WO2014187365A1 - Dérivés oxabicyclo, procédé de préparation et utilisation de ceux-ci - Google Patents

Dérivés oxabicyclo, procédé de préparation et utilisation de ceux-ci Download PDF

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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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group
membered
alkyl
cycloalkyl
alkoxy
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PCT/CN2014/078325
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Chinese (zh)
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李瑶
石宗军
陈雷
徐波
叶飞
魏用刚
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四川海思科制药有限公司
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Priority to CN201480000530.4A priority Critical patent/CN104619713B/zh
Publication of WO2014187365A1 publication Critical patent/WO2014187365A1/fr

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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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  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé oxabicyclo, son procédé de préparation et son utilisation, et plus particulièrement des dérivés oxabicyclo représentés par la formule générale (I) ou des hydrates, des solvates, des stéréoisomères de ces derniers, ou encore des sels pharmaceutiquement acceptables, des promédicaments, des co-cristaux, des procédés de préparation, des compositions pharmaceutiques comprenant ces dérivés et des utilisations pharmaceutiques pour préparer des inhibiteurs du transporteur de glucose dépendant du sodium (SGLT); la définition de chaque substituant dans la formule générale (I) étant la même que dans la description.
PCT/CN2014/078325 2013-05-24 2014-05-23 Dérivés oxabicyclo, procédé de préparation et utilisation de ceux-ci WO2014187365A1 (fr)

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WO2015043473A1 (fr) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine
CN105646603A (zh) * 2016-03-01 2016-06-08 孙霖 埃格列净晶型a及制备方法
CN105646604A (zh) * 2016-03-01 2016-06-08 孙霖 埃格列净晶型b及制备方法
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN106674294A (zh) * 2015-11-06 2017-05-17 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的结晶形式
CN107515255A (zh) * 2016-06-17 2017-12-26 中美华世通生物医药科技（武汉）有限公司 利用高效液相色谱仪测定达格列净及其有关物质的方法
WO2018124468A1 (fr) * 2016-12-30 2018-07-05 한미약품주식회사 Composition pharmaceutique contenant de la dapagliflozine l-proline pour prévenir ou traiter le diabète
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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CN108239055B (zh) * 2016-12-23 2023-07-18 杭州领业医药科技有限公司 一种thr1442 l-天冬氨酸共晶、其制备方法及药物组合物
CN113218936B (zh) * 2021-06-07 2021-09-10 江苏欣诺科催化剂有限公司 锇酸钾的纯度检测方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015043473A1 (fr) * 2013-09-25 2015-04-02 Sunshine Lake Pharma Co., Ltd. Dérivés de glucopyranosyl et leurs utilisations en médecine
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN106674294A (zh) * 2015-11-06 2017-05-17 广东东阳光药业有限公司 吡喃葡萄糖基衍生物的结晶形式
CN105646603A (zh) * 2016-03-01 2016-06-08 孙霖 埃格列净晶型a及制备方法
CN105646604A (zh) * 2016-03-01 2016-06-08 孙霖 埃格列净晶型b及制备方法
CN107515255A (zh) * 2016-06-17 2017-12-26 中美华世通生物医药科技（武汉）有限公司 利用高效液相色谱仪测定达格列净及其有关物质的方法
WO2018124468A1 (fr) * 2016-12-30 2018-07-05 한미약품주식회사 Composition pharmaceutique contenant de la dapagliflozine l-proline pour prévenir ou traiter le diabète
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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