CH 2 ) m -NHC(=0)-R 13 or -NR 1Q R U , said alkyl group, alkoxy group, alkenyl group, alkynyl group, aryl group, heteroaryl group, spiro group, bridged ring group, And ring base, The cycloalkyl or heterocycloalkyl groups are each independently optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro , isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2--8 alkynyl -R 12, - (CH 2) m -C 3 - 8 cycloalkyl, - (CH 2) m - (3 to 8- membered heterocyclic group), - (CH 2) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m -(4 to 14-membered cyclo), -(CH 2 ) m - (4 to 14-membered bridged ring), -0-C 3 - 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), - 0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0-(4 to 14-membered ring-based group), -0 - (4 to 14 element bridged ring base), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , Substituting (CH 2 ) m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 ; alkyl Heteroaryl, spiro cycloalkyl group, a cycloalkyl group or a bridged cycloalkyl group and may contain 0 to 5 heteroatoms selected from N, 0 or 3 (= 0) or a group 11 atom; Alternatively, R 5 and R 6 , R 6 and R 7 may form a 3 to 10 membered ring, and the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and is formed. The ring may contain from 0 to 3 heteroatoms or groups selected from N, 0 or 3 (=0) 11 and the cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl , d- 8 alkoxy, -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 _ 8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _i4 aryl, -(CH 2 ) m - (6 to 14 yuan) Heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 Yuanqiao ring group), -0-C 3 -8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered hetero Aryl), -0-(5 to 14 membered spiro group), -0-(4 to 14 membered cyclo), -0-(4 to 14 membered bridged ring), -(CH 2 ) m - C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0) -0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 Substituted by a substituent of m -S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro group, bridged ring or cyclohexyl group may contain 0 to 5 selected from N An atom or group of 0 or S(=0) n ;

R6'和 R7'各自独立选自 H、 羟基 d_3烷氧基或 d_3烷基； R 6 'and R 7 ' are each independently selected from H, hydroxy d_ 3 alkoxy or d 3 alkyl;

W选自单键、 -NH -、 -0-、 -C(=0)-、 -S(=0)n -、 d— 3亚烷基或 ^>P，所述的亚烷基或 任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 d_4烷基、 d_4烷 氧基、 C3— 5环烷基或 3至 5元杂环烷基的取代基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； W is selected from a single bond, -NH -, -0-, -C(=0)-, -S(=0) n -, d- 3 alkylene or ^>P, said alkylene or any Further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, d 4 alkyl, d 4 alkoxy, C 3 -5 cycloalkyl Or a substituent of a 3- to 5-membered heterocycloalkyl group, the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

G选自 6至 14元芳基或 5至 14元杂芳基， 所述的芳基或杂芳基任选进一步被 0至 5 个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基- R12、 -(CH2)m-C2— 8炔基- R12、 -(CH2)m-C3— 8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6— 14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基 )、 -(CH2)m-(4至 14元并环基 )、 -(CH2)m-(4至 14元桥环基 )、 -0 3_8环烷基、 -0-(3 至 8元杂环烷基)、 -0-C6— 14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14 元并环基）、 -0-(4 至 14 元桥环基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-NHC(=0)-R13 、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代，且所述烷基、芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环烷基、 杂环烷基、 烯基或炔基任选进一步 被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 异氰基、 硝基、 羟基、 C 烷基、 d_8烷氧基、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳 基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6 至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14元桥环基)、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、 螺环基、 桥环基 或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； G is selected from a 6 to 14 membered aryl group or a 5 to 14 membered heteroaryl group, and the aryl or heteroaryl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 - 8 cycloalkyl, -(CH 2 ) m - (3 to 8-membered hetero Cycloalkyl), -(CH 2 ) m -C 6 - 14 aryl, -(CH 2 ) m -(6 to 14-membered heteroaryl), -(CH 2 ) m - (5 to 14 membered spiro ring) (), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring), -0 3 -8 cycloalkyl, -0-( 3- to 8-membered heterocycloalkyl), -0-C 6 - 14 aryl, -0-(6 to 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0-( 4 to 14 members and a ring group), -0-(4 to 14 members of the bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0) -0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 Substituent And the alkyl, aryl, spiro group, bridged ring, cyclylene, heteroaryl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl or alkynyl group is optionally further Up to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, isocyano, nitro, hydroxy, C alkyl, d- 8 alkoxy -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -( CH 2 ) m - (6 to 14-membered heteroaryl), -(CH 2 ) m - (5 to 14-membered spiro group), -(CH 2 ) m - (4 to 14-membered ring group), - (CH 2 ) m -(4 to 14 membered bridged ring group), -0-C 3 -8 cycloalkyl group, -0-(3 to 8 membered heterocycloalkyl group), -0-C 6 _ 14 aryl group , -0-(6 To 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0-(4 to 14-membered ring-based group), -0-(4 to 14-membered bridged ring group), -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 .8 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) a substituent substituted with m -C(=0)-0-R 13 , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 ; , a heteroaryl group, a spiro group, a bridged ring group or a bicyclic group may have 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

作为选择， G环上任意两个取代基可以形成一个 3至 8元环， 所形成的环选自环烷基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 5个选自 N、 0或 3(=0)11杂原子或基团， 且所述的环烷基、杂环基、芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、氰基、硝基、异氰基、羟基、醛基、羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2.8 烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6.14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； Alternatively, any two substituents on the G ring may form a 3 to 8 membered ring, the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the resulting ring may contain 0 to 5 selected from N, 0 or 3 (=0) 11 heteroatoms or groups, and said cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy , -(CH 2 ) m -C 2 .8 alkenyl-R 12 , -(CH 2 ) m -C 2 .8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring group) , -0-C 3 -. 8 cycloalkyl, -0- (3 to 8-membered heterocyclic group), -0-C 6 14 aryl group, -0- (6 to 14- membered heteroaryl group), - 0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0) -R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0- R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m - Substituted by a substituent of S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 selected from N, 0 or An atom or group of S(=0) n ;

R8、 R1Q和 R11各自独立选自 H、 羟基、 d— 8烷基、 d— 8烷氧基、 C3— 8环烷基或 3至 8元 杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 8, R 1Q and R 11 are each independently selected from H, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heteroaryl The cycloalkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R9选自 H、 d— 8烷基、 C3—8环烷基或 3至 8元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 8 alkyl, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d— 8烷基、 d— 8烷氧基、 C3— 8环烷基或 3至 8 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

p选自 1、 2或 3 ;  p is selected from 1, 2 or 3;

m选自 0、 1、 2、 3或 4。  m is selected from 0, 1, 2, 3 or 4.

本发明的优选方案， 通式 (I-A)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  A preferred embodiment of the present invention, an oxabicyclic derivative represented by the formula (I-A) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R6'和 R7'各自独立选自 H、羟基、 甲基、 乙基或甲氧基，优选 H或羟基，进一步优选 H。 本发明的优选方案， 一种通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶 剂化物、 药学上可接受的盐、 共晶体或前药：

Figure imgf000009_0001
R 6 'and R 7 ' are each independently selected from H, hydroxy, methyl, ethyl or methoxy, preferably H or hydroxy, further preferably H. A preferred embodiment of the invention, an oxabicyclic derivative of the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:
Figure imgf000009_0001

其中- among them-

X选自 -0-、 -S(=0)n-或 -NR8-; X is selected from -0-, -S(=0) n - or -NR 8 -;

R选自 H、 d— 8烷基、 -(CH2)m-C2— 8烯基- R12、 -(CH2)m-C2— 8炔基- R12、 -(CH2)m-C(=0)-R13、R is selected from H, d- 8 alkyl, - (CH 2) m -C 2 - 8 alkenyl, - R 12, - (CH 2 ) m -C 2 - 8 alkynyl, - R 12, - (CH 2 ) m -C(=0)-R 13 ,

-(CH2)m-C(=0)-0-R13、 -^！！^ ^环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4 至 14元桥环基)或 -(CH2)m-S(=0)n-R9， 所述的烷基、 烯基、 炔基、 芳基、 杂芳基、 螺环基、 桥环基、并环基、环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2— 8 烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6.14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 且所述的杂环烷基、 杂芳基、 螺环基、桥环基或并环基 可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； -(CH 2 ) m -C(=0)-0-R 13 , -^! ! ^^cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m - (6 to 14 yuan) Heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14) a bridged ring) or -(CH 2 ) m -S(=0) n -R 9 , said alkyl, alkenyl, alkynyl, aryl, heteroaryl, spiro group, bridged ring group, And the cyclo, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, and nitrate group, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m - C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m - C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m -(4 and to 14-membered cycloalkyl group), - (CH 2) m - (4 to 14-membered bridged-ring group), -0-C 3 - 8 cycloalkyl, -0- (3 to 8-membered heterocyclic group), -0-C 6. 14 aryl group, -0- (6 to 14- membered heteroaryl group), -0- (5 to 14-membered spiro group), -0-(4 to 14-membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , (CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)- 0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) Substituted with a substituent of m -S(=0) n -R 9 ; and the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 selected from N An atom or group of 0 or 3 (=0) 11 ;

R1, R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 d_8烷氧基、 -0-C(=0)-R13、 -0-C(=0)-0-R13、 -0-C(=0)-(CH2)m-C6— 14芳基、 -0-C(=0)-0-C6— 14芳基、 -0-(CH2)m-C6— 14芳基、 -O-硅烷基或 -0-C2— 8烯基， 其中所述的烷氧基、芳基或烯基可任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 羟基、 d— 8烷基、 d— 8烷氧基、 ^8环烷基或 3至 8元杂环烷基的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 8 alkoxy, -0-C(=0)-R 13 , -0-C (=0 )-0-R 13 , -0-C(=0)-(CH 2 ) m -C 6 - 14 aryl, -0-C(=0)-0-C 6 - 14 aryl, -0- (CH 2) m -C 6 - 14 aryl group, -O- or silane group -0-C 2 - 8 alkenyl group, wherein the alkoxy group, an aryl group or alkenyl group may optionally be further 0-5 Substituted by a substituent selected from the group consisting of F, Cl, Br, I, hydroxy, d- 8 alkyl, d- 8 alkoxy, ^ 8 cycloalkyl or 3 to 8 membered heterocycloalkyl; a cycloalkyl group containing from 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 硝基、 羟基、 醛 基、羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基- R12、 -(CH2)m-C2— 8炔基- R12、 -(CH2)m-C3-8 环烷基、 -(CH2)m-(3 至 8元杂环烷基)、 -(CH2)m-C6.14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8 环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环 基)、 -0-(4至 14元并环基)、 -0-(4至 14元桥环基)、 -(CH2)m-C(=0)-R13、-(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-S(=0)n-R9、 -(CH2)m-NHC(=0)-R13、 -NR1QRU

Figure imgf000010_0001
, 所述的烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 螺 环基、 桥环基、 并环基、 环烷基或杂环烷基各自独立地任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d_8烷氧基、 -(CH2)m-C2_8烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3 至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环 基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8环烷基、 -0-(3至 8 元杂环烷基)、 -0-C6— 14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元 并环基）、 -0-(4 至 14 元桥环基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-NHC(=0)-R13 、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； 作为选择， R5与 R6、 R6与 R7任一组可以形成一个 3至 10元环， 所形成的环选自环烷 基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 3个选自 N、 0或 3(=0)11杂原子或 基团， 且所述的环烷基、 杂环基、 芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧 基、 -(CH2)m-C2_8烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3至 8元杂 环烷基)、 -(CH2)m-C6_i4芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4 至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、-0-(3至 8元杂环烷基)、-0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d — 8 alkoxy, —(CH 2 ) m —C 2 —8 alkenyl- R 12 , —(CH 2 ) m —C 2 —8 alkynyl—R 12 , —(CH 2 ) m —C 3 — 8 -cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 . 14 aryl, -(CH 2 ) m -(6 to 14-membered hetero Aryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 member) Bridged ring), -0-C 3 -8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0- (6 to 14-membered heteroaryl) Base), -0- (5 to 14 yuan spiral ring) Base), -0-(4 to 14-membered ring group), -0-(4 to 14-membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -S(=0) n -R 9 , -(CH 2 ) m -NHC(=0)-R 13 , -NR 1Q R U
Figure imgf000010_0001
Said alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, spiro, bridged, cyclo, cycloalkyl or heterocycloalkyl, each independently optionally further From 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8- alkyl, d- 8 alkoxy, -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 To 14-membered heteroaryl), -(CH 2 ) m -(5 to 14-membered spiro group), -(CH 2 ) m -(4 to 14-membered ring group), -(CH 2 ) m -( 4 to 14 membered bridged ring), -0-C 3 - 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 - 14 aryl, -0-(6 to 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0-(4 to 14 membered cyclo), -0-(4 to 14 membered bridged ring), -(CH 2 m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -( CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) a substituent substituted by m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 ; , a heteroaryl group, a spiro group, a bridged ring group or a cyclylene group may contain 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; alternatively, R 5 and R 6 , R Any of 6 and R 7 may form a 3 to 10 membered ring, the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the ring formed may have 0 to 3 rings selected from N, 0 or 3 (=0) 11 heteroatoms or groups, and the cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally from 0 to 5 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, -( CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _i4 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m - (5 to 14 membered spiro ring group), - (CH 2) m - (4 to 14 primitives and ring-yl), - (CH 2) m - (4 to 14 membered Cycloalkyl group), -0-C 3 _ 8 cycloalkyl, -0- (3 to 8-membered heterocyclic group), - 0-C 6 _ 14 aryl group, -0- (6 to 14- membered heteroaryl group ), -0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C( =0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m - 0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 Substituted by a substituent of R n or -(CH 2 ) m -S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro group, bridged ring or cycloalkyl group may contain 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

W选自单键、 -NH -、 -0-、 -C(=0)-、 -S(=0)n -、 d_3亚烷基或 所述的亚烷基或 任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 d_4烷基、 d_4烷 氧基、 C3— 5环烷基或 3至 5元杂环烷基的取代基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； W represents a single bond, -NH -, -0-, -C ( = 0) -, -S (= 0) n -, d_ 3 alkylene group or the alkylene group or optionally substituted with 0 to further 5 is selected from F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, hydroxy, d_ 4 alkyl, d_ 4 alkoxy, C 3 - 5 cycloalkyl or 3-5 yuan Substituted by a substituent of a heterocycloalkyl group containing from 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

G选自 6至 14元芳基或 5至 14元杂芳基， 所述的芳基或杂芳基任选进一步被 0至 5 个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 C 烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -(CH2)m-C3— 8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6— 14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基 )、 -(CH2)m-(4至 14元并环基 )、 -(CH2)m-(4至 14元桥环基 )、 -0 3_8环烷基、 -0-(3 至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14 元并环基）、 -0-(4 至 14 元桥环基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-NHC(=0)-R13 、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代， 其中所述烷基、 芳 基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环烷基、 杂环烷基、 烯基或炔基任选进 一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 异氰基、 硝基、 羟 基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C3— 8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6.14 芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0 3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6 至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14元桥环基)、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -NR1QRU或 -(CH2)m-S(=C n-R9的取代基所取代； 且所述的杂环烷基、 杂芳基、 螺环基、 桥环 基或并环基可含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； G is selected from a 6 to 14 membered aryl group or a 5 to 14 membered heteroaryl group, and the aryl or heteroaryl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, C alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C 3 - 8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 - 14 aryl, -(CH 2 ) m -( 6 to 14 membered heteroaryl), -(CH 2 ) m - (5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring group), -0 3 -8 cycloalkyl group, -0-(3 to 8 membered heterocycloalkyl group), -0-C 6 _ 14 aryl group, -0-(6 to 14 (heteroaryl), -0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n Substituted by a substituent of -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 wherein the alkyl group, the aryl group, the spiro group, the bridged ring group, the azide group, The heteroaryl, alkoxy, cycloalkyl, heterocycloalkyl, alkenyl or alkynyl group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , CF 3 , = 0, cyano, isocyano, nitro, hydroxy, d- 8 alkyl, d- 8 alkoxy, - (CH 2) m -C 3 - 8 cycloalkyl, - (CH 2) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 .14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m - (5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered ring group), -(CH 2 ) m - (4 to 14 membered bridged ring group), -0 3 _ 8 ring Alkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), -0- (5 to 14 membered snail) group), -0- (4-14 yuan and cycloalkyl group), -0- (4-14 yuan bridged ring group), - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2 m - C 2 . 8 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -NR 1Q Substituted with a substituent of R U or -(CH 2 ) m -S (=C n -R 9 ; and the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 atoms or groups selected from N, 0 or S(=0) n ;

作为选择， G环上任意两个取代基可以形成一个 3至 8元环， 所形成的环选自环烷基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 5个选自 N、 0或 3(=0)11杂原子或基团， 且所述的环烷基、杂环基、芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、氰基、硝基、异氰基、羟基、醛基、羧基、 d_8烷基、 d_8烷氧基、 -(CH2)m-C2.8 烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6.14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； Alternatively, any two substituents on the G ring may form a 3 to 8 membered ring, the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the resulting ring may contain 0 to 5 selected from N, 0 or 3 (=0) 11 heteroatoms or groups, and said cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, -(CH 2 ) m -C 2 .8 alkenyl-R 12 , -(CH 2 ) m -C 2 .8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, - (CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -( CH 2 ) m - (5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring), - 0-C 3 -. 8 cycloalkyl, -0- (3 to 8-membered heterocyclic group), -0-C 6 14 aryl group, -0- (6 to 14- membered heteroaryl group), -0- (5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m -S( =0) Substituted by a substituent of n -R 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 selected from N, 0 or S ( =0) an atom or group of n ;

R8、 R1Q和 R11各自独立选自 H、 羟基、 d— 8烷基、 d— 8烷氧基、 C3— 8环烷基或 3至 8元 杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 8, R 1Q and R 11 are each independently selected from H, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heteroaryl a cycloalkyl group containing from 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

R9选自 H、 d— 8烷基、 C3—8环烷基或 3至 8元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R12和 R13各自独立选自 H、 氨基、 羟基、 d— 8烷基、 d— 8烷氧基、 C3— 8环烷基或 3至 8 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 8 alkyl, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ; R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

p选自 1、 2或 3 ;  p is selected from 1, 2 or 3;

m选自 0、 1、 2、 3或 4。  m is selected from 0, 1, 2, 3 or 4.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 d_6烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6.10 芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(5至 12元桥环基)、 -(CH2)m-C2.6烯基 -R12、 -(CH2)m-C2.6炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13或 -(CH2)m-S(=0)n-R9，优选 H、 d— 4烷基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环 基)、 -(CH2)m-(4 至 12元并环基)、 -(CH2)m-(5 至 12 元桥环基)、 -(CH2)m-C2_4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13或 -(CH2)m-S(=0)n-R9， 进一 步优选 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C2_4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13或 -(CH2)m-C(=0)-0-R13， 更优选 H、 d— 4烷 基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-C3— 4环烷基或 -(CH2)m-(3至 4元杂环烷基; )； 其中所述的烷基、 杂环烷基、 环烷基、 芳基、 杂芳基、 螺环基、 并环基、 桥环基、 烯基或炔基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 6烷基、 d— 6 烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6 至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(5至 12 元桥环基)、 -0-C3— 6环烷基、 -0-(3至 6元杂环烷基)、 -0-C6— 1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(5至 12元桥环基)、 -(CH2)m-C2_6烯基 -R12、 -(CH2)m-C2_6 炔 基 -R12 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 CM烷基、 d— 4烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元 杂环烷基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -(CH2)m-C2_4烯基 -R12或 - 3¾)„1 2_4炔 基 -R12的取代基所取代， 进一步优选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取代； 且以上所述的杂芳基、 杂环烷基、 螺环基、 桥环基或并环基的 0至 5个碳原子可以被选自 N、 0或 S(=0)n的原子或基团取代， 优选含 有 0至 3个选自 N、 0或 3(=0)11的原子或基团； R1Q和 R11各自独立选自 H、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环 烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 6 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - C 6 . 10 aryl, —(CH 2 ) m —(6 to 10 membered heteroaryl), —(CH 2 ) m —(5 to 12 membered spiro group), —(CH 2 ) m —(4 Up to 12-membered and cyclic group), -(CH 2 ) m -(5 to 12-membered bridged ring group), -(CH 2 ) m -C 2 . 6 alkenyl-R 12 , -(CH 2 ) m -C . 26 alkynyl group -R 12, - (CH 2) m -C (= 0) -R 13, - (CH 2) m -C (= 0) -0-R 13 or - (CH 2) m - S (= 0) n -R 9 , preferably H, d- 4-alkyl, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-group ), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (5 to 12-membered bridged ring), -(CH 2 ) m -C 2 _ 4 alkenyl-R 12 -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 or -(CH 2 ) m -S(=0) n -R 9 , further preferably H, d 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 2 _ 4 alkenyl-R 12 , -(CH 2 m - C 2 - 4 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 or -(CH 2 ) m -C(=0)-0-R 13 , more preferably H , d- 4 alkyl, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C( =0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -C 3 - 4 cycloalkyl or -(CH 2 ) m -(3 to a 4-membered heterocycloalkyl group; wherein; the alkyl group, heterocycloalkyl group, cycloalkyl group, aryl group, heteroaryl group, spiro group, cyclylene group, bridged ring group, alkenyl group or alkynyl group Further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 6 Alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m -(5 to 12 membered spiro group), -(CH 2 ) m -(4 Up to 12 members and a cyclic group), -(CH 2 ) m - (5 to 12 membered bridged ring group), -0-C 3 - 6 cycloalkyl group, -0-(3 to 6 membered heterocycloalkyl group), -0-C 6 - 1Q aryl group, -0- (6 to 10 membered heteroaryl), -0- (5-12 yuan spiro Group), -0- (4-12 yuan and cycloalkyl group), -0- (5-12 yuan bridged ring group), - (CH 2) m -C 2 _ 6 alkenyl -R 12, - (CH 2 m -C 2 _ 6 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -NR 10 Substituted with a substituent of R n or -(CH 2 ) m -S(=0) n -R 9 , preferably 0 to 4 are selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxyl, carboxyl, amino, the CM alkyl, d- 4 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six- Alkyl), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 2 _ 4 alkenyl-R 12 or - 33⁄4) „ 12 _ 4 alkynyl group of -R 12 substituents, more preferably F, Cl, Br, -CH 2 F, -CHF 2, -CF 3, amino, cyano, hydroxy, carboxy, alkyl D- 4 Or a substituent of the d- 4 alkoxy group; and 0 to 5 carbon atoms of the above heteroaryl, heterocycloalkyl, spiro group, bridged ring or cycloalkyl group may be selected from N Substituting an atom or group of 0 or S(=0) n , preferably containing 0 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ; R 1Q and R 11 are each independently selected from H, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic group Containing 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6 元杂环烷基， 优选 H、 羟基或 d— 4烷基， 进一步优选 H、 羟基或 d— 2烷基； 所述的杂环烷基 含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, hydroxy or d- a 4- alkyl group, further preferably H, a hydroxyl group or a d- 2 alkyl group; the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 Η、 甲基、 乙基、 正丙基、 异丙基、 正丁基、叔丁基、环丙基、环丁基、环戊基、 环己基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 氧杂环己基、 氮杂环戊基、 氮杂环己基、 吡啶基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、甲酰基、乙酰基、 -C(=C -CH2CH3、 -C(=0)-0-CH3或 -C(=0)-0-CH2CH3，且这些基团可以任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 羟基、 氰基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 甲氧基、 乙 氧基、 环丙基、 环丁基、 环戊基、 环己基、 氧杂环己基、 氧杂环丙基、 氧杂环丁基、 氧杂 环戊基、 乙烯基、 丙烯基、 烯丙基、 乙炔基、 丙炔基、 炔丙基、 氨基、 氰基或羟基的取代 基所取代； R is selected from the group consisting of hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxodipropyl, oxa Cyclobutyl, oxolyl, oxetanyl, azacyclopentyl, azacyclohexyl, pyridyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, Formyl, acetyl, -C(=C -CH 2 CH 3 , -C(=0)-0-CH 3 or -C(=0)-0-CH 2 CH 3 , and these groups may be optional Further from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, Methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, oxolyl, vinyl, propylene Substituted with a substituent of an allyl group, an allyl group, an ethynyl group, a propynyl group, a propargyl group, an amino group, a cyano group or a hydroxyl group;

进一步优选地， R选自 H、 -CH2F、 -CHF2、 -CF3、 -CH2CH2F、 -CH2CF3、 -CH2C≡N、 甲 基、 羟基乙基、 乙基、 异丙基、 叔丁基、 环丙基、 环丁基、 氧杂环丙基、 氧杂环丁基、 氧 杂环戊基、 吡啶基、 烯丙基、 炔丙基、 甲酰基、 乙酰基、 、、 -C(=0)-0-CH3或 -C(=0)-0-CH2CH3, 优选 H、 -CHF2、 -CF3、 甲基、 羟基乙基、 环丙基、 乙基或异丙基。 Further preferably, R is selected from the group consisting of H, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 C≡N, methyl, hydroxyethyl, B , isopropyl, tert-butyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, oxolane, pyridyl, allyl, propargyl, formyl, Acetyl, -, -C(=0)-0-CH 3 or -C(=0)-0-CH 2 CH 3 , preferably H, -CHF 2 , -CF 3 , methyl, hydroxyethyl, ring Propyl, ethyl or isopropyl.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

X选自 -0-或 -S -， 优选 -0-。  X is selected from -0- or -S-, preferably -0-.

本发明优选方案， 包括通式 ω所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula ω or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R1, R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、羟基、 -0-CH3、 -0-CH2CH3、 -0-CH2F、 -0-CHF2、 -0-CF3、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CH 2 F, -0-CHF 2 , -0-CF 3 , -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0- C(=0)0-CH 2 CH 3 ,

-O-苄基、 -O-硅烷基、 -O-烯丙基或 -O-乙烯基， 优选 H、 F、 羟基、 -0-CH3、 -0-C(=0)-CH3、-O- benzyl, silyl -O-, -O- or -O- vinyl allyl, preferably H, F, hydroxy, -0-CH 3, -0- C (= 0) -CH 3,

-0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、 -O-苄基或者 -O-硅烷基， 进一步优选 H、 OH、 F、 -0-C(=0)-CH3、 -0-C(=0)0-CH3或者 -0-C(=0)0-CH2CH3。 -0-C(=0)0-CH 3 , -0-C(=0)0-CH 2 CH 3 , -O-benzyl or -O-silane group, further preferably H, OH, F, -0-C(=0)-CH 3 , -0-C(=0)0-CH 3 or -0-C(=0)0-CH 2 CH 3 .

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 硝基、 羟基、 醛 基、羧基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C2— 6烯基 -R12、 -(CH2)m-C2— 6炔基 -R12、 -(CH2)m-C3-6 环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -0-C3_6 环烷基、 -0-(3至 6元杂环烷基)、 -0-C6_14芳基、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-S(=0)n-R9 、 -NR10Rn 、 -(CH2)m-NHC(=0)-R13

Figure imgf000014_0001
, 优选 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷 基、 d— 4烷氧基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2.4炔基 -R12、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3 至 6 元杂环烷基）、 -0-C3-6环烷基、 -0-(3 至 6 元杂环烷基）、 -(CH2)m-C(=0)-R13 , -(CH2)m-C(=0)-0-R13、 -(CH2)m-S(=0)n-R9或 -NR QR11 ;进一步优选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C2— 4烯基 -R12或者 -(CH2)m-C2— 4炔 基 -R12的取代基所取代； 其中所述烷基、 烷氧基、 烯基、 炔基、 芳基、 杂芳基、 环烷基或杂 环烷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、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C2— 6烯基 -R12、 -(CH2)m-C2_6炔基 -R12、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6 至 14 元杂芳基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C3-6 环烷基或 -(CH2)m-(3至 6元杂环烷基;)的取代基所取代；所述的杂环烷基或杂芳基含有 1至 5 个选自 N、 0或 3(=0)11的原子或基团； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, d- 6 alkyl, d — 6 alkoxy, —(CH 2 ) m —C 2 —6 alkenyl-R 12 , —(CH 2 ) m —C 2 —6 alkynyl-R 12 , —(CH 2 ) m —C 3 — 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14-membered hetero Aryl), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6 _ 14 aryl, -(CH 2 ) m -C (=0 )-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0- C(=0)-0-R 13 , -(CH 2 ) m -S(=0) n -R 9 , -NR 10 R n , -(CH 2 ) m -NHC(=0)-R 13
Figure imgf000014_0001
, preferably H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 . 4 alkynyl-R 12 , -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -0-C 3 -6 cycloalkyl, -0-(3 to 6 membered heterocycloalkyl), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0 -R 13 , -(CH 2 ) m -S(=0) n -R 9 or -NR QR 11 ; further preferably F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , amino group, cyanide Base, hydroxy, d-4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 or -(CH 2 ) m -C 2 -4 alkynyl-R 12 Substituted by a substituent; wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group are each independently optionally further selected from 0 to 4 F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 6 alkyl, d- 6 Alkoxy, -(CH 2 ) m -C 2 - 6 alkenyl-R 12 , -(CH 2 ) m -C 2 -6 alkynyl-R 12 , -(CH 2 ) m -C 3 _ 8 -cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14-membered hetero Aryl), -0-C 3 -8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14 membered heteroaryl) ), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0) -R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(= Substituting O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m -S(=0) n -R 9 substituent, preferably F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, amino, cyano, hydroxy, d-4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 a substituent of m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C 3 -6 cycloalkyl or -(CH 2 ) m -(3 to 6-membered heterocycloalkyl;) Substituted; said heterocycloalkyl or heteroaryl contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R9选自 H、 d_4烷基、 C3_6环烷基或 3至 6元杂环烷基， 优选 H、 d_4烷基、 C3_4环烷基 或 3至 4元杂环烷基， 进一步优选 11或 — 4烷基； 所述的杂环烷基含有 1至 5个选自 N、 0 或 3(=0)11的原子或基团； R 9 is selected from H, d_ 4 alkyl, C 3 _ 6 cycloalkyl group or 3 to 6-membered heterocyclic group, preferably H, d_ 4 alkyl, C 3 _ 4 cycloalkyl or heterocyclic 3-4 yuan An alkyl group, further preferably 11 or -4- alkyl; the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R1Q和 R11各自独立选自 H、 d_4烷基、 羟基、 d_4烷氧基、 C3_6环烷基或 3至 6元杂环 烷基， 优选 H、 d— 4烷基或 d— 4烷氧基； 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n 的原子或基团； R 1Q and R 11 are each independently selected from H, d- 4 alkyl, hydroxy, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, d- 4 alkyl or D- 4 alkoxy; said heterocycloalkyl containing 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6 元杂环烷基， 优选 H、 氨基、 羟基、 d— 4烷基或 d— 4烷氧基； 所述的杂环烷基含有 1至 5个 选自 N、 O或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, amino, hydroxy, D- 4 alkyl or d- 4 alkoxy; said heterocycloalkyl contains 1 to 5 An atom or group selected from N, O or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 氨基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、仲丁基、叔丁基、 乙烯基、 丙烯基、烯丙基、 2-丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 环丙基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-环己基、 -0-氧杂环丙基、 -0-氧杂环丁基、 -0-氧杂环戊基、 -0-氧杂环己基、 环丁基、 环戊基、 环己基、 氧杂环丙基、 氧杂环丁基、 氧 杂环戊基或氧杂环己基， 优选 H、 F、 Cl、 Br、 甲基、 乙基、 甲氧基、 乙氧基、 氰基、 羟基、 环丙基、乙炔基或丙炔基； 当被取代时，各自独立地任选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 羟基、 氨基、 甲基、 乙基、 乙烯基、 丙烯基、 烯丙基、 乙炔基、 丙炔基、 炔丙基、 甲氧基、 乙氧基、 环丙基、 环丁基、 氧杂环丙基或氧杂环丁基的取代基 所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy , ethoxy, propoxy, isopropoxy, butoxy, cyclopropyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -0-cyclohexyl, - 0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, -0-oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, oxopropyl , oxetanyl, oxolyl or oxeyl, preferably H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, cyano, hydroxy, cyclopropyl, Ethynyl or propynyl; when substituted, each independently optionally from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, hydroxy , amino, methyl, ethyl, vinyl, propenyl, allyl, ethynyl, propyl Group, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxetanyl or oxetanyl propyl substituents;

进一步优选地， R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 甲氧基、 乙氧基、 氰基、 羟基、 乙炔基或丙炔基。 Further preferably, R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, —CH 2 F, —CHF 2 , —CF 3 , methyl, ethyl, methoxy. , ethoxy, cyano, hydroxy, ethynyl or propynyl.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R5选自 F、 Cl、 甲基、 乙基、 甲氧基、 -CHF2或 -CF3， 优选 Cl。 R 5 is selected from the group consisting of F, Cl, methyl, ethyl, methoxy, -CHF 2 or -CF 3 , preferably Cl.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

G选自 6至 10元芳基或 5至 10元杂芳基， 优选 6至 10元芳基或 5至 6元杂芳基， 进 一步优选苯环、 噻吩或噻唑； 其中所述的苯环、 芳基、 噻吩、 噻唑或杂芳基任选进一步被 0 至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 羧基、 d_6烷基、 d_6烷氧基、 - 3¾)„^3_6环烷基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -O-C6_10 芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元杂环烷 基)、 -(CH2)m-C6— 10芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4 至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、-0-(3至 6元杂环烷基)、-O-C6_10 芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12 元桥环基)、 -NR10Rn或 -(CH2)m-S(=0)n-R9的取代基所取代， 进一步优选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C3— 6 环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 -(CH2)m-C6_io芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3-6 环烷基、 -0-(3至 6元杂环烷基)、 -0-C6— 1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环 基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -NR10Rn或 -(CH2)m-S(=0)n-R9的取代基 所取代； 其中所述烷基、 芳基、 杂芳基、 螺环基、 桥环基、 并环基、 烷氧基、 环烷基或杂 环基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 羟基、 烷基、 d_6烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_io 芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0 3_6环烷基、 -0-(3至 6元杂环烷基)、 -O-C6_10芳基、 -0-(6 至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -NR10Rn或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 羟基、 d— 6烷基、 d— 6烷氧基、 -( ！！^^^环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4 至 12元并环基 )、 -(CH2)m-(4至 12元桥环基 )、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基 )、 -0-(5 至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -NR1QRU或 -(CH2)m-S(=0)n-R9 的取代基所取代， 进一步优选 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 羟 基、 CM烷基、 d— 4烷氧基、 -(CH2)m-C3— 5环烷基、 -(CH2)m-(3至 5元杂环烷基)、 -0-C3— 5环烷 基、 -0-(3至 5元杂环烷基)、 -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代， 更优选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 羟基、 d_4烷基或 d_4烷氧基； 且以上所述的杂环 烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N、 0或 S(=0)n的原子或基 团； G is selected from a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, preferably a 6 to 10 membered aryl group or a 5 to 6 membered heteroaryl group, further preferably a benzene ring, a thiophene or a thiazole; wherein the benzene ring, The aryl, thiophene, thiazole or heteroaryl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, carboxy , d 6 alkyl, d 6 alkoxy, - 33⁄4) „^ 3 -6 cycloalkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cycloalkyl), -(CH 2 ) m - (4 to 12 membered bridged ring group), -0-C 3 _ 6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -OC 6 _ 10 aryl, -0-(6 to 10 membered heteroaryl), -0- (5 to 12 membered spiro ring) Base), -0-(4 to 12-membered ring group), -0-(4 to 12 membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 1 Substituting 0 R n or -(CH 2 ) m -S(=0) n -R 9 is preferably 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , CF 3 , Cyano, nitro, hydroxy, 6 alkyl, D- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-group ), -(CH 2 ) m -C 6 - 10 aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 To 6-membered heterocycloalkyl), -OC 6 _ 10 aryl, -0-(6 to 10 membered heteroaryl), -0-(5 to 12 membered spiro group), -0- (4 to 12) Substituted with a substituent of -0-(4 to 12 membered bridged ring group), -NR 10 R n or -(CH 2 ) m -S(=0) n -R 9 , further preferably 0 to 3 are selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 4 alkyl, d- 4 alkoxy, -(CH 2 m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 -ioaryl, -(CH 2 ) m -( 6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring group), -0-C 3 -6 cycloalkyl group, -0-(3 to 6-membered heterocycloalkyl group), -0-C 6 — 1Q aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring-based group), -0-(4 to Substituted by a substituent of 12-membered bridged ring), -NR 10 R n or -(CH 2 ) m -S(=0) n -R 9 wherein the alkyl group, aryl group, heteroaryl group, spiro ring The group, the bridged ring group, the cyclized group, the alkoxy group, the cycloalkyl group or the heterocyclic group are further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, hydroxy, alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m - (3 to 6-membered hetero Cycloalkyl), -(CH 2 ) m -C 6 _io aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group) ), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0 3 -6 cycloalkyl, -0-(3 To 6-membered heterocycloalkyl), -OC 6 _ 10 aryl, -0-(6 to 10 membered heteroaryl), -0-(5 to 12 membered spiro group), -0- (4 to 12) Molecular ring), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0- R 13, -NR 10 R n or - (CH 2) m -S ( = 0) n -R 9 group substituted with substituents, preferably F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, = 0, cyano, nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (! ! ^^^cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -(5 to 12-membered spiro group), -(CH 2 ) m -( 4 to 12 members and a cyclic group), -(CH 2 ) m - (4 to 12 membered bridged ring group), -0-C 3 -6 cycloalkyl group, -0-(3 to 6 membered heterocycloalkyl) , -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring-based group), -0-(4 to 12-membered bridged ring group), -NR 1Q R U or -(CH 2 Substituting m -S(=0) n -R 9 substituent, further preferably F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, Hydroxy, CM alkyl, d-4 alkoxy, -(CH 2 ) m -C 3 -5 cycloalkyl, -(CH 2 ) m -(3 to 5-membered heterocycloalkyl), -0-C Substituted by a substituent of 3 -5 cycloalkyl, -0-(3 to 5-membered heterocycloalkyl), -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 , Preferred is F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, hydroxy, d 4 alkyl or d 4 alkoxy; and heterocycloalkyl, heterocycle as described above An aryl group, a spiro group, a bridged ring group or a bicyclic group may have 0 to 5 atoms or groups selected from N, 0 or S(=0) n ;

R9选自 H、 d— 6烷基、 C3— 6环烷基或 3至 6元杂环烷基， 优选 H、 d— 4烷基、 C3— 6环烷基 或 3至 6元杂环烷基， 进一步优选 11或^— 4烷基， 更优选 11或^— 2烷基； 所述的杂环烷基 含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 9 is selected from H, d- 6 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 4 alkyl, C 3 - 6 cycloalkyl or 3-6 yuan heterocycloalkyl, or more preferably 11 ^ --4 alkyl, more preferably 11 or ^ - 2 alkyl; said heterocycloalkyl containing 1 to 5 heteroatoms selected from N, 0 or S (= 0) n in Atom or group;

R1Q和 R11各自独立选自 H、 羟基、 氨基、 d_6烷基、 d_6烷氧基、 C3_6环烷基或 3至 6 元杂环烷基， 优选 H、 羟基、 d— 4烷基、 d— 4烷氧基、 C3—6环烷基或 3至 6元杂环烷基， 进 一步优选 H、 d— 2烷基、 d— 2烷氧基或 C3— 4环烷基； 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 1Q and R 11 are each independently selected from H, hydroxy, amino, d- 6 alkyl, d- 6 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, hydroxy, d- 4 alkyl, D- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, into One step is preferably H, d- 2 alkyl, d- 2 alkoxy or C 3 -4 cycloalkyl; said heterocycloalkyl contains 1 to 5 selected from N, 0 or 3 (=0) 11 Atom or group;

R12选自 3至 6元环烷基； R 12 is selected from a 3- to 6-membered cycloalkyl group;

R13选自 H、 氨基、 羟基、 d_6烷基、 d_6烷氧基、 C3_6环烷基或 3至 6元杂环烷基， 优 选 H、氨基、羟基、 d_4烷基、 d_4烷氧基、 3_6环烷基或 3至 6元杂环烷基，进一步优选 H、 氨基、 羟基、 d— 2烷基或 d— 2烷氧基； 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n 的原子或基团； R 13 is selected from H, amino, hydroxy, d- 6 alkyl, d- 6 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, amino, hydroxy, d- 4 alkyl, d_ 4 alkoxy, 3 _ 6 cycloalkyl group or 3 to 6-membered heterocyclic group, more preferably H, amino, hydroxy, d- 2 d- 2 alkyl or alkoxy; the heterocycloalkyl group Containing 1 to 5 atoms or groups selected from N, 0 or S(=0) n ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

G选自 6至 10元芳基或 5至 10元杂芳基， 优选 6至 10元芳基或 5至 6元杂芳基， 进 一步优选苯环、 噻吩或噻挫； 所述的苯环、 噻吩、 噻唑、 芳基或杂芳基任选进一步被 0至 3 个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 6烷基、 d— 6 烷氧基、 -( ！^^ ^环烷基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环 基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代基所取代，优选被 0至 3个选自 F、 Cl、 Br、 -CH2F 、 -CHF2、 -CF3、 =0、 氰基、 硝基、 羟基、 CM烷基、 CM烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元杂环烷基 )、 -0-C3— 6环烷基或 -0-(3至 6元杂环烷基)的取代基所取代，进一 步优选 -CH2F、 -CHF2、 -CF3、 d_4烷基、 d_4烷氧基、 -0-C3_4环烷基或 -0-(3至 6元杂环烷 基；)的取代基所取代， 更优选 d— 4烷氧基或 -0-C3— 4环烷基； 且所述烷基、 芳基、 螺环基、 桥 环基、 并环基、 杂芳基、 烷氧基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br 、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基 、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -0-(5至 12元螺环基) 、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代 基所取代； 且所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N 、 0或 3(=0)11的原子或基团； G is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, preferably 6 to 10 membered aryl or 5 to 6 membered heteroaryl, further preferably benzene ring, thiophene or thiophene; said benzene ring, Thiophene, thiazole, aryl or heteroaryl optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 Alkyl, d- 6 alkoxy, -( !^^^cycloalkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - ( 4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-(5 to 12-membered spiro group), -0- Substituted by (4- to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , preferably from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F , -CHF 2 , -CF 3 , =0, cyano, nitro, hydroxy, CM alkyl, CM alkoxy, -( CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-alkyl), -0-C 3 - 6 cycloalkyl, or -0- (3-6 yuan Heterocycloalkyl) Substituted with substituents, more preferably -CH 2 F, -CHF 2, -CF 3, d_ 4 alkyl, d_ 4 alkoxy, -0-C 3 _ 4 alkyl or cycloalkyl -0- (3-6 yuan Substituted by a substituent of a heterocycloalkyl group;), more preferably a d- 4 alkoxy group or a-0-C 3 -4 cycloalkyl group; and the alkyl group, the aryl group, the spiro group, the bridged ring group, and The cyclo, heteroaryl, alkoxy, cycloalkyl or heterocycloalkyl group is further optionally from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano , nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-group ), -(CH 2 ) m -(5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - (4 to 12 membered bridged ring) Base), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-(5 to 12-membered spiro group), -0- (4 to 12-membered Substituted by a substituent of a ring group), -0-(4 to 12 membered bridged ring group), =0, -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U ; Said heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic ring may contain from 0 to 5 atoms selected from N, 0 or 3 (=0) 11 or Group

进一步地优选， G选自苯环、 噻吩或噻唑； 所述的苯环、 噻吩、 噻唑、 芳基或杂芳基 任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 羟基、 CM烷基、 CM烷氧基、 d— 4烷氧基 -0-C3— 6环烷基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元 杂环烷基 )、 -0-C3— 6环烷基或 -0-(3至 6元杂环烷基)的取代基所取代，优选 F -CH2F -CHF2 -CF3 CM烷基、 CM烷氧基、 d— 4烷氧基 -0-C3— 6环烷基、 -0-(CH2)M-C3— 4环烷基、 -0-(CH2)m-(3 至 6元杂环烷基;)的取代基所取 进一步优选 d— 4烷氧基或 — 4烷氧基 -0-C3— 6环烷基， 更 优选 F、 甲氧基、 、。 ,

Figure imgf000018_0001
、 乙氧基或 -Ο-氧杂环戊基; Further preferably, G is selected from a benzene ring, a thiophene or a thiazole; the benzene ring, thiophene, thiazole, aryl or heteroaryl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F , -CHF 2, -CF 3, = 0, a cyano group, a nitro group, a hydroxyl group, an alkyl group the CM, the CM alkoxy, -0-C 3 d- 4 alkoxy - 6 cycloalkyl, - (CH 2 m -C 3 - 6 cycloalkyl, -(CH 2 ) m - (3 to 6 yuan) Heterocycloalkyl), -0-C 3 - 6 cycloalkyl, or -0- (3 to 6-membered heterocyclic group) substituted with a substituent group, preferably F -CH 2 F -CHF 2 -CF 3 CM alkoxy group, CM alkoxy, d- 4 alkoxy, -0-C 3 - 6 cycloalkyl, -0- (CH 2) m -C 3 - 4 cycloalkyl, -0- (CH 2) m - (3 to 6-membered heterocyclic group;) substituents taken more preferably D- 4 alkoxy or - to C4 alkoxy -0-C 3 - 6 cycloalkyl group, more preferably F, methoxy,, . ,
Figure imgf000018_0001
, ethoxy or -oxime-oxocyclopentyl;

R9选自 H d— 4烷基、 C3— 6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N 0或 3(=0)11的原子或基团； R 9 is selected from H d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring group having 1 to 5 substituents selected or 3 N 0 (= 0) An atom or group of 11 ;

R1Q和 R11各自独立选自 H、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环 烷基， 所述的杂环烷基含有 1至 5个选自 N 0或 3(=0)11的原子或基团； R 1Q and R 11 are each independently selected from H, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic group Containing 1 to 5 atoms or groups selected from N 0 or 3 (=0) 11 ;

n选自 0 1或 2;  n is selected from 0 1 or 2;

m选自 0 1或 2  m is selected from 0 1 or 2

本发明优选方案， 包括通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体 ：  Preferred embodiments of the invention include an oxabicyclic derivative represented by the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or cocrystal:

W选自 d— 3亚烷基、 -C(=0)-

Figure imgf000018_0002
-CH2-或 ；所述的亚烷基、 或\ 各自独立任选进一步被 0至 3个选自 F Cl Br -CF3、 羟基、 d_4烷基、 d_4烷氧 基、 C3— 4环烷基或 3至 5元杂环烷基的取代基所取代，优选被 0至 2个选自 F Cl Br -CF3 甲基、 乙基、 丙基、 甲氧基、 乙氧基、 环丙基或环丁基的取代基所取代； 进一步优选地， W选自 -CH2- -C(CH3)2- -CF2-或 优选 -CH2-或 进一步 优选 -CH2- 本发明优选方案， 包括通式 (II)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共结晶复合物或前药： W is selected from d- 3 alkylene, -C(=0)-
Figure imgf000018_0002
-CH 2 - or; the alkylene group, or \ each independently optionally further from 0 to 3 selected from the group consisting of F Cl Br -CF 3 , hydroxy, d 4 alkyl, d 4 alkoxy, C 3 - Substituted by a substituent of a 4-cycloalkyl group or a 3- to 5-membered heterocycloalkyl group, preferably from 0 to 2 selected from the group consisting of F Cl Br -CF 3 methyl, ethyl, propyl, methoxy, ethoxy, Substituted with a substituent of a cyclopropyl group or a cyclobutyl group; further preferably, W is selected from -CH 2 -C(CH 3 ) 2 - -CF 2 - or preferably -CH 2 - or further preferably -CH 2 - Preferred embodiments of the invention include an oxabicyclic derivative represented by the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof:

Figure imgf000018_0003
Figure imgf000018_0003

(Π)  (Π)

其中- among them-

X选自 -0- -S(=0)n-或 -NR8-; X is selected from -0--S(=0) n - or -NR 8 -;

R选自 H d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C2.4 烯基 -R12 -(CH2)m-C2_4炔基 -R12 -(CH2)m-C(=0)-R13或 -(CH2)m-C(=0)-0-R13， 所述的烷基、 杂环烷基、环烷基、烯基或炔基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 CM烷基、 d— 4烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元 杂环烷基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -(CH2)m-C2_6烯基 -R12或 - 3¾)„1 2_6炔 基 -R12的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 8(=(¾1的原子或基团； R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基、 d— 4烷氧基、R is selected from H d 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C . 24 alkenyl group -R 12 - (CH 2) m -C 2 _ 4 alkynyl group -R 12 - (CH 2) m -C (= 0) -R 13 or - (CH 2) m -C ( = 0)-0-R 13 , the alkyl group, Heterocycloalkyl, cycloalkyl, alkenyl or alkynyl optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, carboxy, amino, CM alkyl, d- 4 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-alkyl), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 2 _ 6 alkenyl-R 12 or - 33⁄4) „ 1 2 _ 6 alkynyl-R Substituted by a substituent of 12 ; the heterocycloalkyl group contains 1 to 5 atoms or groups selected from N, 0 or 8 (= (3⁄4 1 ; R 4 , R 5 , R 6 and R 7 are each independently Is selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl, d- 4 alkoxy,

-(CH2)m-C2_4烯基 -R12、 -(CH2)m-C2_4炔基 -R12、 -( ！^；^ ^环烷基、 -(CH2)m-(3至 6元杂环烷 基)、 -0 3_6环烷基、 -0-(3至 6元杂环烷基)、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-S(=0)n-R9或 -NR1QRU， 所述烷基、 烷氧基、 烯基、 炔基、 环烷基或杂环烷基任选进 一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C3— 6环烷基或 -(CH2)m-(3 至 6元杂环烷基;)的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原 子或基团； - (CH 2) m -C 2 _ 4 alkenyl group -R 12, - (CH 2) m -C 2 _ 4 alkynyl group -R 12, - (^; ^ ^ cycloalkyl, - (CH 2)! m -(3 to 6-membered heterocycloalkyl), -0 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , the alkyl group, the alkoxy group The base, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, amino, Cyano, hydroxy, d- 4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R Substituting a substituent of 12 , -(CH 2 ) m -C 3 - 6 cycloalkyl or -(CH 2 ) m - (3 to 6-membered heterocycloalkyl;); Up to 5 atoms or groups selected from N, 0 or S(=0) n ;

W选自 -NH -、 -0-、 -C(=0)-、 d_3亚烷基或 ^'Ρ , 所述的亚烷基或 各自任选进一 步被 0至 4个选自 F、 Cl、 -CF3、 羟基、 d— 3烷基或 d— 3烷氧基的取代基所取代； W is selected from -NH -, -0-, -C(=0)-, d_ 3 alkylene or ^' Ρ , said alkylene or each optionally further from 0 to 4 selected from F, Cl Substituted with a substituent of -CF 3 , hydroxy, d-3 alkyl or d-3 alkoxy;

G选自 6至 10元芳基或 5至 10元杂芳基，优选选自 6至 10元芳基或 5至 6元杂芳基， 其芳基或杂芳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、 硝基、 羟基、 醛基、 羧基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6 环烷基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元 桥环基 )、 -0-C3-8环烷基、 -0-(3至 8元杂环烷基 )、 -O-C6.10芳基、 -0-(6至 10元杂芳基 )、 -0-(5 至 12元螺环基)、 -0-(4 至 12元并环基)、 -0-(4 至 12元桥环基)、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代， 所述烷基、 芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环烷基或杂环烷基任选进一步被 0至 5个选 自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 异氰基、 硝基、 羟基、 d— 6烷基、 d— 6 烷氧基、 - 3¾)„^3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6 至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12 元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -0-C6_1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-C(=0)-R1\ -(CH2)m-C(=0)-0-R1\ -NR1QRU或 -(CH2)m-S(=0)nR9的取代基所取代； 所述的杂环烷基、 杂 芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； 作为选择， G环上任意两个取代基可以形成一个 3至 8元环， 所形成的环选自环烷基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 3个选自 N、 0或 3(=0)11杂原子或基团， 且其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 羟基、 d— 6烷基或 d— 6烷氧基的取代基所取代； G is selected from 6 to 10 membered aryl or 5 to 10 membered heteroaryl, preferably selected from 6 to 10 membered aryl or 5 to 6 membered heteroaryl, the aryl or heteroaryl group of which is independently optionally further Up to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, aldehyde, carboxyl, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -(3 to 6-membered heterocycloalkane (), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group) -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -8 cycloalkyl, -0-( 3 to 8 membered heterocycloalkyl), -OC 6 .10 aryl, -0-(6 to 10 membered heteroaryl), -0-(5 to 12 membered spiro group), -0-(4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0 -R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC (=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 substitution Replaced by Or a aryl group, a spiro group, a bridged ring group, a cyclized group, a heteroaryl group, an alkoxy group, a cycloalkyl group or a heterocycloalkyl group, optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, isocyano, nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, - 33⁄4) „^ 3 _ 6 Cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl) Base), -(CH 2 ) m -(5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - (4 to 12 member bridge) Cyclo), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6 _ 1Q aryl, -0-(6 to 10 membered heteroaryl) ), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring-based group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -C ( =0)-R 1 \ -(CH 2 ) m -C(=0)-0-R 1 \ -NR 1Q R U or -(CH 2 ) m -S(=0) n substituent of R 9 Substituted; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; Alternatively, any two substituents on the G ring may form a 3 to 8 membered ring, the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the resulting ring may contain 0 to 3 selected from N, 0 or 3 (=0) 11 heteroatoms or groups, and wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from F Substituted with a substituent of Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, hydroxy, d- 6 alkyl or d- 6 alkoxy;

R8、 R1Q和 R11各自独立选自 H、 羟基、 d_6烷基、 d_6烷氧基、 C3_6环烷基或 3至 6元 杂环烷基， 优选 H、 d— 4烷基、 d— 4烷氧基、 C3—6环烷基或 3至 6元杂环烷基； 所述的杂环 烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 8 , R 1Q and R 11 are each independently selected from H, hydroxy, d- 6 alkyl, d- 6 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably H, d- 4 alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group; said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or S (= 0) An atom or group of n ;

R9选自 H、 d— 6烷基、 C3—6环烷基或 3至 6元杂环烷基， 优选 H、 d— 4烷基、 C3— 6环烷基 或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R12和 R13各自独立选自 H、 氨基、 羟基、 d— 6烷基、 d— 6烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 优选 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环烷 基； 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 6 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 4 alkyl, C 3 - 6 cycloalkyl or 3-6 yuan a heterocycloalkyl group, the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; R 12 and R 13 are each independently selected from H, an amino group, a hydroxyl group, d- 6 alkyl, d- 6 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group; said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) or a group 11 atom;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

p选自 1、 2或 3 ;  p is selected from 1, 2 or 3;

m选自 0、 1、 2、 3或 4。  m is selected from 0, 1, 2, 3 or 4.

本发明优选方案， 包括通式 (II)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共结晶复合物或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, wherein:

X选自 -0-或 -s(=o)n-; X is selected from -0- or -s(=o) n - ;

R选自 H、 d_4烷基、 -( ！！ ^^环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C2_4 烯基 -R12、 -(CH2)m-C2_4炔基 -R12、 -(CH2)m-C(=0)-R13或 -(CH2)m-C(=0)-0-R13， 所述的烷基、 杂环烷基、 环烷基、 烯基或炔基任选进一步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基或 d— 4烷氧基的取代基所取代， 所述的杂环烷基含有 1 至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d_ 4 alkyl, - (!! ^^ cycloalkyl, - (CH 2) m - (3 to six-alkyl), - (CH 2) m -C 2 _ 4 alkenyl group -R 12, - (CH 2) m -C 2 _ 4 alkynyl group -R 12, - (CH 2) m -C (= 0) -R 13 or - (CH 2) m -C ( = 0) -0-R 13, the alkyl, heterocycloalkyl, cycloalkyl, alkenyl or alkynyl group is optionally further selected from 0-5 F, Cl, -CH 2 F, -CHF 2, - Substituted by a substituent of CF 3 , cyano, hydroxy, carboxy, amino, d- 4 alkyl or d- 4 alkoxy, said heterocycloalkyl contains 1 to 3 selected from N, 0 or 3 ( =0) an atom or group of 11 ;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C2_4烯基 -R12或 -(CH2)m-C2_4炔基 -R12， 优选 H、 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙 基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 乙烯基、 丙烯基、 烯丙基、 2- 丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基或 丁氧基； 其中所述烷基、 烷氧基、 烯基或炔基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 羟基、 d— 4烷基或 d— 4烷氧基的取代基所取代， 优选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 羟基、 甲基、 乙基、 甲氧基或乙氧基的取代基 所取代； 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； w选自 -c(=o)-、 d— 3亚烷基或 ^^p， 优选 -c¾-或 Δ ； 所述的亚烷基或 ^^各自 任选进一步被 0至 4个选自 F、 Cl、 -CF3、 羟基、 d— 3烷基或 d— 3烷氧基的取代基所取代， 优选 F、 Cl、 Br、 -CF3、 甲基、 乙基、 正丙基、 甲氧基或乙氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl, d- 4 alkoxy, -(CH 2 ) m -C 2 _ 4 alkenyl group -R 12 or - (CH 2) m -C 2 _ 4 -R 12 alkynyl group, preferably H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyl Alkyn-1-yl, methoxy, ethoxy, propoxy, isopropoxy or butoxy; wherein the alkyl, alkoxy, alkenyl or alkynyl group is each independently optionally further Substituted to 4 substituents selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, d- 4 alkyl or d- 4 alkoxy, preferably 0 to 3 Substituted with a substituent selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, methyl, ethyl, methoxy or ethoxy; 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ; w is selected from -c(=o)-, d- 3 alkylene or ^^p, preferably -c3⁄4- or Δ; each of said alkylene groups or optionally further selected from 0 to 4 selected from F Substituted with a substituent of Cl, -CF 3 , hydroxy, d- 3 alkyl or d- 3 alkoxy, preferably F, Cl, Br, -CF 3 , methyl, ethyl, n-propyl, methoxy Substituted by a substituent of a ethoxy group or an ethoxy group;

G选自苯环、 噻吩或噻唑， 其中苯环、 噻唑或噻吩任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、硝基、 羟基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C6_10芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元 桥环基 )、 -0-C3— 6环烷基、 -0-(3至 6元杂环烷基 )、 -0-C6— 10芳基、 -0-(6至 10元杂芳基 )、 -0-(5 至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU 的取代基所取代； 其中所述烷基、 芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环 烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、羟基、 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5 至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -0-C6_1()芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4 至 12元并环基)、 -0-(4至 12元桥环基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代基所取 代， 优选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 烷基、 d_6烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3 至 6 元杂环烷基）、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代基所取代； 且以上所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein the benzene ring, thiazole or thiophene is further optionally 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, and nitrate group, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-alkyl), -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 6 _ 10 aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl) , -(CH 2 ) m -(5 to 12-membered spiro group), -(CH 2 ) m -(4 to 12-membered ring-based group), -(CH 2 ) m - (4 to 12-membered bridged ring group) ), -0-C 3 - 6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6 - 10 aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12 membered spiro group), -0-(4 to 12 membered ring group), -0-(4 to 12 membered bridged ring group), -(CH 2 ) m -S (=0 Substituted by a substituent of n -R 9 or -NR 1Q R U ; wherein the alkyl group, aryl group, spiro group, bridged ring group, cyclylene group, heteroaryl group, alkoxy group, cycloalkyl group or The heterocycloalkyl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, 6 alkyl, d- 6 Alkoxy , -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group) -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-( 3- to 6-membered heterocycloalkyl), -0-C 6 _ 1() aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0 - (4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), =0, -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U Substituted by a substituent, preferably further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, alkyl, d- 6 alkoxy , -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6 membered heterocycloalkyl), =0, -(CH 2 ) m -S(=0) Substituted with a substituent of n -R 9 or -NR 1Q R U ; and the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group described above may contain 0 to 5 selected from N An atom or group of 0 or S(=0) n ;

R9选自 H、 d— 4烷基、 C3— 6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ;

R1Q和 R11各自独立选自 H、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 1Q and R 11 are each independently selected from H, d 4 alkyl, d 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, said heterocycloalkyl containing 1 to 5 An atom or group selected from N, 0 or S(=0) n ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

p选自 1或 2;  p is selected from 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括通式 (II)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共结晶复合物或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (II) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, wherein:

R选自 H、 d— 4烷基、、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 - 3¾)„^3_4环烷基或 -(CH2)m-(3至 4元杂环烷基)， 所述的烷基、 烯 基、 炔基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氨 基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取代， 且所述的杂环烷基含有 1 至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , - 33⁄4) „^ 3 _ 4 cycloalkyl or —(CH 2 ) m —(3 to 4 membered heterocycloalkyl), Or an alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, Substituted with a substituent of a hydroxyl group, a carboxyl group, a d- 4 alkyl group or a d- 4 alkoxy group, and the heterocycloalkyl group contains 1 to 3 atoms selected from N, 0 or 3 (=0) 11 or Group

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、仲丁基、叔丁基、 乙烯基、 丙烯基、烯丙基、 2-丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基或丁氧基， 当被取代 时， 各自独立地任选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、羟基、 甲基、 乙基、 甲氧基或乙氧基的取代基所取代； W选自 -CH2-或 ， 且 -CH2-或 各自独立任选进一步被 0至 2个选自 F、 Cl、R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy, B Oxyl, propoxy, isopropoxy or butoxy, when substituted, are each independently optionally from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3, hydroxy, methyl, ethyl, methoxy or ethoxy substituents; W is selected from -CH 2 - or, and -CH 2 - or are each independently optionally further substituted by 0-2 selected from F, Cl,

Br、 -CF3、 甲基、 乙基、 正丙基、 甲氧基或乙氧基的取代基所取代； Substituted by a substituent of Br, -CF 3 , methyl, ethyl, n-propyl, methoxy or ethoxy;

G选自苯环、 噻吩或噻唑， 其中苯环、 噻唑或噻吩各自独立任选进一步被 0至 3个选 自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、氰基、硝基、羟基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6 环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6 至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12 元桥环基)、 -0-C3— 6环烷基、 -0-(3至 6元杂环烷基)、 -0-C6— 1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9 或 -NR1QRU的取代基所取代， 所述烷基、芳基、螺环基、桥环基、并环基、杂芳基、烷氧基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、羟基、 d_6烷基、 d_6烷氧基、 - 3 )„^3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代基所取代； 且所述的杂环烷基、 杂芳基、 螺环基、 桥环 基、 并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein each of the benzene ring, the thiazole or the thiophene is optionally further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano , nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, - (CH 2) m -C 3 - 6 cycloalkyl, - (CH 2) m - (3 to six-group ), -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m -(6 to 10 yuan heteroaryl) Base), -(CH 2 ) m -(5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - (4 to 12 member bridge) Cyclo), -0-C 3 - 6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6 - 1Q aryl, -0-(6 to 10 membered heteroaryl) ), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -S ( =0) Substituted by a substituent of n -R 9 or -NR 1Q R U , said alkyl group, aryl group, spiro group, bridged ring group, carboxy group, heteroaryl group, alkoxy group, cycloalkyl group Or a heterocycloalkyl group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 alkyl, d_ 6 alkoxy , - 3 ) „^ 3 _ 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), =0, -(CH 2 ) m -S(=0) n -R 9 Or substituted with a substituent of -NR 1Q R U ; and the heterocycloalkyl, heteroaryl, spiro group, bridged ring group, and cyclylene group may contain 0 to 5 selected from N, 0 or 3 ( =0) an atom or group of 11 ;

R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ;

R1Q和 R11各自独立选自 H、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 1Q and R 11 are each independently selected from H, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic group containing 1 Up to 5 atoms or groups selected from N, 0 or S(=0) n ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括通式 (III)所示的氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 : Preferred embodiments of the invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer thereof, a hydrate thereof, a solvent Compound, pharmaceutically acceptable salt,

Figure imgf000023_0001
Figure imgf000023_0001

(III)  (III)

其中- R选自 H、 d— 6烷基、 -(CH2)m-C2— 6烯基 -R12、 -(CH2)m-C2— 6炔基 -R12、 -(CH2)m-C(=0)-R13、Wherein - R is selected from the group consisting of H, d- 6 alkyl, -(CH 2 ) m -C 2 - 6 alkenyl-R 12 , -(CH 2 ) m -C 2 - 6 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 ,

- 3¾)„1 (=0)-0-1 13、-：¾)111 3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)或 -(CH2)m-S(=0)n-R9， 优选 H、 d— 4烷基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 - 3¾)„1 3_4环烷基或 -(CH2)m-(3至 4元杂环烷基)， 进一步优选 H、 3烷基； 所述的烷基、烯基、炔基、环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取 代； 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； - 33⁄4) „ 1 (=0)-0-1 13 , -: 3⁄4) 111 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl) or -(CH 2 ) m -S(=0) n -R 9 , preferably H, d- 4 alkyl, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 - 4 alkyne -R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , - 33⁄4) „ 1 3 _ 4 cycloalkyl Or -(CH 2 ) m -(3 to 4 membered heterocycloalkyl), further preferably H, 3 alkyl; the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group optionally further From 0 to 5 substituents selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, hydroxy, carboxy, d- 4 alkyl or d- 4 alkoxy Substituted; the heterocycloalkyl group contains 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R1', R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、羟基、 d_6烷基、 d_6烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 -(CH2)m-C6— 1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环 基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3— 6环烷基、 -0-(3至 6 元杂环烷基)、 -0-C6_1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元 并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU， 优选 H、 F、 Cl、 d— 6烷氧 基、 -0-C3— 6环烷基或 -0-(3至 6元杂环烷基)， 进一步优选 H、 ？或^— 3烷氧基； 所述烷基、 芳基、 杂芳基、 烷氧基、 环烷基、 杂环烷基、 螺环基、 桥环基或并环基任选进一步被 0至 5 个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 硝基、 羟基、 d_6烷基、 d— 6烷 氧基、 -( ^^^环烷基、 -(CH2)m-(3至 6元杂环烷基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU 的取代基所取代； 所述的杂环烷基、 杂芳基、 螺环基、 桥环基、 并环基可含有 0至 3个选 自 0或 3(=0)11的原子或基团； R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -C 3 -6 cycloalkyl, -( CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 - 1Q aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), -(CH 2 ) m - (4 to 12-membered bridged ring group), -0 -C 3 - 6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0-C 6 - 1Q aryl, -0-(6 to 10 membered heteroaryl), -0-( 5 to 12 membered spiro group), -0-(4 to 12 membered ring group), -0-(4 to 12 membered bridged ring group), -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U, preferably H, F, Cl, d- 6 alkoxy, -0-C 3 - 6 cycloalkyl, or -0- (3 to 6-membered heterocyclic group), more preferably H , ? Or ^ --3 alkoxy; said alkyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocycloalkyl, spiro cycloalkyl group, a cycloalkyl group or a bridged cycloalkyl group and optionally further substituted with from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, -( ^ ^^cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), =0, -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U Substituted by a substituent; the heterocycloalkyl, heteroaryl, spiro group, bridged ring group, and cyclylene group may contain 0 to 3 atoms or groups selected from 0 or 3 (=0) 11 ;

作为选择， R2'、 R3'、 R4'和 R5'任意相邻的两个基团可以形成一个 4至 8元环， 优 选 4至 6元环， 进一步优选 4元环； 所形成的环选自环烷基、 杂环烷基、 芳基或杂芳基， 所形成的杂环烷基或杂芳基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团， 且所述环烷 基、 杂环烷基、 芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氰 基、 羟基、 d— 4烷基或 d— 4烷氧基的取代基所取代。 R9选自 H、 d— 4烷基、 ^6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 3个 选自 N、 0或 3(=0)11的原子或基团； Alternatively, two adjacent groups of R 2 ', R 3 ', R 4 ' and R 5 ' may form a 4- to 8-membered ring, preferably a 4- to 6-membered ring, further preferably a 4-membered ring; The ring is selected from a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, and the heterocycloalkyl or heteroaryl group formed contains 1 to 3 atoms selected from N, 0 or 3 (=0) 11 Or a group, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , -CF 3 , cyanide Substituted by a substituent of a hydroxy group, a d- 4 alkyl group or a d-4 alkoxy group. R 9 is selected from H, d- 4 alkyl, ^ 6 cycloalkyl or 3 to 6 membered heterocycloalkyl, and said heterocycloalkyl contains 1 to 3 selected from N, 0 or 3 (=0) An atom or group of 11 ;

R1Q和 R11各自独立选自 H、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 3个选自 N、 0或 S(=0;»n的原子或基团； R 1Q and R 11 are each independently selected from H, d 4 alkyl, d 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, said heterocycloalkyl containing 1 to 3 An atom or group selected from N, 0 or S (=0; » n ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6 元杂环烷基， 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, said heterocycloalkyl Containing 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1、 2、 3或 4， 优选 0、 1或 2。  m is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

本发明优选方案， 包括通式 (III)所示的氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 d— 4烷基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -( ¾)„1-¾_4环烷基或 -(CH2)m-(3至 4元杂环烷基)， 优选 H或 d_4烷 基， 所述的烷基、 烯基、 炔基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取代； 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -( 3⁄4)„ 1 -3⁄4_ 4 cycloalkyl or -(CH 2 ) m -( a 3- to 4-membered heterocycloalkyl group, preferably H or d- 4 alkyl, said alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl optionally further from 0 to 5 selected from F, Substituted by a substituent of Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , an amino group, a cyano group, a hydroxyl group, a carboxyl group, a d-4 alkyl group or a d-4 alkoxy group; The group contains 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R1', R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、羟基、 6烷基、 d— 6烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12 元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基)、 -0-(5至 12元螺环基)、 -0-(4至 12元 并环基)、 -0-(4至 12元桥环基)或 -NR1QRU， 优选 H、 F、 Cl、 d— 6烷氧基、 -0-C3— 6环烷基或 -0-(3至 6元杂环烷基)， 进一步优选 H、 F、 -0-(3至 6元杂环烷基)或 d— 3烷氧基； 所述烷 基、 螺环基、 桥环基、 并环基、 烷氧基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、氨基、氰基、硝基、羟基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3-6 环烷基、 -(CH2)m-(3至 6元杂环烷基 )、 =0或 -NR1QRU的取代基所取代； 所述的杂环烷基、 螺环基、 桥环基、 并环基可含有 0至 3个选自 N、 0或 3(=0)11的原子或基团； R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, 6 alkyl, D- 6 alkoxy, - (CH 2) m- 0- (CH 2) m-0-R 12, - (CH 2) m -C 3 - 6 cycloalkyl, - ( CH 2 ) m -(3 to 6-membered heterocycloalkyl), CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), -( CH 2 ) m - (4 to 12 membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 to 6-membered heterocycloalkyl), -0- (5 to 12 membered spiro ring) Base, -0-(4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group) or -NR 1Q R U , preferably H, F, Cl, d- 6 alkoxy, - 0-C 3 - 6 cycloalkyl or -0-(3 to 6-membered heterocycloalkyl), further preferably H, F, -0-(3 to 6-membered heterocycloalkyl) or d- 3 alkoxy The alkyl group, spiro group, bridged ring group, cyclized group, alkoxy group, cycloalkyl group or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 -6 cycloalkyl, - (CH 2) m - (3 to 6 membered heteromonocyclyl Alkyl), = 0, or -NR 1Q R U of substituents; a heterocycloalkyl group, the spiro group, a bridged cycloalkyl group, a cycloalkyl group and may contain 0 to 3 heteroatoms selected from N, 0 or 3 (=0) an atom or group of 11 ;

R1Q和 R11各自独立选自 H、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6元杂环烷基， 优选 11或^— 4烷基， 进一步优选 11或^— 2烷基； 所述的杂环烷基含有 1至 3个选自 N、 0 或 3(=0)11的原子或基团， 优选含有 1个 N或 0原子； R 1Q and R 11 are each independently selected from H, d- 4 alkyl, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, preferably 11 or -4- alkyl, further preferably or 11 ^ - 2 alkyl; said heterocycloalkyl containing 1 to 3 heteroatoms selected from N, 0 or 3 (= 0) or a group 11 atom, preferably a N or 0 atom;

R12和 R13各自独立选自 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 优选 H、 氨基、 羟基或 d— 4烷基， 进一步优选 H、 氨基、 羟基或 d— 2烷基； 所 述的杂环烷基含有 1至 3个选自 N、 0或 S(=0;»n的原子或基团，优选含有 1个 N或 0原子； n选自 0、 1或 2， 优选 0; m选自 0、 1或 2， 优选 0。 R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, amino, hydroxy or d- 4 alkyl, more preferably H, amino, hydroxy or d- 2 alkyl; said heterocycloalkyl containing 1 to 3 heteroatoms selected from N, 0 or S (= 0; »n atoms or a group, preferably containing 1 N or 0 atom; n is selected from 0, 1 or 2, preferably 0; m is selected from 0, 1 or 2, preferably 0.

本发明优选方案， 包括通式 (III)所示的氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 甲基、 乙基、正丙基、异丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、 乙烯基、 丙烯基、 烯丙基、 乙炔基、 炔丙基、 乙酰基、 -C(=0)-CH2CH3、 -C(=0)-CH3、 -C(=0)0-CH2CH3、 -C(=0)-OCH3或 -C(=0)-OCH2CH3， 且这些基团可以任选进一步被 0至 5 个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 氨基、 氰基或羟基的取代基所取代； R is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxecyclopropyl, oxetanyl, vinyl, propenyl, allyl, acetylene Base, propargyl group, acetyl group, -C(=0)-CH 2 CH 3 , -C(=0)-CH 3 , -C(=0)0-CH 2 CH 3 , -C(=0) -OCH 3 or -C(=0)-OCH 2 CH 3 , and these groups may optionally be further from 0 to 5 selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , -CF 3 , methyl Substituted with a substituent of an ethyl group, an amino group, a cyano group or a hydroxyl group;

R1', R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 氰基、 '、。〜。、、 羟基、 甲基、 乙 基、 正丙基、 异丙基、 正丁基、 异丁基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧 基、 叔丁氧基、 环丙基、环丁基、 -0-环丙基、 -0-环丁基、 -0-氧杂环丙基、 -0-氧杂环丁基、 - -CH2-环丙基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 氧杂环己基、 呋喃基、 噻吩基、 R 1 ', R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, cyano, and . ~. ,, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, uncle butoxy, cyclopropyl, cyclobutyl, -0- cyclopropyl, cyclobutyl -0-, -0- propyl oxetane, oxetanyl -0-, - -CH 2 - ring Propyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, furyl, thienyl,

Figure imgf000025_0001
优选 H、 F、 Cl、 乙氧基、 甲氧基、 环丙基、 , -0-氧杂环丁基或 -0-氧杂环戊基，
Figure imgf000025_0001
Preference is given to H, F, Cl, ethoxy, methoxy, cyclopropyl, , 0-oxetanyl or 0-oxocyclopentyl,

Rl R2'和 R5'进一步优选 H或者 F， R3'和 R4'进一步优选 F、 乙氧基、 , 甲氧基 或 -0-氧杂环戊基； 当以上所述的基团进一步被取代时， 任意进一步被 0至 4个1^、 Cl、 甲 基、 乙基、 正丙基、 异丙基、 环丙基、 氰基、 甲氧基或乙氧基的取代基所取代。 R l R 2 'and R 5 ' are further preferably H or F, and R 3 'and R 4 ' are further preferably F, ethoxy, methoxy or-0-oxocyclopentyl; When the group is further substituted, it is optionally further substituted with 0 to 4 substituents of 1^, Cl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyano, methoxy or ethoxy. Replace.

本发明优选方案， 包括通式 (III)所示的氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 d— 3烷基、 -(CH2)m-C2— 3烯基 -R12、 -(CH2)m-C2— 3炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 - 3¾)„^3_4环烷基或 -(CH2)m-(3至 4元杂环烷基)， 所述的烷基、 烯 基、炔基、环烷基或杂环烷基任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 环丙基、 d— 2烷基或 d— 2烷氧基的取代基所取代， 所述的杂环烷基含有 1个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 3 alkyl, -(CH 2 ) m -C 2 -3 alkenyl-R 12 , -(CH 2 ) m -C 2 -3 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , - 33⁄4) „^ 3 _ 4 cycloalkyl or -(CH 2 ) m -(3 To a 4-membered heterocycloalkyl group, the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group is further further selected 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 , an amino group, a cyano group, a hydroxyl group, a cyclopropyl group, a d- 2 alkyl group or a d- 2 alkoxy group, the heterocycloalkyl group having 1 selected from N An atom or group of 0 or 3 (=0) 11 ;

R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 -CF3、 羟基、 d— 3烷基、 d— 3烷氧基、 -(CH2)m-C3_5环烷基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(3至 5元杂环烷基)、 -0-C3_5环烷 基、 -0-P至 6元杂环烷基;)或 -NR1QRU， 所述烷基、 烷氧基、 环烷基或杂环烷基任选进一步 被 0至 3个选自 F、 Cl、 羟基、 d— 3烷基、 d— 3烷氧基、 =0或 -NR1QRU的取代基所取代， 且 所述的杂环烷基可含有 1个选自 N、 0或 3(=0)11的原子或基团； R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, -CF 3 , hydroxy, d- 3 alkyl, d- 3 alkoxy, -( CH 2 ) m -C 3 _ 5 cycloalkyl, -(CH 2 )m-0-(CH 2 )m-0-R 12 , -(CH 2 ) m -(3 to 5-membered heterocycloalkyl) , -0-C 3 _ 5 cycloalkyl, -0-P to 6-membered heterocycloalkyl;) or -NR 1Q R U , said alkyl, alkoxy, cycloalkyl or heterocycloalkyl Further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, hydroxy, d- 3 alkyl, d- 3 alkoxy, =0 or -NR 1Q R U , and The heterocycloalkyl group may contain one atom or group selected from N, 0 or 3 (=0) 11 ;

R10和 R11各自独立选自 H或 d— 4烷基； R 10 and R 11 are each independently selected from H or d- 4 alkyl;

R12选自 H; R 12 is selected from H;

R13各自独立选自 H、 氨基、 羟基或 d_3烷基； R 13 is each independently selected from H, amino, hydroxy or d- 3- alkyl;

n选自 0;  n is selected from 0;

m选自 0。  m is selected from 0.

本发明优选方案， 包括通式 (III)所示的氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the present invention include an oxabicyclic derivative represented by the formula (III) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 甲基、乙基、正丙基、异丙基、 2-羟基乙基、 -CH2C≡N、 -CH2CHF2、 -CH2CF3、 环丙基、 环丁基、 氧杂环丙基、 吡啶基、 氧杂环丁基、 氧杂环戊基、 乙烯基、 烯丙基、 炔 丙基、 -C(=0)-CH3、 -C(=0)-CH2CH3、 -C(=0)-OCH3、 -C(=0)-OCH2CH3、 -CF3、 -CHF2、 -CH2F 或^ i， 优选 H、 甲基、 乙基、 异丙基、 环丙基、 氧杂环丙基、 -CH2C≡N、 -CHF2或者吡 啶基； R is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, -CH 2 C≡N, -CH 2 CHF 2 , -CH 2 CF 3 , cyclopropyl, cyclobutane Base, oxetanyl, pyridyl, oxetanyl, oxolane, vinyl, allyl, propargyl, -C(=0)-CH 3 , -C(=0) -CH 2 CH 3 , -C(=0)-OCH 3 , -C(=0)-OCH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 F or ^ i, preferably H, methyl, Ethyl, isopropyl, cyclopropyl, oxyheteropropyl, -CH 2 C≡N, -CHF 2 or pyridyl;

R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 甲氧基、 乙氧基、 正丙氧基、 异丙 氧基、 环丙基、 -0-氧杂环丁基、 -(CH2)m-0-(CH2)m-0-R12或 -0-氧杂环戊基。 R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl , -0-oxetanyl, -(CH 2 )m-0-(CH 2 )m-0-R 12 or -0-oxocyclopentyl.

本发明优选方案， 包括通式 (I-B)所示氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶 ：  Preferred embodiments of the invention include oxabicyclic derivatives of the formula (I-B) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts thereof, eutectics thereof:

Figure imgf000026_0001
Figure imgf000026_0001

(I-B)  (I-B)

其中：  among them:

R选自 H、 d— 4烷基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C(=0)-R13、 - 3¾)„1 (=0)-0-1 13、-：¾)111 3_4环烷基、 -(CH2)m-(3至 4元杂环烷基)或 -(CH2)m-S(=0)n-R9， 优选 11或^— 3烷基； 所述的烷基、 烯基、 炔基、 环烷基或杂环烷基任选进一步被 0至 4个 选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基 的取代基所取代； 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团， 优选 含有 1个 N或 0原子； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C(=0)-R 13 , - 33⁄4) „ 1 (=0)-0-1 13 , -:3⁄4) 111 3 _ 4 cycloalkyl, -(CH 2 ) m - (3 to 4 yuan) Heterocycloalkyl) or -(CH 2 ) m -S(=0) n -R 9 , preferably 11 or -3- alkyl; alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclic ring The alkyl group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, hydroxy, carboxy, d- 4 alkyl or d- 4 alkane Substituted by a substituent of an oxy group; the heterocycloalkyl group having 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 , preferably containing 1 N or 0 atom;

R3'和 R4'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 6 烷基、 烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6 至 10 元杂芳基)、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(5 至 12 元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3_6环烷基、 -0-(3至 6元杂环 烷基)、 -0-C6— 1()芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基) 、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU， 优选 H、 F、 羟基、 C1-6烷基、 C1-6烷氧基或 -0-(3至 6元杂环烷基)， 进一步优选 H、 F、 C1-4烷氧基或 -0-(3至 5元杂环 烷基; )，更优选 F或 C1-4烷氧基； 所述烷基、 芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷 氧基、 环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3 、 氨基、 氰基、 硝基、 羟基、 C1-6 烷基、 C1-6 烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取代基所取代，优选 F、 Cl、 -CH2F 、 -CHF2、 -CF3、 羟基、 d— 4烷基、 d— 4烷氧基所述的杂环烷基、 杂芳基、 螺环基、 桥环基 、 并环基可含有 0至 3个选自 N、 0或 3(=0)11的原子或基团； R 3 'and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 alkyl, alkoxy, -(CH 2 )mC 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, -(CH 2 ) m - (6 to 10 membered heteroaryl), -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 To 6-membered heterocycloalkyl), -0-C 6 - 1 () aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0- (4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 )mS(=0) n -R 9 or -NR 1Q R U , preferably H, F, hydroxyl group , C1-6 alkyl, C1-6 alkoxy or -0-(3 to 6-membered heterocycloalkyl), further preferably H, F, C1-4 alkoxy or -0-(3 to 5 membered hetero Cycloalkyl;), more preferably F or C1-4 alkoxy; alkyl, aryl, spiro, bridged, cyclized, heteroaryl, alkoxy, cycloalkyl or hetero The cycloalkyl group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH2F, -CHF 2 , -CF 3 , amino, cyano, nitro, hydroxy, C1-6 alkyl, C1- 6 alkoxy, - (CH 2) mC 3 - 6 cycloalkyl, - (CH 2) m- ( 3 to six-alkyl), = 0, - (CH 2) mS (= 0) nR Substituted by a substituent of 9 or -NR 1Q R U , preferably a heterocyclic ring as defined by F, Cl, -CH 2 F , -CHF 2 , -CF 3 , hydroxy, d-4 alkyl, d-4 alkoxy Alkyl, An aryl group, a spiro group, a bridged cycloalkyl group, a cycloalkyl group and may contain 0 to 3 heteroatoms selected from N, 0 or 3 (= 0) or a group 11 atom;

R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 优选 H、 d— 3烷基或 C3— 4环烷 基， 进一步优选 H或 d— 2烷基； 所述的杂环烷基含有 1至 3个选自 N、 0或 S(=0)n的原子 或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 3 alkyl or C 3 - 4 cycloalkyl, more preferably H or d- 2 alkyl; said heterocycloalkyl containing 1 to 3 heteroatoms selected from N, 0 or S (= 0) n or a group of atoms;

R1Q和 R11各自独立选自 H、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环烷基， 优选 H、 d— 3烷基或 C3— 4环烷基， 进一步优选 11或 — 2烷基； 所述的杂环烷基含有 1至 3个 选自 N、 0或 3(=0)11的原子或基团； R 1Q and R 11 are each independently selected from H, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 3 alkyl or a C 3 - 4 cycloalkyl group, further preferably 11 or - 2 alkyl group; the heterocycloalkyl group having 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 优选 H、 氨基、 羟基、 d— 4烷基或 d— 4烷氧基， 进一步优选 H、 氨基、 羟基、 2烷基或 d— 2烷氧基； 所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； n选自 0、 1或 2， 优选 0或 1， 进一步优选 0; R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, amino, a hydroxyl group, a d- 4 alkyl group or a d- 4 alkoxy group, further preferably H, an amino group, a hydroxyl group, a 2 alkyl group or a d- 2 alkoxy group; the heterocycloalkyl group having 1 to 3 selected from N, 0 or 3 (=0) 11 atoms or groups; n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0;

m选自 0、 1或 2， 优选 0或 1， 进一步优选 0。  m is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.

本发明优选方案， 包括通式 (I-B)所示氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R3'和 R4'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 4 烷基、 d_4烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4 至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3— 6环烷基、-0-(3至 6元杂环烷基)、-0-C6— 1() 芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12 元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU， 优选 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰 基、硝基、羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-C6_1Q芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3— 6环烷基、 -0-(3至 6元杂环烷基)、 -O-C6.10 芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12 元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU，进一步优选 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d_4烷基、 d_4烷氧基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷 基 )、 -0-C3— 6环烷基或 -0-(3至 6元杂环烷基 )， 更优选 1^或 — 4烷氧基； 所述烷基、 芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环烷基或杂环烷基任选进一步被 0至 5个选 自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 硝基、 羟基、 d— 4烷基、 d— 4烷氧基、 -( ！！ ^^环烷基、 -(CH2)m-(3至 6元杂环烷基)、 =0、 -(CH2)m-S(=0)n-R9或 -NR1QRU的取 代基所取代， 优选 F、 Cl、 -CH2F、 -CHF2、 -CF3、 羟基、 d— 4烷基、 d— 4烷氧基； 所述的杂 环烷基、 杂芳基、 螺环基、 桥环基、 并环基可含有 0至 3个选自 N、 0或 3(=0)11的原子或 基团； R 3 'and R 4 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 4 alkyl, d- 4 alkoxy , -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1Q aryl, - (CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -(5 to 12 membered spiro ring) (), -(CH 2 ) m - (4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 - 6 cycloalkyl, -0 -(3 to 6-membered heterocycloalkyl), -0-C 6 -1() aryl, -0-(6 to 10 membered heteroaryl), -0-(5 to 12 membered spiro group), -0-(4 to 12-membered ring group), -0-(4 to 12 membered bridged ring group), -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d-4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 3--6 cycloalkyl, - (CH 2) m - (3 to six-alkyl), - (CH 2) m -C 6 _ 1Q aryl, - (CH 2) m - (6 to 10 (heteroaryl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring-based group), -(CH 2 ) m - (4 to 12-membered bridged ring group), -0-C 3 - 6 cycloalkyl group, -0-(3 to 6-membered heterocycloalkyl group), -OC 6 . 10 Aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring group), -0- (4 to 12 yuan) Bridged ring), -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , further preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d 4 alkyl, d 4 alkoxy, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkane) a group, -0-C 3 - 6 cycloalkyl or -0-(3 to 6-membered heterocycloalkyl), more preferably 1 ^ or - 4 alkoxy; said alkyl, aryl, spiro group , a bridged ring group, a cyclized group, a heteroaryl group, an alkoxy group, a cycloalkyl group or a heterocycloalkyl group, optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino, cyano, nitro, hydroxy, d- 4 alkyl, d- 4 alkoxy, -( !! ^^cycloalkyl, -(CH 2 ) m -(3 to 6 Substituted by a substituent of a heterocycloalkyl), =0, -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , preferably F, Cl, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, d - 4 alkyl, d - 4 alkoxy; said heterocycloalkyl, heteroaryl, spiro, bridge The cyclic group and the cyclylene group may have 0 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 优选 H、 d— 3烷基或 C3— 4环烷 基， 进一步优选 H或 d— 2烷基； 所述的杂环烷基含有 1至 3个选自 N、 0或 S(=0)n的原子 或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 3 alkyl or C 3 - 4 cycloalkyl, more preferably H or d- 2 alkyl; said heterocycloalkyl containing 1 to 3 heteroatoms selected from N, 0 or S (= 0) n or a group of atoms;

R1Q、 R11 和 R12各自独立选自 H、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6元杂环 烷基， 优选 H、 d— 3烷基或 C3— 4环烷基， 进一步优选 11或 — 2烷基； 所述的杂环烷基含有 1 至 3个选自 N、 0或 3(=0)11的原子或基团； R 1Q, R 11 and R 12 are each independently selected from H, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, preferably H, d- 3 Or an alkyl group or a C 3 -4 cycloalkyl group, further preferably 11 or 2 alkyl groups; the heterocycloalkyl group having 1 to 3 atoms or groups selected from N, 0 or 3 (=0) 11 ;

n选自 0、 1或 2， 优选 0或 1， 进一步优选 0;  n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0;

m选自 0、 1或 2， 优选 0或 1， 进一步优选 0。  m is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.

本发明优选方案， 包括通式 (I-B)所示氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R3'和 R4'各自独立选自 H、 F、 d_4烷氧基或者 〜°^7， 优选 H、 F、 乙氧基或者 。〜。 本发明优选方案， 包括通式 (I-B)所示化合物或其立体异构体、 水合物， 溶剂化物、 药 学上可接受的盐、 共晶体或前药， 其中： R3'选自乙氧基或者 〜°^ 。 R 3 'and R 4 ' are each independently selected from H, F, d- 4 alkoxy or ~°^7, preferably H, F, ethoxy or. ~. Preferred embodiments of the invention include a compound of the formula (IB): or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R 3 ' is selected from an ethoxy group Or ~°^.

本发明优选方案， 包括通式 (I-B)所示氧杂双环衍生物或其立体异构体、 水合物， 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the invention include an oxabicyclic derivative of the formula (I-B) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R4'选自 11或？。 Is R 4 ' selected from 11 or? .

本发明优选方案， 所述通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中：  According to a preferred embodiment of the present invention, the oxabicyclic derivative represented by the formula (I): or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(6至 8元杂芳基)或者 -(CH2)m-(3至 6元杂环烷基 )， 所述的烷基、 杂芳基、 杂环烷基或者环烷基任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基、 d— 4烷氧基、 -0-C3— 6 环烷基或者 -0-P至 6元杂环烷基;)的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl) or -(CH 2 ) m -( 3 to 6-membered heterocycloalkyl), said alkyl, heteroaryl, heterocycloalkyl or cycloalkyl optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3, cyano, hydroxy, carboxy, amino, d- 4-alkyl, d- 4 alkoxy, -0-C 3 - 6 cycloalkyl, or -0-P to 6-membered heterocycloalkyl; Substituted by a substituent; the heterocycloalkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 d_8烷氧基、 -0-C(=0)-R13 、RR 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 8 alkoxy, -0-C(=0)-R 13 ,

-0-C(=0)-0-R13、 -O-苄基、 -O-硅烷基、 -O-烯丙基或 -O-乙烯基； ， 其中所述的烷氧基进一 步被 0至 5个选自 F、 Cl、 Br、 I、 羟基、 d_4烷基或 d_4烷氧基； -0-C(=0)-0-R 13 , -O-benzyl, -O-silyl, -O-allyl or -O-vinyl; wherein the alkoxy group is further Up to 5 selected from F, Cl, Br, I, hydroxy, d- 4 alkyl or d- 4 alkoxy;

X选自 -0-或 -S-;  X is selected from -0- or -S-;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基或者 d— 4烷氧 基， 所述烷基、 烷氧基、 烯基、 炔基、 环烷基或杂环烷基各自独立地任选进一步被 0至 4 个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 羟基、 d— 4烷基或者 d— 4烷氧 基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy, said alkyl, alkoxy Or an alkenyl, alkynyl, cycloalkyl or heterocycloalkyl group, each independently optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, Substituted with a substituent of an amino group, a cyano group, a hydroxyl group, a d- 4 alkyl group or a d- 4 alkoxy group;

W选自 d— 3亚烷基、 -c(=o 或者 ^ 所述的亚烷基或 各自独立任选进一步被W is selected from the group consisting of d- 3 alkylene, -c(=o or ^ alkylene or each independently optionally further

0至 3个选自 F、 Cl、 Br、 -CF3、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 4环烷基或 3至 5元杂环 烷基的取代基所取代。 0 to 3 substituents selected from F, Cl, Br, -CF 3 , hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -4 cycloalkyl or 3 to 5 membered heterocycloalkyl Replaced.

环 G选自苯环、 噻吩或噻唑， 其中苯环、 噻唑或噻吩任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、氰基、硝基、羟基、 d_6烷基、 d_6烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -( ！！^^^环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4 至 12元并环基 )、 -(CH2)m-(4至 12元桥环基 )、 -0 3_6环烷基、 -0-(3至 6元杂环烷基 )、 -0-(5 至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU 的取代基所取代， 且所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个 选自 N、 0或 3(=0)11的原子或基团； Ring G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein the benzene ring, thiazole or thiophene is further optionally 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, Nitro, hydroxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -( !!^^^cycloalkyl, -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m - (4 to 12-membered ring group), - (CH 2 ) m - (4 to 12 membered bridged ring group), -0 3 -6 cycloalkyl group, -0-(3 to 6 membered heterocycloalkyl group), -0-(5 to 12 membered spiro group) ), -0-(4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U Substituted by a substituent, and the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 atoms selected from N, 0 or 3 (=0) 11 Or group;

R9选自 H、 d— 4烷基、 ^6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 4 alkyl, ^ 6 cycloalkyl or 3 to 6 membered heterocycloalkyl, and said heterocycloalkyl contains 1 to 5 selected from N, 0 or 3 (=0) An atom or group of 11 ;

R1Q和 R11各自独立选自 H、 羟基、 d_4烷基、 C3_6环烷基、 3至 6元杂环烷基或 d_4烷 氧基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 1Q and R 11 are each independently selected from H, hydroxy, d- 4 alkyl, C 3 -6 cycloalkyl, 3 to 6-membered heterocycloalkyl or d 4 alkoxy, said heterocycloalkyl containing 1 Up to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ;

R12和 R13各自独立选自 H、 氨基、 羟基、 d_4烷基、 d_4烷氧基、 C3_6环烷基或 3至 6 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -6 cycloalkyl or 3 to 6 membered heterocycloalkyl, said heterocycloalkyl Containing 1 to 5 atoms or groups selected from N, 0 or S(=0)n;

p选自 1、 2或 3 ;  p is selected from 1, 2 or 3;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。 本发明优选方案， 所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中： m is selected from 0, 1 or 2. Preferred embodiments of the invention, the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R选自 H、 甲基、 乙基、 环丙基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 氮杂环戊基 或者吡啶基， 且这些基团可以任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 甲氧基、 乙氧基、 环丙基、 氨基、 氰基或羟基的取代基所取代； R is selected from H, methyl, ethyl, cyclopropyl, oxetanyl, oxetanyl, oxetanyl, azacyclopentyl or pyridyl, and these groups may optionally be further From 0 to 4 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, amino, cyano or hydroxy Substituted by a substituent;

X选自 -0-或 -S-;  X is selected from -0- or -S-;

R1, R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、羟基、 -0-CH3、 -0-CH2CH3、 -0-CH2F、 -0-CHF2、 -0-CF3、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、R 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CH 2 F, -0-CHF 2 , -0-CF 3 , -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0- C(=0)0-CH 2 CH 3 ,

-o-苄基、 -o-硅烷基、 -o-烯丙基或 -o-乙烯基； -o-benzyl, -o-silyl, -o-allyl or -o-vinyl;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 甲基、 乙基、 甲氧基、 乙氧基、 氰基、 羟基、 乙炔基或丙炔基； R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, methyl, ethyl, methoxy, ethoxy, cyano, hydroxy, ethynyl or propynyl;

W选自 -CH2-或 ， 且 -CH2-或 ^ 各自独立任选进一步被 0至 2个选自 F、 Cl、 Br、 -CF3、 甲基、 乙基、 正丙基、 甲氧基或者乙氧基的取代基所取代； W is selected from -CH 2 - or , and -CH 2 - or ^ are each independently optionally further 0 to 2 selected from the group consisting of F, Cl, Br, -CF 3 , methyl, ethyl, n-propyl, methoxy Substituted by a substituent of a ethoxy group or an ethoxy group;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中包括通式 (Π)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共结晶复合物或前药：  Preferred embodiments of the present invention, the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof, including oxygen represented by the formula (Π) a heterobicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof:

Figure imgf000030_0001
其中-
Figure imgf000030_0001
among them-

X选自 -0-或 -S-; X is selected from -0- or -S-;

R选自 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(6至 8元杂芳基)、 或者 -(CH2)m-(3 至 6元杂环烷基 )， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基或者 d— 4烷氧基的取代 基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl), or -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), wherein the alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, Substituted by a substituent of -CHF 2 , -CF 3 , cyano, hydroxy, carboxy, amino, d- 4 alkyl or d- 4 alkoxy, said heterocycloalkyl containing 1 to 5 selected from N An atom or group of 0 or 3 (=0) 11 ;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基或者 d— 4烷氧 基； W选自 d— 3亚烷基或 ^>P， 所述的亚烷基或 "'Ρ各自任选进一步被 0至 4个选自 F、 Cl、 -CF3、 羟基、 d— 3烷基或 d— 3烷氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy; W is selected from d-3 alkylene or ^>P, and each of the alkylene or "' oxime is further further selected from 0 to 4 selected from the group consisting of F, Cl, -CF 3 , hydroxy, d - 3 alkyl Or substituted with a substituent of a d-3 alkoxy group;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

p选自 1或 2;  p is selected from 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、共结晶复合物或前药， 其中包括通式 (III)所示的氧杂双环衍生物或其立体异 构体、 水合物， 溶剂化物、 上可接受的盐、 共晶体或前药：  Preferred embodiments of the present invention, the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, which comprises the formula (III) Oxybibicyclic derivatives or stereoisomers, hydrates, solvates, acceptable salts, co-crystals or prodrugs thereof:

Figure imgf000031_0001
其中-
Figure imgf000031_0001
among them-

R选自 H、 d_4烷基、 -(CH2)m-C3_4环烷基、 -(CH2)m-(6至 8元杂芳基)或 -(CH2)m-(3至 4 元杂环烷基 )， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取 代， 且所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 _ 4 cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl) or -(CH 2 ) m -( a 3- to 4-membered heterocycloalkyl group, wherein the alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, - Substituted with a substituent of CHF 2 , -CF 3 , an amino group, a cyano group, a hydroxyl group, a carboxyl group, a d- 4 alkyl group or a d- 4 alkoxy group, and the heterocycloalkyl group contains 1 to 3 selected from N An atom or group of 0 or 3 (=0) 11 ;

R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、羟基、 CM烷基、 d_4烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C3_6环烷基或者 -(CH2)m-(3 至 6元杂环烷基 )， 所述烷基、 烷氧基、 环烷基或者杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 硝基、 羟基、 d— 4烷基或者 d— 4烷氧 基的取代基所取代； 且所述的杂环烷基可含有 0至 3个选自 N、 0或 3(=(¾的原子或基团； 作为选择， R1' R2'、 R3'、 R4'和 R5'任意相邻的两个基团可以形成一个 4至 6元环， 所 形成的环选自环烷基、 杂环烷基、 芳基或杂芳基， 所形成的杂环烷基或杂芳基含有 1 至 3 个选自 N、 0或 3(=0)11的原子或基团， 且所述环烷基、 杂环烷基、 芳基或杂芳基任选进一 步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4烷基或 d— 4烷氧基的取 代基所取代； R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, CM alkyl, d- 4 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -C 3 -6 cycloalkyl or -CH 2 ) m - (3 to 6-membered heterocycloalkyl), optionally further 0 to 5 selected from F, Cl, Br, I, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl group Substituted with a substituent of -CH 2 F, -CHF 2 , -CF 3 , =0, an amino group, a cyano group, a nitro group, a hydroxyl group, a d- 4 alkyl group or a d- 4 alkoxy group; The alkyl group may contain from 0 to 3 atoms or groups selected from N, 0 or 3 (= (3⁄4; alternatively, R 1 'R 2 ', R 3 ', R 4 ' and R 5 ' are arbitrarily adjacent The two groups may form a 4 to 6 membered ring, the ring formed is selected from a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and the heterocycloalkyl group or heteroaryl group formed has 1 to 3 An atom or group selected from N, 0 or 3 (=0) 11 , and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from F, Cl , -CH 2 F, - Substituted with a substituent of CHF 2 , -CF 3 , cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy;

R12选自 3至 6元环烷基； R 12 is selected from a 3- to 6-membered cycloalkyl group;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。 本发明优选方案， 包括通式 (1)、 （II)或者 (III)所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药， 其中： m is selected from 0, 1 or 2. Preferred embodiments of the invention include oxabicyclic derivatives of the formula (1), (II) or (III) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts thereof, co-crystals or Prodrug, where:

R选自 H、 d_4烷基、 -(CH2)m-C3_4环烷基、 -(CH2)m-(6元杂芳基)或 -(CH2)m-(3至 4元杂 环烷基 )，所述的烷基、环烷基、杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取代； 且所述 的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d 4 alkyl, -(CH 2 ) m -C 3 _ 4 cycloalkyl, -(CH 2 ) m -(6-membered heteroaryl) or -(CH 2 ) m - (3 to a 4-membered heterocycloalkyl group, wherein the alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , Substituted with a substituent of CF 3 , amino, cyano, hydroxy, carboxy, d- 4 alkyl or d- 4 alkoxy; and said heterocycloalkyl contains 1 to 3 selected from N, 0 or 3 (=0) an atom or group of 11 ;

R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、 羟基、 CM烷基、 -(CH2)m-0-(CH2)m-0-R12或者 d_4烷氧基； R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, CM alkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 or d_ 4 alkoxy;

R12选自 3至 6元环烷基； R 12 is selected from a 3- to 6-membered cycloalkyl group;

n选自 0、 1或 2;  n is selected from 0, 1 or 2;

m选自 0、 1或 2。  m is selected from 0, 1 or 2.

本发明优选方案， 包括所述的通式①、 （II)或者 (III)的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药， 其中：  Preferred embodiments of the invention include the oxabicyclic derivatives of the formula 1, (II) or (III) or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, co-crystals thereof or Medicine, where:

R选自 H、 甲基、 乙基、 正丙基、 异丙基、 2-羟基乙基、 -CH2CHF2、 -CH2CF3、 -CF3、 -CHF2、 -CH2F、 -CH2C≡N、 环丙基、 环丁基、 氧杂环丙基、 吡啶基、 氧杂环丁基或 R is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 C≡N, cyclopropyl, cyclobutyl, oxopropyl, pyridyl, oxetanyl or

R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 甲氧基、 乙氧基、环丙基、 '、。〜。、、 -0-氧杂环丁基或 -0-氧杂环戊基。 R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, methoxy, ethoxy, cyclopropyl, ',. ~. , -0-oxetanyl or -0-oxocyclopentyl.

本发明优选方案， 所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、共结晶复合物或前药， 其中包括通式 (IV)所示的氧杂双环衍生物或其立体异 构体、 水合物， 溶剂化物、 药学上可接受的盐、 共晶体或前药：  Preferred embodiments of the present invention, the oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, which comprises the formula (IV) Oxybibicyclic derivatives or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, co-crystals or prodrugs thereof:

Figure imgf000032_0001
Figure imgf000032_0001

(IV)  (IV)

其中，  among them,

X选自 -0-或 -S- ;  X is selected from -0- or -S-;

R选自 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(6元杂芳基)或者 -(CH2)m-(3至 6元 杂环烷基 )， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基或者 d— 4烷氧基的取代基所 取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(6-membered heteroaryl) or -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), said alkyl, cycloalkyl, heteroaryl or heterocycloalkyl optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 Substituted with a substituent of -CF 3 , cyano, hydroxy, carboxy, amino, d- 4 alkyl or d- 4 alkoxy, said heterocycloalkyl containing from 1 to 5 selected from N, 0 or An atom or group of 3 (=0) 11 ;

n选自 0、 1或 2; m选自 0、 1、 2、 3或 4。 n is selected from 0, 1 or 2; m is selected from 0, 1, 2, 3 or 4.

本发明优选方案，通式 (IV)所述的氧杂双环衍生物或其立体异构体、水合物、溶剂化物、 药学上可接受的盐、 共晶体或前药， 其中：  According to a preferred embodiment of the present invention, the oxabicyclic derivative of the formula (IV) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

X选自 -0-或 -S-;  X is selected from -0- or -S-;

R选自甲基、 乙基、 异丙基、 ^、0 -CHF2、 "-^Ν , 环丙基或吡啶基; R is selected from the group consisting of methyl, ethyl, isopropyl, ^, 0- C HF 2 , "-^, cyclopropyl or pyridyl;

本发明优选方案， 本发明涉及化合物选自， 但不限于：  In a preferred embodiment of the invention, the invention relates to a compound selected from, but not limited to:

化合物编号 化学结构式 中文名称  Compound number chemical structure Chinese name

化合物 1 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基  Compound 1 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)

)苯基) -1-乙氧基 -6,8-二氧杂二环 [3.2.1]辛 烷 -2,3,4-三醇  Phenyl)-1-ethoxy-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

化合物 2 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基  Compound 2 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxyphenyl)

)苯基) -1-甲氧基―6,8—二氧杂二环 [3.2.1]辛 烷 -2,3,4-三醇 ) Phenyl) -1-methoxy - 6, 8 - dioxabicyclo [3 2.1] octane-2,3,4-triol

化合物 2-1 (lS,2S,3R,4R,5S)-5-(3-(4-乙氧基苄基)苯基  Compound 2-1 (lS, 2S, 3R, 4R, 5S)-5-(3-(4-ethoxybenzyl)phenyl

)-1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4- 三醇  )-1-methoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol

化合物 3 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基  Compound 3 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)

)苯基)小(2-羟基乙基) -6,8-二氧二环 [3.2.1] 辛烷 -2,3,4-三醇  Phenyl) small (2-hydroxyethyl)-6,8-dioxobicyclo[3.2.1] octane-2,3,4-triol

化合物 4 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟 苄基)苯基 1-异丙基氧基 -6,8-二氧二环 [3.  Compound 4 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl 1-isopropyloxy-6,8 - Dioxane [3.

2.1]辛烷 -2,3,4-三醇  2.1] Octane-2,3,4-triol

化合物 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟 苄基)苯基) -1-乙氧基 -6,8-二氧二环 [3.2.1] 辛烷 -2,3,4-三醇  Compound (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-ethoxy-6,8- Dioxodicyclo[3.2.1]octane-2,3,4-triol

化合物 6 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟 苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1] 辛烷 -2,3,4-三醇  Compound 6 (1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-methoxy-6,8 -dioxobicyclo[3.2.1]octane-2,3,4-triol

化合物 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基氧 基乙氧基；)苄基)苯基 )- 1 -甲氧基 -6,8-二氧二

Figure imgf000033_0001
环 [3.2.1]辛烷 -2,3,4-三醇 化合物 8 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基氧 基乙氧基；)苄基；)苯基 )- 1 -二氟甲氧基 -6,8-二 氧二环 [3.2.1]辛烷 -2,3,4-三醇 化合物 9 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基 Compound (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy))benzyl)phenyl)-1-methoxy -6,8-dioxo
Figure imgf000033_0001
Cyclo [3.2.1] octane-2,3,4-triol Compound 8 (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy))benzyl;)phenyl)- 1 -di Fluoromethoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 9 (1 S,2S,3R,4R,5S)-5-(4-chloro -3-(4-ethoxybenzyl)

)苯基) -1-环丙基氧基 -6,8-二氧二环 [3.2.1]  Phenyl)-1-cyclopropyloxy-6,8-dioxobicyclo[3.2.1]

辛烷 -2,3,4-三醇  Octane-2,3,4-triol

化合物 10 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄 基)苯基) - 2,3,4-三羟基 -6,8-二氧二环  Compound 10 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8- Dioxane

[3.2.1]辛烷 -1-基;)氧基)乙腈 化合物 11 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基  [3.2.1] Octane-1-yl;)oxy)acetonitrile Compound 11 (1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)

)苯基) -1- (二氟甲氧基 )-6,8-二氧二环 [3.2.1]  Phenyl)-1-(difluoromethoxy)-6,8-dioxobicyclo[3.2.1]

辛烷 -2,3,4-三醇  Octane-2,3,4-triol

化合物 12 (1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基  Compound 12 (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)

)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷- Phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane-

2,3,4-三醇与 L-苯丙氨酸的 1 : 1络合物 化合物 13 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[ 1:1 complex compound of 2,3,4-triol and L-phenylalanine 13 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxy Benzyl)phenyl)-2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[

3.2.1]辛烷 -4-基 乙酸酯 化合物 13-1 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[  3.2.1] Octane-4-yl acetate compound 13-1 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[

3.2.1]辛烷 -3-基 乙酸酯 化合物 13-2 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[  3.2.1] Octane-3-yl acetate compound 13-2 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[

3.2.1]辛烷 -2-基 乙酸酯 化合物 14 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[  3.2.1] Octane-2-yl acetate compound 14 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2 ,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[

3.2.1]辛烷 -4-基碳酸乙酯 3.2.1] Octane-4-ylethyl carbonate

Figure imgf000034_0001
化合物 14-1 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[
Figure imgf000034_0001
Compound 14-1 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy -6,8-dioxobicyclo[

3.2.1]辛烷 -3-基碳酸乙酉 I 化合物 14-2 (lS,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环[3.2.1] Octane-3-ylethyl carbonate I compound 14-2 (lS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[

3.2.1]辛烷 -2-基碳酸乙酯 3.2.1] Octane-2-ylethyl carbonate

化合物 15 (lR,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基  Compound 15 (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)

)苯基) -1- (吡啶 -2-基巯基 )-6,8-二氧二环 [3.

Figure imgf000035_0001
2.1]辛烷 -2,3,4-三醇 本发明还涉及一种通式 0V)所示的化合物或其立体异构体，其作为合成通式 (I)氧杂双环 衍生物的中间体： Phenyl)-1-(pyridin-2-ylindenyl)-6,8-dioxobicyclo[3.
Figure imgf000035_0001
2.1] Octane-2,3,4-triol The present invention also relates to a compound of the formula 0V) or a stereoisomer thereof, which is an intermediate for the synthesis of an oxabicyclic derivative of the formula (I) :

Figure imgf000035_0002
其中 R R2、 R3、 R4、 R5、 R6、 R7、 W和环 G与通式 (I)化合物所述定义一致。
Figure imgf000035_0002
Wherein RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W and ring G are identical to the definitions of the compounds of formula (I).

优选地， I 1、 R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、羟基、 d— 8烷氧基、 -0-C(=0)-R13、 -0-C(=0)-0-R13、 -0-C(=0)-(CH2)m-C6— 14芳基、 -0-C(=0)-0-C6— 14芳基、 -0-(CH2)m-C6— 14芳基、 -O-硅烷基或 -0-C2— 8烯基， 其中所述的烷氧基、 芳基、 环烷基或烯基可任选进一步被 0至 5 个选自 F、 Cl、 Br、 I、 羟基、 d_8烷基、 d_8烷氧基、 C3_8环烷基或 3至 8元杂环烷基的取 代基所取代；优选 I 1、 R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、羟基、 -0-CH3、 -0-CH2CH3、 -0-CH2F、 -O-CHF2、 -O-CF3、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、 -O-苄基、 -O-硅烷基、 -O-烯丙基或 -O-乙烯基， 进一步优选 H、 F、 -0-C(=0 CH3或羟基， 更优选羟基。 Preferably, I 1 , R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, d- 8 alkoxy, -0-C(=0)-R 13 , -0- C(=0)-0-R 13 , -0-C(=0)-(CH 2 ) m -C 6 - 14 aryl, -0-C(=0)-0-C 6 - 14 aryl , -0-(CH 2 ) m -C 6 -14 aryl, -O-silyl or -0-C 2 -8 alkenyl, wherein the alkoxy, aryl, cycloalkyl or alkenyl group Optionally further substituted by 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 -8 cycloalkyl or 3 to 8 membered heterocycloalkyl Substituted; preferably, I 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CH 2 F , -O-CHF2, -O-CF3, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0-C(=0)0-CH 2 CH 3 , -O-benzyl, -O-silyl, -O-allyl or -O-vinyl, further preferably H, F, -0-C (=0 CH 3 or a hydroxyl group, more preferably a hydroxyl group.

优选地， R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基、 d— 4 烷氧基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6 元杂环烷基）、 -0-C3-6 环烷基、 -0-(3 至 6 元杂环烷基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R1\ -(CH2)m-S(=0)n-R9或 -NR1QRU， 所述烷基、 烷氧基、 烯基、 炔基、 环 烷基或杂环烷基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、氨基、氰基、羟基、 d— 4烷基、 d— 4烷氧基、 -(CH2)m-C2— 4烯基 -R12、 -(CH2)m-C2— 4炔基 -R12、 -(CH2)m-C3— 6环烷基或 -(CH2)m-(3至 6元杂环烷基)的取代基所取代； 优选 R4、 R5、 R6和 R7 各自独立地选 β Η、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 甲氧基、 乙氧基、 氰 基、羟基、硝基、 乙炔基或丙炔基， 进一步优选 F、 Cl、 甲基、 乙基、 甲氧基、 -CHF2或 -CF3 ; 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； 进一步优选地， R5选自 F、 Cl、 甲基、 乙基、 甲氧基、 -CHF2或 -CF3， 进一步优选 Cl、 甲基、 乙基或甲氧基， 更进 一步优选 Cl。 Preferably, R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, d- 4- alkyl, d- 4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 -4 alkynyl-R 12 , -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6 membered heterocycloalkyl), -0-C 3 -6 cycloalkyl, -0-(3 to 6 membered heterocycloalkyl), -(CH 2 ) m -C(=0)- R 13 , -(CH 2 ) m -C(=0)-0-R 1 \ -(CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , the alkyl group, the alkane The oxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl groups are each independently optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , = 0, amino, cyano, hydroxy, d-4 alkyl, d-4 alkoxy, -(CH 2 ) m -C 2 - 4 alkenyl-R 12 , -(CH 2 ) m -C 2 - 4 alkynyl-R 12 , Substituted by a substituent of -(CH 2 ) m -C 3 - 6 cycloalkyl or -(CH 2 ) m - (3 to 6-membered heterocycloalkyl); preferably R 4 , R 5 , R 6 and R 7 Each independently selected β Η, F, Cl, Br, —CH 2 F, —CHF 2 , —CF 3 , methyl, ethyl, methoxy, ethoxy, cyano, hydroxy, nitro, ethynyl Or propynyl, further preferably F, Cl, methyl, ethyl, methoxy, -CHF 2 or -CF 3 ; said heterocycloalkyl contains 1 to 5 selected from N, 0 or 3 (= 0) an atom or a group of 11 ; further preferably, R 5 is selected from the group consisting of F, Cl, methyl, ethyl, methoxy, -CHF 2 or -CF 3 , further preferably Cl, methyl, ethyl or methyl The oxy group is still more preferably Cl.

优选地， G选自 6至 10元芳基或 5至 6元杂芳基， 优选苯环、 噻吩或噻唑； 其中所述 的苯环、噻吩、噻唑、芳基或杂芳基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 羧基、 d— 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3 至 6元杂环烷基)、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C6.10芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基)、 -0-C3-6 环烷基、 -0-(3至 6元杂环烷基)、 -0-C6_1Q芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环 基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-C(=0)-R13、-(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-NHC(=0)-R13 、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d_6烷基、 d_6烷氧基、 -0-C3_6环烷基或 -0-(3 至 6元杂环烷基)的取代基所取代， 进一步优选 F、 Cl、 -CH2F、 -CHF2、 -CF3、 羟基、 d— 4 烷基、 CM烷氧基、 -0-C3— 5环烷基或 -0-(3至 5元杂环烷基)的取代基所取代， 更优选 F、 d.4 烷氧基或 -O-P至 5元杂环烷基; I； 且所述烷基、 芳基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 羧基、 6烷基、 d— 6烷氧基、 -(CH2)m-C3— 6环烷基、 -(CH2)m-(3至 6元 杂环烷基)、 -(CH2)m-C6_1()芳基、 -(CH2)m-(6至 10元杂芳基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4至 12元并环基)、 -(CH2)m-(4至 12元桥环基 )、 -0-C3— 6环烷基、 -0-(3至 6元杂环 烷基)、 -0-C6_1()芳基、 -0-(6至 10元杂芳基)、 -0-(5至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4 至 12 元桥环基）、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代， 优选被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 d— 4烷基或 d— 4烷氧基的取代基所取代， 进一步优选被 0至 3个 选自 F、 Cl、 羟基或 d— 4烷基； 以上所述的杂环烷基、 杂芳基、 螺环基、 桥环基、 并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； Preferably, G is selected from a 6 to 10 membered aryl group or a 5 to 6 membered heteroaryl group, preferably a benzene ring, thiophene or thiazole; wherein the benzene ring, thiophene, thiazole, aryl or heteroaryl group is optionally further 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, carboxy, d- 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -0-(CH 2 ) m -0- R 12 , -(CH 2 ) m -C 6 . 10 aryl, -(CH 2 ) m -(6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group) -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-( 3- to 6-membered heterocycloalkyl), -0-C 6 - 1Q aryl, -0-(6 to 10-membered heteroaryl), -0-(5 to 12-membered spiro group), -0-( 4 to 12-membered ring group), -0-(4 to 12-membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0) -0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 ) m -S(=0) n -R 9 Replacement Substituted, preferably F, Cl, Br, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, hydroxy, d_ 6 alkyl, d_ 6 alkoxy, -0-C 3 _ 6 cycloalkyl Substituted with an alkyl group or a substituent of -0-(3 to 6-membered heterocycloalkyl), further preferably F, Cl, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, d- 4 alkyl, CM Substituted with a substituent of alkoxy, -0-C 3 -5 cycloalkyl or -0-(3 to 5-membered heterocycloalkyl), more preferably F, d.4 alkoxy or -OP to 5 a heterocycloalkyl group; I; and the alkyl group, aryl group, spiro group, bridged ring group, cyclylene group, heteroaryl group, alkoxy group, cycloalkyl group or heterocycloalkyl group, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, carboxy, 6 alkyl, d- 6 alkoxy, -(CH 2 m -C 3 - 6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 1() aryl, -(CH 2 ) m - (6 to 10 membered heteroaryl), -(CH 2 ) m - (5 to 12 membered spiro group), -(CH 2 ) m - (4 to 12 membered cyclo), -(CH 2 ) m - (4 to 12 is membered bridged ring group), -0-C 3 - 6 cycloalkyl, -0- (3 to 6-membered heterocyclic Group), -0-C 6 _ 1 () aryl, -0- (6 to 10 membered heteroaryl), -0- (5-12 yuan spiro ring group), -0- (4-12 yuan, and Ring group), -0-(4 to 12 member bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 Substituting -NR 10 R n or -(CH 2 ) m -S(=0) n -R 9 , preferably 0 to 3 selected from F, Cl, Br, I, -CH 2 F, Substituted with a substituent of -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 4 alkyl or d- 4 alkoxy, further preferably from 0 to 3 selected from F, Cl, hydroxy or d — 4 alkyl; the heterocycloalkyl, heteroaryl, spiro group, bridged ring group, and cyclylene group described above may contain 0 to 5 atoms selected from N, 0 or S(=0) n or Group

R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 优选 11或^— 4烷基， 进一步优 选 11或 — 2烷基； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, or preferably 11 ^ --4 alkyl, or more preferably 11 - 2 alkyl;

R1Q和 R11各自独立选自 H、 d— 4烷基、 氨基、 羟基、 C3— 6环烷基、 3至 6元杂环烷基或 CM烷氧基， 优选优选11、 d— 4烷基、氨基、羟基或 d— 4烷氧基， 进一步优选 11或^— 2烷基； n选自 0、 1或 2， 优选 0或 1， 进一步优选 0; R 1Q and R 11 are each independently selected from H, d- 4-alkyl, amino, hydroxy, C 3 - 6 cycloalkyl, 3 to 6-membered heterocyclic group or CM alkoxy, preferably preferably 11, d- 4 alkyl, amino, hydroxy or d- 4 alkoxy, further preferably 11 or -2- alkyl; n is selected from 0, 1 or 2, preferably 0 or 1, Further preferably 0;

m选自 0、 1或 2， 优选 0或 1， 进一步优选 0。  m is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0.

本发明优选方案， 一种通式 (IV)所示的化合物或其立体异构体， 其中 R R2和 R3各自 独立地选自 H、 羟基、 -0-CH3、 -0-CH2CH3、 -0-CHF2、 -0-CF3、 -0-CH2F、 F、 Cl、 Br、 I、 -0-C(=0)-甲基、 -0-C(=0)-乙基、 -O-烯丙基或 -O-乙烯基， 优选 H、 F、 -0-C(=0)-CH3或羟 基， 进一步优选 OH。 A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer thereof, wherein RR 2 and R 3 are each independently selected from the group consisting of H, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CHF 2 , -0-CF 3 , -0-CH 2 F, F, Cl, Br, I, -0-C(=0)-methyl, -0-C(=0)- Ethyl, -O-allyl or -O-vinyl, preferably H, F, -0-C(=0)-CH 3 or a hydroxyl group, further preferably OH.

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 氨基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、仲丁基、叔丁基、 乙烯基、 丙烯基、烯丙基、 2-丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 丁氧基、 环丙基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-环己基、 -0-氧杂环丙基、 -0-氧杂环丁基、 -0-氧杂环戊基、 -0-氧杂环己基、 环丁基、 环戊基、 环己基、 氧杂环丙基、 氧杂环丁基、 氧 杂环戊基或氧杂环己基， 优选 H、 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 乙烯基、 丙烯基、 烯丙基、 2-丁烯 -1-基、 乙炔基、 丙 炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基或丁氧基， 进一步优 选11、 F、 Cl、 甲基、 乙基、 甲基、 乙基； 当以上所述基团被取代时， 各自独立地任选进一 步被 0至 3选自 F、 Cl、 Br、 氰基、 羟基、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 乙烯基、 丙 烯基、 烯丙基、 乙炔基、 丙炔基、 炔丙基、 甲氧基、 乙氧基、 环丙基、 环丁基、 氧杂环丙 基、 氧杂环丁基， 优选 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 甲基、 乙基、 正丙基、 甲氧基或乙氧基的取代基所取代， 优选 F、 Cl、 甲基或乙基； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy , ethoxy, propoxy, isopropoxy, butoxy, cyclopropyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -0-cyclohexyl, - 0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, -0-oxetanyl, cyclobutyl, cyclopentyl, cyclohexyl, oxopropyl , oxetanyl, oxolyl or oxeyl, preferably H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-buten-1-yl, ethynyl, propynyl, propargyl, 2-butyn-1-yl , methoxy, ethoxy, n-propoxy, isopropoxy or butoxy, further preferably 11 F, Cl, methyl, ethyl, methyl, ethyl; when the above groups are substituted, each independently optionally further selected from 0 to 3 is selected from the group consisting of F, Cl, Br, cyano, hydroxy, - CH 2 F, -CHF 2 , -CF 3 , methyl, ethyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, oxetanyl, oxetanyl, preferably F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, methyl, ethyl, n-propyl Substituted by a substituent of a methoxy or ethoxy group, preferably F, Cl, methyl or ethyl;

G选自苯基， 任选进一步被 0至 5个选自 F、 Cl、 Br、氰基、羟基、 氨基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 戊基、 异戊基、 新戊基、 己基、 乙 烯基、 丙烯基、 烯丙基、 2-丁烯 -1-基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧基、 叔丁氧基、 环丙基、 环丁基、 环戊基、 环己基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-环己基、 。〜。、、 -0-氧杂环丙基、 -0-氧杂环 丁基、 -0-氧杂环戊基、 -0-氧杂环己基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 氧杂环己 基、 氮杂环丙基、 氮杂环丁基、 氮杂环戊基、 氮杂环己基、 -C(=0)-CH3、 -C(=0)-CH2CH3、 -C(=0)-OCH3、 -C(=0)-OCH2CH3、 苯基、 吡啶基、 嘧啶基、 呋喃基、 噻吩基、 吡咯基、 咪 唑基、 吡唑基、

Figure imgf000038_0001
G is selected from phenyl, optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, vinyl, propenyl, allyl, 2-buten-1-yl, ethynyl, propynyl, propargyl , 2-butyn-1-yl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -0-cyclopropyl, -0-cyclobutyl, -0-cyclopentyl, -0-cyclohexyl, . ~. ,, -0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, -0-oxetanyl, oxacyclopropyl, oxetanyl, oxygen Heterocyclic pentyl, oxetanyl, azacyclopropyl, azetidinyl, azacyclopentyl, azacyclohexyl, -C(=0)-CH 3 , -C(=0)- CH 2 CH 3 , -C(=0)-OCH 3 , -C(=0)-OCH 2 CH 3 , phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazole base,
Figure imgf000038_0001

的取代基所取代， 优选被 0至 3个选择 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异 丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁 氧基、 叔丁氧基、 环丙基、 环丁基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-氧杂环丙基、 Substituted by a substituent, preferably selected from 0 to 3, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-Butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropyl, -0- Cyclobutyl, -0-cyclopentyl, -0-oxopropyl,

-0-氧杂环了《、 、 、。〜。、、 ·0·氧杂环腿、 氧杂环腿、 氧杂环了《、 氧杂环戊基、 呋喃基、 噻吩基、 吡咯基、 -0-oxo-heterocyclic ", , ,. ~. , · · · Oxygen heterocyclic legs, oxygen heterocyclic legs, oxygen heterocyclic ", oxetanyl, furyl, thienyl, pyrrolyl,

Figure imgf000038_0002
Figure imgf000038_0002

丁基、 异丁基、 仲丁基、 叔丁基、 甲氧基、 乙氧基、 丙氧基、 异丙氧基、 正丁氧基、 环丙 基、 环丁基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-氧杂环丙基、 -0-氧杂环丁基、 -0-氧 杂环戊基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 呋喃基、 噻吩基或吡咯基， 进一步优 选 F、 Cl、 、 。〜。、、 甲氧基、 乙氧基、 环丙基、 -0-氧杂环丁基或 -0-氧杂环戊基； 当上述基团被取代时， 任选进一步被 0至 4个1^、 Cl、 Br、 I、 甲基、 乙基、 正丙基、 氰基、 异丙基、 环丙基、 甲氧基或乙氧基的取代基所取代， 优选被 0至 2个1^、 Cl、 甲基或乙基的 取代基所取代。 Butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropane , -0-cyclobutyl, -0-cyclopentyl, -0-oxopropyl, -0-oxetanyl, -0-oxocyclopentyl, oxolane, oxygen A heterocyclic butyl group, an oxolyl group, a furyl group, a thienyl group or a pyrrolyl group is further preferably F, Cl, or . ~. , methoxy, ethoxy, cyclopropyl, -0-oxetanyl or -0-oxocyclopentyl; when the above group is substituted, optionally further from 0 to 4 1 ^ Substituted with a substituent of Cl, Br, I, methyl, ethyl, n-propyl, cyano, isopropyl, cyclopropyl, methoxy or ethoxy, preferably from 0 to 2, Substituted by a substituent of Cl, methyl or ethyl.

本发明优选方案， 一种通式 (IV)所示的化合物或其立体异构体， 其中：  A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer thereof, wherein:

R R2和 R3各自独立地选自 H、羟基、 -0-CH3、 -0-CH2CH3、 -0-CHF2、 -0-CF3、 -0-CH2F、 F、 Cl、 Br、 I、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、RR 2 and R 3 are each independently selected from H, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CHF 2 , -0-CF 3 , -0-CH 2 F, F, Cl , Br, I, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0-C(= 0) 0-CH 2 CH 3 ,

-o-烯丙基或 -o-乙烯基； -o-allyl or -o-vinyl;

R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、仲丁基、叔丁基、 乙烯基、 丙烯基、烯丙基、 2-丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基或正丁氧基， 当被 取代时， 各自独立地任选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 羟基、 甲基、 乙基、 甲氧基或乙氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, Propynyl, propargyl, 2-butyn-1-yl, methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy, when substituted, are each independently optional Substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, methyl, ethyl, methoxy or ethoxy;

环 G选自苯基， 任选进一步被 0至 3个选择 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙 基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧基、 环丙基、 环丁基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-氧杂环丙基、 -0-氧 Ring G is selected from phenyl, optionally further selected from 0 to 3 F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropyl, -0-cyclobutyl Base, -0-cyclopentyl, -0-oxopropyl, -0-oxygen

-0-氧杂环戊基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 呋喃基、 噻吩基、 吡  -0-oxocyclopentyl, oxacyclopropyl, oxetanyl, oxetanyl, furyl, thienyl, pyridyl

Figure imgf000039_0001
。或 当被取代时， 任意进一步被 0至 4 个 F、 Cl、 Br、 I、 甲基、 乙基、 正丙基、 异丙基、 环丙基、 氰基、 甲氧基或乙氧基的取代 基所取代。
Figure imgf000039_0001
. Or when further substituted, any further from 0 to 4 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyano, methoxy or ethoxy Substituted by a substituent.

本发明还涉及一种制备通式①所述氧杂双环衍生物的方法， 该方法包括：  The present invention also relates to a process for the preparation of an oxabicyclic derivative of the formula 1, which comprises:

Figure imgf000039_0002
Figure imgf000039_0002

V卜 a Vl-b  V Bu a Vl-b

通式 (VI-a)化合物在强碱条件下发生消除反应， 得到通式 (VI-b)化合物；  The compound of the formula (VI-a) is subjected to elimination reaction under strong base conditions to obtain a compound of the formula (VI-b);

其中优选在氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-a)在强碱条 件下发生消除反应， 得到化合物 (VI-b);  Preferably, in a polar aprotic solvent, the compound (VI-a) undergoes a elimination reaction under a strong base condition under a nitrogen atmosphere to obtain a compound (VI-b);

所述极性非质子性溶剂可选自， 但不限于： 1,4-二氧六环、 Ν,Ν-二甲基甲酰胺或 Ν,Ν- 二甲基甲酰胺 /正己烷混合溶剂 (V/V = 1 :5-5: 1)；  The polar aprotic solvent may be selected from, but not limited to: 1,4-dioxane, hydrazine, hydrazine-dimethylformamide or hydrazine, hydrazine-dimethylformamide/n-hexane mixed solvent ( V/V = 1 :5-5: 1);

其中强碱可选自 (但不限于; I： 1,8-二氮杂二环 [5.4.0]十一碳 -7-烯 (简称 DBU)、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧化钾、 氢氧化钠、 氢氧化锂、 氢化铝锂、 叔丁基 锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基锂或氢氧化钡；  Wherein the strong base may be selected from (but not limited to; I: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide , sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide;

其中优选条件为： 氮气氛下， 以 Ν,Ν-二甲基甲酰胺为溶剂， 30~40'C下化合物 (VI-a)在 氢化钠为碱的条 2~8小时; The preferred conditions are as follows: under a nitrogen atmosphere, using hydrazine, hydrazine-dimethylformamide as a solvent, and the compound (VI-a) at 30-40 ° C is Sodium hydride is a strip of alkali for 2 to 8 hours;

Figure imgf000040_0001
Figure imgf000040_0001

Vl-b Vl-c  Vl-b Vl-c

通式 (VI-b)化合物发生环氧化反应， 得到通式 (VI-c)化合物；  An epoxidation reaction of a compound of the formula (VI-b) to give a compound of the formula (VI-c);

其中优选在氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-b)在氧化剂 条件下发生环氧化反应， 得到化合物 (VI-c);  Preferably, in a polar aprotic solvent, the compound (VI-b) is epoxidized under an oxidizing agent at a suitable temperature to obtain a compound (VI-c);

其中极性非质子性溶剂可选自， 但不限于： 二氯甲烷、 氯仿或 1,2-二氯乙烷； 其中氧化剂可选自 (但不限于; I： 四氧化锇、 锇酸钾、 双氧水、 氧气、 过氧叔丁醇、 过氧 单硫酸钾、 过氧丙酮、 三氟过氧丙酮或间氯过氧苯甲酸；  The polar aprotic solvent may be selected from, but not limited to: dichloromethane, chloroform or 1,2-dichloroethane; wherein the oxidizing agent may be selected from (but not limited to; I: osmium tetroxide, potassium citrate, Hydrogen peroxide, oxygen, peroxybutanol, potassium peroxymonosulfate, peroxyacetone, trifluoroperoxyacetone or m-chloroperoxybenzoic acid;

优选条件为： 以二氯甲烷为溶剂， 10~35'C下化合物 (VI-b)在以间氯过氧苯甲酸为氧化 剂的条件下发生环氧化反应， 搅拌反应 2~8小时；  Preferably, the compound (VI-b) is epoxidized under the condition of using m-chloroperoxybenzoic acid as an oxidizing agent in a solvent of dichloromethane at a temperature of 10 to 35 ° C, and the reaction is stirred for 2 to 8 hours;

其中还优选在氮气气氛下， 以二氯甲烷为溶剂， 10~35'C下化合物 (VI-b)在以间氯过氧 苯甲酸为氧化剂 2~8小时；  Preferably, the compound (VI-b) is treated with m-chloroperoxybenzoic acid as an oxidizing agent at a temperature of 10 to 35 ° C for 2 to 8 hours under a nitrogen atmosphere using dichloromethane as a solvent;

Figure imgf000040_0002
通式 (VI-c)化合物在酸性条件下发生开环反应， 得到通式 (VI-d)化合物；
Figure imgf000040_0002
The compound of the formula (VI-c) undergoes a ring opening reaction under acidic conditions to obtain a compound of the formula (VI-d);

其中优选非质子性溶剂 /水的混合溶剂中， 在适宜的温度下， 化合物 (VI-c)在酸性条件下 发生开环反应， 得到化合物 (VI-d); Preferably, in a mixed solvent of an aprotic solvent/water, the compound (VI-c) undergoes a ring-opening reaction under acidic conditions at a suitable temperature to obtain a compound (VI-d) ;

其中更优选在氮气氛下，非质子性溶剂 /水的混合溶剂中，在适宜的温度下，化合物 (VI-c) 在酸性条件下发生开环反应， 得到化合物 (VI-d); More preferably, in a mixed solvent of aprotic solvent/water under a nitrogen atmosphere, the compound (VI-c) undergoes a ring-opening reaction under acidic conditions at a suitable temperature to obtain a compound (VI-d) ;

其中非质子性溶剂 /水的混合溶剂可选， 自但不限于： 四氢呋喃/水^/¥ = 1 :5〜5: 1；)、 1,4- 二氧六环 /水 (V/V = 1:5〜5: 1)或者丙酮 /水 (V/V = 1 :5〜5: 1)； A mixed solvent of aprotic solvent/water is optional, but not limited to: tetrahydrofuran/water ^/¥ = 1 : 5~5: 1;), 1,4-dioxane/water (V/V = 1:5~5: 1) or acetone/water (V/V = 1: 5~5: 1);

其中酸可选自 (但不限于)： 三氟乙酸、 甲磺酸、 三氟甲磺酸、 对甲苯磺酸、 对甲苯磺酸 吡啶盐、 盐酸、 硫酸或者醋酸；  Wherein the acid may be selected from, but not limited to, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, hydrochloric acid, sulfuric acid or acetic acid;

优选条件为： 以四氢呋喃 /水 （V/V = 4: 1) 混合溶剂为反应溶剂， 以三氟乙酸为酸， 10~40°C下化合物 (VI-c)发生开环反应， 搅拌反应 10~20小时； 进一步优选条件为： 氮气氛下， 以四氢呋喃 /水（V/V = 4:1)混合溶剂为反应溶剂， 以 三氟乙酸为酸， 10~40°C (； VI-c)发生开环反应， 搅拌反应 10~20小时； The preferred conditions are as follows: a mixed solvent of tetrahydrofuran/water (V/V = 4:1) is used as a reaction solvent, trifluoroacetic acid is used as an acid, and a compound (VI-c) is subjected to a ring-opening reaction at 10 to 40 ° C, and the reaction is stirred. ~20 hours; Further preferred conditions are as follows: under a nitrogen atmosphere, a mixed solvent of tetrahydrofuran/water (V/V = 4:1) is used as a reaction solvent, and trifluoroacetic acid is used as an acid, and a ring opening reaction occurs at 10 to 40 ° C (; VI-c). , stirring the reaction for 10 to 20 hours;

Figure imgf000041_0001
Figure imgf000041_0001

通式 (VI-d)化合物在强碱下发生关环反应， 得到通式 (Vl-e)化合物；  The compound of the formula (VI-d) undergoes a ring closure reaction under a strong base to give a compound of the formula (Vl-e);

其中优选质子性溶剂中， 在适宜的温度下， 化合物 (VI-d)在强碱下发生关环反应， 得到 化合物 (VI-e);  Preferably, in the protic solvent, the compound (VI-d) undergoes a ring closure reaction under a strong base at a suitable temperature to obtain a compound (VI-e);

其中更优选氮气氛下， 质子性溶剂中， 在适宜的温度下， 化合物 (VI-d)在强碱下发生关 环反应， 得到化合物 (VI-e);  More preferably, the compound (VI-d) undergoes a ring-closing reaction under a strong base in a protic solvent at a suitable temperature under a nitrogen atmosphere to obtain a compound (VI-e);

其中质子性溶剂选自， 但不限于： 甲醇、 乙醇、 叔丁醇或异丙醇；  Wherein the protic solvent is selected from, but not limited to: methanol, ethanol, tert-butanol or isopropanol;

其中强碱选自， 但不限于： DBU、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧 化钾、 氢氧化钠、 氢氧化锂、 氢化铝锂、 叔丁基锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基 锂或者氢氧化钡；  The strong base is selected from, but not limited to: DBU, sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, tert-butyl Potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide;

优选条件为： 以甲醇为溶剂， 甲醇钠作碱， 10~35°C下化合物 CVI-d)搅拌反应 1~5小时； 进一步优选条件为： 氮气氛下， 以甲醇为溶剂， 甲醇钠作碱， 10~35'C下化合物 (VI-d) 搅拌反应 1~5小时；  The preferred conditions are as follows: using methanol as a solvent, sodium methoxide as a base, and stirring the compound CVI-d at 10 to 35 ° C for 1 to 5 hours; further preferred conditions are: under a nitrogen atmosphere, methanol as a solvent, sodium methoxide as a base , the compound (VI-d) is stirred at 10~35'C for 1~5 hours;

Figure imgf000041_0002
Figure imgf000041_0002

通式 (VI-e)化合物在强碱下亲电取代反应， 得到通式 (VI)化合物；  The compound of the formula (VI-e) is electrophilically substituted under a strong base to give a compound of the formula (VI);

其中优选极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-e)在强碱下发生亲电取代 反应， 得到化合物 CVI);  Preferably, in a polar aprotic solvent, at a suitable temperature, the compound (VI-e) undergoes an electrophilic substitution reaction under a strong base to obtain a compound CVI);

其中更优选氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-e)在强碱下 发生亲电取代反应， 得到化合物 (VI);  More preferably, in a polar aprotic solvent in a nitrogen atmosphere, at a suitable temperature, the compound (VI-e) undergoes an electrophilic substitution reaction under a strong base to obtain a compound (VI);

其中极性非质子性溶剂可选自， 但不限于： 1,4-二氧六环、 Ν,Ν-二甲基甲酰胺或 Ν,Ν- 二甲基甲酰胺 /正己烷混合溶剂 (V/V = 1:5-5:1)；  The polar aprotic solvent may be selected from, but not limited to: 1,4-dioxane, hydrazine, hydrazine-dimethylformamide or hydrazine, hydrazine-dimethylformamide/n-hexane mixed solvent (V) /V = 1:5-5:1);

其中强碱可选自， 但不限于： 1,8-二氮杂二环 [5.4.0]十一碳 -7-烯 (简称 DBU)、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧化钾、 氢氧化钠、 氢氧化锂、 氢化铝锂、 叔丁基 锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基锂或者氢氧化钡； 优选条件为： 以 Ν,Ν-二甲基甲酰胺为溶剂， 10~35°C下化合物 (； VI-e)搅拌反应 1~6小时； 进一步优选条件为： 氮气氛下， 以 Ν,Ν-二甲基甲酰胺为溶剂， 10~35'C下化合物 (VI-e) 搅拌反应 1~ The strong base may be selected from, but not limited to: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, ethanol Sodium, potassium hydroxide, sodium hydroxide, lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; The preferred conditions are as follows: using hydrazine, hydrazine-dimethylformamide as a solvent, and stirring the compound (; VI-e) at 10 to 35 ° C for 1 to 6 hours; further preferred conditions are: under nitrogen atmosphere, Ν, Ν -Dimethylformamide is the solvent, and the compound (VI-e) is stirred at 10~35'C.

Figure imgf000042_0001
Figure imgf000042_0001

通式 (VI)化合物脱去保护基 P， 得到化合物 (I);  The compound of the formula (VI) is deprotected P to give the compound (I);

其中优选在质子或非质子性溶剂中， 在适宜的温度和催化剂下， 化合物 (VI)脱除保护基 P， 得到化合物 (I);  Wherein the compound (I) is preferably removed in a protic or aprotic solvent at a suitable temperature and a catalyst to obtain the compound (I);

其中质子或非质子性溶剂可选自， 但不限于： 甲醇、 乙醇、 异丙醇、 甲酸、 冰醋酸、 四氢呋喃或乙腈；  Wherein the protic or aprotic solvent may be selected from, but not limited to: methanol, ethanol, isopropanol, formic acid, glacial acetic acid, tetrahydrofuran or acetonitrile;

其中催化剂可选用： 钯 /炭、氢氧化钯 /炭、 甲酸铵和钯 /炭、三氯化硼、三氟乙酸、盐酸、 硫酸、 磷酸、 氢氧化锂、 碳酸钾-甲醇、 甲醇-甲醇钠、 氯化钯、 四正丁基氟化铵、 氟化氢- 吡啶或氟化氢-三乙胺；  The catalyst can be selected from: palladium/carbon, palladium hydroxide/carbon, ammonium formate and palladium/carbon, boron trichloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, lithium hydroxide, potassium carbonate-methanol, methanol-sodium methoxide. , palladium chloride, tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine or hydrogen fluoride-triethylamine;

优选条件为： 以甲醇为溶剂， 10%钯 /炭作催化剂， 在氢气存在下， 室温常压反应 1~10 小时；  The preferred conditions are as follows: using methanol as a solvent, 10% palladium/carbon as a catalyst, and reacting at room temperature under normal pressure for 1 to 10 hours in the presence of hydrogen;

其中：  among them:

R1 , R2和 R3选自羟基、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH 或者 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3; R 1 , R 2 and R 3 are selected from a hydroxyl group, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH or -0-C(=0)0-CH 3 , -0-C(=0)0-CH 2 CH 3 ;

X为 0;  X is 0;

W、 R、 G、 R4、 R5、 R6和 R7定义如通式 (I)或 (II)中所述；W, R, G, R 4 , R 5 , R 6 and R 7 are as defined in formula (I) or (II);

'为 F、 Cl、 Br或 I;  '为 F, Cl, Br or I;

P为羟基保护基， P优选自 d— 4烷基、 -C^C -d— 6烷基、 苄基、 对甲氧基苄基、 苯甲酰 基、 烯丙基、 三甲基硅基、 三乙基硅基、 叔丁基二甲基硅基或叔丁基二苯基硅基， 进一步 优选苄基、 乙酰基或烯丙基； P is a hydroxy protecting group, and P is preferably selected from d-4 alkyl, -C^C-d- 6 alkyl, benzyl, p-methoxybenzyl, benzoyl, allyl, trimethylsilyl, a triethylsilyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, further preferably a benzyl group, an acetyl group or an allyl group;

Y选自 H、 d_4烷基、三氟甲磺酸基、 甲磺酰基、对甲苯磺酰基或乙酰基， 优选 H、 d_4 烷基、 甲磺酰基或乙酰基， 进一步优选甲基。 Y is selected from H, d- 4 alkyl, trifluoromethanesulfonate, methylsulfonyl, p-toluenesulfonyl or acetyl, preferably H, d- 4 alkyl, methylsulfonyl or acetyl, more preferably methyl.

本发明前面任意通式所示的化合物或其立体异构体或其药学上可接受的盐， 其中所述 的盐包括， 但不限于钠盐、 钾盐、 钙盐、 镁盐、 钡盐、 铵盐、 三甲胺盐、 三乙胺盐、 吡啶 盐、 甲基吡啶盐、 2,6-二甲基吡啶盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二 环己基铵盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 甲酸盐、 三氟乙酸盐、 乙酸 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、 丙二酸盐、 苹果 酸盐、 2-羟基丙酸盐、 草酸盐、 羟乙酸盐、 水杨酸盐、 葡萄糖醛酸盐、 半乳糖醛酸盐、 枸橼 酸盐、 门冬氨酸盐、 谷氨酸盐、 苯甲酸盐、 肉桂酸盐、 对甲苯磺酸盐、 苯磺酸盐、 甲磺酸 盐、 乙磺酸盐、 三氟甲磺酸盐或它们的组合， 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。 A compound of any of the preceding formulas, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the salt includes, but is not limited to, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a barium salt, Ammonium salt, trimethylamine salt, triethylamine salt, pyridinium salt, methylpyridine salt, 2,6-lutidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, two Cyclohexylammonium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, trifluoroacetate, acetate, maleate, tartrate, citrate, amber Acid salt, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronide, galactose Acid salt, citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, besylate, methanesulfonate, ethanesulfonate, three Fluoromethanesulfonate or a combination thereof, preferably sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride, hydrobromide salt, sulfate salt, phosphate salt, trifluoroethyl Acid salt, acetate, maleate salt, aspartate, glutamate, malate or a combination thereof.

本发明前面任意通式所述的化合物或其药学上可接受的共晶体， 其中所述的共晶体是 所述化合物与氨基酸、 有机酸、 水、 和 /或其他溶剂形成的共晶体， 其中氨基酸选自 L-赖氨 酸、 L-色氨酸、 L-苯丙氨酸、 L-苏氨酸、 L-异亮氨酸、 L-亮氨酸、 L-缬氨酸、 L-精氨酸、 L- 组氨酸、 L-丙氨酸、 L-天冬氨酸、 L-天冬酰胺、 L-半胱氨酸、 L-谷氨酰胺、 L-谷氨酸、 L- 甲硫氨酸、 L-脯氨酸、 L-丝氨酸、 L-酪氨酸、 L-甘氨酸、 L-焦谷氨酸、 D-赖氨酸、 D-色氨酸、 D-苯丙氨酸、 D-苏氨酸、 D-异亮氨酸、 D-亮氨酸、 D-缬氨酸、 D-精氨酸、 D-组氨酸、 D-丙 氨酸、 D-天冬氨酸、 D-天冬酰胺、 D-半胱氨酸、 D-谷氨酰胺、 D-谷氨酸、 D-甲硫氨酸、 D- 脯氨酸、 D-丝氨酸、 D-酪氨酸、 D-甘氨酸或 D-焦谷氨酸， 氨基酸优选 L-苯丙氨酸、 L-脯氨 酸或 L-焦谷氨酸， 溶剂优选 1,2-乙二醇、 1,2-丙二醇或 1-甲基 -1,2-乙二醇。  A compound of any of the preceding formulas, or a pharmaceutically acceptable co-crystal thereof, wherein said co-crystal is a co-crystal of said compound with an amino acid, an organic acid, water, and/or other solvent, wherein the amino acid Selected from L-lysine, L-tryptophan, L-phenylalanine, L-threonine, L-isoleucine, L-leucine, L-valine, L-arginine Acid, L-histidine, L-alanine, L-aspartic acid, L-asparagine, L-cysteine, L-glutamine, L-glutamic acid, L-methyl sulfide Acid, L-valine, L-serine, L-tyrosine, L-glycine, L-pyroglutamic acid, D-lysine, D-tryptophan, D-phenylalanine, D -threonine, D-isoleucine, D-leucine, D-valine, D-arginine, D-histidine, D-alanine, D-aspartic acid, D - asparagine, D-cysteine, D-glutamine, D-glutamic acid, D-methionine, D-valine, D-serine, D-tyrosine, D-glycine Or D-pyroglutamic acid, the amino acid is preferably L-phenylalanine, L-valine or L-pyroglutamic acid, and the solvent is preferably 1,2-B. Alcohol, 1-methyl-1,2-propanediol or 1,2-ethanediol.

本发明涉及一种药物组合物， 所述的组合物包括有效剂量的通式 ω所述的氧杂双环衍 生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药和 /或一种或 多种其他治疗剂及药学上可接受的载体、 赋形剂或稀释剂。  The present invention relates to a pharmaceutical composition comprising an effective amount of an oxabicyclic derivative of the formula ω or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, A crystal or prodrug and/or one or more additional therapeutic agents and a pharmaceutically acceptable carrier, excipient or diluent.

本发明优选所述的其他治疗剂包括：  Other therapeutic agents preferred in the present invention include:

(a) SGLT-2抑制剂或药学上可接受的盐； 和 /或  (a) an SGLT-2 inhibitor 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)双胍类、 噻唑烷二酮类、 磺酰脲类、 列奈类、 （X-葡萄糖苷酶抑制剂或胰高血糖素样 肽 -1类似物， 或其药学上可接受的盐或前药；  (c) biguanides, thiazolidinediones, sulfonylureas, linoleides, (X-glucosidase inhibitors or glucagon-like peptide-1 analogues, or pharmaceutically acceptable salts thereof or Prodrug

其中优选所述的 SGLT-2抑制剂选自达格列净 (Dapagliflozin)、坎格列净 (Canagliflozin)、 阿格列净 (Atigliflozin)、 恩帕列净（Empagliflozin)、 依帕列净（Ipragliflozin)、 托伏列净 (Tofogliflozin), 卢斯列净 (Luseogliflozin)、 瑞格列净 (Remogliflozin)、 舍格列净 (Sergliflozin) 或依托列净 (Ertugliflozin);  Preferably, the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, Atigliflozin, Empagliflozin, and Ipragliflozin. ), Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin;

其中优选所述的 DPP-IV抑制剂选自利拉列汀 (Linagliptin)、 西他列汀 (Sitagliptin)、维格 列汀 (Vildagliptin)、 阿格列汀 (Alogliptin)、沙格列汀 (Saxagliptin)、地那列汀 (Denagliptin)、卡 格列汀（Carmegliptin)、 MK-3102 ( Omarigliptin ) 、 美格列汀（Melogliptin)、 MK-3102 ( Omarigliptin) 、 度格列汀 (Dutogliptin)、 替格列汀 (Teneligliptin)、 吉格列汀 (Gemigliptin) 或曲格列汀 (Trelagliptin); Preferably, the DPP-IV inhibitor is selected from the group consisting of Linagliptin, sitagliptin, Vildagliptin, Alogliptin, and Saxagliptin. ), Denagliptin, Carmegliptin, MK-3102 (Omarigliptin), Melogliptin, MK-3102 (Omarigliptin), Dugtogliptin, Tigri Teneligliptin, Geigliptin Or treglifleurin (Trelagliptin);

其中优选所述的治疗剂双胍类治疗剂选自二甲双胍或苯乙双胍， 噻唑烷二酮类治疗剂 选自环格列酮 (Ciglitazone)、 吡咯列酮 (Pioglitazone)、 罗格列酮 (Rosiglitazone)、 曲格列酮 (Troglitazone), 发格列酮 (Farglitazar)或达格列酮 (Darglitazoan), 磺酰脲类治疗剂选自格列美 脲（Glimepiride)、 甲苯磺丁脲（Tolglybutamide)、 格列波脲（Glibomuride)、 格列本脲 (Glibenclamide),格列喹酮 (Gliquidone)、格列吡嗪 (Glipizide)或格列齐特 (Gliclazipe), 列奈类 治疗剂选自那格列奈 (Nateglinide)、瑞格列奈 (Repaglinide)或米格列奈 (Mitiglinide), α-葡萄糖 苷酶抑制剂选自阿卡波糖 (Acarbose)、 伏格列波糖 (Voglibose)或米格列醇 (Miglitol), 胰高血 糖素样肽 -1类似物选自艾塞那肽 (Exenatide)或利拉鲁肽 (LimglUtide;»。 Preferably, the therapeutic agent biguanide therapeutic agent is selected from the group consisting of metformin or phenformin, and the thiazolidinedione therapeutic agent is selected from the group consisting of Ciglitazone, Pioglitazone, and Rosiglitazone. , Troglitazone, Farglitazar or Darglitazoan, sulfonylurea therapeutic agent selected from Glimepiride, Tolglybutamide, Grid Glibomuride, Glibenclamide, Gliquidone, Glipizide or Gliclazipe. The therapeutic agent of Lenna is selected from nateglinide. (Nateglinide), Repaglinide or Mitiglinide, the α-glucosidase inhibitor is selected from the group consisting of Acarbose, Voglibose or Miglitol. (Miglitol), the glucagon-like peptide-1 analogue is selected from Exenatide or Liraglutide (Limgl U tide;».

本发明所述药物组合物可以制成固体口服制剂、 液体口服制剂、 注射剂等剂型。 口服 直接包括片剂、 分散片、 糖衣剂、 颗粒剂、 干粉剂、 胶囊剂和溶液剂， 注射剂包括小针、 大输液和冻干粉针等。  The pharmaceutical composition of the present invention can be formulated into a solid oral preparation, a liquid oral preparation, an injection or the like. Oral directly includes tablets, dispersible tablets, dragees, granules, dry powders, capsules and solutions, and injections include small needles, large infusions, and lyophilized powders.

进一步， 本发明涉及通式 (I)所述的化合物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或其前药作为钠依赖性葡糖转运蛋白抑制剂的用途；  Further, the present invention relates to a compound of the formula (I) or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof thereof as a sodium-dependent glucose transporter inhibitor the use of;

其中钠依赖性葡糖转运蛋白抑制剂的用途选自代谢性疾病；  The use of the sodium-dependent glucose transporter inhibitor is selected from the group consisting of metabolic diseases;

所述的代谢性疾病选自糖尿病、 糖尿病性视网膜病、 糖尿病性神经病、 糖尿病性肾病、 胰岛素抗性、 高血糖、 高胰岛素血症、 脂肪酸或甘油的升高的水平、 高脂血症、 肥胖症、 高甘油三脂血症、 X综合症、 糖尿病并发症、 动脉粥样硬化或高血压；  The metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity Symptoms, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension;

其中糖尿病优选 II型糖尿病。  Among them, diabetes is preferably type II diabetes.

除非有相反的陈述， 在说明书和权利要求书中使用的术语具有下述含义。  Terms used in the specification and claims have the following meanings unless stated to the contrary.

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， 及本发明所述基团和化合物中所涉及的碳、 氢、 氧、 硫、 氮或卤素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， 又称为重氢 )、 氚 （Τ， 又称为超重氢 )， 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 19F， 氯的同位素包括 35C1和 37C1， 溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen 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 (Τ, also known as super heavy hydrogen), oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 C1 and 37 C1, and the bromine isotopes include 79 Br and 81 Br.

"烷基 "是指直链和支链的饱和脂肪族烃基团， 主链包括 1至 20个碳原子， 优选为 1至 12个碳原子， 进一步优选为 1至 8个碳原子， 更优选为 1至 6个碳原子， 再进一步优选 1 至 4个碳原子的直链与支链基团， 最优选 1至 2个碳原子。 烷基的实例包括但不限于甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 正戊基、 2-戊基、 3-戊基、 2- 甲基 -2-丁基、 3-甲基 -2-丁基、 3-甲基 -1-丁基、 2-甲基 -1-丁基、 正己基、 2-己基、 3-己基、 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、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2,2-二甲基戊基、 2,3-二甲基戊基、 2,4-二甲基戊基、 3,3-二甲基戊基、 2-乙基戊基、 3-乙基 戊基、 正辛基、 2,2-二甲基己基、 2,3-二甲基己基、 2,4-二甲基己基、 2,5-二甲基己基、 3,3- 二甲基己基、 4,4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己基、 2-甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基、 正壬基、 2-甲基 -2-乙基己基和正癸基等。 烷基可以是取代的或未取代 的， 当被取代时， 取代基可以在任何可使用的连接点上被取代， 取代基优选为 1至 5个选 自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基 硫基、 硫代羰基、 硅烷基或 -NRbR 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷 基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环烷基。 Ra与 Rd各自独立选自芳基、杂芳基、烷基、烷氧基、 环烷基、 杂环烷基、 羰基、 酯基、 桥环基、 螺环基、 并环基。 "Alkyl" means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably Further, 1 to 6 carbon atoms, still more preferably a linear or branched group of 1 to 4 carbon atoms, and most preferably 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl Base, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3 -hexyl, 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, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,2-dimethyl Pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl Base, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,3-dimethylhexyl, 4,4 - dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, ruthenium Base, 2-methyl-2-ethylhexyl and n-decyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available linking point, and the substituent is preferably from 1 to 5 selected from F, Cl, Br, I, alkyl. , cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, fluorenyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro group, Cyclo-, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R a , -0-(CH 2 ) m -C(= 0) -R a , -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R wherein R b is R e is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R b And R e may form a five or six membered cycloalkyl or heterocycloalkyl group. R a and R d are each independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro, and cyclylene.

"亚烷基"是指上述烷基去除两个氢原子衍生的直链或支链烷烃， 包括 -(CH2)V-(V为 1至"Alkylene" means a straight or branched chain alkane derived from the removal of two hydrogen atoms from the above alkyl group, including -(CH 2 ) V - ( V is 1 to

18的整数)， 亚烷基实施例包括但不限于亚甲基、 亚乙基和亚丙基等。 亚烷基可以是取代的 或未取代的， 当被取代时， 取代基优选为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷 氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环 基、桥环基、螺环基、并环基、羟基烷基、 =0、羰基、醛、羧酸、羧酸酯、 -(CH2)m-C(=0)-R\ -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, sulfur Alcohol, hydroxy, nitro, fluorenyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, Aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R\ -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C (=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl -R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R e , wherein R b and R e are independently selected from the group consisting of H, hydroxy, amino, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group. Or a heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"烷氧基"是指 -0-烷基， 其中烷基如本文上述定义。 烷氧基可以是取代的或未取代的， 烷氧基实施例包括但不限于甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 正丁氧基、 异丁氧基、 叔丁氧基、仲丁氧基、正戊氧基和正己氧基等。当被取代时，取代基优选为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 0Rd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基 硫基、 硫代羰基、 硅烷基或 -NRbR 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷 基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基 Ra与 Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环 烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "Alkoxy" means a-0-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, untertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy. When substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyanide , isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , - (CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , 0R d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 or 2), aryl Thio, thiocarbonyl, silane or -NR b R wherein R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a heterocyclic group R a and R d are each independently selected from an aryl group, a heteroaryl group, An alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a fluorenylene group.

"烷氧基烷基 "指与烷氧基相连的烷基。烷氧基烷基可以是取代的或未取代的，其非限制 性实施例包括， 甲氧基甲基、 甲氧基乙基、 乙氧基甲基、 乙氧基乙基、 丙氧基甲基、 丙氧 基乙基、 2-丙氧基甲基、 丁氧基丙基、 叔丁氧基乙基、 戊氧基乙基、 己氧基乙基、 环丙氧基 甲基、 环丙氧基乙基、 环丙氧基丙基和环己氧基甲基； 当被取代时， 取代基优选为 1 至 5 个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨 基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc, -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基 硫基、 硫代羰基、 硅烷基或 -NRbR 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷 基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "Alkoxyalkyl" means an alkyl group attached to an alkoxy group. The alkoxyalkyl group can be substituted or unsubstituted, non-limiting examples of which include, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy , propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropyloxymethyl, cyclopropane Oxyethyl, cyclopropyloxypropyl and cyclohexyloxymethyl; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkane Oxyl, haloalkyl, thiol, hydroxy, nitro, fluorenyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclo, hydroxyalkane Base, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or - (CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R wherein R b and R e are independently selected from Including H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R b and R e can be formed A five or six membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"烯基 "是指至少含一个碳 -碳双键组成的如本文上述定义的烷基，优选含有 2至 20个碳 原子， 进一步优选 2至 12个碳原子， 更优选在主链上有 2至 8个碳原子， 烯基可以是取代 的或未取代的。 非限制性实施例包括乙烯基、 烯丙基、 1-丙烯基、 2-丙烯基、 1-丁烯基、 2- 丁烯基、 3-丁烯基、 1-戊烯基、 2-戊烯基、 3-戊烯基、 4-戊烯基、 1-甲基 -1-丁烯基、 2-甲基 -1- 丁烯基、 2-甲基 -3-丁烯基、 1-己烯基、 2-己烯基、 3-己烯基、 4-己烯基、 5-己烯基、 1-甲基 -1- 戊烯基、 2-甲基 -1-戊烯基、 1-庚烯基、 2-庚烯基、 3-庚烯基、 4-庚烯基、 1-辛烯基、 3-辛烯 基、 1-壬烯基、 3-壬烯基、 1-癸烯基、 4-癸烯基、 1,3-丁二烯、 1,3-戊二烯、 1,4-戊二烯、 1,4- 己二烯、 3-十一烯基、 4-十二烯基和 4,8,12-十四碳三烯基等。 当被取代时， 取代基为 1至 5 个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨 基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc, -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基 硫基、 硫代羰基、 硅烷基或 -NRbR 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷 基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "炔基"是指包含至少一个碳 -碳三键组成的如本文上述定义的烷基，优选含有 2至 20个 碳原子， 进一步优选 2至 8个碳原子， 更优选在主链上有 2至 4个碳原子的炔基。 炔基可 以是取代的或未取代的。 非限制性实施例包括乙炔基、 1-丙炔基、 2-丙炔基、 丁炔基、 2-丁 炔基、 3-丁炔基、 1-甲基 -2-丙炔基、 4-戊炔基、 3-戊炔基、 1-甲基 -2-丁炔基、 2-己炔基、 3- 己炔基、 2-庚炔基、 3-庚炔基、 4-庚炔基、 3-辛炔基、 3-壬炔基、 4-癸炔基、 3-十一炔基和 4-十二炔基等； 当被取代时， 取代基优选为一个或多个以下基团， 独立地选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧 酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷 基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元 环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "Alkenyl" means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 in the main chain. Up to 8 carbon atoms, the alkenyl group may be substituted or unsubstituted. Non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1- Decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-undecyl, 4 - Dodecenyl and 4,8,12-tetradecenetrienyl and the like. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -( CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 Or 2) an arylthio group, a thiocarbonyl group, a silyl group or -NR b R wherein R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, hetero A cyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a. "Alkynyl" means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl group up to 4 carbon atoms. An alkynyl group can be substituted or unsubstituted. Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl , 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups , independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano, aryl, hetero Aryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylate, -(CH 2 ) m -C(=0)- R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio group, thiocarbonyl group, a silyl group, or -NR b R e, wherein R e and R b is independently selected from They include H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl group, alternatively, R b and R e may be formed A five or six membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"氨基 "是指 -NH2， 可以是取代的或未取代的， 当被取代时， 取代基优选为 1至 3个以 下基团， 独立地选自烷基、 环烷基、 卤代烷基、 硫醇、 羟基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧 酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷 基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元 环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "Amino" means -NH 2 and may be substituted or unsubstituted. When substituted, the substituent is preferably 1 to 3 or less, independently selected from alkyl, cycloalkyl, haloalkyl, sulphur Alcohol, hydroxy, decyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro group, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxy Acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(= 0) -NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), an arylthio group, a thiocarbonyl group, a silyl group or -NR b R e , wherein R b and R e are independently selected from the group consisting of H, a hydroxyl group, an amino group, a carbonyl group, An alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a hetero group. Ring base. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"烷硫基"是指 -S-烷基或 -S- (未被取代环烷基 )， 非限制性实施例包括甲硫基、 乙硫基、 丙硫基和丁硫基等。  "Alkylthio" means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.

"酰基 "或"羰基"是指 -C(=0)-Ra基团， 其中 Ra如上文定义。 "Acyl" or "carbonyl" refers to a -C(=0)-R a group, wherein R a is as defined above.

"酸"是指 -C(=0)-H。  "Acid" means -C(=0)-H.

"=0"是指 =0。  "=0" means =0.

"硫代 "是指 =S。  "Thio" means =S.

"卤素 "是指氟、 氯、 溴、 碘。  "Halogen" means fluorine, chlorine, bromine, or iodine.

"羟基 "是指 -OH。  "Hydroxy" means -OH.

"氰基 "是指 -C≡N。 "异氰基"是指 -N≡C。 "Cyano" means -C≡N. "Isocyano" means -N≡C.

"硝基 "是指 -N02。 "Nitro" means -N0 2 .

"羧酸 "是指 -C(=0)-OH。  "Carboxylic acid" means -C(=0)-OH.

"羧酸酯"是指 -C(=0)-0-Rd， Rd选自烷基、 环烷基或杂环基。 "Carboxylic acid ester" means -C(=0)-0-R d and R d is selected from an alkyl group, a cycloalkyl group or a heterocyclic group.

"卤代烷基"是指卤素取代的如本文上述定义的烷基，非限制性实施例包括一氟甲基、二 氟甲基、 三氟甲基、 一溴甲基、 二溴甲基、 三溴甲基、 1-氟乙基 -2-基、 2-氟乙基 -2-基、 1,1- 二氟乙基 -2-基、 1,2-二氟乙基 -2-基、 1,1,1-氟乙基 -2-基、 1-溴乙基 -2-基、 2-溴乙基 -2-基和 1,1,1- 三溴乙基 -2-基等。  "Haloalkyl" means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo. Methyl, 1-fluoroethyl-2-yl, 2-fluoroethyl-2-yl, 1,1-difluoroethyl-2-yl, 1,2-difluoroethyl-2-yl, 1 1,1-fluoroethyl-2-yl, 1-bromoethyl-2-yl, 2-bromoethyl-2-yl and 1,1,1-tribromoethyl-2-yl and the like.

"巯基 "是指 -SH。  "巯基" means -SH.

"硫醇 "是指烷基中的一个或多个氢原子被巯基取代的烃， 非限制性实施例包括甲硫醇、 乙硫醇、 1,2-二硫醇。  "Mercaptan" means a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a mercapto group, and non-limiting examples include methyl mercaptan, ethyl mercaptan, 1,2-dithiol.

"硫酰基"或"硫代羰基"是指 -C(=S)-Ra基团， 其中 Ra如上文定义。 "Sulfyl" or "thiocarbonyl" refers to a -C(=S)-R a group, wherein R a is as defined above.

"羟烷基"是指烷基被一个或多个羟基取代， 优选为被 1、 2或 3个羟基取代， 烷基优选 为低级烷基。 非限制性实施例包括羟甲基、 2-羟乙基、 1-羟乙基、 1,2-二羟基丙基、 1,3-二羟 基丙基和 2,3-二羟基丙基等。  "Hydroxyalkyl" means that the alkyl group is substituted by one or more hydroxyl groups, preferably by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a lower alkyl group. Non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl, and the like.

"环烷基"是指饱和或不饱和的单环环烃基， 可以是取代的或未取代的， 环碳原子包括 3 至 20个碳原子， 优选 3至 10个碳原子， 进一步优选 3至 8个碳原子， 非限制性实施例包 括环丙基、 环丁基、 环戊基、 环己基、 环庚基、 环辛基、 环丙烯基、 环丁烯基、 环戊烯基、 环己烯基、 环庚烯基、 1,5-环辛二烯基、 1,4-环己二烯基和环庚三烯基等。 当被取代时， 取 代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝 基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟 基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺 酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 "Cycloalkyl" means a saturated or unsaturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene A group, a cycloheptenyl group, a 1,5-cyclooctadienyl group, a 1,4-cyclohexadienyl group, a cycloheptatrienyl group, and the like. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -( CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 Or 2) an arylthio group, a thiocarbonyl group, a silyl group or -NR b R e , wherein R b and R e are independently selected from the group consisting of H, a hydroxyl group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"杂环烷基"或"杂环基"是指取代的或未取代的饱和或不饱和的至少含有 1 至 5个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基团的非芳香环系统， 非芳香环系统包含 3至 20个环 原子， 优选 3至 10个环原子， 更优选 3至 8个环原子。 杂环基环中选择性取代的 N、 S可 被氧化成各种氧化态。 非限制性实施例包括氧杂环丙烷基、 氧杂环丁基、 氧杂环戊基、 氧 杂环己基、 氧杂环己基、 氧杂环辛基、 氮杂环丙烷基、 氮杂环丁基、 氮杂环戊基、 氮杂环 己基、 氮杂环丙烯基、 1,3二氧环戊基、 1,4-二氧环戊基、 1,3-二氧环戊基、 1,3-二氧环己基、 1,3-二硫环己基、 氮杂环庚烯基、 吗啉基、 哌嗪基、 吡啶基、 呋喃基、 噻吩基、 吡咯基、 吡 喃基、 N-烷基吡咯基、 嘧啶基、 吡嗪基、 哒嗪基、 咪唑基、 哌啶基、 硫代吗啉基、 二氢吡 喃、 噻二唑基、 噁唑基、 噁二唑基、 吡唑基、 1 ,4-二氧杂环己二烯基、 2H-1,2-噁嗪基、 2,5- "Heterocycloalkyl" or "heterocyclyl" means substituted or unsubstituted, saturated or unsaturated, having at least 1 to 5 selected from N, 0, S, S (=0) or S (=0) 2 A heteroatom or group non-aromatic ring system, the non-aromatic ring system comprising 3 to 20 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms. The selectively substituted N, S in the heterocyclyl ring can be oxidized to various oxidation states. Non-limiting examples include oxiranyl, oxetanyl, oxolane, oxetan, oxetan, oxetanyl, aziridine, azetidin Base, azacyclopentyl, nitrogen heterocycle Hexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3- Dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, Pyridazinyl, imidazolyl, piperidinyl, thiomorpholinyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxan Alkenyl, 2H-1,2-oxazinyl, 2,5-

Figure imgf000049_0001
Figure imgf000049_0001

等。 当被取代时， 取代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷 基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中Wait. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -( CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 Or 2) an arylthio group, a thiocarbonyl group, a silyl group or -NR b R e , wherein

Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option And R b and R e may form a five- or six-membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"螺环"是指取代的或未取代的单环之间共用一个碳原子 (称螺原子；)的 5至 20元多环基 团， 其可以包含 0至 5个双键， 且可以含有 0至 5个选自 N、 0或 S(=0)n的杂原子。 优选 一步优选为 6 至 12 元， 更有选 6 至 10元， 其非限定性实例包括

Figure imgf000049_0002
"Spiro" refers to a 5- to 20-membered polycyclic group that shares a carbon atom (called a spiro atom;) between a substituted or unsubstituted monocyclic ring, which may contain 0 to 5 double bonds, and may contain 0 Up to 5 heteroatoms selected from N, 0 or S(=0) n . Preferably, one step is preferably 6 to 12 yuan, more preferably 6 to 10 yuan, non-limiting examples of which include
Figure imgf000049_0002

- χ 。 >ο >θ— ο ¾-OCo j i- χ. >ο> θ- ο ¾ -OCo ji

ύο - >ο ioo γοο O

Figure imgf000049_0003
Ύο - >ο ioo γ οο O
Figure imgf000049_0003

。 当被取代时， 取代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环 基、并环基、羟基烷基、 =0、羰基、醛、羧酸、羧酸酯、 -(CH2)m-C(=0)-R\ -0-(CH2)m-C(=0)-R\. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro, cyclo, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R\ -0-(CH 2 ) m -C(=0)-R\

-(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂芳基、 磺酰基、 三氟甲磺 酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or - (CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R e , wherein R b and R e are independently selected Including H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Acyl, Alternatively, R b and R e may form a five or six membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"并环 "是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团，其中 一个或多个环可以含有 0个或多个双键， 且可以是取代的或未取代， 并环体系中的各个环 可以含 0至 5个选自 N、 3(=0)11或0的杂原子。 优选为 5至 20元， 进一步优选为 5至 14 "Paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain zero or more double bonds, and may be The substituted or unsubstituted, each ring in the cis ring system may contain from 0 to 5 heteroatoms selected from N, 3 (=0) 11 or 0. Preferably it is 5 to 20 yuan, further preferably 5 to 14

12 元， 再进一步 5 至 10 元。 非限定性实例包括  12 yuan, further 5 to 10 yuan. Non-limiting examples include

Figure imgf000050_0001
Figure imgf000050_0001

卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥 环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 Haloalkyl, thiol, hydroxy, nitro, fluorenyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged, spiro, cyclyl, hydroxyalkyl, 0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 ) m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 m - alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R e , wherein R b and R e are independently selected from the group consisting of H , hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an alternative, R b and R e may form five or A six-membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"桥环"是指任意两个不直接连接的碳原子的多环基团，可以含有 0个或多个双键，且可 以是取代的或未取代的， 并环体系中的任意环可以含 0至 5个选自 N、 3(=(¾1或0杂原子 或基团 (其中 n为 1、 1、 2)。 环原子包含 5至 20个原子， 优选为 5至 14个原子， 进一步优 5至 12个， 在进一步 5至 10个。 非限定性实例包括 "Bridge ring" refers to any two polycyclic groups of carbon atoms that are not directly bonded, may contain zero or more double bonds, and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 are selected from N, 3 (=(3⁄4 1 or 0 heteroatoms or groups (where n is 1, 1, 2). The ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further Excellent 5 to 12, in further 5 to 10. Non-limiting examples include

Figure imgf000050_0002
Figure imgf000050_0002

和金刚烷。 当被取代时， 取代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥 环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中And adamantane. When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -(CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl , silane group or -NR b R e , wherein

Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基或并环基。 R b and R e are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option And R b and R e may form a five- or six-membered cycloalkyl or heterocyclic group. R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or cis a.

"苄基 "是指 -CH2-苯基， 所述苯基为取代的或未取代的， 其非限制性实施例包括 -CH2- 苯基、 -CH2 -对甲基苯基等。 "Benzyl" refers to -CH 2 - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH 2 - phenyl, -CH 2 - p-methylphenyl and the like.

"芳基 "是指取代的或未取代的 6至 14元环状芳香基团，包括单环芳香基和稠环芳香基。 优选 6至 14元芳香环， 进一步优选 6至 10元芳香环， 其非限制性实例包括苯基、 萘基、 蒽基和菲基等。 所述芳基环可以稠合于杂芳基、 杂环基或环烷基环上， 其中与母体结构连 接在一起的环为芳基环， 非限制性实施例包含：  "Aryl" means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups. A 6 to 14 membered aromatic ring is preferred, and a 6 to 10 membered aromatic ring is further preferred, and non-limiting examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

Figure imgf000051_0001
Figure imgf000051_0001

当被取代时， 取代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷 基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 ORd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基、 并环基。 When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -( CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 Or 2) an arylthio group, a thiocarbonyl group, a silyl group or -NR b R e , wherein R b and R e are independently selected from the group consisting of H, a hydroxyl group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a heterocyclic group. R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"杂芳基"是指取代或未取代的 5至 14元芳香环， 且含有 1至 5个选自 N、 0或 S(=0)n 杂原子或基团， 优选 5至 10元杂芳香环， 进一步优选 5至 6元。 杂芳基的非限制性实施例 包括但不限于吡啶基、 呋喃基、 噻吩基、 吡啶基、 吡喃基、 N-烷基吡咯基、 嘧啶基、 吡嗪 基、 哒嗪基、 咪唑基、 哌啶基、 吗啉、 硫代吗啉、 1,3-二噻烷、 苯并咪唑、 哌叮基、 苯并咪 唑、 苯并吡啶、 吡咯并吡啶等。 所述杂芳基环可以稠合于芳基、 杂环基或环烷基环上， 其 中 与母体结构连接在一起 的环为杂芳基环 ， 非限制性实施例包含

Figure imgf000052_0001
和 ' "Heteroaryl" means a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, 0 or S(=0) n , preferably 5 to 10 membered aromatic The ring is further preferably 5 to 6 yuan. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include
Figure imgf000052_0001
with'

当被取代时， 取代基为 1至 5个选自 F、 Cl、 Br、 I、 烷基、 环烷基、 烷氧基、 卤代烷 基、 硫醇、 羟基、 硝基、 巯基、 氨基、 氰基、 异氰基、 芳基、 杂芳基、 杂环基、 桥环基、 螺环基、 并环基、 羟基烷基、 =0、 羰基、 醛、 羧酸、 羧酸酯、 -(CH2)m-C(=0)-Ra、 -0-(CH2)m-C(=0)-Ra、 -(CH2)m-C(=0)-NRbRc、 -(CH2)mS(=0)nRa、 -(CH2)m -烯基 -Ra、 0Rd或 -(CH2)m -炔基 -Ra (其中 m、 n为 0、 1或 2)、 芳基硫基、 硫代羰基、 硅烷基或 -NRbRe， 其中 Rb与 Re独立选自包括 H、 羟基、 氨基、 羰基、 烷基、 烷氧基、 环烷基、 杂环基、 芳基、 杂 芳基、 磺酰基、 三氟甲磺酰基， 作为选择， Rb与 Re可形成五或六元环烷基或杂环基。 Ra与 Rd各自独立选自芳基、 杂芳基、 烷基、 烷氧基、 环烷基、 杂环基、 羰基、 酯基、 桥环基、 螺环基、 并环基。 When substituted, the substituent is from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano , isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, carboxylic acid ester, -(CH 2 m -C(=0)-R a , -0-(CH 2 ) m -C(=0)-R a , -(CH 2 ) m -C(=0)-NR b R c , -( CH 2 ) m S(=0) n R a , -(CH 2 ) m -alkenyl-R a , 0R d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 Or 2) an arylthio group, a thiocarbonyl group, a silyl group or -NR b R e , wherein R b and R e are independently selected from the group consisting of H, a hydroxyl group, an amino group, a carbonyl group, an alkyl group, an alkoxy group, a cycloalkyl group And a heterocyclic group, an aryl group, a heteroaryl group, a sulfonyl group, a trifluoromethanesulfonyl group, and R b and R e may form a five- or six-membered cycloalkyl group or a heterocyclic group. R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.

"芳基硫基"是指如本文定义的 -S-芳基或 -S-杂芳基。芳基硫基实例包括但不限于苯硫基、 吡啶基硫基、 呋喃基硫基、 噻吩基硫基、 嘧啶基硫基等。  "Arylthio" means an -S-aryl or -S-heteroaryl group as defined herein. Examples of arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, pyrimidinylthio, and the like.

"硅烷基"是指硅甲烷中的一个或多个氢原子被烷基取代所形成的基团，实施例包括但不 限于三甲基硅基、 三乙基硅基、 叔丁基二甲基硅基和叔丁基二苯基硅基等。  "Silyl" refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.

术语"单键"是指化学单键， 例如" A与 B之间为一个单键"表示 A与 B之间存在一个化 学单键， 即： A-B。  The term "single bond" refers to a chemical single bond, such as "a single bond between A and B" means that there is an chemical single bond between A and B, namely: A-B.

"任选 "或"任选地 "是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件 或环境发生或不发生的场合。 如： "任选被 F取代的烷基"指烷基可以但不必须被 F取代， 说明包括烷基被 F取代的情形和烷基不被 F取代的情形。  "Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.

"药学上可接受的盐 "或"其药学上可接受的盐 "指的是保持游离酸或游离碱的生物有效 性和特性， 且所述的游离酸通过与无毒的无机碱或有机碱， 或所述的游离酸通过与无毒的 无机酸或有机酸反应获得的那些盐， 包括碱金属盐， 如钠盐、 钾盐、 锂盐等； 碱土金属盐， 如钙盐、 镁盐等； 其他金属盐， 如铁盐、 铜盐、 钴盐等； 有机碱盐， 如铵盐、 三乙胺盐、 吡啶盐、 甲基吡啶盐、 2,6-二甲基吡啶盐、 乙醇胺盐、 二乙醇胺盐、三乙醇胺盐、环己胺盐、 乙二胺盐、 胍盐、 异丙基胺盐、 三甲基胺盐、 三丙基胺盐、 三乙醇胺盐、 二乙醇胺盐、 乙 醇胺盐、 二甲基乙醇胺盐、 二环己基胺盐、 咖啡碱盐、 普鲁卡因盐、 胆碱盐、 甜菜碱盐、 苯明青霉素盐、 葡萄糖胺盐、 N-甲基葡糖胺盐、 可可碱盐、 氨丁三醇盐、 嘌吟盐、 哌嗪盐、 吗啉盐、 哌啶盐、 N-乙基哌啶盐、 四甲基胺盐、 二苄基胺盐和苯基甘氨酸烷基酯盐等； 氢 卤酸盐， 如氢氟酸盐、 盐酸盐、 氢碘酸盐、 氢溴酸盐等； 无机酸盐， 如硝酸盐、 硫酸盐、 高氯酸盐、 磷酸盐等； 低级烷磺酸盐， 如甲磺酸盐、 三氟甲磺酸盐、 乙磺酸盐等； 芳基磺 酸盐， 如苯磺酸盐、 对甲苯磺酸盐等； 有机酸盐， 如蚁酸盐、 富马酸盐、 甲酸盐、 三氟乙 酸盐、 糠酸盐、 葡萄糖酸盐、 谷氨酸盐、 乙醇酸盐、 羟乙磺酸盐、 乳酸盐、 马来酸盐、 苹 果酸盐、 扁桃酸盐、 粘液酸盐、 双羟萘酸盐、 泛酸盐、 硬脂酸盐、 琥珀酸盐、 磺胺酸盐、 酒石酸盐、 丙二酸盐、 2-羟基丙酸盐、 柠檬酸盐、 水杨酸盐、 草酸盐、 羟乙酸盐、 葡萄糖醛 酸盐、 半乳糖醛酸盐、 枸橼酸盐、 赖氨酸盐、 精氨酸盐、 门冬氨酸盐、 肉桂酸盐等。 "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or a salt obtained by reacting the free acid with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc. Other metal salts, such as iron salts, copper salts, cobalt salts, etc.; organic base salts, such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-lutidine salts, ethanolamine salts, Diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, phosphonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, Dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt , tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine , N-ethylpiperidine salt, tetramethylamine salt, dibenzylamine salt and phenylglycine alkyl ester salt; etc.; hydrohalide salt, such as hydrofluoric acid salt, hydrochloride salt, hydroiodide salt, Hydrobromide, etc.; inorganic acid salts such as nitrates, sulfates, perchlorates, phosphates, etc.; lower alkane sulfonates such as methanesulfonate, triflate, ethanesulfonate, etc. An aryl sulfonate such as besylate, p-toluenesulfonate, etc.; an organic acid salt such as formic acid salt, fumarate, formate, trifluoroethyl Acid salt, citrate, gluconate, glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, dihydroxynaphthalene Acid salt, pantothenate, stearate, succinate, sulfonate, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, hydroxyethyl Acid salts, glucuronates, galacturonates, citrates, lysine salts, arginine salts, aspartates, cinnamate salts, and the like.

"药物组合物 "表示一种或多种文本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 /和临床上使用的用于治疗、预防糖尿病的药物或 /和 SGLT-2抑制剂或 /和 DPP-IV 抑制剂与其他组成成分的混合物，其中其它组分包含生理学 /药学上可接受的载体和赋形剂。 临床上使用的用于治疗、预防糖尿病的药物包括双胍、 噻唑烷二酮、磺酰脲、 列奈、 （X-葡萄 糖苷酶抑制剂、 GLP-1 类似物或其药学上可接受的盐， 例如二甲双胍、 苯乙双胍、 环格列 酮（ Ciglitazone )、吡咯列酮 ( Pioglitazone )、罗格列酮（ Rosiglitazone )、曲格列酮（ Troglitazone )、 发格列酮 (Farglitazar) 、 达格列酮 (Darglitazoan) 、 格列美脲 ( Glimepiride ) 、 甲苯磺丁 脲 (Tolglybutamide) 、 格列波脲 ( Glibornuride) 、 格列本脲 ( Glibenclamide) 、 格列喹酮 ( Gliquidone) 、 格列吡嗪（glipizide) 、 格列齐特 (gliclazipe) 、 那格列奈（Nateglinide) 、 瑞格列奈 （Repaglinide) 、 米格列奈 （mitiglinide) 、 阿卡波糖 （Acarbose ) 、 伏格列波糖 (Voglibose) 、 米格列醇 (Miglitol) 、 艾塞那肽 (Exenatide) 或利拉鲁肽 ( Liraglutide ) ， SGLT-2 抑制剂例如达格列净 （Dapagliflozin ) 、 坎格列净 （ Canagliflozin ) 、 恩帕列净 ( Empagliflozin ) 、 依帕列净 （ Ipragliflozin ) 、 托伏列净 （ Tofogliflozin ) 、 卢斯列净 ( Luseogliflozin ) 、 瑞格列净 ( Remogliflozin ) 、 舍格列净 ( Sergliflozin ) 或依托列净 (Ertugliflozin) ， DPP-IV抑制剂例如利拉列汀 (Linagliptin) 、 西他列汀 ( Sitagliptin) 、 MK-3102 ( Omarigliptin) 、 维格列汀 （Vildagliptin) 、 阿格列汀 （Alogliptin) 、 沙格列汀 ( Saxagliptin)、地那列汀（Denagliptin)、卡格列汀（Carmegliptin)、美格列汀 (Melogliptin)、 度格列汀 （Dutogliptin) 、 替格列汀 （Teneligliptin) 、 吉格列汀 （Gemigliptin) 或曲格列汀 (Trelagliptin) 。 药物组合物的目的是促进化合物对生物体的给药。  "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 a clinically used drug for the treatment, prevention of diabetes or/and SGLT - 2 Inhibitors or/and mixtures of DPP-IV inhibitors with other ingredients, wherein the other components comprise physiological/pharmaceutically acceptable carriers and excipients. Drugs for clinical use and for the prevention of diabetes include biguanide, thiazolidinedione, sulfonylurea, linoleide, (X-glucosidase inhibitor, GLP-1 analogue or a pharmaceutically acceptable salt thereof, For example, metformin, phenformin, Ciglitazone, Pioglitazone, Rosiglitazone, Troglitazone, Farglitazar, Daglitazone (Darglitazoan), Glimepiride, Tolglybutamide, Glibornuride, Glibenclamide, Gliquidone, Glipizide ), gliclazipe, Nateglinide, Repaglinide, mitiglinide, Acarbose, Voglibose , Miglitol, Exenatide or Liraglutide, SGLT-2 inhibitors such as dapagliflozin, Canagliflozin , Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or backing Ertugliflozin, DPP-IV inhibitors such as Linagliptin, Sitagliptin, MK-3102 (Omarigliptin), Vildagliptin, Alogliptin , Saxagliptin, Denagliptin, Carmegliptin, Melogliptin, Dutogliptin, Teneligliptin, Kyrgyzstan Gemigliptin or Trelagliptin. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

"载体 "指的是不会对生物体产生明显剌激且不会消除所给予化合物的生物活性和特性 的载体或稀释剂。  "Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"赋形剂"指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的 实例包括但不限于碳酸钙、 磷酸钙、 各种糖和不同类型的淀粉、 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、 崩解剂等。  "Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, etc.

"前药 "是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化 合物。 本发明的前药通过修饰在该化合物中的酚基团来制备， 该修饰可以按常规的操作或 在体内被除去， 而得到母体化合物。 当本发明的前体药物被施予哺乳动物个体时， 前体药 物被割裂而分别形成游离的羟基。 前药的例子包括， 但不限于本发明化合物的酚羟基和磷 酸成钠盐衍生物。 "Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to provide the parent compound. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphorus of the compounds of the invention The acid forms a sodium salt derivative.

"共晶体"或"共晶"是指活性药物成分 （active pharmaceutical ingredient, API)和共晶形 成物 （cocrystal former, CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中 API和 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。所述"共晶形成物"包括但不限于各种药学上可接受的酸、碱、非离子化合物、水、 氨基酸、 醇或其他溶剂， 其非限制性实例包括丙氨酸 CAla)、 缬氨酸 （； Val)、 亮氨酸 （； Leu)、 异亮氨酸 （Ile)、脯氨酸 （Pro)、苯丙氨酸 （Phe)、色氨酸 （Trp)、蛋氨酸 （Met)、甘氨酸 （Gly)、 丝氨酸 （Ser)、 苏氨酸 （Thi、 半胱氨酸 （Cys 酪氨酸 （Tyr^N 天冬酰胺 （Asn)、 谷氨酰胺 (Gin), 赖氨酸 （Lys)、 精氨酸 （Arg)、 组氨酸（His)、 天冬氨酸 （Asp)、 谷氨酸 （Glu)、 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、 赖氨酸、 精氨酸、 门冬氨酸、 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、 三乙醇胺、 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、 氨丁三醇、 嘌吟、 哌嗪、 哌啶、 N-乙基哌啶、 甲醇、 乙醇、 丁 炔二醇、 1 ,2-丙二醇、 （R)l ,2-丙二醇、 （S)l ,2-丙二醇或 1-甲基 -1 ,2-乙二醇。  "Co-crystal" or "eutectic" refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds. The pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components. A eutectic is a multicomponent crystal that contains both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed by a neutral solid with a salt or solvate. The "eutectic former" includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols, or other solvents, non-limiting examples of which include alanine CAla), hydrazine Acid (; Val), leucine (; Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), Serine (Ser), Threonine (Thi, Cysteine (Cys Tyrosine (Tyr^N Asparagine (Asn), Glutamine (Gin), Lysine (Lys), Fine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, C 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, Glutamate, glycolic acid, isethionate, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, dihydroxynaphthalene , pantothenic acid, stearic 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, lysine Acid, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, three Ethylamine, tripropylamine, diethanolamine, ethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, gall Alkali, betaine, phenylpheniticin, ethylenediamine, glucosamine, methylglucamine, theobromine, tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, methanol, ethanol, Butynediol, 1,2-propanediol, (R)l, 2-propanediol, (S)l, 2-propanediol or 1-methyl-1,2-ethanediol.

"X 综合症 "是指代谢综合症的病症、 疾病和疾患。 详细描述见 Johannsson J. Clin. Endocrinol. Metab.,1997,82,727-734。  "X Syndrome" refers to the conditions, diseases, and conditions of metabolic syndrome. For a detailed description, see Johannsson J. Clin. Endocrinol. Metab., 1997, 82, 727-734.

"有效剂量"指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的， 包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减 轻至某种程度的化合物的量。  "Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.

"溶剂化物"指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非 化学计量的溶剂。 当溶剂为水时， 则为水合物。  "Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"IC5Q"指半数抑制浓度， 指达到最大抑制效果一半时的浓度。 "IC 5Q " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

本发明化合物的合成方法 Method for synthesizing the compound of the present invention

为了完成本发明的目的， 本发明采用如下技术方案：  In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

本发明通式 ω所述的化合物或其可药用的盐或其立体异构体的制备方法， 包括如下步 骤： The preparation method of the compound of the formula ω of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof comprises the following steps:

Figure imgf000055_0001
其中-
Figure imgf000055_0001
among them-

R R2和 R3选自羟基、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH 或者 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3 ; R R2 and R 3 are selected from hydroxy, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH or -0-C(=0)0-CH 3 , -0- C(=0)0-CH 2 CH 3 ;

X为 O;  X is O;

W、 R、 G、 R4、 R5、 R6和 R7定义如通式 (I)中所述；W, R, G, R 4 , R 5 , R 6 and R 7 are as defined in the general formula (I);

'为 F、 Cl、 Br或 I;  '为 F, Cl, Br or I;

P为羟基保护基， P优选自 CM烷基、 -C^C -d— 6烷基、 苄基、 对甲氧基苄基、 苯甲酰 基、 烯丙基、 三甲基硅基、 三乙基硅基、 叔丁基二甲基硅基或叔丁基二苯基硅基， 进一步 优选苄基、 乙酰基、 烯丙基； P is a hydroxy protecting group, and P is preferably selected from CM alkyl, -C^C-d- 6 alkyl, benzyl, p-methoxybenzyl, benzoyl, allyl, trimethylsilyl, triethyl a silyl group, a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, further preferably a benzyl group, an acetyl group or an allyl group;

Y选自 H、 d_4烷基、三氟甲磺酸基、 甲磺酰基、对甲苯磺酰基或乙酰基， 优选 H、 d_4 烷基、 甲磺酰基或乙酰基， 进一步优选甲基； Y is selected from H, d- 4 alkyl, trifluoromethanesulfonate, methylsulfonyl, p-toluenesulfonyl or acetyl, preferably H, d- 4 alkyl, methylsulfonyl or acetyl, further preferably methyl;

(1)氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-a)在强碱条件下发 生消除反应， 得到化合物VI-b); 极性非质子性溶剂可选自， 但不限于： 1 ,4-二氧六环、 Ν,Ν- 二甲基甲酰胺或 Ν,Ν-二甲基甲酰胺 /正己烷混合溶剂， 其强碱可选自， 但不限于： 1 ,8-二氮 杂二环 [5.4.0]十一碳 -7-烯 (简称 DBU)、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧化 钾、 氢氧化钠、 氢氧化锂、 氢化铝锂、 叔丁基锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基锂 或者氢氧化钡；优选条件为：氮气氛下，以 Ν,Ν-二甲基甲酰胺为溶剂， 30~40'C下化合物 (VI-a) 在氢化钠为碱的条件下发生消除反应， 搅拌反应 2~8小时；  (1) Under a nitrogen atmosphere, in a polar aprotic solvent, at a suitable temperature, the compound (VI-a) undergoes a elimination reaction under a strong base condition to obtain a compound VI-b); a polar aprotic solvent may be used. Selected from, but not limited to: 1, 4-dioxane, hydrazine, hydrazine-dimethylformamide or hydrazine, hydrazine-dimethylformamide/n-hexane mixed solvent, the strong base can be selected from, but not Limited to: 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide , lithium hydroxide, lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: 氮, Ν-dimethyl under nitrogen atmosphere The base formamide is a solvent, and the compound (VI-a) at 30-40 ° C is eliminated under the condition of sodium hydride as a base, and the reaction is stirred for 2 to 8 hours;

(2)氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-b)在氧化剂条件下 发生环氧化反应， 得到化合物 (VI-c); 极性非质子性溶剂可选自， 但不限于： 二氯甲烷、 氯 仿或 1,2-二氯乙烷， 其氧化剂可选自， 但不限于： 四氧化锇、 锇酸钾、 双氧水、 氧气、 过氧 叔丁醇、 过氧单硫酸钾、 过氧丙酮、 三氟过氧丙酮或间氯过氧苯甲酸； 优选条件为： 氮气 氛下， 以二氯甲烷为溶剂， 10~35'C下化合物 (VI-b)在以间氯过氧苯甲酸为氧化剂的条件下 发生环氧化反应， 搅拌反应 2~8小时； (2) Under a nitrogen atmosphere, in a polar aprotic solvent, at a suitable temperature, the compound (VI-b) is under oxidizing conditions. The epoxidation reaction occurs to obtain the compound (VI-c); the polar aprotic solvent may be selected from, but not limited to: dichloromethane, chloroform or 1,2-dichloroethane, the oxidizing agent may be selected from, but Not limited to: osmium tetroxide, potassium citrate, hydrogen peroxide, oxygen, peroxybutanol, potassium peroxymonosulfate, peroxyacetone, trifluoroperoxyacetone or m-chloroperoxybenzoic acid; preferred conditions are: nitrogen atmosphere Next, using dichloromethane as a solvent, the compound (VI-b) at 10~35'C is epoxidized under the condition of m-chloroperoxybenzoic acid as an oxidizing agent, and the reaction is stirred for 2-8 hours;

(3)氮气氛下， 非质子性溶剂 /水的混合溶剂中， 在适宜的温度下， 化合物 (VI-c)在酸性 条件下发生开环反应， 得到化合物 (VI-d); 非质子性溶剂 /水的混合溶剂可选， 自但不限于： 四氢呋喃 /水、 1,4-二氧六环 /水或者丙酮 /水， 酸可选自， 但不限于： 三氟乙酸、 甲磺酸、 三 氟甲磺酸、 对甲苯磺酸、 对甲苯磺酸吡啶盐、 盐酸、 硫酸或者醋酸； 优选条件为： 氮气氛 下， 以四氢呋喃 /水（V/V = 4:l) 混合溶剂为反应溶剂， 以三氟乙酸为酸， 10~40°C下化合物 (VI-c)发生开环反应， 搅拌反应 10~20小时；  (3) Under a nitrogen atmosphere, in a mixed solvent of an aprotic solvent/water, at a suitable temperature, the compound (VI-c) undergoes a ring-opening reaction under acidic conditions to obtain a compound (VI-d); aprotic A solvent/water mixed solvent may be selected, but not limited to: tetrahydrofuran/water, 1,4-dioxane/water or acetone/water, and the acid may be selected from, but not limited to: trifluoroacetic acid, methanesulfonic acid, Trifluoromethanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, hydrochloric acid, sulfuric acid or acetic acid; preferred conditions are: a mixed solvent of tetrahydrofuran/water (V/V = 4:1) as a reaction solvent under a nitrogen atmosphere Using trifluoroacetic acid as the acid, the compound (VI-c) is subjected to a ring-opening reaction at 10 to 40 ° C, and the reaction is stirred for 10 to 20 hours;

(4)氮气氛下， 质子性溶剂中， 在适宜的温度下， 化合物 (VI-d)在强碱下发生关环反应， 得到化合物 (VI-e); 质子性溶剂选自， 但不限于： 甲醇、 乙醇、叔丁醇或异丙醇， 强碱选自， 但不限于： DBU、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧化钾、 氢氧化钠、 氢 氧化锂、 氢化铝锂、 叔丁基锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基锂或者氢氧化钡； 优 选条件为： 氮气氛下， 以甲醇为溶剂， 甲醇钠作碱， 10~35°C下化合物 CVI-d)搅拌反应 1~5 小时； (4) Under a nitrogen atmosphere, in a protic solvent, at a suitable temperature, the compound (VI-d) undergoes a ring-closing reaction under a strong base to obtain a compound (VI-e) ; the protic solvent is selected from, but not limited to, : methanol, ethanol, tert-butanol or isopropanol, strong base selected from, but not limited to: DBU, sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide , lithium aluminum hydride, t-butyl lithium, t-butyl potassium, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: under nitrogen atmosphere, methanol as solvent, sodium methoxide as alkali, 10 The compound CVI-d) is stirred at ~35 ° C for 1 to 5 hours;

(5)氮气氛下， 极性非质子性溶剂中， 在适宜的温度下， 化合物 (VI-e)在强碱下发生亲 电取代反应， 得到化合物 CVI); 极性非质子性溶剂可选自， 但不限于： 1,4-二氧六环、 Ν,Ν- 二甲基甲酰胺或 Ν,Ν-二甲基甲酰胺 /正己烷混合溶剂， 其强碱可选自， 但不限于： 1,8-二氮 杂二环 [5.4.0]十一碳 -7-烯 (简称 DBU)、 氢化钠、 氢化钙、 氨基钠、 甲醇钠、 乙醇钠、 氢氧化 钾、 氢氧化钠、 氢氧化锂、 氢化铝锂、 叔丁基锂、 叔丁基钾、 叔丁醇钾、 二异丙基氨基锂 或者氢氧化钡；优选条件为：氮气氛下，以 Ν,Ν-二甲基甲酰胺为溶剂， 10~35'C下化合物 (VI-e) 搅拌反应 1~6小时；  (5) Under a nitrogen atmosphere, in a polar aprotic solvent, at a suitable temperature, the compound (VI-e) undergoes an electrophilic substitution reaction under a strong base to obtain a compound CVI); a polar aprotic solvent is optional. Since, but not limited to: 1,4-dioxane, hydrazine, hydrazine-dimethylformamide or hydrazine, hydrazine-dimethylformamide/n-hexane mixed solvent, the strong base may be selected from, but not limited to : 1,8-diazabicyclo[5.4.0]undec-7-ene (abbreviated as DBU), sodium hydride, calcium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, Lithium hydroxide, lithium aluminum hydride, t-butyl lithium, potassium t-butylate, potassium t-butoxide, lithium diisopropylamide or cesium hydroxide; preferred conditions are: Ν, Ν-dimethyl under nitrogen atmosphere The formamide is used as a solvent, and the compound (VI-e) is stirred at 10 to 35 ° C for 1 to 6 hours;

(6)质子或非质子性溶剂中， 在适宜的温度和催化剂下， 化合物 (VI)脱除保护基 P， 得 到化合物 质子或非质子性溶剂可选自， 但不限于： 甲醇、 乙醇、 异丙醇、 甲酸、 冰醋 酸、 四氢呋喃或乙腈， 催化剂可选用： 钯 /炭、 氢氧化钯 /炭、 甲酸铵和钯 /炭、 三氯化硼、 三 氟乙酸、 盐酸、 硫酸、 磷酸、 氢氧化锂、 碳酸钾-甲醇、 甲醇-甲醇钠、 氯化钯、 四正丁基氟 化铵、 氟化氢 -吡啶或氟化氢-三乙胺； 优选条件为： 以甲醇为溶剂， 10%钯 /炭作催化剂， 在 氢气存在下， 室温常压反应 1~10小时。 具体实施方式 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。 化合物的结构是通过核磁共振（NMR)和 /或质谱（MS)来确定的。 (6) In a protic or aprotic solvent, the compound (VI) is removed from the protecting group P at a suitable temperature and a catalyst to obtain a compound proton or an aprotic solvent, which may be selected from, but not limited to: methanol, ethanol, and different Propanol, formic acid, glacial acetic acid, tetrahydrofuran or acetonitrile, catalysts can be used: palladium / carbon, palladium hydroxide / carbon, ammonium formate and palladium / carbon, boron trichloride, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydroxide Lithium, potassium carbonate-methanol, methanol-methanol sodium, palladium chloride, tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine or hydrogen fluoride-triethylamine; preferred conditions are: methanol as solvent, 10% palladium/carbon as catalyst , in the presence of hydrogen, room temperature and pressure reaction for 1 to 10 hours. detailed description 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. The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).

NMR位移 （δ) 以 10- 6(ppm)的单位给出。 The NMR shift (δ) is given in units of 10 - 6 (ppm).

NMR 的测定是用 （Bruker ADVANCE III 400) 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)， 内标为四甲基硅烷（TMS)， ^MR 信息以下列格式来列表： 化学位移 （多重峰 (s,单峰； d, 双重峰； t, 三重峰； q, 四重峰； m, 多重峰 )，质子数 )。 NMR was measured using a (Bruker ADVANCE III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), internal standard. For tetramethylsilane (TMS), the ^MR information is listed in the following format: Chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) , the number of protons).

MS的测定用 （Agilent 6120B)。  For the determination of MS (Agilent 6120B).

HPLC的测定使用安捷伦 1260DAD高压液相色谱仪（Zorba x 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 HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x 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 a 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.

化合物名称使用 ChemBioDraw ultra 12工具命名。  Compound names were named using the ChemBioDraw ultra 12 tool.

无特殊说明， 氢化钠、 三苯基磷、 硫代硫酸钠、 甲醇钠、 碘、 三氟乙酸、 二环己基碳 二亚胺、邻二氯苯购买于成都市科龙化工试剂厂； 过氧苯甲酸购买于爱斯特（成都） 医药技 术有限公司； 碘乙烷、 4-二甲氨基吡啶、 氯化硼、 2-巯基吡啶 -N-氧化物、 二乙胺基三氟化 硫购买于安耐吉化学； 钯碳购买于成都聚慧化工科技有限公司； 四氢硼锂、 戴斯马丁购买 于上海泰坦科技股份有限公司； 2-碘丙烷购买于上海毕得医药科技有限公司；氯甲酸乙酯购 买于国药集团化学试剂有限公司； 醋酸碘苯购买于上海德默医药科技有限公司。  Unless otherwise specified, sodium hydride, triphenylphosphine, sodium thiosulfate, sodium methoxide, iodine, trifluoroacetic acid, dicyclohexylcarbodiimide, o-dichlorobenzene were purchased from Chengdu Kelon Chemical Reagent Factory; Benzoic acid was purchased from Ester (Chengdu) Pharmaceutical Technology Co., Ltd.; ethyl iodide, 4-dimethylaminopyridine, boron chloride, 2-mercaptopyridine-N-oxide, diethylaminosulfur trifluoride purchased from An Naiji Chemical; Palladium Carbon purchased from Chengdu Juhui Chemical Technology Co., Ltd.; Lithium tetrahydroborate, Days Martin purchased from Shanghai Titan Technology Co., Ltd.; 2-Iodopropane purchased from Shanghai Bied Pharmaceutical Technology Co., Ltd.; Ethyl ester was purchased from Sinopharm Chemical Reagent Co., Ltd.; iodobenzene acetate was purchased from Shanghai Demer Pharmaceutical Technology Co., Ltd.

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 2L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 2 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， 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。  Room temperature is the optimum reaction temperature, which is 20 ° C ~ 30 ° C.

Bn: 苄基；  Bn: benzyl;

Et: 乙基；  Et: ethyl;

Ac: 乙酰基；  Ac: acetyl group;

Me: 甲基。 中间体 1 : Me: methyl. Intermediate 1:

(l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1] 辛烷 -1-醇 （中间体 1)  (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6 , 8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 1)

(l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo

[3. [3.

Figure imgf000058_0001
Figure imgf000058_0001

第一步： （2S,3R,4S,5S,6S)-3,4,5-三苄氧基 -2-(4-氯 -3-(4-乙氧基苯基)苯基) -6- (碘甲基) -2- 甲氧基-四氢吡喃 （IB)  First step: (2S, 3R, 4S, 5S, 6S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6 - (iodomethyl)-2-methoxy-tetrahydropyran (IB)

(2S,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(iodomethyl) -2-methoxytetrahydro-2H-pyra  (2S,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(iodomethyl)-2-methoxytetrahydro- 2H-pyra

Figure imgf000058_0002
Figure imgf000058_0002

将甲苯（100 mL)加入（(2R,3R,4S,5R,6S)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-乙氧基苄基) 苯基) -6-甲氧基四氢 -2H-吡喃 -2-基)甲醇 1A (10.00 g, 14.10 mmol, 上海喀露蓝科技有限公 司）、 三苯基磷（7.40 g, 28.20 mmol)和咪唑（4.1 1 g, 60.50 mmol) 的混合物中， 再加入碘 (7.16 g, 28.20 mmol), 70。C下搅拌反应 3小时。 将混合物用乙酸乙酯 （90 mL)稀释， 有机 相依次用硫代硫酸钠（60 mL, 10%)和饱和食盐水（60 mL)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用柱层析分离纯化 (乙酸乙酯： 正己烷 = 1 :30) , 得淡黄色糖浆物 (2S,3R,4S,5S,6S)-3,4,5-三苄氧基 -2-(4-氯 -3-(4-乙氧基苯基)苯基) -6- (碘甲基) -2-甲氧基-四氢吡 喃 lB (9.60 g,产率 83%)。  Add toluene (100 mL) to ((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxybenzyl) Base) phenyl)-6-methoxytetrahydro-2H-pyran-2-yl)methanol 1A (10.00 g, 14.10 mmol, Shanghai Karlu Blue Technology Co., Ltd.), triphenylphosphine (7.40 g, 28.20 In a mixture of mmol and imidazole (4.1 1 g, 60.50 mmol), additional iodine (7.16 g, 28.20 mmol), 70 was added. The reaction was stirred at C for 3 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. . The residue was purified by column chromatography (ethyl acetate:hexane = 1 : 30) to give pale yellow syrup (2S,3R,4S,5S,6S)-3,4,5-tribenzyloxy-2 -(4-Chloro-3-(4-ethoxyphenyl)phenyl)-6-(iodomethyl)-2-methoxy-tetrahydropyran 1B (9.60 g, yield 83%).

¾ NMR(400 MHz): 57.20-7.40(m, 16H), 7.00-7.18(m, 4H), 6.76(d, 2H), 4.74-4.99(m, 4H), 4.49(d, IH), 3.86-4.20(m, 6H), 3.53-3.59(m, 3H), 3.30-3.34(m, 2H), 3.08(s, 3H), 1.39(t, 3H)。 第二步： （2S,3R,4S,5S)-3,4,5-三苄氧基 -2-(4-氯 -3-(4-乙氧基苯基)苯基) -2-甲氧基-四氢吡 喃 -6-甲叉基-四氢吡喃 （1C) 3⁄4 NMR (400 MHz): 57.20-7.40 (m, 16H), 7.00-7.18 (m, 4H), 6.76 (d, 2H), 4.74-4.99 (m, 4H), 4.49(d, IH), 3.86-4.20 (m, 6H), 3.53-3.59 (m, 3H), 3.30-3.34 (m, 2H), 3.08 (s, 3H), 1.39 (t, 3H). Second step: (2S, 3R, 4S, 5S)-3,4,5-tribenzyloxy-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-2-methyl Oxy-tetrahydropyran-6-methylene-tetrahydropyran (1C)

(2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-methoxy-6- methylenetetrahydro-2H-pyran  (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-methoxy-6- methylenetetrahydro-2H-pyran

Figure imgf000059_0001
Figure imgf000059_0001

将 (2S,3R,4S,5S,6S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基苯基)苯基) -6- (碘甲基) -2-甲 氧基-四氢吡喃 1B (3.85 g, 4.70 mmol)溶于 Ν,Ν-二甲基甲酰胺 （30 mL) 中， 搅拌均匀， 加 入氢化钠 （0.23 g, 9.40 mmol)。氮气氛下，在 30°C下搅拌反应 3小时。用饱和氯化铵溶液（60 mL)稀释反应液， 乙酸乙酯 （100 mL X 3)萃取， 有机相用水（100 mL)洗涤， 无水硫酸钠 干燥， 过滤， 将滤液减压浓缩。 残留物用柱层析分离纯化（乙酸乙酯： 正己烷 = 1 :20), 得 淡黄色糖浆物 (2S,3R,4S,5S 3,4,5-三苄氧基 -2-(4-氯 -3-(4-乙氧基苯基)苯基) -2-甲氧基-四氢吡 喃 -6-甲叉基-四氢吡喃 1C (3.00 g,产率 90%)。 (2S,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6 - (Iodomethyl)-2-methoxy-tetrahydropyran 1B (3.85 g, 4.70 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (30 mL), stirred well, sodium hydride (0.23) g, 9.40 mmol). The reaction was stirred at 30 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was diluted with saturated ammonium chloride solution (60 mL), and extracted (100 mL X 3), the organic phase washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and ethyl acetate. The residue was purified by column chromatography (ethyl acetate:hexane = 1 : 20) to afford pale yellow syrup (2S,3R,4S,5S 3,4,5-tribenzyloxy-2-(4- Chloro-3-(4-ethoxyphenyl)phenyl)-2-methoxy-tetrahydropyran-6-methylidene-tetrahydropyran 1C (3.00 g, yield 90%).

¾ NMR(400 MHz): δ 7.16-7.59(m, 16H), 7.05(d, 2H), 6.9 l(d, 2H), 6.76(d, 2H), 4.66-4.92(m, 6H), 4.36(d, IH), 4.07(d, 2H), 3.91-3.97(m, 5H), 3.73(d, IH), 3.01(s, 3H), 1.38(t, 3H)。  3⁄4 NMR (400 MHz): δ 7.16-7.59 (m, 16H), 7.05 (d, 2H), 6.9 l (d, 2H), 6.76 (d, 2H), 4.66-4.92 (m, 6H), 4.36 ( d, IH), 4.07 (d, 2H), 3.91-3.97 (m, 5H), 3.73 (d, IH), 3.01 (s, 3H), 1.38 (t, 3H).

第三步： （5S,6R,7R,8S)-6,7,8-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -5-甲氧基 -1,4- 二氧螺 [2.5]辛烷（1D)  The third step: (5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) 5-methoxy-1,4-dioxo[2.5]octane (1D)

(5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5-methoxy-l,4- dioxaspiro[2.5]octane  (5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5-methoxy-l,4-dioxaspiro[2.5] Octane

Figure imgf000059_0002
Figure imgf000059_0002

将 (2S,3R,4S,5S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基苯基)苯基) -2-甲氧基-四氢吡喃 -6-甲叉基-四氢吡喃 1C (0.50 g, 0.71 mmol)溶于二氯甲烷（6 mL) 中， 搅拌均匀， 加入碳酸 氢钠溶液（2 mL, 0.5 M)和间氯过氧苯甲酸（0.25 g, 1.42 mmol), 室温下搅拌反应 4小时。 向反应液中加入二氯甲烷（10 mL)， 分液， 水相用二氯甲烷（50 mL x 3)萃取， 合并有机相 并依次用氢氧化钠溶液（50 mL, 1 M)和水（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 将滤液 减压浓缩， 得到淡黄色糖浆物 (5S,6RJR,8S)-6,7,8-三 ( 基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯 基) -5-甲氧基 -1,4-二氧螺 [2.5]辛烷 1D (0.40 g,粗产物)。 (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxyphenyl)phenyl)-2-yl Oxy-tetrahydropyran-6-methylidene-tetrahydropyran 1C (0.50 g, 0.71 mmol) was dissolved in dichloromethane (6 mL), stirred well, and sodium hydrogen carbonate solution (2 mL, 0.5 M) and m-chloroperoxybenzoic acid (0.25 g, 1.42 mmol) were stirred at room temperature for 4 hours. Dichloromethane (10 mL) was added to the reaction mixture, and the mixture was evaporated. mjjjjjjjjjjjjjjjj Washed with 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give pale yellow syrup (5S,6RJR,8S)-6,7,8-tris(yloxy)-5-(4- Chloro-3-(4-ethoxybenzyl)benzene -5-Methoxy-1,4-dioxospiro[2.5]octane 1D (0.40 g, crude).

第四步： （2R,3S,4S)-2,3,4-三苄氧基 -1-(4-氯 -3-(4-乙氧基苯基)苯基) -6-羟基己烷基 -1 酮 (1E)  Step 4: (2R,3S,4S)-2,3,4-Tribenzyloxy-1-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6-hydroxyhexane Ketone-1 (1E)

(2R,3S,4S)-2,3,4-tris(benzyloxy)-l-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-hydroxyhexane-l  (2R,3S,4S)-2,3,4-tris(benzyloxy)-l-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-hydroxyhexane-l

Figure imgf000060_0001
Figure imgf000060_0001

将上步粗产物 (5S,6R,7R,8S)-6,7,8-三 (苄氧基) -5-(4-氯 -3-(4-乙氧苄基)苯基) -5-甲氧基 -1,4-二氧螺 [2.5]辛烷 1D溶于四氢呋喃和水的混合溶剂 （20 mL, V/V=4: l) 中，搅拌均匀，加 入三氟乙酸 （0.06 g, 0.56 mmol),在 30。C下搅拌反应过夜。反应液用饱和碳酸氢钠溶液（30 mL)稀释， 乙酸乙酯 （50 mL x 3)萃取。 有机相用水（50mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用柱层析分离纯化（乙酸乙酯： 正己烷 = 1 :5)， 得到淡黄色 糖浆物 (2R,3S,4S)-2,3,4-三苄氧基 -1-(4-氯 -3-(4-乙氧基苯基)苯基) -6-羟基己烷基 -1,5-二酮 1E (0.29 g, 两步产率 60%)。  The crude product (5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-5 -Methoxy-1,4-dioxospiro[2.5]octane 1D is dissolved in a mixed solvent of tetrahydrofuran and water (20 mL, V/V = 4:1), stirred well, and added trifluoroacetic acid (0.06 g) , 0.56 mmol), at 30. The reaction was stirred overnight at C. The reaction mixture was diluted with aq. sodium hydrogen sulfate (30 mL). The organic phase was washed with water (50 mL EtOAc) The residue was purified by column chromatography (ethyl acetate:hexane = 1 : 5) to afford pale yellow syrup (2R,3S,4S)-2,3,4-tribenzyloxy-1-(4- Chloro-3-(4-ethoxyphenyl)phenyl)-6-hydroxyhexane-l,5-dione 1E (0.29 g, 60% yield in two steps).

¾ NMR(400 MHz): δ 7.16-7.26(m, 16H), 6.97(d, 4H), 6.76(d, 2H), 4.76(d, 1H), 4.55(d, 2H): 4.30-4.41(m, 5H), 4.22(t, 1H), 4.10-4.22(m, 2H), 3.93-4.01(m, 4H), 1.36(t, 3H)。 3⁄4 NMR (400 MHz): δ 7.16-7.26 (m, 16H), 6.97 (d, 4H), 6.76 (d, 2H), 4.76 (d, 1H), 4.55 (d, 2H) : 4.30-4.41 (m) 5H), 4.22(t, 1H), 4.10-4.22(m, 2H), 3.93-4.01(m, 4H), 1.36(t, 3H).

第五步： （lS,2S,3S,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基)苯基) -6,8-二氧杂二 环 [3.2.1]辛烷 -1-醇（中间体 1)  Step 5: (lS, 2S, 3S, 4R, 5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6 ,8-Dioxabicyclo[3.2.1]octane-1-ol (Intermediate 1)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2.1]octan-l-ol  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2.1] Octan-l-ol

Figure imgf000060_0002
Figure imgf000060_0002

将 (2R,3S,4S)-2,3,4-三苄氧基 -1-(4-氯 -3-(4-乙氧基苯基)苯基) -6-羟基己烷基 -1,5-二酮 3d (300mg, 0.43mmol), 溶于甲醇 （30 mL) 中， 滴加甲醇钠溶液（0.65 mmol甲醇钠溶于 5 mL 甲醇中，科龙)， 氮气氛， 室温下搅拌反应 2个小时。 反应液用饱和氯化铵溶液（50 mL)稀 释， 二氯甲烷（60 mL x 3)萃取。 有机相用水（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩。 残留物用柱层析分离纯化 （乙酸乙酯： 正己烷 = 1 : 10) , 得到白色固体 (lS,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苯基)苯基) -6,8-二氧杂二环 [3.2.1]辛 烷 -1-醇 (中间体 1) (0.18 g,产率 60%)。 (2R,3S,4S)-2,3,4-Tribenzyloxy-1-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6-hydroxyhexaneyl-1 , 5-dione 3d (300mg, 0.43mmol), dissolved in methanol (30mL), added sodium methoxide solution (0.65mmol sodium methoxide dissolved in 5mL methanol, Kelon), nitrogen atmosphere, stirring at room temperature 2 hours. The reaction solution was diluted with a saturated aqueous solution of ammonium chloride (50 mL) and then evaporated. The organic phase was washed with water (50 mL) The residue was purified by column chromatography (ethyl acetate: hexane = 1 : 10) to give white solid (l, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy) - 5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6,8-dioxabicyclo[3.2.1] octane Alkan-1-ol (Intermediate 1) (0.18 g, yield 60%).

¾ NMR(400 MHz): δ 7.14-7.37(m, 16H), 7.08(d, 2H), 6.88(d, 2H), 6.77(d, 2H), 4.80-5.01(m, 4H), 4.43(d, IH), 4.30(d, IH), 3.89-4.03(m, 7H), 3.68(t, IH), 3.54(t, IH), 1.41(t, 3H)。  3⁄4 NMR (400 MHz): δ 7.14-7.37 (m, 16H), 7.08 (d, 2H), 6.88 (d, 2H), 6.77 (d, 2H), 4.80-5.01 (m, 4H), 4.43 (d , IH), 4.30 (d, IH), 3.89-4.03 (m, 7H), 3.68 (t, IH), 3.54 (t, IH), 1.41 (t, 3H).

中间体 2  Intermediate 2

(lS,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1] 辛烷 -1-醇 （中间体 2)  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6, 8-dioxobicyclo[3.2.1]octane-1-ol (intermediate 2)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo -l-ol  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo -l-ol

Figure imgf000061_0001
Figure imgf000061_0001

将 ((2R,3R,4S,5R,6S)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-乙氧基 -3-氟代苄基)苯基) -6-甲氧 基四氢 -2H-吡喃 -2-基)甲醇 2A (10.00 g, 13.8 mmol, 上海喀露蓝科技有限公司 )、 三苯基磷 (7.23 g, 27.6 mmol)和咪唑 (4.70 g, 69.0 mmol)溶于甲苯 (100 mL)中， 加入碘 (7.01 g, 27.6 mmol), 在 70°C搅拌反应 3小时。 反应液用乙酸乙酯 （90 mL)稀释， 有机相依次用 10%的 硫代硫酸钠 （60 mL)和饱和食盐水（60 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残 留物用柱层析分离纯化 （乙酸乙酯 /正己烷 = 1 :30) , 得到淡黄色糖浆物 (2S,3R,4S,5S,6S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基苄基)苯基) -6- (碘代甲基) -2-甲氧基 四氢 -2H-吡喃 2B (10.0 g,产率 85%)。 ((2R,3R,4S,5R,6S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6-methoxytetrahydro-2H-pyran-2-yl)methanol 2A (10.00 g, 13.8 mmol, Shanghai Karlu Blue Technology Co., Ltd.), triphenylphosphine (7.23 g, 27.6 mmol) And imidazole (4.70 g, 69.0 mmol) was dissolved in toluene (100 mL), iodine (7.01 g, 27.6 mmol) was added, and the reaction was stirred at 70 ° C for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Residual The residue was purified by column chromatography (ethyl acetate / n-hexane = 1 : 30) to give pale yellow syrup (2S,3R,4S,5S,6S)-3,4,5-tris (benzyloxy) -2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6-(iodomethyl)-2-methoxytetrahydro-2H-pyran 2B (10.0 g, Yield 85%).

第二步：（2S,3R,4S,5S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基 -3-氟苯基)苯基) -2-甲氧基 -6-甲叉基四氢 -2H-吡喃 (2C)  Second step: (2S, 3R, 4S, 5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxy-3-fluorophenyl) Phenyl)-2-methoxy-6-methylidenetetrahydro-2H-pyran (2C)

(2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-2-methoxy -6-methylenetetrahydro-2H-pyr  (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-2-methoxy-6-methylenetetrahydro- 2H-pyr

Figure imgf000062_0001
Figure imgf000062_0001

将 (2S,3R,4S,5S,6S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基苄基)苯基) -6- (碘代甲基) -2- 甲氧基四氢 -2H-吡喃 2B (9.5 0 g, 11.4 mmol)溶于 Ν,Ν-二甲基甲酰胺 （100 mL) 中， 搅拌均 匀， 加入氢化钠 （0.55 g, 22.8 mmol)， 氮气氛， 在 30°C下搅拌反应 3小时。 反应液用饱和氯 化铵溶液（100 mL)稀释， 乙酸乙酯 （100 mL x 3)萃取。有机相用水（80 mL x 3)洗涤， 无 水硫酸钠干燥， 过滤， 减压浓缩。 残留物用柱层析分离纯化（乙酸乙酯 /正己烷 = 1:20)， 得 淡黄色糖浆物 (2S,3R,4S,5S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基 -3-氟苯基)苯基) -2-甲氧 基 -6-甲叉基四氢 -2H-吡喃 2C (6.40 g, 80%)。  (2S,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6 - (Iodomethyl)-2-methoxytetrahydro-2H-pyran 2B (9.50 g, 11.4 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (100 mL), stirred well, Sodium hydride (0.55 g, 22.8 mmol) was stirred at 30 ° C for 3 hours under nitrogen. The reaction solution was diluted with a saturated aqueous solution of ammonium chloride (100 mL) and ethyl acetate (100 mL? The organic phase was washed with water (80 mL EtOAc)EtOAc. The residue was purified by column chromatography (ethyl acetate / hexane = 1:20) to afford pale yellow syrup (2S,3R,4S,5S)-3,4,5-tris(benzyloxy) 2-(4-Chloro-3-(4-ethoxy-3-fluorophenyl)phenyl)-2-methoxy-6-methylidenetetrahydro-2H-pyran 2C (6.40 g, 80 %).

¾ NMR (400 MHz, CDC13): δ 7.40 -7.25 (m, 13H), 7.21 -7.13 (m, 3H), 6.92 (d, 2H), 6.82 (m, 3H), 4.84 -4.65 (m, 6H), 4.39 (d, IH), 4.11 -3.99 (m, 4H), 3.93 (m, 3H), 3.73 (d, IH), 3.02 (s, 3H), 1.42 (d, 3H 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.40 -7.25 (m, 13H), 7.21 -7.13 (m, 3H), 6.92 (d, 2H), 6.82 (m, 3H), 4.84 -4.65 (m, 6H) ), 4.39 (d, IH), 4.11 -3.99 (m, 4H), 3.93 (m, 3H), 3.73 (d, IH), 3.02 (s, 3H), 1.42 (d, 3H)

第三步：（5S,6RJR,8S)-6,7,8-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -5-甲氧基 -1,4-二氧螺环 [2.5]辛烷（2D)  Third step: (5S,6RJR,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl -5-methoxy-1,4-dioxospiro[2.5]octane (2D)

(5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-5-methoxy -l,4-dioxaspiro[2.5]octane  (5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-5-methoxy -l,4- Dioxaspiro[2.5]octane

Figure imgf000062_0002
Figure imgf000062_0002

将 (2S,3R,4S,5S)-3,4,5-三 (苄基氧基) -2-(4-氯 -3-(4-乙氧基 -3-氟苯基)苯基) -2-甲氧基 -6-甲 叉基四氢 -2H-吡喃 2C (6.40 g, 9.0 mmol)溶于二氯甲烷（60 mL)， 搅拌均匀， 加入碳酸氢钠 溶液（10 mL, 0.5 M)及间氯过氧苯甲酸 （3.10 g, 18.0 mmol)， 室温下搅拌反应 2.5小时。 反 应液用二氯甲烷（60 mL)稀释， 水相用二氯甲烷（60 mL x 3;»萃取， 合并有机相。 有机相 依次用的氢氧化钠 （50 mL, 1 M)和水（50 mL) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 得到淡黄色糖浆物 (5S,6R,7R,8S)-6,7,8-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -5- 甲氧基 -1,4-二氧螺环 [2.5]辛烷 2D (7.10 g,粗产物)， 直接用于下一步反应。 (2S,3R,4S,5S)-3,4,5-tris(benzyloxy)-2-(4-chloro-3-(4-ethoxy-3-fluorophenyl)phenyl) 2-methoxy-6-methylidenetetrahydro-2H-pyran 2C (6.40 g, 9.0 mmol) was dissolved in dichloromethane (60 mL), stirred well, and sodium hydrogen carbonate solution (10 mL, 0.5 M) and m-chloroperoxybenzoic acid (3.10 g, 18.0 mmol) were stirred at room temperature for 2.5 hours. Counter The solution was diluted with dichloromethane (60 mL) and the aqueous phase was extracted with dichloromethane (60 mL×3;», and organic phase was combined. Organic phase sodium hydroxide (50 mL, 1 M) and water (50) (mL) Washed, dried over anhydrous sodium sulfate, filtered, and evaporated, evaporated, evaporated.. Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-5-methoxy-1,4-dioxospiro[2.5]octane 2D (7.10 g, crude), directly Used for the next reaction.

第四步： （2R,3S,4S)-2,3,4-三 (苄基氧基) -1-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6-羟基己烷 基 -1,5-二酮 (2E)  Step 4: (2R,3S,4S)-2,3,4-Tris(benzyloxy)-1-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl -6-Hydroxyhexyl-1,5-dione (2E)

(2R,3S,4S)-2,3,4-tris(benzyloxy)-l -(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6- hydroxyhexane- 1 ,5-dione  (2R,3S,4S)-2,3,4-tris(benzyloxy)-l-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6- hydroxyhexane- 1 ,5-dione

Figure imgf000063_0001
Figure imgf000063_0001

将上步粗产物 (5S,6R,7R,8S)-6,7,8-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -5- 甲氧基 -1,4-二氧螺环 [2.5]辛烷 2D溶于四氢呋喃和水（60 mL, V/V=4: l) 的混合溶液中，搅拌 均匀，加入三氟乙酸 （0.57 g, 5 mmol),在 30°C下反应过夜。反应液用饱和碳酸氢钠溶液（50 mL)稀释， 乙酸乙酯 （80 mL x 3)萃取。 有机相用水（80 mL x 3)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留物用柱层析分离纯化（乙酸乙酯 /正己烷 = 1:6), 得到淡黄色糖浆物 (2R,3S,4S)-2,3,4-三 (苄基氧基) -1-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6-羟基己烷基 -1,5-二酮 2E (3.50 g, 两步产率 60%)。  The crude product (5S,6R,7R,8S)-6,7,8-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-5-methoxy-1,4-dioxospiro[2.5]octane 2D is dissolved in a mixed solution of tetrahydrofuran and water (60 mL, V/V = 4:1), and stirred well. Trifluoroacetic acid (0.57 g, 5 mmol) was added and the reaction was carried out at 30 ° C overnight. The reaction mixture was diluted with aq. sodium hydrogen sulfate (50 mL). The organic phase was washed with EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography (ethyl acetate /hexanehexane = 1: 6) to afford pale yellow syrup (2R,3S,4S)-2,3,4-tris(benzyloxy)-1- (4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6-hydroxyhexane-l,5-dione 2E (3.50 g, a two-step yield of 60%).

^ NMR (400 MHz, CDC13): δ 7.39 -7.11 (m, 16H), 6.98 (d, 2H), 6.83 -6.72 (m, 3H), 4.76 ( 1H), 4.60 (d, 1H), 4.45 -4.30 (m, 6H), 4.13 (q, 2H), 4.00 (m, 3H), 3.91 (s, 2H), 1.41 (t, 3H)。 ^ NMR (400 MHz, CDC1 3 ): δ 7.39 -7.11 (m, 16H), 6.98 (d, 2H), 6.83 -6.72 (m, 3H), 4.76 ( 1H), 4.60 (d, 1H), 4.45 - 4.30 (m, 6H), 4.13 (q, 2H), 4.00 (m, 3H), 3.91 (s, 2H), 1.41 (t, 3H).

第五步： （lS,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6,8- 二氧杂二环 [3.2.1]辛烷 -1-醇 (中间体 2)  Step 5: (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6,8-dioxabicyclo[3.2.1]octane-1-ol (intermediate 2)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8- dioxabicyclo[3.2. ljoctan- 1 -ol  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8- dioxabicyclo[ 3.2. ljoctan- 1 -ol

Figure imgf000063_0002
Figure imgf000063_0002

将 (2R,3S,4S)-2,3,4-三 (苄基氧基) -l-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6-羟基己烷基 -1,5- 二酮 2E (3.50 g, 4.70 mmol)溶于甲醇 （200 mL),滴加甲醇钠溶液（7.1 mmol甲醇钠溶于 20 mL甲醇中 )， 氮气氛， 室温下搅拌反应 2小时。 反应液用饱和氯化铵溶液（150 mL)稀释， 二氯甲垸（80 mL x 3)萃取。 有机相用水（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓 缩。 残留物用柱层析分离纯化 （乙酸乙酯 /正己垸 = 1 : 10)， 得到白色固体 (l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6,8-二氧杂二环 [3.2.1]辛垸 -1-醇 (中间体 2) (1.50 g,产率 50%)。 (2R,3S,4S)-2,3,4-Tris(benzyloxy)-l-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6 -Hydroxyhexyl-1,5-dione 2E (3.50 g, 4.70 mmol) dissolved in methanol (200 mL), sodium methoxide solution (7.1 mmol of sodium methoxide in 20 mL of methanol), nitrogen atmosphere, room temperature The reaction was stirred for 2 hours. The reaction solution was diluted with a saturated ammonium chloride solution (150 mL). Extraction of methylene chloride (80 mL x 3). The organic phase was washed with water (50 mL) The residue was purified by column chromatography (ethyl acetate / hexanes = 1 : 10) to afford white solid (1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy) -5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octan-1-ol (intermediate) 2) (1.50 g, yield 50%).

lH NMR (400 MHz, CDC13): δ 7.39 -7.23 (m, 13H), 7.16 (m, 3H), 6.90 -6.74 (m, 5H), 4.85 (m, 4H)， 4.42 (d, IH), 4.29 (d, IH), 4.02 (m, 4H), 3.91 -3.83 (m, 3H), 3.65 (d, IH), 3.53 -3.46 (m, IH), 1.41 (t, 3H)。 lH NMR (400 MHz, CDC1 3 ): δ 7.39 -7.23 (m, 13H), 7.16 (m, 3H), 6.90 -6.74 (m, 5H), 4.85 (m, 4H), 4.42 (d, IH), 4.29 (d, IH), 4.02 (m, 4H), 3.91 -3.83 (m, 3H), 3.65 (d, IH), 3.53 - 3.46 (m, IH), 1.41 (t, 3H).

中间体 3  Intermediate 3

(l S,2S,3S,4R,5S)-2,3，4-三 (苄氧基) -5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) -6,8-二 氧二环 [3.2.1 ]辛烷 -1-醇 (中间体 3)  (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)) Benzyl)phenyl)-6,8-dioxobicyclo[3.2.1 ]octane-1-ol (Intermediate 3)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) - -dioxabicyclo[3.2.1]octan-l-ol  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) - -dioxabicyclo[3.2. 1]octan-l-ol

Figure imgf000064_0001
Figure imgf000064_0001

第一步： 2-环丙基氧基乙醇 (3B)  First step: 2-cyclopropyloxyethanol (3B)

2-cyclopropoxyethanol 将镁粉（8.9 g, 0.36 mol)与催化量单质碘混合，在氮气氛、 40~55°C下，将二溴乙烷（46 g, 0.24 mol) 的四氢呋喃 （200 mL)溶液加入混合物中。将 2-(2-溴乙基 )-1,3-二氧戊环 3A (10 g, 0.056 mol) 的四氢呋喃 （75 mL)溶液加入反应中， 45°C反应 16小时。 用氯化铵水溶液 (200 mL)猝灭反应， 二氯甲烷（100 mL x 2)萃取， 有机相用饱和氯化钠溶液（100 mL x 2) 洗涤， 无水硫酸镁干燥， 过滤， 减压浓缩。 残留物用柱层析分离纯化（石油醚 /乙酸乙酯 = 10: 1), 得到淡黄色油状物 2-环丙基氧基乙醇 3B(1.08 g,产率 19%)。 2-cyclopropoxyethanol Mix magnesium powder (8.9 g, 0.36 mol) with catalytic amount of elemental iodine, and add dibromoethane (46 g, 0.24 mol) in tetrahydrofuran (200 mL) to the mixture under nitrogen atmosphere at 40-55 °C. . A solution of 2-(2-bromoethyl)-1,3-dioxolane 3A (10 g, 0.056 mol) in tetrahydrofuran (75 mL) was added to the reaction, which was reacted at 45 ° C for 16 hours. The reaction was quenched with aqueous EtOAc (EtOAc) (EtOAc (EtOAc) concentrate. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc

第二步： 2-环丙基氧基乙基 4-甲基苯磺酸酯 (3C)  Second step: 2-cyclopropyloxyethyl 4-methylbenzenesulfonate (3C)

2-cyclopropoxyethyl 4-methylbenzenesulfonate

Figure imgf000065_0001
2-cyclopropoxyethyl 4-methylbenzenesulfonate
Figure imgf000065_0001

将 2-环丙基氧基乙醇 3B (500 mg, 4.9 mmol)加入氢氧化钠 （588 mg, 14.7 mmol)水溶 液（4 mL) 与四氢呋喃 （7 mL) 的混合溶液中，冷却至 0°C，将对甲苯磺酰氯 （1 g, 5.4 mmol) 的四氢呋喃 （4 mL)溶液滴加至混合物中， 0°C下反应 6 小时。 将反应液用乙酸乙酯（ 10 mL x 2)萃取， 有机相用饱和氯化钠溶液（10 mL x 2)洗涤， 无水硫酸钠干燥， 过滤， 减压 浓缩。残留物用柱层析分离纯化（石油醚 /乙酸乙酯 = 30: 1)， 得到无色油状物 2-环丙基氧基 乙基 4-甲基苯磺酸酯 3C(540 mg,产率 43%)。  2-Cyclopropyloxyethanol 3B (500 mg, 4.9 mmol) was added to a mixture of sodium hydroxide (588 mg, 14.7 mmol) (4 mL) and tetrahydrofuran (7 mL) and cooled to 0 ° C, A solution of p-toluenesulfonyl chloride (1 g, 5.4 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture, which was reacted at 0 ° C for 6 hours. The reaction mixture was extracted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography (EtOAc /EtOAcEtOAcEtOAc 43%).

¾ NMR (400 MHz, CDC13): δ 7.80-7.78 (d, 2H), 7.33-7.35 (d, 2H), 4.16-4.14 (t, 2H), 3.69-3.66 (t, 3H), 3.27-3.22 (m, 1H), 2.45 (s, 3H), 0.50-0.48 (m, 2H), 0.43-0.42 (m, 2H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.80-7.78 (d, 2H), 7.33-7.35 (d, 2H), 4.16-4.14 (t, 2H), 3.69-3.66 (t, 3H), 3.27-3.22 (m, 1H), 2.45 (s, 3H), 0.50-0.48 (m, 2H), 0.43-0.42 (m, 2H).

第三步： 4-溴 -1-氯 -2-(4-(2-环丙基氧基乙氧基)苄基)苯 (3E)  The third step: 4-bromo-1-chloro-2-(4-(2-cyclopropyloxyethoxy)benzyl)benzene (3E)

4-bromo- 1 -chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene

Figure imgf000065_0002
4-bromo- 1 -chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene
Figure imgf000065_0002

将 4-(5-溴 -2-氯苄基)苯酚 3D(500 mg, 1.69 mmol) 与碳酸铯 (1.1 g, 3.38 mmol) 混合物 溶于 Ν,Ν-二甲基甲酰胺（3 mL) 中， 室温下搅拌反应 0.5小时。 将 2-环丙基氧基乙基 4-甲 基苯磺酸酯 3C(432 mg, 1.69 mmol)加入反应中， 室温搅拌反应过夜。 用水（3 mL)稀释反 应液， 乙酸乙酯 （5 mL X 2)萃取， 有机相分别用水 (5 mL x 1)、 饱和氯化钠溶液 (5 mL x 1) 洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留物用柱层析分离纯化（石油醚 /乙酸乙酯 = 20: 1)，得到无色油状物 4-溴 -1-氯 -2-(4-(2-环丙基氧基乙氧基)苄基)苯 3E(520 mg,产率 81%)。  Mixture of 4-(5-bromo-2-chlorobenzyl)phenol 3D (500 mg, 1.69 mmol) with cesium carbonate (1.1 g, 3.38 mmol) in hydrazine, hydrazine-dimethylformamide (3 mL) The reaction was stirred at room temperature for 0.5 hours. 2-Cyclopropyloxyethyl 4-methylbenzenesulfonate 3C (432 mg, 1.69 mmol) was added to the reaction, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (3 mL), EtOAc (EtOAc (EtOAc) Filter and concentrate under reduced pressure. The residue was purified by column chromatography (EtOAc /EtOAcEtOAcEtOAcEtOAc Benzyl)benzene 3E (520 mg, yield 81%).

¾ NMR (400 MHz, CDC13): δ 7.27-7.19 (m, 3H), 7.08-7.06 (m, 2H), 6.86-6.84 (m, 2H), 4.09-4.06 (t, 2H), 3.97 (s, 2H), 3.85-3.83 (t, 2H), 3.40-3.37 (m, 1H), 0.64-0.60 (m, 2H), 0.50-0.45 (m, 2H)。 第四步： （2S,3R,4R,5R)-2,3,4,6-四 (苄基氧基) - 1 -(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯 基)己烷 -1,5-二醇 (3G) 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.27-7.19 (m, 3H), 7.08-7.06 (m, 2H), 6.86-6.84 (m, 2H), 4.09-4.06 (t, 2H), 3.97 (s , 2H), 3.85-3.83 (t, 2H), 3.40-3.37 (m, 1H), 0.64-0.60 (m, 2H), 0.50-0.45 (m, 2H). Fourth step: (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-1 -(4-chloro-3-(4-(2-cyclopropyloxy) Ethoxy)benzyl)phenyl)hexane-1,5-diol (3G)

(2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-l-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl) phenyl)hexane- 1 ,5-diol  (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-l-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl) phenyl)hexane- 1 ,5- Diol

Figure imgf000066_0001
Figure imgf000066_0001

将 4-溴 -1-氯 -2-(4-(2-环丙基氧基乙氧基)苄基)苯 3E的四氢呋喃溶液（2 mol/L, 5 mL)加 入到镁条（1.21 g, 50.5 mmol) 与 2粒碘单质混合物中， 加热引发反应。 继续滴加 4-溴 -1-氯 -2-(4-(2-环丙基氧基乙氧基)苄基)苯 3E的四氢呋喃溶液（2 mol/L, 35 mL), 升温至 80°C搅拌 反应 1小时。 Add 4-bromo-1-chloro-2-(4-(2-cyclopropyloxyethoxy)benzyl)benzene 3E in tetrahydrofuran (2 mol/L, 5 mL) to magnesium strip (1.21 g) , 50.5 mmol) In a mixture with two iodine simple substances, the reaction is initiated by heating. Continue to add 4-bromo-1-chloro- 2- (4-(2-cyclopropyloxyethoxy)benzyl)benzene 3E in tetrahydrofuran (2 mol / L, 35 mL), warm to 80 ° The reaction was stirred for 1 hour.

将 (3R,4S,5R,6R)-3,4,5-三 (苄基氧基) -6- ((苄基氧基)甲基)四氢 -2H-吡喃 -2-醇 3F的干燥的 四氢呋喃 （40 mL)溶液在冰浴下滴加至上述反应液中， 升温至 70°C搅拌反应 2小时。 冰浴 下用 lmol/L稀盐酸调节反应液至中性， 分液， 水相用乙酸乙酯 （40 mL X 2)萃取， 合并有 机相， 用饱和氯化钠溶液 (60 mL x l)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留物用柱 层析分离纯化（石油醚 /乙酸乙酯 = 9: 1)，得到淡黄色油状物 (2S,3R,4R,5R)-2,3,4,6-四 (苄基氧 基) -1-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基)己烷 -1,5-二醇 3G(15.2 g,产率 92%)。 (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-ol 3F A dry tetrahydrofuran (40 mL) solution was added dropwise to the above reaction mixture in an ice bath, and the mixture was warmed to 70 ° C and stirred for 2 hours. The reaction mixture was adjusted to neutral with 1 mol/L of dilute hydrochloric acid, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (40 mL X 2 ). The organic phase was combined and washed with saturated sodium chloride solution (60 mL×l). Dry over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc:EtOAc )-1-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,5-diol 3G (15.2 g, yield 92%) ).

¾ NMR (400 MHz, CDC13): δ 7.38-7.28 (m, 12H), 7.25-7.21 (m, 5H), 7.17-7.16 (d, IH), 7.11-7.02 (m, 7H), 4.58-4.51 (m, 3H), 4.46-4.36 (m, 3H), 4.29 (s, 2H), 4.07-3.90 (m, 6H), 3.80-3.78 (m, 3H), 3.75-3.74 (t, IH), 3.69-3.67 (m, IH), 3.59-3.58 (d, 2H), 3.38-3.34 (m, IH), 0.62-0.58 (m, 2H), 0.49-0.44 (m, 2H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.38-7.28 (m, 12H), 7.25-7.21 (m, 5H), 7.17-7.16 (d, IH), 7.11-7.02 (m, 7H), 4.58-4.51 (m, 3H), 4.46-4.36 (m, 3H), 4.29 (s, 2H), 4.07-3.90 (m, 6H), 3.80-3.78 (m, 3H), 3.75-3.74 (t, IH), 3.69 -3.67 (m, IH), 3.59-3.58 (d, 2H), 3.38-3.34 (m, IH), 0.62-0.58 (m, 2H), 0.49-0.44 (m, 2H).

第五步： （2S,3R,4R,5S,6R)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基) 苯基)己烷 -1,2,6-三基三乙酸酯 (3H)  Step 5: (2S, 3R, 4R, 5S, 6R)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropyloxy) Ethoxy)benzyl)phenyl)hexane-1,2,6-triyltriacetate (3H)

(2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) hexane- 1 ,2,6-triyl triacetate  (2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) hexane- 1 , 2, 6-triyl triacetate

Figure imgf000066_0002
Figure imgf000066_0002

将 (2S,3R,4R,5R)-2,3,4,6-四 (苄基氧基) -l-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基)己 烷 -1,5-二醇 3G(14.83 g, 17.6 mmol)溶于乙酸酐 （90 mL) 中， 冰浴下将对甲苯磺酸 (3.9 g, 22.9 mmol),升温至 70°C搅拌反应 2小时。将反应液加入冰水中，二氯甲烷（200 mL x 3)萃 取，有机相用饱和碳酸氢钠溶液（250 mL x 2)、水（200 mL x 2)、饱和食盐水（200 mL x 2)洗 涤， 无水硫酸钠干燥， 过滤， 浓缩得到黑色液体 (2S,3R,4R,5S,6R)-3,4,5-三 (苄基氧基) -6-(4- 氯—3-(4-(2-环丙基氧基乙氧基；)苄基；)苯基；)己烷 -1,2,6-三基三乙酸酯 3H粗品 （15.3 g), 直接 投入下一步反应。 (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)-l-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)hexane-1,5-diol 3G (14.83 g, 17.6 mmol) in acetic anhydride (90 mL), p-toluenesulfonic acid (3.9 g, 22.9 mmol) The temperature was raised to 70 ° C and the reaction was stirred for 2 hours. The reaction solution was added to ice water, extracted with dichloromethane (200 mL×3), and the organic phase was saturated sodium bicarbonate (250 mL x 2), water (200 mL x 2), brine (200 mL x 2) Wash Dry, dry anhydrous sodium sulfate, filtered, concentrated to give a black liquid (2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-( 4-(2-cyclopropyloxyethoxy;)benzyl;)phenyl;)hexane-1,2,6-triyltriacetate 3H crude (15.3 g), directly into the next reaction .

第六步： （3R,4R,5S)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) 己烷 -1,2,6-三醇 (31)  Step 6: (3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)) Benzyl)phenyl)hexane-1,2,6-triol (31)

(3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) hexane-l,2,6-triol  (3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) hexane-l,2,6-triol

Figure imgf000067_0001
Figure imgf000067_0001

冰浴下， 将碳酸钾 （7.17 g, 51.9 mmol) 加入上述粗品 (2S,3R,4R,5S,6R)-3,4,5-三 (苄基氧 基) -6-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基)己烷 -1,2,6-三基三乙酸酯 3H (15.3 g) 的 甲醇 （86 mL)溶液， 升至室温搅拌反应 2小时。 过滤除去碳酸钾， 用氯化铵稀溶液将反应 液调节至中性， 减压浓缩除去甲醇， 残余物用二氯甲烷（100 mL x 3)萃取， 有机相用饱和食 盐水（150 mL x l)洗涤，无水硫酸钠干燥， 过滤， 减压浓缩。残留物用柱层析分离纯化（石 油醚 /乙酸乙酯 = 4: 1),得到黑色液体 (3R,4R,5S)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-(2-环丙基氧 基乙氧基)苄基)苯基)己烷 -1,2,6-三醇 31(4.6 g,产率 36%)。  Potassium carbonate (7.17 g, 51.9 mmol) was added to the above crude (2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-(4-chloro- 3-(4-(2-Cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,2,6-triyltriacetate 3H (15.3 g) in methanol (86 mL) The reaction was stirred at room temperature for 2 hours. The potassium carbonate was removed by filtration, the reaction solution was adjusted to neutral with a dilute aqueous solution of ammonium chloride, and the mixture was concentrated to remove methanol. The residue was extracted with dichloromethane (100 mL x 3), and the organic phase was saturated with brine (150 mL xl) Washed, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (peel ether / ethyl acetate = 4: 1) to give a white liquid (3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4) -Chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,2,6-triol 31 (4.6 g, yield 36%).

¾ NMR(400 MHz): δ 7.15-7.37(m, 16H), 6.09-7.09(m, 4H), 6.78(d, 2H), 4.34-4.54(m, 4H), 4.22(d, IH), 4.02-4.15(m, 4H), 3.88-3.98(m, 4H), 3.68-3.82(m, 6H), 3.40-3.34(m, IH), 0.60-0.62 (m, 2H), 0.46-0.48 (m, 2H)。  3⁄4 NMR (400 MHz): δ 7.15-7.37 (m, 16H), 6.09-7.09 (m, 4H), 6.78 (d, 2H), 4.34-4.54 (m, 4H), 4.22 (d, IH), 4.02 -4.15(m, 4H), 3.88-3.98(m, 4H), 3.68-3.82(m, 6H), 3.40-3.34(m, IH), 0.60-0.62 (m, 2H), 0.46-0.48 (m, 2H).

第七步： （2S,3R,4R)-2,3,4-三 (苄氧基) -6-((四叔丁基二甲基硅烷基)氧基) -l-(4-氯 -3-(4-(2- 环丙基氧基乙氧基；)苄基；)苯基；)己烷 -1,5-二醇 (3 J)  Step 7: (2S,3R,4R)-2,3,4-Tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-l-(4-chloro- 3-(4-(2-cyclopropyloxyethoxy;)benzyl;)phenyl;)hexane-1,5-diol (3 J)

(2S,3R,4R)-2,3,4-tris(benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)hexane- 1 ,5-diol  (2S,3R,4R)-2,3,4-tris(benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl Hexane- 1 ,5-diol

Figure imgf000067_0002
Figure imgf000067_0002

将 (3R,4R,5S)-3,4,5-三 (苄基氧基) -6-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基）己烷 -1,2,6-三醇 31(4.6 g, 6.27 mmol)溶于二氯甲烷 (12 mL) 中， 加入咪唑 (0.64 g, 7.53 mmol), 冰浴下逐勺加入叔丁基二甲基氯硅 （1.13 g, 7.53 mmol),升至室温搅拌反应 3小时。将水（35 mL), 二氯甲烷（20 mL)加入反应液中， 分液， 水相用二氯甲烷（40 mL x 3;»萃取， 合并有 机相， 无水硫酸钠干燥， 过滤， 减压浓缩， 得到黑色油状液体 (2S,3R,4R 2,3,4-三 (苄氧 基 )-6- ((四叔丁基二甲基硅烷基)氧基) 氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基）己烷 -1,5-二醇 3J粗品 （5 g)， 直接进行下一步反应。 (3R,4R,5S)-3,4,5-tris(benzyloxy)-6-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl) Phenyl)hexane-1,2,6-triol 31 (4.6 g, 6.27 mmol) was dissolved in dichloromethane (12 mL), then EtOAc (0.64 g, 7. Butyldimethylsilyl chloride (1.13 g, 7.53 mmol) was stirred at room temperature for 3 hours. Water (35 mL), methylene chloride (20 mL) was added to the reaction mixture, and the mixture was separated and evaporated with methylene chloride (40 mL×3; Concentrated by pressure to obtain a black oily liquid (2S, 3R, 4R 2, 3, 4-tris (benzyloxy) -6-((Tetra-tert-butyldimethylsilyl)oxy)chloro-3-(4-( 2 -cyclopropyloxyethoxy)benzyl)phenyl)hexane-1, The crude 5-diol 3J (5 g) was directly subjected to the next reaction.

第八步： （2R,3R,4S)-2,3,4-三 (苄氧基) -6-((四叔丁基二甲基硅烷基)氧基) -1-(4-氯 -3-(4-(2- 环丙基氧基乙氧基)苄基)苯基)己烷- 1 ,5-二酮 (3K)  Step 8: (2R,3R,4S)-2,3,4-Tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-1-(4-chloro- 3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane- 1 ,5-dione (3K)

(2R,3R,4S)-2,3,4-tris(benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)hexane- 1 ,5-dione  (2R,3R,4S)-2,3,4-tris(benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-l-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl )hexane- 1 ,5-dione

Figure imgf000068_0001
Figure imgf000068_0001

将二甲基亚砜（2.79 g,35.79 mmol) 与二氯甲烷（10 mL) 混合，干冰-乙醇冷却下，滴加 三氟乙酸酐 （5.57 g, 26.55 mmol) 的二氯甲烷溶液（10 mL)， 搅拌反应 20分钟。 滴加上述 化合物 (2S,3R,4R)-2,3,4-三 (苄氧基) -6-((四叔丁基二甲基硅烷基)氧基) -1-(4-氯 -3-(4-(2-环丙基 氧基乙氧基)苄基)苯基)己烷 -1,5-二醇 3J粗品 （5 g) 的二氯甲烷（10 mL) 溶液，搅拌 1小时。 将三乙胺 （4.84 g, 47.9 mmol) 与二氯甲烷（5 mL) 的混合液滴加到反应液中，搅拌 15分钟， 升至室温搅拌反应 0.5小时。 缓慢将水（40 mL)在冰浴条件下加入反应液中， 分液， 水相 用二氯甲烷（50 mL x 2)萃取，有机相用饱和碳酸氢钠洗涤至体系为碱性，水洗一次，干燥， 过滤， 减压浓缩得到黄色油状液体 (2R,3R,4S)-2,3,4-三 (苄氧基) -6- ((四叔丁基二甲基硅烷基) 氧基)小 (4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基)己烷 -1,5-二酮 3K粗品 (5.54 g), 直接进 行下一步反应。  Mix dimethyl sulfoxide (2.79 g, 35.79 mmol) with dichloromethane (10 mL), dry ice-ethanol, and add trifluoroacetic anhydride (5.57 g, 26.55 mmol) in dichloromethane (10 mL) ), the reaction was stirred for 20 minutes. The above compound (2S,3R,4R)-2,3,4-tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-1-(4-chloro-) was added dropwise. 3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,5-diol 3J crude (5 g) in dichloromethane (10 mL) hour. A mixture of triethylamine (4.84 g, 47.9 mmol) and dichloromethane (5 mL) was added dropwise to the reaction mixture, stirred for 15 minutes, and allowed to warm to room temperature and stirred for 0.5 hour. Slowly, water (40 mL) was added to the reaction solution under ice-cooling, and the mixture was separated. The aqueous phase was extracted with dichloromethane (50 mL×2). The organic phase was washed with saturated sodium bicarbonate until the system was alkaline and washed once. , dried, filtered, and concentrated under reduced vacuo to dryness crystals crystalsssssssssssssssssssssssssssss Small (4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,5-dione 3K crude (5.54 g). .

第九步： （lS,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基) 苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 3) Step 9: (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxy) Ethoxy)benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 3)

-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)  -2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)

Figure imgf000068_0002
Figure imgf000068_0002

将上述 (2R,3R,4S)-2,3,4-三 (苄氧基) -6- ((四叔丁基二甲基硅烷基)氧基) -1-(4-氯 -3-(4-(2-环 丙基氧基乙氧基)苄基)苯基)己烷 -1,5-二酮 3K粗品 （5.54 g)溶于四氢呋喃 （11 mL) 中， 冰 浴下滴加四丁基氟化铵（2.5 g, 9.6 mmol) 的四氢呋喃 （2.5 mL)溶液， 升至室温搅拌反应 1 小时。 加入水（20 mL) 猝灭反应， 分液， 水相用乙酸乙酯 （30 mL x 3)萃取， 合并有机相 并用饱和氯化钠 （50 mL x l)洗涤， 干燥， 过滤， 减压浓缩。 残留物用柱层析分离纯化（石 油醚 /乙酸乙酯 = 12: 1)，得到淡黄色固体(18,28,38,4! ,58)-2,3,4-三( 基氧基)-5-(4-氯-3-(4-(2- 环丙基氧基乙氧基)苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 3) (1.57 g,产率 33%)。 The above (2R,3R,4S)-2,3,4-tris(benzyloxy)-6-((tetra-tert-butyldimethylsilyl)oxy)-1-(4-chloro-3- (4-(2-Cyclopropyloxyethoxy)benzyl)phenyl)hexane-1,5-dione 3K crude (5.54 g) was dissolved in tetrahydrofuran (11 mL). A solution of tetrabutylammonium fluoride (2.5 g, 9.6 mmol) in tetrahydrofuran (2.5 mL) was stirred at room temperature for 1 hour. After the addition of water (20 mL), EtOAc (EtOAc)EtOAc. Separation and purification of the residue by column chromatography Oleic ether / ethyl acetate = 12: 1) to give a pale yellow solid (18, 28, 38, 4!, 58)-2,3,4-tris(yloxy)-5-(4-chloro-3 -(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 3) (1.57 g , yield 33%).

¾ NMR(400 MHz): δ 7.36-7.23(m, 13H), 7.14-7.10(m, 3H), 7.03(d, 2H), 6.82(d, 2H), 6.75(d, 2H), 4.93-4.76 (m, 4H), 4.38 (d, IH), 4.27(d, IH), 4.04-3.98 (m, 4H), 3.87-3.86 (m, 2H), 3.80-3.84 (m, 2H), 3.63 (d, IH), 3.47 (d,lH), 3.39-3.35 (m, 2H), 0.62-0.60 (m, 2H), 0.48-0.46 (m, 2H) o 实施例 1  3⁄4 NMR (400 MHz): δ 7.36-7.23 (m, 13H), 7.14-7.10 (m, 3H), 7.03 (d, 2H), 6.82 (d, 2H), 6.75 (d, 2H), 4.93-4.76 (m, 4H), 4.38 (d, IH), 4.27(d, IH), 4.04-3.98 (m, 4H), 3.87-3.86 (m, 2H), 3.80-3.84 (m, 2H), 3.63 (d , IH), 3.47 (d, lH), 3.39-3.35 (m, 2H), 0.62-0.60 (m, 2H), 0.48-0.46 (m, 2H) o Example 1

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基）苯基) -1-乙氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 1)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-ethoxy-6,8-dioxobicyclo[3.2 .1] Octane-2,3,4-triol (Compound 1)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo[3.2.1 ]  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo[3.2.1 ]

Figure imgf000069_0001
Figure imgf000069_0001

第一步：（lS,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙氧基 -6,8- 二氧杂二环 [3.2.1]辛烷（la)  First step: (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1-ethoxy-6,8-dioxabicyclo[3.2.1]octane (la)

(lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8 -dioxabicyclo[3.2.1]octane  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo[ 3.2.1]octane

Figure imgf000069_0002
Figure imgf000069_0002

(lS,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1] 辛烷 -1-醇 (中间体 l) (0.4 g, 0.58 mmol)溶于 Ν,Ν-二甲基甲酰胺 （10 mL)， 搅拌均匀， 加入碘 乙烷（0.18 g, 1.16 mmol)， 冰浴下加入氢化钠 （0.03 g, 1.16 mmol, )。 氮气氛， 室温下搅拌反 应 3小时。 反应液用饱和氯化铵溶液（20 mL) 稀释， 乙酸乙酯 （30 mL x 3)萃取。 有机相 依次用饱和食盐水（90 mL)和水（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留 物用柱层析分离纯化（乙酸乙酯 /正己烷 = 1 : 15)，得到白色固体 (lS,2S,3R,4R,5S)-2,3,4-三 (苄 氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙氧基 -6,8-二氧杂二环 [3.2.1]辛烷 la (0.35 g,产率 83%) (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6, 8-Dioxodicyclo[3.2.1]octane-1-ol (intermediate l) (0.4 g, 0.58 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (10 mL). Ethane (0.18 g, 1.16 mmol) was added EtOAc (EtOAc m. The reaction was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction was diluted with a saturated aqueous solution of ammonium chloride (20 mL) and ethyl acetate (30 mL The organic layer was washed with EtOAc EtOAc EtOAc. The residue was purified by column chromatography (ethyl acetate / hexane = 1 : 15) to afford white solid (lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy) -5 -(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-ethoxy-6,8-dioxabicyclo[3.2.1]octane la (0.35 g, yield 83%)

O NMR (400 MHz, CDC13): δ 7.43 (d, IH), 7.39 -7.24 (m, 12H), 7.22 -7.13 (m, 3H), 7.09 (d, 2H), 6.90 -6.85 (m, 2H), 6.79 -6.75 (m, 2H), 4.98 (d, IH), 4.89 (d, IH), 4.80 (d, 2H), 4.31 (d, IH), 4.24 (d, IH), 4.01 (m, 4H), 3.90 (m, 3H), 3.85 -3.75 (m, 2H), 3.73 -3.63 (m, 2H), 1.41 (t, 3H),

Figure imgf000070_0001
O NMR (400 MHz, CDC1 3 ): δ 7.43 (d, IH), 7.39 -7.24 (m, 12H), 7.22 -7.13 (m, 3H), 7.09 (d, 2H), 6.90 -6.85 (m, 2H ), 6.79 -6.75 (m, 2H), 4.98 (d, IH), 4.89 (d, IH), 4.80 (d, 2H), 4.31 (d, IH), 4.24 (d, IH), 4.01 (m, 4H), 3.90 (m, 3H), 3.85 -3.75 (m, 2H), 3.73 -3.63 (m, 2H), 1.41 (t, 3H),
Figure imgf000070_0001

第二步：（1 S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) - 1 -乙氧基 -6,8-二氧杂二环 [3.2.1 ] 辛烷 -2,3,4-三醇 （化合物 1)  Second step: (1 S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-ethoxy-6,8-di Oxabicyclo[3.2.1 ]octane-2,3,4-triol (compound 1)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo[3.2.1] octane-2,3,4 -triol

Figure imgf000070_0002
Figure imgf000070_0002

将 (lS,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙氧基 -6,8-二氧 杂二环 [3.2.1]辛烷 la (0.35 g, 0.48 mmol)、邻二氯苯 (0.71 g, 4.8 mmol)和钯炭 (0.35 g, 10%) 加入甲醇和四氢呋喃 （20 mL, V/V = 1 : 1) 的混合溶剂中， 氢气置换三次， 室温下搅拌反应 4.5小时。 反应混合物用甲醇 （25 mL)稀释， 抽滤， 用甲醇和二氯甲烷的混合溶剂 （60 mL, V/V=l : l)洗涤， 合并滤液并减压浓缩。 残留物用柱层析分离纯化（甲醇 /二氯甲烷 = 1:25)， 得到白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙氧基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 1) (0.17 g, 81%)。  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1- Ethoxy-6,8-dioxabicyclo[3.2.1]octane la (0.35 g, 0.48 mmol), o-dichlorobenzene (0.71 g, 4.8 mmol) and palladium on carbon (0.35 g, 10%) A mixed solvent of methanol and tetrahydrofuran (20 mL, V/V = 1:1) was added, and the mixture was replaced with hydrogen three times, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by column chromatography (methanol / methylene chloride = 1:25) to afford white solid (1S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-1-ethoxy-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 1) (0.17 g, 81%).

¾ NMR (400 MHz, MeOD): δ 7.40 (s, IH), 7.38 -7.33 (m, 2H), 7.08 (d, 2H), 6.79 (d, 2H), 4.10 (d, IH), 4.02 (s, 2H), 3.97 (q, 2H), 3.85 -3.78 (m, 2H), 3.69 (m, IH), 3.63 -3.57 (m, 2H), 3.52 (d, IH), 1.34 (t, 3H), 1.19 (t, 3H)。  3⁄4 NMR (400 MHz, MeOD): δ 7.40 (s, IH), 7.38 -7.33 (m, 2H), 7.08 (d, 2H), 6.79 (d, 2H), 4.10 (d, IH), 4.02 (s , 2H), 3.97 (q, 2H), 3.85 -3.78 (m, 2H), 3.69 (m, IH), 3.63 -3.57 (m, 2H), 3.52 (d, IH), 1.34 (t, 3H), 1.19 (t, 3H).

MS m/z (API): 405.3 [M-OCH2CH3]。  MS m/z (API): 405.3 [M-OCH2CH3].

HPLC: 94.10%。 实施例 2  HPLC: 94.10%. Example 2

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 2)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-dioxabicyclo[ 3.2.1] Octane-2,3,4-triol (Compound 2)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1 ]octane-2,3,4-triol  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1 ]octane-2,3,4 -triol

Figure imgf000070_0003
Figure imgf000071_0001
第一步： （l S,2S,3R,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8- 二氧杂二环 [3.2.1]辛烷（2a)
Figure imgf000070_0003
Figure imgf000071_0001
First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl) - 1-methoxy-6,8-dioxabicyclo[3.2.1]octane (2a)

(l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6 ,8-dioxabicyclo[3.2.1]octane  (l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6 ,8-dioxabicyclo [3.2.1]octane

Figure imgf000071_0002
Figure imgf000071_0002

将 (l S,2S,3S,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基)苯基) -6,8-二氧杂二环 [3.2.1] 辛烷 -1-醇 (中间体 l) (0.24 g, 0.35 mmol)溶于 Ν,Ν-二甲基甲酰胺 （4 mL) 中， 搅拌均匀， 加 入碘甲烷（0.10 g, 0.70 mmol)。 冰水浴下加入氢化钠 （0.02 g, 0 .70 mmol)， 氮气氛， 室温下 搅拌反应 3小时。 反应液用饱和氯化铵溶液（20 mL)稀释， 乙酸乙酯 （30 mL x 3)萃取。 有机相依次用饱和食盐水（90 mL)和水（50 mL)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减 压浓缩。 残留物用柱层析分离纯化（乙酸乙酯： 正己烷 = 1 : 15) , 得到白色固体 (l S,2S,3R,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂二环 [3.2.1]辛烷 2a (0.21 g,产率 90%)。  (l S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-6,8 -dioxabicyclo[3.2.1]octane-1-ol (intermediate l) (0.24 g, 0.35 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (4 mL) Methyl iodide (0.10 g, 0.70 mmol). Sodium hydride (0.02 g, 0.70 mmol) was added under ice water, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with aq. EtOAc (20 mL) The organic phase was washed with brine (90 mL) and water (50 mL). The residue was purified by column chromatography (ethyl acetate: hexane = 1 : 15) to afford white solid (1S,2S,3R,4R,5S)-2,3,4-tribenzyloxy-5- (4-Chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-dioxabicyclo[3.2.1]octane 2a (0.21 g, yield 90 %).

¾ NMR(400 MHz, CDC13): δ 7.13-7.35(m, 16H), 7.06(d, 2H), 6.85(d, 2H), 6.75(d, 2H),3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.13-7.35 (m, 16H), 7.06 (d, 2H), 6.85 (d, 2H), 6.75 (d, 2H),

4.74-4.95(m, 4H), 4.27(d, IH), 4.20(d, IH), 3.80-4.01(m, 8H), 3.62(t, IH), 3.43(s, 3H), 1.38(t, 3H)。 4.74-4.95(m, 4H), 4.27(d, IH), 4.20(d, IH), 3.80-4.01(m, 8H), 3.62(t, IH), 3.43(s, 3H), 1.38(t, 3H).

MS m/z (API)： 405.1 [M-OCH3]。 MS m/z (API): 405.1 [M-OCH 3 ].

第二步：（l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂二环 [3.2.1] 辛烷 -2,3,4-三醇 （化合物 2)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-di Oxabicyclo[3.2.1] octane-2,3,4-triol (compound 2)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1] octane-2,3,4-triol  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1] octane-2,3, 4-triol

Figure imgf000071_0003
Figure imgf000071_0003

(l S,2S,3R,4R,5S)-5-(3-(4-乙氧基苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三 醇 (化合物 2-1) (l S,2S,3R,4R,5S)-5-(3-(4-ethoxybenzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1] Octane-2,3,4-three Alcohol (Compound 2-1)

(lS,2S,3R,4R,5S)-5-(3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1]octane-2 ,3,4-triol  (lS, 2S, 3R, 4R, 5S)-5-(3-(4-ethoxybenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo[3.2.1]octane-2 ,3,4-triol

Figure imgf000072_0001
将 (lS,2S,3R,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂 二环 [3.2.1]辛烷 2a (1.60 g, 2.30 mmol)、邻二氯苯 (3.33 g, 23.00 mmol)和钯碳 (1.60 g, 10%) 悬浮于甲醇和四氢呋喃 （120 mL, V/V=l : l) 混合溶剂中， 氢气置换反应体系三次。 氢气氛， 室温下搅拌反应 4个小时。反应液用甲醇 （100 mL)稀释，抽滤，用甲醇和二氯甲烷（50 mL, V/V=l : l) 的混合溶剂洗涤滤饼。 合并滤液， 减压浓缩， 残留物用硅胶柱层析分离纯化 （甲 醇 /二氯甲烷 = 1:20), 得到白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧 基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4-三醇（化合物 2) (0.70 g, 产率 70%) 、 (lS,2S,3R,4R,5S)-5-(3-(4-乙氧基苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化 合物 2-1) (8 mg, 0.8%)
Figure imgf000072_0001
(lS, 2S, 3R, 4R, 5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy Base-6,8-dioxabicyclo[3.2.1]octane 2a (1.60 g, 2.30 mmol), o-dichlorobenzene (3.33 g, 23.00 mmol) and palladium on carbon (1.60 g, 10%) suspended in In a mixed solvent of methanol and tetrahydrofuran (120 mL, V/V = 1 : 1), the reaction system was replaced with hydrogen three times. The reaction was stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction solution was diluted with methanol (100 mL), filtered, and then filtered, and the mixture was washed with a solvent mixture of methanol and dichloromethane (50 mL, V/V = l: l). The filtrate was combined, and the residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjj 3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (compound 2) (0.70 g, yield 70%), (lS, 2S, 3R, 4R, 5S)-5-(3-(4-ethoxybenzyl)phenyl)-1-methoxy-6,8- Dioxodicyclo[3.2.1]octane-2,3,4-triol (Compound 2-1) (8 mg, 0.8%)

化合物 2: ¾ NMR(400 MHz, MeOD): δ 7.39(s, 1Η), 7.23-7.30(m, 2H), 7.04(d, 2H), 6.74(d, Compound 2: 3⁄4 NMR (400 MHz, MeOD): δ 7.39 (s, 1 Η), 7.23-7.30 (m, 2H), 7.04 (d, 2H), 6.74 (d,

2H), 3.85-4.02(m, 6H), 3.75(t, 1H), 3.61-3.68(m, 2H), 3.35(s, 3H), 1.33(t, 3H); 2H), 3.85-4.02 (m, 6H), 3.75 (t, 1H), 3.61-3.68 (m, 2H), 3.35 (s, 3H), 1.33 (t, 3H);

HPLC: 95.15%；  HPLC: 95.15%;

化合物 2-1： ¾ NMR (400 MHz, MeOD) δ 7.42― 7.32 (m, 2H), 7.26 (d, 1H), 7.14 (d, 1H), 7.11― 7.06 (m, 2H), 6.81― 6.77 (m, 2H), 4.12― 4.01 (m, 2H), 3.97 (q, 2H), 3.90 (s, 2H), 3.66― 3.53 (m, 3H), 3.45 (d, 3H), 1.34 (t, 3H);  Compound 2-1: 3⁄4 NMR (400 MHz, MeOD) δ 7.42 - 7.32 (m, 2H), 7.26 (d, 1H), 7.14 (d, 1H), 7.11 - 7.06 (m, 2H), 6.81 - 6.77 ( m, 2H), 4.12― 4.01 (m, 2H), 3.97 (q, 2H), 3.90 (s, 2H), 3.66-3.53 (m, 3H), 3.45 (d, 3H), 1.34 (t, 3H) ;

HPLC: 77.6%。 实施例 3  HPLC: 77.6%. Example 3

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -l-(2-羟基乙基) -6,8-二氧二环 [3.2.1]辛 烷 -2,3,4-三醇 （化合物 3)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1 -(2-hydroxyethyl)-6,8-dioxo Bicyclo[3.2.1]octane-2,3,4-triol (compound 3)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-hydroxyethoxy)-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol

Figure imgf000072_0002
Figure imgf000073_0001
(lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-hydroxyethoxy)-6,8-dioxabicyclo [3.2.1]octane-2 , 3,4-triol
Figure imgf000072_0002
Figure imgf000073_0001

8'9-(lAu3qd(iAzu3qA oqi3-i7)-£-oJOiqo-i7)-S-(A oiAzu3q)sui-i7'£'^-(SS'"ai'"a£'S^'Sl)))-^ 二-8'9-(¾*(¾^¾¾2 )-£-¾ )- -(¾¾¾^)三 '£'乙-(8 ¾7'¾£'8乙'81)))-乙  8'9-(lAu3qd(iAzu3qA oqi3-i7)-£-oJOiqo-i7)-S-(A oiAzu3q)sui-i7'£'^-(SS'"ai'"a£'S^'Sl)) )-^ 2-8'9-(3⁄4*(3⁄4^3⁄43⁄42 )-£-3⁄4 )- -(3⁄43⁄43^4^) three '£' B-(8 3⁄47'3⁄4£'8 B'81)))-B

°(H£ '1) Γ\ '(Η£ '1)8 ε·ΐ °(H£ '1) Γ\ '(Η£ '1)8 ε·ΐ

'(HI 'V)Z9'£ '(HI 'P)89'£ 'CHS ¾ 90Ή8·£ '(HS '(Ηΐ 'Ρ)98 (HI 'P)90'S \ΉΖ iV)i 9 \ΉΖ 'Ρ)£8'9 %iiZ '？) WL '(Η9ΐ ^)βί' L-\Y L 9 :(ZH OO^W HT

Figure imgf000073_0003
'(HI 'V)Z9'£ '(HI 'P)89'£ 'CHS 3⁄4 90Ή8·£ '(HS '(Ηΐ 'Ρ)98 (HI 'P)90'S \ΉΖ i V)i 9 \ΉΖ 'Ρ)£8'9 %iiZ '? ) WL '(Η9ΐ ^)βί' L-\YL 9 :( Z H OO^WH T
Figure imgf000073_0003

[ΐτε]¾:¾:-8'9-(¾*(¾*¾¾2 ) -ε-驚 三 '£'z-(ss'¾i7'¾£'sfsi)))-乙- [ΐτε]3⁄4:3⁄4:-8'9-(3⁄4*(3⁄4*3⁄43⁄42) -ε-惊三 '£'z-(ss'3⁄4i7'3⁄4£'sfsi)))-B-

°m . 'w ' 士 邈^ ¾ ' (^osi) ¾

Figure imgf000073_0004
°m . 'w '士邈^ 3⁄4 ' (^osi) 3⁄4
Figure imgf000073_0004

阜 。 (εχτιι00ΐ) '¾¾ (i^ ooi) wm m n^ m ^ °^、「/ε^^Hey. (εχτιι 00ΐ ) ' 3⁄43⁄4 (i^ ooi) wm mn^ m ^ °^, "/ε^^

#1?止 g ' 霄 '(louiui0S '^ ZVO) [¾ ¾Υ 止^ ¾ 'douiuisrn '§ 88 )#1?止g '霄'(louiui 0 S '^ ZVO) [3⁄4 3⁄4Υ 止 ^ 3⁄4 'douiuisrn '§ 88 )

YH '(，06)

Figure imgf000073_0005
YH '(,06)
Figure imgf000073_0005

¾:¾:-8'9-(¾*(¾*¾ -ε-驚 三 '£'Z-(SS'¾l7'S£'SfSI)琳  3⁄4:3⁄4:-8'9-(3⁄4*(3⁄4*3⁄4 -ε-惊三'£'Z-(SS'3⁄4l7'S£'SfSI) Lynn

Figure imgf000073_0006
Figure imgf000073_0006

9-(lAu3qd(iAzu3qA oqi3-i7)-£-OJOiqo-i7)-S-(A oiAzu3q)sui-i7'£¾-(SS'"ai'"a£'S^'Sl)))-Z;  9-(lAu3qd(iAzu3qA oqi3-i7)-£-OJOiqo-i7)-S-(A oiAzu3q)sui-i7'£3⁄4-(SS'"ai'"a£'S^'Sl)))-Z ;

(κε) (匿 -ΐ-¾*[ΐτε]¾:¾ (κε) (匿-ΐ-3⁄4*[ΐτε]3⁄4:3⁄4

-8'9-(¾*(¾^¾¾2 )-£-¾ )-£-¾¾^三 '£'乙-(8£'¾1 ¾£'8乙'81))) ¾2 -8'9-(3⁄4*(3⁄4^3⁄43⁄42 )-£-3⁄4 )-£-3⁄43⁄4^三 '£' B-(8£'3⁄41 3⁄4£'8B'81))) 3⁄42

Figure imgf000073_0007
Figure imgf000073_0007

S9C.8l/M0Z OAV 将乙基 -2-(((lS,2S,3R,4R,5S)-2,3,4-三苄氧基 -5-(4-氯 -3-(4-乙氧基苯基） 苯基) -6,8-二氧杂 二环 [3.2.1]辛烷 -1-基)氧基)乙酸乙酯 3a (1.00 g, 1.30 mmol)溶于四氢呋喃 （50 mL)中， 搅拌 均匀， 加入四氢硼锂 （0.11 g, 5.20 mmol)， 氮气氛， 室温下搅拌反应 5小时。 反应液用饱和 氯化铵溶液（50 mL)稀释， 乙酸乙酯 （100 mL x 3)萃取。 有机相用水（100 mL)洗涤， 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（乙酸乙酯 /正己烷 = 1 : 10)， 得到淡黄色糖浆 2-(((lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8- 二氧二环 [3.2.1]辛烷 -1-基)氧基)乙醇 3b (0.73 g,产率 76%)。 S9C.8l/M0Z OAV Ethyl-2-(((lS,2S,3R,4R,5S)-2,3,4-tribenzyloxy-5-(4-chloro-3-(4-ethoxyphenyl)benzene) Ethyl -6,8-dioxabicyclo[3.2.1]octane-1-yl)oxy)acetate 3a (1.00 g, 1.30 mmol) was dissolved in tetrahydrofuran (50 mL). Lithium tetrahydroborate (0.11 g, 5.20 mmol) was added, and the mixture was stirred at room temperature for 5 hours under nitrogen. The reaction solution was diluted with a saturated aqueous solution of ammonium chloride (50 mL) and ethyl acetate (100 mL? The organic phase was washed with EtOAc EtOAc m. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 10) to yield of pale yellow syrup 2-(((lS,2S,3R,4R,5S)-2,3,4-tri ( Benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)oxy Ethanol 3b (0.73 g, yield 76%).

¾ NMR(400 MHz): δ 7.12-7.34(m, 16H), 7.05(d, 2H), 6.85(d, 2H), 6.74(d, 2H), 4.78-4.92(m, 4H), 4.24-4.28(m, 2H), 3.73-3.92(m, 7H), 3.63-3.70(m, 6H), 1.38(t, 3H)。  3⁄4 NMR (400 MHz): δ 7.12-7.34 (m, 16H), 7.05 (d, 2H), 6.85 (d, 2H), 6.74 (d, 2H), 4.78-4.92 (m, 4H), 4.24-4.28 (m, 2H), 3.73-3.92 (m, 7H), 3.63-3.70 (m, 6H), 1.38 (t, 3H).

第三步： （lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -l-(2-羟基乙氧基) -6,8-二氧二 环 [3.2.1]辛烷 -2,3,4-三醇（化合物 3)  The third step: (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-hydroxyethoxy)-6 , 8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 3)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-hydroxyethoxy)-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-hydroxyethoxy)-6,8-dioxabicyclo [3.2.1]octane-2 , 3,4-triol

Figure imgf000074_0001
Figure imgf000074_0001

将 2-(((lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 2-(((lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene) Base) -6,8-dioxane

[3.2.1]辛烷 -1-基)氧基)乙醇 3b (0.52 g, 0.70 mmol)、 邻二氯苯 (1.00 g, 7.00 mmol)和钯炭 (0.50 g, 10%)悬浮于甲醇和四氢呋喃 （30 mL, V/V = 1 : 1) 的混合溶剂中，氢气置换三次，室 温下搅拌反应 2小时。 将反应混合物用甲醇（90 mL)稀释， 抽滤， 用甲醇和二氯甲烷的混 合溶剂 （60 mL, V/V=l : l)洗涤， 合并滤液， 减压浓缩。 残留物用硅胶柱层析分离纯化（甲 醇 /二氯甲烷 = 1 :20)， 得到白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-(2-羟 基乙氧基) -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 3) (0.26 g, 80%)。 [3.2.1] Octane-1-yl)oxy)ethanol 3b (0.52 g, 0.70 mmol), o-dichlorobenzene (1.00 g, 7.00 mmol) and palladium on carbon (0.50 g, 10%) suspended in methanol and In a mixed solvent of tetrahydrofuran (30 mL, V/V = 1:1), the hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (methanol / methylene chloride = 1 : 20) to afford white solid (1S,2S,3R,4R,5S)-5-(4-chloro-3-(4- ethoxy) Benzyl)phenyl)-1-(2-hydroxyethoxy)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 3) (0.26 g , 80%).

¾ NMR(400 MHz): δ 7.40(s, 1Η), 7.36(t, 2H), 7.08(d, 2H), 6.79(d, 2H), 4.1 l(d, 1H), 4.02(s, 2H), 3.98 (q, 2H), 3.80-3.86(m, 2H), 3.65-3.73(m, 4H), 3.6 l(t, 1H), 3.53(d, 1H), 1.35(t, 3H)。  3⁄4 NMR (400 MHz): δ 7.40 (s, 1 Η), 7.36 (t, 2H), 7.08 (d, 2H), 6.79 (d, 2H), 4.1 l(d, 1H), 4.02 (s, 2H) , 3.98 (q, 2H), 3.80-3.86 (m, 2H), 3.65-3.73 (m, 4H), 3.6 l (t, 1H), 3.53 (d, 1H), 1.35 (t, 3H).

HPLC: 95.89%。  HPLC: 95.89%.

MS m/z (API): 489.0[M+Na]。 实施例 4  MS m/z (API): 489.0 [M+Na]. Example 4

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 3-氟苄基)苯基) -1-异丙基 -6,8-二氧杂二环 [3.2.1]辛 烷 -2,3,4-三醇 （化合物 4)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-isopropyl-6,8-dioxa Bicyclo[3.2.1]octane-2,3,4-triol (compound 4)

(1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- 1 -isopropoxy-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol (1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- 1 -isopropoxy-6,8-dioxabicyclo [3.2.1]octane- 2,3,4-triol

Figure imgf000075_0001
Figure imgf000075_0001

中间体 2 4a 化合物 4  Intermediate 2 4a compound 4

第一步: (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-异丙基 First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene -1-isopropyl

-6,8-二氧杂二环 [3.2.1]辛烷 (4a) -6,8-dioxabicyclo[3.2.1]octane (4a)

(l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- l -isopropoxy-6,8-dioxabicyclo[3.2 1]octane  (l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- l -isopropoxy-6 , 8-dioxabicyclo[3.2 1]octane

Figure imgf000075_0002
Figure imgf000075_0002

将 (l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6,8-二氧耳 环 [3.2.1]辛烷 -1-醇 (中间体 2) <;0.5 g, 0.7mmoi;)溶于 Ν,Ν-二甲基甲酰胺 （5 mL)， 搅拌均匀， 加入 2-碘丙烷（0.134 g, 2.8 mmol)， 冰浴下加入氢化钠 （0.476 g, 2.8 mmol)， 氮气氛， 室温 下搅拌反应 2小时。 用饱和氯化铵溶液（20 mL)稀释反应液， 乙酸乙酯 （10 mL x 3)萃取。 有机相用饱和食盐水（90 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留物用柱层析 分离纯化 （乙酸乙酯 /正己烷 = 1 :20-1 : 15) , 得到无色糖浆 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧 基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-异丙基 -6,8-二氧二环 [3.2.1]辛烷 4a (50 mg, 产率 10.5%)。  (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl) -6,8-dioxo earring [3.2.1]octane-1-ol (intermediate 2) <;0.5 g, 0.7mmoi;) soluble in hydrazine, hydrazine-dimethylformamide (5 mL After stirring, 2-iodopropane (0.134 g, 2.8 mmol) was added, and sodium hydride (0.476 g, 2.8 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with aq. EtOAc (20 mL) The organic layer was washed with EtOAcq. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1 : 20-1 : 15) to give colorless syrup (l S,2S,3R,4R,5S)-2,3,4-tri ( Benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-isopropyl-6,8-dioxobicyclo[3.2.1]octane 4a (50 mg, yield 10.5%).

¾ NMR (400 MHz, CDC13): δ 7.39 -7.21 (m, 13H), 7.21 -7.08 (m, 3H), 6.94 -6.73 (m, 5H), 4.98 (d, IH), 4.87 (d, IH), 4.76 (dd, 2H), 4.32 (d, IH), 4.20 (d, IH), 4.14 (dt, IH), 4.04 (q, 2H), 3.98 (s, 2H), 3.91 (d, IH), 3.88 -3.80 (m, 2H), 3.76 (d, IH), 3.59 (d, IH), 1.42 (t, 3H), 1.21 (d, 3H), 1.15 (d, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.39 -7.21 (m, 13H), 7.21 -7.08 (m, 3H), 6.94 -6.73 (m, 5H), 4.98 (d, IH), 4.87 (d, IH ), 4.76 (dd, 2H), 4.32 (d, IH), 4.20 (d, IH), 4.14 (dt, IH), 4.04 (q, 2H), 3.98 (s, 2H), 3.91 (d, IH) , 3.88 -3.80 (m, 2H), 3.76 (d, IH), 3.59 (d, IH), 1.42 (t, 3H), 1.21 (d, 3H), 1.15 (d, 3H).

第二步：（l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-异丙基氧基 -6,8-二氧二 环 [3.2.1]辛烷 -2,3,4-三醇（化合物 4)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-isopropyloxy -6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 4)

(1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- 1 -isopropoxy-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol

Figure imgf000076_0001
(1 S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)- 1 -isopropoxy-6,8-dioxabicyclo [3.2.1]octane- 2,3,4-triol
Figure imgf000076_0001

将 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-异丙基 -6,8-二 氧二环 [3.2.1]辛烷 4a (50 mg, 0.066 mmol)、 邻二氯苯 (0.10 g, 0.66 mmol)和钯炭 (0.05 g, 10%)加入甲醇和四氢呋喃 （2mL,V/V=l:l) 的混合溶剂中， 氢气置换三次， 室温下搅拌反 应 2小时。 反应液用甲醇（15 mL)稀释， 抽滤， 用甲醇和二氯甲烷的混合溶剂洗涤， 合并 滤液， 减压浓缩， 残留物用柱层析分离纯化 （甲醇 /二氯甲烷 = 1:20), 得到无色糖浆 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-异丙基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4- 三醇 (化合物 4) (25 mg,产率 78%)。 (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1 -isopropyl-6,8-dioxobicyclo[3.2.1]octane 4a (50 mg, 0.066 mmol), o-dichlorobenzene (0.10 g, 0.66 mmol) and palladium on carbon (0.05 g, 10%) A mixed solvent of methanol and tetrahydrofuran (2 mL, V/V = 1 : 1) was added, and the mixture was replaced with hydrogen three times, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) , obtaining a colorless syrup (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-isopropyl-6,8-di Oxabicyclo[3.2.1]octane-2,3,4-triol (compound 4) (25 mg, yield 78%).

¾ NMR (400 MHz, CD3OD): δ 7.38 (d, 3H), 7.02 -6.79 (m, 3H), 4.21 (dt, IH), 4.13 -3.97 (m, 5H), 3.75 (dd, IH), 3.65 -3.54 (m, 2H), 3.49 (d, IH), 1.38 (t, 3H), 1.19 (d, 3H), 1.16 (d, 3H)。 3⁄4 NMR (400 MHz, CD 3 OD): δ 7.38 (d, 3H), 7.02 -6.79 (m, 3H), 4.21 (dt, IH), 4.13 -3.97 (m, 5H), 3.75 (dd, IH) , 3.65 -3.54 (m, 2H), 3.49 (d, IH), 1.38 (t, 3H), 1.19 (d, 3H), 1.16 (d, 3H).

MS m/z (API)： 423.1 [M-OCH(CH3)2]。 实施例 5 MS m/z (API): 423.1 [M-OCH (CH 3 ) 2 ]. Example 5

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-乙氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 5)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-ethoxy-6,8-dioxo Bicyclo[3.2.1]octane-2,3,4-triol (compound 5)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo [3.2.  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo [3.2.

Figure imgf000076_0002
Figure imgf000076_0002

巾 |'uj体 2 5a 化合物 5  Towel |'uj body 2 5a compound 5

第一步： （lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-乙 氧基 -6,8-二氧二环 [3.2.1]辛烷 (5a)  First step: (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-1-ethoxy-6,8-dioxobicyclo[3.2.1]octane (5a)

(lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l- ethoxy-6,8-dioxabicyclo[3.2.1]octane  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-ethoxy-6, 8-dioxabicyclo[3.2.1]octane

Figure imgf000076_0003
将 (l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6,8-二氧二 环 [3.2.1]辛烷 -1-醇 (中间体 2) (0.30 g, 0.5 mmol)溶于 Ν,Ν-二甲基甲酰胺（10 mL)，搅拌均匀， 加入碘乙烷 (0.15 g, 1.0 mmol), 冰浴下加入氢化钠 (0.02 g, 1.0 mmol), 氮气氛， 室温下搅 拌反应 2小时。 反应液用饱和氯化铵溶液（20 mL)稀释， 乙酸乙酯 （50 mL x 3;»萃取。 有 机相依次用饱和食盐水（90 mL)和水（50 mL)洗涤， 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 （乙酸乙酯 /正己烷 = 1 : 15) , 得到白色固体 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-乙氧基 -6,8-二氧 二环 [3.2.1]辛烷 5a (0.29 g,产率 96%)。
Figure imgf000076_0003
(l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 2) (0.30 g, 0.5 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (10 mL) Stir well, add iodoethane (0.15 g, 1.0 mmol), and add sodium hydride (0.02 g, 1.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with aq. EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 15) to afford white solid (1 S, 2S, 3R, 4R, 5S)-2,3,4 -tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-ethoxy-6,8-dioxobicyclo[ 3.2.1] Octane 5a (0.29 g, yield 96%).

¾ NMR (400 MHz, CDC13): δ 7.40 -7.22 (m, 13H), 7.21 -7.10 (m, 3H), 6.92 -6.74 (m, 5H), 4.95 (d, IH), 4.87 (d, IH), 4.77 (d, 2H), 4.31 (d, IH), 4.21 (d, IH), 4.02 (m, 4H), 3.93 -3.85 (m, 3H), 3.79 (m, 2H), 3.66 (m, 2H), 1.41 (t, 3H), 1.22 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.40 -7.22 (m, 13H), 7.21 -7.10 (m, 3H), 6.92 -6.74 (m, 5H), 4.95 (d, IH), 4.87 (d, IH ), 4.77 (d, 2H), 4.31 (d, IH), 4.21 (d, IH), 4.02 (m, 4H), 3.93 -3.85 (m, 3H), 3.79 (m, 2H), 3.66 (m, 2H), 1.41 (t, 3H), 1.22 (t, 3H).

第二步： （l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-乙氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 5)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-ethoxy-6 , 8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 5)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-ethoxy-6,8-dioxabicyclo [3.2.1]octane- 2,3,4-triol

Figure imgf000077_0001
Figure imgf000077_0001

将 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-乙氧基 -6,8-二氧二环 [3.2.1]辛烷 5a (0.28 g, 0.40 mmol)、邻二氯苯 (0.45 g, 4.0 mmol)和钯碳 (0.30 10%)溶于甲醇和四氢呋喃 （20 mL, V/V = l : l) 的混合溶剂中， 氢气置换三次， 室温下搅拌 反应 2小时。反应液用甲醇和二氯甲烷（20 mL, V/V = l : l)稀释， 抽滤， 用甲醇和二氯甲烷 (60 mL, V/V = l : l) 的混合溶剂洗涤， 合并滤液， 减压浓缩。 残留物用硅胶柱层析分离纯化 (甲醇 /二氯甲烷 = 1 :30) , 得到白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯 基) -1-乙氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 5) (0.15 g,产率 86%)。 (l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-1-ethoxy-6,8-dioxobicyclo[3.2.1]octane 5a (0.28 g, 0.40 mmol), o-dichlorobenzene (0.45 g, 4.0 mmol) and palladium on carbon (0.30) 10%) Dissolved in a mixed solvent of methanol and tetrahydrofuran (20 mL, V/V = 1 : 1), three times of hydrogen, and stirred at room temperature for 2 hours. The reaction solution was diluted with methanol and dichloromethane (20 mL, V/V = 1 : l), filtered, and washed with a mixture solvent of methanol and methylene chloride (60 mL, V/V = l: l). , concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / methylene chloride = 1 : 30) to afford white solid (1S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy) 3-fluorobenzyl)phenyl)-1-ethoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 5) (0.15 g, Yield 86%).

¾ NMR (400 MHz, MeOD): δ 7.42 (s, IH), 7.41 -7.35 (m, 2H), 6.96 (t, IH), 6.90 (d, 2H), 4.12 -4.08 (m, IH), 4.07 (s, IH), 4.04 (t, 3H), 3.85 -3.80 (m, 2H), 3.75 -3.66 (m, IH), 3.64 -3.57 (m, 2H), 3.52 (d, IH), 1.38 (t, 3H), 1.20 (t, 3H)。  3⁄4 NMR (400 MHz, MeOD): δ 7.42 (s, IH), 7.41 -7.35 (m, 2H), 6.96 (t, IH), 6.90 (d, 2H), 4.12 -4.08 (m, IH), 4.07 (s, IH), 4.04 (t, 3H), 3.85 -3.80 (m, 2H), 3.75 -3.66 (m, IH), 3.64 -3.57 (m, 2H), 3.52 (d, IH), 1.38 (t , 3H), 1.20 (t, 3H).

HPLC: 96.46%。  HPLC: 96.46%.

MS m/z (API) : 423.0[M-OCH2CH3]。 实施例 6 MS m / z (API): 423.0 [M-OCH 2 CH 3]. Example 6

(l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 6) (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-methoxy-6,8-di Oxybicyclo[3.2.1]octane -2,3,4-triol (compound 6)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo [3.2.1]octane- 2,3,4-triol

第一步： （l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-甲 氧基 -6,8-二氧二环 [3.2.1]辛烷（6a)  First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluoro) Benzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane (6a)

(l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l- methoxy-6,8-dioxabicyclo[3.2.1]octane  (l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-methoxy-6 , 8-dioxabicyclo[3.2.1]octane

Figure imgf000078_0002
Figure imgf000078_0002

将 (l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -6,8-二氧二 环 [3.2.1]辛烷 -1-醇 (中间体 2) (0.35 g, 0.5 mmol)、 Ν,Ν-二甲基甲酰胺 （10 mL)， 搅拌均匀， 加 入碘甲烷（0.17 g, 1.0 mmol)， 冰浴下加入氢化钠 （0.02 g, 1.0 mmol)， 氮气氛， 室温下搅拌 反应 2小时。 反应液用饱和氯化铵溶液（30 mL)稀释， 乙酸乙酯（50 mL X 3)萃取。 有机 相依次用饱和食盐水（90 mL)和水（90 mL)洗涤， 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 （乙酸乙酯 /正己烷 = 1 : 15) , 得到白色固体 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-甲氧基 -6,8-二氧 二环 [3.2.1]辛烷 6a (0.33 g,产率 90%)。 (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 2) (0.35 g, 0.5 mmol), hydrazine, hydrazine-dimethylformamide (10 mL), After stirring well, iodomethane (0.17 g, 1.0 mmol) was added, and sodium hydride (0.02 g, 1.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with saturated ammonium chloride solution (30 mL), ethyl acetate (50 mL X 3) and extracted. The organic layer was washed with EtOAc EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate /hexanes -5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane 6a (0.33 g, yield 90%).

¾ NMR (400 MHz, CDC13): δ 7.40 -7.22 (m, 13H), 7.22 -7.09 (m, 3H), 6.94 -6.73 (m, 5H), 4.94 (d, IH), 4.86 (d, IH), 4.77 (m, 2H), 4.31 (d, IH), 4.20 (d, IH), 4.08 -3.96 (m, 4H), 3.93 -3.86 (m, 3H), 3.83 (d, IH), 3.66 -3.61 (m, IH), 3.44 (s, 3H), 1.41 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.40 -7.22 (m, 13H), 7.22 -7.09 (m, 3H), 6.94 -6.73 (m, 5H), 4.94 (d, IH), 4.86 (d, IH ), 4.77 (m, 2H), 4.31 (d, IH), 4.20 (d, IH), 4.08 -3.96 (m, 4H), 3.93 -3.86 (m, 3H), 3.83 (d, IH), 3.66 - 3.61 (m, IH), 3.44 (s, 3H), 1.41 (t, 3H).

第二步： （l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基 -3-氟苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 6)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-methoxy-6 , 8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 6)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo [3.2.1]octane-2,3,4-triol 3irepo[ I '1' £]o AoiqB oi -g'9-A oqi3ui- \ - (lAu3qd(iAzu3q(A oqi3A odojdo Ao-^)-i7)-£-oJOiqo-i7)-S-(A oiAzu3q)sui-i7'£'^-(SS'"ai'"a£'S^'Sl) (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-l-methoxy-6,8-dioxabicyclo [3.2.1]octane- 2,3,4-triol 3irepo[ I '1' £]o AoiqB oi -g'9-A oqi3ui- \ - (lAu3qd(iAzu3q(A oqi3A odojdo Ao-^)-i7)-£-oJOiqo-i7)-S-(A oiAzu3q) Sui-i7'£'^-(SS'"ai'"a£'S^'Sl)

Οε)¾ΐ[ΐτε]¾:¾:-8'9-¾¾ώ-ΐ-(¾* Οε)3⁄4ΐ[ΐτε]3⁄4:3⁄4:-8'9-3⁄43⁄4ώ-ΐ-(3⁄4*

(¾^(¾¾2¾¾¾ ¾-乙) )-£-¾ )- -(¾¾¾^)三 '£'乙-(8 '¾17'¾£'8乙'81) :^-Μ (3⁄4^(3⁄43⁄423⁄43⁄43⁄4 3⁄4-B) )-£-3⁄4 )- -(3⁄43⁄43^4^) three '£' B-(8 '3⁄417'3⁄4£'8 B'81) : ^-Μ

Figure imgf000079_0001
Figure imgf000079_0001

pUl-|7'£'^-3UB o[| "£]o A0iqB OI  pUl-|7'£'^-3UB o[| "£]o A0iqB OI

-8'9-A oqi3ui-i-(iAu3qd(iAzu3q(A oqi3A odojdo Ao-^)-i7)-£-oJOiqo-i7)-S-(sg'"ai'"a£'S^'Sl)  -8'9-A oqi3ui-i-(iAu3qd(iAzu3q(A oqi3A odojdo Ao-^)-i7)-£-oJOiqo-i7)-S-(sg'"ai'"a£'S^'Sl)

( 賴三 'ε'ζ-¾ΐ[ΐτε] si ¾-¾--8'9-S¾i-i-(S*(S^(S¾ S¾S ^H)-£-»-^)-s-(ss¾i7¾£'s^si)  ( Lai San 'ε'ζ-3⁄4ΐ[ΐτε] si 3⁄4-3⁄4--8'9-S3⁄4i-i-(S*(S^(S3⁄4 S3⁄4S ^H)-£-»-^)-s-(ss3⁄4i73⁄4 £'s^si)

L um^  L um^

。 [¾ o ] ΐ·ε乙 i : (idv) zAu sn . [3⁄4 o ] ΐ·ε乙i : (idv) z Au sn

°%Li'96 ldH  °%Li'96 ldH

°(H£ Ί) 8£'l '(H£ 'S) 9Vi '(Ηΐ 'P) '(Ηΐ 'P) 09'£ '(HI ¾ Wi '(HI ¾ ^£ '(HS ¾ ZO' - 01

Figure imgf000079_0002
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Figure imgf000079_0002
' Z HW OOI7) 3⁄4W H T

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Figure imgf000079_0003
Figure imgf000080_0001
Figure imgf000079_0003
Figure imgf000080_0001

氮气氛下， 将 (l S,2S,3S,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄 基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 3) (0.3 g, 0.4 mmol)溶于 Ν,Ν-二甲基甲酰胺 (4 mL),冰浴冷却至 0°C，加入碘甲烷（1 14 mg, 0.8 mmol),搅拌均匀。将氢化钠 （19 mg, 0.8 mmol)分批多次加入反应中， 升至室温搅拌反应 1小时。 冰浴下用氯化铵调节混合体系至 中性，水相用乙酸乙酯 (20mL x 3)，合并有机相并用水（20 mL x 2)、饱和食盐水（20 mL x l) 洗涤， 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 = 25: 1),得到淡黄色液体 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-(2-环丙基氧基 乙氧基)苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 3a (84 mg,产率 27%)。  Under the nitrogen atmosphere, (l S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyl) Oxyethoxy)benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 3) (0.3 g, 0.4 mmol) dissolved in hydrazine, hydrazine- Dimethylformamide (4 mL) was cooled to 0 ° C in an ice-bath and EtOAc (1 14 mg, Sodium hydride (19 mg, 0.8 mmol) was added portionwise to the reaction in portions, and the mixture was stirred at room temperature for 1 hour. The mixture was adjusted to neutral with ammonium chloride under ice bath, and the aqueous phase was combined with ethyl acetate (20 mL×3). The organic phase was combined and washed with water (20 mL×2), brine (20 mL×l) Dry over sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 25: 1) to afford pale yellow liquid (1S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy) -5-(4-Chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2 .1] Octane 3a (84 mg, yield 27%).

¾ NMR(400 MHz): δ 7.1 1-7.39(m, 16H), 7.06(d, 2H), 6.85(d, 2H), 6.75(d, 2H), 3⁄4 NMR (400 MHz): δ 7.1 1-7.39 (m, 16H), 7.06 (d, 2H), 6.85 (d, 2H), 6.75 (d, 2H),

4.74-4.95(m, 4H), 4.27(d, IH), 4.20(d, IH), 3.96-4.10(m, 4H), 3.90-3.86 (m, 3H), 3.84-3.80 (m, 3H), 3.62(t, IH), 3.43(s, 3H), 3.36-3.39 (m, IH), 0.62-0.61 (m, 2H), 0.49-0.47 (m, 2H)。 4.74-4.95(m, 4H), 4.27(d, IH), 4.20(d, IH), 3.96-4.10(m, 4H), 3.90-3.86 (m, 3H), 3.84-3.80 (m, 3H), 3.62(t, IH), 3.43(s, 3H), 3.36-3.39 (m, IH), 0.62-0.61 (m, 2H), 0.49-0.47 (m, 2H).

第二步： （l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) -1-甲氧基 -6,8- 二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 7)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-1- Methoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 7)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-methoxy-6,8- dioxabicyclo[3.2.1]octane-2,3,4-tri

Figure imgf000080_0002
(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-methoxy-6,8- dioxabicyclo[3.2.1]octane -2,3,4-tri
Figure imgf000080_0002

将（1 S,2S,3R,4R,5S)-2,3,4-三（苄基氧基 )-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基）苄基）苯 基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 3a (84 mg, 0.1 1 mmol)溶于四氢呋喃 （1 mL) 与甲醇 (1 mL) 的混合溶剂中， 加入邻二氯苯（162 mg, 1.1 mmol)、 钯炭（67 mg,质量分数 80%)。 反应体系用氢气置换 3次， 氢气氛下室温搅拌反应 1小时。 过滤反应液， 除去钯炭， 滤饼 用二氯甲烷与甲醇的混合液（V/V = 1 : 1 , 20 mL)洗涤， 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)， 得白色固体 (l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基 氧基乙氧基)苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 7) (30 mg, 55%)  (1 S,2S,3R,4R,5S)-2,3,4-Tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane 3a (84 mg, 0.1 1 mmol) dissolved in tetrahydrofuran (1 mL) with methanol (1 To a mixed solvent of mL), o-dichlorobenzene (162 mg, 1.1 mmol) and palladium on carbon (67 mg, mass fraction 80%) were added. The reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, and the palladium carbon was removed. The filter cake was washed with a mixture of dichloromethane and methanol (V/V = 1:1, 20 mL), and the filtrate was concentrated under reduced pressure. Ether / ethyl acetate = 20: 1) to give a white solid (1S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 7) (30 mg, 55%)

Ή NMR(400 MHz): δ 7.33-7.41(m, 3Η), 7.09(d, 2H), 6.83(d, 2H), 4.1 1-4.05(m, 5H), 3.95(d IH), 3.85-3.83(m, 2H), 3.79-3.76(m, 2H), 3.71(d, IH), 3.47(s, 3H), 3.39 (m, IH), 0.63-0.60 2H), 0.50-0.47 (m, 2H)。 HPLC: 95.40%。 实施例 8 NMR NMR (400 MHz): δ 7.33-7.41 (m, 3 Η), 7.09 (d, 2H), 6.83 (d, 2H), 4.1 1-4.05 (m, 5H), 3.95 (d IH), 3.85-3.83 (m, 2H), 3.79-3.76(m, 2H), 3.71(d, IH), 3.47(s, 3H), 3.39 (m, IH), 0.63-0.60 2H), 0.50-0.47 (m, 2H) . HPLC: 95.40%. Example 8

(l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) -1-二氟甲氧基 -6,8-二氧 二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 8)  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-1-difluoromethoxy Base-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 8)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-difluoromethoxy (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-difluoromethoxy

- -dioxabicyclo[3.2.1 ]octane-2,3,4-triol - -dioxabicyclo[3.2.1 ]octane-2,3,4-triol

Figure imgf000081_0001
Figure imgf000081_0001

中间体 3 8a 化合物 8  Intermediate 3 8a compound 8

第一步： （l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基) 苯基) -1-二氟甲氧基 -6,8-二氧二环 [3.2.1]辛烷 (8a)  First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxy) Ethyloxy)benzyl)phenyl)-1-difluoromethoxy-6,8-dioxobicyclo[3.2.1]octane (8a)

(lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) - 1 -difluoromethoxy-6,8-dioxabicyclo[3.2.1] octane  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl) - 1 -difluoromethoxy-6 ,8-dioxabicyclo[3.2.1] octane

Figure imgf000081_0002
Figure imgf000081_0002

将（1 S,2S,3S,4R,5S)-2,3,4-三（苄基氧基 )-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基）苄基）苯 基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 3) (0.8 g, 1.07 mmol)溶于乙腈 (12 mL)和水 (2 mL) 中， 冰浴冷却至 -5°C， 加入氢氧化钾 （0.72 g, 12.8 mmol)， 搅拌均匀。 保持 -5°C下一次 性加入溴氟甲基膦酸二乙酯 （0.85 g, 3.2 mmol), 升至室温搅拌反应 2小时。 冰浴下加入水 (30 mL),用乙酸乙酯 （50 mL x 3)萃取，合并有机相并依次用饱和氯化铵溶液（30 mL x 2)、 饱和食盐水（20 mL x 2)洗涤， 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 = 30: 1) , 得到淡黄色液体 (l S,2S,3R,4R,5S)-2,3,4-三（苄基氧 基 )-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) -1-二氟甲氧基 -6,8-二氧二环 [3.2.1]辛烷 8a (300 mg,产率 35%)。 (1 S, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-ol (Intermediate 3) (0.8 g, 1.07 mmol) dissolved in acetonitrile (12 mL) 2 mL), cool to -5 ° C in an ice bath, add potassium hydroxide (0.72 g, 12.8 mmol), and mix well. Diethyl bromofluoromethylphosphonate (0.85 g, 3.2 mmol) was added in one portion at -5 ° C, and the reaction was stirred at room temperature for 2 hours. Water (30 mL) was added to an ice-bath, and extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed successively with saturated aqueous ammonium chloride (30 mL x 2) and saturated brine (20 mL x 2) Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 30: 1) to give pale yellow liquid (1S, 2S, 3R, 4R, 5S)-2,3,4-tris (benzyloxy) 5- (4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-1-difluoromethoxy-6,8-dioxobicyclo [3.2.1] Octane 8a (300 mg, yield 35%).

19F NMR (376 MHz, CDC13)： δ -79.52, -79.99, -84.00, -84.47。 19 F NMR (376 MHz, CDC1 3 ): δ -79.52, -79.99, -84.00, -84.47.

¾ NMR (400 MHz, CDC13): δ 7.39 - 7.26 (m, 11H), 7.25 -7.20 (m, 2H), 7.20 -7.10 (m, 3H), 7.04 (t, 2H), 6.85 -6.80 (m, 2H), 6.80 -6.75 (m, 2H), 6.73- 6.37 (t, IH), 4.95 (d, IH), 4.84 (d, IH), 4.76 (d, 2H), 4.45 (d,l H), 4.27 (d, IH), 4.08 -3.98 (m, 4H), 3.95 (dd, IH), 3.89 -3.86 (m, IH), 3.86 -3.80 (m, 3H), 3.77 (d, IH), 3.65 (d, IH), 3.38 (tt, IH), 0.64 -0.58 (m, 2H), 0.51 -0.44 (m, 2H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.39 - 7.26 (m, 11H), 7.25 -7.20 (m, 2H), 7.20 -7.10 (m, 3H), 7.04 (t, 2H), 6.85 -6.80 (m , 2H), 6.80 -6.75 (m, 2H), 6.73- 6.37 (t, IH), 4.95 (d, IH), 4.84 (d, IH), 4.76 (d, 2H), 4.45 (d, l H), 4.27 (d, IH), 4.08 -3.98 (m, 4H), 3.95 (dd, IH), 3.89 -3.86 (m, IH), 3.86 -3.80 (m, 3H), 3.77 (d, IH), 3.65 (d, IH), 3.38 (tt, IH), 0.64 -0.58 (m, 2H), 0.51 -0.44 (m, 2H).

第二步： （lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基)苄基)苯基) -1-二氟甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 8)  Second step: (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy)benzyl)phenyl)-1-1-2 Fluoromethoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 8)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-difluoromethoxy -6,8-dioxabicyclo[3.2.1]octane- -triol  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-l-difluoromethoxy-6,8-dioxabicyclo[3.2.1]octane- -triol

Figure imgf000082_0001
Figure imgf000082_0001

将（1 S,2S,3R,4R,5S)-2,3,4-三（苄基氧基 )-5-(4-氯 -3-(4-(2-环丙基氧基乙氧基）苄基）苯 基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 8a (300 mg, 0.37 mmol)溶于四氢呋喃 （3 mL) 与甲醇 (3 mL) 的混合溶剂中，加入邻二氯苯（540 mg, 3.76 mmol)、钯炭（300 mg,质量分数 80%)。 反应体系用氢气置换 3次， 氢气氛下室温搅拌反应 3小时。 过滤反应液， 除去钯炭， 滤饼 用二氯甲烷与甲醇的混合液（V/V = l : l, 20 mL x 3)洗涤， 将滤液减压浓缩， 残留物用硅胶 柱层析分离纯化（二氯甲烷 /甲醇 = 30: 1)， 得白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-(2-环丙 基氧基乙氧基)苄基)苯基) -1-二氟甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 8) (120 mg,产率 63%)。  (1 S,2S,3R,4R,5S)-2,3,4-Tris(benzyloxy)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane 8a (300 mg, 0.37 mmol) dissolved in tetrahydrofuran (3 mL) with methanol (3 mL To the mixed solvent, o-dichlorobenzene (540 mg, 3.76 mmol) and palladium on carbon (300 mg, mass fraction 80%) were added. The reaction system was replaced with hydrogen three times, and the reaction was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered to remove palladium on carbon, and the filter cake was washed with a mixture of dichloromethane and methanol (V/V = 1 : 1 , 20 mL x 3), and the filtrate was concentrated under reduced pressure. (Dichloromethane/methanol = 30:1) gave white solid (1S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-(2-cyclopropyloxyethoxy) Benzyl)phenyl)-1-difluoromethoxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 8) (120 mg, yield 63%).

19F NMR (376 MHz, CDC13) : 5 -81.31, -81.77, -82.50, -82.96。 19 F NMR (376 MHz, CDC1 3 ): 5 -81.31, -81.77, -82.50, -82.96.

¾ NMR (400 MHz, CDC13): δ 7.38 (d, IH), 7.34 -7.27 (m, 2H), 7.08 (d, 2H), 6.85 -6.80 (m, 2H), 6.72 -6.36 (t, IH), 4.32 (d, IH), 4.08 -4.02 (m, 4H), 3.94 (d, IH), 3.85 -3.79 (m, 2H), 3.76 (d, IH), 3.71 (m, 2H), 3.37 (m, IH), 0.64 -0.57 (m, 2H), 0.50 -0.44 (m, 2H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.38 (d, IH), 7.34 -7.27 (m, 2H), 7.08 (d, 2H), 6.85 -6.80 (m, 2H), 6.72 -6.36 (t, IH ), 4.32 (d, IH), 4.08 -4.02 (m, 4H), 3.94 (d, IH), 3.85 -3.79 (m, 2H), 3.76 (d, IH), 3.71 (m, 2H), 3.37 ( m, IH), 0.64 -0.57 (m, 2H), 0.50 -0.44 (m, 2H).

HPLC: 95.6%。 实施例 9  HPLC: 95.6%. Example 9

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-环丙基氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 9)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-cyclopropyloxy-6,8-dioxobicyclo [3.2.1] Octane-2,3,4-triol (Compound 9)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy-6,8-dioxabicyclo[ 3.2.1]octane-2,3,4-triol

Figure imgf000082_0002
(lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy-6,8-dioxabicyclo[ 3.2.1]octane-2,3,4 -triol
Figure imgf000082_0002

Figure imgf000083_0001
Figure imgf000083_0002
第一步： （l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-(2-碘乙 基氧基 )-6,8-二氧二环 [3.2.1]辛烷 (9a)
Figure imgf000083_0001
Figure imgf000083_0002
First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene -1-(2-iodoethyloxy)-6,8-dioxobicyclo[3.2.1]octane (9a)

(lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-iodoethoxy) -6,8-dioxabicyclo[3.2.1]octane

Figure imgf000083_0003
(lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(2-iodoethoxy)-6, 8-dioxabicyclo[3.2.1]octane
Figure imgf000083_0003

将 2-(((l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-基)氧基)乙醇 3b (4.8 g, 6.52 mmol)溶于甲苯（65 mL), 加入三苯基膦（3.4 g, 13.0 mmol)和咪唑 (2.2 g, 32.6 mmol), 冰水浴下加入碘 (3.3 g, 13.0 mmol), 升温至 70°C反 应 1小时。冷至室温， 加入乙酸乙酯 （100 mL)稀释反应液， 冰水浴下滴加硫代硫酸钠水溶 液至反应液颜色消失， 加入水（100 mL)分层， 水层用乙酸乙酯（200 mL X 2)萃取， 合并 有机层， 依次用 2M稀盐酸 (100 mL)、 10%碳酸氢钠水溶液（100 mL)洗涤， 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（乙酸乙酯 /正己烷 = 1 :20~1 : 10)， 得到 淡黄色糖浆 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-(2-碘乙基 氧基) -6,8-二氧二环 [3.2.1]辛烷 9a(5.4 g,产率 98%)。 2-(((l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)oxy)ethanol 3b (4.8 g, 6.52 mmol) dissolved in toluene (65 mL). 3.4 g, 13.0 mmol) and imidazole (2.2 g, 32.6 mmol) were added with iodine (3.3 g, 13.0 mmol) under ice-water bath and warmed to 70 ° C for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (100 mL), and aqueous sodium thiosulfate solution was added dropwise to an ice-water bath until the color of the reaction mixture disappeared, and water (100 mL) was added to separate layers. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 20 to 1 : 10) to afford pale yellow syrup (l S, 2S, 3R, 4R, 5S)-2,3,4- (benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(2-iodoethyloxy)-6,8-dioxobicyclo[ 3.2.1] Octane 9a (5.4 g, yield 98%).

¾ NMR (400 MHz, CDC13): δ 7.35 -7.10 (m, 16H), 7.06 (d, 2H), 6.84 (d, 2H), 6.75 (d, 2H), 5.02 (d, IH), 4.87 (d, IH), 4.79-4.75 (m, 2H), 4.23-4.29 (m, 2H), 4.02-3.74 (m, 10H), 3.62 (d, 1H): 3.22 (t, 2H), 1.38 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.35 -7.10 (m, 16H), 7.06 (d, 2H), 6.84 (d, 2H), 6.75 (d, 2H), 5.02 (d, IH), 4.87 ( d, IH), 4.79-4.75 (m, 2H), 4.23-4.29 (m, 2H), 4.02-3.74 (m, 10H), 3.62 (d, 1H) : 3.22 (t, 2H), 1.38 (t, 3H).

第二步： （l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙烯基 氧基) -6,8-二氧二环 [3.2.1]辛烷 (9b)  Second step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene ))-1-vinyloxy)-6,8-dioxobicyclo[3.2.1]octane (9b)

(l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(vinyloxy) -6,8-dioxabicyclo[3.2.1]octane

Figure imgf000084_0001
(l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(vinyloxy) -6,8 -dioxabicyclo[3.2.1]octane
Figure imgf000084_0001

将 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -l-(2-碘乙基氧 基) -6,8-二氧二环 [3.2.1]辛烷 9a (5.4 g, 6.38 mmol)溶于 Ν,Ν-二甲基甲酰胺 （65 mL)， 在冰水 浴下分批加入氢化钠 （1.55 g, 32.3 mmol), 升温至 35°C反应 1小时。冰水浴下加入饱和氯化 铵水溶液（30 mL)和水（50 mL)， 用乙酸乙酯 （150 mL x 2)萃取， 合并有机层， 用氯化铵 水溶液（80 mL)洗涤，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（乙 酸乙酯 /正己烷 = 1 :20), 得到淡黄色糖浆 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4- 乙氧基苄基)苯基) -1-乙烯基氧基) -6,8-二氧二环 [3.2.1]辛烷 9b(3.4 g,产率 74%)。  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l -(2-iodoethyloxy)-6,8-dioxobicyclo[3.2.1]octane 9a (5.4 g, 6.38 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (65 mL), Sodium hydride (1.55 g, 32.3 mmol) was added portionwise in an ice water bath and the mixture was warmed to 35 ° C for 1 hour. Add a saturated aqueous solution of ammonium chloride (30 mL) and water (50 mL), and ethyl acetate (150 mL×2). The sodium was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 20) to give pale yellow syrup (lS,2S,3R,4R,5S)-2,3,4-tri(benzyloxy) -5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-vinyloxy)-6,8-dioxobicyclo[3.2.1]octane 9b (3.4 g, yield 74%).

¾ NMR (400 MHz, CDC13): δ 7.39 -7.11 (m, 16H), 7.05 (d, 2H), 6.84 (d, 2H), 6.74 (d, 2H), 6.60 (dd, IH), 4.97 (d, IH), 4.86 (d, IH), 4.78 (d, 2H), 4.75 (d, IH), 4.70 (dd, 2H), 4.36-4.35 (m, IH), 4.07-3.87(m, 7H), 3.77 (dd, IH), 3.66 (d, IH), 1.37 (t, 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.39 -7.11 (m, 16H), 7.05 (d, 2H), 6.84 (d, 2H), 6.74 (d, 2H), 6.60 (dd, IH), 4.97 ( d, IH), 4.86 (d, IH), 4.78 (d, 2H), 4.75 (d, IH), 4.70 (dd, 2H), 4.36-4.35 (m, IH), 4.07-3.87 (m, 7H) , 3.77 (dd, IH), 3.66 (d, IH), 1.37 (t, 3H).

第三步： （lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-环丙基 氧基 -6,8-二氧二环 [3.2.1]辛烷 (9c)  The third step: (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl -1-cyclopropyloxy-6,8-dioxobicyclo[3.2.1]octane (9c)

(lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy- 6,8-dioxabicyclo[3.2.1]octane

Figure imgf000084_0002
(lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy- 6,8-dioxabicyclo[ 3.2.1]octane
Figure imgf000084_0002

将二氯甲烷（13 mL) 置于反应瓶中，冰水浴下加入二乙基锌 （0.89 g, 7.24 mmol),搅拌 5分钟后加入二碘甲烷（1.93 g, 7.24 mmol), 升温至 5°C， 加入 (lS,2S,3R,4R,5S)-2,3,4-三 (苄 基氧基 )-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-乙烯基氧基) -6,8-二氧二环 [3.2.1]辛烷 9b(1.30 g, 1.81 mmol), 升至室温搅拌反应 24小时。 冰水浴下加入饱和氯化胺水溶液（50 mL)， 分层， 水层用二氯甲烷（80 mL x 3)萃取， 合并有机层， 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 （乙酸乙酯 /正己烷 = 1 :50) , 得到淡黄色糖浆 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-环丙基氧基 -6,8-二氧 二环 [3.2.1]辛烷 9c (0.50 g,产率 37.6%)。  Dichloromethane (13 mL) was placed in a reaction flask, and diethylzinc (0.89 g, 7.24 mmol) was added in an ice water bath. After stirring for 5 minutes, diiodomethane (1.93 g, 7.24 mmol) was added and the temperature was raised to 5 ° C, adding (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1-Vinyloxy)-6,8-dioxobicyclo[3.2.1]octane 9b (1.30 g, 1.81 mmol) was stirred at room temperature for 24 hours. Aqueous aqueous ammonium chloride (50 mL) was added and evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 50) to give pale yellow syrup (1S, 2S, 3R, 4R, 5S)-2,3,4-tris (benzyloxy) -5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-cyclopropyloxy-6,8-dioxobicyclo[3.2.1]octane 9c (0.50 g, yield 37.6%).

¾ NMR (400 MHz, CDC13): δ 7.40 -7.09 (m, 16H), 7.06 (d, 2H), 6.84 (d, 2H), 6.79 -6.73 3⁄4 NMR (400 MHz, CDC13): δ 7.40 -7.09 (m, 16H), 7.06 (d, 2H), 6.84 (d, 2H), 6.79 -6.73

(m, 2H), 5.01 (d, IH), 4.86 (d, IH), 4.77 (dd,2H), 4.26 (dd, 2H), 4.07 -3.72 (m, 1 IH), 3.62 (d, 1H): 3.22 (t, 2H), 1.38 (t,3H)。 (m, 2H), 5.01 (d, IH), 4.86 (d, IH), 4.77 (dd, 2H), 4.26 (dd, 2H), 4.07 -3.72 (m, 1 IH), 3.62 (d, 1H) : 3.22 (t, 2H), 1.38 (t, 3H).

第四步： （lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-环丙基氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 9) Fourth step: (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-cyclopropyloxy-6,8- Dioxane [3.2.1] Octane-2,3,4-triol (Compound 9)

(lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy-6,8-dioxabicyclo[ 3.2.1]octane-2,3,4-triol

Figure imgf000085_0001
(lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-cyclopropoxy-6,8-dioxabicyclo[ 3.2.1]octane-2,3,4 -triol
Figure imgf000085_0001

将 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-环丙基氧基 -6,8-二氧二环 [3.2.1]辛烷 9c (0.50 g, 0.68 mmol)溶于四氢呋喃 （3 mL) 与甲醇 （3 mL) 的混 合溶剂中， 加入邻二氯苯（l.O mg, 6.8 mmol)、 钯炭（0.4 g,质量分数 80%)。 反应体系用氢 气置换 4次， 氢气氛下室温搅拌反应 1小时。 过滤反应液， 除去钯炭， 滤饼用二氯甲烷与 甲醇的混合液（V/V = l : l, 60 mL x 3)洗涤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯 化（二氯甲烷 /甲醇 = 50: 1), 得白色固体 (lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- 环丙基氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇化合物 9 (0.25 g,产率 80%)。  (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1 - cyclopropyloxy-6,8-dioxobicyclo[3.2.1]octane 9c (0.50 g, 0.68 mmol) dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (3 mL) Dichlorobenzene (10 mg, 6.8 mmol), palladium on carbon (0.4 g, mass fraction 80%). The reaction system was replaced with hydrogen for 4 times, and the reaction was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered to remove palladium on carbon, and the filter cake was washed with a mixture of dichloromethane and methanol (V/V = 1 : l, 60 mL x 3), and the filtrate was concentrated under reduced pressure. (dichloromethane/methanol = 50: 1) gave white solid (1S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -1 - Cyclopropyloxy-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol compound 9 (0.25 g, yield 80%).

¾ NMR (400 MHz, MeOD): δ 7.37 (d, 3H), 7.11 -7.06 (m, 2H), 6.83 -6.78 (m, 2H), 4.10 (d, IH), 4.03 (s, 2H), 3.98 (q, 2H), 3.90 (dd, IH), 3.81 (dd, IH), 3.66 -3.56 (m, 2H), 3.51 (d, IH), 1.35 (t, 3H), 0.73 (ddd, IH), 0.59 (ddd, IH), 0.55 -0.48 (m, 2H)。  3⁄4 NMR (400 MHz, MeOD): δ 7.37 (d, 3H), 7.11 -7.06 (m, 2H), 6.83 -6.78 (m, 2H), 4.10 (d, IH), 4.03 (s, 2H), 3.98 (q, 2H), 3.90 (dd, IH), 3.81 (dd, IH), 3.66 -3.56 (m, 2H), 3.51 (d, IH), 1.35 (t, 3H), 0.73 (ddd, IH), 0.59 (ddd, IH), 0.55 -0.48 (m, 2H).

HPLC: 96.1%。 实施例 10  HPLC: 96.1%. Example 10

(lS,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) - 2,3,4-三羟基 -6,8-二氧二环 [3.2.1]辛烷 -1-基)氧基)乙腈 (化合物 10)  (lS, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxo Cyclo[3.2.1]octane-1-yl)oxy)acetonitrile (Compound 10)

2-(((lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2. ljoctan- 1 -yl)oxy)acetonitril  2-(((lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2. ljoctan - 1 -yl)oxy)acetonitril

Figure imgf000085_0002
Figure imgf000085_0002

第一步： 2-(((lS,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧 二环 [3.2.1]辛烷 -1-基)氧基)乙腈 (10a)  First step: 2-(((lS,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)oxy)acetonitrile (10a)

2-(((l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8- dioxabicyclo[3.2. ljoctan- 1 -yl)oxy)acetonitrile

Figure imgf000086_0001
2-(((S S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8- dioxabicyclo [3.2. ljoctan- 1 -yl)oxy)acetonitrile
Figure imgf000086_0001

将（l S,2S,3S,4R,5S)-2,3,4-三（苄基氧基) -5-(4-氯 -3-(4-乙氧基苯基）苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 l) (1.50 g, 2.17 mmol)溶于 Ν,Ν-二甲基甲酰胺 （15 mL)， 冰浴下加 入氢化钠 （0.21 g, 4.40 mmol)， 搅拌 5 分钟， 加入溴乙腈（0.52 g, 4.33 mmol)， 氮气氛、 室 温下搅拌反应 3小时。反应液用水（25 mL)稀释， 加入饱和氯化铵溶液调节 pH值至 7， 乙 酸乙酯 （40 mL x 3)萃取。 有机相依次用饱和氯化铵水溶液（30 mL) 、 水（30 mL)洗涤， 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 （乙酸乙酯 /正己烷 = 1 : 10) , 得到淡黄色糖浆 2-(((l S,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯 基) -6,8-二氧二环 [3.2.1]辛烷 -1-基)氧基)乙腈 10a(0.70 g,产率 44%)。  (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl) 6,8-Dioxabicyclo[3.2.1]octane-1-ol (Intermediate l) (1.50 g, 2.17 mmol) dissolved in EtOAc EtOAc (EtOAc) Sodium hydride (0.21 g, 4.40 mmol) was added, stirred for 5 min, bromoacetonitrile (0.52 g, 4.33 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with water (25 mL), and then filtered and evaporated. The organic layer was washed with EtOAc EtOAc EtOAc. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 : 10) to give pale yellow syrup 2-(((s), 2S,3R,4R,5S)-2,3,4- (benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)oxy Acetonitrile 10a (0.70 g, yield 44%).

1HNMR(400 MHz): δ 7.1 l-7.37(m, 16H), 7.07(d, 2H), 6.84(d, 2H), 6.75(d, 2H), 4.83-4.91(m, 1H NMR (400 MHz): δ 7.1 l-7.37 (m, 16H), 7.07 (d, 2H), 6.84 (d, 2H), 6.75 (d, 2H), 4.83-4.91 (m,

2H), 4.78-4.73(m, 2H), 4.33(d, 2H), 4.31-4.25(m, 2H), 4.06-3.93(m, 4H), 3.88(s, 2H), 3.86(d, 1H): 1.38(t, 3H), 1.24(t, 3H)。 2H), 4.78-4.73(m, 2H), 4.33(d, 2H), 4.31-4.25(m, 2H), 4.06-3.93(m, 4H), 3.88(s, 2H), 3.86(d, 1H) : 1.38(t, 3H), 1.24(t, 3H).

第二步： （l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) - 2,3,4-三羟基 -6,8-二氧二环 [3.2.1]辛烷 -1-基)氧基)乙腈 (化合物 10)  Second step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6, 8-Dioxodicyclo[3.2.1]octane-1-yl)oxy)acetonitrile (Compound 10)

2-(((lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2. ljoctan- 1 -yl)oxy)acetonitrile  2-(((lS,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2. ljoctan - 1 -yl)oxy)acetonitrile

Figure imgf000086_0002
Figure imgf000086_0002

将 2-(((l S,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-基)氧基)乙腈 10a (0.50 g, 0.68 mmol)溶于二氯甲烷 (10 mL), 降温至 -74°C， 氮气保护下滴加三氯化硼的甲苯溶液（12.2 mL， 12.2 mmol), 保持 -74。C搅拌反应 4小时。 反应液用二氯甲烷（10 mL)稀释， 缓慢加入甲醇 （26 mL)， 浓缩， 残余物溶于二氯甲烷 (80 mL), 用饱和碳酸氢钠水溶液（50 mL)洗涤， 水层用二氯甲烷（40 mL x 3)萃取， 合并有机 层， 无水硫酸钠干燥， 过滤， 减压浓缩。 柱层析纯化 (二氯甲烷 /甲醇 = 40: 1), 得到白色固 体 (l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) - 2,3,4-三羟基 -6,8-二氧二环 [3.2.1]辛烷 -1- 基)氧基)乙腈 (化合物 10) (0.13 g, 产率 41%)。  2-(((l S,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene) -6,8-Dioxabicyclo[3.2.1]octane-1-yl)oxy)acetonitrile 10a (0.50 g, 0.68 mmol) dissolved in dichloromethane (10 mL), cooled to -74 C. A solution of boron trichloride in toluene (12.2 mL, 12.2 mmol) was added dropwise under nitrogen to afford -74. The reaction was stirred for 4 hours. The reaction mixture was diluted with methylene chloride (10 mL). EtOAc (EtOAc) The mixture was extracted with chloromethane (40 mL). Purification by column chromatography (dichloromethane / methanol = 40: 1) toield of white solid (1S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl) - 2,3,4-trihydroxy-6,8-dioxobicyclo[3.2.1]octane-1-yl)oxy)acetonitrile (compound 10) (0.13 g, yield 41%) .

1HNMR(400 MHz): δ 7.44(s, IH), 7.37(s, 2H), 7.09(d, 2H), 6.79(d, 2H), 4.57(s, 2H), 4.17(d, IH), 4.03(s, IH), 3.98 (q, 2H), 3.81(dd, IH), 3.69(dd, IH), 3.60(t, IH), 3.54(d, IH), 1.35(t, 3H)。 1 H NMR (400 MHz): δ 7.44 (s, IH), 7.37 (s, 2H), 7.09 (d, 2H), 6.79 (d, 2H), 4.57 (s, 2H), 4.17 (d, IH), 4.03(s, IH), 3.98 (q, 2H), 3.81 (dd, IH), 3.69 (dd, IH), 3.60 (t, IH), 3.54 (d, IH), 1.35 (t, 3H).

HPLC: 96.51%。 MS m/z (API) : 462.1 [M+H 实施例 1 1 HPLC: 96.51%. MS m/z (API): 462.1 [M+H Example 1 1

(l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- (二氟甲氧基 )-6,8-二氧二环 [3.2.1]辛 烷 -2,3,4-三醇 (化合物 11)  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluoromethoxy)-6,8-di Oxybicyclo[3.2.1]octane-2,3,4-triol (compound 11)

(lR,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(difluoromethoxy)-6,8-dioxabicyclo -2,3,4-triol  (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(difluoromethoxy)-6,8-dioxabicyclo -2,3,4-triol

Figure imgf000087_0001
Figure imgf000087_0001

中间体 1 1 1 a 化合物 11  Intermediate 1 1 1 a compound 11

第一步： （l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-( 氧基) -6,8-二氧二环 [3.2.1]辛烷 (11a)  First step: (l S, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)benzene Base)-1-(oxy)-6,8-dioxobicyclo[3.2.1]octane (11a)

( l R,2S,3R,4R,5S)-2,3 ,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- l -( difluoromethoxy)-6,8-dioxabicycl  ( l R, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)- l -( difluoromethoxy)-6,8 -dioxabicycl

Figure imgf000087_0002
Figure imgf000087_0002

将（l S,2S,3S,4R,5S)-2,3,4-三（苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基）苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-醇 (中间体 l) (12.5 g, 18 mmol)溶于乙腈 (150 mL)和水 (25 mL) 中， 冰浴冷 却至 -5°C， 加入氢氧化钾 （12.1 g, 216 mmol)， 搅拌均匀。保持 -5°C条件下一次性加入溴氟甲 基膦酸二乙酯 （14.4 g, 54 mmol)， 升至室温搅拌反应 3小时。 冰浴下加入水（100 mL)， 用 乙酸乙酯 （200 mL x 3) 萃取， 合并有机相并用饱和氯化铵溶液（150 mL x 3)、水（100 mL x 2)洗涤， 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 = 30: 1),得到淡黄色液体 (l S,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基) 苯基) -1- (二氟甲氧基 )-6,8-二氧二环 [3.2.1]辛烷 11a (6.3 g,产率 47%)。  (l S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) 6,8-Dioxabicyclo[3.2.1]octane-1-ol (Intermediate l) (12.5 g, 18 mmol) dissolved in EtOAc (150 mL) At -5 ° C, potassium hydroxide (12.1 g, 216 mmol) was added and stirred well. Diethyl bromofluoromethylphosphonate (14.4 g, 54 mmol) was added in one portion at -5 ° C, and the mixture was stirred at room temperature for 3 hours. Water (100 mL) was added to an ice bath, and extracted with ethyl acetate (200 mL×3). The organic phase was combined and washed with saturated aqueous ammonium chloride (150 mL x 3), water (100 mL x 2), anhydrous sulfuric acid The sodium was dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl ether / ethyl acetate = 30: 1) to afford pale yellow liquid (1S, 2S, 3R, 4R, 5S)-2,3,4-tris (benzyloxy) -5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-1-(difluoromethoxy)-6,8-dioxobicyclo[3.2.1]octane 11a (6.3 g, yield 47%).

19F NMR (376 MHz, CDC13): δ -79.51 , -79.97, -84.03, -84.49。 1 9 F NMR (376 MHz, CDC1 3 ): δ -79.51, -79.97, -84.03, -84.49.

¾ NMR (400 MHz, CDC13): δ 7.39 -7.27 (m, 1 IH), 7.25 -7.10 (m, 5H), 7.05 (t, 2H), 6.83 ( 2H), 6.78 -6.71 (m, 2H), 6.71 - 6.37 (t, IH), 4.95 (d, IH), 4.83 (t, IH), 4.76 (d, 2H), 4.45 (d, IH), 4.26 (d, IH), 3.99 (tt, 5H), 3.87 (dd, 2H), 3.78 (d, IH), 3.66 (d, IH), 1.38 (t, 3H)。

Figure imgf000088_0001
3⁄4 NMR (400 MHz, CDC1 3 ): δ 7.39 -7.27 (m, 1 IH), 7.25 -7.10 (m, 5H), 7.05 (t, 2H), 6.83 ( 2H), 6.78 -6.71 (m, 2H) , 6.71 - 6.37 (t, IH), 4.95 (d, IH), 4.83 (t, IH), 4.76 (d, 2H), 4.45 (d, IH), 4.26 (d, IH), 3.99 (tt, 5H ), 3.87 (dd, 2H), 3.78 (d, IH), 3.66 (d, IH), 1.38 (t, 3H).
Figure imgf000088_0001

Figure imgf000088_0002
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S9C.8l/M0Z OAV 第一步： （l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1] 辛烷 -2,3,4-三醇与 L-苯丙 1 : 1络合物 (化合物 12)

Figure imgf000089_0001
S9C.8l/M0Z OAV First step: (l S, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methoxy-6,8-di Oxybicyclo[3.2.1]octane-2,3,4-triol and L-phenylpropan-1 :1 complex (compound 12)
Figure imgf000089_0001

将 (l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 2) (1.09 g, 2.5 mmol), L-苯丙氨酸 (0.45 g, 2.75 mmol)溶于乙醇 (4 mL) 和水（8 mL) 中， 加热至 85°C下回流反应 30分钟， 搅拌下缓慢冷却至室温， 在冰浴下继续 放置 30分钟， 抽滤， 用乙醇与水的混合溶剂（5 mL, V/V = 1 : 1)洗涤， 50°C下恒温干燥 1 小时， 得到白色固体 (lS,2S,3R,4R,5S)-2,3,4-三 (苄基氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- 甲氧基 -6,8-二氧二环 [3.2.1]辛烷与 L-苯丙氨酸的 1 : 1络合物化合物 12 (1.28 g,产率 85%)。  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methoxy-6,8-dioxobicyclo [3.2.1] Octane-2,3,4-triol (Compound 2) (1.09 g, 2.5 mmol), L-phenylalanine (0.45 g, 2.75 mmol) dissolved in ethanol (4 mL) and water (8 mL), heat to 85 ° C for 30 minutes under reflux, slowly cool to room temperature with stirring, continue to stand for 30 minutes in an ice bath, suction filtration, using a mixed solvent of ethanol and water (5 mL, V / V = 1 : 1) Washing, drying at 50 ° C for 1 hour at a constant temperature to obtain a white solid (lS, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4- 1:1 complex of chloro-3-(4-ethoxybenzyl)phenyl)-1-methoxy-6,8-dioxobicyclo[3.2.1]octane and L-phenylalanine Compound 12 (1.28 g, yield 85%).

¾ NMR (400 MHz, MeOD): δ 7.43 (d, IH), 7.41 -7.27 (m, 7H), 7.14 -7.08 (m, 2H), 6.85 -6.80 (m, 2H), 4.1 1 (d, IH), 4.06 (s, 2H), 4.01 (q, 2H), 3.86 (dd, IH), 3.80 (dd, IH), 3.68 -3.63 IH), 3.62 (d, IH), 3.54 (d, IH), 3.48 (s, 3H), 3.38 -3.33 (m, IH), 3.02 (dd, IH), 1.38 (t, 3H)。 实施例 13  3⁄4 NMR (400 MHz, MeOD): δ 7.43 (d, IH), 7.41 -7.27 (m, 7H), 7.14 -7.08 (m, 2H), 6.85 -6.80 (m, 2H), 4.1 1 (d, IH ), 4.06 (s, 2H), 4.01 (q, 2H), 3.86 (dd, IH), 3.80 (dd, IH), 3.68 -3.63 IH), 3.62 (d, IH), 3.54 (d, IH), 3.48 (s, 3H), 3.38 -3.33 (m, IH), 3.02 (dd, IH), 1.38 (t, 3H). Example 13

(l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基）苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -4-基 乙酸酯 (化合物 13)  (l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy-6, 8-dioxobicyclo[3.2.1]octane-4-yl acetate (compound 13)

(l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy- l -methoxy-6,8- dioxabicyclo [3.2.1 ] octan-4-yl acetate

Figure imgf000089_0002
(l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy- l -methoxy-6,8- dioxabicyclo [3.2.1 ] Octan-4-yl acetate
Figure imgf000089_0002

(l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基）苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -3-基 乙酸酯 (化合物 13-1)  (l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy-6, 8-dioxobicyclo[3.2.1]octane-3-yl acetate (compound 13-1)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,4-dihydroxy- l -methoxy-6,8- dioxabicyclo [3.2.1 ] octan-3 -yl acetate

Figure imgf000089_0003
(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,4-dihydroxy- l -methoxy-6,8- dioxabicyclo [3.2.1 ] Octan-3 -yl acetate
Figure imgf000089_0003

(l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基）苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2-基 乙酸酯 (化合物 13-2)  (l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy-6, 8-dioxobicyclo[3.2.1]octane-2-yl acetate (compound 13-2)

(l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydroxy- l -methoxy-6,8- dioxabicyclo[3.2.1 ]octan-2-yl acetate (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,4-dihydroxy- l -methoxy-6,8- dioxabicyclo[3.2.1 ] Octan-2-yl acetate

Figure imgf000090_0001
Figure imgf000090_0001

(l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4-三醇化合物 2(0.545 g, 1.25 mmol) 与二氯甲烷（2.5 mL) 混合， 搅拌均匀， 将三乙胺 (0.378 g, 3.75mmol) 加入到混合物中， 氮气保护下， 降温至 0°C， 加入乙酰氯 （0.097 g, 1.25mmol), 室温搅拌过夜。 以饱和氯化铵溶液（20 mL)稀释， 乙酸乙酯萃取 (3 x 15 mL)， 有机相用水（30 mL)洗涤， 无水硫酸钠干燥， 过滤， 减压浓缩。 柱层析分离， 洗脱剂： 二 氯甲烷： 甲醇 = 50: 1， 得淡黄色固体 (l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -2,3-二 羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -4-基 乙酸酯 (化合物 13) (23 mg, 产率 3%)、 (l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛 烷 -3-基 乙酸酯 (化合物 13-1) (56 mg,产率 6%)、 （l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基) 苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2-基 乙酸酯 (化合物 13-2) (60 mg,产率 8%)。  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-dioxabicyclo [3.2.1] Octane-2,3,4-triol compound 2 (0.545 g, 1.25 mmol) was mixed with dichloromethane (2.5 mL), stirred well, and triethylamine (0.378 g, 3.75 mmol) was added To the mixture, under a nitrogen atmosphere, was cooled to 0 ° C. EtOAc (0.097 g, 1.25 mmol). Dilute with aq. EtOAc (EtOAc) (EtOAc)EtOAc. Column chromatography separation, eluent: dichloromethane: methanol = 50:1, pale yellow solid (l S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[3.2.1]octane-4-yl acetate (Compound 13) (23 mg , yield 3%), (l S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1 -Methoxy-6,8-dioxobicyclo[3.2.1]octane-3-yl acetate (Compound 13-1) (56 mg, yield 6%), (l S, 2S, 3S , 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[ 3.2.1] Octane-2-yl acetate (Compound 13-2) (60 mg, yield 8%).

化合物 13： ¾ NMR (400 MHz, MeOD): δ 7.46 (s, IH), 7.42― 7.36 (m, 2H), 7.10 (d, 2H), 6.81 (d, 2H), 5.33 (dd, IH), 4.15 (d, 2H), 4.05 (s, 2H), 3.98 (q, 2H), 3.81 (t, IH), 3.68 (dd, IH), 3.42 (s, 3H), 2.13 (s, 3H), 1.36 (t, 3H);  Compound 13: 3⁄4 NMR (400 MHz, MeOD): δ 7.46 (s, IH), 7.42 - 7.36 (m, 2H), 7.10 (d, 2H), 6.81 (d, 2H), 5.33 (dd, IH), 4.15 (d, 2H), 4.05 (s, 2H), 3.98 (q, 2H), 3.81 (t, IH), 3.68 (dd, IH), 3.42 (s, 3H), 2.13 (s, 3H), 1.36 (t, 3H);

HPLC: 96.8%；  HPLC: 96.8%;

化合物 13-1： ^ NMR (400 MHz, MeOD): δ 7.50― 7.33 (m, 3H), 7.1 1 (d, 2H), 6.83 (d, 2H), 5.18 (t, IH), 4.23 (d, IH), 4.10 - 3.95 (m, 5H), 3.70 (t, 2H), 3.49 (s, 3H), 2.12 (s, 3H), 1.37 (t, 3H);  Compound 13-1: ^ NMR (400 MHz, MeOD): δ 7.50 - 7.33 (m, 3H), 7.1 1 (d, 2H), 6.83 (d, 2H), 5.18 (t, IH), 4.23 (d, (I, M.

HPLC: 98.3%；  HPLC: 98.3%;

化合物 13-2： ^ NMR (400 MHz, MeOD): δ 7.28 - 7.16 (m, 3H), 6.94 (d, 2H), 6.70 (d, 2H), yyy dobcco3. e cboeixail22lthlarnat--</ RTI><RTIgt; Yyy dobcco3. e cboeixail22lthlarnat--

()((yy)¾y)yyy,,,,,,ss35s5coo3eobee3ddoeo8l2H.4H.4hlr4thxnzlhnl4ihrxlmthx6------------

Figure imgf000091_0001
()((yy)3⁄4y)yyy,,,,,,ss35s5coo3eobee3ddoeo8l2H.4H.4hlr4thxnzlhnl4ihrxlmthx6------------
Figure imgf000091_0001

,,,,,,,.......s.s mt I ,,,,,,,.......ss mt I

Figure imgf000092_0001
Figure imgf000092_0001

(l S,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苯基)苯基) -1-甲氧基 -6,8-二氧杂二环 [3.2.1]辛烷 -2,3,4-三醇化合物 2(0.872 g, 2 mmol) 与二氯甲烷（4 mL) 混合，搅拌均匀，将三乙胺 （0.606 g, 6 mmol)加到混合物中， 氮气保护下， 降温至 0°C， 加入氯甲酸乙酯 （0.216 g, 2 mmol)， 室温下搅拌过夜。 用饱和氯化铵溶液（20 mL)稀释， 乙酸乙酯 （3 x 15 mL)萃取。 有机相 用水（30 mL)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 柱层析分离纯化 (二氯甲烷 /甲醇 = 100: 1),得淡黄色固体 (l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -2,3-二羟基 -1- 甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -4-基 碳酸乙酯（化合物 14) (13 mg, 产率 1.5%)、 (l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛 烷 -3-基碳酸乙酯 (化合物 14-1) (23 mg,产率 2.3%)、（l S,2S,3S,4R,5S)-5-(4-氯 -3-(4-乙氧基苄 基)苯基) -2,3-二羟基 -1-甲氧基 -6,8-二氧二环 [3.2.1]辛烷 -2-基碳酸乙酯 (化合物 14-2) (35 mg, 产率 3.5%)。  (l S,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxyphenyl)phenyl)-1-methoxy-6,8-dioxabicyclo [3.2.1] Octane-2,3,4-triol compound 2 (0.872 g, 2 mmol) was mixed with dichloromethane (4 mL), stirred well, and triethylamine (0.606 g, 6 mmol) To the mixture, under a nitrogen atmosphere, cooled to 0 ° C, ethyl chloroacetate (0.216 g, 2 mmol). It was diluted with a saturated aqueous solution of ammonium chloride (20 mL) and ethyl acetate (3×15 mL). The organic phase was washed with water (30 mL). Purified by column chromatography (dichloromethane / methanol = 100: 1) to give pale yellow solid (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)- 2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[3.2.1]octane-4-ylethyl carbonate (Compound 14) (13 mg, produced Rate 1.5%), (l S, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methyl Ethoxy-6,8-dioxobicyclo[3.2.1]octane-3-ylethyl carbonate (Compound 14-1) (23 mg, yield 2.3%), (l S, 2S, 3S, 4R , 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3-dihydroxy-1-methoxy-6,8-dioxobicyclo[3.2. 1] Octane-2-ylethyl carbonate (Compound 14-2) (35 mg, yield 3.5%).

化合物 14: HPLC: 92.8%；  Compound 14: HPLC: 92.8%;

化合物 14-1: ¾ NMR (400 MHz, MeOD): δ 7.45 (s, IH), 7.42― 7.35 (m, 2H), 7.1 1 (d, 2H), 6.83 (d, 2H), 4.95 (t, IH), 4.25― 4.17 (m, 3H), 4.07― 3.98 (m, 5H), 3.72 (dd, 2H), 3.49 (s, 3H), 1.37 (t, 3H), 1.30 (t, 3H);  Compound 14-1: 3⁄4 NMR (400 MHz, MeOD): δ 7.45 (s, IH), 7.42 - 7.35 (m, 2H), 7.1 1 (d, 2H), 6.83 (d, 2H), 4.95 (t, IH), 4.25― 4.17 (m, 3H), 4.07― 3.98 (m, 5H), 3.72 (dd, 2H), 3.49 (s, 3H), 1.37 (t, 3H), 1.30 (t, 3H);

HPLC: 91.6%；  HPLC: 91.6%;

化合物 14-2: ¾ NMR (400 MHz, MeOD): δ 7.36 (t, 3H), 7.06 (d, 2H), 6.81 (d, 2H), 4.80 (d, IH), 4.16 (d, IH), 3.89-4.00 (m, 7H), 3.81 (t,lH), 3.67 (d,lH), 3.49 (s, 3H), 1.36 (t, 3H), 1.06 (t, 3H);  </ RTI> <RTIgt; 3.89-4.00 (m, 7H), 3.81 (t, lH), 3.67 (d, lH), 3.49 (s, 3H), 1.36 (t, 3H), 1.06 (t, 3H);

HPLC: 92.4%。 实施例 15  HPLC: 92.4%. Example 15

(lR,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- (吡啶 -2-基巯基 )-6,8-二氧二环 [3.2.1] 辛烷 -2,3,4-三醇 (化合物 15) (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(pyridin-2-ylindenyl)-6,8-di Oxybicyclo[3.2.1] Octane-2,3,4-triol (compound 15)

(lR,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(pyridin-2-ylthio)-6,8-dioxabicyclo -2,3,4-triol  (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(pyridin-2-ylthio)-6,8-dioxabicyclo -2,3,4 -triol

Figure imgf000093_0001
Figure imgf000093_0001

15d 1 5e 化合物 15 第一步：（lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-甲醛 (15b) 15d 1 5e Compound 15 First step: (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl) -6,8-dioxobicyclo[3.2.1]octane-1-carbaldehyde (15b)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2. l]octane-l-carbaldehyde  (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2. l] Octane-l-carbaldehyde

Figure imgf000093_0002
Figure imgf000093_0002

室温下， 将 ((lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧 二环 [3.2.1]辛烷 -1-基)甲醇 15a (13 g, 18.5 mmol,上海喀露蓝科技有限公司）溶于 1,2-二氯乙 烷（156 mL)， 加入醋酸碘苯 (14 g, 49.9 mmol)， 加热回流反应 6小时。 将反应液抽滤， 用二 氯甲烷（70 mL)洗涤滤饼， 滤液用饱和硫代硫酸钠溶液（50 mL), 饱和碳酸氢钠溶液（50 mL)洗涤。 水相用二氯甲烷（50 mL)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 减压浓 缩， 直接投入下一步反应。  ((lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl at room temperature -6,8-Dioxabicyclo[3.2.1]octane-1-yl)methanol 15a (13 g, 18.5 mmol, Shanghai Karlu Blue Technology Co., Ltd.) was dissolved in 1,2-dichloroethane ( 156 mL), iodobenzene acetate (14 g, 49.9 mmol) was added, and the mixture was heated under reflux for 6 hours. The reaction mixture was suction filtered, and the filtered cake was washed with methylene chloride (EtOAc) (EtOAc) The aqueous phase was extracted with methylene chloride (50 mL). EtOAc was evaporated.

第二步：（lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-甲酸 (15c)  Second step: (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -6,8-dioxobicyclo[3.2.1]octane-1-carboxylic acid (15c)

(lS,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2.1 joctane- 1 -carboxylic acid

Figure imgf000094_0001
(lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo [3.2.1 joctane - 1 -carboxylic acid
Figure imgf000094_0001

室温下， 将第一步产品（lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯 基) -6,8-二氧二环 [3.2.1]辛烷 -1-甲醛 15b粗品加入水（27 mL)和乙腈（108 mL) 的混合溶液 中， 冰浴下， 依次加入二水磷酸氢钠 （0.78 g, 5 mmol)、双氧水（30%, 4.2 g, 37 mmol)、亚氯 酸钠 （5.0 g, 55.5 mol 升至室温反应 2小时。 冰浴冷却反应液， 滴加硫代硫酸钠 (10%, 50 mL), 搅拌 10分钟， 加入乙酸乙酯 （70 mL)和水（70 mL)， 分液。水层用乙酸乙酯 (70 mL x 2)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 减压浓缩， 残留物用硅胶柱层析分析纯化 (石 油醚 /乙酸乙酯 = 6: 1 ~ 3: 1)， 得到白色固体 (lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙 氧基苄基)苯基 )-6,8-二氧二环 [3.2.1]辛烷 -1-甲酸 15c(10 g,产率 75%)。  The first step product (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl) Phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-carbaldehyde 15b was added to a mixed solution of water (27 mL) and acetonitrile (108 mL). Sodium hydrogen phosphate (0.78 g, 5 mmol), hydrogen peroxide (30%, 4.2 g, 37 mmol), sodium chlorite (5.0 g, 55.5 mol to room temperature for 2 hours. Cool the reaction solution in ice bath, add sulfur Sodium sulphate (10%, 50 mL), EtOAc (EtOAc) The organic layer was dried over anhydrous sodium sulfate (MgSO4). , 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2. 1] Octane-1-carboxylic acid 15c (10 g, yield 75%).

1H NMR (400 MHz, CDC13): δ 7.44 (s, 1H), 7.23 (d, 15H), 7.03 (d, 2H), 6.84 (d, 2H), 6.72 1H NMR (400 MHz, CDC13): δ 7.44 (s, 1H), 7.23 (d, 15H), 7.03 (d, 2H), 6.84 (d, 2H), 6.72

(d, 2H), 4.87― 4.70 (m, 3H), 4.63 (d, 1H), 4.50 (d, 1H), 4.22 (d, 1H), 4.14 (t, 2H), 4.08― 3.89 (m, 6H), 3.84 (d, 1H), 3.72 (d, 1H), 1.36 (t, 3H)。 (d, 2H), 4.87 - 4.70 (m, 3H), 4.63 (d, 1H), 4.50 (d, 1H), 4.22 (d, 1H), 4.14 (t, 2H), 4.08 - 3.89 (m, 6H ), 3.84 (d, 1H), 3.72 (d, 1H), 1.36 (t, 3H).

第三、第四步：2-(((lR,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8- 二氧二环 [3.2.1]辛烷 -1-基)巯基)吡啶 (15e)  Third and fourth steps: 2-(((lR, 2S, 3R, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxy) Benzyl)phenyl)-6,8-dioxobicyclo[3.2.1]octane-1-yl)indenyl)pyridine (15e)

2-(((lR,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8- dioxabicyclo[3.2.1 ] octan- 1 -yl)thio)pyridine  2-(((lR,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8- dioxabicyclo[ 3.2.1 ] octan- 1 -yl)thio)pyridine

Figure imgf000094_0002
Figure imgf000094_0002

室温下，将 (lS,2S,3S,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二 环 [3.2.1]辛烷 -1-甲酸 15c(4 g, 5.57 mmol)、 二环己基碳二亚胺 （1.4 g, 6.13 mmol)、 4-二甲氨 基吡啶 （68 mg, 0.56 mmol)溶于二氯甲烷 (20 mL)中。避光下，加入 2-巯基吡啶 -N-氧化物 (2.1 g, 16.7 mmol), 室温搅拌反应过夜。 加入硫粉 (620 mg, 2.42 mmol)， 在 500瓦钨灯光照反应 1小时。 冰浴冷却反应液， 加入硼氢化钠 (4.2 g, 111.4 mmol) 的甲醇溶液 (45 mL)， 升至室温 反应 30分钟。将反应液过滤， 滤液中加入饱和氯化铵 (lOOmL), 分液， 水层用二氯甲烷（50 mL x 2)萃取， 合并有机相， 无水硫酸钠干燥， 过滤， 减压浓缩。 残留物溶于乙醇与四氢呋 喃的混合溶剂 (5 mL, V/V = 1: 1) 中， 冰浴下加入氢氧化钠 （122 mg, 3.05 mmol)， 室温搅拌 30 分钟， 浓缩。 硅胶柱层析分析纯化（石油醚 /乙酸乙酯 = 15: 1) , 得到白色固体 2-(((lR,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛 烷 -1-基)巯基)吡啶 15e(560 mg,产率 12.8%)。 (lS, 2S, 3S, 4R, 5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -6,8-Dioxabicyclo[3.2.1]octane-1-carboxylic acid 15c (4 g, 5.57 mmol), dicyclohexylcarbodiimide (1.4 g, 6.13 mmol), 4-dimethylaminopyridine (68 mg, 0.56 mmol) was dissolved in dichloromethane (20 mL). In the dark, 2-pyridylpyridine-N-oxide (2.1 g, 16.7 mmol) was added, and the mixture was stirred at room temperature overnight. Sulfur powder (620 mg, 2.42 mmol) was added and the reaction was carried out for 1 hour under a 500 watt tungsten lamp. The reaction solution was cooled in an ice-bath, and sodium borohydride (4.2 g, 111.4 mmol) in methanol (45 mL) was added and the mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was filtered, and EtOAc EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m v The residue was dissolved in a mixture of ethanol and THF (5 mL, V/V = 1: 1). Purification by silica gel column chromatography (petrole ether / ethyl acetate = 15: 1) to afford 2-(((l,,,,,,,,,,,,,,,,,, -5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxobicyclo[3.2.1] octane Alkyl-1-yl)indenyl)pyridine 15e (560 mg, yield 12.8%).

¾ NMR (400 MHz, CDC13): δ 8.50 (d, 1H), 7.53 (ddd, 2H), 7.40― 7.26 (m, 11H), 7.23― 7.09 (m, 6H), 7.05 (d, 2H), 6.87 (d, 2H), 6.75 (d, 2H), 4.87― 4.76 (m, 3H), 4.65 (d, 1H), 4.55 (d, J = 8.1 Hz, 1H), 4.27 (d, 1H), 4.11 (dd, 1H), 4.05 - 3.92 (m, 5H), 3.92 - 3.83 (m, 2H), 3.71 (d, 1H), 1.39 (t, 3H);  3⁄4 NMR (400 MHz, CDC13): δ 8.50 (d, 1H), 7.53 (ddd, 2H), 7.40― 7.26 (m, 11H), 7.23― 7.09 (m, 6H), 7.05 (d, 2H), 6.87 (d, 2H), 6.75 (d, 2H), 4.87 - 4.76 (m, 3H), 4.65 (d, 1H), 4.55 (d, J = 8.1 Hz, 1H), 4.27 (d, 1H), 4.11 ( Dd, 1H), 4.05 - 3.92 (m, 5H), 3.92 - 3.83 (m, 2H), 3.71 (d, 1H), 1.39 (t, 3H);

LC-MS (APCI): 786.3[M+1]。  LC-MS (APCI): 786.3 [M+1].

第五步： （lR,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- (吡啶 -2-基硫基 )-6,8-二氧二 环 [3.2.1]辛烷 -2,3,4-三醇 (化合物 15)  Step 5: (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(pyridin-2-ylthio)- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol (Compound 15)

(lR,2S,3R,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(pyridin-2-ylthio)-6,8-dioxabicyclo[ 3.2.1]octane-2,3,4-triol  (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-l-(pyridin-2-ylthio)-6,8-dioxabicyclo[ 3.2.1]octane -2,3,4-triol

Figure imgf000095_0001
Figure imgf000095_0001

将 2-(((lR,2S,3R,4R,5S)-2,3,4-三 (苄氧基) -5-(4-氯 -3-(4-乙氧基苄基)苯基) -6,8-二氧二环 [3.2.1]辛烷 -1-基)巯基)吡啶 15e(130 mg, 0.17 mmol)溶于二氯甲烷中， 降温至 -70°C， 滴加氯 化硼 (3.4 mL, 1 mol/L, 3.4 mmol), 滴加完毕继续搅拌反应 1.5小时。 向反应体系中滴加二氯 甲烷与甲醇的混合溶剂 (10 mL, V/V=l : l)， 滴加水（10 mL)、 饱和碳酸氢钠 （20 mL)。 分液， 水相用二氯甲烷（10 mL x 2)萃取， 合并有机相， 用饱和碳酸氢钠 （10 mL x 2)洗条， 无水 硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析分析纯化 (二氯甲烷 /甲醇 = 40: 1 ~ 30: 1)， 得到白色固体 (lR,2S,3R,4R,5S)-5-(4-氯 -3-(4-乙氧基苄基)苯基) -1- (吡啶 -2-基硫基 )-6,8-二氧 二环 [3.2.1]辛烷 -2,3,4-三醇 （化合物 15) (20 mg,产率 23%)。  2-(((lR,2S,3R,4R,5S)-2,3,4-tris(benzyloxy)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl) -6,8-Dioxabicyclo[3.2.1]octane-1-yl)indenyl)pyridine 15e (130 mg, 0.17 mmol) dissolved in dichloromethane, cooled to -70 ° C, dropwise Boron (3.4 mL, 1 mol/L, 3.4 mmol) was added and the reaction was stirred for 1.5 hours. A mixed solvent of methylene chloride and methanol (10 mL, V/V = 1:1) was added dropwise to the reaction mixture, and water (10 mL) and saturated sodium hydrogen carbonate (20 mL) were added dropwise. The mixture was separated with EtOAc (EtOAc) (EtOAc m. Purification by silica gel column chromatography (dichloromethane/methanol = 40: 1 to 30: 1) to afford white solid (lR, 2S, 3R, 4R, 5S)-5-(4-chloro-3-(4-B Oxybenzyl)phenyl)-1-(pyridin-2-ylthio)-6,8-dioxobicyclo[3.2.1]octane-2,3,4-triol (compound 15) ( 20 mg, yield 23%).

¾ NMR (400 MHz, MeOD): δ 8.38 (dt, 1H), 7.57 (dd, 2H), 7.34― 7.15 (m, 4H), 7.00 (d, 3⁄4 NMR (400 MHz, MeOD): δ 8.38 (dt, 1H), 7.57 (dd, 2H), 7.34― 7.15 (m, 4H), 7.00 (d,

2H), 6.73 (d, 2H), 4.32 (d, 1H), 3.92 (dt, 4H), 3.61 (d, 2H), 3.56 (t, 1H), 3.47 (d, 1H), 1.31 - 1.21 (m, 3H); 2H), 6.73 (d, 2H), 4.32 (d, 1H), 3.92 (dt, 4H), 3.61 (d, 2H), 3.56 (t, 1H), 3.47 (d, 1H), 1.31 - 1.21 (m , 3H);

LC-MS (APCI): 516.0[M+1]。 生物测试  LC-MS (APCI): 516.0 [M+1]. Biological test

1. SGLT-2体外抑制试验  1. SGLT-2 in vitro inhibition test

利用 SGLT-2体外抑制试验评价本发明化合物的活性。  The activity of the compounds of the invention was evaluated using the SGLT-2 in vitro inhibition assay.

试验方法如下：将受试化合物溶解于 DMSOC二甲亚砜；)中制备储存液，之后稀释至所需 浓度。 试验开始前一天， 将 hSGLT-2细胞铺于 96孔板中， F12完全培养基培养。 培养 48 小时后， 每孔细胞用 pH值为 7.4的缓冲液洗 3次。 每孔加入 ΙΟΟμΙ含有不同受试化合物和 [14C]-cx-甲基-葡萄糖苷（10 μα/ml) 的缓冲液。 37°C孵育 2小时后中止反应，并用缓冲液洗 5次。每孔加入 20μ1预冷的 100 mM NaOH使细胞充分裂解。最后每孔加入 80 μΐ Microscint 40， 用 MicroBeta Trilux (PerkinElmer)液闪仪检测， 试验结果见表 1。 The test method is as follows: The test compound is dissolved in DMSOC dimethyl sulfoxide;) to prepare a stock solution, which is then diluted to the desired concentration. One day before the start of the experiment, hSGLT-2 cells were plated in 96-well plates and cultured in F12 complete medium. After 48 hours of culture, each well was washed 3 times with a buffer of pH 7.4. A buffer containing different test compounds and [14C]-cx-methyl-glucoside (10 μα/ml) was added to each well. After incubation at 37 ° C for 2 hours, stop the reaction and wash with buffer 5 times. The cells were fully lysed by the addition of 20 μl of pre-cooled 100 mM NaOH per well. Finally, 80 μM Microscint 40 was added to each well and examined with a MicroBeta Trilux (PerkinElmer) liquid scintillation test. The test results are shown in Table 1.

表 1 SGLT-2体外抑制试验结果  Table 1 SGLT-2 in vitro inhibition test results

Figure imgf000096_0001
Figure imgf000096_0001

结论： 本发明化合物可明显抑制 SGLT-2活性。  Conclusion: The compounds of the invention significantly inhibit SGLT-2 activity.

2. SGLT-1/SGLT-2体外选择性测定  2. SGLT-1/SGLT-2 in vitro selective assay

利用 SGLT-1、 SGLT-2体外抑制试验评价化合物 2、 化合物 11的选择性。  The selectivity of Compound 2, Compound 11 was evaluated by the SGLT-1, SGLT-2 in vitro inhibition assay.

试验方法如下：将受试化合物溶解于 DMSOC二甲亚砜；)中制备储存液，之后稀释至所需 浓度。试验开始前一天， 将 hSGLTl细胞铺于 96孔板中， F12完全培养基培养。 培养 48小 时后， 每孔细胞用 pH值为 7.4的缓冲液洗 3次。 每孔加入 ΙΟΟμΙ含有不同受试化合物和 [14C]-cx-甲基-葡萄糖苷（ΙΟ μα/ml) 的缓冲液。 37°C孵育 2小时后中止反应，并用缓冲液洗 5次。每孔加入 20μ1预冷的 100 mM NaOH使细胞充分裂解。最后每孔加入 80 μΐ Microscint 40， 用 MicroBeta Trilux (PerkinElmer)液闪仪检测， 试验结果见表 2。  The test method is as follows: The test compound is dissolved in DMSOC dimethyl sulfoxide;) to prepare a stock solution, which is then diluted to the desired concentration. One day before the start of the experiment, hSGLT1 cells were plated in 96-well plates and cultured in F12 complete medium. After 48 hours of culture, each well was washed 3 times with a buffer of pH 7.4. A buffer containing different test compounds and [14C]-cx-methyl-glucoside (ΙΟ μα/ml) was added to each well. After incubation at 37 ° C for 2 hours, the reaction was stopped and washed 5 times with buffer. The cells were fully lysed by the addition of 20 μl of pre-cooled 100 mM NaOH per well. Finally, 80 μM Microscint 40 was added to each well and examined with a MicroBeta Trilux (PerkinElmer) liquid scintillation test. The test results are shown in Table 2.

表 2试验结果  Table 2 test results

Figure imgf000096_0002
Figure imgf000096_0002

结论： 本发明化合物 2和 11对 SGLT-2选择性高。  Conclusion: Compounds 2 and 11 of the present invention are highly selective for SGLT-2.

3.尿糖试验  3. Urine sugar test

研究目的 利用尿糖实验评价本发明化合物在大鼠中的活性。 Research purposes The activity of the compounds of the present invention in rats was evaluated using a urine glucose test.

受试化合物  Test compound

化合物 1、 2、 5、 6、 8、 11、 12、 13、 13-1、 13-2、 14、 14-1、 14-2。  Compounds 1, 2, 5, 6, 8, 11, 12, 13, 13-1, 13-2, 14, 14-1, 14-2.

试验动物  Test animal

SD(Sprague Dawley)大鼠， 8周龄， 雄性， 购自成都达硕生物科技有限公司， 动物生产 合格证号： SOXK (川) 2008-24。  SD (Sprague Dawley) rat, 8 weeks old, male, purchased from Chengdu Dashuo Biotechnology Co., Ltd., animal production certificate number: SOXK (chuan) 2008-24.

试验方法  experiment method

称取 l.Omg受试化合物， 先用 0.05ml的二甲基亚砜溶解， 再加入 0.05ml的 Solutol, 待 溶解后再加入 0.95ml的生理盐水， 配制成 1.0mg/ml的溶液。 再称取葡萄糖溶于超纯水中， 制备 50%葡萄糖溶液， 备用。 将 SD大鼠禁食 18小时后， 测量每只动物的体重， 并按照体 重将动物分组， 每组 3只大鼠。然后将大鼠单独装入代谢笼， 按照 3mg/kg和 10mg/kg剂量 将受试化合物灌服到各只动物， 对照组灌服生理盐水。 30分钟后， 所有动物口服葡萄糖溶 液（2g/kg)。 1小时后， 给动物添加饲料， 24小时后， 收集动物尿液， 使用尿糖试剂盒测试 尿糖含量， 试验结果见表 3、 表 4。  The test compound was weighed and dissolved in 0.05 ml of dimethyl sulfoxide, and then 0.05 ml of Solutol was added. After dissolution, 0.95 ml of physiological saline was added to prepare a 1.0 mg/ml solution. The glucose was weighed and dissolved in ultrapure water to prepare a 50% glucose solution for use. After the SD rats were fasted for 18 hours, the body weight of each animal was measured, and the animals were grouped according to the body weight, and 3 rats in each group. The rats were then individually loaded into metabolic cages, and the test compounds were administered to each animal at doses of 3 mg/kg and 10 mg/kg, and the control group was administered with physiological saline. After 30 minutes, all animals were orally administered a glucose solution (2 g/kg). After 1 hour, the animals were added with feed. After 24 hours, the animal urine was collected and the urine sugar content was tested using a urine sugar kit. The test results are shown in Table 3 and Table 4.

表 3大鼠以 3mg/kg剂量灌服的尿糖试验结果  Table 3 Results of urine glucose test administered by rats at a dose of 3 mg/kg

Figure imgf000097_0001
化合物 1 1221
Figure imgf000097_0001
Compound 1 1221

化合物 5 768  Compound 5 768

化合物 6 899  Compound 6 899

化合物 8 2481  Compound 8 2481

化合物 1 1 2693 结论： 本发明化合物可明显增加大鼠尿糖量。  Compound 1 1 2693 Conclusion: The compounds of the invention significantly increase the amount of urine glucose in rats.

4、 猴尿糖实验  4, monkey urine test

研究目的  Research purposes

利用尿糖实验评价本发明化合物在猴中的活性。  The activity of the compounds of the invention in monkeys was evaluated using a urine glucose assay.

受试化合物  Test compound

化合物 2、 8、 1 1。  Compound 2, 8, 1 1.

试验动物  Test animal

体重年龄较为接近的正常成年猴， 8只， 雌雄各半。  Normal adult monkeys with a similar age and weight, 8 males and half females.

试验方法  experiment method

1、 将猴分为 4组， 分别为空白组、 Canagliflozin组、 化合物 2组、 化合物 8组， 每组 各 2只， 1雌 1雄。 单独于代谢笼中禁食 18小时， 不禁水。  1. The monkeys were divided into 4 groups, namely blank group, Canagliflozin group, compound 2 group, and compound 8 group, each group consisting of 2 animals, 1 female and 1 male. Fasting alone in the metabolic cage for 18 hours, can not help but water.

2、 第二天， 收集尿液， 测量体积， 取样冻存与 -20度。 称量动物体重， 按体重给予原 料药胶囊， 剂量为 25mg/kg; 对照组给予空胶囊。 2. The next day, urine was collected, the volume was measured, and the sample was stored frozen at -20 degrees. The body weight of the animals was weighed, and the drug capsules were administered at a dose of 25 mg/kg according to the body weight ; the control group was given empty capsules.

3、 30分钟后， 每只动物灌服 50%的葡萄糖溶液， 剂量为 2g/kg; 1个小时后， 给予动 物饲料。 3. After 30 minutes, each animal was given 50% glucose solution at a dose of 2 g/kg ; after 1 hour, the animals were given a feed.

4、分别于 0-6h、 6-24h、 24-48h、 48-72h、 72-96h后， 收集各只动物的尿液， 测量体积， 取样冻存与 -20度。  4. After 0-6h, 6-24h, 24-48h, 48-72h, 72-96h, the urine of each animal was collected, the volume was measured, and the sample was frozen and stored at -20 degrees.

表 5猴尿糖实验  Table 5 monkey urine glucose test

Figure imgf000098_0001
Figure imgf000099_0001
结论： 本发明化合物与上市的药物坎格列净相比， 更有效的促进尿糖。
Figure imgf000098_0001
Figure imgf000099_0001
Conclusion: The compounds of the present invention are more effective in promoting urinary glucose than the marketed drug cangliflozin.

Claims

权利要求书 i、 通式 ω所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受 的盐、 共晶体或前药： Claims i, an oxabicyclic derivative of the formula ω or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:
Figure imgf000100_0001
其中-
Figure imgf000100_0001
among them- X选自 -0-、 -S(=0)n-或- NR8-; X is selected from -0-, -S(=0) n - or -NR 8 -; R选自 H、 d— 8烷基、 -(CH2)m-C2— 8烯基- R12、 -(CH2)m-C2— 8炔基- R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -^！！^ ^环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4 至 14元桥环基)或 -(CH2)m-S(=0)n-R9， 其中所述的烷基、 烯基、 炔基、 芳基、 杂芳基、 螺环 基、桥环基、并环基、环烷基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、氰基、硝基、异氰基、羟基、醛基、羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2_8 烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 且所述的杂环烷基、 杂芳基、 螺环基、桥环基或并环基 可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 8 alkyl, - (CH 2) m -C 2 - 8 alkenyl, - R 12, - (CH 2 ) m -C 2 - 8 alkynyl, - R 12, - (CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -^! ! ^^cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m - (6 to 14 yuan) Heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14) a bridged ring) or -(CH 2 ) m -S(=0) n -R 9 , wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, spiro group, bridged ring group And a cyclo, cycloalkyl or heterocycloalkyl group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, Nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy, -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m -( 4 to 14 members and a cyclic group), -(CH 2 ) m - (4 to 14 membered bridged ring group), -0-C 3 -8 cycloalkyl group, -0-(3 to 8 membered heterocycloalkyl group) , -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), -0- (5 to 14 yuan) Spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0- R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m - S (= 0) n -R 9 is substituted with a substituent; and said heterocycloalkyl, heteroaryl, spiro cycloalkyl group, a cycloalkyl group or a bridged cycloalkyl group and may contain 0 to 5 heteroatoms selected from N, 0 Or 3 (=0) 11 atoms or groups; R1, R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 d_8烷氧基、 -0-C(=0)-R13、 -0-C(=0)-0-R13、 -0-C(=0)-(CH2)m-C6— 14芳基、 -0-C(=0)-0-C6— 14芳基、 -0-(CH2)m-C6— 14芳基、 -O-硅烷基或 -0-C2— 8烯基， 其中所述的烷氧基、芳基或烯基可任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 羟基、 d— 8烷基、 d— 8烷氧基、 C3—8环烷基或 3至 8元杂环烷基的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 8 alkoxy, -0-C(=0)-R 13 , -0-C (=0 )-0-R 13 , -0-C(=0)-(CH 2 ) m -C 6 - 14 aryl, -0-C(=0)-0-C 6 - 14 aryl, -0- (CH 2) m -C 6 - 14 aryl group, -O- or silane group -0-C 2 - 8 alkenyl group, wherein the alkoxy group, an aryl group or alkenyl group may optionally be further 0-5 selected from F, Cl, Br, I, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group substituents; the Heterocycloalkyl contains 1 to 5 atoms or groups selected from N, 0 or S(=0) n ; R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 I、 氰基、 异氰基、 硝基、 羟基、 醛 基、羧基、 C 烷基、 d— 8烷氧基、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -(CH2)m-C3-8 环烷基、 -(CH2)m-(3 至 8元杂环烷基)、 -(CH2)m-C6.14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3— 8 环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环 基)、 -0-(4至 14元并环基)、 -0-(4至 14元桥环基)、 -(CH2)m-C(=0)-R13、-(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13 、 -(CH2)m-S(=0)n-R9 、 -NR10Rn 、 -(CH2)m-NHC(=0)-R13
Figure imgf000101_0001
所述的杂环烷基、 杂芳基、 螺环基、 桥环 基或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团， 所述烷基、 烷氧基、烯基、 炔基、环烷基或杂环烷基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 羟基、 d— 4烷基或者^— 4烷氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, isocyano, nitro, hydroxy, aldehyde, carboxyl, C alkyl, d- 8 alkoxy, - (CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (CH 2) m -C 3 - 8 Cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 .14 aryl, -(CH 2 ) m -(6 to 14-membered heteroaryl) (), -(CH 2 ) m - (5 to 14-membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14-membered bridge) Cyclo), -0-C 3 - 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl) ), -0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C( =0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m - 0-C(=0)-0-R 13 , -(CH 2 ) m -S(=0) n -R 9 , -NR 10 R n , -(CH 2 ) m -NHC(=0)-R 13
Figure imgf000101_0001
The heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 , the alkane The radical, alkoxy, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are each independently optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3, = 0, amino, cyano, hydroxy, alkyl or D- ^ 4 - 4 alkoxy group substituted with substituted; 作为选择， R5与 R6、 R6与 R7任一组可以形成一个 3至 10元环， 所形成的环选自环烷 基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 3个选自 N、 0或 3(=0)11杂原子或 基团， 且所述的环烷基、 杂环基、 芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 d— 8烷基、 d— 8烷氧 基、 -(CH2)m-C2_8烯基 -R12、 -(CH2)m-C2_8炔基 -R12、 -( ！^；^ ^环烷基、 -(CH2)m-(3至 8元杂 环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4 至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、-0-(3至 8元杂环烷基)、-0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； Alternatively, R 5 and R 6 , R 6 and R 7 may form a 3 to 10 membered ring, and the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and is formed. The ring may contain from 0 to 3 heteroatoms or groups selected from N, 0 or 3 (=0) 11 and the cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl , d- 8 alkoxy, -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 -8 alkynyl-R 12 , -( !^;^ ^环Alkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl) ), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring) Base), -0-C 3 -8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl) , -0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(= 0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0- R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m - Substituted by a substituent of S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 selected from N, 0 or An atom or group of S(=0) n ; W选自单键、 -NH -、 -0-、 -C(=0)-、 -S(=0)n -、 d_3亚烷基或 所述的亚烷基或 "'Ρ 任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 d— 4烷基、 d— 4烷 氧基、 C3— 5环烷基或 3至 5元杂环烷基的取代基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； W is selected from a single bond, -NH -, -0-, -C(=0)-, -S(=0) n -, d_ 3 alkylene or the alkylene group or "'Ρ optionally further From 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, d- 4 alkyl, d- 4 alkoxy, C 3 -5 cycloalkyl Or a substituent of a 3- to 5-membered heterocycloalkyl group, the heterocycloalkyl group having 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; 环 G选自 6至 14元芳基或 5至 14元杂芳基， 所述的芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 异氰基、 羟基、 醛基、 羧基、 8烷基、 d— 8烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2— 8炔基 -R12、 -( ！！^ ^环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_14芳基、 -(CH2)m-(6至 14元 杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环 基)、 -0-C3— 8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6— 14芳基、 -0-(6至 14元杂芳基)、 -0-(5 至 14元螺环基)、 -0-(4 至 14元并环基)、 -0-(4 至 14元桥环基)、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -(CH2)m-0-C(=0)-R13、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn, -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代， 其中所述烷基、 芳 基、 螺环基、 桥环基、 并环基、 杂芳基、 烷氧基、 环烷基、 杂环烷基、 烯基或炔基任选进 一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氰基、 异氰基、 硝基、 羟 基、 烷基、 d_8烷氧基、 -(CH2)m-C3_8环烷基、 -(CH2)m-(3至 8元杂环烷基)、 -(CH2)m-C6_i4 芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14芳基、 -0-(6 至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14元桥环基)、 -(CH2)m-C2— 8烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C(=0)-R13、 -(CH2)m-C(=0)-0-R13、 -NR1QRU或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、 螺环基、 桥环基 或并环基可含有 0至 5个选自 N、 0或 3(=0)11的原子或基团； Ring G is selected from 6 to 14 membered aryl or 5 to 14 membered heteroaryl, optionally further 0 to 5 selected from F, Cl, Br, I, -CH 2 F -CHF 2 , -CF 3 , cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, -8 alkyl, d- 8 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12, - ( CH 2) m -C 2 - 8 alkenyl -R 12, - (CH 2) m -C 2 - 8 alkynyl group -R 12, - (!! ^ ^ cycloalkyl -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 _ 14 aryl, -(CH 2 ) m -(6 to 14 membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring group) , -0-C 3 - 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 - 14 aryl, -0-(6 to 14-membered heteroaryl), - 0-(5 To 14-membered spiro group), -0-(4 to 14-membered ring group), -0-(4 to 14-membered bridged ring group), -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0) -0-R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 1Q R U or -(CH 2 Substituted by a substituent of m -S(=0) n -R 9 wherein the alkyl group, the aryl group, the spiro group, the bridged ring group, the cycloalkyl group, the heteroaryl group, the alkoxy group, the cycloalkyl group And a heterocycloalkyl, alkenyl or alkynyl group optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, isocyanide Base, nitro, hydroxy, alkyl, d- 8 alkoxy, -(CH 2 ) m -C 3 -8 cycloalkyl, -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), - (CH 2 ) m -C 6 _i4 aryl, -(CH 2 ) m -(6 to 14-membered heteroaryl), -(CH 2 ) m -(5 to 14-membered spiro group), -(CH 2 m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring), -0-C 3 -8 cycloalkyl, -0- (3 to 8 membered) Cycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), -0-(5 to 14-membered spiro group), -0- (4 to 14) And a ring-based group, -0-(4 to 14-membered bridged ring group), -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 .8 alkynyl- R 12 , -(CH 2 ) m -C(=0)-R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -NR 1Q R U or -(CH 2 ) m - Substituted by a substituent of S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or cyclylene may contain 0 to 5 selected from N, 0 or An atom or group of 3 (=0) 11 ; 作为选择， 环 G上任意两个取代基可以形成一个 3至 8元环， 所形成的环选自环烷基、 杂环基、 芳基或杂芳基， 而且所形成的环可含 0至 5个选自 N、 0或 3(=0)11杂原子或基团， 且所述的环烷基、杂环基、芳基或杂芳基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、氰基、硝基、异氰基、羟基、醛基、羧基、 d— 8烷基、 d— 8烷氧基、 -(CH2)m-C2_8 烯基 -R12、 -(CH2)m-C2.8炔基 -R12、 -(CH2)m-C3-8环烷基、 -(CH2)m-(3 至 8 元杂环烷基）、 -(CH2)m-C6— 14芳基、 -(CH2)m-(6至 14元杂芳基)、 -(CH2)m-(5至 14元螺环基)、 -(CH2)m-(4至 14元并环基)、 -(CH2)m-(4至 14元桥环基)、 -0-C3_8环烷基、 -0-(3至 8元杂环烷基)、 -0-C6_14 芳基、 -0-(6至 14元杂芳基)、 -0-(5至 14元螺环基)、 -0-(4至 14元并环基)、 -0-(4至 14 元 桥环 基） 、 -(CH2)m-C(=0)-R13 、 -(CH2)m-C(=0)-0-R13 、 -(CH2)m-0-C(=0)-R13 、 -(CH2)m-0-C(=0)-0-R13、 -(CH2)m-NHC(=0)-R13、 -(CH2)m-C(=O)-NR10Rn、 -NR10Rn 或 -(CH2)m-S(=0)n-R9的取代基所取代； 所述的杂环烷基、 杂芳基、螺环基、桥环基或并环基可 含有 0至 5个选自 N、 0或 S(=0)n的原子或基团； Alternatively, any two substituents on ring G may form a 3 to 8 membered ring, the ring formed is selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the resulting ring may contain 0 to 5 selected from N, 0 or 3 (=0) 11 heteroatoms or groups, and said cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from 0 to 5 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , =0, cyano, nitro, isocyano, hydroxy, aldehyde, carboxyl, d- 8 alkyl, d- 8 alkoxy , -(CH 2 ) m -C 2 -8 alkenyl-R 12 , -(CH 2 ) m -C 2 .8 alkynyl-R 12 , -(CH 2 ) m -C 3 -8 cycloalkyl -(CH 2 ) m -(3 to 8 membered heterocycloalkyl), -(CH 2 ) m -C 6 -14 aryl, -(CH 2 ) m -(6 to 14-membered heteroaryl), -(CH 2 ) m -(5 to 14 membered spiro group), -(CH 2 ) m - (4 to 14 membered cyclo), -(CH 2 ) m - (4 to 14 membered bridged ring group) , -0-C 3 _ 8 cycloalkyl, -0-(3 to 8 membered heterocycloalkyl), -0-C 6 _ 14 aryl, -0-(6 to 14-membered heteroaryl), - 0-(5 to 14 membered spiro group), -0-(4 to 14 membered ring group), -0-(4 to 14 membered bridged ring group), -(CH 2 ) m -C(=0) -R 13 , -(CH 2 ) m -C(=0)-0-R 13 , -(CH 2 ) m -0-C(=0)-R 13 , -(CH 2 ) m -0-C(=0)-0- R 13 , -(CH 2 ) m -NHC(=0)-R 13 , -(CH 2 ) m -C(=O)-NR 10 R n , -NR 10 R n or -(CH 2 ) m - Substituted by a substituent of S(=0) n -R 9 ; the heterocycloalkyl, heteroaryl, spiro, bridged or bicyclic group may contain 0 to 5 selected from N, 0 or An atom or group of S(=0) n ; R8、 R1Q和 R11各自独立选自 H、 羟基、 d_8烷基、 d_8烷氧基、 C3_8环烷基或 3至 8元 杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； R 8 , R 1Q and R 11 are each independently selected from H, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 -8 cycloalkyl or 3 to 8 membered heterocycloalkyl, said heterocycloalkane The group contains 1 to 5 atoms or groups selected from N, 0 or S(=0) n ; R9选自 H、 d— 8烷基、 ^8环烷基或 3至 8元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 8 alkyl, ^ 8 cycloalkyl or 3 to 8 membered heterocycloalkyl, and said heterocycloalkyl contains 1 to 5 selected from N, 0 or 3 (=0) An atom or group of 11 ; R12和 R13各自独立选自 H、 氨基、 羟基、 d— 8烷基、 d— 8烷氧基、 C3— 8环烷基或 3至 8 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 8 alkyl, d- 8 alkoxy, C 3 - 8 cycloalkyl or 3 to 8-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; n选自 0、 1或 2;  n is selected from 0, 1 or 2; p选自 1、 2或 3 ; m选自 0、 1、 2、 3或 4。 p is selected from 1, 2 or 3; m is selected from 0, 1, 2, 3 or 4. 2、 根据权利要求 1所述通式 (I)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂 化物、 药学上可接受的盐、 共晶体或前药， 其中： The oxabicyclic derivative represented by the formula (I) according to Claim 1, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R选自 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(6至 8元杂芳基)或者 -(CH2)m-(3至 6元杂环烷基 )， 所述的烷基、 杂环烷基、 杂芳基或者环烷基任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基、 d— 4烷氧基、 -0-C3— 6 环烷基或者 -0-P至 6元杂环烷基;)的取代基所取代； 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl) or -(CH 2 ) m -( a 3- to 6-membered heterocycloalkyl group, wherein the alkyl group, heterocycloalkyl group, heteroaryl group or cycloalkyl group is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, CHF 2, -CF 3, cyano, hydroxy, carboxy, amino, d- 4-alkyl, d- 4 alkoxy, -0-C 3 - 6 cycloalkyl, or -0-P to 6-membered heterocycloalkyl Substituted by a substituent of the group ;); the heterocycloalkyl group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; R1 , R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、 羟基、 d_4烷氧基、 -0-C(=0)-R13 、 -0-C(=0)-0-R13、 -O-苄基、 -O-硅烷基、 -O-烯丙基或 -O-乙烯基， 其中所述的烷氧基进一步 被 0至 5个选自 F、 Cl、 Br、 I、 羟基、 d— 4烷基或 d— 4烷氧基； R 1 , R 2 and R 3 are each independently selected from H, F, Cl, Br, I, hydroxy, d- 4 alkoxy, -0-C(=0)-R 13 , -0-C (=0 -0-R 13 , -O-benzyl, -O-silyl, -O-allyl or -O-vinyl, wherein the alkoxy group is further from 0 to 5 selected from F, Cl , Br, I, hydroxy, d- 4 alkyl or d- 4 alkoxy; X选自 -0-或 -S-;  X is selected from -0- or -S-; R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基或者 d— 4烷氧 基， 所述烷基或烷氧基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 羟基、 d— 4烷基或者 — 4烷氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy, said alkyl or alkoxy Each of them is optionally further optionally 0 to 4 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , =0, amino, cyano, hydroxy, d-4 alkyl or -4 Substituted by a substituent of an alkoxy group; W选自 d— 3亚烷基、 -c(=o 或者 ^'p， 所述的亚烷基或 各自独立任选进一步被W is selected from d- 3 alkylene, -c(=o or ^'p, said alkylene or each independently optionally further 0至 3个选自 F、 Cl、 Br、 -CF3、 羟基、 d_4烷基、 d_4烷氧基、 C3_4环烷基或 3至 5元杂环 烷基的取代基所取代； 0-3 is selected from F, Cl, Br, -CF 3 , hydroxy, d_ 4 alkyl, d_ 4 alkoxy, C 3 _ 4 cycloalkyl group or 3 to 5-membered heterocyclic group substituted with a substituent group ; 环 G选自苯环、 噻吩或噻唑， 其中苯环、 噻唑或噻吩任选进一步被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、氰基、硝基、羟基、 C 6烷基、 d— 6烷氧基、 -(CH2)m-0-(CH2)m-0-R12、Ring G is selected from the group consisting of a benzene ring, a thiophene or a thiazole, wherein the benzene ring, thiazole or thiophene is further optionally 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, Nitro, hydroxy, C 6 alkyl, d- 6 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH2)m-C3_6环烷基、 -(CH2)m-(3至 6元杂环烷基)、 -(CH2)m-(5至 12元螺环基)、 -(CH2)m-(4 至 12元并环基 )、 -(CH2)m-(4至 12元桥环基 )、 -0-C3_6环烷基、 -0-(3至 6元杂环烷基 )、 -0-(5 至 12元螺环基)、 -0-(4至 12元并环基)、 -0-(4至 12元桥环基)、 -(CH2)m-S(=0)n-R9或 -NR1QRU 的取代基所取代， 且所述的杂环烷基、 杂芳基、 螺环基、 桥环基或并环基可含有 0至 5个 选自 N、 0或 3(=0)11的原子或基团； -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(3 to 6-membered heterocycloalkyl), -(CH 2 ) m - (5 to 12-membered spiro group), -(CH 2 ) m -(4 to 12-membered cyclo), -(CH 2 ) m - (4 to 12-membered bridged ring), -0-C 3 -6 cycloalkyl, -0-(3 To 6-membered heterocycloalkyl), -0-(5 to 12-membered spiro group), -0-(4 to 12-membered ring group), -0-(4 to 12 membered bridged ring group), -( Substituted by a substituent of CH 2 ) m -S(=0) n -R 9 or -NR 1Q R U , and said heterocycloalkyl, heteroaryl, spiro group, bridged ring or cyclylene group May contain 0 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; R9选自 H、 d— 4烷基、 C3—6环烷基或 3至 6元杂环烷基， 所述的杂环烷基含有 1至 5个 选自 N、 0或 3(=0)11的原子或基团； R 9 is selected from H, d- 4 alkyl, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring group containing 1 to 5 heteroatoms selected from N, 0 or 3 (= 0) an atom or group of 11 ; R1Q和 R11各自独立选自 H、 羟基、 d_4烷基、 C3_6环烷基、 3至 6元杂环烷基或 d_4烷 氧基， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R 1Q and R 11 are each independently selected from H, hydroxy, d- 4 alkyl, C 3 -6 cycloalkyl, 3 to 6-membered heterocycloalkyl or d 4 alkoxy, said heterocycloalkyl containing 1 Up to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; R12和 R13各自独立选自 H、 氨基、 羟基、 d— 4烷基、 d— 4烷氧基、 C3— 6环烷基或 3至 6 元杂环烷基， 所述的杂环烷基含有 1至 5个选自 N、 0或 S(=0)n的原子或基团； p选自 1、 2或 3 ; R 12 and R 13 are each independently selected from H, amino, hydroxy, d- 4-alkyl, d- 4 alkoxy, C 3 - 6 cycloalkyl, or 3 to 6-membered heterocyclic group, said heterocyclic ring The alkyl group contains 1 to 5 atoms or groups selected from N, 0 or S(=0)n; p is selected from 1, 2 or 3; n选自 0、 1或 2;  n is selected from 0, 1 or 2; m选自 0、 1或 2。  m is selected from 0, 1 or 2. 3、 根据权利要求 2所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中： The oxabicyclic derivative according to claim 2, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R选自 H、 甲基、 乙基、 环丙基、 氧杂环丙基、 氧杂环丁基、 氧杂环戊基、 氮杂环戊基 或者吡啶基， 且这些基团可以任选进一步被 0至 4个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 甲基、 乙基、 甲氧基、 乙氧基、 环丙基、 氨基、 氰基或羟基的取代基所取代； R is selected from H, methyl, ethyl, cyclopropyl, oxetanyl, oxetanyl, oxetanyl, azacyclopentyl or pyridyl, and these groups may optionally be further From 0 to 4 selected from F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl, amino, cyano or hydroxy Substituted by a substituent; X选自 -0-或 -S-;  X is selected from -0- or -S-; R R2和 R3各自独立地选自 H、 F、 Cl、 Br、 I、羟基、 -0-CH3、 -0-CH2CH3、 -0-CH2F、RR 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CH 2 F, -0-CHF2、 -0-CF3、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、-0-CHF 2 , -0-CF 3 , -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0-C(=0)0-CH 2 CH 3 , -o-苄基、 -o-硅烷基、 -o-烯丙基或 -o-乙烯基； -o-benzyl, -o-silyl, -o-allyl or -o-vinyl; R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 甲基、 乙基、 甲氧基、 乙氧基、 氰基、 羟基、 乙炔基或丙炔基； W选自 -CH2-或 ， 且 -CH2-或 ^ 各自独立任选进一步被 0至 2个选自 F、 Cl、R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, methyl, ethyl, methoxy, ethoxy, cyano, hydroxy, ethynyl or propynyl; From -CH 2 - or, and -CH 2 - or ^ are each independently optionally further from 0 to 2 selected from F, Cl, Br、 -CF3、 甲基、 乙基、 正丙基、 甲氧基或者乙氧基的取代基所取代； Substituted by a substituent of Br, -CF 3 , methyl, ethyl, n-propyl, methoxy or ethoxy; n选自 0、 1或 2;  n is selected from 0, 1 or 2; m选自 0、 1或 2。  m is selected from 0, 1 or 2. 4、 根据权利要求 2所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中包括通式 (II)所示的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共结晶复合物或前药： The oxabicyclic derivative according to claim 2, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof, which comprises the formula (II) Oxabicyclic derivatives or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, co-crystal complexes or prodrugs thereof:
Figure imgf000104_0001
其中-
Figure imgf000104_0001
among them- X选自 -0-或 -S-; X is selected from -0- or -S-; R选自 H、 d_4烷基、 -(CH2)m-C3_6环烷基、 -(CH2)m-(6至 8元杂芳基)、 或者 -(CH2)m-(3 至 6元杂环烷基 )， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d— 4烷基或者 d— 4烷氧基的取代 基所取代， 所述的杂环烷基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -6 cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl), or -(CH 2 ) m - (3 to 6-membered heterocycloalkyl), said alkyl, cycloalkyl, heteroaryl or heterocycloalkyl optionally further selected from 0 to 5 selected from F, Substituted by a substituent of Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, carboxy, amino, d- 4 alkyl or d- 4 alkoxy, said heterocycloalkane The group contains 1 to 5 atoms or groups selected from N, 0 or 3 (=0) 11 ; R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 d— 4烷基或者 d— 4烷氧 基； R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy; W选自 d— 3亚烷基或 ^" 所述的亚烷基或 各自任选进一步被 0至 4个选自 F、 Cl、 -CF3、 羟基、 d— 3烷基或 d— 3烷氧基的取代基所取代； W is selected from alkylene or ^ d- 3 'or said alkylene is optionally further substituted with 0 to 4 substituents selected from F, Cl, -CF 3, hydroxy, d- 3 alkyl or alkoxy d- 3 Substituted by a substituent of an oxy group; n选自 0、 1或 2;  n is selected from 0, 1 or 2; p选自 1或 2;  p is selected from 1 or 2; m选自 0、 1或 2。  m is selected from 0, 1 or 2. 5、 根据权利要求 1所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、共结晶复合物或前药， 其中包括通式 (III)所示的氧杂双环衍生物或其立体异 构体、 水合物， 溶剂化物、 上可接受的盐、 共晶体或前药： The oxabicyclic derivative according to claim 1, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, which comprises the formula (III) An oxabicyclic derivative or a stereoisomer, hydrate, solvate, acceptable salt, co-crystal or prodrug thereof:
Figure imgf000105_0001
Figure imgf000105_0001
 (III)  (III) 其中- among them- R选自 H、 d_4烷基、 -( ！！ -^^环烷基、 -(CH2)m-(6至 8元杂芳基)或 -(CH2)m-(3至 4 元杂环烷基 )， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取 代， 且所述的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d 4 alkyl, -( !! -^^cycloalkyl, -(CH 2 ) m -(6 to 8 membered heteroaryl) or -(CH 2 ) m - (3 to 4 member) a heterocycloalkyl group, said alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , Substituted with a substituent of CF 3 , amino, cyano, hydroxy, carboxy, d- 4 alkyl or d- 4 alkoxy, and said heterocycloalkyl contains 1 to 3 selected from N, 0 or 3 (=0) an atom or group of 11 ; R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、羟基、 d_4烷基、 d_4烷氧基、 -(CH2)m-0-(CH2)m-0-R12、 -(CH2)m-C3_6环烷基或者 -(CH2)m-(3 至 6元杂环烷基 )， 所述烷基、 烷氧基、 环烷基或者杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 =0、 氨基、 氰基、 硝基、 羟基、 d— 4烷基或者 d— 4烷氧 基的取代基所取代； 且所述的杂环烷基可含有 0至 3个选自 N、 0或 8(=0)11的原子或基团； 作为选择， R1' R2'、 R3'、 R4'和 R5'任意相邻的两个基团可以形成一个 4至 6元环， 所 形成的环选自环烷基、 杂环烷基、 芳基或杂芳基， 所形成的杂环烷基或杂芳基含有 1 至 3 个选自 N、 0或 3(=0)11的原子或基团， 且所述环烷基、 杂环烷基、 芳基或杂芳基任选进一 步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 d— 4烷基或 d— 4烷氧基的取 代基所取代； R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, d 4 alkyl, d 4 alkoxy, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 , -(CH 2 ) m -C 3 -6 cycloalkyl or -( CH 2 ) m -(3 to 6-membered heterocycloalkyl), optionally further 0 to 5 selected from F, Cl, Br, I Substituted with a substituent of -CH 2 F, -CHF 2 , -CF 3 , =0, an amino group, a cyano group, a nitro group, a hydroxyl group, a d- 4 alkyl group or a d- 4 alkoxy group; The cycloalkyl group may have 0 to 3 atoms or groups selected from N, 0 or 8 (=0) 11 ; alternatively, R 1 'R 2 ', R 3 ', R 4 ' and R 5 'arbitrary phases The two adjacent groups may form a 4- to 6-membered ring, and the ring formed is selected from a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and the heterocycloalkyl group or heteroaryl group formed contains 1 ring. Up to 3 atoms or groups selected from N, 0 or 3 (=0) 11 and optionally the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group The step is substituted with 0 to 5 substituents selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy, d- 4 alkyl or d- 4 alkoxy; R12选自 3至 6元环烷基； R 12 is selected from a 3- to 6-membered cycloalkyl group; n选自 0、 1或 2;  n is selected from 0, 1 or 2; m选自 0、 1或 2。  m is selected from 0, 1 or 2. 6、 根据权利要求 5所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中： The oxabicyclic derivative according to claim 5, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R选自 H、 d— 4烷基、 -(CH2)m-C3— 4环烷基、 -(CH2)m-(6元杂芳基)或 -(CH2)m-(3至 4元杂 环烷基 )，所述的烷基、环烷基、杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 -CH2F、 -CHF2、 -CF3、 氨基、 氰基、 羟基、 羧基、 d— 4烷基或 d— 4烷氧基的取代基所取代； 且所述 的杂环烷基含有 1至 3个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d- 4 alkyl, -(CH 2 ) m -C 3 -4 cycloalkyl, -(CH 2 ) m -(6-membered heteroaryl) or -(CH 2 ) m -(3 To a 4-membered heterocycloalkyl group, the alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, -CH 2 F, -CHF 2 , Substituted with a substituent of -CF 3 , amino, cyano, hydroxy, carboxy, d- 4 alkyl or d- 4 alkoxy; and said heterocycloalkyl contains 1 to 3 selected from N, 0 or An atom or group of 3 (=0) 11 ; R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 硝 基、 羟基、 CM烷基、 -(CH2)m-0-(CH2)m-0-R12或者 d_4烷氧基； R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, Hydroxy, CM alkyl, -(CH 2 ) m -0-(CH 2 ) m -0-R 12 or d_ 4 alkoxy; R12选自 3至 6元环烷基； R 12 is selected from a 3- to 6-membered cycloalkyl group; n选自 0、 1或 2;  n is selected from 0, 1 or 2; m选自 0、 1或 2。  m is selected from 0, 1 or 2. 7、 根据权利要求 6所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中： The oxabicyclic derivative according to claim 6, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: R选自 H、 甲基、 乙基、 正丙基、 异丙基、 2-羟基乙基、 -CH2CHF2、 -CH2CF3、 -CF3、 -CHF2、 -CH2F、 -CH2C≡N、 环丙基、 环丁基、 氧杂环丙基、 吡啶基、 氧杂环丁 R is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, -CH 2 CHF 2 , -CH 2 CF 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 C≡N, cyclopropyl, cyclobutyl, oxopropyl, pyridyl, oxetane R1'. R2'、 R3'、 R4'和 R5'各自独立选自 H、 F、 Cl、 甲氧基、 乙氧基、环丙基、
Figure imgf000106_0001
R 1 '. R 2 ', R 3 ', R 4 ' and R 5 ' are each independently selected from the group consisting of H, F, Cl, methoxy, ethoxy, cyclopropyl,
Figure imgf000106_0001
 -0-氧杂环丁基或 -0-氧杂环戊基。 -0-oxetanyl or -0-oxocyclopentyl. 8、 根据权利要求 2所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、共结晶复合物或前药， 其中包括通式 (IV)所示的氧杂双环衍生物或其立体异 构体、 水合物， 溶剂化物、 药学上可接受的盐、 共晶体或前药： The oxabicyclic derivative according to claim 2, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal complex or prodrug thereof, which comprises the formula (IV) An oxabicyclic derivative or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:
Figure imgf000106_0002
Figure imgf000106_0002
 (IV)  (IV) 其中 X选自 -o-或 -S-; among them X is selected from -o- or -S-; R选自 H、 d_4烷基、 -(CH2)m-C3_ 垸基、 -(CH2)m-(6元杂芳基)或者 -(CH2)m-(3至 6元 杂环烷基)， 所述的烷基、 环烷基、 杂芳基或杂环烷基任选进一步被 0至 5个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 氰基、 羟基、 羧基、 氨基、 d_4烷基或者 _4烷氧基的取代基所 取代， 所述的杂环垸基含有 1至 5个选自 N、 0或 3(=0)11的原子或基团； R is selected from H, d 4 alkyl, -(CH 2 ) m -C 3 _ fluorenyl, -(CH 2 ) m -(6-membered heteroaryl) or -(CH 2 ) m - (3 to 6 a heterocycloalkyl group, said alkyl, cycloalkyl, heteroaryl or heterocycloalkyl group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , Substituted by a substituent of CF 3 , cyano, hydroxy, carboxy, amino, d 4 alkyl or -4 -alkoxy, said heterocyclic fluorenyl contains 1 to 5 selected from N, 0 or 3 (=0) An atom or group of 11 ; n选自 0、 1或 2;  n 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. 9、 根据权利要求 8所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或前药， 其中： The oxabicyclic derivative according to claim 8, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: X选自 -0-或 -S-;  X is selected from -0- or -S-; R选自甲基、 乙基、 异丙基、 '^ΟΗ、 -CHF2、 ^N、 环丙基或吡啶基。 R is selected from the group consisting of methyl, ethyl, isopropyl, '^ΟΗ, -C HF 2 , ^N, cyclopropyl or pyridyl. 10、 根据权利要求 1~9所述的任何一项氧杂双环衍生物或其立体异构体、 水合物、 溶 、 药学上可接受的盐、 共晶体或前药， 其中该氧杂双环衍生物选自： The oxabibicyclic derivative according to any one of claims 1 to 9, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, cocrystal or prodrug thereof, wherein the oxabicyclic derivative The object is selected from:
Figure imgf000107_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0001
 11、 根据权利要求 1~10中任一项所述的氧杂双环衍生物或其立体异构体、 水合物、 溶 剂化物、 药学上可接受的盐、 共晶体或前药， 其中所述的盐选自钠盐、 钾盐、 钙盐、 镁盐、 钡盐、 铵盐、 三甲胺盐、 三乙胺盐、 吡啶盐、 甲基吡啶盐、 2,6-二甲基吡啶盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二环己基铵盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 硝酸 盐、 磷酸盐、 甲酸盐、 三氟乙酸盐、 乙酸盐、 马来酸盐、 酒石酸盐、 柠檬酸盐、 琥珀酸盐、 扁桃酸盐、 富马酸盐、丙二酸盐、苹果酸盐、 2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、 葡萄糖醛酸盐、 半乳糖醛酸盐、 枸橼酸盐、 门冬氨酸盐、 谷氨酸盐、 苯甲酸盐、 肉桂酸盐、 对甲苯磺酸盐、 苯磺酸盐、 甲磺酸盐、 乙磺酸盐、 三氟甲磺酸盐或它们的组合。 The oxabicyclic derivative according to any one of claims 1 to 10, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein The salt is selected from the group consisting of sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, triethylamine salt, pyridinium salt, methylpyridine salt, 2,6-dimethylpyridine salt, ethanolamine salt , diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylammonium salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, trifluoroacetate, acetic acid Salt, maleate, tartrate, citrate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolic acid Salt, salicylate, glucuronide, galacturonate, citrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzene Sulfonate, methanesulfonate, ethanesulfonate, triflate or combinations thereof. 12、 根据权利要求 1~10中任一项所述的氧杂双环衍生物或其立体异构体、 水合物、 溶 剂化物、 药学上可接受的盐、 共晶体或前药， 其中所述的共晶体是所述化合物与氨基酸、 有机酸、 水、 和 /或其他溶剂形成的共晶体， 其中氨基酸选自 L-赖氨酸、 L-色氨酸、 L-苯丙 氨酸、 L-苏氨酸、 L-异亮氨酸、 L-亮氨酸、 L-缬氨酸、 L-精氨酸、 L-组氨酸、 L-丙氨酸、 L- 天冬氨酸、 L-天冬酰胺、 L-半胱氨酸、 L-谷氨酰胺、 L-谷氨酸、 L-甲硫氨酸、 L-脯氨酸、 L- 丝氨酸、 L-酪氨酸、 L-甘氨酸、 L-焦谷氨酸、 D-赖氨酸、 D-色氨酸、 D-苯丙氨酸、 D-苏氨 酸、 D-异亮氨酸、 D-亮氨酸、 D-缬氨酸、 D-精氨酸、 D-组氨酸、 D-丙氨酸、 D-天冬氨酸、 D-天冬酰胺、 D-半胱氨酸、 D-谷氨酰胺、 D-谷氨酸、 D-甲硫氨酸、 D-脯氨酸、 D-丝氨酸、 D-酪氨酸、 D-甘氨酸或 D-焦谷氨酸。 13、 根据权利要求 12中所述的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药， 其中所述的共晶体是所述化合物与氨基酸、 水、 和 /或 其他溶剂形成的共晶体， 所述氨基酸选自 L-苯丙氨酸、 L-脯氨酸或 L-焦谷氨酸， 所述溶剂 选自 1,2-乙二醇、 1,2-丙二醇或 1-甲基 -1,2-乙二醇。 The oxabibicyclic derivative according to any one of claims 1 to 10, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein A co-crystal is a co-crystal formed by the compound with an amino acid, an organic acid, water, and/or other solvent, wherein the amino acid is selected from the group consisting of L-lysine, L-tryptophan, L-phenylalanine, L-Su Acid, L-isoleucine, L-leucine, L-valine, L-arginine, L-histidine, L-alanine, L-aspartic acid, L-day Asparagine, L-cysteine, L-glutamine, L-glutamic acid, L-methionine, L-valine, L-serine, L-tyrosine, L-glycine, L - pyroglutamic acid, D-lysine, D-tryptophan, D-phenylalanine, D-threonine, D-isoleucine, D-leucine, D-valine, D-arginine, D-histidine, D-alanine, D-aspartic acid, D-asparagine, D-cysteine, D-glutamine, D-glutamic acid, D-methionine, D-valine, D-serine, D-tyrosine, D-glycine or D-pyroglutamic acid. The oxabicyclic derivative according to claim 12, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein said co-crystal is said a co-crystal of a compound with an amino acid, water, and/or other solvent selected from the group consisting of L-phenylalanine, L-valine or L-pyroglutamic acid, said solvent being selected from 1,2- Ethylene glycol, 1,2-propanediol or 1-methyl-1,2-ethanediol. 14、一种如下列通式 0V)所示的合成如权利要求 1所述的通式 (I)的氧杂双环衍生物或其 立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前药的中间体或其立体异 构体：
Figure imgf000109_0001
14. An oxabicyclic derivative of the formula (I) as defined in the following formula 0V), or a stereoisomer, hydrate, solvate thereof, pharmaceutically acceptable thereof An intermediate of a salt, co-crystal or prodrug or a stereoisomer thereof:
Figure imgf000109_0001
 (IV)  (IV) 其中 R R2、 R3、 R4、 R5、 R6、 R7、 W和环 G与权利要求 1~4任一项所述的定义 Wherein RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , W and ring G are as defined in any one of claims 1 to 4 15、 根据权利要求 14所述的中间体或其立体异构体， 其中： 15. An intermediate according to claim 14 or a stereoisomer thereof, wherein: R R2和 R3各自独立地选自 H、羟基、 -0-CH3、 -0-CH2CH3、 -0-CHF2、 -0-CF3、 -0-CH2F、 F、 Cl、 Br、 I、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3、 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3、RR 2 and R 3 are each independently selected from H, hydroxy, -0-CH 3 , -0-CH 2 CH 3 , -0-CHF 2 , -0-CF 3 , -0-CH 2 F, F, Cl , Br, I, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 , -0-C(=0)0-CH 3 , -0-C(= 0) 0-CH 2 CH 3 , -o-烯丙基或 -o-乙烯基； -o-allyl or -o-vinyl; R4、 R5、 R6和 R7各自独立地选自 H、 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、仲丁基、叔丁基、 乙烯基、 丙烯基、烯丙基、 2-丁烯基、 乙炔基、 丙炔基、 炔丙基、 2-丁炔 -1-基、 甲氧基、 乙氧基、 正丙氧基、 异丙氧基或正丁氧基， 当被 取代时， 各自独立地任选被 0至 3个选自 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 羟基、 甲基、 乙基、 甲氧基或乙氧基的取代基所取代； R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of H, F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, vinyl, propenyl, allyl, 2-butenyl, ethynyl, propynyl, propargyl, 2-butyn-1-yl, methoxy, B Oxyl, n-propoxy, isopropoxy or n-butoxy, when substituted, are each independently optionally from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , Substituted with a substituent of -CF 3 , hydroxy, methyl, ethyl, methoxy or ethoxy; 环 G选自苯基， 任选进一步被 0至 3个选择 F、 Cl、 Br、 氰基、 羟基、 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 甲氧基、 乙氧基、 正丙氧基、 异丙 氧基、 正丁氧基、 环丙基、 环丁基、 -0-环丙基、 -0-环丁基、 -0-环戊基、 -0-氧杂环丙基、 - -氧杂环丁基、 -0-氧杂环戊基、氧杂环丙基、氧杂环丁基、氧杂环戊基、呋喃基、 噻吩基、  Ring G is selected from phenyl, optionally further selected from 0 to 3 F, Cl, Br, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclopropyl, cyclobutyl, -0-cyclopropyl, -0-cyclobutyl , -0-cyclopentyl, -0-oxopropyl, -oxetanyl, -0-oxocyclopentyl, oxacyclopropyl, oxetanyl, oxocycle Pentyl, furyl, thienyl,
Figure imgf000109_0002
、 - 或 L 、, 当被取代时， 任意进一步被 0至 4 个 F、 Cl、 Br、 I、 甲基、 乙基、 正丙基、 异丙基、 环丙基、 氰基、 甲氧基或乙氧基的取代 基所取代。 种制备如权利要求 1所述的通式 (I)氧杂双环衍生物的方法， 该方法包括:
Figure imgf000110_0001
Figure imgf000109_0002
, - or L ,, when substituted, optionally further from 0 to 4 F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyano, methoxy Or substituted with an ethoxy group substituent. A method of preparing the oxabicyclic derivative of the formula (I) according to claim 1, the method comprising:
Figure imgf000110_0001
 Vi a vi-b  Vi a vi-b 通式 (VI-a)化合物在强碱条件下发生消除反应， 得到通式 (VI-b)化合物; The compound of the formula (VI-a) is subjected to elimination reaction under strong base conditions to obtain a compound of the formula (VI-b);
Figure imgf000110_0002
Figure imgf000110_0002
 通式 (VI-b)化合物发生环氧化反应， 得到通式 (VI-c)化合物; An epoxidation reaction of a compound of the formula (VI-b) to give a compound of the formula (VI-c);
Figure imgf000110_0003
Figure imgf000110_0003
 通式 (VI-c)化合物在酸性条件下发生开环反应， 得到通式VI-d)化合物; The compound of the formula (VI-c) undergoes a ring opening reaction under acidic conditions to give a compound of the formula VI-d);
Figure imgf000110_0004
Figure imgf000110_0004
 通式 (VI-d)化合物在强碱下发生关环反应， 得到通式 (VI-e)化合物; The compound of the formula (VI-d) undergoes a ring closure reaction under a strong base to give a compound of the formula (VI-e);
Figure imgf000110_0005
Figure imgf000110_0005
 通式 (VI-e)化合物在强碱下亲电取代反应， 得到通式 (VI-f)化合物; The compound of the formula (VI-e) is electrophilically substituted under a strong base to give a compound of the formula (VI-f);
Figure imgf000110_0006
Figure imgf000110_0006
 VI  VI 通式 (VI)化合物脱去保护基 P， 得到通式化合物 (I); 其中-The compound of the formula (VI) is deprotected to give a compound of the formula (I); among them- R R2和 R3选自羟基、 -0-C(=0)-CH3、 -0-C(=0)-CH2CH3或者 -0-C(=0)0-CH3、 -0-C(=0)0-CH2CH3; R R2 and R 3 are selected from the group consisting of hydroxyl, -0-C(=0)-CH 3 , -0-C(=0)-CH 2 CH 3 or -0-C(=0)0-CH 3 , -0 -C(=0)0-CH 2 CH 3 ; x选自 o;  x is selected from o; W、 R、 G、 R4、 R5、 R6和 R7定义如权利要求 1-4所述的任一项所述； W, R, G, R 4 , R 5 , R 6 and R 7 are defined as defined in any one of claims 1-4; ，为 F、 Cl、 Br或 I;  , is F, Cl, Br or I; P选自 CM烷基、 -Q^C -d— 6烷基、 -Q^C O-d— 6烷基、 苄基、 对甲氧基苄基、 苯甲酰 基、 烯丙基、 三甲基硅基、 三乙基硅基、 叔丁基二甲基硅基或叔丁基二苯基硅基； P is selected from CM alkyl, -Q^C-d- 6 alkyl, -Q^C Od- 6 alkyl, benzyl, p-methoxybenzyl, benzoyl, allyl, trimethylsilane Base, triethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl; Y选自 H、 d— 4烷基、 甲磺酰基或乙酰基。 17、 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 1~10中任一项所述 的氧杂双环衍生物或其立体异构体、 水合物、 溶剂化物、 药学上可接受的盐、 共晶体或前 药和 /或一种或多种其他治疗剂及药学上可接受的载体或赋形剂。 Y is selected from H, d- 4 alkyl, methanesulfonyl or acetyl. A pharmaceutical composition, comprising an effective amount of the oxabicyclic derivative according to any one of claims 1 to 10, or a stereoisomer, hydrate, solvate thereof, pharmaceutically An acceptable salt, co-crystal or prodrug and/or one or more additional therapeutic agents and a pharmaceutically acceptable carrier or excipient. 18、 根据权利要求 17所述的组合物， 其中所述的其他治疗剂包括： 18. The composition of claim 17 wherein said additional therapeutic agent comprises: (a) SGLT-2抑制剂或药学上可接受的盐， 和 /或  (a) a SGLT-2 inhibitor 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)双胍类、 噻唑烷二酮类、 磺酰脲类、 列奈类、 （X-葡萄糖苷酶抑制剂或胰高血糖 素样肽 -1类似物， 或其药学上可接受的盐或前药。  (c) biguanides, thiazolidinediones, sulfonylureas, linoleides, (X-glucosidase inhibitors or glucagon-like peptide-1 analogues, or pharmaceutically acceptable salts thereof or Prodrug. 19、 根据权利要求 18所述的组合物， 其中： 所述的 SGLT-2抑制剂选自达格列净、 坎 格列净、 阿格列净、 恩帕列净、 依帕列净、 托伏列净、 卢斯列净、 瑞格列净、 舍格列净或 依托列净， 所述的 DPP-IV抑制剂选自利拉列汀、 西他列汀、 维格列汀、 阿格列汀、 沙格列 汀、 地那列汀、 卡格列汀、 MK-3102、 美格列汀、 度格列汀、 替格列汀、 吉格列汀或曲格 列汀， 所述的双胍类治疗剂选自二甲双胍或苯乙双胍； 噻唑烷二酮类治疗剂选自环格列酮、 吡咯列酮、 罗格列酮、 曲格列酮、 发格列酮或达格列酮， 磺酰脲类治疗剂选自格列美脲、 甲苯磺丁脲、 格列波脲、 格列本脲、 格列喹酮、 格列吡嗪或格列齐特， 列奈类治疗剂选自 那格列奈、瑞格列奈或米格列奈， （X-葡萄糖苷酶抑制剂选自阿卡波糖、伏格列波糖或米格列 醇， 胰高血糖素样肽 -1类似物选自艾塞那肽或利拉鲁肽。 19. The composition of claim 18, wherein: the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, cangliflozin, agliflozin, enpagliflozin, empagliflozin, and Voltepsin, lustigmine, repaglinide, shegliflozin or retinoic acid, said DPP-IV inhibitor is selected from the group consisting of linagliptin, sitagliptin, vildagliptin, aga The combination of statin, saxagliptin, dinalapine, carbagliptin, MK-3102, meglitin, dygliptin, tiglietine, gigliptin or troglitazone The biguanide therapeutic agent is selected from the group consisting of metformin or phenformin; the thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, glitazone or daglitazone. The sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, tolbutamide, glibenclamide, glibenclamide, gliclazide, glipizide or gliclazide, and the therapeutic agent of the linoleamide is selected from the group consisting of Nateglinide, repaglinide or mitiglinide, (X-glucosidase inhibitors are selected from acarbose, voglibose or miglitol, glucagon-like peptide-1 Analogs selected exenatide or liraglutide. 20、 权利要求 1~10中任一项所述的化合物或其立体异构体、 水合物、 溶剂化物、 药学 上可接受的盐、 共晶体或其前药在制备钠依赖性葡糖转运蛋白抑制剂中的应用。 The compound according to any one of claims 1 to 10, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt thereof, eutectic or prodrug thereof, for preparing a sodium-dependent glucose transporter Application in inhibitors. 21、 根据权利要求 20中所述的应用， 其中所述的钠依赖性葡糖转运蛋白抑制剂用于制 备治疗代谢性疾病的药物。 22、 根据权利要求 21中所述的应用， 其中所述的代谢性疾病选自糖尿病、 糖尿病性视 网膜病、 糖尿病性神经病、 糖尿病性肾病、 胰岛素抗性、 高血糖、 高胰岛素血症、 脂肪酸 或甘油的升高的水平、 高脂血症、 肥胖症、 高甘油三脂血症、 X综合症、 糖尿病并发症、 动脉粥样硬化或高血压。 21. Use according to claim 20 wherein said sodium-dependent glucose transporter inhibitor is used in the manufacture of a medicament for the treatment of a metabolic disorder. 22. The use according to claim 21, wherein said metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acids or Elevated levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension. 23、 根据权利要求 22中所述的用途， 其中所述的糖尿病为 II型糖尿病。 23. The use according to claim 22, wherein said diabetes is type II diabetes.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015043473A1 (en) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN105646604A (en) * 2016-03-01 2016-06-08 孙霖 Crystal form B of ertugliflozin and preparation method
CN105646603A (en) * 2016-03-01 2016-06-08 孙霖 Crystal form A of ertugliflozin and preparation method
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN106674294A (en) * 2015-11-06 2017-05-17 广东东阳光药业有限公司 Crystalline form of glucopyranosyl derivatives
CN107515255A (en) * 2016-06-17 2017-12-26 中美华世通生物医药科技（武汉）有限公司 Utilize high performance liquid chromatograph measure Dapagliflozin and its method about material
WO2018124468A1 (en) * 2016-12-30 2018-07-05 한미약품주식회사 Dapagliflozin l-proline-containing pharmaceutical composition for preventing or treating diabetes
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108239055B (en) * 2016-12-23 2023-07-18 杭州领业医药科技有限公司 THR 1442L-aspartic acid eutectic crystal, preparation method and pharmaceutical composition thereof
CN113218936B (en) * 2021-06-07 2021-09-10 江苏欣诺科催化剂有限公司 Method for detecting purity of potassium osmate

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011051864A1 (en) * 2009-11-02 2011-05-05 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
CN102149717A (en) * 2008-08-28 2011-08-10 辉瑞大药厂 Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
CN102372722A (en) * 2010-08-10 2012-03-14 江苏恒瑞医药股份有限公司 C-aryl glucoside derivative, preparation method thereof and application of C-aryl glucoside derivative in medicine
WO2012172566A2 (en) * 2011-06-13 2012-12-20 Panacea Biotec Ltd. Novel sglt inhibitors
WO2013038429A2 (en) * 2011-09-13 2013-03-21 Panacea Biotec Ltd. Novel sglt inhibitors
CN103570657A (en) * 2012-07-19 2014-02-12 天津药物研究院 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof
CN103772449A (en) * 2012-10-26 2014-05-07 上海阳帆医药科技有限公司 C-aryl glucoside derivative as well as preparation method and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102149717A (en) * 2008-08-28 2011-08-10 辉瑞大药厂 Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
WO2011051864A1 (en) * 2009-11-02 2011-05-05 Pfizer Inc. Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives
CN102372722A (en) * 2010-08-10 2012-03-14 江苏恒瑞医药股份有限公司 C-aryl glucoside derivative, preparation method thereof and application of C-aryl glucoside derivative in medicine
WO2012172566A2 (en) * 2011-06-13 2012-12-20 Panacea Biotec Ltd. Novel sglt inhibitors
WO2013038429A2 (en) * 2011-09-13 2013-03-21 Panacea Biotec Ltd. Novel sglt inhibitors
CN103570657A (en) * 2012-07-19 2014-02-12 天津药物研究院 Phenyl-glucoside derivative containing gem-dimethyl, preparation method and use thereof
CN103772449A (en) * 2012-10-26 2014-05-07 上海阳帆医药科技有限公司 C-aryl glucoside derivative as well as preparation method and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015043473A1 (en) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN106674294A (en) * 2015-11-06 2017-05-17 广东东阳光药业有限公司 Crystalline form of glucopyranosyl derivatives
CN105646604A (en) * 2016-03-01 2016-06-08 孙霖 Crystal form B of ertugliflozin and preparation method
CN105646603A (en) * 2016-03-01 2016-06-08 孙霖 Crystal form A of ertugliflozin and preparation method
CN107515255A (en) * 2016-06-17 2017-12-26 中美华世通生物医药科技（武汉）有限公司 Utilize high performance liquid chromatograph measure Dapagliflozin and its method about material
WO2018124468A1 (en) * 2016-12-30 2018-07-05 한미약품주식회사 Dapagliflozin l-proline-containing pharmaceutical composition for preventing or treating diabetes
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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