WO2022053013A1 - 苯并含氧杂环类化合物及其医药应用 - Google Patents

苯并含氧杂环类化合物及其医药应用 Download PDF

Info

Publication number
WO2022053013A1
WO2022053013A1 PCT/CN2021/117623 CN2021117623W WO2022053013A1 WO 2022053013 A1 WO2022053013 A1 WO 2022053013A1 CN 2021117623 W CN2021117623 W CN 2021117623W WO 2022053013 A1 WO2022053013 A1 WO 2022053013A1
Authority
WO
WIPO (PCT)
Prior art keywords
iib
group
compound
heterocyclic
alkyl
Prior art date
Application number
PCT/CN2021/117623
Other languages
English (en)
French (fr)
Inventor
詹正云
Original Assignee
上海爱博医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020237012127A priority Critical patent/KR20230123918A/ko
Priority to IL301278A priority patent/IL301278A/en
Priority to BR112023004430A priority patent/BR112023004430A2/pt
Priority to MX2023002926A priority patent/MX2023002926A/es
Priority to US18/044,881 priority patent/US20230339919A1/en
Priority to EP21866065.2A priority patent/EP4212528A4/en
Application filed by 上海爱博医药科技有限公司 filed Critical 上海爱博医药科技有限公司
Priority to PE2023001137A priority patent/PE20231319A1/es
Priority to JP2023516184A priority patent/JP2023540636A/ja
Priority to CA3194769A priority patent/CA3194769A1/en
Priority to AU2021342090A priority patent/AU2021342090A1/en
Publication of WO2022053013A1 publication Critical patent/WO2022053013A1/zh
Priority to CONC2023/0004369A priority patent/CO2023004369A2/es

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the invention relates to a novel benzo-oxygen-containing heterocyclic compound, especially a benzo-five-membered-oxygen-containing heterocyclic compound, which can be used as an agonist of GPR40 target to reduce blood sugar by stimulating pancreatic beta cells to release insulin level, safe and effective treatment of diseases such as type II diabetes.
  • Diabetes mellitus is a chronic endocrine and metabolic disease characterized by hyperglycemia caused by defective insulin secretion, insulin resistance, or both. Diabetes can severely damage the body's major organ systems, causing heart disease, stroke, nerve damage, kidney failure, blindness, and infections that can lead to amputation.
  • Type 2 diabetes accounts for about 90% of all diabetes cases, and patients are often able to produce insulin on their own, but not enough insulin or use it properly.
  • Clinically commonly used drugs for the treatment of diabetes include insulin secretagogues, which are currently the first-line hypoglycemic drugs.
  • Such drugs include sulfonylureas such as glipizide and non-sulfonylureas such as metformin.
  • the main common side effects of hypoglycemic drugs are gastrointestinal discomfort, edema, hypoglycemia, etc. Some patients may experience a strong feeling of fasting, cold sweat, general weakness, palpitations, trembling hands and feet, dizzy eyes, and headache due to the side effects of hypoglycemia. , daze and other phenomena, severe coma may occur. Therefore, the research and development of new anti-type II diabetes drugs with high safety, no hypoglycemic side effects, and convenient and effective oral administration is still the direction of scientists' efforts to explore.
  • GPR40 G protein-coupled receptor 40
  • FFAR1 free fatty acid receptor 1
  • GPR40 agonists lower blood glucose levels by stimulating insulin release from pancreatic beta cells.
  • Drugs that activate GPR40 could therefore effectively control blood sugar levels by helping diabetics release more insulin.
  • the characteristic of these drugs is that they promote insulin secretion only when blood sugar concentrations are high, thus greatly reducing the risk of hypoglycemia.
  • TAK-875 developed by Takeda Corporation of Japan. It is a selective GPR40 agonist and has entered Phase III clinical trials.
  • TAK-875 has no effect on insulin secretion.
  • TAK-875 showed good efficacy, the Japanese company Takeda terminated its clinical study in 2013 due to the problem of liver toxicity caused by its drug.
  • the present invention relates to compounds that activate GPR40 targets, as well as cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates of said compounds or pharmaceutically acceptable salts or mixtures thereof.
  • the present invention also relates to pharmaceutically acceptable compositions comprising the compounds, and related methods, for the treatment of conditions such as diabetes and related metabolic diseases in which a beneficial effect can be obtained from activation of GPR40 targets.
  • the present invention provides a benzo-oxygen-containing heterocyclic compound which is different from the existing structure.
  • the benzofive-membered oxygen-containing heterocyclic compound of the present invention has better inhibitory activity on type II diabetes, can be more effectively used for the treatment of type II diabetes patients, and has better safety.
  • the first aspect of the present invention provides a compound represented by formula Ib, its cis-trans isomer, enantiomer, diastereomer, racemate, tautomer and solvate , hydrates, or pharmaceutically acceptable salts or mixtures thereof;
  • n 0, 1 or 2;
  • E is selected from: hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH 2 ), Aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, aryl, aryloxy, or heterocyclic aryl;
  • G 1 is CH, or C(Rb); wherein, Rb is hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamine, ring Alkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclic, heterocyclic aryl, or heterocyclic aryl
  • G 1 is -C-;
  • E is -O-, -C(RcRd)-, -OC(RcRd)-, -C(RcRd)O-, or -NRe- ;
  • Rc and Rd are hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, hydrocarbyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamine, cycloalkylamine respectively group, alkylaminocarbonyl group, cycloalkylaminocarbonyl group, aryl group, aryloxy group, heterocyclic group, heterocyclic aryl group, or heterocyclic aryloxy group, Rc and Rd can be connected to each other to form a cycloalkyl group , or a heterocyclic group;
  • Re is hydrogen, deuterium (D), alkyl, cycloalkyl, al
  • L 1 and L 2 are each independently -O-, -S-, -C(O)-, -S(O) 2 -, -CH 2 -, -C(R f R g )-, -OC( R f R g )-, -C(R f R g )O-, -N(Re)-, -N(Rc)C(R f R g )-, or -C(R f R g )N( Re)-; wherein, R f and R g are hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkylamine, respectively group, cycloalkylamino group, alkylaminocarbonyl group, cycloalkylaminocarbonyl group, aryl group, aryloxy group, heterocyclic group, heterocyclic aryl
  • R 1 , R 2 and R 3 are each independently hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, aminocarbonyl (H 2 NCO), alkyl, alkoxy group, alkoxycarbonyl group, alkylaminocarbonyl group, alkylcarbonylamino group, aryl group, aryloxy group, or heterocyclic aryl group; wherein, R 2 and L 1 in formula Ib can be connected to each other to form a 4- 8-membered heterocyclic compound, L 1 is -CH-;
  • R 4 , R 5 and R 5b are each independently hydrogen, deuterium (D), halogen, hydroxy, amino, nitrile, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, any optionally substituted alkenyl, optionally substituted alkynyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonylamino, aryl, aryloxy, or heterocyclic aryl; Wherein, R 5 and R 5b can be connected to each other to form a cycloalkyl group, a heterocyclic group, or a heterocyclic aryl group;
  • R 6 is carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, alkylsulfonamidocarbonyl, cycloalkylsulfonamidocarbonyl, heterocyclyl, or heterocycle Aryl; or R 6 and the ortho-position substituent R 5 can be connected to each other to form a heterocyclic group or a heterocyclic aryl group;
  • X 5 , X 6 and X 7 are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl (H 2 NCO), alkyl, heterocycle Alkyl, alkoxy, heteroatom substituted alkyloxy, alkylamino (NR i R j ), heteroatom substituted alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonyl Amine, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonamido, cycloalkylsulfonamido, aryl, aryloxy, arylaminocarbonyl, arylcarbonylamino, Aryloxycarbonylamino, heterocyclic aryl, heterocyclic aryloxy, or heterocyclic arylamine; wherein, R i and R j are each independently hydrogen, deuterium (
  • Y and Y 1 are each independently -O-, -S-, -CH 2 -, -CHF-, -CF 2 -, -CCl 2 -, -C(R f R g )-, or -N(Re )-; wherein, the definitions of R f and R g are respectively the same as described in R f and R g in the above-mentioned L 1 , and the definition of Re is the same as described in the above-mentioned E of Re;
  • Z and Z 1 are each independently selected from: -O-, -S-, -CH 2 -, -CHF-, -CF 2 -, -C(R f R g )-, -N(Re)-, or -C(O)-; wherein, the definitions of R f and R g are the same as those described for R f and R g in L 1 above, respectively, and the definition of Re is the same as that described for Re in E above.
  • a second aspect of the present invention provides a compound of formula IIb:
  • n, E, G 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , X 5 , X 6 , X 7 , Y, Y 1 , Z are as in claim 1 n, E, G 1 , L 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , X 5 , X 6 , X 7 , Y, Y 1 , Z have the same definitions;
  • R 7 is hydroxyl, alkoxy, alkylamine, cycloalkylamine, heterocyclic amine, alkylsulfonamide, cycloalkylsulfonamide, aryloxy, heterocyclic aryloxy, aryl An amine group, or a heterocyclic arylamine group; or R 7 and the vicinal substituent R 5 can be connected to each other to form a heterocyclic ring.
  • n 0 or 1;
  • E When E is not directly connected to G 1 to form a cyclic compound, E is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, or alkoxy; G 1 is -CH-, or -C(Rb)-; Wherein, Rb is hydrogen, alkyl, optionally substituted alkenyl, optionally substituted alkynyl, alkoxy, or Rb and R 4 are interconnected to form an oxygen-containing heterocyclic group; R 4 is hydrogen, Alkyl, alkoxy, optionally substituted alkynyl, or R4 and Rb are connected to each other to form an oxygen - containing heterocyclic group;
  • E and G 1 are directly connected to form a cyclic compound, E is -OC(RcRd)-, G 1 is -C-, R 4 is hydrogen, wherein Rc and Rd are each independently hydrogen;
  • L 1 is -CH 2 -, or when R 2 and L 1 in formula IIb are connected to each other to form a 5-6 membered heterocyclic compound, L 1 is -OCH-;
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, alkyl or alkoxy;
  • R 5 is hydrogen, halogen, hydroxyl, amino, alkylamino, alkyl or alkoxy;
  • R 5b is hydrogen, halogen, alkyl or alkoxy
  • R 7 is alkoxy, hydroxyl, alkylsulfonamido, or cycloalkylsulfonamido
  • X 5 is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamine (NR i R j ), alkylcarbonylamine group, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonamido, cycloalkylsulfonamido, aryl, or aryloxycarbonylamino; wherein , R i and R j are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl;
  • X 6 and X 7 are each independently hydrogen, deuterium (D), halogen, C 1 -C 8 alkylamino or C 1 -C 8 alkoxycarbonylamino;
  • Y 1 is -CH 2 -, -CHF-, -CF 2 -, or -C(CH 3 ) 2 -;
  • Z is -O-, or -CH 2 -.
  • n 0 and Y is absent;
  • E When E is not directly connected to G 1 to form a cyclic compound, E is hydrogen or halogen; G 1 is -CH-, or -C(Rb)-, wherein Rb is alkyl, alkenyl, alkynyl or alkoxy group; R 4 is hydrogen, alkyl or alkoxy;
  • E and G 1 are directly connected to form a cyclic compound, E is -OC(RcRd)-, G 1 is -C-, R 4 is hydrogen, wherein Rc and Rd are each independently hydrogen;
  • L 1 is -CH 2 -, or when R 2 and L 1 in formula IIb are connected to each other to form a 5-6 membered heterocyclic compound, L 1 is -OCH-;
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, or alkoxy;
  • R 5 is hydrogen, halogen, hydroxyl, amino, alkyl or alkoxy
  • R 5b is hydrogen, halogen, alkyl or alkoxy
  • R 7 is selected from: alkoxy, hydroxyl, alkylsulfonamido, or cycloalkylsulfonamido;
  • X 5 is hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylamine (NR i R j ), alkylcarbonylamine group, alkylaminocarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonamido, cycloalkylsulfonamido, aryl, or aryloxycarbonylamino; wherein , R i and R j are each independently hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or cycloalkoxycarbonyl;
  • X 6 is hydrogen, deuterium (D), halogen, C 1 -C 8 alkylamino group or C 1 -C 8 alkoxycarbonylamino group;
  • X 7 is hydrogen
  • Y 1 is -CH 2 -, -CHF-, -CF 2 -, or -C(CH 3 ) 2 -;
  • Z is -O-.
  • the compounds of the present invention have a structure selected from the group consisting of:
  • compositions comprising (i) a therapeutically effective amount of at least one compound of formula Ib or IIb, its cis-trans isomer, enantiomer, diastereomer isomers, racemates, tautomers, solvates, hydrates, or pharmaceutically acceptable salts or mixtures thereof; and (ii) pharmaceutically acceptable diluents and/or excipients.
  • the present invention also relates to the use of the compound or composition in the preparation of a medicament for use as a GPR40 agonist.
  • the present invention also provides a method of treating or preventing diabetes or a related metabolic syndrome comprising administering to a patient a therapeutically effective amount of the compound or composition.
  • the present invention also relates to the use of the compound or composition in the manufacture of a medicament for the treatment or prevention of diabetes or related metabolic syndrome.
  • the compounds or compositions of the present invention are particularly useful in the treatment of type II diabetes.
  • the compound of the present invention can promote the secretion of insulin only when the blood glucose concentration of the type II diabetic patients is relatively high, so it can effectively reduce the risk of hypoglycemia of the patients. Meanwhile, compared with the commercially available drugs, the compounds of the present invention have better GPR40 target selectivity and safety.
  • the "alkyl” refers to a branched or straight-chain saturated aliphatic hydrocarbon group including 1 to 20 carbon atoms, which consists only of carbon and hydrogen atoms.
  • the alkyl group has one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl), or one to six carbon atoms (C1-C6 alkyl) ), and it is attached to the rest of the molecule by a single bond.
  • Exemplary alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, and each of these isomers, etc.
  • the alkyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( NH2 ), amino Carbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamine base, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, alkylureido, aryl, aryloxy, heteroaryl, heteroaryloxy, fused-ring aryl, Fused-ring heterocyclic aryl, fused-ringoxy, fused-ring aryloxy, fused-ring heterocyclic aryloxy, arylureido, or heterocycl
  • alkylene wherein "sub” means a second-order group derived by removing one hydrogen atom from an alkyl group comprising 1 to 20 carbon atoms, For example, methylene, ethylene, propylene and the like.
  • aryl group refers to any stable monocyclic, bicyclic, tricyclic or tetracyclic rings each of which may contain up to 7 carbon atoms, wherein at least one ring is an aromatic hydrocarbon ring system group.
  • exemplary aryl groups are hydrocarbon ring system groups containing hydrogen and 6-9 carbon atoms and at least one aromatic ring; hydrocarbon ring system groups containing hydrogen and 9-12 carbon atoms and at least one aromatic ring; containing hydrogen and 12-15 carbon atoms and a hydrocarbon ring system group of at least one aromatic ring; or a hydrocarbon ring system group containing hydrogen and 15-18 carbon atoms and at least one aromatic ring.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl groups include, but are not limited to, aryl groups derived from the following compositions: benzene, biphenyl, anthracene, azulene, fluorene, indane, indene, naphthalene, phenanthrene, pyrene, and the like.
  • "Optionally substituted aryl” means: an aryl group or a substituted aryl group.
  • the aryl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino ( NH2 ), amino Carbonyl ( H2NCO ), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, alkyl-sulfonyl-alkoxy, cycloalkyl, cycloalkoxy, Cycloalkoxycarbonyl, cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, aryl, aryloxy, heterocyclic aryl, fused ring aryl, fused ring Alkyl, fused cycloalkyl, fused epoxy, unsubstituted or benzene or biphenyl group containing 1 to 4 of the
  • heterocyclic aryl group refers to a stable monocyclic, bicyclic or tricyclic ring containing up to 7 atoms in each ring, wherein at least one ring is an aromatic ring, and At least one of the rings contains 1-4 heteroatoms selected from O, N, and/or S.
  • Heterocyclic aryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thiophene base, benzothiazolyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, Pyrimidyl, pyrrolyl, tetrahydroquinoline.
  • heterocyclic aryl should also be understood to include any quaternary ammonium salt or N-oxide derivative of a nitrogen-containing heterocyclic aryl group.
  • the heterocyclic aryl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( NH2 ) , aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkane amino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, aryl, aryloxy, heterocyclic aryl, fused aryl, fused cycloalkyl, fuse
  • the "fused-ring aryl group” refers to a stable bicyclic or tricyclic ring containing up to 7 atoms in each ring, wherein at least one ring is an aromatic ring.
  • the fused ring aryl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( NH2 ) , aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkane amino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, aryl, aryloxy, heterocyclic aryl, fuse
  • the "fused-ring heterocyclic aryl group” refers to a stable bicyclic or tricyclic ring containing up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains 1 -4 heteroatoms selected from O, N, and/or S.
  • the fused ring heterocyclic aryl may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino (NH 2 ), aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, Cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, heterocyclic, aryl, aryloxy, heterocyclic aryl, fused aryl, fused cycloalkyl, fused cycloalkane group, fused epoxy group, unsubstituted or benzene or biphenyl group containing 1 to 4 of the above-mentioned optional substituent
  • alkoxy group refers to the generated group after the alkyl group is connected with an oxygen atom, that is, R is an alkyl group as defined above for the alkyl group.
  • alkoxy groups include, but are not limited to: -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), -O-isopropyl group (isopropoxy), -O-tert-butyl (tert-butoxy), etc.
  • alkenyl refers to a branched and straight chain unsaturated aliphatic containing 1 to 3 "carbon-carbon double bonds" including 2 to 20 carbon atoms. Alkenyl, preferably 2 to 10 carbon atoms (C 2 -C 10 alkenyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 alkenyl), and their various isomers, etc., which are attached to the remainder of the molecule by a single bond.
  • alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • the alkenyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino ( NH2 ), amino Carbonyl (H 2 NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkane aminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, heteroaryl, fused aryl, fused heteroaryl, arylureido, or heterocycle Aryl urei
  • alkynyl refers to a branched and straight chain unsaturated aliphatic containing 1 to 2 "carbon-carbon triple bonds" including 2 to 20 carbon atoms.
  • Alkynyl preferably 2 to 10 carbon atoms (C 2 -C 10 alkynyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 alkynyl), and their various isomers, etc., which are attached to the remainder of the molecule by a single bond.
  • alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • the alkynyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, carboxyl, amino ( NH2 ), amino Carbonyl (H 2 NCO), alkyl, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkylamino, cycloalkane aminocarbonyl, cycloalkenyl, cyclic ether, heterocyclyl, alkylureido, aryl, heteroaryl, fused aryl, fused heteroaryl, aryl
  • alkylthio group refers to the generated group after the alkyl group is connected with the sulfur atom, that is, R is an alkyl group as defined above for the alkyl group.
  • aryloxy group refers to the generated group after the aryl group is connected to an oxygen atom, that is, Ar is an aryl group and has the same definition as described above for the aryl group.
  • arylamino group refers to an amino group in which one hydrogen in “NH 3 " is substituted by an aryl group, wherein the definition of the aryl group is the same as the above-mentioned aryl group.
  • heterocyclic arylamine group refers to an amine group in which one hydrogen in “NH 3 " is substituted by a heterocyclic aryl group, wherein the definition of the heterocyclic aryl group is the same as the above Heterocyclic aryl groups are the same.
  • cycloalkyl refers to an all-carbon monocyclic or polycyclic group, wherein each ring does not contain double bonds or triple bonds. preferably has 3-20 carbon atoms, has 3 to 15 carbon atoms, preferably has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, has 4 carbon atoms A ring of carbon atoms, or a ring with 3 carbon atoms.
  • cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • the cycloalkyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( NH2 ), Aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkyl Amine group, cycloalkylaminocarbonyl group, cycloalkenyl group, cyclic ether group, heterocyclic group, alkylureido group, aryl group, aryloxy group, heterocyclic aryl group, heterocyclic aryloxy group, fused ring aryl group , fused ring heterocyclic aryl group, fused ring oxygen group, fused ring aryl
  • the "cycloalkenyl” refers to an all-carbon monocyclic or polycyclic group, wherein one ring or each ring may contain one or more "carbon-carbon double bonds". preferably has 3-20 carbon atoms, has 3 to 15 carbon atoms, preferably has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, has 4 carbon atoms A ring of carbon atoms, or a ring with 3 carbon atoms.
  • cycloalkenyl groups include, for example: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl.
  • the cycloalkenyl group may be optionally substituted with a group selected from the group consisting of deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxyl, carboxyl, amino ( NH2 ), Aminocarbonyl (H 2 NCO), alkyl, alkoxy, alkoxycarbonyl, alkylcarbonylamino, alkylaminocarbonyl, cycloalkyl, cycloalkoxy, cycloalkoxycarbonyl, cycloalkyl Amine group, cycloalkylaminocarbonyl group, cycloalkenyl group, cyclic ether group, heterocyclic group, alkylureido group, aryl group, aryloxy group, heterocyclic aryl group, heterocyclic aryloxy group, fused ring aryl group , fused-ring heterocyclic aryl, fused-ring aryloxy, fused-ring
  • cyclic ether group refers to a cycloalkyl group having an ether group on the ring.
  • heterocyclic group is an aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from O, N and S, and includes a bicyclic group .
  • heterocyclyl includes the aforementioned heterocyclic aryl groups and their dihydro or tetrahydro analogs, and includes, but is not limited to, the following “heterocyclyl” groups: benzimidazolyl, benzofuranyl, benzopyrazolyl , benzotriazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, isobenzofuranyl, pyridopyridyl, heterocyclic groups can be connected with other organic small molecular groups through carbon atoms or heteroatoms The groups are linked to form new compounds with medicinal effects.
  • fused-ring aryl group refers to two or more aryl groups and/or heterocyclic aryl groups, polycyclic organic compounds formed by fused rings, and the The fused-ring aryl group can also be defined by the present invention as an alkyl group, an alkoxy group, an alkylthio group, an aryloxy group, an arylamino group, a heterocyclic group, a cycloalkyl group, a cycloalkoxy group, a cycloalkoxycarbonyl group, Cycloalkylamino, cycloalkylaminocarbonyl, cycloalkenyl, cyclic ether, aryl, halogen, carbonyl, hydroxyl, heterocyclic aryl and other groups are substituted in a reasonable manner -; which - includes but is not limited to Naphthalene, anthracene, quinone, phenanthrene, fluorene, benz
  • fused cycloalkyl refers to a non-aromatic polycyclic system formed after one or more double bonds in a fused aryl group are reduced, wherein the carbon number is "C 10 -20 ".
  • fused cycloalkyl aryl group refers to a group formed after the hydrogen on the carbon in the aryl group is replaced by a fused cycloalkyl group, wherein the carbon number is "C 15-20 ".
  • the "fused epoxy group” refers to a group formed by connecting a fused ring aryl group or a fused ring alkyl group with oxygen, that is, Ar is a C 10-20 fused ring aryl group or a fused ring alkyl group.
  • alkoxycarbonyl refers to the resulting group after the connection of an alkoxy group and a carbonyl group, that is, R is C 1-20 alkyl.
  • aryloxycarbonyl group refers to the generated group after the aryloxy group is connected with the carbonyl group, that is, Ar is a C 6-20 aryl group.
  • heterocyclicoxy group refers to the generated group after the heterocyclic group is connected with oxygen, that is, R is C 2-20 heterocyclyl.
  • alkylamine group refers to the generated group after the alkyl group is connected with the amine group, that is, R is C 1-20 alkyl.
  • alkylaminocarbonyl group refers to the generated group after the alkylamino group is connected with the carbonyl group, that is, R is C 1-20 alkyl.
  • arylamine group refers to the generated group after the aryl group is connected with the amine group, that is, Ar is a C 6-20 aryl group.
  • heterocyclic amine group refers to the generated group after the heterocyclic group and the amine group are connected, that is, R is C 2-20 heterocyclyl.
  • arylaminosulfonyl group refers to the generated group after the arylamino group is connected with the sulfonyl group, that is, Ar is a C 6-20 aryl group.
  • alkylaminosulfonyl group refers to the resulting group after the connection of an alkylamino group and a sulfonyl group, that is, R is C 1-20 alkyl.
  • heterocyclic aminosulfonyl group refers to the resulting group after the connection of a heterocyclic amino group and a sulfonyl group, that is, R is C 2-20 heterocyclyl.
  • alkylsulfonamide group refers to the generated group after the alkyl group is connected with the sulfonamide group, that is, R is C 1-20 alkyl.
  • heterocyclic sulfonamide group refers to the generated group after the heterocyclic group and the sulfonamide group are connected, that is, R is C 2-20 heterocyclyl.
  • the "arylsulfonamide group” refers to the generated group after the aryl group is connected with the sulfonamide group, that is, Ar is a C 6-20 aryl group.
  • alkylamine sulfonamide group refers to the generated group after the alkylamine group is connected with the sulfonamide group, that is, R is C 1-20 alkyl.
  • alkylcarbonylamine group refers to a group formed by connecting an alkyl group to a carbonyl group and then connecting to an amine group, that is, R is C 1-20 alkyl.
  • alkyl ureido group refers to the group formed after the alkyl group is connected with the urea group, that is, R is C 1-20 alkyl.
  • aryl ureido group refers to a group formed after an aryl group is connected to a urea group, that is, Ar is a C 6-20 aryl group.
  • alkyl thiourea group refers to the group formed by connecting an alkyl group to a thiourea group, that is, R is C 1-20 alkyl.
  • halogen means "fluorine, chlorine, bromine, or iodine atom”.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • the present invention innovatively designs and introduces the following heterocyclic functional group containing novel benzo-oxygen-containing heterocycles: (wherein R8 is halogen, hydroxyl, amino, carboxyl, alkylsulfonyloxy, arylsulfonyloxy, or a leaving group that can be substituted), and synthesized a class of effective therapeutic type II Benzo five-membered oxygen-containing heterocycles as novel GPR40 target agonists for diabetes.
  • the present invention generally relates to compounds encompassed by Formula Ib, their cis-trans isomers, enantiomers, diastereomers, racemates, tautomers, solvates, hydrates, or Pharmaceutically acceptable salts or mixtures thereof:
  • n, E, G 1 , L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 5b , R 6 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj , X5, X6 , X7 , Y, Y1 , Z and Z1 are as defined in the specification.
  • n 0, Y does not exist, and Y 1 and Z 1 are directly single-bonded.
  • E and G1 are linked to form a cyclic compound.
  • E and G 1 are linked to form a five-membered cyclic compound.
  • G 1 is -C- and E is -O-, -C(RcRd)-, -OC(RcRd)- or -C(RcRd)O-.
  • Rc and Rd are independently selected from: hydrogen, deuterium (D), alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, alkoxycarbonyl, alkyl amino, cycloalkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, aryl, aryloxy, heterocyclyl, heterocyclylaryl, or heterocyclylaryloxy.
  • Rc and Rd can be linked to each other to form a cycloalkyl or heterocyclic group.
  • G 1 is -C- and E is -OC(RcRd)- or -C(RcRd)O-, wherein Rc and Rd are independently selected from: hydrogen, deuterium (D), C 1 - C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkylamino, C 3 -C 8 cycloalkylamino, C 1 -C 8 alkylaminocarbonyl, C 3 -C 8 cycloalkylamine carbonyl, aryl, aryloxy, heterocyclyl, heteroaryl, or heteroaryloxy.
  • G1 is -C- and E is -OC(RcRd)- or -C
  • L 1 and L 2 are each independently selected from: -O-, -S-, -C(O)-, -SO 2 -, -CH 2 -, -C(RfRg)-, - OC(RfRg)-, -C(RfRg)O-, -N(Re)-, -N(Rc)C(RfRg)-, or -C(RfRg)N(Re)-.
  • one of L 1 and L 2 is -CH 2 - and the other is -O-.
  • R 2 and L 1 in formula Ib are connected to each other to form a 5-6 membered heterocyclic compound, and at least one of L 1 and L 2 is -OCH-.
  • R 1 , R 2 and R 3 are each independently hydrogen, deuterium (D), halogen, trifluoromethyl, trifluoromethoxy, nitrile, hydroxy, aminocarbonyl (H 2 NCO) , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkylaminocarbonyl, C 1 -C 8 alkylcarbonylamino, Aryl, aryloxy, or heterocyclic aryl.
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, or C 1 -C 8 alkoxy.
  • R 4 and R 5 are each independently selected from: hydrogen, halogen, hydroxy, amino, or alkoxy. In preferred embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1 -C 8 alkoxy.
  • R 6 is -COR 7 .
  • R 7 is -OH, alkoxy, alkylamino, cycloalkylamino, heterocyclic amino, alkylsulfonamido, cycloalkylsulfonamido, aryloxy , a heterocyclic aryloxy group, an arylamine group, or a heterocyclic arylamine group; or R 7 and the ortho-positioned substituent R 5 can be connected to each other to form a heterocyclic ring.
  • R 7 is C 1 -C 8 alkoxy, hydroxy, C 1 -C 8 alkylsulfonamido, or C 3 -C 8 cycloalkylsulfonamido.
  • Y 1 is selected from: -oxygen-, -sulfur-, -CH2- , -CHF-, -CF2-, -CCl2-, -C ( RfRg ) -, or- N(Re)-. In a preferred embodiment, Y 1 is selected from: CH 2 , -CHF-, CF 2 , or C(CH 3 ) 2 .
  • Z and Z 1 are independently selected from: -O-, -S-, -CH 2 -, -CHF-, -CF 2 -, -C(R f R g )-, -N( Re)-, or -C(O)-; wherein, the definitions of R f and R g are the same as those described for R f and R g in L 1 above, respectively, and the definition of Re is the same as that described for Re in E above.
  • at least one of Z and Z 1 is -O-.
  • both Z and Z 1 are -O-.
  • Z is -O-.
  • Z 1 is -O-.
  • X5, X6 and X7 are each independently hydrogen, deuterium (D), halogen, nitrile, amino, trifluoromethyl, trifluoromethoxy, aminocarbonyl ( H2NCO ) , alkyl, heterocycloalkyl, alkoxy, heteroatom substituted alkyloxy, alkylamine (NR i R j ), heteroatom substituted alkylamine, alkoxycarbonyl, alkylamine carbonyl, alkylcarbonylamino, alkoxycarbonylamino, cycloalkoxycarbonylamino, alkylsulfonamido, cycloalkylsulfonamido, aryl, aryloxy, arylaminocarbonyl, Arylcarbonylamino, aryloxycarbonylamino, heterocyclic aryl, heterocyclic aryloxy, or heterocyclic arylamino; wherein R i and R j are each independently hydrogen, deuterium (D
  • X 5 is selected from the group consisting of: hydrogen, deuterium (D), halogen, nitrile, amino (NH 2 ), trifluoromethyl, trifluoromethoxy, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 1 -C 8 alkylcarbonylamino, C 1 -C 8 alkylaminocarbonylamino, C 1 -C 8 alkoxycarbonyl Amine , C3 - C8cycloalkoxycarbonylamino , C1- C8alkylsulfonamido , C3 - C8cycloalkylsulfonamido , aryl, or aryloxycarbonylamino.
  • X 5 is selected from the group consisting of: hydrogen, deuterium (D), halogen, nitrile, trifluoromethyl, trifluoromethoxy, C 1 -C
  • X 6 and X 7 are each independently selected from: hydrogen, deuterium (D), halogen, C 1 -C 8 alkylamino, or C 1 -C 8 alkoxycarbonylamino.
  • X 6 is selected from: hydrogen, deuterium (D), halogen, C 1 -C 8 alkylamino or C 1 -C 8 alkoxycarbonylamino
  • X 7 is selected from: hydrogen.
  • the compounds of the present invention may exist in various isomeric forms, as well as in one or more tautomeric forms, including two single tautomers, and mixtures of tautomers.
  • the term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including tautomeric forms of the compounds.
  • the compounds described herein may possess asymmetric centers and thus exist in different enantiomeric and diastereomeric forms.
  • the compounds of the present invention may be in the form of optical isomers or diastereomers. Accordingly, the present invention encompasses the compounds of the present invention and their use as described herein in the form of their optical isomers, diastereomers and mixtures thereof, including racemic mixtures.
  • Optical isomers of the compounds of the present invention can be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, or by chemical separation of stereoisomers using optically active resolving agents.
  • stereoisomer refers to a stereoisomer of a compound that is substantially free of other stereoisomers of the compound.
  • a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound.
  • a stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound.
  • a typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, eg, greater than about 90% by weight of the compound of one stereoisomer and less than about 10% by weight of the other stereoisomer of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound A stereoisomer, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound.
  • the described structure shall prevail.
  • the stereochemistry of a structure or part of a structure is not indicated by eg bold or dashed lines, the structure or part of a structure should be understood to encompass all stereoisomers thereof.
  • the structures and names may be represented as single enantiomers to help describe the associated stereochemistry. Those skilled in the art of organic synthesis will know how to prepare the individual enantiomers of the compounds described in their preparation.
  • salts are pharmaceutically acceptable, organic or inorganic acid or base salts of the compounds of the present invention.
  • Typical pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth metal salts, ammonium salts, water-soluble salts and water-insoluble salts such as acetate salts, stilbene sulfonate (4,4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulphate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camphorsulfonate Acid salt, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, ethanedisulfonate, propionate lauryl sulfate, ethanesulfonate, fumaric acid Salt, Glucoheptonate, Gluconate, Glutamate, Gly
  • the compounds of the present invention may be isotopically labeled in which one or more atoms are replaced by atoms having different atomic masses or mass numbers.
  • isotopes that may be incorporated into compounds of Formula Ib or IIb include: isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, or iodine. Examples of such isotopes are: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36Cl , 123I and 125I .
  • radiolabeled compounds can be used to measure biodistribution, tissue concentration, and kinetics of transport and excretion from biological tissues, including subjects to which the labeled compounds are administered. Labeled compounds are also used to determine therapeutic effect, site or mode of action, and binding affinity of candidate therapeutics to pharmacologically important targets. Thus, certain radiolabeled compounds of Formula Ib or IIb are useful in drug and/or tissue distribution studies.
  • the radioisotopes tritium, ie, 3 H, and carbon-14, ie, 14 C, are particularly useful for this purpose because of their ease of incorporation and ready detection means.
  • positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N can provide labeled analogs of the compounds of the invention, which are useful in positron emission tomography (PET) studies, eg, for Detection of substance receptor occupancy.
  • Isotopically-labeled compounds of formula Ib or IIb can generally be prepared by conventional techniques known to those skilled in the art or by means analogous to those described in the Preparations and Examples section below, using suitable isotopically-labeled reagents .
  • Embodiments of the invention described herein are also intended to encompass the in vivo metabolites of compounds of Formula Ib or IIb. These products can be derived, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. processes primarily attributable to the enzymatic activity following administration of the compounds of the present invention. Accordingly, the present invention includes compounds that are produced in the form of by-products based on enzymatic or non-enzymatic activity on the compounds of the present invention after administration of the compounds of the present invention to a mammal for a period of time sufficient to produce the metabolites.
  • Metabolites are typically identified by administering a detectable dose of a radiolabeled compound of the invention to a subject, such as a rat, mouse, guinea pig, monkey or human, which persists throughout the process A sufficient period of time for metabolism to occur, and the metabolites are isolated from urine, blood, or other biological samples obtained from subjects receiving the radiolabeled compound.
  • a subject such as a rat, mouse, guinea pig, monkey or human
  • the present invention also provides pharmaceutically acceptable salt forms of the compounds of Formula Ib or IIb.
  • the scope of the present invention encompasses acid and base addition salts formed by contacting a pharmaceutically suitable acid or a pharmaceutically suitable base with a compound of the present invention.
  • “Pharmaceutically acceptable acid addition salts” refers to those salts that retain the bioavailability and properties of the free base, are not biologically or otherwise undesirable, and are formed using inorganic acids such as, but not limited to , hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid , benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, Ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxye
  • “Pharmaceutically acceptable base addition salts” refers to those salts that retain the bioavailability and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, iso- Propylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine , Arginine, Histidine, Caffeine, Procaine, Hebamine, Choline, Betaine, Phenylbenzylamine, Benzathine Penicillin, Ethylenediamine, Glucosamine, Methylglucamine, Cocoa Alkali, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Particular
  • Crystallization generally yields solvates of the compounds of the present invention.
  • the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist in hydrated forms, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention may be true solvates, while in other cases the compounds of the present invention may retain only indefinite water or a mixture of water plus some indefinite solvent.
  • Stepoisomer refers to a compound that is made up of the same atoms bound by the same bonds, but has different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof, and includes “enantiomers,” which means that the molecules of two stereoisomers are non-superimposable mirror images of each other.
  • the compounds of the present invention may contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other determinable in terms of absolute stereochemistry Stereoisomeric forms, eg (R)- or (S)-, or, for amino acids, (D)- or (L)-.
  • Stereoisomeric forms eg (R)- or (S)-, or, for amino acids, (D)- or (L)-.
  • the present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. such as chromatography and fractional crystallization.
  • the compound of formula Ib or IIb is formulated in the form of a pharmaceutically acceptable composition comprising an amount of the compound of formula Ib or IIb after administration of the pharmaceutical composition to a mammal , an amount effective to treat the particular disease or condition of interest.
  • the pharmaceutical compositions of the present invention may comprise a compound of formula Ib or IIb in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / Colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers, all approved by the U.S. Food and Drug Administration as acceptable.
  • mammal includes humans and domestic animals, eg, laboratory animals and domestic pets (eg, cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), and non-domestic animals, eg, wild animals and the like.
  • compositions of the present invention can be prepared by combining the compounds of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semi-solid, liquid or gaseous formulations such as , tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • suitable routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral includes, subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the pharmaceutical compositions of the present invention are formulated to allow the active ingredients contained therein to be bioavailable after the compositions are administered to a patient.
  • the composition to be administered to a subject or patient can be in the form of one or more dosage units, eg, a tablet can be a single dosage unit and a container of a compound of the invention in aerosol form can contain multiple dosage units. Actual methods of preparing such dosage forms are known, or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science (Philadelphia College of Pharmacy and Science, 2000).
  • the composition to be administered contains a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat the disease or condition of interest in accordance with the teachings of the present invention.
  • the pharmaceutical compositions of the present invention may be in solid or liquid form.
  • the carrier is a granule, whereby the composition is, for example, in tablet or powder form.
  • the carrier can be a liquid, wherein the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, which can be used, for example, for administration by inhalation.
  • the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included as solid or liquid forms contemplated herein.
  • the pharmaceutical composition can be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gums, flakes and the like.
  • Such solid compositions will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth or gelatin; excipients such as starch, lactose or dextrin , disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or Sterotex; glidants, such as colloidal silicon dioxide ; sweetening agents, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate, or orange flavoring; and coloring agents.
  • excipients such as starch, lactose or dextrin , disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide ; sweetening agents, such as sucrose or saccharin; flavoring agents, such as peppermint,
  • the pharmaceutical composition is in the form of a capsule (eg, a gelatin capsule), it may contain, in addition to materials of the above type, a liquid carrier, eg, polyethylene glycol or an oil.
  • a liquid carrier eg, polyethylene glycol or an oil.
  • the pharmaceutical composition may be in liquid form such as an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred compositions may contain, in addition to the compounds of the present invention, one or more sweetening agents, preservatives, dyes/colorants and flavor enhancers.
  • one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.
  • Liquid pharmaceutical compositions of the present invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's Solutions, isotonic sodium chloride; fixed oils, such as synthetic mono- or diglycerides, polyethylene glycol, glycerol, propylene glycol, or other solvents, which can be used as a solvent or suspending medium; antibacterial agents, such as benzyl alcohol or p-hydroxyl Methyl benzoate; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as EDTA; buffers, such as acetate, citrate, or phosphate, and tonicity-adjusting agents such as Sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.
  • compositions of the present invention can be prepared by any method well known in the art of pharmacy.
  • pharmaceutical compositions intended for administration by injection can be prepared by combining a compound of the present invention with sterile, distilled water to form a solution.
  • Surfactants can be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compounds of the present invention, thereby facilitating dissolution or uniform suspension of the compounds in aqueous delivery systems.
  • Administration of a compound of the present invention or a pharmaceutically acceptable salt thereof in a therapeutically effective amount will vary depending on various factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the age of the patient, Body weight, general health, sex, diet, mode and time of administration, rate of excretion, co-administration, severity of particular disease or condition, and subject being treated.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound of the present invention which (when administered to a mammal, preferably a human) is sufficient to provide effective treatment of a Mnk-related disorder or disease in the mammal, preferably a human, as described below.
  • the amount of a compound of the present invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated, but can be determined by those skilled in the art based on their knowledge and knowledge. SUMMARY OF THE INVENTION is routinely determined.
  • a compound of the present invention, or a pharmaceutically acceptable salt thereof may also be administered prior to, concurrently with, or subsequent to administration of one or more other therapeutic agents.
  • Such combination therapy includes the administration of a single pharmaceutical dosage formulation comprising the compound of the present invention and one or more other active substances, as well as the administration of the compound of the present invention and each active substance in separate pharmaceutical dosage formulations.
  • the compounds of the present invention and the other active substances may be administered to a patient together in a single oral dosage composition (eg, a tablet or capsule), or the substances may be administered in separate oral dosage formulations.
  • the compounds of the present invention and one or more other active agents may be administered at substantially the same time (ie, simultaneously), or at separate staggered times (ie, sequentially); combination therapy is understood to include all of these plan.
  • the present invention further optimizes the structure of the GPR40 target agonist compound formula Ib-IIb through structure-activity relationship (SAR) research, and can effectively reduce the risk of hypoglycemia and more safely and effectively treat type II diabetes.
  • SAR structure-activity relationship
  • the benzo-oxyheterocyclic compounds of the present invention can stimulate the release of insulin from islet beta cells by activating the GPR40 target to lower blood glucose levels, and the compounds of formula Ib-IIb are characterized by higher blood glucose concentrations only in patients with type II diabetes Insulin secretion can be promoted only when the insulin is regulated, so it can effectively reduce the risk of hypoglycemia in patients, and has better GPR40 target selectivity and safety.
  • RM-2b The raw materials RM-Ib (1.0eq), SM-1b (1.0eq), and DIAD and PPh3 (1.2eq) were added to THF (5x) in a round-bottom reaction flask, respectively, Nitrogen replacement and protection, the reaction is tracked and detected by TLC and/or HPLC to the end of the reaction, and RM-2b (or RM-IIb) is obtained after routine operations such as post-treatment;
  • target product Ib-IIb hydrolyze RM-Ib (or RM-IIb, 1 eq) in a mixed solution of LiOH in MeOH-H 2 O (1:1, 10X) in a round-bottomed reaction flask, respectively, TLC And/or HPLC detects the end of the reaction, and after routine operations such as post-treatment and purification, the target product Ib-IIb is obtained.
  • the synthetic reaction scheme 2b is as follows:
  • RM-2b In a round-bottom reaction flask, mix the raw materials RM-Ib (1.0eq), SM-1b (1.0eq), and alkaline reagents (such as potassium phosphate or potassium carbonate, 2-3eq) respectively Add to DMF (5x), replace with nitrogen and protect the reaction to proceed, TLC and/or HPLC track and detect until the end of the reaction, slowly pour the reaction solution into 40X ice water under stirring, and obtain RM after routine operations such as post-processing and purification. -Ib (or RM-IIb).
  • target product IIb hydrolyze RM-Ib (or RM-IIb) in a mixed solution of LiOH in MeOH-H 2 O (1:1, 10X) in a round-bottom reaction flask, respectively, TLC and/or HPLC After detection to the end of the reaction, the target product Ib-IIb is obtained after routine operations such as post-treatment and purification.
  • Table 1 Raw materials SM-Ib-01 to SM-Ib-30 used in the present invention and their structures
  • the first step reaction firstly obtain the key intermediates in a solvent (eg: DMSO or DMF) through the raw material RM-Ib-01 and another raw material SM1-01 under the action of an inorganic base (eg: K 3 PO 4 ) in a solvent (eg: DMSO or DMF) Compound (RM-Ib-01);
  • a solvent eg: DMSO or DMF
  • an inorganic base eg: K 3 PO 4
  • the second step reaction then the intermediate (RM-2b-01) is hydrolyzed in a solvent (such as MeOH or a mixed solvent of methanol and water) under the action of an inorganic base (such as LiOH) to obtain the target product Ib-01 .
  • a solvent such as MeOH or a mixed solvent of methanol and water
  • an inorganic base such as LiOH
  • Infrared spectral data were analyzed and obtained using a Fourier Transform AVATAR TM 360E.SP TM infrared instrument from Thermo Nicolet, and were expressed in cm ⁇ 1 .
  • the molecular weight of the organic carboxylic acid (-COOH) compound of formula Ib-IIb is mainly anion mode ESI-MS [(MH) + ], but some ester intermediate compounds of formula RM-IIb and Ib-IIb contain amine groups Molecular weights of isocompounds are ESI-MS in positive mode [(M+H) + ].
  • the special raw materials and intermediates mentioned in the present invention are provided by Zannan Technology Co., Ltd., etc., and all other chemical reagents are obtained from Shanghai Reagent Company, Aldrich Company (Aldrich), Acros Company (Acros) and other reagents. Supplier purchases. If the intermediates or products required for the reaction in the synthesis process are not enough for the next step and other tests, the synthesis is repeated several times until a sufficient number is reached.
  • the GPR40 activity test and pharmacological and toxicological tests of the compounds prepared in the present invention are completed by CRO service units in Shanghai and Beijing and other places.
  • CDI N,N'-Carbonyldiimidazole
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • HMTA Hexamethylenetetramine
  • PE petroleum ether
  • the synthetic method for preparing compound IIb-3 is the same as that in Example 1, and product IIb-3 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-3 (0.48mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-3 was hydrolyzed from the intermediate to obtain a white solid product IIb-3 (0.039 g), two-step yield: 20%.
  • the synthetic method for preparing compound IIb-4 is the same as in Example 1, and through etherification and hydrolysis reaction, product IIb-4 is obtained, wherein compound RM-Ib-4 (0.24 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain The intermediate RM-IIb-4 was hydrolyzed to obtain a light yellow solid product IIb-4 (0.060 g), two-step yield: 76%.
  • the synthetic method for preparing compound IIb-5 is the same as that in Example 1, and the product IIb-5 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-5 (0.54 mmol) is used to replace compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-5 was hydrolyzed from the intermediate to obtain a white solid product IIb-5 (0.068 g), two-step yield: 34.8%.
  • the synthetic method for preparing compound IIb-6 is the same as that in Example 1, and the product IIb-6 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-6 (0.41 mmol) is used to replace compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-6 was hydrolyzed from the intermediate to obtain a white solid product IIb-6 (0.090 g), two-step yield: 63.6%.
  • the synthetic method for preparing compound IIb-7 is the same as that in Example 1, and product IIb-7 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-6 (0.35 mmol) is used to replace compound RM-Ib-1 in the reaction, and compound SM1-2 (0.35 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-7, which was hydrolyzed to obtain white solid product IIb-7 (0.085 g), two-step yield: 70.8%.
  • the synthetic method for preparing compound IIb-8 is the same as that of Example 1, and the product IIb-8 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-7 (0.24 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-8 was hydrolyzed from the intermediate to obtain a white solid product IIb-8 (0.059 g), the two-step yield: 65.5%.
  • the synthetic method for preparing compound IIb-9 is the same as that in Example 2, and product IIb-9 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-8 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction to obtain intermediate
  • the body RM-IIb-9 was hydrolyzed from the intermediate to obtain a white solid product IIb-9 (0.035 g), two-step yield: 45%.
  • the synthetic method for preparing compound IIb-10 is the same as that in Example 1, and the product IIb-10 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-9 (0.65 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-10 was hydrolyzed from the intermediate to obtain a white solid product IIb-10 (0.196 g), two-step yield: 53.2%.
  • the synthetic method for preparing compound IIb-11 is the same as that in Example 2, and the product IIb-11 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-10 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction to obtain intermediate
  • the body RM-IIb-11 was hydrolyzed from the intermediate to obtain a white solid product IIb-11 (0.033 g), two-step yield: 37%.
  • the synthetic method for preparing compound IIb-12 is the same as that in Example 2, and the product IIb-12 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-11 (0.63 mmol) is used instead of compound RM-Ib-2 to obtain intermediate
  • the body RM-IIb-12 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-12 (0.028 g), the yield in two steps: 12.8%.
  • the synthetic method for preparing compound IIb-13 is the same as that of Example 1, and the product IIb-13 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-12 (0.43 mmol) is used instead of compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-13 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-13 (0.060 g), the two-step yield: 40%.
  • the synthetic method for preparing compound IIb-14 is the same as that of Example 1, and the product IIb-14 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-13 (0.22 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-14 was hydrolyzed from the intermediate to obtain a white solid product IIb-14 (0.045 g), the two-step yield: 51.3%.
  • the synthetic method for preparing compound IIb-15 is the same as that in Example 1, and the product IIb-15 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-14 (0.42 mmol) is used instead of compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-15 was hydrolyzed from the intermediate to obtain a white solid product IIb-15 (0.072 g), two-step yield: 54%.
  • the synthetic method for preparing compound IIb-16 is the same as that of Example 1, and the product IIb-16 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-15 (0.39 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-16 was hydrolyzed from the intermediate to obtain a white solid product IIb-16 (0.032 g), two-step yield: 19.7%.
  • the synthetic method for preparing compound IIb-17 is the same as that of Example 1, and the product IIb-17 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.28mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-17 was hydrolyzed from the intermediate to obtain a white solid product IIb-17 (0.020 g), two-step yield: 15.8%.
  • the synthetic method for preparing compound IIb-18 is the same as that in Example 1, and product IIb-18 is obtained through etherification and hydrolysis reaction.
  • compound RM-Ib-16 (0.22 mmol) was used instead of compound RM-Ib-1
  • compound SM1-2 (0.22 mmol) was used instead of compound SM1-1 to react to obtain intermediate RM-IIb-18.
  • the product was hydrolyzed to obtain a white solid product IIb-18 (0.009 g), two-step yield: 11.4%.
  • the synthetic method for preparing compound IIb-19 is the same as that of Example 1, and the product IIb-19 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-17 (0.91 mmol) is used instead of compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-19 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-19 (0.231 g), two-step yield: 72.8%.
  • the synthetic method for preparing compound IIb-20 is the same as that in Example 1, and the product IIb-20 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-18 (0.64mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-20 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-20 (0.166 g), the yield in two steps: 71.2%.
  • the synthetic method for preparing compound IIb-21 is the same as that of Example 1, and the product IIb-21 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-19 (0.57mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-21 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-21 (0.072 g), the two-step yield: 28.4%.
  • the synthetic method for preparing compound IIb-22 is the same as that in Example 1, and the product IIb-22 is obtained through etherification and hydrolysis reaction, wherein in the reaction, compound RM-Ib-20 (0.43 mmol) is used to replace compound RM-Ib-1 to obtain intermediate
  • the body RM-IIb-22 was hydrolyzed from the intermediate to obtain light yellow oily substance IIb-22 (0.150 g), two-step yield: 80%.
  • the synthetic method for preparing compound IIb-23 is the same as that of Example 1, and the product IIb-23 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-21 (0.13 mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-23 was hydrolyzed from the intermediate to obtain the light yellow solid product IIb-23 (0.0033 g), the two-step yield: 6.2%.
  • the synthetic method for preparing compound IIb-24 is the same as that in Example 1, and the product IIb-24 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-22 (0.38mmol) is used to replace compound RM-Ib-1 in the reaction to obtain intermediate
  • the body RM-IIb-24 was hydrolyzed from the intermediate to obtain a light yellow solid product IIb-24 (0.028 g), the yield in two steps: 18.8%.
  • the synthetic method for preparing compound IIb-25 is the same as that in Example 1, and the product IIb-25 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-5 (0.54 mmol) is used to replace compound RM-Ib-1 in the reaction, and the compound SM1-2 (0.54 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-25, which was hydrolyzed to obtain white solid product IIb-25 (0.085 g), two-step yield: 44%.
  • the synthetic method for preparing compound IIb-26 is the same as that of Example 1, and the product IIb-26 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.22 mmol) is used to replace compound RM-Ib-1 in the reaction, compound SM1-3 (0.22 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-26, which was hydrolyzed to obtain white solid product IIb-26 (0.045 g), two-step yield: 21%.
  • the synthetic method for preparing compound IIb-27 is the same as that in Example 1, and product IIb-27 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.22 mmol) is used to replace compound RM-Ib-1 in the reaction, and compound SM1-4 (0.22 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-27, which was hydrolyzed to obtain white solid product IIb-27 (0.070 g), two-step yield: 28%.
  • the synthetic method for preparing compound IIb-28 is the same as that in Example 1, and the product IIb-28 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.48mmol) is used instead of compound RM-Ib-1 in the reaction, and the compound SM1-5 (0.48 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-28, which was hydrolyzed to obtain white solid product IIb-28 (0.070 g), two-step yield: 36%.
  • the synthetic method for preparing compound IIb-29 is the same as that of Example 1, and the product IIb-29 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (1.0 mmol) is used instead of compound RM-Ib-1 in the reaction, and the compound SM1-6 (1.0 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-29, which was hydrolyzed to obtain white solid product IIb-29 (0.070 g), two-step yield: 18%.
  • the raw material IIb-17 (0.188g, 0.52mmol) was dissolved in 1mL of THF and 1mL of MTBE, under nitrogen protection, the dry ice acetone bath was cooled to -78 degrees, LiHMDS (1M, 1.4mL, 1.4mmol) was added dropwise, stirring 0.5h, TMSCl (0.14g, 1.3mmol) was added dropwise, stirred for 0.5h, NBS (0.11g, 0,62mmol) was added, slowly raised to room temperature, and the reaction was completed for 5h.
  • the raw material IIb-30 (0.035 g, 0.08 mmol) was added to concentrated ammonia water (3 mL), and the reaction was completed by heating in an oil bath at 100 degrees for 2.5 h. HPLC showed that after the reaction was completed, the reaction solution was concentrated and dried under reduced pressure to obtain a light yellow solid product IIb-31 (0.025 g), one-step yield: 83%.
  • the raw material RM-IIb-17 (0.29 g, 0.78 mmol) was dissolved in 2 mL of THF, under nitrogen protection, the dry ice acetone bath was cooled to -70 degrees, LiHMDS (1 M, 0.8 mL, 0.8 mmol) was added dropwise, and stirred for 0.5 h , dropwise added (PhSO 2 ) NF/THF (0.29 g, 0.93 mmol) solution, slowly raised to room temperature, reacted for 2 h, and the reaction was completed.
  • the raw material RM-IIb-17 (0.24g, 0.65mmol) was dissolved in 2mL of THF, under nitrogen protection, the dry ice acetone bath was cooled to -70 degrees, LiHMDS (1M, 0.8mL, 0.8mmol) was added dropwise, and stirred for 0.5h , dropwise added (PhSO 2 )NF/THF (0.24g, 0.78mmol) solution, slowly raised to room temperature, reacted for 2h, the reaction was completed.
  • the synthetic method for preparing compound IIb-34 is the same as that of Example 1, and the product IIb-34 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.36 mmol) is used instead of compound RM-Ib-1 in the reaction, and compound SM1-7 (0.36 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-32, which was hydrolyzed to obtain white solid product IIb-34 (0.021 g), two-step yield: 14%.
  • the synthetic method for preparing compound IIb-35 is the same as that of Example 1, and product IIb-35 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-6 (0.27mmol) is used to replace compound RM-Ib-1 in the reaction, and compound SM1-8 (0.27 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-33, which was hydrolyzed to obtain light yellow solid product IIb-35 (0.056 g), two-step yield: 60%.
  • the synthetic method for preparing compound IIb-36 is the same as that in Example 1, and product IIb-36 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-6 (0.27 mmol) is used to replace compound RM-Ib-1 in the reaction, and the compound SM1-9 (0.27 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-34, which was hydrolyzed to obtain light yellow solid product IIb-36 (0.072 g), two-step yield: 75%.
  • the synthetic method for preparing compound IIb-37 is the same as that in Example 1, and the product IIb-37 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-6 (0.27mmol) is used to replace compound RM-Ib-1 in the reaction, and compound SM1-10 (0.27 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-35, which was hydrolyzed to obtain light yellow solid product IIb-37 (0.055 g), two-step yield: 53%.
  • the synthetic method for preparing compound IIb-38 is the same as that in Example 2, and the product IIb-38 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-23 (0.16mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.16 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-36, which was hydrolyzed to obtain white solid product IIb-38 (0.040 g), two-step yield: 44%.
  • the synthetic method for preparing compound IIb-39 is the same as that of Example 1, and the product IIb-39 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-5 (0.35mmol) is used to replace compound RM-Ib-1 in the reaction, and the compound SM1-7 (0.35 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-37, which was hydrolyzed to obtain white solid product IIb-39 (0.021 g), two-step yield: 15%.
  • the synthetic method for preparing compound IIb-40 is the same as that of Example 2, and the product IIb-40 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-24 (0.31 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.31 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-38, which was hydrolyzed to obtain white solid product IIb-40 (0.067 g), two-step yield: 47%.
  • the synthetic method for preparing compound IIb-41 is the same as that of Example 2, and product IIb-41 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-25 (0.10 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.10 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-39, which was hydrolyzed to obtain white solid product IIb-41 (0.014 g), two-step yield: 36%.
  • the synthetic method for preparing compound IIb-42 is the same as that in Example 2, and the product IIb-42 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-26 (0.13 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-2 (0.13 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-40, which was hydrolyzed to obtain white solid product IIb-42 (0.029 g), two-step yield: 58%.
  • the synthetic method for preparing compound IIb-43 is the same as that in Example 2, and the product IIb-43 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-27 (0.09mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.09 mmol) was used to replace compound SM1-1 to obtain intermediate RM-IIb-41, which was hydrolyzed to obtain white solid product IIb-43 (0.012 g), two-step yield: 31%.
  • the synthetic method for preparing compound IIb-45 is the same as that in Example 2, and product IIb-45 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-28 (0.14 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-2 (0.14 mmol) was used to replace compound SM1-1 to obtain intermediate RM-IIb-42, which was hydrolyzed to obtain white solid product IIb-45 (0.035 g), two-step yield: 66%.
  • the synthetic method for preparing compound IIb-46 is the same as that in Example 2, and product IIb-46 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-29 (0.12mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.12 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-43, which was hydrolyzed to obtain white solid product IIb-46 (0.030 g), two-step yield: 52%.
  • the raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and under cooling in an ice-water bath, methyl chloroformate (0.015 g, 0.15 mmol) was added, at room temperature The reaction was stirred overnight and the reaction was complete. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain the intermediate RM-IIb-45 (0.049 g).
  • the raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and under cooling in an ice-water bath, cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added, The reaction was stirred at room temperature overnight and the reaction was complete. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain the intermediate RM-IIb-46 (0.050 g).
  • the raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, under ice-water bath cooling, phenyl chloroformate (0.024 g, 0.15 mmol) was added, room temperature The reaction was stirred overnight and the reaction was complete. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain an intermediate (0.050 g).
  • the intermediate was redissolved in 2 mL of DMF, DMAP (0.025 g, 0.2 mmol) and tert-butylamine (0.015 g, 0.2 mmol) were added, and the reaction was stirred at room temperature for 3 h. The reaction was completed. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain the intermediate RM-IIb-47 (0.040 g).
  • the raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and under cooling in an ice-water bath, cyclopentyl chloroformate (0.023 g, 0.15 mmol) was added, The reaction was stirred at room temperature overnight and the reaction was complete. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain the intermediate RM-IIb-48 (0.045 g).
  • the raw material RM-IIb-44 (0.050 g, 0.13 mmol) was dissolved in 2 mL of DCM, DMAP (0.039 g, 0.32 mmol) was added, and under cooling in an ice-water bath, isopropanesulfonyl chloride (0.022 g, 0.15 mmol) was added, room temperature The reaction was stirred overnight and the reaction was complete. HPLC showed that after the reaction was completed, the reaction solution was separated and purified by post-treatment column chromatography to obtain the intermediate RM-IIb-49 (0.015 g).
  • the synthetic method for preparing compound IIb-52 is the same as that in Example 2, and product IIb-52 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-30 (0.06mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.06 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-50, which was hydrolyzed to obtain white solid product IIb-52 (0.004 g), two-step yield: 15%.
  • the synthetic method for preparing compound IIb-53 is the same as that of Example 2, and the product IIb-53 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-31 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction, and the compound SM1-2 (0.24 mmol) was used to replace compound SM1-1 to obtain intermediate RM-IIb-51, which was hydrolyzed to obtain white solid product IIb-53 (0.018 g), two-step yield: 19%.
  • the synthetic method for preparing compound IIb-54 is the same as that of Example 2, and the product IIb-54 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-32 (0.24 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-2 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-52, which was hydrolyzed to obtain white solid product IIb-54 (0.028 g), two-step yield: 27%.
  • the synthetic method for preparing compound IIb-55 is the same as that in Example 2, and product IIb-55 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-33 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction, and the compound SM1-2 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-53, which was hydrolyzed to obtain white solid product IIb-55 (0.020 g), two-step yield: 22%.
  • the synthetic method for preparing compound IIb-56 is the same as that in Example 2, and product IIb-56 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-34 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-2 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-54, which was hydrolyzed to obtain white solid product IIb-56 (0.028 g), two-step yield: 30%.
  • the synthetic method for preparing compound IIb-57 is the same as that in Example 2, and product IIb-57 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-35 (0.23 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-11 (0.23 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-55, which was hydrolyzed to obtain white solid product IIb-57 (0.018 g), two-step yield: 21%.
  • the synthetic method for preparing compound IIb-58 is the same as that of Example 2, and the product IIb-58 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-36 (0.23 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-11 (0.23 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-56, which was hydrolyzed to obtain white solid product IIb-58 (0.026 g), two-step yield: 30%.
  • the synthetic method for preparing compound IIb-59 is the same as that of Example 2, and the product IIb-59 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-27 (0.23 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-11 (0.23 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-57, which was hydrolyzed to obtain white solid product IIb-59 (0.016 g), two-step yield: 30%.
  • the synthetic method for preparing compound IIb-60 is the same as that of Example 2, and the product IIb-60 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-27 (0.24 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-8 (0.24 mmol) was used to replace compound SM1-1 to obtain intermediate RM-IIb-58, which was hydrolyzed to obtain white solid product IIb-60 (0.021 g), two-step yield: 20%.
  • the synthetic method for preparing compound IIb-61 is the same as that in Example 1, and the product IIb-61 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.24 mmol) is used instead of compound RM-Ib-1 in the reaction, and compound SM1-8 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-59, which was hydrolyzed to obtain white solid product IIb-61 (0.026 g), two-step yield: 30%.
  • the synthetic method for preparing compound IIb-62 is the same as that of Example 1, and the product IIb-62 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-16 (0.24mmol) is used to replace compound RM-Ib-1 in the reaction, and compound SM1-12 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-60, which was hydrolyzed to obtain white solid product IIb-62 (0.015 g), two-step yield: 16%.
  • the synthetic method for preparing compound IIb-63 is the same as that in Example 2, and the product IIb-63 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-29 (0.24 mmol) is used instead of compound RM-Ib-2 in the reaction, and the compound SM1-8 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-61, which was hydrolyzed to obtain white solid product IIb-63 (0.020 g), two-step yield: 17%.
  • the synthetic method for preparing compound IIb-64 is the same as that of Example 2, and product IIb-64 is obtained through etherification and hydrolysis reaction, wherein compound RM-Ib-29 (0.24 mmol) is used to replace compound RM-Ib-2 in the reaction, and compound SM1-12 (0.24 mmol) replaced compound SM1-1 to obtain intermediate RM-IIb-62, which was hydrolyzed to obtain white solid product IIb-64 (0.015 g), two-step yield: 13%.
  • the compounds prepared in the present invention can be preliminarily determined and screened for their effect on GPR40 by the following preclinical in vitro inhibitory activity test experiments, and then the efficacy and safety can be further confirmed by clinical trials. Other methods will also be apparent to those of ordinary skill in the art.
  • the compounds of the present invention are passed through Compounds IIb-01 to IIb-64 and a
  • the reference compound Ref-1 (TAK-875) was used to evaluate the activity of GPR40 in an experimental test, and compared the test results, it was found that the inhibitory activity (EC 50 ) of many compounds was better than that of the reference compound.
  • the GPR40 agonist activity test results of each compound of the formula IIb novel structure are listed in the following Table 3 and Table 2; wherein, the GPR40 agonist activity range (EC 50 ) of the compound of the present invention is marked as "A" at ⁇ 10nM; Activities in the range of 10-100 nM are designated as “B”; activities > 100 nM are designated as "C”.
  • the present invention used 18-22 g of healthy small Mice, all adopt a single dose of 600 mg/kg, 1 administration, observe the toxic reaction produced by the experimental animals in 5 consecutive days to evaluate the toxicity of the test substance to the body, and carry out acute toxicity (Acute Toxocity Study, MTD)
  • MTD acute Toxocity Study
  • the method of detecting the absorption capacity of BSEP bile salt transporter to the substrate Taurocholic Acid (TCA) by LC/MS/MS was used to preliminarily determine whether the candidate compound has inhibitory effect on the transport process of BSEP transporter.
  • the BSEP protein micromembrane sacs with reverse absorption ability were obtained by transfecting BSEP gene into Hi5 cells, and the micromembrane sacs were capable of taurocholic acid TCA absorption and uptake.
  • the principle of this experiment is to carry out the substrate absorption experiment of BSEP protein micromembrane sacs in the presence of energy ATP, the substrate taurocholic acid TCA and the candidate compound to be tested.
  • the micromembrane sacs are completely washed away. After remaining energy, substrate and candidate compound, the micromembrane sac is cleaved to release the absorbed substrate taurocholic acid TCA, and then LC/MS/MS is used to detect taurocholic acid TCA to determine whether the candidate compound inhibits TCA transfer process.
  • the initial concentration of the sample was 100 mM, and it was diluted by a 2-fold gradient with a Bravo instrument, with a total of 11 concentration gradients; the lowest point concentration was 97.65 ⁇ M.
  • the initial concentration of the control compound (Glyburide) was 20 mM, which was diluted 2-fold with a Bravo instrument, with a total of 11 concentration gradients; the lowest point concentration was 19.53 ⁇ M.
  • HPE Positive control
  • ZPE negative control
  • Activity detection result in above-mentioned table 3 and table 4 shows: (1) the activity (EC50) of the five-membered heterocyclic compound containing 1-2 oxygen atoms in all kinds of novel benzoheterocyclic compounds of the present invention is obviously better than similar structures A six-membered heterocyclic compound containing 1-2 oxygen atoms; (2) in the compound of formula IIb of the present invention, the activity of the benzo-oxygen-containing five-membered heterocyclic compound when Z 1 is "oxygen (O)" is better than that of similar structures The activity of the corresponding compound when Z 1 is "CH 2 "; (3) the benzo-oxygenated five-membered heterocyclic compounds IIb-18, IIb-25, IIb-43 and IIb-46 of the present invention have shown the GPR40 target It has very good activity (EC 50 : ⁇ 10nM), which is better than that of the similar control compound TAK-875. It is a novel GPR40 agonist with relatively good activity in the current research field and has the advantages of medicine in
  • the 3 benzo-oxygenated five-membered heterocyclic compounds listed in Table 4 above not only showed good activity, but also the BSEP side effects that may lead to liver damage were all greater than 25, which was significantly better than that of Japan's Takeda Corporation because of liver toxicity.
  • the new drug of TAK-875 in Phase III clinical trial, and the completed Acute Toxocity Study (MTD) test results show the safety of the three highly active compounds IIb-18, IIb-25 and IIb-43 listed in Table 4
  • the survival rate of the mice after administration of the new compound at a dose of 600 mg/kg for 5 days was 100%, and no abnormality occurred during the drug administration and 5-day recovery period, and no abnormality was found in the autopsy results. Therefore, there are several highly active compounds in the novel benzo-oxygenated five-membered heterocyclic compound IIb designed and synthesized by the present invention, which has the value of further animal and clinical tests and popularization and application.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明公开了式Ib或IIb所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物，含有该化合物的药物组合物以及所述化合物作为GPR40激动剂的用途，其中n、E、G1、L1、L2、R1、R2、R3、R4、R5、R5b、R6、R7、X5、X6、X7、Y、Y1、Z、Z1以及化合物中各元素可能的同位素取代标记如说明书中所定义。

Description

苯并含氧杂环类化合物及其医药应用 技术领域
本发明涉及一种新型苯并含氧杂环类化合物、尤其是苯并五元含氧杂环类化合物，所述化合物可作为GPR40靶点的激动剂，通过刺激胰岛β细胞释放胰岛素来降低血糖水平，安全有效地治疗II型糖尿病等疾病。
背景技术
糖尿病是一种以胰岛素分泌缺陷、胰岛素抵抗或两者并存所致的高血糖为特征的慢性内分泌和代谢性疾病。糖尿病会严重损害身体各主要器官系统，造成心脏病、中风、神经损伤、肾功能衰竭、失明以及可能导致截肢的感染，该病并发症多发，致残率和死亡率较高。
II型糖尿病占糖尿病病例总数的90％左右，患者通常自己能够产生胰岛素，但不能产生足够的胰岛素或无法妥善利用。临床上常用的治疗糖尿病的药物有促胰岛素分泌剂是目前一线降糖药，这类药物有磺脲类如格列吡嗪等以及非磺脲类如二甲双胍等。降糖药共同的主要副作用为胃肠道不适、水肿、低血糖等，有些患者有可能会因为低血糖的副作用出现强烈空腹感、出冷汗、全身无力、心悸、手脚发抖、眼睛发花、头疼、发呆等现象，严重时会发生昏迷。因此研发安全性高、没有低血糖副作用、口服方便有效的新型抗II型糖尿病的药物仍是科学家努力探索的方向。
近期研究发现游离脂肪酸受体1(FFAR1)，或称为G蛋白偶联受体40(GPR40)在刺激和调节胰岛素生成过程中起到关键作用。当餐后血中葡萄糖和脂肪酸升高时，GPR40激动剂通过刺激胰岛β细胞释放胰岛素来降低血糖水平。因此能激活GPR40的药物可以通过帮助糖尿病患者释放更多的胰岛素进而有效地控制血糖水平。此类药物的特点是仅在血糖浓度较高时，才会促进胰岛素的分泌，因此大大降低了产生低血糖的风险。此类药物的代表由日本武田公司研发的TAK-875,它是一种选择性GPR40激动剂，曾经进入III期临床， 研究结果显示当血糖水平正常时，TAK-875对胰岛素分泌无任何作用，临床上，采用50mg给药剂量，每天一次，病人疗效较好、耐受性也良好，并且其引起低血糖的风险明显低于对照组的磺酰脲类药物，验证了TAK-875诱导的胰岛素分泌是血糖依赖性的。虽然TAK-875表现出良好的疗效，但是由于其药物产生的肝毒性问题，日本武田公司在2013年终止其临床研究。值得一提的是TAK-875肝毒性问题研究显示与该药的作用机理无关，主要是其分子结构设计不够安全造成的问题。因此，该GPR40靶点仍然是一个很好的开发思路，具有非常重要的应用前景。
Figure PCTCN2021117623-appb-000001
化合物TAK-875的结构
目前公开了一系列的GPR40激动剂的专利申请，其中包括W02005087710、W02007106469A1、WO2004106276A1、W02010143733A1、CN103030646A1、WO2013104257A1、WO2015062486A1等。
因此，尽管在该领域中已经取得了一些进步，本领域中仍然极其需要能特异性激活GPR40靶点的治疗糖尿病和相关代谢性疾病的GPR40激动剂以及相关联的组合物和疾病治疗方法。本发明致力于满足该需求，并提供其它相关的优点。
发明内容
本发明涉及激活GPR40靶点的化合物，以及所述化合物的顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物。本发明还涉及包含所述化合物的药学上可接受的组合物，以及相关的方法，以用于治疗能从激活GPR40靶点中获得有益效果的病症，例如糖尿病和相关代谢性疾病。
本发明提供了一种与现有结构不同的苯并含氧杂环类化合物。本发明的苯并五元含氧杂环类化合物对II型糖尿病具有更好的抑制活性，可以更有效地用于治疗II型糖尿病患者，并且具有较好的安全性。
本发明的第一方面提供一种式Ib所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物；
Figure PCTCN2021117623-appb-000002
其中，
n＝0,1或2；
n＝0时,Y不存在，Y 1与Y邻位的Z 1直接单键连接成五元杂环；
E不与G 1直接连接成环状化合物时，E选自：氢、氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、芳基、芳氧基、或杂环芳基；G 1为CH、或C(Rb)；其中，Rb为氢、氘(D)、烷基、环烷基、烯烃基、炔烃基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基，或Rb和R 4之间可以互相连接成环烷基、或杂环基团；
E与G 1连接成环状化合物时，G 1为-C-；E为-O-、-C(RcRd)-、-OC(RcRd)-、-C(RcRd)O-、或-NRe-；其中，Rc和Rd分别为氢、氘(D)、烷基、环烷基、烯基、烃基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基，Rc和Rd之间可以互相连接成环烷基、或杂环基团；Re为氢、氘(D)、烷基、环烷基、烷基羰基、烷氧基羰基、环烷氧基羰基、烷基胺基羰基、环烷基胺基羰基、烷基磺酰基、或芳基磺酰基；
L 1和L 2各自独立地为-O-、-S-、–C(O)–、–S(O) 2–、-CH 2-、-C(R fR g)-、-OC(R fR g)-、-C(R fR g)O-、-N(Re)-、-N(Rc)C(R fR g)-、或-C(R fR g)N(Re)-；其中，R f和R g分别为氢、氘(D)、烷基、环烷基、烯基、炔基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、 芳氧基、杂环基、杂环芳基、或杂环芳氧基，Re的定义与上述E中的Re所述相同；
R 1、R 2和R 3各自独立地为氢、氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、芳基、芳氧基、或杂环芳基；其中，式Ib中R 2与L 1之间可以相互连接成4-8元的杂环化合物，L 1为-CH-；
R 4、R 5和R 5b各自独立地为氢、氘(D)、卤素、羟基、氨基、腈基、烷基、烷氧基、环烷基、杂环烷基、环烷氧基、任选取代的烯基、任选取代的炔基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、烷氧基羰基胺基、芳基、芳氧基、或杂环芳基；其中，R 5和R 5b之间可以相互连接成为环烷基、杂环基、或杂环芳基；
R 6为羧基、烷氧基羰基、芳氧基羰基、烷基胺基羰基、环烷基胺基羰基、烷基磺酰胺基羰基、环烷基磺酰胺基羰基、杂环基、或杂环芳基；或R 6与邻位的取代基R 5之间可以相互连接成为杂环基、或杂环芳基；
X 5、X 6和X 7各自独立地为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、氨基羰基(H 2NCO)、烷基、杂环烷基、烷氧基、杂原子取代的烷基氧基、烷基胺基(NR iR j)、杂原子取代的烷基胺基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、芳氧基、芳基胺基羰基、芳基羰基胺基、芳氧基羰基胺基、杂环芳基、杂环芳基氧基、或杂环芳基胺基；其中，R i和R j各自独立地为氢、氘(D)、烷基、杂环烷基、烷基羰基、烷氧基羰基、环烷氧基羰基、烷基胺基羰基、烷基磺酰基、环烷基磺酰基、芳基、芳氧基羰基、芳基胺基羰基、杂环芳基，或R i和R j相互连接成含1-3个杂原子的3-8元杂环；
Y和Y 1各自独立地为-O-、-S-、-CH 2-、-CHF-、-CF 2-、-CCl 2-、-C(R fR g)-、或-N(Re)-；其中，R f和R g的定义分别与上述L 1中的R f和R g所述相同，Re的定义与上述E中的Re所述相同；
Z和Z 1各自独立地选自：-O-、-S-、-CH 2-、-CHF-、-CF 2-、-C(R fR g)-、-N(Re)-、或–C(O)–；其中，R f和R g的定义分别与上述L 1中的R f和R g所述相同，Re的定义与上述E中的Re所述相同。
本发明的第二方面提供一种式IIb的化合物：
Figure PCTCN2021117623-appb-000003
其中，
n、E、G 1、L 1、R 1、R 2、R 3、R 4、R 5、R 5b、X 5、X 6、X 7、Y、Y 1、Z的定义与权利要求1中n、E、G 1、L 1、R 1、R 2、R 3、R 4、R 5、R 5b、X 5、X 6、X 7、Y、Y 1、Z的定义相同；
R 7为羟基、烷氧基、烷基胺基、环烷基胺基、杂环胺基、烷基磺酰胺基、环烷基磺酰胺基、芳氧基、杂环芳氧基、芳基胺基、或杂环芳基胺基；或R 7与邻位的取代基R 5之间可以相互连接成为杂环。
在一些优选的实施方式中，n＝0或1；
n＝0时,Y不存在，Y 1与Y邻位的氧直接单键连接成五元杂环；
n＝1时,Y为-CH 2-；
E不与G 1直接连接成环状化合物时，E为氢、卤素、三氟甲基、三氟甲氧基、或烷氧基；G 1为-CH-、或-C(Rb)-；其中，Rb为氢、烷基、任选取代的烯基、任选取代的炔基、烷氧基、或Rb和R 4之间互相连接成含氧的杂环基团；R 4为氢、烷基、烷氧基、任选取代的炔基，或R 4和Rb之间互相连接成含氧的杂环基团；
E与G 1直接连接成环状化合物时，E为-OC(RcRd)-，G 1为-C-，R 4为氢，其中Rc和Rd各自独立地为氢；
L 1为-CH 2-，或当式IIb中R 2与L 1之间相互连接成5-6元的杂环化合物时，L 1为-OCH-；
R 1、R 2和R 3各自独立地为氢、卤素、烷基或烷氧基；
R 5为氢、卤素、羟基、氨基、烷基氨基、烷基或烷氧基；
R 5b为氢、卤素、烷基或烷氧基；
R 7为烷氧基、羟基、烷基磺酰胺基、或环烷基磺酰胺基；
X 5为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、烷基、烷氧基、烷基胺基(NR iR j)、烷基羰基胺基、烷基胺基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、或芳氧基羰基胺基；其中，R i和R j各自独立地为氢、烷基、烷基羰基、烷氧基羰基、或环烷氧基羰基；
X 6和X 7各自独立地为氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基；
Y 1为-CH 2-、-CHF-、-CF 2-、或-C(CH 3) 2-；
Z为-O-、或-CH 2-。
在一些更优选的实施方式中，n＝0，Y不存在；
E不与G 1直接连接成环状化合物时，E为氢、或卤素；G 1为-CH-、或-C(Rb)-，其中，Rb为烷基、烯基、炔基或烷氧基；R 4为氢、烷基或烷氧基；
E与G 1直接连接成环状化合物，E为-OC(RcRd)-，G 1为-C-，R 4为氢，其中Rc和Rd各自独立地为氢；
L 1为-CH 2-，或当式IIb中R 2与L 1之间相互连接成5-6元的杂环化合物时，L 1为-OCH-；
R 1、R 2和R 3各自独立地为氢、卤素、或烷氧基；
R 5为氢、卤素、羟基、氨基、烷基或烷氧基；
R 5b为氢、卤素、烷基或烷氧基；
R 7选自：烷氧基、羟基、烷基磺酰胺基、或环烷基磺酰胺基；
X 5为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、烷基、烷氧基、烷基胺基(NR iR j)、烷基羰基胺基、烷基胺基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、或芳氧基羰基胺基；其中，R i和R j各自独立地为氢、烷基、烷基羰基、烷氧基羰基、或环烷氧基羰基；
X 6为氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基；
X 7为氢；
Y 1为-CH 2-、-CHF-、-CF 2-、或-C(CH 3) 2-；
Z为-O-。
在一些具体的实施方式中，本发明的化合物具有选自下组的结构：
Figure PCTCN2021117623-appb-000004
本发明的另一方面提供了一种组合物，其包含(i)治疗有效量的至少一种式Ib或IIb的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物；以及(ii)药学上可接受的稀释剂和/或赋形剂。
本发明还涉及所述的化合物或组合物在制备用作GPR40激动剂的药物中的用途。
本发明还提供了治疗或预防糖尿病或相关代谢综合症的方法，包括向患者施用治疗有效量的所述化合物或组合物。
本发明还涉及所述的化合物或组合物在制备用于治疗或预防糖尿病或相 关代谢综合症的药物中的用途。
在优选的实施方式中，本发明的化合物或组合物尤其适用于II型糖尿病的治疗。本发明的化合物仅在II型糖尿病患者的血糖浓度较高时，才会促进胰岛素的分泌，因此可以有效降低患者产生低血糖的风险。同时，相对于市售药物而言，本发明的化合物具有更好的GPR40靶点选择性和安全性。
在下面的详细描述中，本发明的上述实施方式和其他方面是显而易见的。为此，本文阐述了各种参考文献，其更详细地描述了某些背景信息，过程，化合物和/或组合物，并且各自通过引用整体并入本文。
发明详述
在以下描述中，为了提供对本发明各实施方式的透彻理解，陈述了一些具体的细节。然而，本领域技术人员应理解，可以在不要求这些细节的情况下实施本发明。除非上下文中另有说明，贯穿本发明说明书和权利要求书，词语“包含”及其变化形式，例如，“包含”和“包括”理解为开放、可兼形式(即，“包括(包含)但不限于”)。
说明书中提及的“一个实施方式”或“一种实施方式”表示连同实施方式描述的具体特征、结构或特性包括在本发明的至少一个实施方式中。因此，在说明书中各处出现的短语“在一个实施方式中”或“在一种实施方式中”不一定全部都涉及同一个实施方式。而且，具体的特征、结构、或性质可以任何合适的方式组合在一个或多个实施方式中。
I.定义
本发明中，没有特别指定的时候，所述的“烷基”，意指包括1～20个碳原子的支链和直链的饱和脂族烃基，其仅由碳和氢原子组成。在优选的实施方式中，所述烷基具有一至十二个碳原子(C1-C12烷基)、一至八个碳原子(C1-C8烷基)或一至六个碳原子(C1-C6烷基)，并且其通过单键与分子的剩余部分相连。示例性的烷基基团包括：甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、庚基、辛基，及它们的各种异构体等。所述烷基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟 基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、芳氧基、杂环芳基、杂环芳基氧基、稠环芳基、稠环杂环芳基、稠环氧基、稠环芳氧基、稠环杂环芳氧基、芳基脲基、或杂环芳基脲基。
本发明中，没有特别指定的时候，所述的“亚烷基”，其中“亚”意指包括1～20个碳原子的烷基中再除去1个氢原子衍生成的二阶基团，例如亚甲基、亚乙基、亚丙基等。
本发明中，没有特别指定的时候，所述的“芳基”是指任何稳定的每个环可包含最高达7个碳原子的单环、二环、三环或四环，其中至少一个环是芳香环的烃环系基团。示例性的芳基是包含氢和6-9个碳原子和至少一个芳环的烃环系基团；包含氢和9-12个碳原子和至少一个芳环的烃环系基团；包含氢和12-15个碳原子和至少一个芳环的烃环系基团；或包含氢和15-18个碳原子和至少一个芳环的烃环系基团。出于本发明目的，芳基基团可以是单环、双环、三环或四环环系，其可包括稠合或桥接环系。芳基基团包括但不限于，源自如下构成的芳基基团：苯、联苯、蒽、薁、芴、茚满、茚、萘、菲、芘等。“任选取代的芳基”指：芳基基团或取代的芳基基团。所述芳基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、烷基-磺酰基-烷氧基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、芳基、芳氧基、杂环芳基、稠环芳基、稠环烷基、稠环烷基、稠环氧基、未取代或含1～4个上述任选取代基的苯或联苯基。
本发明中，没有特别指定的时候，所述的“杂环芳基”表示每个环可包含最高达7个原子的稳定单环、二环或三环，其中至少一个环是芳香环、并且其中至少一个环含有1-4个选自O、N、和/或S的杂原子。在此定义范围内的杂环芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻唑基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶 基、吡咯基、四氢喹啉。另外，“杂环芳基”还应当理解为包括任何含氮杂环芳基的季铵盐或N-氧化物衍生物。所述杂环芳基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、芳基、芳氧基、杂环芳基、稠环芳基、稠环烷基、稠环烷基、稠环氧基、未取代或含1～4个上述任选取代基的苯或联苯基。
本发明中，没有特别指定的时候，所述的“稠环芳基”表示每个环可包含最高达7个原子的稳定二环或者三环，其中至少一个环是芳香环。所述稠环芳基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、芳基、芳氧基、杂环芳基、稠环芳基、稠环烷基、稠环烷基、稠环氧基、未取代或含1～4个上述任选取代基的苯或联苯基。
本发明中，没有特别指定的时候，所述的“稠环杂环芳基”表示每个环可包含最高达7个原子的稳定二环或者三环，其中至少一个环是芳香环并且含有1-4个选自O、N、和/或S的杂原子。所述稠环杂环芳基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、芳基、芳氧基、杂环芳基、稠环芳基、稠环烷基、稠环烷基、稠环氧基、未取代或含1～4个上述任选取代基的苯或联苯基。
本发明中，没有特别指定的时候，所述的“烷氧基”表示烷基与氧原子连接后的生成基团，即
Figure PCTCN2021117623-appb-000005
R为烷基，其定义与上述烷基所述相同。烷氧基基团的示例包括但不限于：–O-甲基(甲氧基)，-O-乙基(乙氧基)，-O-丙基(丙氧基)，-O-异丙基(异丙氧基)，-O-叔丁基(叔丁氧基)等。
本发明中，没有特别指定的时候，所述的“烯基”，意指包括2～20个碳原子的支链和直链的含1～3个“碳碳双键”的不饱和脂族烯基，优选2～10个碳 原子(C 2-C 10烯基)，更优选2～8个碳原子(C 2-C 8烯基)或2～6个碳原子(C 2-C 6烯基)，及它们的各种异构体等，其通过单键与分子的剩余部分相连。烯基的示例包括但不限于：乙烯基，丙烯基，丁烯基，戊烯基，己烯基等。所述烯基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、杂环芳基、稠环芳基、稠环杂环芳基、芳基脲基、或杂环芳基脲基。
本发明中，没有特别指定的时候，所述的“炔基”，意指包括2～20个碳原子的支链和直链的含1～2个“碳碳三键”的不饱和脂族炔基，优选2～10个碳原子(C 2-C 10炔基)，更优选2～8个碳原子(C 2-C 8炔基)或2～6个碳原子(C 2-C 6炔基)，及它们的各种异构体等，其通过单键与分子的剩余部分相连。炔基的示例包括但不限于：乙炔基，丙炔基，丁炔基，戊炔基，己炔基等。所述炔基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、杂环芳基、稠环芳基、稠环杂环芳基、芳基脲基、或杂环芳基脲基。
本发明中，没有特别指定的时候，所述的“烷硫基”表示烷基与硫原子连接后的生成基团，即
Figure PCTCN2021117623-appb-000006
R为烷基，其定义与上述烷基所述相同。
本发明中，没有特别指定的时候，所述的“芳氧基”表示芳基与氧原子连接后的生成基团，即
Figure PCTCN2021117623-appb-000007
Ar为芳基，其定义与上述芳基所述相同。
本发明中，没有特别指定的时候，所述的“芳胺基”是指“NH 3”中的一个氢被芳基取代后的胺基，其中芳基的定义与上述芳基所述相同。
本发明中，没有特别指定的时候，所述的“杂环芳胺基”是指“NH 3”中的一个氢被杂环芳基取代后的胺基，其中杂环芳基的定义与上述杂环芳基所述相同。
本发明中，没有特别指定的时候，所述的“环烷基”指全碳单环或多环基团，其中每个环不含有双键或三键。优选具有3-20个碳原子，具有3至15个碳原 子，优选具有3至10个碳原子，3至8个碳原子，3至6个碳原子，3至5个碳原子，具有4个碳原子的环，或具有3个碳原子的环。环烷基的示例包括例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。所述环烷基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、芳氧基、杂环芳基、杂环芳基氧基、稠环芳基、稠环杂环芳基、稠环氧基、稠环芳氧基、稠环杂环芳氧基、芳基脲基、或杂环芳基脲基，其中芳基的定义与上述芳基所述相同。
本发明中，没有特别指定的时候，所述的“环烯基”指全碳单环或多环基团，其中一个环或每个环可以含有一个或多个“碳碳双键”。优选具有3-20个碳原子，具有3至15个碳原子，优选具有3至10个碳原子，3至8个碳原子，3至6个碳原子，3至5个碳原子，具有4个碳原子的环，或具有3个碳原子的环。环烯基的示例包括例如：环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基。所述环烯基可任选地被选自下组的基团取代：氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、杂环基、烷基脲基、芳基、芳氧基、杂环芳基、杂环芳基氧基、稠环芳基、稠环杂环芳基、稠环氧基、稠环芳氧基、稠环杂环芳氧基、芳基脲基、或杂环芳基脲基。当环烯基的取代基取代在碳碳双键上且使双键达到饱和时，可以形成环烷基。
本发明中，没有特别指定的时候，所述的“环醚基”是指环上带有醚基的环烷基。
本发明中，没有特别指定的时候，所述的“杂环基”为含有选自O、N和S的杂原子中的一个或多个的芳香或者非芳香杂环，并且包括二环基团。因此，“杂环基”包括上述杂环芳基以及其二氢或者四氢类似物，并且包含但不限于以下“杂环基”：苯并咪唑基、苯并呋喃基、苯并吡唑基、苯并三唑基、苯并噻唑基、苯并噻吩基、苯并噁唑基、异苯并呋喃基、吡啶并吡啶基，杂环基可以通 过碳原子或者杂原子与其它有机小分子基团进行连接成新的有药用效果的化合物。
本发明中，没有特别指定的时候，所述的“稠环芳基”指两个或两个以上的芳基和/或杂环芳基，通过稠环形成的多环有机化合物，所述的稠环芳基也可以被本发明中定义的烷基、烷氧基、烷硫基、芳氧基、芳胺基、杂环基、环烷基、环烷氧基、环烷氧基羰基、环烷基胺基、环烷基胺基羰基、环烯基、环醚基、芳基、卤素、羰基、羟基、杂环芳基等基团以合理的方式取代-；其中-包含但不限于萘、蒽、醌、菲、芴、苯并咪唑基、呋喃并呋喃基、噻吩并噻吩基、苊基(acenaphthyl)、
Figure PCTCN2021117623-appb-000008
Figure PCTCN2021117623-appb-000009
本发明中，没有特别指定的时候，所述的“稠环烷基”表示稠环芳基中的一个或多个双键被还原后生成的非芳香多环体系，其中碳数为“C 10-20”。
本发明中，没有特别指定的时候，所述的“稠环烷基芳基”表示芳基中碳上的氢被稠环烷基取代后生成的基团，其中碳数为“C 15-20”。
本发明中，没有特别指定的时候，所述的“稠环氧基”表示稠环芳基或者稠环烷基与氧连接形成的基团，即
Figure PCTCN2021117623-appb-000010
Ar为C 10-20稠环芳基或者稠环烷基。
本发明中，没有特别指定的时候，所述的“烷氧基羰基”表示烷氧基与羰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000011
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“芳氧基羰基”表示芳氧基与羰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000012
Ar为C 6-20芳基。
本发明中，没有特别指定的时候，所述的“杂环氧基”表示杂环基与氧连接后的生成基团，即
Figure PCTCN2021117623-appb-000013
R为C 2-20杂环基。
本发明中，没有特别指定的时候，所述的“烷基胺基”表示烷基与胺基连接 后的生成基团，即
Figure PCTCN2021117623-appb-000014
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“烷基胺基羰基”表示烷基胺基与羰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000015
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“芳胺基”表示芳基与胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000016
Ar为C 6-20芳基。
本发明中，没有特别指定的时候，所述的“杂环胺基”表示杂环基与胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000017
R为C 2-20杂环基。
本发明中，没有特别指定的时候，所述的“芳胺基磺酰基”表示芳胺基与磺酰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000018
Ar为C 6-20芳基。
本发明中，没有特别指定的时候，所述的“烷基胺基磺酰基”表示烷基胺基与磺酰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000019
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“杂环胺基磺酰基”表示杂环胺基与磺酰基连接后的生成基团，即
Figure PCTCN2021117623-appb-000020
R为C 2-20杂环基。
本发明中，没有特别指定的时候，所述的“烷基磺酰胺基”表示烷基与磺酰胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000021
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“杂环磺酰胺基”表示杂环基与磺酰胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000022
R为C 2-20杂环基。
本发明中，没有特别指定的时候，所述的“芳基磺酰胺基”表示芳基与磺酰胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000023
Ar为C 6-20芳基。
本发明中，没有特别指定的时候，所述的“烷基胺基磺酰胺基”表示烷基胺基与磺酰胺基连接后的生成基团，即
Figure PCTCN2021117623-appb-000024
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“烷基羰基胺基”表示烷基与羰基 连接后再与胺基相连生成的基团，即
Figure PCTCN2021117623-appb-000025
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“烷基脲基”表示烷基与脲基连接后生成的基团，即
Figure PCTCN2021117623-appb-000026
R为C 1-20烷基。
本发明中，没有特别指定的时候，所述的“芳基脲基”表示芳基与脲基连接后生成的基团，即
Figure PCTCN2021117623-appb-000027
Ar为C 6-20芳基。
本发明中，没有特别指定的时候，所述的“烷基硫脲基”表示烷基与硫脲基连接后生成的基团，即
Figure PCTCN2021117623-appb-000028
R为C 1-20烷基。
本发明中，所述的术语“卤素”表示为“氟、氯、溴、或碘原子”。
本发明中，所述的术语“羟基”表示为
Figure PCTCN2021117623-appb-000029
本发明中，所述的术语“胺基”表示为
Figure PCTCN2021117623-appb-000030
本发明中，所述的术语“氰基”表示为
Figure PCTCN2021117623-appb-000031
本发明中，所述的术语“羧基”表示为
Figure PCTCN2021117623-appb-000032
本发明中，所述的术语“磺酰基”表示为
Figure PCTCN2021117623-appb-000033
本发明中，所述的术语“磺酰胺基”表示为
Figure PCTCN2021117623-appb-000034
本发明中，所述的术语“羰基”表示为
Figure PCTCN2021117623-appb-000035
本发明中，所述的“脲基”表示为
Figure PCTCN2021117623-appb-000036
本发明中，所述的“硫脲基”表示为
Figure PCTCN2021117623-appb-000037
术语“卤素”是指氟、氯、溴和碘。
II.本发明的化合物
本发明创新性地设计引入了下列一种含新型苯并含氧杂环类的杂环功能团：
Figure PCTCN2021117623-appb-000038
(其中，R 8为卤素、羟基、氨基、羧基、烷基磺酰氧基、芳基 磺酰氧基、或可以被取代的离去基团)，并且合成出了一类能够有效治疗II型糖尿病的新型GPR40靶点激动剂的苯并五元含氧杂环类化合物。
本发明一般涉及由式Ib涵盖的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物：
Figure PCTCN2021117623-appb-000039
对于式Ib的化合物，n、E、G 1、L 1、L 2、R 1、R 2、R 3、R 4、R 5、R 5b、R 6、Ra、Rb、Rc、Rd、Re、Rf、Rg、Ri、Rj、X 5、X 6、X 7、Y、Y 1、Z和Z 1如说明书中所定义。
下文还描述了式Ib化合物的具体实施方式。
在一个实施方式中，n＝0，Y不存在，Y 1与Z 1直接单键连接。
在一个实施方式中，E与G 1连接成环状化合物。在一个优选的实施方式中，E与G 1连接成五元环状化合物。在一个优选的实施方式中，G 1为-C-，E为-O-、-C(RcRd)-、-OC(RcRd)-或-C(RcRd)O-。在一个实施方式中，Rc和Rd独立地选自：氢、氘(D)、烷基、环烷基、烯基、炔基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基。在另一个实施方式中，Rc和Rd之间可以互相连接成环烷基或杂环基团。在优选的实施方式中，G 1为-C-，E为-OC(RcRd)-或-C(RcRd)O-，其中Rc和Rd独立地选自：氢、氘(D)、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、C 3-C 8环烷氧基、C 1-C 8烷氧基羰基、C 1-C 8烷基胺基、C 3-C 8环烷基胺基、C 1-C 8烷基胺基羰基、C 3-C 8环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基。在更优选的实施方式中，G 1为-C-，E为-OC(RcRd)-或-C(RcRd)O-，其中Rc和Rd分别为氢。
在一个实施方式中，L 1和L 2各自独立地选自：-O-、-S-、-C(O)-、-SO 2-、 -CH 2-、-C(RfRg)-、-OC(RfRg)-、-C(RfRg)O-、-N(Re)-、-N(Rc)C(RfRg)-、或-C(RfRg)N(Re)-。在一个优选的实施方式中，L 1和L 2中的一个为-CH 2-，另一个为-O-。在另一个优选的实施方式中，式Ib中R 2与L 1之间相互连接成5-6元的杂环化合物，L 1和L 2中至少一个为-OCH-。
在一个实施方式中，R 1、R 2和R 3各自独立地为氢、氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、氨基羰基(H 2NCO)、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷氧基羰基、C 1-C 8烷基胺基羰基、C 1-C 8烷基羰基胺基、芳基、芳氧基、或杂环芳基。在优选的实施方式中，R 1、R 2和R 3各自独立地为氢、卤素、或C 1-C 8烷氧基。
在一个实施方式中，R 4和R 5各自独立地选自：氢、卤素、羟基、氨基、或烷氧基。在优选的实施方式中，R 4和R 5各自独立地为氢、卤素、或C 1-C 8烷氧基。
在一个实施方式中，R 6为-COR 7。在一个优选的实施方式中，R 7为-OH、烷氧基、烷基胺基、环烷基胺基、杂环胺基、烷基磺酰胺基、环烷基磺酰胺基、芳氧基、杂环芳氧基、芳基胺基、或杂环芳基胺基；或R 7与邻位的取代基R 5之间可以相互连接成为杂环。在一个优选的实施方式中，R 7为C 1-C 8烷氧基、羟基、C 1-C 8烷基磺酰胺基、或C 3-C 8环烷基磺酰胺基。
在一个实施方式中，Y 1选自：-氧-、-硫-、-CH 2-、-CHF-、-CF 2-、-CCl 2-、-C(R fR g)-、或-N(Re)-。在优选的实施方式中，Y 1选自：CH 2、-CHF-、CF 2、或C(CH 3) 2。
在一个实施方式中，Z和Z 1独立地选自：-O-、-S-、-CH 2-、-CHF-、-CF 2-、-C(R fR g)-、-N(Re)-、或–C(O)–；其中，R f和R g的定义分别与上述L 1中的R f和R g所述相同，Re的定义与上述E中的Re所述相同。在一个更优选的实施方式中，Z和Z 1中至少一个为-O-。在一个更优选的实施方式中，Z和Z 1均为-O-。
在一个实施方式中，Z为-O-。
在一个实施方式中，Z 1为-O-。
在一个实施方式中，X 5、X 6和X 7各自独立地为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、氨基羰基(H 2NCO)、烷基、杂环烷基、烷氧基、 杂原子取代的烷基氧基、烷基胺基(NR iR j)、杂原子取代的烷基胺基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、芳氧基、芳基胺基羰基、芳基羰基胺基、芳氧基羰基胺基、杂环芳基、杂环芳基氧基、或杂环芳基胺基；其中，R i和R j各自独立地为氢、氘(D)、烷基、杂环烷基、烷基羰基、烷氧基羰基、环烷氧基羰基、烷基胺基羰基、烷基磺酰基、环烷基磺酰基、芳基、芳氧基羰基、芳基胺基羰基、杂环芳基，或R i和R j相互连接成含1-3个杂原子的3-8元杂环。
在一个实施方式中，X 5选自：氢、氘(D)、卤素、腈基、氨基(NH 2)、三氟甲基、三氟甲氧基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷基胺基、C 1-C 8烷基羰基胺基、C 1-C 8烷基胺基羰基胺基、C 1-C 8烷氧基羰基胺基、C 3-C 8环烷氧基羰基胺基、C 1-C 8烷基磺酰胺基、C 3-C 8环烷基磺酰胺基、芳基、或芳氧基羰基胺基。在优选的实施方式中，X 5选自：氢、氘(D)、卤素、腈基、三氟甲基、三氟甲氧基、C 1-C 8烷氧基羰基胺基。
在一个实施方式中，X 6和X 7各自独立地选自：氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基。在优选的实施方式中，X 6选自：氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基，X 7选自：氢。
本发明化合物可以多种异构形式，以及一种或多种互变异构形式存在，包括两种单一互变异构体，和互变异构体的混合物。术语"异构体"意在涵盖本发明化合物的全部异构形式，包括所述化合物的互变异构形式。
本文所述的一些化合物可具有不对称中心，并因此以不同的对映和非对映异构形式存在。本发明化合物可以是光学异构体或非对映异构体的形式。因此，本发明涵盖本发明的化合物和它们如本文所述的以其光学异构体、非对映异构体及其混合物，包括外消旋混合物的形式的应用。本发明化合物的光学异构体可通过已知技术获得，例如不对称合成、手性色谱法，或通过利用光学活性拆分剂对立体异构体进行化学分离。
除非另有指示，"立体异构体"指，化合物的一种立体异构体，其基本不含该化合物的其它立体异构体。因此，具有一个手性中心的立体异构纯的化合物基本不含该化合物的相反对映异构体。具有两个手性中心的立体异构纯的 化合物基本不含该化合物的其他非对映异构体。典型的立体异构纯的化合物包含大于约80重量％的该化合物的一种立体异构体和小于约20重量％的该化合物的其它立体异构体，例如，大于约90重量％的该化合物的一种立体异构体和小于约10重量％的该化合物的其它立体异构体，或大于约95重量％的该化合物的一种立体异构体和小于约5重量％的该化合物的其它立体异构体，或大于约97重量％的该化合物的一种立体异构体和小于约3重量％的该化合物的其它立体异构体。
如果在描述的结构和对该结构给定的名称之间存在差异，则以描述的结构为准。此外，若结构或结构的部分的立体化学未用例如粗或虚线指示，则该结构或结构的部分应被理解为涵盖其全部立体异构体。然而，在其中存在多于一个手性中心的一些情况中，结构和名称可以单一对映异构体的形式表示，以助于描述相关的立体化学。有机合成领域的技术人员应知晓用制备所述化合物的单一对映异构体的方法制备它们的情况。
本说明书中，"药学上可接受的盐"是本发明化合物的药学上可接受的、有机或无机酸或碱盐。典型的药物上可接受的盐例如包括碱金属盐、碱土金属盐、铵盐、水溶性盐和水不溶性盐，例如乙酸盐、氨茋磺酸盐(4,4-二氨基茋-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、丙酸酯月桂硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酸基阿散酸盐、六氟磷酸盐、己基间苯二酚盐、哈胺、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘酸盐、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲磺酸盐、粘液酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(1，1-亚甲基-双-2-羟基-3-萘甲酸盐，双羟萘酸盐、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐、苏拉酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐、甲苯磺酸盐、三乙碘化物和戊酸盐。药学上可接受的盐可在其结构中具有超过一个的带电原子。在该情况中，该 药学上可接受的盐可具有多个抗衡离子。因此，药学上可接受的盐可具有一个或多个带电原子和/或一个或多个抗衡离子。
本发明的化合物可以是其中一个或多个原子被具有不同原子质量或质量数的原子代替的同位素标记的。可被纳入式Ib或IIb化合物的同位素的示例包括：氢、碳、氮、氧、磷、氟、氯或碘的同位素。此类同位素的示例分别是： 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 36Cl、 123I和 125I。这些带有放射性标记的化合物可用于检测生物分布、组织浓度，和从生物组织，包括给予该带标记的化合物的对象，运输和排出的动力学。带标记的化合物还用于确定治疗效果、作用位点或模式，以及候选治疗物对药理学上重要的靶标的结合亲和性。因此，式Ib或IIb的某些放射性物质标记的化合物可用于药物和/或组织分布研究。放射性同位素氚，即 3H，和碳-14，即 14C，特别有用于该目的，因为它们易于纳入并且检测手段现成。
用重同位素如氘即 2H取代能提供因代谢稳定性较高(例如含氘化合物的体内半衰期延长)而产生的某些治疗优势。用氘取代氢能减小获得疗效所需的剂量，并因此可优选用于发现或临床环境。
正电子发射型同位素(例如 11C， 18F， 15O和 13N)的取代能提供本发明化合物的经标记的类似物，其有用于正电子成象术(PET)研究，例如，用于检测物质受体占用率。同位素标记的式Ib或IIb的化合物可一般地通过本领域技术人员已知的常规技术或通过与下文所述的制备和实施例部分中描述的那些类似的方式，采用合适的同位素标记试剂来制备。
本文所述的本发明实施方式还意在涵盖式Ib或IIb化合物的体内代谢产物。这些产物可源自，例如，主要归因于本发明化合物给予后的酶促活性的氧化、还原、水解、酰胺化、酯化等过程。因此，本发明包括这样的化合物，它们在将本发明化合物给予哺乳动物足以产生代谢产物的一段时间之后，以基于对本发明化合物发挥酶促或非酶促活性的副产物的形式产生。代谢产物，尤其是具有药物活性的代谢物，通常通过如下方式鉴定：向对象，例如大鼠、小鼠、豚鼠、猴子或人类给予可检测剂量的放射性标记的本发明化合物，其持续在此过程中发生代谢的一段足够的时间，和，从获自接受所述放射性标记的化合物的对象的尿液、血液或其它生物样品分离所述代谢产物。
本发明还提供式Ib或IIb化合物的药学上可接受的盐形式。本发明范围涵盖酸加成盐和碱加成盐，其通过使药学上合适的酸或药学上合适的碱与本发明化合物接触来形成。
“药学上可接受的酸加成盐”指：保留生物有效性和游离碱的性质的那些盐，它们不是在生物或其它方面中不希望的，并且它们的形成采用无机酸，例如但不限于，盐酸、氢溴酸、硫酸、硝酸、磷酸等，以及有机酸，例如但不限于，乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
“药学上可接受的碱加成盐”指：保留生物有效性和游离酸的性质的那些盐，它们不是生物学或其它方面中不希望的。这些盐通过向游离酸添加无机碱或有机碱来制备。源自无机碱的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐是铵、钠、钾、钙、和镁盐。源自有机碱的盐包括但不限于，如下物质的盐：伯胺、仲胺和叔胺、取代的胺，包括天然产生的取代的胺、环胺和碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苯乙苄胺、苄星青霉素、乙二胺、葡糖胺、甲基葡萄糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱是异丙基胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱和咖啡因。
结晶化通常产生本发明化合物的溶剂合物。本文中所用术语“溶剂合物” 指：包含本发明化合物的一个或多个分子与溶剂的一个分子或多个分子的聚集体。溶剂可以是水，此时溶剂合物可以是水合物。或者，溶剂可以是有机溶剂。因此，本发明化合物可以水合物形式存在，包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及对应的溶剂合物形式。本发明化合物可以是真溶剂合物，而在其它情况中，本发明化合物可以仅保留不定水或是水加上一些不定溶剂的混合物。
“立体异构体”指：一种化合物，其通过由相同键键连的相同原子组成，但具有不同的三维结构，它们是不可互换的。本发明设想各种立体异构体及其混合物，并且包括“对映异构体”，其指：两个立体异构体的分子不可重叠地彼此互成镜像。
本发明化合物，或其药学上可接受的盐，可包含一个或多个不对称中心，由此产生对映异构体、非对映异构体，和就绝对立体化学而言可确定的其它立体异构形式，例如(R)-或(S)-，或者，对于氨基酸而言如(D)-或(L)-。本发明意在包括所有这些可能的异构体，以及它们的外消旋和光学纯形式。光学活性的(+)和(-)、(R)-和(S)-或者(D)-和(L)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分，例如色谱和分级结晶。用于制备/分离个体对映体的传统技术包括从合适的光学纯前体手性合成或采用例如手性高压液相色谱法(HPLC)来拆分外消旋体(或盐或衍生物的外消旋体)。当本文所述的化合物包含烯双键或其它几何不对称中心时，除非另有说明，其意在表示该化合物包括E和Z几何异构体。同样，还意在包括全部互变异构形式。
III.药物组合物
在一个实施方式中，式Ib或IIb的化合物，以药学上可接受的组合物的形式配制，所述组合物包含一定量的式Ib或IIb化合物，在给予所述药物组合物至哺乳动物后，该量有效于治疗感兴趣的特定疾病或病症。本发明的药物组合物可包含式Ib或IIb化合物，其与药学上可接受的运载体、稀释剂或赋形剂相组合。
就此而言，“药学上可接受的运载体、稀释剂或赋形剂”包括但不限于任何佐剂、运载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、风 味增强剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂，或乳化剂，其均被美国食品和药物管理局批准为是人类或家畜可接受的。
此外，“哺乳动物”包括人和家畜，例如，实验动物和家养宠物(例如，猫、狗、猪、牛、绵羊、山羊、马、兔)，和非家畜，例如，野生动物等。
本发明的药物组合物可通过将本发明化合物与合适的药学上可接受的运载体、稀释剂或赋形剂联合来制备，并且可制成固体、半固体、液体或气体形式的制剂，例如，片剂、胶囊、粉末、颗粒、软膏、溶液、栓剂、注射剂、吸入剂、凝胶、微球，和气溶胶。给予此类药物组合物的典型途径包括但不限于，口服、局部、经皮、吸入、肠胃外、舌下、颊、直肠、阴道，和鼻内。本文所用术语肠胃外包括，皮下注射、静脉内、肌内、胸骨内注射或输注技术。本发明的药物组合物配制为允许其中含有的活性成分在将组合物给予患者后是生物可利用的。将给予对象或患者的组合物可使用一种或多种剂量单位的形式，例如片剂可以是单个剂量单位，且气溶胶形式的本发明的化合物的容器可含有多个剂量单位。制备这种剂型的实际方法是已知的，或是本领域技术人员所明白的；例如参见《雷明顿：药物科学和实践》(Remington:The Science和Practice of Pharmacy)，第20版(费城药物与科学学院(Philadelphia College of Pharmacy和Science)，2000)。在任何情况下待给予的组合物含有治疗有效量的本发明化合物或其药学上可接受的盐，以根据本发明的教导治疗感兴趣的疾病或病症。
本发明的药物组合物可以是固体或液体形式。一方面，运载体是颗粒，从而组合物是，例如，片剂或粉末形式。运载体可以是液体，其中，所述组合物是，例如，口服型糖浆、可注射的液体，或气溶胶，其可用于，例如，吸入式给予。意图用于经口给予时，所述药物组合物优选是固体或液体形式，其中，半固体、半液体、悬液和凝胶形式包括在本文考虑的固体或液体形式中。
作为用于经口给予的固体组合物，该药物组合物可配制成粉末、颗粒、压缩片剂、丸剂、胶囊、咀嚼胶、薄片等形式。此类固体组合物将通常包含一种或多种惰性稀释剂或可食用运载体。此外，可存在一种或多种如下物质：粘合剂，如羧甲基纤维素、乙基纤维素、微晶纤维素、黄蓍胶或明胶；赋形剂，如淀粉、乳糖或糊精，崩解剂，如藻酸、藻酸钠、普利莫尔(Primogel)、玉米淀粉等；润滑剂，如硬脂酸镁或斯泰特(Sterotex)；助流剂，如胶体二氧化硅；甜 味剂，如蔗糖或糖精；调味剂，例如薄荷、水杨酸甲酯或橙味调味剂；和着色剂。
若该药物组合物是胶囊(例如，明胶胶囊)形式，除了上述类型的物质之外，其可包含液体运载体，例如，聚乙二醇或油。
该药物组合物可以是液体形式，例如酏剂、糖浆、溶液、乳液或悬浮液。作为两个示例，该液体可以是用于口服给药或用于通过注射递送。若旨在进行经口给药，除了本发明化合物之外，优选的组合物可含有一种或多种甜味剂、防腐剂、染料/着色剂和风味增强剂。对于旨在通过注射给药的组合物，可包含表面活性剂、防腐剂、润湿剂、分散剂、助悬剂、缓冲剂、稳定剂和等张剂中的一种或多种。
本发明的液体药物组合物，无论它们是溶液、悬液还是其它类似形式，可包括一种或多种如下佐剂：无菌稀释剂，如注射用水、盐水溶液，优选生理盐水、林格氏溶液、等渗氯化钠；不挥发油，例如可用作溶剂或悬浮介质的合成甘油单酯或甘油二酯、聚乙二醇、甘油、丙二醇或其它溶剂；抗菌剂，如苄醇或对羟基苯甲酸甲酯；抗氧化剂，如抗坏血酸或亚硫酸氢钠；螯合剂，如乙二胺四乙酸；缓冲剂，如乙酸盐、柠檬酸盐或磷酸盐，和用于调节张力的试剂，如氯化钠或葡萄糖。胃肠道外制剂可封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。生理盐水是优选的佐剂。可注射的药物组合物优选是无菌的。
本发明的药物组合物可通过药学领域中熟知的任何方法制备。例如，意图通过注射给予的药物组合物可通过将本发明化合物与无菌、蒸馏水组合以形成溶液来制备。可添加表面活性剂来促进形成均一溶液或悬液。表面活性剂是与本发明化合物非共价相互作用的化合物，从而促进所述化合物在水性递送系统中的溶解或均匀悬浮。
IV.治疗应用
给予治疗有效量的本发明化合物或其药学上可接受的盐，所述治疗有效量根据各种因素而变化，包括所用特定化合物的活性、该化合物的代谢稳定性和作用时长、患者的年龄、体重、总体健康状况、性别、饮食、给予方式和时间、 排泄速率、联合用药、具体疾病或病症的严重程度和接受治疗的对象。
“有效量”或“治疗有效量”指：本发明化合物的一定量，其(当给予哺乳动物，优选人类时)足以提供对于该哺乳动物(优选人类)中Mnk相关病症或疾病的有效治疗，如下所述。构成“治疗有效量”的本发明化合物的量将根据化合物、病症及其严重性、给予方式，以及待治疗的哺乳动物的年龄而变化，但可由本领域技术人员根据其所掌握的知识和本发明内容来常规地确定。
本发明的化合物，或其药学上可接受的盐，也可在一种或多种其它治疗剂的给予之前、同时或之后给予。此类联合治疗包括给予单一药物剂量制剂，其包含本发明化合物和一种或多种其它活性物质，以及在分开的药物剂量制剂中给予本发明化合物和各活性物质。例如，本发明化合物和其它活性物质可在单一口服剂量组合物(例如片剂或胶囊)中一起给予患者，或各物质在分开的口服剂量制剂中给予。使用单独的剂量制剂时，本发明的化合物和一种或多种其他活性剂可在基本相同时间(即同时)给予，或在单独的交错时间(即依次)给予；应理解组合疗法包括所有这些方案。
本发明还通过构效关系(SAR)进一步研究优化了GPR40靶点激动剂化合物式Ib-IIb的结构，并且能有效降低产生低血糖的风险，更加安全有效地治疗II型糖尿病。
本发明的苯并含氧杂环类化合物能通过激活GPR40靶点刺激胰岛β细胞释放胰岛素来降低血糖水平，并且此类式Ib-IIb化合物的特点是仅在II型糖尿病患者的血糖浓度较高时，才会促进胰岛素的分泌，因此可以有效降低患者产生低血糖的风险，并且具有更好的GPR40靶点选择性和安全性。
具体实施方式:
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规熟知的方法和条件，或按照商品说明书选择实施完成。
本发明合成新型苯并含氧杂环化合物过程中的化学试剂和溶剂的英文缩写注释全部汇总列在实施例中仪器及原料说明部分。
本发明的关健创新点是按下列方案1和2中所示的合成反应路线1或2， 首先通过原料RM-1b分别与原料SM-1(如下列SM-1a或RM-1b结构的试剂)反应分别制备目标产物Ib-IIb或中间体RM-2b；当R 7为烷氧基(如：R 7＝OCH 3或OEt)时，可以再通过LiOH水解反应合成出本发明式IIb中R 7为羟基的各个目标产物。
Figure PCTCN2021117623-appb-000040
上述的合成反应路线1b如下：
Figure PCTCN2021117623-appb-000041
方案1：式Ib-IIb化合物的合成反应
在上述合成反应路线1b中操作如下：
1、RM-2b的合成:在圆底反应瓶中将原料RM-Ib(1.0eq)、SM-1b(1.0eq)，和DIAD与PPh 3(1.2eq)分别加到THF(5x)中，氮气置换并保护，反应通过TLC和/或HPLC跟踪检测至反应结束，经后处理等常规操作后得到RM-2b(或RM-IIb)；
2、目标产物Ib-IIb的合成:在圆底反应瓶中分别将RM-Ib(或RM-IIb,1eq)在LiOH的MeOH-H 2O混合溶液(1:1，10X)中水解，TLC和/或HPLC检测至反应结束后，经后处理和纯化等常规操作后得到目标产物Ib-IIb。
合成反应路线2b如下：
Figure PCTCN2021117623-appb-000042
方案2：式Ib-IIb化合物的合成反应
在上述合成反应路线2中操作如下:
1、RM-2b的合成:在圆底反应瓶中将原料RM-Ib(1.0eq)、SM-1b(1.0eq)，和碱性试剂(如：磷酸钾或碳酸钾，2-3eq)分别加到DMF(5x)中，氮气置换并保护反应进行，TLC和/或HPLC跟踪检测至反应结束，搅拌下将反应液缓慢倒入至40X冰水中，经后处理和纯化等常规操作后得到RM-Ib(或RM-IIb)。
2、目标产物IIb的合成:在圆底反应瓶中分别将RM-Ib(或RM-IIb)在LiOH的MeOH-H 2O混合溶液(1:1，10X)中水解，TLC和/或HPLC检测至反应结束后，经后处理和纯化等常规操作后得到目标产物Ib-IIb。
上述合成的式Ib-IIb化合物，其中的n、L 1、R 1、R 2、R 3、R 5、R 5b、R 7、Ra、Rb、Rc、Rd、Re、X 5、X 6、Y、Y 1、和Z分别与本发明权利要求1-4中的n、L 1、R 1、R 2、R 3、R 5、R 5b、R 7、Ra、Rb、Rc、Rd、Re、X 5、X 6、Y、 Y 1、和Z定义相同。本发明式Ib-IIb中化合物的合成反应实例分别如下3所示，具体每个不同结构化合物的制备过程中分别采用下列表1中的苯并含氧杂环原料RM-1b以及表2中的原料SM-1顺利合成得到：
Figure PCTCN2021117623-appb-000043
Figure PCTCN2021117623-appb-000044
Figure PCTCN2021117623-appb-000045
表1：本发明中所用的原料SM-Ib-01至SM-Ib-30及其结构
Figure PCTCN2021117623-appb-000046
表2：本发明中所用的原料SM1-01至SM1-15及其结构
采用上述的原料RM-1b和SM1，然后通过下列方案3中合成反应路线制备中间体RM-2b，最终通过水解反应分别合成出式Ib-IIb的各个具体化合物。具体反应实例分别如下：
Figure PCTCN2021117623-appb-000047
方案3：式Ib-IIb化合物的合成反应实例
在上述方案3合成反应实例中:
第一步反应:首先通过原料RM-Ib-01与另一原料SM1-01在无机碱(如：K 3PO 4)的作用下在溶剂(如：DMSO或DMF)中先得到关键的中间体化合物(RM-Ib-01)；
第二步反应：然后将中间体(RM-2b-01)在无机碱(如：LiOH)的作用下在溶剂(如：MeOH或甲醇和水的混合溶剂)中水解反应得到目标产物Ib-01。
通过上述方案1、2、3中合成反应路线的第一步反应分别得到的中间体化合物RM-2b的中间体结构分别如下列RM-2b结构式系列所示；以及第二步水解反应分别得到式IIb目标产物，其结构分别如下列式IIb结构式系列所示：
RM-2b结构式系列：
Figure PCTCN2021117623-appb-000048
Figure PCTCN2021117623-appb-000049
Figure PCTCN2021117623-appb-000050
Figure PCTCN2021117623-appb-000051
Figure PCTCN2021117623-appb-000052
Figure PCTCN2021117623-appb-000053
式IIb结构式系列
Figure PCTCN2021117623-appb-000054
Figure PCTCN2021117623-appb-000055
Figure PCTCN2021117623-appb-000056
Figure PCTCN2021117623-appb-000057
Figure PCTCN2021117623-appb-000058
Figure PCTCN2021117623-appb-000059
Figure PCTCN2021117623-appb-000060
具体每一步反应的实验条件和产品分析结果分别列于实施例中。
具体有关上述每个式Ib-IIb新型结构化合物的合成和分析结果，详见本发明最后的实施例，每个化合物的化学及其手性不对称纯度通过手性色谱柱HPLC测定，相应的化学结构表征分别由LC-MS和/或氢谱核磁共振( 1H-NMR)分析确定。
以下通过实施例说明本发明各类中间体和化合物的合成和效果。
实施例中涉及到的仪器及原料说明如下：
红外光谱数据是采用赛莫尼克莱公司(Thermo Nicolet)公司的Fourier Transform AVATAR TM 360E.S.P TM红外仪分析得到，以cm -1为单位来表示。
核磁共振氢谱是Varian Mercury Plus 400(400MHz)核磁仪分析得到。化学位移以四甲基硅烷为内标来记录，以ppm为单位来表示(CHCl 3：δ＝7.26ppm)。记录的数据信息如下：化学位移及其裂分和偶合常数(s:单重峰；d:双 重峰；t:三重峰；q:四重峰；br:宽峰；m:多重峰)。
质谱数据除其他需要，都采用菲尼根高级LCQ公司(Finnigan LCQ Advantage)的液质联用仪进行分析。本发明中式Ib-IIb有机羧酸(-COOH)化合物的分子量主要为阴离子模式ESI-MS[(M-H) +]，但式RM-IIb的酯类中间体化合物和Ib-IIb中有些含胺基等化合物的分子量为阳离子模式ESI-MS[(M+H) +]。
本发明中渉及的特殊原料和中间体由赞南科技有限公司等订制加工提供，其他所有化学试剂从上海试剂公司、阿尔得里奇公司(Aldrich)、阿克罗公司(Acros)等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步等试验，则重复多次合成至足够数量为止。本发明所制备化合物的GPR40活性测试以及药理、毒理等试验由上海和北京等地的CRO服务单位完成。
本发明及其实施例中渉及的有关化学原料、试剂和溶剂的英文缩写注释如下：
AIBN：偶氮二异丁腈
Boc:叔丁氧基羰基
(Boc) 2O：二碳酸二叔丁酯
CDI：N,N'-羰基二咪唑
DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯
Et：乙基
EDCI：N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺盐酸盐
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
NBS：N-溴代丁二酰亚胺
SOCl 2：氯化亚砜
Pd/C：钯炭
DMAP：4-二甲氨基吡啶
HMTA：六亚甲基四胺
DIEA：N,N-二异丙基乙胺
Py：吡啶
HBr：氢溴酸
HCl：盐酸
HOAc：冰乙酸
TFA：三氟乙酸
TsOH：对甲苯磺酸
NaOH：氢氧化钠
LiOH：氢氧化锂
ACN：乙腈
DCM：二氯甲烷
DCE：二氯乙烷
DMF：N,N-二甲基甲酰胺
DMSO：二甲亚砜
Et 2O：二乙醚
EA：乙酸乙酯
PE：石油醚
THF：四氢呋喃
TBME：甲基叔丁基醚
实施例1
化合物IIb-1的合成
合成反应如下列通式一：
Figure PCTCN2021117623-appb-000061
第一步：
将原料RM-Ib-1(0.051g，0.24mmol)和SM1-1(0.050g，0.24mmol，1.0eq.)溶于2mL的DMF中，搅拌下加入碳酸钾(0.050g，0.36mmol，1.5eq.)，氮气保护下，加热到90度，反应过夜，反应完成。HPLC显示反应结束后将反应液冷却到室温，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，浓缩得中间体RM-IIb-1(0.1g)。
经质谱分析确证，RM-IIb-1的ESI-MS[(M+H) +]:m/z理论值343.1,实测值343.0。
第二步：
向中间体RM-IIb-1中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到浅黄色固体产物IIb-1(0.040g)，两步收率:50.7％。
经检测，产物IIb-1的 1H NMR(400MHz,CDCl 3):δ7.07-7.05(m,1H),6.95-6.93(m,1H),6.86-6.79(m,2H),6.52-6.49(m,2H),5.99(s,2H),5.01(s,2H),4.78-4.74(m,1H),4.31-4.27(m,1H),3.83-3.80(m,1H),2.83-2.78(m,1H),2.65-2.59(m,1H)。
质谱分析确证，IIb-1的ESI-MS[(M-H) +]:m/z理论值327.1,实测值327.0。
实施例2
化合物IIb-2的合成
合成反应如下列通式二：
Figure PCTCN2021117623-appb-000062
第一步：
将原料RM-Ib-2(0.043g，0.19mmol)，SM1-1(0.039g，0.19mmol，1.0eq.)和PPh 3(0.146g，0.56mmol，3eq.)溶于4mL的THF中，氮气保护，冰水浴冷却下，搅拌中加入DIAD(0.113g，0.56mmol，3eq.)，加完后冰水浴搅拌1h，20-30度，反应过夜，反应完成。HPLC显示反应结束后将反应液冷却到室温，加水，加入DCM萃取，再合并有机相，用食盐水洗涤后干燥，浓缩得粗品；将粗品用TLC刮板分离得中间体RM-IIb-2。
经质谱分析确证，RM-IIb-2的ESI-MS[(M+H) +]:m/z理论值421.0,实测值421.1。
第二步：
向中间体RM-IIb-2中加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到浅黄色固体产物IIb-2(0.025g)，两步收率:33％。
经检测，产物IIb-2的 1H NMR(400MHz,CDCl 3):δ7.09-7.05(m,2H),6.92(m,1H),6.50-6.46(m,2H),6.01(s,2H),4.95(s,2H),4.79-4.75(m,1H),4.31-4.28(m,1H),3.84-3.79(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H)。
质谱分析确证，IIb-2的ESI-MS[(M-H) +]:m/z理论值405.0,实测值405.2。
实施例3
化合物IIb-3的合成
制备化合物IIb-3的合成方法与实施例1相同，经醚化和水解反应得产物IIb-3，其中在反应中采用化合物RM-Ib-3(0.48mmol)代替化合物RM-Ib-1得到中间体RM-IIb-3，由中间体经水解得到白色固体产物IIb-3(0.039g)，两步收率:20％。
经质谱分析确证，IIb-3的ESI-MS[(M-H) +]:m/z理论值405.0,实测值404.8。
实施例4
化合物IIb-4的合成
制备化合物IIb-4的合成方法与实施例1相同，经醚化和水解反应得产物IIb-4，其中在反应中采用化合物RM-Ib-4(0.24mmol)代替化合物RM-Ib-1,得到中间体RM-IIb-4，由中间体经水解得到浅黄色固体产物IIb-4(0.060g)，两步收率:76％。
经检测，产物IIb-4的 1H NMR(400MHz,CDCl 3):δ7.07-7.05(m,1H),6.91-6.86(m,2H),6.81-6.79(m,1H),6.49-6.45(m,2H),5.96(s,2H),4.91(s,2H),4.78-4.74(m,1H),4.31-4.27(m,1H),3.83-3.79(m,1H),2.84-2.78(m,1H),2.65-2.59(m,1H)。
质谱分析确证，IIb-4的ESI-MS[(M-H) +]:m/z理论值327.1,实测值327.0。
实施例5
化合物IIb-5的合成
制备化合物IIb-5的合成方法与实施例1相同，经醚化和水解反应得产物IIb-5，其中在反应中采用化合物RM-Ib-5(0.54mmol)代替化合物RM-Ib-1得到中间体RM-IIb-5，由中间体经水解得到白色固体产物IIb-5(0.068g)，两步产率:34.8％。
经检测，产物IIb-5的 1H NMR(400MHz,CDCl 3):δ7.08-7.06(m,1H),6.95(s,1H),6.78(s,1H),6.50-6.46(m,2H),6.02(s,2H),4.95(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.83-3.80(m,1H),2.84-2.78(m,1H),2.66-2.59(m,1H)。
质谱分析确证，IIb-5的ESI-MS[(M-H) +]:m/z理论值361.1,实测值360.9。
实施例6
化合物IIb-6的合成
制备化合物IIb-6的合成方法与实施例1相同，经醚化和水解反应得产物IIb-6，其中在反应中采用化合物RM-Ib-6(0.41mmol)代替化合物RM-Ib-1得到中间体RM-IIb-6，由中间体经水解得到白色固体产物IIb-6(0.090g)，两步产率:63.6％。
经检测，产物IIb-6的 1H NMR(400MHz,DMSO):δ7.10-7.09(m,1H),6.92-6.89(m,1H),6.74-6.71(m,1H),6.46-6.44(m,2H),6.08(s,2H),4.93(s,2H),4.69-4.64(m,1H),4.19-4.15(m,1H),3.69-3.64(m,1H),2.71-2.65(m,1H),2.48-2.43(m,1H)。 19F NMR(376MHz,DMSO)δ-120.47。
质谱分析确证，IIb-6的ESI-MS[(M-H) +]:m/z理论值345.1,实测值345.0。
实施例7
化合物IIb-7的合成
制备化合物IIb-7的合成方法与实施例1相同，经醚化和水解反应得产物IIb-7，其中在反应中采用化合物RM-Ib-6(0.35mmol)代替化合物RM-Ib-1，化合物SM1-2(0.35mmol)代替化合物SM1-1得到中间体RM-IIb-7，由中间体经水解得到白色固体产物IIb-7(0.085g)，两步产率:70.8％。
经检测，产物IIb-7的 1H NMR(400MHz,CDCl 3):δ7.07-7.05(m,1H),6.66-6.63(m,1H),6.56-6.54(m,1H),6.49-6.46(m,2H),6.01(s,2H),4.96(s,2H),4.79-4.74(m,1H),4.31-4.27(m,1H),3.84-3.77(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H)； 19F NMR(376MHz,CDCl 3):δ-119.95。
经质谱分析确证，IIb-7的ESI-MS[(M-H) +]:m/z理论值345.1,实测值345.2。
实施例8
化合物IIb-8的合成
制备化合物IIb-8的合成方法与实施例1相同，经醚化和水解反应得产物IIb-8，其中在反应中采用化合物RM-Ib-7(0.24mmol)代替化合物RM-Ib-1得到中间体RM-IIb-8，由中间体经水解得到白色固体产物IIb-8(0.059g)，两步收率:65.5％。
经检测，产物IIb-8的 1H NMR(400MHz,CDCl 3):δ7.09-7.07(m,2H),6.79-6.76(m,1H),6.57-6.54(m,2H),5.35(s,2H),4.79-4.75(m,1H),4.32-4.25(m,5H),3.84-3.80(m,1H),2.84-2.79(m,1H),2.65-2.59(m,1H)。
质谱分析确证，IIb-8的ESI-MS[(M-H) +]:m/z理论值419.0,实测值418.9。
实施例9
化合物IIb-9的合成
制备化合物IIb-9的合成方法与实施例2相同，经醚化和水解反应得产物IIb-9，其中在反应中采用化合物RM-Ib-8(0.24mmol)代替化合物RM-Ib-2得到中间体RM-IIb-9，由中间体经水解得到白色固体产物IIb-9(0.035g)，两步收率:45％。
经质谱分析确证，IIb-9的ESI-MS[(M-H) +]:m/z理论值419.0,实测值418.8。
实施例10
化合物IIb-10的合成
制备化合物IIb-10的合成方法与实施例1相同，经醚化和水解反应得产物IIb-10，其中在反应中采用化合物RM-Ib-9(0.65mmol)代替化合物RM-Ib-1得到中间体RM-IIb-10，由中间体经水解得到白色固体产物IIb-10(0.196g)，两步收率:53.2％。
经检测，产物IIb-10的 1H NMR(400MHz,CDCl 3):δ7.34(s,1H),7.07-7.05(m,1H),7.00(m,1H),6.48(m,1H),6.51-6.46(m,2H),4.98(s,2H),4.79-4.74(m,1H),4.31-4.27(m,5H),3.85-3.78(m,1H),2.84-2.79(m,1H),2.66-2.60(m,1H)。
质谱分析确证，IIb-10的ESI-MS[(M-H) +]:m/z理论值375.1,实测值 374.9。
实施例11
化合物IIb-11的合成
制备化合物IIb-11的合成方法与实施例2相同，经醚化和水解反应得产物IIb-11，其中在反应中采用化合物RM-Ib-10(0.24mmol)代替化合物RM-Ib-2得到中间体RM-IIb-11，由中间体经水解得到白色固体产物IIb-11(0.033g)，两步收率:37％。
经质谱分析确证，IIb-11的ESI-MS[(M-H) +]:m/z理论值359.1,实测值359.0。
实施例12
化合物IIb-12的合成
制备化合物IIb-12的合成方法与实施例2相同，经醚化和水解反应得产物IIb-12，其中在反应中采用化合物RM-Ib-11(0.63mmol)代替化合物RM-Ib-2得到中间体RM-IIb-12，由中间体经水解得到浅黄色固体产物IIb-12(0.028g)，两步收率:12.8％。
经质谱分析确证，IIb-12的ESI-MS[(M-H) +]:m/z理论值345.1,实测值344.9。
实施例13
化合物IIb-13的合成
制备化合物IIb-13的合成方法与实施例1相同，经醚化和水解反应得产物IIb-13，其中在反应中采用化合物RM-Ib-12(0.43mmol)代替化合物RM-Ib-1得到中间体RM-IIb-13，由中间体经水解得到浅黄色固体产物IIb-13(0.060g)，两步收率:40％。
经检测，产物IIb-13的 1H NMR(400MHz,CDCl 3):δ6.92-6.90(m,1H),6.65-6.62(m,1H),6.49-6.39(m,3H),5.90(s,2H),4.90(s,2H),4.62-4.58(m,1H),4.20-4.16(m,1H),3.64-3.61(m,1H),2.87-2.57(m,1H),2.41-2.19(m,1H)。
质谱分析确证，IIb-13的ESI-MS[(M-H) +]:m/z理论值345.0,实测值345.0。
实施例14
化合物IIb-14的合成
制备化合物IIb-14的合成方法与实施例1相同，经醚化和水解反应得产物IIb-14，其中在反应中采用化合物RM-Ib-13(0.22mmol)代替化合物RM-Ib-1得到中间体RM-IIb-14，由中间体经水解得到白色固体产物IIb-14(0.045g)，两步收率:51.3％。
经检测，产物IIb-14的 1H NMR(400MHz,CDCl 3):δ7.28(s,1H),7.08-7.06(m,1H),7.00(s,1H),6.51-6.47(m,2H),6.09(s,2H),5.00(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.84-3.79(m,1H),2.84-2.78(m,1H),2.66-2.59(m,1H)。
质谱分析确证，IIb-14的ESI-MS[(M-H) +]:m/z理论值395.1,实测值395.0。
实施例15
化合物IIb-15的合成
制备化合物IIb-15的合成方法与实施例1相同，经醚化和水解反应得产物IIb-15，其中在反应中采用化合物RM-Ib-14(0.42mmol)代替化合物RM-Ib-1得到中间体RM-IIb-15，由中间体经水解得到白色固体产物IIb-15(0.072g)，两步收率:54％。
经检测，产物IIb-15的 1H NMR(400MHz,CDCl 3):δ7.34(s,1H),7.08-7.06(m,1H),7.00(s,1H),6.48-6.43(m,2H),6.11(s,2H),4.98(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.83-3.80(m,1H),2.83-2.78(m,1H),2.65-2.59(m,1H)。
质谱分析确证，IIb-15的ESI-MS[(M-H) +]:m/z理论值352.1,实测值352.0。
实施例16
化合物IIb-16的合成
制备化合物IIb-16的合成方法与实施例1相同，经醚化和水解反应得产物IIb-16，其中在反应中采用化合物RM-Ib-15(0.39mmol)代替化合物RM-Ib-1得到中间体RM-IIb-16，由中间体经水解得到白色固体产物IIb-16(0.032g)，两步收率:19.7％。
经检测，产物IIb-16的 1H NMR(400MHz,CDCl 3):δ7.51-7.48(m,2H),7.29-7.27(m,2H),7.06-7.04(m,1H),6.47-6.43(m,2H),4.97(s,2H),4.78-4.74(m, 1H),4.30-4.27(m,1H),3.83-3.78(m,1H),2.83-2.77(m,1H),2.65-2.58(m,1H)。
质谱分析确证，IIb-16的ESI-MS[(M-H) +]:m/z理论值405.0，实测值404.8。
实施例17
化合物IIb-17的合成
制备化合物IIb-17的合成方法与实施例1相同，经醚化和水解反应得产物IIb-17，其中在反应中采用化合物RM-Ib-16(0.28mmol)代替化合物RM-Ib-1得到中间体RM-IIb-17，由中间体经水解得到白色固体产物IIb-17(0.020g)，两步收率:15.8％。
经检测，产物IIb-17的 1H NMR(400MHz,CDCl 3):δ7.30-7.18(m,1H),7.10-7.06(m,1H),7.03-7.01(m,1H),6.50-6.46(m,2H),5.07(s,2H),4.79-4.75(m,1H),4.31-4.27(m,1H),3.84-3.79(m,1H),2.83-2.78(m,1H),2.65-2.58(m,1H)。 19F NMR(376MHz,CDCl 3):δ-49.74。
质谱分析确证，IIb-17的ESI-MS[(M-H) +]:m/z理论值363.1,实测值362.9。
实施例18
化合物IIb-18的合成
制备化合物IIb-18的合成方法与实施例1相同，经醚化和水解反应得产物IIb-18。其中，在反应中采用化合物RM-Ib-16(0.22mmol)代替化合物RM-Ib-1，和化合物SM1-2(0.22mmol)代替化合物SM1-1反应得到中间体RM-IIb-18，由中间体经水解得到白色固体产物IIb-18(0.009g)，两步收率:11.4％。
经检测，产物IIb-18的 1H NMR(400MHz,CDCl 3):δ7.20-7.18(m,1H),7.10-7.03(m,2H),7.01(m,1H),6.51-6.46(m,2H),5.07(s,2H),4.79-4.75(m,1H),4.32-4.28(m,1H),3.84-3.79(m,1H),2.85-2.79(m,1H),2.66-2.60(m,1H)； 19F NMR(376MHz,CDCl 3):δ-49.63。
经质谱分析确证，IIb-18的ESI-MS[(M-H) +]:m/z理论值363.1,实测值363.1。
实施例19
化合物IIb-19的合成
制备化合物IIb-19的合成方法与实施例1相同，经醚化和水解反应得产物IIb-19，其中在反应中采用化合物RM-Ib-17(0.91mmol)代替化合物RM-Ib-1得到中间体RM-IIb-19，由中间体经水解得到浅黄色固体产物IIb-19(0.231g)，两步收率:72.8％。
经检测，产物IIb-19的 1H NMR(400MHz,CDCl 3):δ7.06-7.04(m,1H),7.00-6.98(m,1H),6.84-6.83(m,2H),6.53-6.48(m,2H),5.02(s,2H),4.78-4.74(m,1H),4.30-4.23(m,5H),3.83-3.77(m,1H),2.82-2.77(m,1H),2.63-2.57(m,1H)。
质谱分析确证，IIb-19的ESI-MS[(M-H) +]:m/z理论值341.1,实测值341.0。
实施例20
化合物IIb-20的合成
制备化合物IIb-20的合成方法与实施例1相同，经醚化和水解反应得产物IIb-20，其中在反应中采用化合物RM-Ib-18(0.64mmol)代替化合物RM-Ib-1得到中间体RM-IIb-20，由中间体经水解得到浅黄色固体产物IIb-20(0.166g)，两步收率:71.2％。
经检测，产物IIb-20的 1H NMR(400MHz,CDCl 3):δ7.05-7.03(m,1H),6.91-6.89(m,1H),6.80-6.76(m,1H),6.70-6.68(m,1H),6.52-6.49(m,2H),4.98(s,2H),4.77-4.73(m,1H),4.30-4.26(m,1H),3.82-3.77(m,1H),2.81-2.76(m,1H),2.62-2.55(m,1H),1.69(s,6H)。
质谱分析确证，IIb-20的ESI-MS[(M-H) +]:m/z理论值355.1,实测值355.0。
实施例21
化合物IIb-21的合成
制备化合物IIb-21的合成方法与实施例1相同，经醚化和水解反应得产物IIb-21，其中在反应中采用化合物RM-Ib-19(0.57mmol)代替化合物RM-Ib-1得到中间体RM-IIb-21，由中间体经水解得到浅黄色固体产物IIb-21(0.072g)，两步收率:28.4％。
经质谱分析确证，IIb-21的ESI-MS[(M-H) +]:m/z理论值441.0,实测值 440.8。
实施例22
化合物IIb-22的合成
制备化合物IIb-22的合成方法与实施例1相同，经醚化和水解反应得产物IIb-22，其中在反应中采用化合物RM-Ib-20(0.43mmol)代替化合物RM-Ib-1得到中间体RM-IIb-22，由中间体经水解得到浅黄色油状物IIb-22(0.150g)，两步收率:80％。
经质谱分析确证，IIb-22的ESI-MS[(M-H) +]:m/z理论值435.0,实测值434.9。
实施例23
化合物IIb-23的合成
制备化合物IIb-23的合成方法与实施例1相同，经醚化和水解反应得产物IIb-23，其中在反应中采用化合物RM-Ib-21(0.13mmol)代替化合物RM-Ib-1得到中间体RM-IIb-23，由中间体经水解得到浅黄色固体产物IIb-23(0.0033g)，两步收率:6.2％。
经质谱分析确证，IIb-23的ESI-MS[(M-H) +]:m/z理论值397.0,实测值397.3。
实施例24
化合物IIb-24的合成
制备化合物IIb-24的合成方法与实施例1相同，经醚化和水解反应得产物IIb-24，其中在反应中采用化合物RM-Ib-22(0.38mmol)代替化合物RM-Ib-1得到中间体RM-IIb-24，由中间体经水解得到浅黄色固体产物IIb-24(0.028g)，两步收率:18.8％。
经质谱分析确证，IIb-24的ESI-MS[(M-H) +]:m/z理论值397.0,实测值397.4。
实施例25
化合物IIb-25的合成
制备化合物IIb-25的合成方法与实施例1相同，经醚化和水解反应得产物IIb-25，其中在反应中采用化合物RM-Ib-5(0.54mmol)代替化合物RM-Ib-1， 化合物SM1-2(0.54mmol)代替化合物SM1-1得到中间体RM-IIb-25，由中间体经水解得到白色固体产物IIb-25(0.085g)，两步产率:44％。
经检测，产物IIb-25的 1H NMR(400MHz,CDCl 3):δ7.07-7.05(m,1H),6.94(m,1H),6.78-6.77(m,1H),6.50-6.45(m,2H),6.02(s,2H),4.95(s,2H),4.79-4.74(m,1H),4.31-4.27(m,1H),3.84-3.79(m,1H),2.84-2.79(m,1H),2.66-2.59(m,1H)。
经质谱分析确证，IIb-25的ESI-MS[(M-H) +]：m/z理论值361.0，实测值361.0。
实施例26
化合物IIb-26的合成
制备化合物IIb-26的合成方法与实施例1相同，经醚化和水解反应得产物IIb-26，其中在反应中采用化合物RM-Ib-16(0.22mmol)代替化合物RM-Ib-1，化合物SM1-3(0.22mmol)代替化合物SM1-1得到中间体RM-IIb-26，由中间体经水解得到白色固体产物IIb-26(0.045g)，两步收率:21％。
经检测，产物IIb-26的 1H NMR(400MHz,CDCl 3):δ7.33(s,1H),7.32-7.30(m,1H),7.13-7.09(m,1H),7.06-7.02(m,1H),6.50(s,1H),5.13(s,2H),4.80-4.76(m,1H),4.32-4.29(m,1H),3.845-3.81(m,1H),2.83-2.78(m,1H),2.67-2.60(m,1H)。
质谱分析确证，IIb-26的ESI-MS[(M-H) +]:m/z理论值441.0，实测值441.0。
实施例27
化合物IIb-27的合成
制备化合物IIb-27的合成方法与实施例1相同，经醚化和水解反应得产物IIb-27，其中在反应中采用化合物RM-Ib-16(0.22mmol)代替化合物RM-Ib-1，化合物SM1-4(0.22mmol)代替化合物SM1-1得到中间体RM-IIb-27，由中间体经水解得到白色固体产物IIb-27(0.070g)，两步收率:28％。
经检测，产物IIb-27的 1H NMR(400MHz,CDCl 3):δ7.43-7.41(m,1H),7.32(s,1H),7.14-7.10(m,1H),7.06-7.04(m,1H),5.08(s,2H),4.93-4.88(m,1H),4.45-4.41(m,1H),4.00-3.96(m,1H),2.88-2.82(m,2H),2.74-2.67(m,1H)； 19F  NMR(376MHz,CDCl 3):δ-49.68。
质谱分析确证，IIb-27的ESI-MS[(M-H) +]：m/z理论值520.9，实测值520.9。
实施例28
化合物IIb-28的合成
制备化合物IIb-28的合成方法与实施例1相同，经醚化和水解反应得产物IIb-28，其中在反应中采用化合物RM-Ib-16(0.48mmol)代替化合物RM-Ib-1，化合物SM1-5(0.48mmol)代替化合物SM1-1得到中间体RM-IIb-28，由中间体经水解得到白色固体产物IIb-28(0.070g)，两步收率:36％。
经检测，产物IIb-28的 1H NMR(400MHz,CDCl 3):δ7.29-7.26(m,1H),7.18(s,1H),7.12-7.08(m,1H),7.04-7.02(m,1H),6.50(s,2H),5.14(s,2H),4.80-4.75(m,1H),4.32-4.28(m,1H),3.84-3.80(m,1H),2.83-2.77(m,1H),2.66-2.60(m,1H)。
质谱分析确证，IIb-28的ESI-MS[(M-H) +]：m/z理论值397.0，实测值397.0。
实施例29
化合物IIb-29的合成
制备化合物IIb-29的合成方法与实施例1相同，经醚化和水解反应得产物IIb-29，其中在反应中采用化合物RM-Ib-16(1.0mmol)代替化合物RM-Ib-1，化合物SM1-6(1.0mmol)代替化合物SM1-1得到中间体RM-IIb-29，由中间体经水解得到白色固体产物IIb-29(0.070g)，两步收率:18％。
质谱分析确证，IIb-29的ESI-MS[(M-H) +]：m/z理论值381.1，实测值381.0。
实施例30
化合物IIb-30的合成
将原料IIb-17(0.188g，0.52mmol)溶于1mL的THF和1mL的MTBE中，氮气保护下，干冰丙酮浴冷却到-78度，滴加LiHMDS(1M，1.4mL，1.4mmol),搅拌0.5h,滴加入TMSCl(0.14g，1.3mmol)，搅拌0.5h,加入NBS(0.11g，0,62mmol)，缓慢升到室温，反应5h，反应完成。HPLC显示反应结束后将反 应液加水，加盐酸(1N)中和到pH约为2，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到浅黄色固体产物IIb-30(0.055g)，一步收率:24％。
经质谱分析确证，IIb-30的ESI-MS[(M-H) +]:m/z理论值441.0,实测值440.9。
实施例31
化合物IIb-31的合成
将原料IIb-30(0.035g，0.08mmol)加入浓氨水(3mL)，在100度油浴加热反应2.5h反应完成。HPLC显示反应结束后将反应液减压浓缩干燥得到浅黄色固体产物IIb-31(0.025g)，一步收率:83％。
经质谱分析确证，IIb-31的ESI-MS[(M+H) +]:m/z理论值380.1,实测值380.0。
实施例32
化合物IIb-32的合成
第一步：
将原料RM-IIb-17(0.29g，0.78mmol)溶于2mL的THF中，氮气保护下，干冰丙酮浴冷却到-70度，滴加LiHMDS(1M，0.8mL，0.8mmol)，搅拌0.5h，滴加入(PhSO 2)NF/THF(0.29g，0.93mmol)溶液，缓慢升到室温，反应2h，反应完成。HPLC显示反应结束后将反应液加水，加盐酸(1N)中和到pH约为2，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到中间体RM-IIb-30(0.043g)。
第二步：
向中间体RM-IIb-30中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-32(0.018g)，两步收率:6％。
经质谱分析确证，IIb-32的ESI-MS[(M-H) +]:m/z理论值379.1,实测值379.0。
实施例33
化合物IIb-33的合成
第一步：
将原料RM-IIb-17(0.24g，0.65mmol)溶于2mL的THF中，氮气保护下，干冰丙酮浴冷却到-70度，滴加LiHMDS(1M，0.8mL，0.8mmol)，搅拌0.5h，滴加入(PhSO 2)NF/THF(0.24g，0.78mmol)溶液，缓慢升到室温，反应2h，反应完成。HPLC显示反应结束后将反应液加水，加盐酸(1N)中和到pH约为2，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到中间体RM-IIb-31和RM-IIb-32(0.045g)。
第二步：
向中间体RM-IIb-31和RM-IIb-32中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到浅黄色固体产物IIb-33和IIb-34(0.030g)，两步收率:12％。
经质谱分析确证，IIb-33的ESI-MS[(M-H) +]:m/z理论值381.1,实测值381.0。
实施例34
化合物IIb-34的合成
制备化合物IIb-34的合成方法与实施例1相同，经醚化和水解反应得产物IIb-34，其中在反应中采用化合物RM-Ib-16(0.36mmol)代替化合物RM-Ib-1，化合物SM1-7(0.36mmol)代替化合物SM1-1得到中间体RM-IIb-32，由中间体经水解得到白色固体产物IIb-34(0.021g)，两步收率:14％。
经质谱分析确证，IIb-34的ESI-MS[(M-H) +]:m/z理论值399.0,实测值399.0。
实施例35
化合物IIb-35的合成
制备化合物IIb-35的合成方法与实施例1相同，经醚化和水解反应得产物IIb-35，其中在反应中采用化合物RM-Ib-6(0.27mmol)代替化合物RM-Ib-1，化合物SM1-8(0.27mmol)代替化合物SM1-1得到中间体RM-IIb-33，由中间体经水解得到浅黄色固体产物IIb-35(0.056g)，两步收率:60％。
经检测，产物IIb-35的 1H NMR(400MHz,CDCl 3):δ7.12-7.10(m,1H),6.85(m,1H),6.80-6.78(m,1H),6.69-6.66(m,1H),6.57-6.54(m,1H),6.01(s,2H),4.99(s,2H),3.56-3.52(m,1H),2.92-2.77(m,3H),2.51-2.41(m,2H),1.81-1.74(m,1H)。
质谱分析确证，IIb-35的ESI-MS[(M-H) +]:m/z理论值343.1,实测值343.0。
实施例36
化合物IIb-36的合成
制备化合物IIb-36的合成方法与实施例1相同，经醚化和水解反应得产物IIb-36，其中在反应中采用化合物RM-Ib-6(0.27mmol)代替化合物RM-Ib-1，化合物SM1-9(0.27mmol)代替化合物SM1-1得到中间体RM-IIb-34，由中间体经水解得到浅黄色固体产物IIb-36(0.072g)，两步收率:75％。
经检测，产物IIb-36的 1H NMR(400MHz,CDCl 3):δ7.31-7.26(m,2H),6.93-6.91(m,2H),6.69-6.68(m,1H),6.66(m,1H),6.01(s,2H),4.99(s,2H),2.64(s,2H),1.45(s,6H)。
质谱分析确证，IIb-36的ESI-MS[(M-H) +]:m/z理论值345.1,实测值345.0。
实施例37
化合物IIb-37的合成
制备化合物IIb-37的合成方法与实施例1相同，经醚化和水解反应得产物IIb-37，其中在反应中采用化合物RM-Ib-6(0.27mmol)代替化合物RM-Ib-1，化合物SM1-10(0.27mmol)代替化合物SM1-1得到中间体RM-IIb-35，由中间体经水解得到浅黄色固体产物IIb-37(0.055g)，两步收率:53％。
经检测，产物IIb-37的 1H NMR(400MHz,CDCl 3):δ7.41-7.39(m,2H), 6.95-6.92(m,2H),6.67-6.63(m,1H),6.57-6.55(m,1H),6.03-6.01(m,2H),4.99(s,2H),4.13-4.10(m,2H),3.83-3.82(m,2H),2.98(s,2H)。
质谱分析确证，IIb-37的ESI-MS[(M-H) +]:m/z理论值375.1,实测值374.9。
实施例38
化合物IIb-38的合成
制备化合物IIb-38的合成方法与实施例2相同，经醚化和水解反应得产物IIb-38，其中在反应中采用化合物RM-Ib-23(0.16mmol)代替化合物RM-Ib-2，化合物SM1-2(0.16mmol)代替化合物SM1-1得到中间体RM-IIb-36，由中间体经水解得到白色固体产物IIb-38(0.040g)，两步收率:44％。
经质谱分析确证，IIb-38的ESI-MS[(M-H) +]:m/z理论值567.2,实测值567.0。
实施例39
化合物IIb-39的合成
制备化合物IIb-39的合成方法与实施例1相同，经醚化和水解反应得产物IIb-39，其中在反应中采用化合物RM-Ib-5(0.35mmol)代替化合物RM-Ib-1，化合物SM1-7(0.35mmol)代替化合物SM1-1得到中间体RM-IIb-37，由中间体经水解得到白色固体产物IIb-39(0.021g)，两步收率:15％。
经质谱分析确证，IIb-39的ESI-MS[(M-H) +]:m/z理论值397.0,实测值397.0。
实施例40
化合物IIb-40的合成
制备化合物IIb-40的合成方法与实施例2相同，经醚化和水解反应得产物IIb-40，其中在反应中采用化合物RM-Ib-24(0.31mmol)代替化合物RM-Ib-2，化合物SM1-2(0.31mmol)代替化合物SM1-1得到中间体RM-IIb-38，由中间体经水解得到白色固体产物IIb-40(0.067g)，两步收率:47％。
经质谱分析确证，IIb-40的ESI-MS[(M-H) +]:m/z理论值453.0,实测值453.0。
实施例41
化合物IIb-41的合成
制备化合物IIb-41的合成方法与实施例2相同，经醚化和水解反应得产物IIb-41，其中在反应中采用化合物RM-Ib-25(0.10mmol)代替化合物RM-Ib-2，化合物SM1-2(0.10mmol)代替化合物SM1-1得到中间体RM-IIb-39，由中间体经水解得到白色固体产物IIb-41(0.014g)，两步收率:36％。
经质谱分析确证，IIb-41的ESI-MS[(M+H) +]:m/z理论值372.1,实测值372.1。
实施例42
化合物IIb-42的合成
制备化合物IIb-42的合成方法与实施例2相同，经醚化和水解反应得产物IIb-42，其中在反应中采用化合物RM-Ib-26(0.13mmol)代替化合物RM-Ib-2，化合物SM1-2(0.13mmol)代替化合物SM1-1得到中间体RM-IIb-40，由中间体经水解得到白色固体产物IIb-42(0.029g)，两步收率:58％。
经质谱分析确证，IIb-42的ESI-MS[(M+H) +]:m/z理论值372.1,实测值372.1。
实施例43
化合物IIb-43的合成
制备化合物IIb-43的合成方法与实施例2相同，经醚化和水解反应得产物IIb-43，其中在反应中采用化合物RM-Ib-27(0.09mmol)代替化合物RM-Ib-2，化合物SM1-2(0.09mmol)代替化合物SM1-1得到中间体RM-IIb-41，由中间体经水解得到白色固体产物IIb-43(0.012g)，两步收率:31％。
经检测，产物IIb-43的 1H NMR(400MHz,CDCl 3):δ7.06-7.03(m,2H),6.73(s,1H),6.49-6.46(m,2H),5.96(s,2H),4.95(s,2H),4.78-4.73(m,1H),4.30-4.26(m,1H),3.82-3.78(m,1H),2.83-2.77(m,1H),2.65-2.58(m,1H),1.49(s,9H)。
经质谱分析确证，IIb-43的ESI-MS[(M-H) +]:m/z理论值442.1,实测值442.2。
实施例44
化合物IIb-44的合成
将化合物IIb-43(0.017g,0.04mmol)加入HCl/MeOH(6N,2mL)中，室温搅拌 1h，检测反应完，浓缩得到白色固体产物IIb-44(0.015g)，一步收率:91％。
经质谱分析确证，IIb-44的ESI-MS[(M+H) +]:m/z理论值344.1,实测值344.1。
实施例45
化合物IIb-45的合成
制备化合物IIb-45的合成方法与实施例2相同，经醚化和水解反应得产物IIb-45，其中在反应中采用化合物RM-Ib-28(0.14mmol)代替化合物RM-Ib-2，化合物SM1-2(0.14mmol)代替化合物SM1-1得到中间体RM-IIb-42，由中间体经水解得到白色固体产物IIb-45(0.035g)，两步收率:66％。
经质谱分析确证，IIb-45的ESI-MS[(M-H) +]:m/z理论值357.3,实测值357.2。
实施例46
化合物IIb-46的合成
制备化合物IIb-46的合成方法与实施例2相同，经醚化和水解反应得产物IIb-46，其中在反应中采用化合物RM-Ib-29(0.12mmol)代替化合物RM-Ib-2，化合物SM1-2(0.12mmol)代替化合物SM1-1得到中间体RM-IIb-43，由中间体经水解得到白色固体产物IIb-46(0.030g)，两步收率:52％。
经质谱分析确证，IIb-46的ESI-MS[(M-H) +]:m/z理论值478.4,实测值478.3。
实施例47
化合物IIb-47的合成
第一步：
将化合物RM-IIb-41(0.6g,1.31mmol)加入HCl/MeOH(6N,12mL)中，室温搅拌过夜，检测反应完，浓缩得到白色固体中间产物RM-IIb-44(0.5g)。
第二步：
将原料RM-IIb-44(0.050g，0.13mmol)溶于2mL的DCM中，加入DMAP(0.039g，0.32mmol)，冰水浴冷却下，加入氯甲酸甲酯(0.015g，0.15mmol)， 室温搅拌反应过夜，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体RM-IIb-45(0.049g)。
第三步：
向中间体RM-IIb-45中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-47(0.047g)，两步收率:92％。
经质谱分析确证，IIb-47的ESI-MS[(M-H) +]:m/z理论值400.4,实测值400.3。
实施例48
化合物IIb-48的合成
第一步：
将原料RM-IIb-44(0.050g，0.13mmol)溶于2mL的DCM中，加入DMAP(0.039g，0.32mmol)，冰水浴冷却下，加入氯甲酸环戊酯(0.023g，0.15mmol)，室温搅拌反应过夜，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体RM-IIb-46(0.050g)。
第二步：
向中间体RM-IIb-46中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-48(0.040g)，两步收率:70％。
经质谱分析确证，IIb-48的ESI-MS[(M-H) +]:m/z理论值454.5,实测值454.5。
实施例49
化合物IIb-49的合成
第一步：
将原料RM-IIb-44(0.050g，0.13mmol)溶于2mL的DCM中，加入 DMAP(0.039g，0.32mmol)，冰水浴冷却下，加入氯甲酸苯酯(0.024g，0.15mmol)，室温搅拌反应过夜，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体(0.050g)。
第二步：
将中间体再溶于2mL的DMF中，加入DMAP(0.025g，0.2mmol)和叔丁胺(0.015g，0.2mmol)，室温搅拌反应3h，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体RM-IIb-47(0.040g)。
第三步：
向中间体RM-IIb-47中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-49(0.020g)，三步收率:35％。
经质谱分析确证，IIb-49的ESI-MS[(M-H) +]:m/z理论值441.5,实测值441.4。
实施例50
化合物IIb-50的合成
第一步：
将原料RM-IIb-44(0.050g，0.13mmol)溶于2mL的DCM中，加入DMAP(0.039g，0.32mmol)，冰水浴冷却下，加入氯甲酸环戊酯(0.023g，0.15mmol)，室温搅拌反应过夜，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体RM-IIb-48(0.045g)。
第二步：
向中间体RM-IIb-48中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-50(0.020g)，两步收率:46％。
经质谱分析确证，IIb-50的ESI-MS[(M-H) +]:m/z理论值426.7,实测值 426.4。
实施例51
化合物IIb-51的合成
第一步：
将原料RM-IIb-44(0.050g，0.13mmol)溶于2mL的DCM中，加入DMAP(0.039g，0.32mmol)，冰水浴冷却下，加入异丙磺酰氯(0.022g，0.15mmol)，室温搅拌反应过夜，反应完成。HPLC显示反应结束后将反应液后处理柱层析分离纯化，得到中间体RM-IIb-49(0.015g)。
第二步：
向中间体RM-IIb-49中依次加入MeOH(2mL)，THF(1mL)和LiOH水溶液(1N，1mL)，室温搅拌1h,HPLC显示反应结束后将反应液用盐酸(1N)中和到pH约为4，加水，加入乙酸乙酯萃取，再合并有机相，用食盐水洗涤后干燥，最后柱层析分离纯化，得到白色固体产物IIb-51(0.009g)，两步收率:16％。
经质谱分析确证，IIb-51的ESI-MS[(M-H) +]:m/z理论值448.5,实测值448.3。
实施例52
化合物IIb-52的合成
制备化合物IIb-52的合成方法与实施例2相同，经醚化和水解反应得产物IIb-52，其中在反应中采用化合物RM-Ib-30(0.06mmol)代替化合物RM-Ib-2，化合物SM1-2(0.06mmol)代替化合物SM1-1得到中间体RM-IIb-50，由中间体经水解得到白色固体产物IIb-52(0.004g)，两步收率:15％。
经质谱分析确证，IIb-52的ESI-MS[(M-H) +]:m/z理论值411.1,实测值411.2。
实施例53
化合物IIb-53的合成
制备化合物IIb-53的合成方法与实施例2相同，经醚化和水解反应得产物IIb-53，其中在反应中采用化合物RM-Ib-31(0.24mmol)代替化合物RM-Ib-2，化合物SM1-2(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-51， 由中间体经水解得到白色固体产物IIb-53(0.018g)，两步收率:19％。
经质谱分析确证，IIb-53的ESI-MS[(M-H) +]:m/z理论值395.1,实测值395.2。
实施例54
化合物IIb-54的合成
制备化合物IIb-54的合成方法与实施例2相同，经醚化和水解反应得产物IIb-54，其中在反应中采用化合物RM-Ib-32(0.24mmol)代替化合物RM-Ib-2，化合物SM1-2(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-52，由中间体经水解得到白色固体产物IIb-54(0.028g)，两步收率:27％。
经质谱分析确证，IIb-54的ESI-MS[(M-H) +]:m/z理论值431.0,实测值431.1。
实施例55
化合物IIb-55的合成
制备化合物IIb-55的合成方法与实施例2相同，经醚化和水解反应得产物IIb-55，其中在反应中采用化合物RM-Ib-33(0.24mmol)代替化合物RM-Ib-2，化合物SM1-2(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-53，由中间体经水解得到白色固体产物IIb-55(0.020g)，两步收率:22％。
经质谱分析确证，IIb-55的ESI-MS[(M-H) +]:m/z理论值381.1,实测值381.2。
实施例56
化合物IIb-56的合成
制备化合物IIb-56的合成方法与实施例2相同，经醚化和水解反应得产物IIb-56，其中在反应中采用化合物RM-Ib-34(0.24mmol)代替化合物RM-Ib-2，化合物SM1-2(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-54，由中间体经水解得到白色固体产物IIb-56(0.028g)，两步收率:30％。
经质谱分析确证，IIb-56的ESI-MS[(M-H) +]:m/z理论值397.0,实测值397.1。
实施例57
化合物IIb-57的合成
制备化合物IIb-57的合成方法与实施例2相同，经醚化和水解反应得产物IIb-57，其中在反应中采用化合物RM-Ib-35(0.23mmol)代替化合物RM-Ib-2，化合物SM1-11(0.23mmol)代替化合物SM1-1得到中间体RM-IIb-55，由中间体经水解得到白色固体产物IIb-57(0.018g)，两步收率:21％。
经质谱分析确证，IIb-57的ESI-MS[(M-H) +]:m/z理论值363.1,实测值363.2。
实施例58
化合物IIb-58的合成
制备化合物IIb-58的合成方法与实施例2相同，经醚化和水解反应得产物IIb-58，其中在反应中采用化合物RM-Ib-36(0.23mmol)代替化合物RM-Ib-2，化合物SM1-11(0.23mmol)代替化合物SM1-1得到中间体RM-IIb-56，由中间体经水解得到白色固体产物IIb-58(0.026g)，两步收率:30％。
经质谱分析确证，IIb-58的ESI-MS[(M-H) +]:m/z理论值379.0,实测值379.1。
实施例59
化合物IIb-59的合成
制备化合物IIb-59的合成方法与实施例2相同，经醚化和水解反应得产物IIb-59，其中在反应中采用化合物RM-Ib-27(0.23mmol)代替化合物RM-Ib-2，化合物SM1-11(0.23mmol)代替化合物SM1-1得到中间体RM-IIb-57，由中间体经水解得到白色固体产物IIb-59(0.016g)，两步收率:30％。
经质谱分析确证，IIb-59的ESI-MS[(M-H) +]:m/z理论值460.1,实测值460.2。
实施例60
化合物IIb-60的合成
制备化合物IIb-60的合成方法与实施例2相同，经醚化和水解反应得产物IIb-60，其中在反应中采用化合物RM-Ib-27(0.24mmol)代替化合物RM-Ib-2，化合物SM1-8(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-58，由中间体经水解得到白色固体产物IIb-60(0.021g)，两步收率:20％。
经质谱分析确证，IIb-60的ESI-MS[(M-H) +]:m/z理论值442.2,实测值 442.1。
实施例61
化合物IIb-61的合成
制备化合物IIb-61的合成方法与实施例1相同，经醚化和水解反应得产物IIb-61，其中在反应中采用化合物RM-Ib-16(0.24mmol)代替化合物RM-Ib-1，化合物SM1-8(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-59，由中间体经水解得到白色固体产物IIb-61(0.026g)，两步收率:30％。
经质谱分析确证，IIb-61的ESI-MS[(M-H) +]:m/z理论值361.1,实测值361.2。
实施例62
化合物IIb-62的合成
制备化合物IIb-62的合成方法与实施例1相同，经醚化和水解反应得产物IIb-62，其中在反应中采用化合物RM-Ib-16(0.24mmol)代替化合物RM-Ib-1，化合物SM1-12(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-60，由中间体经水解得到白色固体产物IIb-62(0.015g)，两步收率:16％。
经质谱分析确证，IIb-62的ESI-MS[(M-H) +]:m/z理论值373.1,实测值373.1。
实施例63
化合物IIb-63的合成
制备化合物IIb-63的合成方法与实施例2相同，经醚化和水解反应得产物IIb-63，其中在反应中采用化合物RM-Ib-29(0.24mmol)代替化合物RM-Ib-2，化合物SM1-8(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-61，由中间体经水解得到白色固体产物IIb-63(0.020g)，两步收率:17％。
经质谱分析确证，IIb-63的ESI-MS[(M-H) +]:m/z理论值476.2,实测值476.2。
实施例64
化合物IIb-64的合成
制备化合物IIb-64的合成方法与实施例2相同，经醚化和水解反应得产 物IIb-64，其中在反应中采用化合物RM-Ib-29(0.24mmol)代替化合物RM-Ib-2，化合物SM1-12(0.24mmol)代替化合物SM1-1得到中间体RM-IIb-62，由中间体经水解得到白色固体产物IIb-64(0.015g)，两步收率:13％。
经质谱分析确证，IIb-64的ESI-MS[(M-H) +]:m/z理论值488.2,实测值488.3。
实施例65
化合物的GPR40活性检测方法：
本发明所制备的化合物可藉由下列临床前体外抑制活性测试实验初步测定筛选其对GPR40的效果，然后藉由临床试验进一步加以确认疗效和安全性。其它方法对本领域中具一般技术之人员而言亦是显而易见的。日本武田公司之前研发的GPR40激动剂TAK-875在临床前和临床试验结果研究表明，离体试验的结果与相关体内活性试验结果具有一致性。
本发明化合物、或其立体异构物、互变异构物、酯化或酰胺化的前体药物、或其药学上可接受的盐及其混合物，通过化合物IIb-01至IIb-64和一个参照化合物Ref-1(TAK-875)对GPR40活性的评价实验测试，测试结果对比发现有许多化合物的抑制活性(EC 50)优于参照化合物。
在384孔板中接种CHO-K1/GPR40细胞，接种密度为10000个/孔。细胞在37℃，5％CO2培养箱条件下培养24小时。实验后，弃去细胞培养液，迅速在每孔中加入30μl含2.5mMProbenecid的1X
Figure PCTCN2021117623-appb-000063
Calcium 6染料，并在37℃避光孵育2小时。测定时，在孔中加入不同浓度药物(15μl/孔)并读取荧光值。荧光激发波长为494nm，发射波长为516nm。FLIPR仪器数据，根据公式Y＝Bottom+(Top-Bottom)/(1+(EC50/X)^HillSlope)得出EC 50。
每个式IIb新型结构化合物的GPR40激动剂活性测试结果列于以下表3和表2；其中，本发明中化合物的GPR40激动剂的活性效果范围(EC 50)在<10nM标示为“A”；活性范围在10-100nM标示为“B”；活性范围>100nM标示为“C”。
表3：式IIb化合物的GPR40激动剂活性检测结果
编号 化合物 GPR40活性 编号 化合物 GPR40活性
1 IIb-01 C 2 IIb-02 C
3 IIb-03 C 4 IIb-04 B
5 IIb-05 B 6 IIb-06 B
7 IIb-07 B 8 IIb-08 C
9 IIb-09 C 10 IIb-10 C
11 IIb-11 C 12 IIb-12 C
13 IIb-13 C 14 IIb-14 B
15 IIb-15 B 16 IIb-16 C
17 IIb-17 B 18 IIb-18 A
19 IIb-19 C 20 IIb-20 B
21 IIb-21 B 22 IIb-22 C
23 IIb-23 B 24 IIb-24 C
25 IIb-25 A 26 IIb-26 C
27 IIb-27 C 28 IIb-28 C
29 IIb-29 C 30 IIb-30 C
31 IIb-31 C 32 IIb-32 C
33 IIb-33 B 34 IIb-34 C
35 IIb-35 B 36 IIb-36 C
37 IIb-37 C 38 IIb-38 B
39 IIb-39 C 40 IIb-40 B
41 IIb-41 C 42 IIb-42 C
43 IIb-43 A 44 IIb-44 C
45 IIb-45 C 46 IIb-46 A
47 IIb-47 C 48 IIb-48 B
49 IIb-49 C 50 IIb-50 C
51 IIb-51 C 52 IIb-52 C
53 IIb-53 B 54 IIb-54 B
55 IIb-55 B 56 IIb-56 B
57 IIb-57 B 58 IIb-58 B
59 IIb-59 B 60 Ref-1 B
61 IIb-61 B 62 IIb-62 B
63 IIb-63 B 64 IIb-64 B
65 Ref-1 B      
实施例66
化合物毒性筛选试验
为了测试新化合物(IIb-01至IIb-64)中一些活性较高(EC 50<10nM)化合物(IIb-18、IIb-25和IIb-43)的毒性，本发明采用18-22g的健康小鼠，均采用单一剂量600mg/kg，1次灌服给药，在连续5天内观察实验动物所产生的毒性反应来评估受试物对机体的毒性大小，进行急性毒性(Acute Toxocity Study,MTD)试验，结果表明该类化合物的总体毒性很小(LD 50:>600)，小鼠给药后存活率为100％，服药和5天恢复期间体重和体内外观察无任何异常发生，解剖结果也无发现体内心、肝、肺、肾、肠等各种脏器有任何变化异常，一般认定所测试的化合物在适当剂量以内为安全无毒。为此，本发明的几个高活性化合物经体外实验测定，不仅对2型糖尿病有较好的疗效，而且安全可靠。
实施例67
化合物的BSEP(Bile Salt Export Pump)胆盐转运效果检测方法：
本实验通过应用LC/MS/MS检测BSEP胆盐转运体对底物牛磺胆酸(Taurocholic Acid,以下简称TCA)吸收能力的方法，对候选化合物在BSEP转运体转运过程是否具有抑制作用进行初步研究。具有反向吸收能力的BSEP蛋白微膜囊经由Hi5细胞转染BSEP基因所得到，此微膜囊能够进行牛磺胆酸TCA吸收及摄取。本实验原理即在能量ATP与底物牛磺胆酸TCA以及待测候选化合物同时存在条件下，进行BSEP蛋白微膜囊的底物吸收实验，在一定转运作用时间后，完全洗去微膜囊外剩余能量、底物与候选化合物后，对微膜囊进行裂解释放所吸收的底物牛磺胆酸TCA，进而使用LC/MS/MS检测牛磺胆酸TCA以确定候选化合物是否抑制了TCA转运过程。
样品处理：
1.将化合物分别使用100％DMSO溶解至100mM，存贮在-20度冰箱，所有化合物完全溶解。
2.样品起始浓度100mM，用Bravo仪器2倍梯度稀释，共11个浓度梯度；最低点浓度为97.65μM。
3.对照化合物(Glyburide)起始浓度20mM,用Bravo仪器2倍梯度稀释，共11个浓度梯度；最低点浓度为19.53μM。
4.用ECHO自动加样仪转移300nl化合物到中间板。
5.阳性对照(HPE)孔及阴性对照(ZPE)孔也各转300nl DMSO。
实验操作步骤：
1.分别加入ATP缓冲液14.7μl到化合物及ZPE相应的孔中。
2.分别加入AMP缓冲液14.7μl到HPE相应的孔中。
3. 25摄氏度振板10分钟。
4.分别向所有孔中加入BSEP-Hi5-VT Vesicle溶液15ul并于25摄氏度振板40分钟。
5.立即向所有孔中加入5ul 0.5M EDTA溶液，再加入65μl缓冲液B，全部反应结束。
6.使用加样仪器从反应结束的化合物板转移95μl液体至过滤板。
7.在过滤板下放置液体接收板后，使用离心机离去液体,并将接收板中接收的液体弃去。
8.在过滤板中加入90μl缓冲液B，重复步骤7，重复步骤7和8，共将过滤板洗三次。
9.过滤板晾干过夜。
10.第二天加入81μl 80％甲醇/水溶液至过滤板。
11.过滤板贴膜后振板15分钟。
12.在过滤板下放置新的液体接收板，并离心5分种，将过滤板中所有液体过滤至接收板中。
13.在液体接收板中每个孔加入13.5μl内标溶液，用封膜封板。
14.使用LC/MS/MS,检测接收板中牛磺胆酸的含量。
表4：优化的GPR40激动剂活性及其潜在副作用的对比
Figure PCTCN2021117623-appb-000064
注：表4中显示的化合物对BSEP的抑制结果(IC50)低于25uM时[如：Ref-1(TAK-875)的值为7.1，明显低于25]，则该化合物的BSEP抑制副作用将有可能会导致体内肝脏受损的潜在风险。
上述表3和表4中活性检测结果表明:(1)本发明的各类新型苯并杂环化合物中含1-2个氧原子的五元杂环化合物的活性(EC50)明显优于同类结构含1-2个氧原子的六元杂环化合物；(2)本发明的式IIb化合物中Z 1为“氧(O)”时的苯并含氧五元杂环化合物的活性优于同类结构中Z 1为“CH 2”时相应化合物的活性；(3)本发明的苯并含氧五元杂环化合物IIb-18、IIb-25、IIb-43和IIb-46对GPR40靶点显示了很好的活性(EC 50：<10nM)，优于同类对照的化合物TAK-875，是目前该研究领域中活性比较好、在活性和安全性等具有成药优势的新型GPR40激动剂。
上述表4中所列的3个苯并含氧五元杂环化合物不仅显示较好的活性，而且可能导致肝脏受损的BSEP副作用结果均大于25，明显优于日本武田公司因为肝脏毒性问题终止临床三期试验的TAK-875新药，并且完成的急性毒性(Acute Toxocity Study,MTD)试验结果表明表4中所列的3个高活性化合物IIb-18、IIb-25和IIb-43的安全性较好，小鼠灌服剂量600mg/kg的新化合物5天后存活率为100％，服药和5天恢复期间无异常发生，解剖结果也无发现任何异常。故本发明设计合成的新型苯并含氧五元杂环化合物IIb中有几个高活 性化合物具有进一步进行动物和临床试验和推广应用的价值。
由此可见，本发明在GPR40靶点激动剂的创新研究中发现了几个活性效果更好的化合物(如：IIb-18、IIb-25和IIb-43)，并且TMD高剂量(600mg/kg/天)急毒试验的毒性很低，BSEP(>25uM)、hERG(>30uM)和Ames等检测结果显示没有相关的副作用，有关结果均优于目前已知的参照化合物TAK-875，为发明一个具有较好GPR40靶点选择性、能安全高效治疗II型糖尿病患者的GPR40靶点激动剂新药填定了基础。
根据上述详细说明可对实施方式进行这些和其他改变。总体而言，权利要求中所用的术语应不被认为是将权利要求限制到本说明书和权利要求中公开的具体的实施方式，而应认为是包括遵循与所列权利要求等同的完全范围的所有可能的实施方式。因此，权利要求并不受本公开内容限制。

Claims (10)

  1. 一种式Ib所示的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物；
    Figure PCTCN2021117623-appb-100001
    其中，
    n＝0,1或2；
    n＝0时,Y不存在，Y 1与Y邻位的Z 1直接单键连接成五元杂环；
    E不与G 1直接连接成环状化合物时，E选自：氢、氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、羧基、氨基(NH 2)、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基羰基胺基、烷基胺基羰基、芳基、芳氧基、或杂环芳基；G 1为CH、或C(Rb)；其中，Rb为氢、氘(D)、烷基、环烷基、烯烃基、炔烃基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基，或Rb和R 4之间可以互相连接成环烷基、或杂环基团；
    E与G 1连接成环状化合物时，G 1为-C-；E为-O-、-C(RcRd)-、-OC(RcRd)-、-C(RcRd)O-、或-NRe-；其中，Rc和Rd分别为氢、氘(D)、烷基、环烷基、烯基、烃基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基，Rc和Rd之间可以互相连接成环烷基、或杂环基团；Re为氢、氘(D)、烷基、环烷基、烷基羰基、烷氧基羰基、环烷氧基羰基、烷基胺基羰基、环烷基胺基羰基、烷基磺酰基、或芳基磺酰基；
    L 1和L 2各自独立地为-O-、-S-、–C(O)–、–S(O) 2–、-CH 2-、-C(R fR g)-、-OC(R fR g)-、-C(R fR g)O-、-N(Re)-、-N(Rc)C(R fR g)-、或-C(R fR g)N(Re)-；其中， R f和R g分别为氢、氘(D)、烷基、环烷基、烯基、炔基、烷氧基、环烷氧基、烷氧基羰基、烷基胺基、环烷基胺基、烷基胺基羰基、环烷基胺基羰基、芳基、芳氧基、杂环基、杂环芳基、或杂环芳氧基，Re的定义与上述E中的Re所述相同；
    R 1、R 2和R 3各自独立地为氢、氘(D)、卤素、三氟甲基、三氟甲氧基、腈基、羟基、氨基羰基(H 2NCO)、烷基、烷氧基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、芳基、芳氧基、或杂环芳基；其中，式Ib中R 2与L 1之间可以相互连接成4-8元的杂环化合物，L 1为-CH-；
    R 4、R 5和R 5b各自独立地为氢、氘(D)、卤素、羟基、氨基、腈基、烷基、烷氧基、环烷基、杂环烷基、环烷氧基、任选取代的烯基、任选取代的炔基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、烷氧基羰基胺基、芳基、芳氧基、或杂环芳基；其中，R 5和R 5b之间可以相互连接成为环烷基、杂环基、或杂环芳基；
    R 6为羧基、烷氧基羰基、芳氧基羰基、烷基胺基羰基、环烷基胺基羰基、烷基磺酰胺基羰基、环烷基磺酰胺基羰基、杂环基、或杂环芳基；或R 6与邻位的取代基R 5之间可以相互连接成为杂环基、或杂环芳基；
    X 5、X 6和X 7各自独立地为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、氨基羰基(H 2NCO)、烷基、杂环烷基、烷氧基、杂原子取代的烷基氧基、烷基胺基(NR iR j)、杂原子取代的烷基胺基、烷氧基羰基、烷基胺基羰基、烷基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、芳氧基、芳基胺基羰基、芳基羰基胺基、芳氧基羰基胺基、杂环芳基、杂环芳基氧基、或杂环芳基胺基；其中，R i和R j各自独立地为氢、氘(D)、烷基、杂环烷基、烷基羰基、烷氧基羰基、环烷氧基羰基、烷基胺基羰基、烷基磺酰基、环烷基磺酰基、芳基、芳氧基羰基、芳基胺基羰基、杂环芳基，或R i和R j相互连接成含1-3个杂原子的3-8元杂环；
    Y和Y 1各自独立地为-O-、-S-、-CH 2-、-CHF-、-CF 2-、-CCl 2-、-C(R fR g)-、或-N(Re)-；其中，R f和R g的定义分别与上述L 1中的R f和R g所述相同，Re的定义与上述E中的Re所述相同；
    Z和Z 1各自独立地选自：-O-、-S-、-CH 2-、-CHF-、-CF 2-、-C(R fR g)-、-N(Re)-、 或–C(O)–；其中，R f和R g的定义分别与上述L 1中的R f和R g所述相同，Re的定义与上述E中的Re所述相同。
  2. 如权利要求1所述的化合物，其顺反异构体、对映异构体、非对映异构体、外消旋体、互变异构体、溶剂合物、水合物、或药学上可接受的盐或它们的混合物，其中，所述化合物具有IIb的结构：
    Figure PCTCN2021117623-appb-100002
    其中，
    n、E、G 1、L 1、R 1、R 2、R 3、R 4、R 5、R 5b、X 5、X 6、X 7、Y、Y 1、Z的定义与权利要求1中n、E、G 1、L 1、R 1、R 2、R 3、R 4、R 5、R 5b、X 5、X 6、X 7、Y、Y 1、Z的定义相同；
    R 7为羟基、烷氧基、烷基胺基、环烷基胺基、杂环胺基、烷基磺酰胺基、环烷基磺酰胺基、芳氧基、杂环芳氧基、芳基胺基、或杂环芳基胺基；或R 7与邻位的取代基R 5之间可以相互连接成为杂环。
  3. 如权利要求2所述的化合物，其特征在于，
    n＝0或1；
    n＝0时,Y不存在，Y 1与Y邻位的氧直接单键连接成五元杂环；
    n＝1时,Y为-CH 2-；
    E不与G 1直接连接成环状化合物时，E为氢、卤素、三氟甲基、三氟甲氧基、或烷氧基；G 1为-CH-、或-C(Rb)-；其中，Rb为氢、烷基、任选取代的烯基、任选取代的炔基、烷氧基、或Rb和R 4之间互相连接成含氧的杂环基团；
    R 4为氢、烷基、烷氧基、任选取代的炔基，或R 4和Rb之间互相连接成含氧的杂环基团；
    E与G 1直接连接成环状化合物时，E为-OC(RcRd)-，G 1为-C-，R 4为氢， 其中Rc和Rd各自独立地为氢；
    L 1为-CH 2-，或当式IIb中R 2与L 1之间相互连接成5-6元的杂环化合物时，L 1为-OCH-；
    R 1、R 2和R 3各自独立地为氢、卤素、烷基或烷氧基；
    R 5为氢、卤素、羟基、氨基、烷基氨基、烷基或烷氧基；
    R 5b为氢、卤素、烷基或烷氧基；
    R 7为烷氧基、羟基、烷基磺酰胺基、或环烷基磺酰胺基；
    X 5为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、烷基、烷氧基、烷基胺基(NR iR j)、烷基羰基胺基、烷基胺基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、或芳氧基羰基胺基；其中，R i和R j各自独立地为氢、烷基、烷基羰基、烷氧基羰基、或环烷氧基羰基；
    X 6和X 7各自独立地为氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基；
    Y为-CH 2-、或n＝0时，Y不存在；
    Y 1为-CH 2-、-CHF-、-CF 2-、或-C(CH 3) 2-；
    Z为-O-、或-CH 2-。
  4. 如权利要求3所述的化合物，其特征在于，
    n＝0，Y不存在；
    E不与G 1直接连接成环状化合物时，E为氢、或卤素；G 1为-CH-、或-C(Rb)-，其中，Rb为烷基、烯基、炔基或烷氧基；R 4为氢、烷基或烷氧基；
    E与G 1直接连接成环状化合物，E为-OC(RcRd)-，G 1为-C-，R 4为氢，其中Rc和Rd各自独立地为氢；
    L 1为-CH 2-，或当式IIb中R 2与L 1之间相互连接成5-6元的杂环化合物时，L 1为-OCH-；
    R 1、R 2和R 3各自独立地为氢、卤素、或烷氧基；
    R 5为氢、卤素、羟基、氨基、烷基或烷氧基；
    R 5b为氢、卤素、烷基或烷氧基；
    R 7选自：烷氧基、羟基、烷基磺酰胺基、或环烷基磺酰胺基；
    X 5为氢、氘(D)、卤素、腈基、氨基、三氟甲基、三氟甲氧基、烷基、烷氧基、烷基胺基(NR iR j)、烷基羰基胺基、烷基胺基羰基胺基、烷氧基羰基胺基、环烷氧基羰基胺基、烷基磺酰胺基、环烷基磺酰胺基、芳基、或芳氧基羰基胺基；其中，R i和R j各自独立地为氢、烷基、烷基羰基、烷氧基羰基、或环烷氧基羰基；
    X 6为氢、氘(D)、卤素、C 1-C 8烷基胺基或C 1-C 8烷氧基羰基胺基；
    X 7为氢；
    Y 1为-CH 2-、-CHF-、-CF 2-、或-C(CH 3) 2-；
    Z为-O-。
  5. 如权利要求2所述的化合物，其特征在于，所述化合物具有选自下组的结构：
    Figure PCTCN2021117623-appb-100003
    Figure PCTCN2021117623-appb-100004
  6. 一种组合物，其包含如权利要求1-5中任一项所述的化合物或其药学上可以接受的盐以及药学上可接受的稀释剂和/或赋形剂。
  7. 如权利要求1-5中任一项所述的化合物或权利要求6所述的组合物在制备用作GPR40激动剂的药物中的用途。
  8. 一种治疗或预防糖尿病或相关代谢综合症的方法，其特征在于向患者施用有效剂量的如权利要求1-5中任一项所述的化合物或权利要求6所述的组合物。
  9. 如权利要求1-5中任一项所述的化合物或权利要求6所述的组合物在制备用于治疗或预防糖尿病或相关代谢综合症的药物中的用途。
  10. 如权利要求9所述的用途，所述糖尿病是II型糖尿病。
PCT/CN2021/117623 2020-09-10 2021-09-10 苯并含氧杂环类化合物及其医药应用 WO2022053013A1 (zh)

Priority Applications (11)

Application Number Priority Date Filing Date Title
IL301278A IL301278A (en) 2020-09-10 2021-09-10 Heterocyclic compound containing benzo oxygen and its medicinal use
BR112023004430A BR112023004430A2 (pt) 2020-09-10 2021-09-10 Compostos heterocíclicos contendo benzo oxigênio e aplicação médica dos mesmos
MX2023002926A MX2023002926A (es) 2020-09-10 2021-09-10 Benzo compuestos heterociclicos que contienen oxigeno y aplicacion medica de los mismos.
US18/044,881 US20230339919A1 (en) 2020-09-10 2021-09-10 Benzo oxygen-containing heterocyclic compounds and medical application thereof
EP21866065.2A EP4212528A4 (en) 2020-09-10 2021-09-10 HETEROCYCLIC COMPOUND CONTAINING BENZOOXYGEN AND MEDICAL USE THEREOF
KR1020237012127A KR20230123918A (ko) 2020-09-10 2021-09-10 벤조 산소 함유 헤테로시클릭계 화합물 및 이의 약학적 응용
PE2023001137A PE20231319A1 (es) 2020-09-10 2021-09-10 Benzo compuestos heterociclicos que contienen oxigeno y aplicacion medica de los mismos
JP2023516184A JP2023540636A (ja) 2020-09-10 2021-09-10 ベンゾ酸素含有複素環化合物及びその医薬用途
CA3194769A CA3194769A1 (en) 2020-09-10 2021-09-10 Benzo oxygen-containing heterocyclic compounds and medical application thereof
AU2021342090A AU2021342090A1 (en) 2020-09-10 2021-09-10 Benzo oxygen-containing heterocyclic compound and medical application thereof
CONC2023/0004369A CO2023004369A2 (es) 2020-09-10 2023-04-05 Benzo compuestos heterocíclicos que contienen oxígeno y aplicación médica de los mismos

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010947909.3A CN114163426B (zh) 2020-09-10 2020-09-10 苯并含氧杂环类化合物及其医药应用
CN202010947909.3 2020-09-10

Publications (1)

Publication Number Publication Date
WO2022053013A1 true WO2022053013A1 (zh) 2022-03-17

Family

ID=80475812

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/117623 WO2022053013A1 (zh) 2020-09-10 2021-09-10 苯并含氧杂环类化合物及其医药应用

Country Status (13)

Country Link
US (1) US20230339919A1 (zh)
EP (1) EP4212528A4 (zh)
JP (1) JP2023540636A (zh)
KR (1) KR20230123918A (zh)
CN (1) CN114163426B (zh)
AU (1) AU2021342090A1 (zh)
BR (1) BR112023004430A2 (zh)
CA (1) CA3194769A1 (zh)
CO (1) CO2023004369A2 (zh)
IL (1) IL301278A (zh)
MX (1) MX2023002926A (zh)
PE (1) PE20231319A1 (zh)
WO (1) WO2022053013A1 (zh)

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011255A1 (fr) * 1997-08-28 1999-03-11 Ono Pharmaceutical Co., Ltd. Regulateurs du recepteur active par les agents de proliferation des peroxysomes
CN1315936A (zh) * 1998-08-07 2001-10-03 艾米斯菲尔技术有限公司 用于送递活性剂的化合物和组合物
WO2004106276A1 (ja) 2003-05-30 2004-12-09 Takeda Pharmaceutical Company Limited 縮合環化合物
WO2005087710A1 (ja) 2004-03-15 2005-09-22 Takeda Pharmaceutical Company Limited アミノフェニルプロパン酸誘導体
EP1688138A1 (en) * 2003-11-26 2006-08-09 Takeda Pharmaceutical Company Limited Receptor function regulating agent
WO2007106469A2 (en) 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
CN101553469A (zh) * 2006-12-01 2009-10-07 安斯泰来制药株式会社 羧酸衍生物
WO2010143733A1 (en) 2009-06-09 2010-12-16 Takeda Pharmaceutical Company Limited Novel fused cyclic compound and use thereof
US20110313003A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
CN103030646A (zh) 2011-09-29 2013-04-10 上海恒瑞医药有限公司 苯并二氧六环类衍生物、其制备方法及其在医药上的应用
WO2013104257A1 (zh) 2012-01-12 2013-07-18 江苏恒瑞医药股份有限公司 多环类衍生物、其制备方法及其在医药上的应用
CN103980235A (zh) * 2008-12-18 2014-08-13 赛马拜制药公司 Gpr120受体激动剂及其用途
CN104418801A (zh) * 2013-08-19 2015-03-18 上海润诺生物科技有限公司 苯并哌啶环与苯并吗啉环类化合物、其制法及医药应用
WO2015062486A1 (en) 2013-10-31 2015-05-07 Sunshine Lake Pharma Co., Ltd. Biphenyl compounds and uses thereof
CN104507921B (zh) * 2013-07-02 2017-02-22 四川海思科制药有限公司 苯并环丁烯类衍生物、其制备方法及其在医药上的应用
CN107001281A (zh) * 2014-10-08 2017-08-01 詹森药业有限公司 取代的苯并噻吩基衍生物作为用于治疗ii型糖尿病的gpr40激动剂

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735408A (zh) * 2002-11-08 2006-02-15 武田药品工业株式会社 受体机能调节剂
CA2801182A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
WO2015044073A1 (en) * 2013-09-26 2015-04-02 Boehringer Ingelheim International Gmbh Process and intermediates for preparing indanyloxydihydrobenzofuranyl acetic acid derivatives as gpr40 agonists
CN105001212B (zh) * 2014-04-16 2018-01-16 江苏柯菲平医药股份有限公司 稠环化合物及其制备方法和应用

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011255A1 (fr) * 1997-08-28 1999-03-11 Ono Pharmaceutical Co., Ltd. Regulateurs du recepteur active par les agents de proliferation des peroxysomes
CN1315936A (zh) * 1998-08-07 2001-10-03 艾米斯菲尔技术有限公司 用于送递活性剂的化合物和组合物
WO2004106276A1 (ja) 2003-05-30 2004-12-09 Takeda Pharmaceutical Company Limited 縮合環化合物
EP1688138A1 (en) * 2003-11-26 2006-08-09 Takeda Pharmaceutical Company Limited Receptor function regulating agent
WO2005087710A1 (ja) 2004-03-15 2005-09-22 Takeda Pharmaceutical Company Limited アミノフェニルプロパン酸誘導体
WO2007106469A2 (en) 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
CN101553469A (zh) * 2006-12-01 2009-10-07 安斯泰来制药株式会社 羧酸衍生物
CN103980235A (zh) * 2008-12-18 2014-08-13 赛马拜制药公司 Gpr120受体激动剂及其用途
WO2010143733A1 (en) 2009-06-09 2010-12-16 Takeda Pharmaceutical Company Limited Novel fused cyclic compound and use thereof
US20110313003A1 (en) * 2010-06-16 2011-12-22 Metabolex, Inc. Gpr120 receptor agonists and uses thereof
CN103030646A (zh) 2011-09-29 2013-04-10 上海恒瑞医药有限公司 苯并二氧六环类衍生物、其制备方法及其在医药上的应用
WO2013104257A1 (zh) 2012-01-12 2013-07-18 江苏恒瑞医药股份有限公司 多环类衍生物、其制备方法及其在医药上的应用
CN103429581B (zh) * 2012-01-12 2015-08-26 江苏恒瑞医药股份有限公司 多环类衍生物、其制备方法及其在医药上的应用
CN104507921B (zh) * 2013-07-02 2017-02-22 四川海思科制药有限公司 苯并环丁烯类衍生物、其制备方法及其在医药上的应用
CN104418801A (zh) * 2013-08-19 2015-03-18 上海润诺生物科技有限公司 苯并哌啶环与苯并吗啉环类化合物、其制法及医药应用
WO2015062486A1 (en) 2013-10-31 2015-05-07 Sunshine Lake Pharma Co., Ltd. Biphenyl compounds and uses thereof
CN107001281A (zh) * 2014-10-08 2017-08-01 詹森药业有限公司 取代的苯并噻吩基衍生物作为用于治疗ii型糖尿病的gpr40激动剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2000
See also references of EP4212528A4

Also Published As

Publication number Publication date
EP4212528A1 (en) 2023-07-19
KR20230123918A (ko) 2023-08-24
CN114163426A (zh) 2022-03-11
JP2023540636A (ja) 2023-09-25
MX2023002926A (es) 2023-06-06
US20230339919A1 (en) 2023-10-26
BR112023004430A2 (pt) 2023-05-09
CO2023004369A2 (es) 2023-06-30
PE20231319A1 (es) 2023-08-24
CN114163426B (zh) 2024-03-19
CA3194769A1 (en) 2022-03-17
EP4212528A4 (en) 2024-03-20
AU2021342090A1 (en) 2023-04-27
IL301278A (en) 2023-05-01

Similar Documents

Publication Publication Date Title
CA3181120A1 (en) Five-membered heteroaromatic imidazole compound and use thereof
WO2022116693A1 (zh) 一类glp-1r受体激动剂化合物及其用途
CN105658643A (zh) Ido抑制剂
CN105518008B (zh) 氨基吡喃环衍生物及其组合物和应用
TW201213329A (en) Pyrazine derivatives as ENaC blockers
TW202227397A (zh) 雙環的－雜環衍生物及相關用途
TW202227433A (zh) 中環或大環之經苄基取代的雜環衍生物及相關用途
CN103038210A (zh) 作为消炎、免疫调节和抗增殖剂的新型化合物的钙盐
CA2461218C (en) Muscarinic agonists
WO2018217757A1 (en) Compositions and methods for preparing and using mitochondrial uncouplers
AU2002332541A1 (en) Muscarinic agonists
CN113480479A (zh) 脲类多靶点酪氨酸激酶抑制剂及其医药应用
WO2022053013A1 (zh) 苯并含氧杂环类化合物及其医药应用
WO2022053012A1 (zh) 苯并含氧杂环类化合物及其医药应用
SG188472A1 (en) Prodrugs of guanfacine
WO2016037592A1 (zh) 一种氨基磺酰基类化合物、其制备方法及用途
TR2023002736T2 (tr) Benzo oksi̇jen barindiran heterosi̇kli̇k bi̇leşi̇kler ve bunlarin tibbi̇ uygulamasi
CA3180417A1 (en) Synthesis of (2s,5r)-5-(2-chlorophenyl)-1-(2&#39;-methoxy-[1,1&#39;-biphenyl]-4-carbonyl)pyrrolidine-2-carboxylic acid
CA3122621A1 (en) Estrogen receptor antagonist
CN116082259B (zh) 氨基甲酸酯基或氨甲酰基取代的5-ht2b拮抗剂
CN113880841B (zh) 一类吲哚衍生物及其用途
AU2023212020A1 (en) 4-substituted-phenyl acetamides and arylureas as agonists for the orphan receptor gpr88
KR20240135652A (ko) 벤즈이미다졸 또는 아자벤즈이미다졸 화합물, 이의 제조 방법 및 그의 용도
TW202325281A (zh) 具有mat2a抑制活性的嘧啶-2(1h)-酮并二環類化合物及其用途
CN111057069A (zh) 一种环状化合物、其应用及组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21866065

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2023516184

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3194769

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2023/002736

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: AU2021342090

Country of ref document: AU

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023004430

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 202317026263

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021866065

Country of ref document: EP

Effective date: 20230411

ENP Entry into the national phase

Ref document number: 2021342090

Country of ref document: AU

Date of ref document: 20210910

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112023004430

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230309

WWE Wipo information: entry into national phase

Ref document number: 523442896

Country of ref document: SA