WO2019134667A1 - 一种SGLTs抑制剂及其应用 - Google Patents

一种SGLTs抑制剂及其应用 Download PDF

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WO2019134667A1
WO2019134667A1 PCT/CN2019/070336 CN2019070336W WO2019134667A1 WO 2019134667 A1 WO2019134667 A1 WO 2019134667A1 CN 2019070336 W CN2019070336 W CN 2019070336W WO 2019134667 A1 WO2019134667 A1 WO 2019134667A1
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group
compound
pharmaceutically acceptable
isomer
acceptable salt
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PCT/CN2019/070336
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English (en)
French (fr)
Inventor
吴成德
毛庆华
李翼
于涛
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to KR1020207018212A priority Critical patent/KR102283677B1/ko
Priority to CN201980005940.0A priority patent/CN111372930B/zh
Priority to ES19735712T priority patent/ES2941108T3/es
Priority to AU2019205072A priority patent/AU2019205072B2/en
Priority to FIEP19735712.2T priority patent/FI3712147T3/fi
Priority to EP19735712.2A priority patent/EP3712147B8/en
Priority to JP2020536649A priority patent/JP6917527B2/ja
Publication of WO2019134667A1 publication Critical patent/WO2019134667A1/zh
Priority to US16/916,108 priority patent/US10822365B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D309/22—Radicals substituted by oxygen atoms
    • 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
    • C07D407/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of compounds that are dual inhibitors of SGLT1/SGLT2, and to the use in the manufacture of a medicament as a dual inhibitor of SGLT1/SGLT2. Specifically, it relates to a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.
  • Diabetes is a metabolic disease characterized by high blood sugar. Hyperglycemia is caused by defects in insulin secretion or its biological effects, or both. In diabetes, long-term abnormal blood glucose levels can lead to serious complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage, and obesity.
  • the treatment of diabetes, early stages, diet control and exercise therapy are the preferred glycemic control programs. When these methods are difficult to control blood sugar, insulin or oral hypoglycemic drugs are needed for treatment.
  • hypoglycemic drugs for clinical treatment including biguanides, sulfonylureas, insulin resistance improvers, levonides, ⁇ -glucosidase inhibitors and dipeptidyl peptidase-IV inhibition.
  • Agents, etc. These drugs have good therapeutic effects, but there are still safety problems in long-term treatment. For example, biguanides are prone to lactic acidosis; sulfonylureas can cause hypoglycemia; insulin resistance improvers cause edema, heart failure and Weight gain; ⁇ -glucosidase inhibitors cause symptoms such as abdominal pain, bloating, and diarrhea. Therefore, there is an urgent need to develop a new safer and more effective hypoglycemic drug to meet the therapeutic needs of diabetes.
  • SGLTs Sodium-glucose cotransporters
  • Family members mainly include SGLT-1 protein and SGLT2 protein. Their functions are It mediates the transmembrane transport of glucose in the gut and kidney and plays a key role in maintaining blood sugar stability in the body.
  • SGLT1 is mainly distributed in intestinal mucosal cells of the small intestine, and is also expressed in a small amount in the myocardium and kidney, which mainly regulates the intestinal absorption process of glucose.
  • SGLT-2 is expressed at high levels in the kidney, it is mainly responsible for the regulation of glucose renal reuptake process, that is, glucose in urine can be actively attached to renal tubular epithelial cells through glomerular filtration and transported through SGLT-2 protein. The inside is reused. In this process, SGLT-2 is responsible for 90% of the reabsorption process, and the remaining 10% is done by SGLT-1. Because the process does not involve the metabolism of glucose, thereby avoiding or reducing the occurrence of adverse reactions of hypoglycemia and reducing the risk of causing cardiovascular diseases, SGLTs have become one of the ideal potential targets for the treatment of diabetes.
  • SGLTs inhibitors especially highly selective SGLT2 inhibitors. They inhibit the reabsorption of glucose by the kidney by inhibiting the activity of SGLT2, thereby increasing the excretion of glucose in the urine and normalizing plasma glucose in diabetic patients.
  • Dapagliflozin Canagliflozin, Luseogliflozin, Ipragliflozin, Tofogliflozin and Engle Six drugs, such as Empagliflozin, have been approved for marketing and become effective drugs for the treatment of diabetes.
  • SGLT1/SGLT2 dual inhibitors have good prospects for development. Therefore, it is urgent to develop a dual inhibitor of SGLT1/SGLT2 with superior efficacy, good pharmacokinetic properties and high safety for the treatment of diabetes and related metabolic disorders.
  • the SGLT1/SGLT2 dual inhibitor Sotagliflozin jointly developed by Lexicon and Sanofi, has completed a clinical phase III study (WO2008042688/WO2012094293).
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • n 1 or 2;
  • n 0, 1 or 2;
  • D is -O- or -C(R 1 )(R 2 )-;
  • Ring A is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, and NH 2 ;
  • R 2 is selected from the group consisting of H, F, Cl, Br, and I;
  • R 1 and R 2 are bonded to form a 5- to 6-membered heterocycloalkyl group
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy Optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R <
  • R is selected from the group consisting of F, Cl, Br, I, OH, and NH 2 ;
  • the 5- to 6-membered heteroaryl group and the 5- to 6-membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 hetero atoms or heteroatoms independently selected from the group consisting of -NH-, -O-, -S- and N. .
  • R 3 above is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et, and -O-CH 3 , and other variables are as defined herein.
  • R 4 is selected from the group consisting of CH 3 and Et, and other variables are as defined in the present invention.
  • Ring A is selected from the group consisting of phenyl and thienyl, and other variables are as defined herein.
  • the ring A is selected from the group consisting of Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the compound described above, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention also provides the following compounds, isomers thereof or pharmaceutically acceptable salts thereof,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating SGLT1/SGLT2-related diseases.
  • the above application is characterized in that the medicament is a medicament for treating diabetes.
  • the compounds of the present invention exhibit superior inhibitory activities against Human-SGLT1 and Human-SGLT2 in vitro and exhibit better hypoglycemic effects in animals.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in A-X, the structure is actually A.
  • substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • the "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • alkyl is used to mean a straight or branched saturated hydrocarbon group, and in some embodiments, the alkyl group is a C 1-12 alkyl group; in other embodiments The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It may be monosubstituted (such as -CH 2 F) or polysubstituted (such as -CF 3 ), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). .
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • alkenyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bond may be located at any position of the group.
  • the alkenyl group is a C 2-8 alkenyl group; in other embodiments, the alkenyl group is a C 2-6 alkenyl group; in other embodiments, the alkenyl group is C 2-4 alkenyl. It may be mono- or poly-substituted and may be monovalent, divalent or multivalent.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like.
  • alkynyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bond may be located at any position of the group.
  • the alkynyl group is a C 2-8 alkynyl group; in other embodiments, the alkynyl group is a C 2-6 alkynyl group; in other embodiments, the alkynyl group is C 2-4 alkynyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • heteroalkyl by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) Oxyl) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkenyl by itself or in conjunction with another term, denotes a stable straight or branched alkenyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkenyl group is a C 2-6 heteroalkenyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkenyl group.
  • the hetero atom or heteroatom group may be located at any internal position of the heteroalkenyl group, including the position at which the alkenyl group is attached to the rest of the molecule, but the terms "alkenyloxy”, “alkenylamino” and “alkenylthio” are customary. By expression, it is meant those alkenyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl by itself or in conjunction with another term, denotes a stable straight or branched alkynyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkynyl group is a C 2-6 heteroalkynyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkynyl group.
  • hetero atom or heteroatom group may be located at any internal position of the heteroalkynyl group, including the position at which the alkynyl group is attached to the rest of the molecule, but the terms "alkynyloxy", “alkynylamino” and “alkynylthio” are customary. By expression, it is meant those alkynyl groups attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl groups include, but are not limited to, Up to two heteroatoms can be continuous, for example
  • cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic or tricyclic systems wherein the bicyclic and tricyclic systems include spiro, co and ring.
  • the cycloalkyl group is a C 3-8 cycloalkyl group; in other embodiments, the cycloalkyl group is a C 3-6 cycloalkyl group; in other embodiments, the The cycloalkyl group is a C 5-6 cycloalkyl group. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane and the like.
  • cycloalkenyl includes any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic The system wherein the bicyclic and tricyclic systems include spiro, parallel and bridged rings, but any ring of this system is non-aromatic.
  • the cycloalkenyl group is a C 3-8 cycloalkenyl group; in other embodiments, the cycloalkenyl group is a C 3-6 cycloalkenyl group; in other embodiments, the The cycloalkenyl group is a C 5-6 cycloalkenyl group.
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkynyl includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position of the group, including monocyclic, bicyclic or tricyclic systems, wherein Bicyclic and tricyclic systems include spiro, parallel and bridging rings. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring. Further, in the case of the "heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene) -2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and
  • heterocyclenyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkenyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, Rings and bridge rings, but any ring of this system is non-aromatic.
  • a heteroatom can occupy the position of attachment of the heterocyclenyl group to the rest of the molecule.
  • the heterocycloalkenyl is 4 to 6 membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is 5 to 6 membered heterocycloalkenyl.
  • heterocycloalkenyl groups include, but are not limited to,
  • heterocycloalkynyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkynyl” group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring.
  • a hetero atom may occupy a position where a heterocyclic alkynyl group is bonded to the rest of the molecule.
  • the heterocycloalkynyl group is a 4 to 6 membered heterocycloalkynyl group; in other embodiments, the heterocycloalkynyl group is a 5 to 6 membered heterocycloalkynyl group.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term “haloalkyl” is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • the alkoxy group is a C 1-3 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S- Pentyloxy.
  • aromatic ring and “aryl” are used interchangeably and the term “aryl ring” or “aryl” means a polyunsaturated carbocyclic ring system which may be monocyclic, bicyclic or poly A ring system in which at least one ring is aromatic, and each ring in the bicyclic and polycyclic ring system is fused together. It may be mono- or poly-substituted, may be monovalent, divalent or multivalent, in some embodiments, the aryl is a C 6-12 aryl; in other embodiments, the aryl It is a C 6-10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). Substituents for any of the above aryl ring systems are selected from the group of acceptable substituents described herein.
  • heteroaryl ring and “heteroaryl” are used interchangeably and the term “heteroaryl” means 1, 2, 3 or 4 independently selected from B, N, O and An aryl (or aromatic ring) of a hetero atom of S, which may be a monocyclic, bicyclic or tricyclic ring system in which the nitrogen atom may be substituted or unsubstituted (ie, N or NR, wherein R is H or has been herein Other substituents are defined, and are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl.
  • the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.) , triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- Triazolyl
  • aralkyl is intended to include those groups in which an aryl group is attached to an alkyl group.
  • the aralkyl group is a C6-10 aryl- C1-4 alkyl group.
  • the aralkyl group is a C 6-10 aryl-C 1-2 alkyl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like.
  • Aryloxy and "arylthio” mean those groups wherein the carbon atom (e.g., methyl) in the aralkyl group has been replaced by an oxygen or sulfur atom, and in some embodiments, the aryloxy group is C. 6-10 Aryl-OC 1-2 alkyl; in other embodiments, the aryloxy group is C 6-10 aryl-C 1-2 alkyl-O-. In some embodiments, the arylthio group is a C 6-10 aryl-SC 1-2 alkyl group; in other embodiments, the arylthio group is a C 6-10 aryl-C 1-2 alkyl group. -S-. Examples of aryloxy and arylthio groups include, but are not limited to, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, and the like.
  • heteroarylkyl is meant to include those heteroaryl groups attached to an alkyl group, in some embodiments, the heteroaryl group is a 5-8 membered heteroaryl -C 1 -4 alkyl; in other embodiments, the heteroarylalkyl group is a 5-6 membered heteroaryl-C 1-2 alkyl group.
  • heteroarylalkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like.
  • Heteroaryloxy and “heteroarylthio” mean those groups in which the carbon atom (eg, methyl) in the heteroaralkyl group has been replaced by an oxygen or sulfur atom, respectively, and in some embodiments, the heteroaryl The oxy group is a 5-8 membered heteroaryl-OC 1-2 alkyl group; in other embodiments, the heteroaryloxy group is a 5-6 membered heteroaryl-C 1-2 alkyl-O- group. In some embodiments, the heteroarylthio group is a 5-8 membered heteroaryl-SC 1-2 alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C 1 -2 alkyl-S-.
  • heteroaryloxy and heteroarylthio groups include, but are not limited to, pyrroleoxymethyl, pyrazolyloxymethyl, 2-pyridyloxymethyl, pyrrolethiomethyl, pyrazolethiomethyl, 2-pyridinethiomethyl Wait.
  • C n-n+m or C n -C n+m includes any one of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range of n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring represents a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • n to n+m also including any range of n to n+m, for example, 3-12 yuan including 3-6 yuan, 3-9 yuan, 5-6 yuan, 5- 7 yuan, 6-7 yuan, 6-8 yuan, and 6-10 yuan.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the compounds of the invention may be used in a variety of uses or indications, including but not limited to the specific uses or indications listed herein.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 1 Results of animal body weight changes from week 1 to week 8;
  • Figure 2 Results of changes in animal food consumption from week 1 to week 8.
  • Step 1 Synthesis of Compound A-1-3.
  • Step 3 Synthesis of Compound A-1.
  • compound B-1-1 (30 g, 127.41 mmol, 1 eq) and tetrahydrofuran (6 mL), and borane tetrahydrofuran complex (1M, 382.23 mL, 3 eq) was added while stirring at 25 ° C. The mixture was reacted for 16 hours. After completion of the reaction, methanol (150 mL) was added dropwise to the reaction mixture at 25 ° C, while nitrogen gas was purged, quenched, and concentrated to dryness at 45 ° C to give compound B-1-2.
  • Lithium aluminum hydride (11 g, 289.82 mmol, 1.25 eq) was dissolved in tetrahydrofuran (200 mL) at 0 ° C.
  • Compound B-2-1 (50 g, 232.51 mmol, 1 eq) was slowly dissolved in tetrahydrofuran (200 mL) at 0 ° C. Air bubbles were generated, and the reaction was heated to 25 ° C for 2 hours.
  • Water (11 mL) was slowly added dropwise at 0 ° C, and a 15% aqueous sodium hydroxide solution (11 mL) was added dropwise, and finally water (33 mL) was added. Filter and filter the filter residue twice with ethyl acetate. The filtrate was suspended.
  • the crude compound B-2-2 was obtained.
  • Each of the fragments B-4 in the following table was synthesized by referring to the synthesis methods of the steps 1 to 8 in Reference Example 9.
  • Each fragment B-5 in the following table was synthesized by referring to the synthesis methods of the steps 1 to 8 in Reference Example 10.
  • the structures in the table also represent their possible isomers.
  • reaction liquid was concentrated under reduced pressure at 45 ° C with a first water pump to remove ethanol, and then concentrated by an oil pump to remove toluene and water to obtain a crude product.
  • the crude product was purified by column chromatography ( petroleum ether / ethyl acetate) to afford the title compound WXD001-1.
  • Example 10 in Table 2 below was synthesized by referring to the synthesis methods of Steps 1 and 2 in Example 2.
  • the structures in Table 2 also represent their possible isomers.
  • the effect of the compound on the transport of glucose to the SGLT1 transporter was examined by measuring the amount of [ 14C ]-labeled glucose that entered the high-expression Human-SGLT1 cells.
  • the cells stably expressing Human-SGLT1 used in the experiment were constructed by Shanghai WuXi PharmaTech.
  • SGLT1 cells were plated in Cytostar-T (PerkinElmer) 96-well cell culture plates and cultured overnight at 37 ° C in 5% CO 2 .
  • the cells were allowed to act on the cells at 37 ° C for 2 hours with 49 uL of experimental buffer, 1 ⁇ L of the gradient diluted compound and 50 ⁇ L of 3 ⁇ M [ 14 C] isotope-labeled sugar solution.
  • the effect of the compound on the transport of glucose to the SGLT2 transporter was examined by measuring the amount of [ 14C ]-labeled glucose that entered the high-expression Human-SGLT2 cells.
  • the cells stably expressing Human-SGLT2 used in the experiment were constructed by Shanghai WuXi PharmaTech.
  • SGLT2 cells were plated in 96-well cell culture plates (Greiner) and cultured overnight at 37 ° C in 5% CO 2 .
  • Stop buffer 10 mM 4-hydroxyethylpiperazineethanesulfonic acid (HEPES), 1.2 mM magnesium chloride (MgCl 2 ), 4.7 mM potassium chloride (KCl), 2.2 mM calcium chloride (CaCl 2 ) 120 mM chlorination Sodium (NaCl) and 1 ⁇ M LX4211.
  • HEPES 4-hydroxyethylpiperazineethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7 mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl chlorination Sodium
  • the cells were allowed to act on the cells at 37 ° C for 2 hours with 49 uL of experimental buffer, 1 ⁇ L of the gradient diluted compound and 50 ⁇ L of 6 ⁇ M [ 14 C] isotope-labeled sugar solution.
  • the cells were lysed with 50 uL of 10% sodium hydroxide solution, and the cell lysate was aspirated into a scintillation vial, and 2 mL of scintillation fluid was added.
  • the compounds of the present invention exhibit superior in vitro inhibitory activity against Human-SGLT1 and Human-SGLT2.
  • mice Male Sprague-Dawley rats were used as test animals, and the plasma concentration of the compounds was measured after a single administration and the pharmacokinetic behavior was evaluated.
  • test compound Six healthy adult male Sprague-Dawley rats were selected, three were intravenous and three were oral.
  • the test compound is mixed with an appropriate amount of the vehicle (10% N-methylpyrrolidone (NMP)/10% polyethylene glycol-15 hydroxystearate/80% water), vortexed and sonicated. A 0.2 mg/mL clear solution was obtained, and the microporous membrane was filtered and used; the oral vehicle was 10% N-methylpyrrolidone (NMP)/10% polyethylene glycol-15 hydroxystearate (solutol)/80% Water, the test compound was mixed with a solvent, vortexed and sonicated to prepare a clear solution of 0.40 mg/mL.
  • NMP N-methylpyrrolidone
  • solutol polyethylene glycol-15 hydroxystearate
  • Rats were given 1 mg/kg intravenously or 2 mg/kg orally, and whole blood was collected for a certain period of time to prepare plasma.
  • the drug concentration was analyzed by LC-MS/MS method and calculated by Phoenix WinNonlin software (Pharsight, USA). Pharmacokinetic parameters.
  • Cmax is the maximum concentration
  • F% oral bioavailability
  • Oral DNAUC AUC PO /Dose (unit oral exposure)
  • AUC PO is oral exposure
  • Dose is drug dose
  • Vd ss distribution volume
  • Cl Clearance rate
  • T 1/2 is the half-life.
  • mice Male Beagle dogs were used as test animals, and the plasma concentration of the compounds was measured after a single administration and the pharmacokinetic behavior was evaluated.
  • test compound Six male Beagle dogs were selected, three for the intravenous injection group and three for the oral group.
  • the test compound was mixed with an appropriate amount of a vehicle (20% polyethylene glycol-400 (PEG400)/10% polyethylene glycol-15 hydroxysulphonate/70% water), vortexed and sonicated.
  • a 1 mg/mL clear solution was prepared, and the microporous membrane was filtered and used;
  • the oral vehicle was 20% polyethylene glycol-400 (PEG400)/10% polyethylene glycol-15 hydroxystearate (solutol)/70 % water, the test compound was mixed with a solvent, vortexed and sonicated to prepare a 1 mg/mL clear solution.
  • Cmax is the maximum concentration
  • F% oral bioavailability
  • Oral DNAUC AUC PO /Dose (unit oral exposure)
  • AUC PO is oral exposure
  • Dose is drug dose
  • Vd ss distribution volume
  • Cl Clearance rate
  • T 1/2 is the half-life.
  • the compounds of the invention have good oral exposure and bioavailability.
  • the compound of the present invention can significantly reduce the blood glucose AUC level in the animal within 2 hours; both can increase the 24-hour urine glucose excretion level of the animal.
  • the compound of the present invention has a low level of urine sugar under the same hypoglycemic effect, and contributes to reducing side effects of urinary tract infection.
  • mice level SPF animal Ordering weeks 5 weeks old Beginning of the experiment 6 weeks old Weight range ⁇ 25g gender male supplier Nanjing Model Animal Research Institute, Nanjing University supplier address Nanjing, Jiangsu, China
  • the temperature in the rearing room is maintained at 20 to 24 ° C and the humidity is maintained at 40 to 70%.
  • the temperature and humidity of the rearing room were monitored in real time by a thermometer and hygrometer, and the temperature and humidity were recorded twice a day (one in the morning and one in the afternoon).
  • the daylighting of the animal husbandry is controlled by an electronic timed lighting system. The lights are turned on for 12 hours every day for 12 hours (7:00 am and 19:00 pm).
  • the mice were housed in a single cage. During the experiment, the animals were fed ad libitum (large mouse breeding feed 17053113, Beijing Keao Xieli Feed Co., Ltd.) and drinking water.
  • the animals were given the corresponding solvent or test sample according to the group, the administration time was: 16:00, and the administration period was 8 weeks.
  • the dose was 5 mg/kg; from the 5th week to the 8th week, the dose was 10 mg/kg.
  • the random blood glucose measurement time is 10:00 in the morning.
  • the animals were given a single glucose solution of 2 g/kg, and the sugar supply time was recorded as 0 points, and before the sugar was given, the sugar was given at 15,30.
  • the animals were tested for blood glucose, and the glucose tolerance curve was plotted against the blood glucose data according to the time, and the area under the curve (AUC) was calculated.
  • the administration time is: 16:00.
  • the animal's body weight was monitored once a day, and the food consumption was monitored twice a week.
  • the compounds of the present invention can reduce the random blood glucose level of the animal; the dose of the compound of the present invention can further reduce the random blood sugar level of the animal.
  • the compounds of the present invention can significantly reduce the fasting blood glucose level of the animal; after increasing the dose, the compounds of the present invention can further reduce the fasting blood glucose level of the animal.
  • the compounds of the present invention can significantly reduce the blood glucose AUC level within 2 hours.
  • the compound of the present invention can significantly reduce the level of glycated hemoglobin (HbA1c) in the animal; and the dose of the compound of the present invention can further reduce the level of glycated hemoglobin (HbA1c) in the animal.

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Abstract

作为SGLT1/SGLT2双重抑制剂的化合物，及其在制备作为SGLT1/SGLT2双重抑制剂的药物中的应用，所述化合物是式（I）所示化合物、其异构体或其药学上可接受的盐。

Description

一种SGLTs抑制剂及其应用
本申请主张如下优先权：
CN201810012284.4，申请日2018.01.05。
技术领域
本发明涉及作为SGLT1/SGLT2双重抑制剂的一类化合物，以及在制备作为SGLT1/SGLT2双重抑制剂的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
糖尿病是一种以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时，长期血糖水平异常可导致严重的并发症，包括心血管疾病、慢性肾功能衰竭、视网膜损伤、神经损伤、微血管损伤和肥胖等。糖尿病的治疗，早期阶段，饮食控制和运动疗法是首选的血糖控制方案。当这些方法难以实现对血糖的控制时，则需要使用胰岛素或者口服降糖类药物进行治疗。目前，己有多种降糖药物用于临床治疗，主要包括双胍类、磺酰脲类、胰岛素耐受改善剂、列奈类、α-葡萄糖苷酶抑制剂和二肽基肽酶-IV抑制剂等。这些药物具有良好的治疗效果，但长期治疗仍存在安全性问题，例如，双胍类易引起乳酸性酸中毒；磺酰脲类会导致低血糖症状；胰岛素耐受改善剂会造成水肿、心脏衰竭和体重增加；α-葡萄糖苷酶抑制剂会引起腹痛、腹胀、腹泻等症状。因此，迫切需要开发出一种更安全、优效的新型降糖药物满足糖尿病的治疗需要。
钠-葡萄糖共转运蛋白(sodium-glucose cotransporters,SGLTs)是一类在小肠黏膜和肾近曲小管中发现的葡萄糖转运蛋白家族，家族成员主要包括SGLT-1蛋白和SGLT2蛋白两类，其功能是介导肠道和肾脏中葡萄糖的跨膜转运，在维持人体血糖稳定中起着关键作用。具体而言，SGLT1主要分布于小肠的肠道粘膜细胞，在心肌和肾脏中也有少量表达，它主要调节葡萄糖的肠道吸收过程。而SGLT-2在肾脏中高水平表达，主要负责葡萄糖肾脏重摄取过程的调节，即尿液中的葡萄糖在经过肾小球过滤时可主动附着于肾小管上皮细胞并通过SGLT-2蛋白转运进胞内被重新利用。在这一过程中，SGLT-2负责了90％的重吸收过程，剩余的10％则有由SGLT-1完成。由于该过程不介入葡萄糖的代谢，从而避免或减轻了低血糖不良反应的发生，降低了引起心血管类疾病的风险，因此，SGLTs已成为治疗糖尿病的理想潜在靶点之一。
鉴于此，一些SGLTs抑制剂，尤其是高选择性的SGLT2抑制剂被相继开发。它们通过抑制SGLT2活性，特异性地抑制肾脏对葡萄糖的重吸收，从而增加葡萄糖在尿中的排泄，使糖尿病患者的血浆葡萄糖正常化。从2012年至今，已有达格列净(Dapagliflozin)，卡格列净(Canagliflozin)，鲁格列净(Luseogliflozin)，伊格列净(Ipragliflozin)，托格列净(Tofogliflozin)和恩格列净(Empagliflozin)等6个药物先后被批准上市，成为治疗糖尿病的有效药物。
除了选择性SGLT2抑制剂，近几年研究发现，抑制SGLT2的同时，对SGLT1部分抑制，既能抑制肾脏葡萄糖的重摄取，又能实现控制肠道对葡萄糖的吸收而不出现腹泻或者其他胃肠道反应；同时，通过 抑制肠道SGLT1减少经胃肠道入血的葡萄糖，能增加餐后GLP-1和PYY水平，从而发挥出较选择性SGLT2抑制剂更佳的降糖作用，并降低了发生尿路感染和肾功能损伤等的风险。因而开发SGLT-1/SGLT2双重抑制剂已成为近年来糖尿病治疗的新靶点和方向。
综上所述，作为新型的糖尿病治疗药物，SGLT1/SGLT2双重抑制剂有着良好的开发前景。因此，急需开发出一种优效、药代性质良好，安全性高的SGLT1/SGLT2双重抑制剂用于糖尿病及相关代谢紊乱疾病的治疗。目前，由Lexicon公司和赛诺菲公司联合开发的SGLT1/SGLT2双抑制剂Sotagliflozin已经完成临床III期研究(WO2008042688/WO2012094293)。
Figure PCTCN2019070336-appb-000001
发明内容
本发明提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019070336-appb-000002
其中，
m为1或2；
n为0、1或2；
D为-O-或-C(R 1)(R 2)-；
环A选自苯基和5～6元杂芳基；
R 1选自H、F、Cl、Br、I、OH和NH 2；
R 2选自H、F、Cl、Br和I；
或者，R 1和R 2连接形成一个5～6元杂环烷基；
R 3选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
R 4选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R选自F、Cl、Br、I、OH和NH 2；
所述5～6元杂芳基和5～6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-O-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自苯基和噻吩基，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2019070336-appb-000003
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019070336-appb-000004
选自
Figure PCTCN2019070336-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019070336-appb-000006
选自
Figure PCTCN2019070336-appb-000007
Figure PCTCN2019070336-appb-000008
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019070336-appb-000009
选自
Figure PCTCN2019070336-appb-000010
Figure PCTCN2019070336-appb-000011
其他变量如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些方案中，上述述的化合物、其异构体或其药学上可接受的盐，选自
Figure PCTCN2019070336-appb-000012
其中，
R 1、R 2、R 3和R 4如本发明所定义。
本发明还提供了下述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019070336-appb-000013
本发明还提供了一种药物组合物，包括治疗有效量的作为活性成分的上述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗SGLT1/SGLT2相 关疾病的药物中的应用。
本发明的一些方案中，上述的应用，其特征在于，所述药物是用于治疗糖尿病的药物。
技术效果
本发明的化合物在体外表现出较优的对Human-SGLT1和Human-SGLT2的抑制活性，在动物体内展现出较好的降糖效果。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019070336-appb-000014
和楔形虚线键
Figure PCTCN2019070336-appb-000015
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019070336-appb-000016
和直形虚线键
Figure PCTCN2019070336-appb-000017
表示立体中心的相对构型，用波浪线
Figure PCTCN2019070336-appb-000018
表示楔形实线键
Figure PCTCN2019070336-appb-000019
或楔形虚线键
Figure PCTCN2019070336-appb-000020
或用波浪线
Figure PCTCN2019070336-appb-000021
表示直形实线键
Figure PCTCN2019070336-appb-000022
和直形虚线键
Figure PCTCN2019070336-appb-000023
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来 制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2019070336-appb-000024
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019070336-appb-000025
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019070336-appb-000026
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶基和哌啶基；另一方面，术语“5～7元杂环烷基”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“烯基”用于表示直链或支链的包含一个或多个碳-碳双键的碳氢基团，碳-碳双键可以位于该基团的任何位置上。在一些实施方案中，所述烯基为C 2-8烯基；在另一些实施方案中，所述烯基为C 2-6烯基；在另一些实施方案中，所述烯基为C 2-4烯基。其可以是单取代或多取代的，可以是一价、 二价或者多价。烯基的实例包括但不限于乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”用于表示直链或支链的包含一个或多个碳-碳三键的碳氢基团，碳-碳三键可以位于该基团的任何位置上。在一些实施方案中，所述炔基为C 2-8炔基；在另一些实施方案中，所述炔基为C 2-6炔基；在另一些实施方案中，所述炔基为C 2-4炔基。其可以是单取代或多取代的，可以是一价、二价或者多价。炔基的实例包括但不限于乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“杂烯基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烯基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烯基为C 2-6杂烯基；在另一些实施方案中，所述杂烷基为C 2-4杂烯基。杂原子或杂原子团可以位于杂烯基的任何内部位置，包括该烯基与分子其余部分的连接位置，但术语“烯基氧基”、“烯基氨基”和“烯基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烯基基团。杂烯基的实例包括但不限于-O-CH＝CH 2、-O-CH＝CHCH 3、-O-CH＝C(CH 3) 2、-CH＝CH-O-CH 3、-O-CH＝CHCH 2CH 3、-CH 2-CH＝CH-OCH 3、-NH-CH＝CH 2、-N(CH＝CH 2)-CH 3、-CH＝CH-NH-CH 3、-CH＝CH-N(CH 3) 2、-S-CH＝CH 2、-S-CH＝CHCH 3、-S-CH＝C(CH 3) 2、-CH 2-S-CH＝CH 2、-S(＝O)-CH＝CH 2和-CH＝CH-S(＝O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH＝CH-NH-OCH 3。
除非另有规定，术语“杂炔基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的炔基原子团或其组合物。在一些实施方案中，杂原子选自B、 O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂炔基为C 2-6杂炔基；在另一些实施方案中，所述杂烷基为C 2-4杂炔基。杂原子或杂原子团可以位于杂炔基的任何内部位置，包括该炔基与分子其余部分的连接位置，但术语“炔基氧基”、“炔基氨基”和“炔基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些炔基基团。杂炔基的实例包括但不限于
Figure PCTCN2019070336-appb-000027
Figure PCTCN2019070336-appb-000028
Figure PCTCN2019070336-appb-000029
至多两个杂原子可以是连续的，例如
Figure PCTCN2019070336-appb-000030
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“环烯基”包括任何稳定的环状烯基，在该基团的任何位点含有一个或多个不饱和的碳-碳双键，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。在一些实施方案中，所述环烯基为C 3-8环烯基；在另一些实施方案中，所述环烯基为C 3-6环烯基；在另一些实施方案中，所述环烯基为C 5-6环烯基。其可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，“环炔基”包括任何稳定的环状炔基，在该基团的任何位点含有一个或多个碳-碳三键，其包含单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。其可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷基。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶 基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“杂环烯基”本身或者与其他术语联合分别表示环化的“杂烯基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。此外，就该“杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。在一些实施方案中，所述杂环烯基为4～6元杂环烯基；在另一些实施方案中，所述杂环烯基为5～6元杂环烯基。杂环烯基的实例包括但不限于
Figure PCTCN2019070336-appb-000031
Figure PCTCN2019070336-appb-000032
除非另有规定，术语“杂环炔基”本身或者与其他术语联合分别表示环化的“杂炔基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环炔基”而言，杂原子可以占据杂环炔基与分子其余部分的连接位置。在一些实施方案中，所述杂环炔基为4～6元杂环炔基；在另一些实施方案中，所述杂环炔基为5～6元杂环炔基。除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。在一些实施方案中，所述烷氧基为C 1-3烷氧基。烷氧基的实例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，本发明术语“芳环”和“芳基”可以互换使用，术语“芳环”或“芳基”表示多不饱和的碳环体系，它可以是单环、双环或多环体系，其中至少一个环是芳香性的，所述双环和多环体系中的各个环稠合在一起。其可以是单取代或多取代的，可以是一价、二价或者多价，在一些实施方案中，所述芳基为C 6-12芳基；在另一些实施方案中，所述芳基为C 6-10芳基。芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。上述任意一个芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，本发明术语“杂芳环”和“杂芳基”可以互换使用，术语“杂芳基”是指含有1、2、3或4个独立选自B、N、O和S的杂原子的芳基(或芳环)，其可以是单环、双环或三环体系，其中氮原子 可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)，且任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。杂芳基可通过杂原子连接到分子的其余部分。在一些实施方案中，所述杂芳基为5-10元杂芳基；在另一些实施方案中，所述杂芳基为5-6元杂芳基。所述杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)、喹啉基(包括3-喹啉基和6-喹啉基等)、吡嗪基、嘌呤基、苯基并噁唑基。上述任意一个杂芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，术语“芳烷基”意在包括芳基附着于烷基的那些基团，在一些实施方案中，所述芳烷基为C 6-10芳基-C 1-4烷基；在另一些实施方案中，所述芳烷基为C 6-10芳基-C 1-2烷基。芳烷基的实例包括但不限于苄基、苯乙基、萘甲基等。“芳氧基”和“芳硫基”分别表示芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述芳氧基为C 6-10芳基-O-C 1-2烷基；在另一些实施方案中，芳氧基为C 6-10芳基-C 1-2烷基-O-。在一些实施方案中，所述芳硫基为C 6-10芳基-S-C 1-2烷基；在另一些实施方案中，芳硫基为C 6-10芳基-C 1-2烷基-S-。芳氧基和芳硫基的实例包括但不限于苯氧基甲基、3-(1-萘氧基)丙基，苯硫基甲基等。
除非另有规定，术语“杂芳烷基”意在包括杂芳基附着于烷基的那些基团，在一些实施方案中，所述杂芳烷基为5-8元杂芳基-C 1-4烷基；在另一些实施方案中，所述杂芳烷基为5-6元杂芳基-C 1-2烷基。杂芳烷基的实例包括但不限于吡咯基甲基、吡唑基甲基、吡啶基甲基、嘧啶基甲基等。“杂芳氧基”和“杂芳硫基”分别表示杂芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述杂芳氧基为5-8元杂芳基-O-C 1-2烷基；在另一些实施方案中，杂芳氧基为5-6元杂芳基-C 1-2烷基-O-。在一些实施方案中，所述杂芳硫基为5-8元杂芳基-S-C 1-2烷基；在另一些实施方案中，杂芳硫基为5-6元杂芳基-C 1-2烷基-S-。杂芳氧基和杂芳硫基的实例包括但不限于吡咯氧甲基、吡唑氧甲基、2-吡啶氧甲基、吡咯硫甲基、吡唑硫甲基、2-吡啶硫甲基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n 至n+m个，例如3-12元环表示3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元包含3-6元、3-9元、5-6元、5-7元、6-7元、6-8元、和6-10元等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以有多种用途或适应症，包括但不限于本申请所列举的具体用途或适应症。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表N-氯代丁二酰亚胺；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；NMP代表N-甲基吡咯烷酮。
化合物经手工或者
Figure PCTCN2019070336-appb-000033
软件命名，市售化合物采用供应商目录名称。
附图说明
图1：第1周至第8周动物体重变化结果；
图2：第1周至第8周动物耗食量变化结果。
具体实施方式
下面经过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段A-1
Figure PCTCN2019070336-appb-000034
合成路线：
Figure PCTCN2019070336-appb-000035
步骤1：化合物A-1-3的合成。
向预先干燥好的三口瓶(500mL)中依次加入化合物A-1-1(20g,84.78mmol,10.87mL,1eq)和四氢呋喃(125mL)，置换氮气，降温至-78℃后缓慢滴加正丁基锂(2.5M,37.64mL,1.11eq)，搅拌0.5小时。最后加入化合物A-1-2(12.5g,93.26mmol,1.1eq)，缓慢升温至0℃搅拌0.5小时。反应完毕后用饱和氯化铵水溶液(200mL)在0～10摄氏度下缓慢淬灭，乙酸乙酯(200mL x 2)萃取，合并有机相，用饱和氯化钠(100mL)洗涤，再用无水硫酸钠干燥，滤去干燥剂后，减压除去溶剂，得到粗品化合物A-1-3，未经纯化直接用于下一步反应。
步骤2：化合物A-1-4的合成。
向预先干燥好的三口瓶(1000mL)中依次加入化合物A-1-3(23.2g,79.82mmol,1eq)和甲苯(600mL)，最后加入一水合对甲苯磺酸(1.82g,9.58mmol,0.12eq)。置换氮气，加热至130℃搅拌10小时(用分水器)。反应完毕后将反应液降温后减压蒸出溶剂。残余物经过柱层析(石油醚/乙酸乙酯体系)分离得到化合物A-1-4。 1H NMR(400MHz,CHLOROFORM-d)δ:7.49-7.43(m,2H),7.27-7.22(m,2H),5.91(dt,J＝1.3,2.6Hz,1H),2.80-2.63(m,4H),2.19(tt,J＝6.7,13.7Hz,2H).
步骤3：化合物A-1的合成。
向预先干燥好的单口瓶(100mL)中依次加入化合物A-1-4(2.9g,10.62mmol,1eq)、频哪醇硼酸酯(5.39g,21.24mmol,2eq)、乙酸钾(3.13g,31.85mmol,3eq)和1,4-二氧六环(30mL)，置换氮气后加入1,1'-双(二苯基磷)二茂铁氯化钯(776.94mg,1.06mmol,0.1eq)。再次置换氮气，加热至70℃搅 拌10小时。反应完毕后将反应液降温，减压蒸出溶剂，残余物经过柱层析(石油醚/乙酸乙酯体系)纯化得到化合物A-1。 1H NMR(400MHz,CHLOROFORM-d)δ:7.78(d,J＝8.4Hz,2H),7.38(d,J＝8.2Hz,2H),5.97(br s,1H),2.79-2.66(m,4H),2.19(tt,J＝6.6,13.7Hz,2H),1.36(s,12H).
参照参考例1中步骤1～3的合成方法，合成下表中各片段A2-8。表中的结构同时代表其可能的异构体。
Figure PCTCN2019070336-appb-000036
Figure PCTCN2019070336-appb-000037
参考例9：片段B-1
Figure PCTCN2019070336-appb-000038
合成路线：
Figure PCTCN2019070336-appb-000039
步骤1：化合物B-1-2的合成
向3L三口瓶中加入加入化合物B-1-1(30g,127.41mmol,1eq)和四氢呋喃(6mL)，边鼓氮气边加入硼烷四氢呋喃络合物(1M,382.23mL,3eq)，25℃下混合液反应16小时。反应完毕后，25℃向反应液中滴入甲醇(150mL)，同时鼓氮气，淬灭完毕，45℃水泵浓缩干得到化合物B-1-2。 1H NMR(400MHz, CHLOROFORM-d)δ＝7.68(d,J＝2.4Hz,1H),7.37(dd,J＝2.2,8.6Hz,1H),7.22(d,J＝8.4Hz,1H),4.77(d,J＝5.3Hz,2H).
步骤2：化合物B-1-3的合成
向三口瓶中加入化合物B-1-2(27g,121.91mmol,1eq)和二甲基甲酰胺(150mL)，抽换氮气后0℃加入钠氢(9.75g,243.82mmol,60％purity,2eq)，半小时后加入烯丙基溴(44.24g,365.73mmol,32.06mL,3eq)，25℃下混合液反应15.5小时。反应完毕后，反应液用饱和氯化铵水溶液(500mL)淬灭，二氯甲烷(100mL x3)萃取，有机相用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机(SiO 2，100-200目，PE:EA＝1：0到10:1)纯化。得到化合物B-1-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.67(d,J＝2.4Hz,1H),7.35(dd,J＝2.4,8.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.08-5.91(m,1H),5.39(q,J＝1.6Hz,1H),5.34(q,J＝1.5Hz,1H),5.29-5.24(q,1H),4.57(s,2H),4.13(td,J＝1.3,5.6Hz,2H).
步骤3：化合物B-1-5的合成
向三口瓶中加入化合物B-1-4(9.9g,36.23mmol,1eq)和THF(70.5mL)，抽换氮气后冷却到0℃加入叔丁基格氏试剂(2M,29.70mL,1.64eq)，0℃下混合液反应1小时。此为反应液1。向三口瓶中加入化合物B-1-3(12.32g,47.09mmol,1.3eq)和四氢呋喃(141mL)，抽换氮气后冷却到-78℃加入正丁基锂(2.5M,21.74mL,1.5eq)，-78℃下混合液反应0.5小时。此为反应液2。然后用注射器把反应液1滴加到反应液2中。-78℃反应1小时，25℃反应13.5小时。反应完毕后反应液用饱和氯化铵水溶液(400mL)淬灭，乙酸乙酯(100mL x 3)萃取，有机相用饱和食盐水(1000mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机(石油醚/乙酸乙酯体系)纯化得到化合物B-1-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.21(s,1H),7.94(dd,J＝2.0,8.4Hz,1H),7.48(d,J＝8.2Hz,1H),6.10(d,J＝3.5Hz,1H),6.05-5.94(m,1H),5.38(dd,J＝1.5,17.2Hz,1H),5.33(d,J＝2.6Hz,1H),5.28-5.23(m,1H),4.65(s,2H),4.63(br d,J＝3.3Hz,1H),4.61(d,J＝3.5Hz,1H),4.15(d,J＝5.5Hz,2H),2.97(d,J＝4.2Hz,1H),1.59(s,3H),1.38(s,3H).
步骤4：化合物B-1-6的合成
向反应瓶中加入化合物B-1-5(8g,21.69mmol,1eq)、七水合氯化铈(9.70g,26.03mmol,2.47mL,1.2eq)和甲醇(180mL)，抽换氮气后0℃加入硼氢化钠(1.64g,43.38mmol,2eq)，25℃下混合液反应16小时。反应完毕后，反应液先用用饱和氯化铵水溶液(250mL)淬灭，再加入饱和食盐水(250mL)，乙酸乙酯(100mL x3)萃取，(若遇到难以分层现象，可以用硅藻土过滤再分液)，有机相无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干得到化合物B-1-6。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.61-7.56(m,1H),7.42-7.31(m,2H),6.05-5.92(m,2H),5.41-5.32(m,1H),5.28-5.18(m,2H),4.64-4.59(m,2H),4.49(d,J＝3.5Hz,1H),4.16-4.03(m,5H),3.36(br s,1H),1.46(s,3H),1.30(s,3H).
步骤5：化合物B-1-7的合成
向反应瓶加入化合物B-1-6(7.2g,19.42mmol,1eq)和水(45mL)、醋酸(44.31g,737.82mmol,42.20mL,38eq)，100℃下混合液反应7小时。反应完毕后，反应液在45℃用水泵减压浓缩干。甲苯(100mL x2)共沸带干。得到化合物B-1-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.42(br d,J＝8.6Hz,1H),7.18(br s,1H),7.09(br d,J＝6.8Hz,1H),5.80(tt,J＝6.0,16.8Hz,1H),5.54-5.08(m,4H),4.58(br d,J＝5.3Hz,1H),4.43(br s,2H),4.08(br s,1H),4.14-3.80(m,3H),3.62-3.28(m,3H),2.20(br s,1H).
步骤6：化合物B-1-8的合成
向单口瓶加入化合物B-1-7(6g,18.14mmol,1eq)、三乙胺(12.11g,119.72mmol,16.66mL,6.6eq)和乙腈(110mL)，然后后依次加入醋酸酐(12.22g,119.72mmol,11.21mL,6.6eq)和二甲胺基吡啶(22.16mg,181.40umol,0.01eq)，25℃下混合液反应16小时。反应完毕后，反应液用饱和硫酸氢钠水溶液(100mL)淬灭，乙酸乙酯(50mL x 3)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机(石油醚/乙酸乙酯体系)纯化得到化合物B-1-8。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.49(d,J＝1.9Hz,1H),7.33(d,J＝8.3Hz,1H),7.25-7.21(dd,1H),5.99(tdd,J＝5.6,10.4,17.2Hz,1H),5.87(d,J＝8.3Hz,1H),5.41-5.36(m,1H),5.36-5.31(m,1H),5.30-5.23(m,2H),5.17-5.10(t,1H),4.61-4.52(m,3H),4.12-4.08(m,2H),2.13-2.10(s,3H),2.07(s,3H),2.04-1.99(s,3H),1.85(s,3H).
步骤7：化合物B-1-9的合成
向反应瓶中加入化合物B-1-8(6.5g,13.03mmol,1eq)、醋酸钠(4.28g,52.11mmol,4eq)、水(13mL)和冰醋酸(117mL)，抽换氮气后冷却到5℃加入二氯化钯(5.08g,28.66mmol,2.2eq)，25℃下混合液反应16小时。反应完毕后，反应液在45℃用水泵减压浓缩干。粗品用快速过柱机(石油醚/乙酸乙酯体系)纯化。得到化合物B-1-9。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.53(d,J＝1.8Hz,1H),7.33(d,J＝8.2Hz,1H),7.21(dd,J＝2.1,8.3Hz,1H),5.87(d,J＝8.2Hz,1H),5.41-5.34(t,1H),5.30-5.23(t,1H),5.15(t,J＝9.6Hz,1H),4.77(br d,J＝2.4Hz,2H),4.56(d,J＝9.9Hz,1H),2.15-2.10(s,3H),2.07(s,3H),2.02(s,3H),1.85(s,3H).
步骤8：化合物B-1的合成
向反应瓶中加入化合物B-1-9(1g,2.18mmol,14.04μL,1eq)、三苯基膦(857.44mg,3.27mmol,1.5eq)和二氯甲烷(20mL)，抽换氮气后搅拌半小时，0℃加入N-溴代丁二酰亚胺(581.85mg,3.27mmol,1.5eq)，25℃下混合液反应15.5小时。反应完毕后，将反应液25℃浓缩干。粗品用快速过柱机(石油醚/乙酸乙酯体系)纯化。得到化合物B-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.44-7.36(m,2H),7.29(s,1H),5.87(d,J＝8.2Hz,1H),5.41-5.34(t,1H),5.30-5.23(m,1H),5.15-5.03(m,1H),4.68-4.59(d,1H), 4.53(t,J＝9.9Hz,2H),2.22(s,1H),2.13(s,2H),2.08-2.05(m,3H),2.04-2.01(m,3H),1.91-1.86(m,3H).
参考例10：片段B-2
Figure PCTCN2019070336-appb-000040
合成路线：
Figure PCTCN2019070336-appb-000041
步骤1：化合物B-2-2的合成
将氢化铝锂(11g,289.82mmol,1.25eq)于0℃溶于四氢呋喃(200mL)，经氮气置换三次后，充满氮气保护。将化合物B-2-1(50g,232.51mmol,1eq)溶于四氢呋喃(200mL)0℃下缓慢加入反应液中。有气泡产生，将反应升温至25℃下反应2小时。0℃下先缓慢滴加水(11mL)，再滴加15％的氢氧化钠水溶液(11mL)，最后加水(33mL)。过滤，并用乙酸乙酯清洗滤渣两次。将滤液悬干。得到粗品化合物B-2-2。
步骤2：化合物B-2-3的合成
将化合物B-2-2(47.9g,238.24mmol,1eq)溶于二甲基甲酰胺(120mL)，0℃下加入钠氢(14.29g,357.36mmol,60％纯度,1.5eq)，25℃下搅拌0.5小时，然后向反应液中缓慢加入3-溴丙烯(57.64g,476.47mmol,41.17mL,2eq)，25℃下继续反应2小时。反应完毕后，0℃下加入水(50mL)淬灭，加入乙酸乙酯(500mL x 2)萃取，然后用水(50mL x 2)洗，再用饱和食盐水(50mL x 2)洗，用无水硫酸钠干燥。粗品通过柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物B-2-3。
步骤3：化合物B-2-4的合成
将化合物B-2-3(18.5g,76.72mmol,1.2eq)在-78℃溶于四氢呋喃(100mL)，经氮气保护后，加入正丁基 锂(2.5M,33.25mL,1.3eq)。在-78℃反应0.5小时。同时将化合物B-1-4(17.47g,63.93mmol,1eq)溶解在四氢呋喃(100mL)中，降温至0℃后，经氮气保护后，滴加叔丁基氯化镁(1.7M,41.37mL,1.1eq)，0℃下反应0.5小时。在-78℃下将镁烷氧溶液缓慢加入到烷基锂溶液。反应液在-78℃下反应0.5小时后，升温至25℃后继续反应15.5小时。反应完毕后，向0℃下向反应液中加入氯化胺溶液(50mL)，加入乙酸乙酯(200mL)稀释反应液后，用水(50mL x 2)洗。合并有机相后用饱和食盐水(50mL x 2)除水，用无水硫酸钠干燥，过滤旋干，粗品用柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物B-2-4。
步骤4：化合物B-2-5的合成
将化合物B-2-4(17.80g,51.09mmol,1eq)溶解在甲醇中(100mL)，降温至0℃，依次加入七水合三氯化铈(22.84g,61.31mmol,5.83mL,1.2eq)，硼氢化钠(3.87g,102.18mmol,2eq)，升温至25℃，反应16小时。反应完毕后，向反应液中加入水(30mL)淬灭悬干。再加入乙酸乙酯(100mL)稀释，用水(50mL x 2)洗涤，再用饱和食盐水(50mL x 2)除水，最后用无水硫酸钠干燥，过滤后减压浓缩干。得到目标化合物B-2-5。
步骤5：化合物B-2-6的合成
将化合物B-2-5(10.22g,29.17mmol,1eq)溶于水(100mL)和冰醋酸(100mL)中，100℃下反应16小时。反应完毕后。将溶剂60℃真空旋干，然后用甲苯带干三次。得到化合物B-2-6。
步骤6：化合物B-2-7的合成
将化合物B-2-6(9.52g,30.68mmol,1eq)和乙酸酐(25.05g,245.41mmol,22.98mL,8eq)溶解到吡啶(40mL)中，25℃下搅拌16小时。反应完毕后，将反应液用乙酸乙酯(200mL)稀释，用1M稀盐酸(100mL x 4)洗涤，有机相再用水(50mL x 2)洗涤，然后用饱和食盐水(50mL x 2)洗涤，最后将有机相用无水硫酸钠干燥，过滤后减压浓缩干。用柱层析(石油醚/乙酸乙酯体系)进行纯化，得到目标化合物B-2-7。
步骤7：化合物B-2-8的合成
将化合物B-2-7(7g,14.63mmol,1eq)和醋酸钾(5.74g,58.52mmol,4eq)溶解在醋酸(135mL)和水(15mL)中，经氮气保护后冰浴下加入二氯化钯(5.71g,32.18mmol,2.2eq)。25℃下反应16小时。反应完毕后，将反应液在45℃真空旋干。粗品用柱层析(石油醚/乙酸乙酯体系)纯化得到产物目标化合物B-2-8。
步骤8：化合物B-2的合成
将化合物B-2-8(2.5g,5.70mmol,1eq)溶解在二氯甲烷(40mL)中，加入三苯基膦(2.24g,8.55mmol,1.5eq)经氮气保护后，搅拌30分钟。降温至0℃，加入N-溴代丁二酰亚胺(1.52g,8.55mmol,1.5eq)，25℃下搅拌2.5小时。反应完毕后，将反应液25℃浓缩干得到粗品。粗品用柱层析(石油醚/乙酸乙酯体系)进行纯化得到目标化合物B-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.85(s,3H),2.01(s, 3H),2.1(s,3H),2.19(s,3H),2.37(s,3H)4.43-4.50(m,2H),4.80-4.83(d,J＝10.4Hz,1H),5.055-5.104(m,1H),5.214-5.249(m,1H),5.553-5.602(m,1H),6.444-6.453(m,1H),7.145-7.165(m,1H),7.209-7.224(m,1H),7.251-7.270(m,1H).
参考例11：片段B-3
Figure PCTCN2019070336-appb-000042
合成路线：
Figure PCTCN2019070336-appb-000043
步骤1：B-3-1的合成
将化合物B-2-7(8.8g,18.39mmol,1eq)溶于1,4-二氧六环(100mL)，加入硫脲(4.20g,55.17mmol,3eq)，置换氮气3次，25℃下加入三氟甲磺酸三甲基硅酯(14.31g,64.37mmol,3.5eq)，升温至60℃反应2小时,降温至25℃，依次加入碘甲烷(13.30g,93.70mmol,5.09eq)，二异丙基乙胺(19.02g,147.13mmol,8eq)，25℃下反应14小时。反应结束后反应液加水(80Ml)稀释，用乙酸乙酯(80mL*3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压旋干得到粗产物。粗产物通过柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物B-3-1，产物经LCMS确证。
步骤2：B-3-2的合成
向反应瓶中加入B-3-1(2g,4.29mmol,1eq)，巴比妥酸(1.10g,8.57mmol,2eq)，乙醇(20mL)，置换氮气3次后，加入四三苯基膦钯(495.37mg,428.68μmol,0.1eq)，在氮气环境下70℃反应16小时。反应结束后，反应液加水(20mL)稀释，乙酸乙酯(20mL*3)萃取，合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物经柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物B-3-2，产物通过LCMS确证。
步骤3：B-3的合成
向反应瓶中加入B-3-2(1.5g,3.52mmol,1eq)，三苯基膦(1.38g,5.28mmol,1.5eq)，二氯甲烷(20mL)，置换氮气3次，在25℃搅拌0.5小时，随后在0℃下加入N-溴代丁二酰亚胺(938.98mg,5.28mmol,1.5 eq)，在25℃下反应1.5小时。反应结束后，反应液加水(20mL)稀释，乙酸乙酯(20mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物用柱层析(石油醚/乙酸乙酯体系)分离纯化得到目标化合物B-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.25(d,J＝6.4Hz,2H),7.18(d,J＝8.4Hz,1H),5.38(t,J＝9.6Hz,1H),5.25(t,J＝9.6Hz,1H),5.13(t,J＝9.6Hz,1H),4.56(d,J＝9.6Hz,1H),4.53(q,J＝10.4Hz,2H),4.43(d,J＝9.6Hz,1H),2.40(s,3H),2.21(s,3H),2.11(s,3H),2.02(s,3H),1.84(s,3H).
参照参考例9中步骤1～8的合成方法，合成下表中各片段B-4。参照参考例10中步骤1～8的合成方法，合成下表中各片段B-5。表中的结构同时代表其可能的异构体。
Figure PCTCN2019070336-appb-000044
参照参考例11中步骤1～3的合成方法，合成下表中各片段B-6。表中的结构同时代表其可能的异构体。
Figure PCTCN2019070336-appb-000045
Figure PCTCN2019070336-appb-000046
实施例1：WXD001
Figure PCTCN2019070336-appb-000047
合成路线：
Figure PCTCN2019070336-appb-000048
步骤1：化合物WXD001-1的合成
向化合物B-1(1g,1.92mmol,1eq)中加入A-1(797.78mg,2.49mmol,1mL,1.3eq)、碳酸钠(2M,1.92mL,2eq)和甲苯(20mL)、乙醇(5mL)、水(5mL)，抽换氮气后加入四三苯基膦钯(221.48mg,191.67μmol,0.1eq)，50℃反应16小时，反应液变黑。反应完毕后，反应液在45℃用先水泵减压浓缩除去乙醇，然后油泵浓缩除去甲苯和水得粗品。粗品用柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物WXD001-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.37(d,J＝8.2Hz,1H),7.30(d,J＝8.2Hz,2H),7.20(dd,J＝2.1,8.3Hz,1H),7.16-7.07(m,3H),5.89(dd,J＝2.1,3.4Hz,1H),5.84(d,J＝8.2Hz,1H),5.38-5.29(m,1H),5.25(dd,J＝8.3,9.6Hz,1H),5.09(t,J＝9.6Hz,1H),4.47(d,J＝9.7Hz,1H),4.12-4.00(m,2H),2.76 -2.65(m,4H),2.21-2.14(m,2H),2.13-2.08(m,3H),2.07-2.05(m,3H),2.03-2.00(m,3H),1.74-1.69(m,3H).
步骤2：化合物WXD001-2的合成
向反应瓶中加入化合物WXD001-1(1g,1.57mmol,1eq)、硫脲(239.73mg,3.15mmol,2eq)和二氧六环(12mL)，抽换氮气后加入三氟甲磺酸三甲基硅酯(874.97mg,3.94mmol,711.35uL,2.5eq)，缓慢升温至80℃反应2小时，冷却至25℃依次加入二异丙基乙胺(1.02g,7.87mmol,1.37mL,5eq)和碘甲烷(670.52mg,4.72mmol,294.09uL,3eq)，25℃混合液反应14小时。反应完毕后反应液用水(5mL)稀释，二氯甲烷(2mL x3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用柱层析(石油醚/乙酸乙酯体系)纯化得到目标化合物WXD001-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.37(d,J＝8.2Hz,1H),7.30(d,J＝8.2Hz,2H),7.19(dd,J＝2.0,8.3Hz,1H),7.14-7.08(m,3H),5.89(br s,1H),5.31(s,1H),5.19(s,1H),5.04(s,1H),4.50(d,J＝9.9Hz,1H),4.38(d,J＝9.9Hz,1H),4.08(d,J＝17.0Hz,2H),2.69(m,J＝6.0,8.1Hz,4H),2.24-2.16(m,2H),2.15(s,3H),2.09(s,3H),2.00(s,3H),1.71(s,3H).
步骤3：化合物WXD001的合成
向反应瓶中加入化合物WXD001-2(760mg,1.22mmol,1eq)、甲醇(6mL)和四氢呋喃(3mL)，然后加入一水合氢氧化锂(1.02g,24.39mmol,20eq)和水(6mL)，25℃下混合液反应16小时。反应完毕后，反应液用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，有机相用饱和食盐水(30mL)洗涤，分液，有机相用无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。用制备高效液相(乙腈/水-氨水体系)纯化得到目标化合物WXD001,SFC显示对映体过量比例为100％。 1H NMR(400MHz,METHANOL-d 4)δ＝7.37(d,J＝8.2Hz,1H),7.34-7.30(m,2H),7.28-7.23(m,2H),7.16(d,J＝8.4Hz,2H),6.00-5.84(m,1H),4.38(d,J＝9.5Hz,1H),4.14(d,J＝9.5Hz,1H),4.11-4.04(d,2H),3.48-3.42(t,1H),3.39-3.32(m,2H),2.72-2.63(m,4H),2.23-2.12(m,2H),2.12(s,3H).
实施例2：WXD002
Figure PCTCN2019070336-appb-000049
合成路线
步骤1：WXD002-1的合成
向反应瓶中加入B-3(40mg,81.74μmol,1eq)，A-3(41.96mg,122.61μmol,1.5eq)，碳酸钠(17.33mg,163.47μmol,2eq)，甲苯(3mL)，乙醇(0.3mL)，水(0.3mL)，，置换氮气3次，加入四三苯基膦钯(9.45mg,8.17μmol,0.1eq)。在氮气环境下50℃反应5小时。反应结束后，反应液加水(5mL)稀释，乙酸乙酯(5mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物经制备TLC(石油醚/乙酸乙酯体系)纯化得到目标化合物WXD002-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.30(d,J＝8.0Hz,2H),7.17-7.12(m,2H),7.03-6.99(m,3H),5.96(t,J＝3.6Hz,1H),5.35(t,J＝9.2Hz,1H),5.23(t,J＝9.6Hz,1H),5.14(t,J＝9.6Hz,1H),4.53(d,J＝10.0Hz,1H),4.39(d,J＝10.0Hz,1H),4.02(s,4H),3.94(d,J＝6.8Hz,2H),2.66-2.62(m,2H),2.46-2.45(m,2H),2.02(s,3H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.93(t,J＝6.4Hz,2H),1.74(s,3H).
步骤2；WXD002的合成
向反应瓶中加入化合物WXD002-1(42mg,67.23μmol,1eq)，甲醇(1mL)，四氢呋喃(0.5mL)，水(1mL)，一水合氢氧化锂(56.42mg,1.34mmol,20eq)，25℃下反应1小时。反应结束后，反应液加水(5mL)稀释，乙酸乙酯(5mL*4)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液旋干得到粗产物。粗产物经过机分(乙腈/水-氨水体系)纯化得到目标化合物WXD002。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.30(d,J＝8.4,2H),7.18-7.13(m,3H),7.09(d,J＝8.0Hz,2H),5.95(t,J＝3.6Hz,1H),4.40(d,J＝9.6Hz,1H),4.14(d,J＝9.2Hz,1H),3.99-3.97(m,6H),3.48-3.35(m,3H),2.62-2.58(m,2H),2.41(s,2H),2.21(s,3H),2.13(s,3H),1.89(t,J＝6.4Hz,2H).
参照实施例1中步骤1～3的合成方法，合成下表1中各实施例3-9。表1中的结构同时代表其可能的异构体。
表1
Figure PCTCN2019070336-appb-000050
Figure PCTCN2019070336-appb-000051
参照实施例2中步骤1～2的合成方法，合成下表2中各实施例10。表2中的结构同时代表其可能的异构体。
表2
Figure PCTCN2019070336-appb-000052
Figure PCTCN2019070336-appb-000053
各实施例的氢谱和质谱数据如表3所示。
表3
Figure PCTCN2019070336-appb-000054
Figure PCTCN2019070336-appb-000055
实验例一、体外细胞活性测试：
实验步骤和方法：
生物学活性实验1：SGLT1葡萄糖转运试验
1.实验目的：
通过测定进入高表达Human-SGLT1细胞内的带[ 14C]标记葡萄糖的量，检测化合物对SGLT1转运体转运葡萄糖活性的影响。
2.实验方法
2.1.细胞准备
实验所用的稳定表达Human-SGLT1的细胞由上海药明康德构建。将SGLT1细胞铺于Cytostar-T(PerkinElmer)96孔细胞培养板中并于5％CO 2，37℃的环境下培养过夜。
2.2.SGLT1葡萄糖转运试验
1)实验缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES),1.2mM氯化镁(MgCl 2),4.7mM氯化钾(KCl),2.2mM氯化钙(CaCl 2)and 120mM氯化钠(NaCl).
2)将化合物用100％二甲基亚砜(DMSO)以1mM为起始浓度，做8个点5倍连续梯度稀释。
3)用实验缓冲液配制3μM[ 14C]标记甲基α-D-吡喃葡萄糖苷(Methyl a-D-glucopyranosid)。
4)用49uL实验缓冲液、1μL梯度稀释的化合物和50μL 3μM[ 14C]同位素标记的糖溶液，在37℃作用于细胞2小时。
5)用同位素检测仪(Micro beta Reader)读数。
6)数据通过GraphPad Prism 5.0软件的计算公式:log(inhibitor)vs.response--Variable slope得到受试化合物的IC 50值。
生物学活性实验2：SGLT2葡萄糖转运试验
1.实验目的：
通过测定进入高表达Human-SGLT2细胞内的带[ 14C]标记葡萄糖的量，检测化合物对SGLT2转运体转运葡萄糖活性的影响。
2.实验方法
2.1.细胞准备
实验所用的稳定表达Human-SGLT2的细胞由上海药明康德构建。将SGLT2细胞铺于96孔细胞培养板(Greiner)中并于5％CO 2，37℃的环境下培养过夜。
2.2.SGLT2葡萄糖转运试验
1)实验缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES)，1.2mM氯化镁(MgCl 2)，4.7mM氯化钾(KCl)，2.2mM氯化钙(CaCl 2)and 120mM氯化钠(NaCl)。
2)终止缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES)，1.2mM氯化镁(MgCl 2)，4.7mM氯化钾(KCl)，2.2mM氯化钙(CaCl 2)120mM氯化钠(NaCl)和1μM LX4211。
3)将化合物用100％二甲基亚砜(DMSO)以10uM为起始浓度，做8个点5倍连续梯度稀释。
4)用实验缓冲液配制6μM[ 14C]标记甲基α-D-吡喃葡萄糖苷(Methyl a-D-glucopyranosid)。
5)用49uL实验缓冲液、1μL梯度稀释的化合物和50μL 6μM[ 14C]同位素标记的糖溶液，在37℃作用于细胞2小时。
6)吸出孔内液体，用终止缓冲液润洗细胞3遍。
7)用50uL10％的氢氧化钠溶液裂解细胞，将细胞裂解液吸到闪烁管内，再加入2mL闪烁液。
8)用同位素检测仪(Tricarb)读数。
9)数据通过GraphPad Prism 5.0软件的计算公式:log(inhibitor)vs.response--Variable slope得到受试化合物的IC 50值。
实验结果见表4：
表4体外细胞活性测试结果
Figure PCTCN2019070336-appb-000056
结论：本发明化合物表现出较优的对Human-SGLT1和Human-SGLT2的体外抑制活性。
实验例二、动物体内药代动力学研究：
大鼠体内药代动力学研究
实验目的：以雄性SD大鼠为受试动物，单次给药后测定化合物血药浓度并评估药代动力学行为。
实验操作：选择健康成年雄性SD大鼠6只，3只为静注组，3只为口服组。待测化合物与适量静注组溶媒(10％N-甲基吡咯烷酮(NMP)/10％聚乙二醇-15羟基硬脂酸酯(solutol)/80％水)混合，涡旋并超声，制备得到0.2mg/mL澄清溶液，微孔滤膜过滤后备用；口服组溶媒为10％N-甲基吡咯烷酮(NMP)/10％聚乙二醇-15羟基硬脂酸酯(solutol)/80％水，待测化合物与溶媒混合后，涡旋并超声，制备得到0.40mg/mL澄清溶液。大鼠1mg/kg静脉给药或2 mg/kg口服给药后，收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果见表5：
表5化合物PK测试结果
Figure PCTCN2019070336-appb-000057
备注；C max为最大浓度；F％为口服生物利用度；Oral DNAUC＝AUC PO/Dose(单位口服暴露量)，AUC PO为口服暴露量，Dose为药物剂量；Vd ss为分布容积；Cl为清除率；T 1/2为半衰期。
比格犬体内药代动力学研究
实验目的：以雄性比格犬(Beagle)犬为受试动物，单次给药后测定化合物血药浓度并评估药代动力学行为。
实验操作：选择雄性Beagle犬6只，3只为静注组，3只为口服组。待测化合物与适量静注组溶媒(20％聚乙二醇-400(PEG400)/10％聚乙二醇-15羟基硬脂酸酯(solutol)/70％水)混合，涡旋并超声，制备得到1mg/mL澄清溶液，微孔滤膜过滤后备用；口服组溶媒为20％聚乙二醇-400(PEG400)/10％聚乙二醇-15羟基硬脂酸酯(solutol)/70％水，待测化合物与溶媒混合后，涡旋并超声，制备得到1mg/mL澄清溶液。犬1mg/kg静脉给药或2mg/kg口服给药后，收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果见表6：
表6化合物PK测试结果
Figure PCTCN2019070336-appb-000058
备注；C max为最大浓度；F％为口服生物利用度；Oral DNAUC＝AUC PO/Dose(单位口服暴露量)，AUC PO为口服暴露量，Dose为药物剂量；Vd ss为分布容积；Cl为清除率；T 1/2为半衰期。
结论：本发明化合物具有较好的口服暴露量和生物利用度。
实验例三、大鼠口服糖尿受量(OGTT)体内药效研究：
第一次大鼠口服糖耐受量(OGTT)体内药效研究：
实验概要:
1.动物:
Figure PCTCN2019070336-appb-000059
2.实验分组:
Figure PCTCN2019070336-appb-000060
实验流程:
1.动物适应及准备:
实验动物抵达设施后需在动物房适应环境1周。
2.禁食与给药
动物在代谢笼中禁食18h，按照上表给予药物或溶剂(2ml/kg)，随后立即给予50％葡萄糖溶液(2g/kg,4ml/kg)。
3.尿糖与血糖测试
动物给糖后2h，恢复进食，收集0min，15min，30min，45min，60min,120min时间点血和0-24h时间段尿分别用于血糖、尿糖(mg/200g)和尿体积测试。
4.数据分析:
所有数值将表示为平均值。统计学分析使用Graphpad Prism 6单因素方差分析Tukey’s多重比较检验来评估。小于0.05的p值被认为具有统计学显着性。
实验结果见表7：
表7大鼠糖耐受量实验结果
Figure PCTCN2019070336-appb-000061
Figure PCTCN2019070336-appb-000062
注：*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
第二次大鼠口服糖耐受量(OGTT)体内药效研究：
实验概要:
1.动物:
Figure PCTCN2019070336-appb-000063
2.实验分组:
Figure PCTCN2019070336-appb-000064
实验流程:
1.动物适应及准备:
实验动物抵达设施后需在动物房适应环境1周。
2.禁食与给药
动物在代谢笼中禁食18h，按照上表给予药物或溶剂(2ml/kg)，随后立即给予50％葡萄糖溶液(2g/kg,4ml/kg)。
3.尿糖与血糖测试
动物给糖后2h，恢复进食，收集0min，15min，30min，45min，60min,120min时间点血和0-24h时间段尿分别用于血糖、尿糖(mg/200g)和尿体积测试。
4.数据分析:
所有数值将表示为平均值。统计学分析使用Graphpad Prism 6单因素方差分析Tukey’s多重比较检验来评估。小于0.05的p值被认为具有统计学显着性。
实验结果见表8：
表8大鼠糖耐受量实验结果
Figure PCTCN2019070336-appb-000065
Figure PCTCN2019070336-appb-000066
注：*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可显著降低动物2小时内血糖AUC水平；均可增加动物24小时尿糖排泄水平。与阳性化合物相比，相同降糖效果下，本发明化合物尿糖水平低，有助于减少尿路感染的副作用发生。
实验例四糖尿病db/db小鼠体内药效研究：
实验概要:
1.动物信息:
种属 db/db小鼠
级别 SPF动物
订购周龄 5周龄
实验开始周龄 6周龄
体重范围 ～25g
性别 雄性
供应商 南京大学南京模式动物研究所
供应商地址 中国江苏南京
2.动物饲养
动物到达设施后，饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在40～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由电子定时开灯系统来控制，每天开灯12小时关灯12小时(上午7：00开，下午19：00关)。小鼠单笼饲养，实验过程中动物自由采食(大小鼠繁殖饲料17053113，北京科澳协力饲料有限公司)和饮水。
3.实验分组:
Figure PCTCN2019070336-appb-000067
实验流程:
1.给药
实验期间，动物按组别相应的给予溶剂或供试品，给药时间为：16:00，给药周期为8周。
第1周到第4周，给药剂量为5mg/kg；第5周到第8周，给药剂量为10mg/kg。
2.血糖水平
每周检测一次随机和空腹血糖水平。
随机血糖测定时间为早上10：00。
空腹血糖检测：小鼠从早上10：00禁食，16：00测完第一次血糖后给药，给药两小时后再次检测血糖。随后恢复喂食。
3.口服糖耐量(OGTT)实验
于实验末期(给药最后前3天)，动物禁食6小时后，单次给予葡萄糖水溶液2g/kg，并将给糖时间记为0点，在给糖前0min，给糖后15，30，60，90，120min分别对动物进行血糖检测，根据时间对血糖数据绘制糖耐量曲线，计算曲线下面积(AUC)。给药时间为：16:00。
4.生化检测
实验第4周和第8周结束后，动物禁食6h，采血测糖化血红蛋白。
5.体重，耗食量
实验期间，每天一次监测动物的体重，每周监测两次耗食量。
6.数据的处理与分析
所有的数据将被录入到Excel文档中，并以mean±S.E.M的方式表示，多组间差异采用graphpad Prism 6软件比较采用单因素方差分析(One-way analysis of variance(ANOVA)，P值小于0.05时被认为有显著性差异。
第1周至第8周随机血糖实验结果见表9：
表9随机血糖实验结果
组别 溶剂对照组 WXD003 WXD010
第1周 27.4±2.26 14.3±2.28*** 16.7±1.00**
第2周 21.8±2.09 15.7±0.88 13.5±2.46*
第3周 25.6±2.65 13.6±1.40*** 14.1±0.97***
第4周 27.4±3.33 13.3±0.81**** 15.4±1.34***
第5周 26.9±3.67 14.1±1.28** 13.2±1.09**
第6周 28.8±1.84 10.1±1.26**** 10.6±1.48****
第7周 27.2±2.63 12.5±1.23**** 9.8±0.82****
第8周 27.6±2.96 14.4±1.77*** 9.2±0.68****
注：*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可降低动物随机血糖水平；增加剂量，本发明化合物能进一步降低动物随机血糖水平。
第1周至第8周空腹血糖实验结果见表10：
表10空腹血糖实验结果
组别 溶剂对照组 WXD003 WXD010
第1周 21.8±3.30 14.8±2.34 14.7±2.50
第2周 26.8±3.26 19.9±1.32 14.4±1.47***
第3周 28.7±3.00 15.8±1.48** 15.8±1.40**
第4周 28.9±3.35 14.3±1.29*** 14.9±1.24***
第5周 25.7±2.82 17.4±1.72* 15.9±0.79*
第6周 28.5±3.15 10.9±1.42**** 11.0±1.67****
第7周 30.0±2.58 11.7±1.30**** 9.6±0.91****
第8周 31.4±1.86 13.0±1.36**** 8.1±0.51****
注：*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可显著降低动物空腹血糖水平；增加剂量后，本发明化合物均能进一步降低动物空腹血糖水平。
第8周口服糖耐量(OGTT)实验结果见表11：
表11第8周口服糖耐量(OGTT)实验结果
Figure PCTCN2019070336-appb-000068
*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可显著降低动物2小时内血糖AUC水平。
第4周和第8周糖化血红蛋白(HbA1c)实验结果见表12：
表12第4周和第8周糖化血红蛋白(HbA1c)实验结果
Figure PCTCN2019070336-appb-000069
*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可显著降低动物糖化血红蛋白(HbA1c)水平；增加剂量,本发明化合物能进一步降低动物糖化血红蛋白(HbA1c)水平。
体重与耗食量结果见图1和图2，得出：给药8周后，相比溶媒对照组，给药组动物体重和耗食量变化水平无明显差异，显示动物对本发明化合物耐受性良好。

Claims (13)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019070336-appb-100001
    其中，
    m为1或2；
    n为0、1或2；
    D为-O-或-C(R 1)(R 2)-；
    环A选自苯基和5～6元杂芳基；
    R 1选自H、F、Cl、Br、I、OH和NH 2；
    R 2选自H、F、Cl、Br和I；
    或者，R 1和R 2连接形成一个5～6元杂环烷基；
    R 3选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
    R 4选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R选自F、Cl、Br、I、OH和NH 2；
    所述5～6元杂芳基和5～6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-O-CH 3。
  3. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 4选自CH 3和Et。
  4. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，环A选自苯基和噻吩基。
  5. 根据权利要求4所述的化合物、其异构体或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2019070336-appb-100002
    Figure PCTCN2019070336-appb-100003
  6. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070336-appb-100004
    选自
    Figure PCTCN2019070336-appb-100005
  7. 根据权利要求6所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070336-appb-100006
    选自
    Figure PCTCN2019070336-appb-100007
  8. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070336-appb-100008
    选自
    Figure PCTCN2019070336-appb-100009
  9. 根据权利要求1～3任意一项所述的化合物、其异构体或其药学上可接受的盐，选自
    Figure PCTCN2019070336-appb-100010
    其中，
    R 1和R 2如权利要求1所定义；
    R 3如权利要求1～2所定义；
    R 4如权利要求1或3所定义。
  10. 下述化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019070336-appb-100011
  11. 一种药物组合物，包括治疗有效量的作为活性成分的根据权利要求1～10任意一项所述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
  12. 根据权利要求1～10任意一项所述化合物或其药学上可接受的盐或根据权利要求11所述的药物组合物在制备治疗SGLT1/SGLT2相关疾病的药物中的应用。
  13. 根据权利要求12所述的应用，其特征在于，所述药物是用于治疗糖尿病的药物。
PCT/CN2019/070336 2018-01-05 2019-01-04 一种SGLTs抑制剂及其应用 Ceased WO2019134667A1 (zh)

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WO2020200153A1 (zh) * 2019-03-29 2020-10-08 南京明德新药研发有限公司 作为sglt1抑制剂的葡糖苷类衍生物及其应用
JP2022533856A (ja) * 2019-07-05 2022-07-26 山東丹紅制薬有限公司 Ｓｇｌｔ阻害剤の結晶形及びその使用
WO2021004388A1 (zh) * 2019-07-05 2021-01-14 山东丹红制药有限公司 一种SGLTs抑制剂的晶型及其应用
CN113993865B (zh) * 2019-07-05 2023-09-22 山东丹红制药有限公司 一种SGLTs抑制剂的晶型及其应用
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CN114026079A (zh) * 2019-07-26 2022-02-08 南京明德新药研发有限公司 一种sglt2/dpp4抑制剂及其应用
JP2022533475A (ja) * 2019-07-26 2022-07-22 メッドシャイン ディスカバリー インコーポレイテッド Ｓｇｌｔ２／ｄｐｐ４阻害剤及びその使用
CN114026079B (zh) * 2019-07-26 2022-10-18 南京明德新药研发有限公司 一种sglt2/dpp4抑制剂及其应用
KR102471055B1 (ko) 2019-07-26 2022-11-28 메드샤인 디스커버리 아이엔씨. Sglt2/dpp4 억제제 및 이의 용도
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WO2021018044A1 (zh) * 2019-07-26 2021-02-04 南京明德新药研发有限公司 一种sglt2/dpp4抑制剂及其应用
US12421269B2 (en) 2019-07-26 2025-09-23 Cgenetech (Suzhou, China) Co., Ltd. SGLT2/DPP4 inhibitor and application thereof
WO2022063305A1 (zh) * 2020-09-27 2022-03-31 南京明德新药研发有限公司 葡糖苷类化合物的晶型及其应用
CN116322675A (zh) * 2020-09-27 2023-06-23 南京明德新药研发有限公司 葡糖苷类化合物的晶型及其应用
WO2022160737A1 (zh) * 2021-01-26 2022-08-04 东宝紫星(杭州)生物医药有限公司 四氢吡喃环类化合物的晶型及其制备方法

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FI3712147T3 (fi) 2023-04-04
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