WO2020200153A1 - 作为sglt1抑制剂的葡糖苷类衍生物及其应用 - Google Patents

作为sglt1抑制剂的葡糖苷类衍生物及其应用 Download PDF

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WO2020200153A1
WO2020200153A1 PCT/CN2020/082007 CN2020082007W WO2020200153A1 WO 2020200153 A1 WO2020200153 A1 WO 2020200153A1 CN 2020082007 W CN2020082007 W CN 2020082007W WO 2020200153 A1 WO2020200153 A1 WO 2020200153A1
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compound
pharmaceutically acceptable
reaction
hours
added
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PCT/CN2020/082007
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English (en)
French (fr)
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李翼
于涛
毛庆华
吴成德
陈曙辉
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南京明德新药研发有限公司
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Priority to EP20784747.6A priority Critical patent/EP3950684B1/en
Priority to JP2021558004A priority patent/JP7210771B2/ja
Priority to CN202080025867.6A priority patent/CN113825750B/zh
Priority to US17/599,308 priority patent/US20220153772A1/en
Publication of WO2020200153A1 publication Critical patent/WO2020200153A1/zh

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    • 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
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to a series of glucoside derivatives as SGLT1 inhibitors and their application in the preparation of drugs for SGLT1 inhibitor-related diseases. Specifically, it relates to derivative compounds represented by formula (II) and formula (I), tautomers thereof, or pharmaceutically acceptable compositions thereof.
  • SGLTs Sodium-glucose cotransporters
  • the members mainly include SGLT1 and SGLT2. Their function is to mediate intestinal and Transmembrane transport of glucose in the kidney.
  • SGLT1 is mainly distributed in the intestinal mucosal cells of the small intestine, and is also slightly expressed in the myocardium and kidney. Its function is mainly to regulate the intestinal absorption of glucose.
  • SGLT2 is expressed at a high level in the kidney and is mainly responsible for the regulation of the process of glucose reuptake in the kidney.
  • the glucose in the urine can actively attach to the renal tubular epithelial cells when filtered by the glomerulus and be transported into the cell by the SGLT2 protein to be reused.
  • SGLTs Because the glucose transport process mediated by SGLTs does not involve sugar metabolism, thereby avoiding the occurrence of adverse reactions of hypoglycemia and reducing the risk of cardiovascular diseases, SGLTs have gradually become one of the ideal targets for the treatment of diabetes.
  • some SGLTs inhibitors especially highly selective SGLT2 inhibitors have been developed one after another. By inhibiting the activity of SGLT2, they specifically inhibit the reabsorption of glucose by the kidneys, thereby increasing the excretion of glucose in the urine and normalizing the blood sugar of diabetic patients. Since 2012, a number of SGLT2 inhibitors have been approved for marketing, becoming effective drugs for the treatment of diabetes.
  • SGLT1 In addition to inhibiting SGLT2, studies in recent years have found that proper inhibition of SGLT1 can prevent the uptake of glucose in the intestines without causing obvious diarrhea or other gastrointestinal reactions. At the same time, inhibiting SGLT1 can reduce the intestinal absorption of glucose into the blood, thereby increasing the concentration of glucose in the distal intestine, leading to increased levels of GLP-1 and PYY after meals, thereby exerting a better hypoglycemic effect and reducing the occurrence of urinary tract The risk of infection and kidney damage. In addition, by controlling the intestinal absorption of glucose, it can also reduce the total energy intake in food, and superimpose the effect of GLP-1 to reduce weight, which can achieve the dual purpose of reducing weight. Therefore, the development of SGLT1 inhibitors has become a new direction for the treatment of diabetes and obesity in recent years.
  • SGLT1 inhibitors have a good development prospect as a new type of diabetes and obesity treatment drugs. But so far, research on SGLT1 inhibitors is still in the clinical stage, and no drugs have been approved for marketing.
  • the SGLT1 inhibitor LX2761 which is developed by Lexicon, which only acts on the gastrointestinal tract, is conducting a phase I clinical study for the treatment of diabetes (WO2014081660).
  • the present invention provides a compound represented by formula (II), its isomers or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl and C 1-6 alkane group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkylamino
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl optionally substituted with 1, 2 or 3 R b ;
  • L is selected from a single bond, -O-, -S-, -C(R c ) 2 -and -N(R d )-;
  • n 0, 1 and 2;
  • n is selected from 1, 2 and 3;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R d is selected from H and CH 3 .
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and The CH 3 , CH 2 CH 3 and Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and Other variables are as defined in the present invention.
  • the upper R 2 is selected from F, Cl, Br, I, OH, NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and are optionally substituted with 1, 2 or 3 R b CH 3 , other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 and CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned L is selected from a single bond, -O- and -S-, and other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkane group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from F, Cl, Br, I, OH and NH 2 ;
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl optionally substituted with 1, 2 or 3 R b ;
  • L is selected from a single bond, -O-, -S-, -C(R c ) 2 -and -N(R d )-;
  • n 0, 1 and 2;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R d is selected from H and CH 3 .
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and The CH 3 , CH 2 CH 3 and Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and Other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and are optionally substituted with 1, 2 or 3 R b CH 3 , other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 and CF 3 , Other variables are as defined in the present invention.
  • the above-mentioned L is selected from a single bond, -O- and -S-, and other variables are as defined in the present invention.
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 and L are as defined in the present invention.
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 2 is selected from F, Cl, Br, I, OH, NH 2 , NH(CH 3 ) and N(CH 3 ) 2 ;
  • R 1 , R 3 , R 4 , R 5 and L are as defined in the present invention.
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula, its isomers or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides a pharmaceutical composition, comprising as an active ingredient a therapeutically effective amount of the compound according to the above, its isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the above-mentioned compound, its isomer or its pharmaceutically acceptable salt or the above-mentioned composition is used in the preparation of SGLT1 inhibitor related drugs.
  • the above application is characterized in that the SGLT1 inhibitor-related drug is a drug for diabetes and obesity.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes 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 methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dotted key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 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, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 1-3 alkylamino means those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
  • C n-n+m or C n -C n+m includes any specific case 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 one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , 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.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; 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 (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • 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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; 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 ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; CB
  • the compound of the present invention has significant human-SGLT1 and Human-SGLT2 in vitro inhibitory activities. At the same time, the compound of the present invention has low oral exposure and bioavailability, and has an effect in the gastrointestinal tract, demonstrating what a selective SGLT1 inhibitor should be. Pharmacokinetic properties; the compound of the present invention can significantly reduce the blood glucose AUC level of the animal within 2 hours in the animal oral glucose tolerance test; the compound of the present invention can significantly reduce the animal test of diabetes induced by STZ combined with high-sugar and high-fat diet.
  • the blood sugar and glycosylated hemoglobin after 6 hours of fasting can effectively control the increase of animal weight; in the experiment of obesity induced by high-sugar and high-fat diet, the compound of the present invention can significantly reduce the weight of the animal in a dose-dependent manner, and can reduce the animal Blood glucose after 6 hours of fasting and 1 hour after meals.
  • Figure 1 shows the blood glucose level of animals 4 weeks after administration
  • Figure 2 shows the level of glycosylated hemoglobin in animals 4 weeks after administration
  • Figure 3 shows the animal body weight change level 4 weeks after administration
  • Figure 4 shows the blood glucose level of animals 7 weeks after administration
  • Figure 5 shows the level of glycosylated hemoglobin in animals 7 weeks after administration
  • Figure 6 shows the animal body weight change level 7 weeks after administration
  • Figure 7 shows the level of animal weight change after 3 weeks of administration
  • Figure 8 shows the rate of animal weight change after 3 weeks of administration
  • Figure 9 shows the blood glucose of the animal after fasting for 6 hours after 3 weeks of administration
  • FIG. 10 Animal blood glucose 1 hour after meal 3 weeks after administration.
  • ⁇ means p ⁇ 0.0001 relative to the normal diet vehicle group
  • * means p ⁇ 0.05 relative to the high-sugar and high-fat diet vehicle group
  • ** means p ⁇ 0.01 relative to the high-sugar and high-fat diet vehicle group
  • ** * Indicates p ⁇ 0.001 relative to the high-sugar and high-fat diet vehicle group
  • **** indicates p ⁇ 0.0001 relative to the high-sugar and high-fat diet vehicle group.
  • reaction solution was diluted with 50 mL of water, extracted with ethyl acetate (50 mL*3), the combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and then the organic phase was spin-dried under reduced pressure to obtain a crude product.
  • Triphenylphosphine (7151mg, 27.3mmol, 1.2eq), DIAD (5513mg, 27.3mmol, 1.2eq), THF (40mL) were added to the reaction flask. Then A-1-3 (5104.7 mg, 27.3 mmol, 1.2 eq) and A-1-2 (5 g, 22.7 mmol, 1 eq) dissolved in THF (40 mL) were added and reacted at 25° C. for 16 hours.
  • reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (100 mL*3), the combined organic phases were dried with anhydrous sodium sulfate, filtered, and the organic phases were spin-dried to obtain a crude product.
  • 1 H NMR 400MHz, CDCl 3 ) ⁇ ppm 7.72-7.75 (m, 2H), 6.84-6.90 (m, 2H), 4.94 (s, 1H), 3.43-3.69 (m, 4H), 2.07-2.23 (m, 2H), 1.47 (s, 9H), 1.34 (s, 12H).
  • A-1-4 (1.28 g, 3.29 mmol, 1 eq), EtOAc (10 mL), hydrogen chloride/EtOAc (4M, 9.04 mL, 11 eq) were added to the reaction flask, and the mixture was stirred at 25° C. for 3 hours. After the reaction, the reaction solution was spin-dried to obtain the crude product A-1-5. The crude product A-1-5 was directly used in the next reaction.
  • Lithium aluminum hydride (11g, 289.82mmol, 1.25eq) was dissolved in tetrahydrofuran (200mL) at 0°C, replaced with nitrogen three times, and filled with nitrogen protection.
  • Compound B-1-1 (50 g, 232.51 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL) and slowly added to the reaction solution at 0°C. Bubbles were generated, and the reaction was heated to 25°C for 2 hours. At 0°C, water (11 mL) was slowly added dropwise, then 15% aqueous sodium hydroxide solution (11 mL) was added dropwise, and finally water (33 mL) was added. Filter, and wash the filter residue twice with ethyl acetate. Suspend the filtrate to dryness. The crude compound B-1-2 was obtained.
  • Dissolve compound B-1-5 (17.80g, 51.09mmol, 1eq) in methanol (100mL), lower the temperature to 0°C, and add cerium trichloride heptahydrate (22.84g, 61.31mmol, 5.83mL, 1.2eq) in sequence , Sodium borohydride (3.87g, 102.18mmol, 2eq), heated to 25°C, and reacted for 16 hours. After the reaction was completed, water (30 mL) was added to the reaction solution to quench and spin dry.
  • reaction solution was diluted with water (80mL), extracted with ethyl acetate (80mL*3), combined the organic phases, washed with saturated brine (50mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was obtained by spin-drying under reduced pressure Crude product.
  • the crude product was purified by column chromatography to obtain the target compound B-1-9. The product was confirmed by LCMS with LC-MS (m/z) 489 [M+Na] + .
  • Compound B-4-3 (13g, 38.88mmol, 1eq) was dissolved in methanol (130mL), the temperature was reduced to 0°C, cerium trichloride heptahydrate (9.58g, 38.88mmol, 1eq), sodium borohydride ( 2.94g, 77.76mmol, 2eq), heated to 25°C, and reacted for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution to quench and spin dry.
  • Compound B-4-5 (9.2g, 31.05mmol, 1eq) was dissolved in 1,4-dioxane (100mL), acetic anhydride (25.36g, 248.38mmol, 23.26mL, 8eq), pyridine (24.56 g, 310.48mmol, 25.06mL, 10eq), 4-dimethylaminopyridine (1.90g, 15.52mmol, 0.5eq), stirred at 80°C for 16 hours.
  • the 1,4-dioxane was removed by concentration under reduced pressure, the reaction solution was diluted with ethyl acetate (100mL), washed with 1M dilute hydrochloric acid (100mL*4), and the organic phase was washed with water (50mL*2) , Then washed with saturated brine (50mL*2), and finally the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the crude product was purified by column chromatography to obtain compound B-4-6, the product was confirmed by LCMS, LC-MS (m/z) 487 [M+Na] + .
  • reaction solution was diluted with water (60mL), extracted with ethyl acetate (60mL*3), and the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain Crude product.
  • the crude product was purified by column chromatography to obtain the target compound B-4-7. The product was confirmed by LCMS with LC-MS (m/z) 475 [M+Na] + .
  • the magnesium alkoxide solution was slowly added to the alkyl lithium solution, and the reaction system was stirred at -70° C. for 0.5 hours, and slowly heated to room temperature (20° C.) and stirred for 1 hour.
  • Saturated ammonium chloride 200mL was added dropwise to the reaction solution to quench the reaction, concentrated to remove the organic solvent, added citric acid to adjust the solution until it was clear, extracted with ethyl acetate (200mL*3), combined the organic phases, and used saturated salt for the organic phase Wash with water (200 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product.
  • the crude product was separated and purified by column chromatography to obtain the target compound B-5-5. The product was confirmed by LCMS, LC-MS (m/z) 405 [M+Na] + .
  • Compound B-5-5 (10.60g, 27.69mmol, 1eq) was dissolved in anhydrous methanol (200mL), the temperature was reduced to 0°C, and cerium trichloride heptahydrate (12.38g, 33.23mmol, 1.20eq), boron Sodium hydride (2.1g, 55.38mmol, 2eq) was heated to 25°C and reacted for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution to quench and spin dry.
  • the compound is compound B-5-7 (10.00g, 29.00mmol, 1eq), triethylamine (16.72g, 165.24mmol, 23.0mL, 5.70eq), acetic anhydride (21.80g, 213.54mmol, 20mL, 7.36eq) , 4-Dimethylaminopyridine (40mg, 327.42 ⁇ mol, 1.13e-2eq) and acetonitrile (100mL) were added to the reaction flask and stirred at 25°C for 2 hours.
  • the reaction solution was cooled to room temperature, methyl iodide (3.06g, 21.56mmol, 1.34mL, 3.07eq) and diisopropylethylamine (4.54g, 35.09mmol, 6.11mL, 5eq) were added, and the reaction system was stirred at 25°C for 15 hour.
  • Water (50mL) was added to the reaction solution, extracted with ethyl acetate (50mL*2), the organic phases were combined, the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was separated and purified by column chromatography to obtain the target compound B-5-9.
  • the reaction solution was filtered, the filtrate was concentrated to obtain a crude product, water (500mL) was added, extracted with ethyl acetate (500mL*3), the organic phases were combined, the organic phases were washed with saturated brine (500mL), dried with anhydrous sodium sulfate, filtered, The filtrate was concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain the target compound B-5-10.
  • the reaction solution was added dropwise to cuprous chloride (10.17g, 102.69mmol, 2.46mL, 1.05eq), concentrated hydrochloric acid (38.55g, 391.21mmol, 37.79mL, 37% purity, 4eq) and water (250mL) at 0°C In the solution. After dripping, the reaction solution was reacted at 70°C for 3 hours. The reaction solution was concentrated to remove acetonitrile, and the residue was cooled to room temperature, filtered, and the filter cake was washed with water (100 mL) three times.
  • Compound B-6-6 (7.40g, 17.40mmol, 1eq) was dissolved in anhydrous methanol (100mL), the temperature was reduced to 0°C, and cerium trichloride heptahydrate (7.77g, 20.88mmol, 1.20eq), boron Sodium hydride (1.32g, 34.8mmol, 2eq) was heated to 25°C and reacted for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution to quench the suspension to dryness.
  • reaction solution was diluted with 20 mL of water, extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a crude product.
  • the crude product is separated and purified by column chromatography to obtain WXD001-1.
  • A-2 (319.44mg, 516.49 ⁇ mol, 1.3eq)
  • B-2 200mg, 397.30 ⁇ mol, 1eq
  • Na 2 CO 3 65.95mg, 794.59 ⁇ mol, 2eq
  • Pd(PPh 3 ) 4 91.82 mg, 79.46 ⁇ mol, 0.2eq
  • reaction solution was spin-dried, and then diluted with water (30 mL), extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine (50 mL), dried with anhydrous sodium sulfate, filtered and spin-dried. Purification is carried out by preparative chromatography plate. Get WXD003-1.
  • WXD003-1 (320mg, 349.72 ⁇ mol, 1eq) was dissolved in MeOH (2mL) THF (1mL) H 2 O (2mL) mixed solvent, and LiOH.H 2 O (293.48mg, 6.99mmol, 20eq) was added at 25°C Stir for 1 hour. After the reaction, ethyl acetate (30 mL) was added to the reaction solution to separate the solution, the organic phase was collected, dried with anhydrous sodium sulfate, filtered and spin-dried. The crude product WXD003-2 was directly used in the next reaction.
  • WXD003-2 (270mg, 342.24 ⁇ mol, 1eq) was dissolved in ethyl acetate (5mL), HCl/EtOAc (4M, 5mL, 58.44eq) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction, the reaction solution was spin-dried directly. Purification by preparative high performance liquid chromatography (column: Xtimate C18 150 ⁇ 25mm ⁇ 5 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 7min) to obtain the product WXD003.
  • the cells stably expressing Human-SGLT1 used in the experiment were constructed by Shanghai WuXi AppTec.
  • the SGLT1 cells were plated on a Cytostar-T (PerkinElmer) 96-well cell culture plate and cultured overnight at 5% CO 2 at 37°C.
  • Experimental buffer 10mM HEPES buffer (Sigma), 1.2mM MgCl 2 , 4.7mM KCl, 2.2mM CaCl 2 and 120mM NaCl.
  • the cells stably expressing Human-SGLT2 used in the experiment were constructed by Shanghai WuXi AppTec.
  • the SGLT2 cells were plated on a 96-well cell culture plate (Greiner) and cultured overnight at 5% CO 2 at 37°C.
  • Stop buffer 10mM HEPES, 1.2mM MgCl 2 , 4.7mM KCl, 2.2mM CaCl 2 , 120mM NaCl and 1 ⁇ M LX4211.
  • Tricarb isotope detector
  • the compound of the present invention exhibits excellent in vitro inhibitory activity on Human-SGLT1 and Human-SGLT2.
  • mice 4 healthy adult male SD rats were selected, 2 were the intravenous injection group, and 2 were the oral group.
  • the compound to be tested is mixed with an appropriate amount of intravenous group solvent (10% NMP/10% solutol/80% water), vortexed and sonicated to prepare a clear solution of 0.5 mg/mL, filtered with a microporous membrane for use; the oral group solvent is 10% NMP/10% solutol/80% water, after mixing the test compound with the solvent, vortex and sonicate to prepare a 1 mg/mL clear solution.
  • whole blood was collected for a certain period of time, and plasma was prepared.
  • the drug concentration was analyzed by LC-MS/MS method, and the drug was calculated by Phoenix WinNonlin software (Pharsight, USA) Generation parameters.
  • NMP N-methylpyrrolidone
  • solutol polyethylene glycol-15 hydroxystearate.
  • C max is the maximum concentration
  • F% is the oral bioavailability
  • DNAUC AUC PO /Dose
  • AUC PO is the oral exposure
  • Dose is the drug dose
  • Vd ss is the volume of distribution
  • Cl is the clearance rate
  • T 1/ 2 is the half-life
  • ND means not detected.
  • the compound of the present invention exhibits low oral exposure and bioavailability, and exhibits the pharmacokinetic properties of SGLT1 selective inhibitors.
  • Group Compound grouping dose Dosing frequency Mode of administration Number of animals per group 1 Vehicle control group - Single dose Gavage 5 2 WXD003 5mg/kg Single dose Gavage 5
  • the administration group can significantly reduce the blood glucose AUC level of the animals within 2 hours.
  • mice After the animals adapt to the environment, divide all the mice into two groups according to their body weight, feed them according to the scheme in Table 8, and inject the vehicle and streptozotocin (STZ) for model building;
  • WXD003 can significantly reduce the blood glucose level of animals after 6 hours of fasting;
  • WXD003 can significantly reduce the glycated hemoglobin level of animals after 6 hours of fasting;
  • WXD003 can effectively control the weight gain of animals.
  • WXD003 can significantly reduce the blood glucose level of animals after 6 hours of fasting. Compared with 4 weeks of administration, after 7 weeks of administration, WXD003 can further reduce the blood glucose level of animals after 6 hours of fasting;
  • WXD003 can significantly reduce the level of glycosylated hemoglobin in animals after 6 hours of fasting;
  • WXD003 can effectively control the weight gain of animals.
  • ⁇ means p ⁇ 0.0001 relative to the normal diet vehicle group
  • * means p ⁇ 0.05 relative to the high-sugar and high-fat diet vehicle group
  • ** means p ⁇ 0.01 relative to the high-sugar and high-fat diet vehicle group
  • ** * Indicates p ⁇ 0.001 relative to the high-sugar and high-fat diet vehicle group
  • **** indicates p ⁇ 0.0001 relative to the high-sugar and high-fat diet vehicle group.
  • the administration group can significantly reduce the blood sugar and glycosylated hemoglobin of the animals after 6 hours of fasting, and can effectively control the weight gain of the animals.
  • mice After the animals adapt to the environment, they are fed high-sugar and high-fat diets (Research Diet, HFHS, D12451) for 20 weeks, and then select mice weighing more than 40 grams to carry out weight loss experiments.
  • high-sugar and high-fat diets Research Diet, HFHS, D12451
  • mice The animals whose body weight meets the standard are first adapted to the vehicle administration, and then all mice are divided into 5 groups according to their body weight to carry out weight loss experiments to test the compound's effect on reducing animal weight.
  • the experimental groups are shown in Table 14:
  • WXD003 can significantly reduce animal weight in a dose-related manner
  • WXD003 can reduce the blood sugar of animals after 6 hours of fasting
  • WXD003 can lower the blood sugar of the animal 1 hour after the meal.
  • the administration group can significantly reduce the body weight of the animals in a dose-dependent manner, and at the same time can reduce the blood glucose of the animals after 6 hours of fasting and 1 hour after meals.

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Abstract

一种作为SGLT1抑制剂的葡糖苷类衍生物，及其在制备SGLT1抑制剂相关疾病的药物中的应用。具体公开了式（II）所示衍生化合物、其互变异构体或其药学上可接受的组合物。

Description

作为SGLT1抑制剂的葡糖苷类衍生物及其应用
相关申请的引用
本申请主张如下优先权：
CN201910251853.5，申请日：2019-03-29；
CN201911104949.5，申请日：2019-11-13；
CN202010105251.1，申请日：2020-02-20。
技术领域
本发明涉及一系列作为SGLT1抑制剂的葡糖苷类衍生物，及其在制备SGLT1抑制剂相关疾病的药物中的应用。具体涉及式(II)和式(I)所示衍生化合物、其互变异构体或其药学上可接受的组合物。
背景技术
肥胖症、糖尿病及其引发的相关代谢紊乱疾病已成为威胁人类健康的重要危险因素。
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，成员主要包括SGLT1和SGLT2两类，其功能是介导肠道和肾脏中葡萄糖的跨膜转运。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，它的功能主要是调节葡萄糖的肠道吸收过程。SGLT2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SGLT2蛋白转运进胞内被重新利用。由于SGLTs介导的葡萄糖转运过程不介入糖的代谢，从而避免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已逐渐成为治疗糖尿病的理想靶点之一。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，使糖尿病患者的血糖正常化。从2012年至今，已有多个SGLT2抑制剂先后被批准上市，成为治疗糖尿病的有效药物。
除了抑制SGLT2，近几年研究发现，适当抑制SGLT1能阻止肠道对葡萄糖的摄取，且不会导致明显的腹泻或者其他胃肠道反应。同时，通过抑制SGLT1能减少经肠道吸收入血的葡萄糖，进而增加肠道远端葡萄糖浓度，导致餐后GLP-1和PYY水平升高，从而发挥较良好的降糖作用，降低发生尿路感染和肾功能损伤等的风险。另外，通过控制肠道对葡萄糖吸收，还能降低食物中总能量的摄入，叠加GLP-1降低体重的作用，可以达到双重降低体重的目的。因此，开发SGLT1抑制剂已成为近年来糖尿病和肥胖症治疗的新方向。
综上所述，SGLT1抑制剂作为新型的糖尿病和肥胖症治疗药物有着良好的开发前景。但迄今为止，关于SGLT1抑制剂的研究仍处于临床阶段，还没有药物批准上市。目前，由Lexicon公司开发的只作用于胃肠道的SGLT1抑制剂LX2761正在针对糖尿病治疗开展临床I期研究(WO2014081660)。
Figure PCTCN2020082007-appb-000001
发明内容
本发明提供了式(II)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020082007-appb-000002
其中，
R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基任选被1、2或3个R a取代；
R 2选自F、Cl、Br、I、OH、NH 2和C 1-3烷氨基；
R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
L选自单键、-O-、-S-、-C(R c) 2-和-N(R d)-；
m选自0、1和2；
n选自1、2和3；
R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2和CH 3；
R d选自H和CH 3。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000003
所述CH 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000004
任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上R 2选自F、Cl、Br、I、OH、NH 2、NH(CH 3)和N(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代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 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自单键、-O-和-S-，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 PCTCN2020082007-appb-000006
选自
Figure PCTCN2020082007-appb-000007
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 PCTCN2020082007-appb-000008
选自
Figure PCTCN2020082007-appb-000009
其他变量如本发明所定义。
本发明提供了式(I)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020082007-appb-000010
其中，
R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基或C 1-6烷氧基任选被1、2或3个R a取代；
R 2选自F、Cl、Br、I、OH和NH 2；
R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
L选自单键、-O-、-S-、-C(R c) 2-和-N(R d)-；
m选自0、1和2；
R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2和CH 3；
R d选自H和CH 3。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000011
所述CH 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000012
任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和
Figure PCTCN2020082007-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代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 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自单键、-O-和-S-，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 PCTCN2020082007-appb-000014
选自
Figure PCTCN2020082007-appb-000015
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 PCTCN2020082007-appb-000016
选自
Figure PCTCN2020082007-appb-000017
其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020082007-appb-000018
其中，
R 1、R 2、R 3、R 4、R 5和L如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020082007-appb-000019
其中，
R 2选自F、Cl、Br、I、OH、NH 2、NH(CH 3)和N(CH 3) 2；
R 1、R 3、R 4、R 5和L如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020082007-appb-000020
其中，
R 1、R 2、R 3、R 4和R 5如本发明所定义。
本发明还提供了下式所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020082007-appb-000021
本发明的一些方案中，上述的化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020082007-appb-000022
Figure PCTCN2020082007-appb-000023
本发明还提供了一种药物组合物，包括作为活性成分的治疗有效量的根据上述的化合物、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。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐或者上述的组合物在制备SGLT1抑制剂相关药物上的应用。
本发明的一些方案中，上述的应用，其特征在于，所述SGLT1抑制剂相关药物是用于糖尿病和肥胖症的药物。
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、有机氨或镁盐或类似的盐。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。
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
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 PCTCN2020082007-appb-000024
和楔形虚线键
Figure PCTCN2020082007-appb-000025
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020082007-appb-000026
和直形虚线键
Figure PCTCN2020082007-appb-000027
表示立体中心的相对构型，用波浪线
Figure PCTCN2020082007-appb-000028
表示楔形实线键
Figure PCTCN2020082007-appb-000029
或楔形虚线键
Figure PCTCN2020082007-appb-000030
或用波浪线
Figure PCTCN2020082007-appb-000031
表示直形实线键
Figure PCTCN2020082007-appb-000032
和直形虚线键
Figure PCTCN2020082007-appb-000033
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“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。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
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 PCTCN2020082007-appb-000034
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 PCTCN2020082007-appb-000035
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 PCTCN2020082007-appb-000036
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，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时， 该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020082007-appb-000037
直形虚线键
Figure PCTCN2020082007-appb-000038
或波浪线
Figure PCTCN2020082007-appb-000039
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2020082007-appb-000040
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2020082007-appb-000041
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2020082007-appb-000042
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2020082007-appb-000043
Figure PCTCN2020082007-appb-000044
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2020082007-appb-000045
仍包括
Figure PCTCN2020082007-appb-000046
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6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，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3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)等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2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元环包括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元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
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通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020082007-appb-000047
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
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；T甲酸代表三氟乙酸；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1-氯吡咯烷-2,5-二酮；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；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd(dba) 2代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；Pd(PPh 3) 4代表四三苯基膦钯；IPA代表异丙醇；DEA代表二乙胺。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020082007-appb-000048
软件命名，市售化合物采用供应商目录名称。
技术效果：
本发明化合物具有显著的Human-SGLT1和Human-SGLT2体外抑制活性，同时，本发明化合物具有低的口服暴露量和生物利用度，在胃肠道发生作用，展现了SGLT1选择性抑制剂应有的药代动力学特性；本发明化合物在动物口服糖耐量实验中，可显著降低动物2小时内血糖AUC水平；本发明化合物在STZ配合高糖高脂饮食诱导的糖尿病动物实验中，可显著降低动物禁食6小时后的血糖和糖化血红蛋白，并能有效控制动物体重的增长；本发明化合物在高糖高脂饮食诱导的肥胖症动物实验中，可剂量依赖地显著降低动物体重，并能降低动物禁食6小时后和餐后1小时的血糖。
附图说明：
图1为给药4周后动物血糖水平；
图2为给药4周后动物糖化血红蛋白水平；
图3为给药4周后动物体重变化水平；
图4为给药7周后动物血糖水平；
图5为给药7周后动物糖化血红蛋白水平；
图6为给药7周后动物体重变化水平；
图7为给药3周后动物体重变化水平；
图8为给药3周后动物体重变化率；
图9为给药3周后动物禁食6小时后血糖；
图10给药3周后动物餐后1小时血糖。
注：^^^^表示相对于正常饮食溶媒组p<0.0001，*表示相对于高糖高脂饮食溶媒组p<0.05，**表示相对于高糖高脂饮食溶媒组p<0.01，***表示相对于高糖高脂饮食溶媒组p<0.001，****表示相对于高糖高脂饮食溶媒组p<0.0001。
具体实施方式
下面通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 PCTCN2020082007-appb-000049
合成路线：
Figure PCTCN2020082007-appb-000050
步骤1：化合物A-1-2的合成。
向反应瓶中依次加入化合物A-1-1(10g,57.80mmol,1eq)，联硼酸频那醇酯(16.15g,63.58mmol,1.1eq)，Pd(dppf)Cl 2(4.23g,5.78mmol,0.1eq)，KOAc(17.02g,173.40mmol,3eq)，二氧六环(120mL)，置换氮气，在100℃下反应2小时。反应结束后反应液加水50mL稀释，用乙酸乙酯(50mL*3)萃取，合并有机相用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤后减压旋干有机相得粗产物。粗产物经柱层析(PE:EA＝50:1)分离纯化。得到A-1-2。 1H NMR(400MHz,CDCl 3)δppm 7.72(d,J＝8.4Hz,2H),6.83(d,J＝8.4Hz,2H),5.40(s,1H),1.34(s,12H)。
步骤2：化合物A-1-4的合成。
向反应瓶中加入三苯基膦(7151mg,27.3mmol,1.2eq)，DIAD(5513mg,27.3mmol,1.2eq)，THF(40mL)。然后加入用THF(40mL)溶解的A-1-3(5104.7mg,27.3mmol,1.2eq)和A-1-2(5g,22.7mmol,1eq)，25℃下反应16小时。反应结束后向反应液中加水100mL稀释，用乙酸乙酯(100mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤后旋干有机相得粗产物。粗产物用柱层析(PE:EA＝19:1-9:1)分离纯化，得到A-1-4。 1H NMR(400MHz,CDCl 3)δppm 7.72-7.75(m,2H),6.84-6.90(m,2H),4.94(s,1H),3.43-3.69(m,4H),2.07-2.23(m,2H),1.47(s,9H),1.34(s,12H)。
步骤3：化合物A-1-5的合成。
向反应瓶中加入A-1-4(1.28g,3.29mmol,1eq)，EtOAc(10mL)，氯化氢/EtOAc(4M,9.04mL,11eq)，25℃下搅拌3小时。反应结束后将反应液旋干得粗产物A-1-5。粗产物A-1-5直接用于下一步反应。
步骤4：化合物A-1的合成。
向反应瓶中加入A-1-5(1.37g,4.74mmol,1eq)，A-1-6(1.58g,4.74mmol,1eq)，HATU(1.80g,4.74mmol,1eq)，THF(15mL)，DIEA(612.29mg,4.74mmol,825.18μL,1eq)，25℃下搅拌2.5小时。反应结束后，向反应液加水20mL稀释，用乙酸乙酯(20mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤旋干得粗产物。粗产物经柱层析(PE:EA＝3:2)分离纯化。得到A-1。 1H NMR(400MHz,CDCl 3)δppm 7.70-7.81(m,2H),7.01-7.13(m,1H),6.81-6.93(m,3H),5.69-5.93(m,1H),4.93-5.06(m,1H),3.48-3.89(m,4H),2.83-3.02(m,2H),2.45-2.61(m,2H),2.21-2.36(m,1H),2.06-2.21(m,1H),1.29-1.41(m,21H)。
参照参考例1中步骤2～4的合成方法，合成片段A-2。
参考例2：片段A-2
Figure PCTCN2020082007-appb-000051
合成路线：
Figure PCTCN2020082007-appb-000052
化合物A-2：
1H NMR(400MHz,CDCl 3)δppm 1.33(s,12H),1.37(d,J＝1.76Hz,9H),1.77-1.95(m,4H),2.50-2.65(m,2H),2.86-3.01(m,2H),3.31-3.44(m,1H),3.56-3.84(m,3H),4.06-4.16(m,1H),4.56-4.70(m,1H),5.66(br d,J＝7.53Hz,1H),6.86-6.93(m,3H),7.04-7.12(m,1H),7.76(d,J＝8.28Hz,2H)。
参考例3：片段A-3
Figure PCTCN2020082007-appb-000053
合成路线：
Figure PCTCN2020082007-appb-000054
步骤1：化合物A-3的合成
将化合物A-2(0.20g,323.37μmol,1eq)，无水N,N-二甲基甲酰胺(3mL)加入到反应瓶中，0℃下，加入氢化钠(30mg,750.00μmol,60％纯度,2.32eq)，在0℃下搅拌0.5小时后加入碘甲烷(0.15g,1.06mmol,65.79μL,3.27eq)，反应体系在20℃下搅拌2小时。将反应液浓缩得粗品，加入水(10mL)，用乙酸乙酯萃取三次(每次10mL)，合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得化合物A-3，粗产物A-3直接用于下一步反应。
参考例4：片段B-1
Figure PCTCN2020082007-appb-000055
合成路线：
Figure PCTCN2020082007-appb-000056
步骤1：化合物B-1-2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-1-1(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-1-2。
步骤2：化合物B-1-3的合成
将化合物B-1-2(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*2)萃取，然后用水(50mL*2)洗，再用饱和食盐水(50mL*2)洗，用无水硫酸钠干燥。粗品通过柱层析纯化得到目标化合物B-1-3，产物经LCMS确证，LC-MS(m/z)263,265[M+Na] +。
步骤3：化合物B-1-5的合成
将化合物B-1-3(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中。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，在0℃下向反应液中加入氯化铵溶液(50mL)，加入乙酸乙酯(200mL)稀释反应液后，用水(50mL*2)洗。合并有机相后用饱和食盐水(50mL*2)除水，用无水硫酸钠干燥，过滤旋干，粗品用柱层析纯化得到目标化合物B-1-5，产物经LCMS确证，LC-MS(m/z)371[M+Na] +。
步骤4：化合物B-1-6的合成
将化合物B-1-5(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)淬灭旋干。再加入乙酸乙酯(100mL)稀释，用水(50mL*2)洗涤，再用饱和食盐水(50mL*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-1-6，产物经LCMS确证，LC-MS(m/z)373[M+Na] +。
步骤5：化合物B-1-7的合成
将化合物B-1-6(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-1-7，产物经LCMS确证，LC-MS(m/z)333[M+Na] +。
步骤6：化合物B-1-8的合成
将化合物B-1-7(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*4)洗涤，有机相再用水(50mL*2)洗涤，然后用饱和食盐水(50mL*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。用柱层析进行纯化，得到目标化合物B-1-8，产物经LCMS确证，LC-MS(m/z)501[M+Na] +。
步骤7：B-1-9的合成
将化合物B-1-8(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。粗产物通过柱层析纯化得到目标化合物B-1-9，产物经LCMS确证，LC-MS(m/z)489[M+Na] +。
步骤8：B-1-10的合成
向反应瓶中加入B-1-9(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。粗产物经柱层析纯化得到目标化合物B-1-10，产物通过LCMS确证，LC-MS(m/z)449[M+Na] +。
步骤9：B-1的合成
向反应瓶中加入B-1-10(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,1.5eq)，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。粗产物用柱层析分离纯化得到目标化合物B-1。 1H NMR(400MHz,CDCl 3)δ7.25(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4中步骤1～9的合成方法，合成表1中各片段。
表1
Figure PCTCN2020082007-appb-000057
Figure PCTCN2020082007-appb-000058
参考例7：片段B-4
Figure PCTCN2020082007-appb-000059
合成路线：
Figure PCTCN2020082007-appb-000060
步骤1：化合物B-4-2的合成
将化合物B-4-1(25g,133.67mmol,1eq)溶于四氢呋喃(250mL)，0℃下加入氢化钠(10.69g,267.33mmol, 60％纯度,2eq)，25℃下搅拌0.5小时，然后向反应液中缓慢加入烯丙基溴(48.51g,401.00mmol,34.65mL,3eq)，25℃下继续反应2小时。反应完毕后，0℃下加入饱和氯化铵水溶液(20mL)淬灭，加入乙酸乙酯(250mL*2)萃取。粗品通过柱层析纯化得到化合物B-4-2， 1H NMR(400MHz,CD 3OD)δppm 4.04(dt,J＝5.5,1.4Hz,2H),4.45-4.52(m,2H),5.17-5.34(m,2H),5.95(ddt,J＝17.2,10.7,5.5,5.5Hz,1H),7.22-7.32(m,2H),7.43(d,J＝7.5Hz,1H),7.51(s,1H)。
步骤2：化合物B-4-3的合成
将化合物B-4-2(14g,61.65mmol,1eq)在-78℃溶于四氢呋喃(140mL)，经氮气保护后，加入正丁基锂(2.5M,27.12mL,1.1eq)，在-78℃反应0.5小时。同时将化合物B-1-4(18.53g,67.81mmol,1.1eq)溶解在四氢呋喃(180mL)中，降温至0℃后，经氮气保护后，滴加叔丁基氯化镁(1.7M,47.14mL,1.3eq)，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中。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铵溶液(100mL)，加入乙酸乙酯(200mL)稀释反应液后，用水(50mL*2)洗。合并有机相后用饱和食盐水(50mL*2)洗，用无水硫酸钠干燥，过滤旋干，粗品用柱层析纯化得到化合物B-4-3，产物经LCMS确证，LC-MS(m/z)357[M+Na] +。
步骤3：化合物B-4-4的合成
将化合物B-4-3(13g,38.88mmol,1eq)溶解在甲醇中(130mL)，降温至0℃，依次加入七水合三氯化铈(9.58g,38.88mmol,1eq)，硼氢化钠(2.94g,77.76mmol,2eq)，升温至25℃，反应16小时。反应完毕后，向反应液中加入饱和氯化铵水溶液(30mL)淬灭旋干。再加入乙酸乙酯(100mL)稀释，用水(50mL*2)洗涤，再用饱和食盐水(50mL*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-4-4，产物经LCMS确证，LC-MS(m/z)359[M+Na] +。
步骤4：化合物B-4-5的合成
将化合物B-4-4(10.8g,32.11mmol,1eq)溶于水(50mL)和冰醋酸(50mL)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-4-5，产物经LCMS确证，LC-MS(m/z)319[M+Na] +。
步骤5：化合物B-4-6的合成
将化合物B-4-5(9.2g,31.05mmol,1eq)溶解到1,4-二氧六环中(100mL)，加入乙酸酐(25.36g,248.38mmol,23.26mL,8eq)，吡啶(24.56g，310.48mmol，25.06mL,10eq)，4-二甲氨基吡啶(1.90g，15.52mmol，0.5eq)，80℃下搅拌16小时。反应完毕后，减压浓缩除去1,4-二氧六环，将反应液用乙酸乙酯(100mL)稀释，用1M稀盐酸(100mL*4)洗涤，有机相再用水(50mL*2)洗涤，然后用饱和食盐水(50mL*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。粗品用柱层析进行纯化，得到化合物B-4-6，产物经LCMS确证，LC-MS(m/z)487[M+Na] +。
步骤6：B-4-7的合成
将化合物B-4-6(6.2g,13.35mmol,1eq)溶于1,4-二氧六环(62mL)，加入硫脲(3.56g,46.72mmol,3.5eq)，置换氮气3次，25℃下加入三氟甲磺酸三甲基硅酯(11.87g,53.40mmol,4eq)，升温至60℃反应1小时，降温至25℃，依次加入碘甲烷(9.47g,66.74mmol,5eq)，二异丙基乙胺(17.25g,133.49mmol,10eq)，25℃下反应15小时。反应结束后反应液加水(60mL)稀释，用乙酸乙酯(60mL*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。粗产物通过柱层析纯化得到目标化合物B-4-7，产物经LCMS确证，LC-MS(m/z)475[M+Na] +。
步骤7：B-4-8的合成
向反应瓶中加入B-4-7(4.4g,9.72mmol,1eq)，巴比妥酸(2.49g,19.45mmol,2eq)，乙醇(44mL)，置换氮气3次后，加入四三苯基膦钯(516.80mg,486.17μmol,0.05eq)，在氮气环境下65℃反应16小时。反应结束后，反应液加碳酸氢钠水溶液调节pH＝7-8，布氏漏斗过滤，收集滤液，加入乙酸乙酯(40mL*2)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。粗产物经柱层析纯化得到目标化合物B-4-8，产物通过LCMS确证，LC-MS(m/z)435[M+Na] +。
步骤8：B-4的合成
将化合物B-4-8(300mg,727.36μmol,1eq)溶于四氢呋喃(3mL)，氮气保护下，0℃加入三溴化磷(98.44mg，363.68μmol，34.18μL，0.5eq)，0℃搅拌3小时。反应结束后，向反应液中加入饱和碳酸钾水溶液洗涤两次，收集有机相，水相加入乙酸乙酯(3mL*2)萃取，合并有机相，水泵减压浓缩至干。粗产物用柱层析分离纯化得到目标化合物B-4。 1H NMR(400MHz,CDCl 3)δppm 1.83-1.86(m,3H),2.02(s,3H),2.10-2.13(m,3H),2.20-2.22(m,3H),4.46-4.49(m,2H),4.54-4.58(m,1H),5.10(t,J＝9.7Hz,1H),5.20-5.27(m,1H),5.31(s,1H),5.34-5.40(m,1H),7.30-7.38(m,4H)。
参考例8：片段B-5
Figure PCTCN2020082007-appb-000061
合成路线：
Figure PCTCN2020082007-appb-000062
步骤1：化合物B-5-2的合成
将化合物B-5-1(11.00g,64.48mmol,1eq)，N-溴代丁二酰亚胺(14.30g,80.34mmol,1.25eq)加入到反应瓶中，0℃下加入硫酸(202.40g,2.06mol,110.00mL,32.00eq)，搅拌1小时。将反应液滴加到冰水中(500mL)，水相用乙酸乙酯萃取三次(200mL*3)，合并有机相，将有机相浓缩得化合物B-5-2，直接用于下一步反应。
步骤2：化合物B-5-3的合成
将化合物B-5-2(19.00g,76.16mmol,1eq)，无水四氢呋喃(50.0mL)加入到反应瓶中，滴加硼烷的四氢呋喃溶液(1M,160.00mL,2.10eq)，反应体系在20℃下搅拌16小时。20℃下，向反应液中滴入甲醇(100mL)，同时鼓氮气，淬灭完毕，混合液在70℃回流1小时，45℃水泵浓缩干得到粗品，加入水(200mL)，用乙酸乙酯萃取(200mL*3)，合并有机相，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得化合物B-5-3。 1H NMR(400MHz,CDCl 3)δppm 7.66(s,1H),7.24(s,1H),4.73(d,J＝6.02Hz,2H),2.38(s,3H),1.88(t,J＝6.27Hz,1H)。
步骤3：化合物B-5-4的合成
将化合物B-5-3(15.60g,66.24mmol,1eq)，无水N,N-二甲基甲酰胺(100mL)加入到反应瓶中，0℃下，加入氢化钠(6.24g,156.01mmol,60％纯度,2.36eq)，反应体系在0℃下搅拌0.5小时，加入3-溴丙烯(24.04g,198.72mmol,3eq)，反应体系在室温(20℃)下搅拌15.5小时。反应液中滴加水(200mL)淬灭反应，用乙酸乙酯萃取(200mL*3)，合并有机相，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析分离纯化得目标化合物B-5-4， 1H NMR(400MHz,CDCl 3)δppm 7.66(s,1H),7.23(s,1H),5.91-6.05(m,1H),5.31-5.42(m,1H),5.19-5.29(m,1H),4.55(s,2H),4.10(dt,J＝5.58,1.35Hz,2H),2.37(s,3H)。
步骤4：化合物B-5-5的合成
将化合物B-5-4(15.30g,55.52mmol,1eq)，无水四氢呋喃(200mL)加入到反应瓶中，-70℃下，氮气保护， 加入正丁基锂(2.5M,27mL,1.22eq)，反应体系在-70℃下搅拌0.5小时。将化合物B-1-4(15.30g,55.99mmol,1.01eq)，无水四氢呋喃(200mL)，加入到反应瓶中，0℃下，氮气保护，加入叔丁基氯化镁(1.7M,54mL,1.65eq)，反应体系在0℃下搅拌0.5小时。将镁烷氧溶液缓慢加入到烷基锂溶液中，反应体系在-70℃下搅拌0.5小时，缓慢升温至室温(20℃)搅拌1小时。向反应液中滴加饱和氯化铵(200mL)淬灭反应，浓缩除去有机溶剂，加入柠檬酸调节溶液至澄清，用乙酸乙酯萃取(200mL*3)，合并有机相，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析分离纯化得目标化合物B-5-5，产物经LCMS确证，LC-MS(m/z)405[M+Na] +。
步骤5：化合物B-5-6的合成
化合物B-5-5(10.60g,27.69mmol,1eq)溶解在无水甲醇(200mL)中，降温至0℃，依次加入七水合三氯化铈(12.38g,33.23mmol,1.20eq)，硼氢化钠(2.1g,55.38mmol,2eq)，升温至25℃，反应16小时。反应完毕后，向反应液中加入饱和氯化铵水溶液(30mL)淬灭旋干。再加入乙酸乙酯(100mL)稀释，用水(50mL*2)洗涤，再用饱和食盐水(50mL*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-5-6，直接用于下一步反应。
步骤6：化合物B-5-7的合成
将化合物B-5-6(9.85g,19.00mmol,1eq)，乙酸(60mL)，水(60mL)加入到反应瓶中，100℃下搅拌8小时。将反应液浓缩得粗品，随后加入甲苯(100mL)浓缩带干，如此重复两次后得目标化合物B-5-7，直接用于下一步反应。
步骤7：化合物B-5-8的合成
将化合物将化合物B-5-7(10.00g,29.00mmol,1eq)，三乙胺(16.72g,165.24mmol,23.0mL,5.70eq)，乙酸酐(21.80g,213.54mmol,20mL,7.36eq)，4-二甲氨基吡啶(40mg,327.42μmol,1.13e-2eq)，乙腈(100mL)加入到反应瓶中，25℃下搅拌2小时。将反应液浓缩得粗品，加入乙酸乙酯(200mL)，用50％饱和硫酸氢钠水溶液萃取(200mL*2)，合并水相，水相用乙酸乙酯萃取(200mL*2)，合并有机相，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析分离纯化得目标化合物B-5-8，产物经LCMS确证，LC-MS(m/z)535[M+Na] +。
步骤8：化合物B-5-9的合成
将化合物B-5-8(3.60g,7.02mmol,1eq)，硫脲(1.08g,14.19mmol,2.02eq)，无水二氧六环(40mL)加入到反应瓶中，反应体系在80℃下搅拌2小时。随后加入三氟甲磺酸三甲基硅酯(3.90g,17.55mmol,3.17mL,2.50eq)，继续在80℃下搅拌1小时。反应液冷却至室温，加入碘甲烷(3.06g,21.56mmol,1.34mL,3.07eq)，二异丙基乙胺(4.54g,35.09mmol,6.11mL,5eq)，反应体系在25℃下搅拌15小时。向反应液中加入水(50mL)，用乙酸乙酯萃取(50mL*2)，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析分离纯化得目标化合物B-5-9。 1H NMR(400MHz,CDCl 3)δppm 7.48(s,1H), 7.15(s,1H),5.98(ddt,J＝17.32,10.60,5.36,5.36Hz,1H),5.22-5.37(m,5H),4.70(d,J＝10.04Hz,1H),4.56(d,J＝2.76Hz,2H),4.54(d,J＝9.79Hz,1H),4.07(ddt,J＝5.49,2.48,1.41,1.41Hz,2H),2.38(s,3H),2.19(s,3H),2.11(s,3H),2.03(s,3H),1.81(s,3H)。
步骤9：化合物B-5-10的合成
将化合物B-5-9(2.70g,5.39mmol,1eq)，巴比妥酸(1.38g,10.78mmol,2.0eq)，无水乙醇(20mL)，无水二氯甲烷(10mL)加入到反应瓶中，氮气氛围下，加入四三苯基膦钯(622mg,0.539mmol,0.1eq)，反应体系在40℃下搅拌12小时。将反应液过滤，滤液浓缩得粗品，加入水(500mL)，用乙酸乙酯萃取(500mL*3)，合并有机相，有机相用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品，经柱层析分离纯化得目标化合物B-5-10。 1H NMR(400MHz,CDCl 3)δppm 7.51(s,1H),7.16(s,1H),5.35-5.41(m,1H),5.26(dt,J＝15.00,9.57Hz,2H),4.68-4.77(m,3H),4.55(d,J＝10.04Hz,1H),2.38(s,3H),2.17-2.23(m,3H),2.11(s,3H),2.02(s,3H),1.81(s,3H)。
步骤10：化合物B-5的合成
将化合物B-5-10(0.60g,468.88μmol,1eq)，无水四氢呋喃(10mL)加入到反应瓶中，氮气保护，0℃下滴加三溴化磷(288.00mg,1.06mmol,0.10mL,2.27eq)，缓慢升至25℃搅拌12小时。向反应液中滴加水(20mL)淬灭反应，浓缩除去有机溶剂，剩余水相用乙酸乙酯萃取(20mL*3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品，经柱层析分离纯化得目标化合物B-5， 1H NMR(400MHz,CDCl 3)δppm 1.83(s,3H),2.03(s,3H),2.11(s,3H),2.20(s,3H),2.40(s,3H),4.50-4.59(m,3H),4.66(d,J＝10.04Hz,1H),5.20-5.40(m,3H),7.20(s,1H),7.41(s,1H)。
参考例9：片段B-6
Figure PCTCN2020082007-appb-000063
合成路线：
Figure PCTCN2020082007-appb-000064
步骤1：化合物B-6-2的合成
向反应瓶中依次加入浓硫酸(70mL)和化合物B-6-1(20g,132.31mmol,1.89mL,1eq)，搅拌至溶解，0℃下分批加入N-溴代丁二酰亚胺(28.26g,158.77mmol,1.2eq)。加完后在30℃搅拌至N-溴代丁二酰亚胺全部溶解，继续在30℃反应0.5小时。将反应液缓慢加入搅拌的冰水(1L)中淬灭，随后在0℃搅拌0.5小时。过滤，滤饼用水(100mL)洗涤三次后收集干燥得到化合物B-6-2，直接用于下一步反应。
步骤2：化合物B-6-3的合成
向反应瓶中依次加入水(250mL)，乙腈(125mL)，化合物B-6-2(25g,97.80mmol,1eq)和浓盐酸(38.55g,391.21mmol,37.79mL,37％纯度,4eq)，搅拌得到悬浊液。0℃下向反应液中加入亚硝酸钠(7.09g,102.69mmol,1.05eq)并搅拌0.5小时。0℃下将该反应液滴加入氯化亚铜(10.17g,102.69mmol,2.46mL,1.05eq)、浓盐酸(38.55g,391.21mmol,37.79mL,37％纯度,4eq)和水(250mL)的溶液中。滴加完后反应液在70℃反应3小时。反应液浓缩除去乙腈，剩余物冷却至室温后，过滤，滤饼用水(100mL)洗涤3次。收集滤饼用乙酸乙酯(200mL)溶解分液，有机相加入无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物B-6-3，产物经LCMS确证，LC-MS(m/z)248.9,250.8[M+H] +。
步骤3：化合物B-6-4的合成
向反应瓶中加入化合物B-6-3(18g,64.93mmol,1eq)和四氢呋喃(300mL)，在氮气氛围下滴加硼烷二甲硫醚(10M,19.48mL,3eq)。加完后在30℃搅拌反应16小时。反应结束后向反应液中滴入甲醇(100mL)淬灭完毕，反应液在70℃回流1小时，减压浓缩得到化合物B-6-4，直接用于下一步反应。
步骤4：化合物B-6-5的合成
向反应瓶中加入化合物B-6-4(16.5g,70.06mmol,1eq)和DMF(180mL)，降温至0℃，加入氢化钠(5.60g,140.12mmol,60％纯度,2eq)，0℃搅拌0.5小时后，向反应液中加入烯丙基溴(25.43g,210.19mmol,3eq)。混合液在30℃搅拌反应10小时。向反应液中加入水(300mL)淬灭，用乙酸乙酯萃取(100mL*3)。有机相合 并后再用饱和食盐水(100mL)洗涤，浓缩得到粗品，经柱层析纯化得到化合物B-6-5，产物经LCMS确证，LC-MS(m/z)275,277[M+H] +。
步骤5：化合物B-6-6的合成
向反应瓶中加入化合物B-6-5(16g,52.26mmol,1eq)和四氢呋喃(160mL)，降温至-78℃，滴加正丁基锂(2.5M,27.17mL,1.3eq)并在-78℃搅拌0.5小时。向反应瓶加入化合物B-1-4(14.28g,52.26mmol,1eq)和四氢呋喃(160mL)，降温至0℃，滴加叔丁基氯化镁(1.7M,49.18mL,1.6eq)并在0-5℃搅拌0.5小时。-78℃下将镁烷氧溶液缓慢滴加到烷基锂溶液中，-78℃搅拌0.5小时后再在25℃搅拌反应2小时。0℃下，向反应液中滴加饱和氯化铵和饱和食盐水混合溶液(体积比1:1，共150mL)淬灭，乙酸乙酯(100mL*3)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化得到化合物B-6-6，产物经LCMS确证，LC-MS(m/z)383[M+H] +。
步骤6：化合物B-6-7的合成
化合物B-6-6(7.40g,17.40mmol,1eq)溶解在无水甲醇(100mL)中，降温至0℃，依次加入七水合三氯化铈(7.77g,20.88mmol,1.20eq)，硼氢化钠(1.32g,34.8mmol,2eq)，升温至25℃，反应16小时。反应完毕后，向反应液中加入饱和氯化铵水溶液(30mL)淬灭悬干。再加入乙酸乙酯(100mL)稀释，用水(50mL*2)洗涤，再用饱和食盐水(50mL*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-6-7，直接用于下一步反应。
步骤7：化合物B-6-8的合成
向250mL单口瓶中加入化合物B-6-7(6.5g,16.89mmol,1eq)，乙酸(40mL)和水(40mL)，100℃下反应16小时。反应液减压浓缩干，甲苯共沸带干(50mL*2)得到化合物B-6-8，直接用于下一步反应。
步骤8：化合物B-6-9的合成
向反应瓶中加入化合物B-6-8(6g,17.40mmol,1eq)，三乙胺(11.62g,114.85mmol,15.99mL,6.6eq)，4-二甲氨基吡啶(212.60mg,1.74mmol,0.1eq)和乙腈(40mL)，然后再加入乙酸酐(11.73g,114.85mmol,10.76mL,6.6eq)，25℃下反应16小时。反应液浓缩除去乙腈后，加入0.5N的盐酸(40mL)，用乙酸乙酯萃取(50mL*3)，有机相用饱和食盐水(50mL)洗涤，减压浓缩得到粗品。粗品经柱层析纯化得到化合物B-6-9。
步骤9：化合物B-6-10的合成
向反应瓶中加入化合物B-6-9(2.5g,4.39mmol,1eq)，硫脲(1.17g,15.35mmol,3.5eq)和二氧六环(30mL)，抽换氮气后加入三氟甲磺酸三甲基硅酯(3.90g,17.55mmol,3.17mL,4eq)，80℃下混合液反应0.5小时。降温至0-5℃，依次加入碘甲烷(1.87g,13.16mmol,819.23μL,3eq)和二异丙基乙胺(2.83g,21.93mmol,3.82mL,5eq)，再在25℃下反应10小时。向反应液中加入水(30mL)，用乙酸乙酯萃取(30mL*3)，有机相合并后用饱和食盐水(30mL)洗涤后浓缩得到粗品，经柱层析纯化得到化合物B-6-10，产物通过LCMS确证， LC-MS(m/z)523[M+Na] +。
步骤10：化合物B-6-11的合成
向反应瓶中加入化合物B-6-10(1.257g,2.515mmol,1eq)，巴比妥酸(644.30mg,5.03mmol,2eq)，四三苯基膦钯(290.63mg,251.50μmol,0.1eq)和EtOH(40mL)抽换氮气后在40℃下搅拌反应16小时。向反应液中加入饱和碳酸钠水溶液(50mL)和乙酸乙酯(50mL)，有大量固体析出，过滤，分液，水相再用乙酸乙酯萃取(50mL*3)。有机相合并后再用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化得到化合物B-6-11，产物通过LCMS确证，LC-MS(m/z)483[M+Na] +。
步骤11：B-6的合成
向反应瓶中加入化合物B-6-11(200mg,418.07μmol,1eq)和四氢呋喃(5mL)，0℃下加入三溴化磷(113.17mg,418.07μmol,39.29μL,1eq)，反应液在0-10℃反应0.5小时。0℃下将反应液倒入碳酸钾水溶液(20mL,1M)，乙酸乙酯萃取(20mL*3)。有机相用无水硫酸钠干燥，浓缩得粗品。粗品经柱层析纯化得到目标化合物B-6。 1H NMR(400MHz,CDCl 3)δppm 1.86(s,3H),2.01(s,3H),2.10(s,3H),2.21(s,3H),2.40(s,3H),4.40(d,J＝10.04Hz,1H),4.51-4.57(m,2H),4.60-4.65(m,1H),5.06(t,J＝9.66Hz,1H),5.17-5.25(m,1H),5.31-5.38(m,1H),7.22(s,1H),7.24(s,1H)。
实施例1：WXD001或WXD002
Figure PCTCN2020082007-appb-000065
合成路线
Figure PCTCN2020082007-appb-000066
步骤1：WXD001-1的合成
向反应瓶中加入B-2(0.35g,695.27μmol,1eq)，A-1(626.19mg,1.04mmol,1.49eq)，Na 2CO 3(147.38mg,1.39mmol,2eq)，甲苯(5mL)，EtOH(1mL)，H 2O(1mL)，置换氮气后加入Pd(PPh 3) 4(160.68mg,139.05μmol,0.2eq)，在50℃下搅拌3小时。反应结束后反应液加水20mL稀释，用乙酸乙酯(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，过滤旋干得粗产物。粗产物经过柱层析分离纯化得到WXD001-1。
步骤2：WXD001-2或WXD001-3的合成
向反应瓶中加入WXD001-1(229mg,254.16μmol,1eq)，LiOH.H 2O(213mg,5.08mmol,20eq)，THF(0.5mL)，MeOH(1mL)，H 2O(1mL)，在25℃下反应1小时。反应结束后，向反应液加水10mL，用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，过滤旋干得粗产物。粗产物经SFC手性拆分(色谱柱：REGIS(s,s)WHELK-O1(250mm×30mm,5μm)；流动相：[0.1％NH 3H 2O-异丙醇]；B(异丙醇)％:40％-40％,min)得到WXD001-2(t＝4.167min)或WXD001-3(t＝2.909min)。
步骤3：WXD001或WXD002的合成
向反应瓶中加入WXD001-2(60mg,77.43μmol,1eq)，EtOAc(3mL)，HCl/EtOAc(4M,1mL,51.66eq)，25℃下反应1小时。反应结束后，减压旋干反应液得粗产物。粗产物经过制备高效液相色谱(色谱柱：Boston Prime C18 150×30mm,5μm；流动相：[水(0.05％氢氧化铵v/v)-乙腈]；B(乙腈)％:47％-77％,8min)得到WXD001。对应SFC(方法：色谱柱:Chiralpak AD-3 100×4.6mm I.D.,3μm；流动相：CO 2-40％甲醇(0.05％DEA)；流速：2.8mL/min；柱温：40℃)，保留时间t＝4.404min。
向反应瓶中加入WXD001-3(60mg,77.43μmol,1eq)，EtOAc(3mL)，HCl/EtOAc(4M,1mL,51.66eq)，25℃下反应1小时。反应结束后，减压旋干反应液得粗产物。粗产物经过制备高效液相色谱(色谱柱：Boston Prime C18 150×30mm 5μm；流动相：[水(0.05％氢氧化铵v/v)-乙腈]；B(乙腈)％:47％-77％,8min)得到WXD002。对应SFC(方法：色谱柱：Chiralpak AD-3 100×4.6mm I.D.,3μm，流动相：CO 2-40％甲醇(0.05％DEA)；流速：2.8mL/min；柱温：40℃)，保留时间t＝5.921min。
实施例2：WXD003
Figure PCTCN2020082007-appb-000067
合成路线
Figure PCTCN2020082007-appb-000068
步骤1：WXD003-1的合成
先将A-2(319.44mg,516.49μmol,1.3eq)，B-2(200mg,397.30μmol,1eq)，Na 2CO 3(65.95mg,794.59μmol,2eq)，Pd(PPh 3) 4(91.82mg,79.46μmol,0.2eq)加入到反应瓶中，经氮气置换三次后，依次加入甲苯(4mL)，EtOH(1mL)，H 2O(1mL)，然后加热到50℃反应16小时。反应结束后将反应液旋干，然后用水(30mL)稀释，用乙酸乙酯(100mL*3)萃取，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤旋干。 通过制备层析板进行纯化。得到WXD003-1。
步骤2：WXD003-2的合成
将WXD003-1(320mg,349.72μmol,1eq)溶于MeOH(2mL)THF(1mL)H 2O(2mL)混合溶剂中，加入LiOH.H 2O(293.48mg,6.99mmol,20eq)，25℃下搅拌1小时。反应结束后，向反应液中加入乙酸乙酯(30mL)待溶液分层后，收集有机相，加入无水硫酸钠干燥，过滤旋干。得到粗品WXD003-2直接用于下一步反应。
步骤3：WXD003的合成
将WXD003-2(270mg,342.24μmol,1eq)溶于乙酸乙酯(5mL)，加入HCl/EtOAc(4M,5mL,58.44eq)，25℃搅拌1小时。反应结束后直接将反应液旋干。通过制备高效液相色谱进行纯化(色谱柱：Xtimate C18 150×25mm×5μm；流动相：[水(0.225％甲酸)-乙腈]；B(乙腈)％:25％-55％,7min)得到产物WXD003。
参照实施例2中步骤1～3的合成方法，用片段B-1替代B-2合成下表2中的化合物WXD004，用A-3替代A-2合成下表2中的化合物WXD005，用片段B-3替代B-2合成下表2中的化合物WXD006，用片段B-4替代B-2合成下表2中的化合物WXD007，用片段B-5替代B-2合成下表2中的化合物WXD008，用片段B-6替代B-2合成下表2中的化合物WXD009。
表2
Figure PCTCN2020082007-appb-000069
Figure PCTCN2020082007-appb-000070
各实施例的氢谱和质谱数据如表3所示。
表3
Figure PCTCN2020082007-appb-000071
Figure PCTCN2020082007-appb-000072
Figure PCTCN2020082007-appb-000073
实验例一、体外细胞活性测试：
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 HEPES缓冲液(Sigma公司),1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2and 120mM NaCl.
2)将化合物用100％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]Methyl a-D-glucopyranosid(标记甲基α-D-吡喃葡萄糖苷)。
4)用49μL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 HEPES,1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2and 120mM NaCl。
2)终止缓冲液:10mM HEPES,1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2,120mM NaCl和1μM LX4211。
3)将化合物用100％DMSO以10μM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]Methyl a-D-glucopyranosid。
5)用49μL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50μL10％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 PCTCN2020082007-appb-000074
Figure PCTCN2020082007-appb-000075
结论：本发明化合物表现出较优的对Human-SGLT1和Human-SGLT2体外抑制活性。
实验例二、体内DMPK研究：
大鼠体内DMPK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4只，2只为静注组，2只为口服组。待测化合物与适量静注组溶媒(10％NMP/10％solutol/80％水)混合，涡旋并超声，制备得到0.5mg/mL澄清溶液，微孔滤膜过滤后备用；口服组溶媒为10％NMP/10％solutol/80％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。大鼠1mg/kg静脉给药或10mg/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。
注NMP:N-甲基吡咯烷酮；solutol:聚乙二醇-15羟基硬脂酸酯。
实验结果见表5：
表5化合物PK测试结果
Figure PCTCN2020082007-appb-000076
注:：C max为最大浓度；F％为口服生物利用度；DNAUC＝AUC PO/Dose，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；ND指未检测到。
结论：本发明化合物表现低的口服暴露量和生物利用度，展现了SGLT1选择性抑制剂应有的药代动力学特性。
实验例三、体内药效研究：
一、大鼠口服糖耐受量(OGTT)体内药效研究：
1.实验动物：
Figure PCTCN2020082007-appb-000077
2.实验分组：
表6.实验分组信息
组别 化合物分组 剂量 给药频率 给药方式 每组动物数
1 溶媒对照组 - 单次给药 灌胃 5
2 WXD003 5mg/kg 单次给药 灌胃 5
3.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
动物禁食6小时后，按照表6给予WXD003或溶媒，随后立即给予50％葡萄糖溶液(2g/kg,4ml/kg)。
3)血糖测试
将给糖时间记为0点，在给糖前0分钟，给糖后15，30，60，90，120分钟，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)。
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。
4.实验结果：
表7大鼠糖耐受量体内药效实验结果
化合物 溶媒对照组 WXD003
OGTT血糖水平AUC 0-2小时(mmol/L×min) 1063.4 624.2****
注：****表示相对于溶媒对照组p<0.0001。
结论：相比溶媒对照组，给药组均可显著降低动物2小时内血糖AUC水平。
二、STZ配合高糖高脂饮食诱导糖尿病小鼠模型体内药效研究
1.实验动物
7周龄C57BL/6J雄性小鼠，购于江苏集萃药康生物科技有限公司。
2.实验内容
1)动物适应环境后，根据体重将所有小鼠分为两组，按表8中的方案进行喂养，并注射溶媒及链脲佐菌素(STZ)进行造模；
表8.STZ造模实验分组信息
Figure PCTCN2020082007-appb-000078
2)根据模型组随机血糖检测结果，随机血糖>11mmol/L入组继续进行给药实验；
3)将符合入组标准的模型组小鼠分为3组，正常组5只，模型给药组每组10只，按照表9中的给药方案进行给药；
表9.实验分组信息
Figure PCTCN2020082007-appb-000079
4)开始给药后，每天监测动物体重变化水平，并在给药4周和7周后，分别检测各组小鼠禁食6小时后的血糖和糖化血红蛋白；
5)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。
3.实验结果
1)给药4周后的实验结果：
a)如表10和附图1所示，给药4周后，WXD003能显著降低动物禁食6小时后的血糖水平；
表10.给药4周后动物血糖
Figure PCTCN2020082007-appb-000080
Figure PCTCN2020082007-appb-000081
b)如表11和附图2所示，给药4周后，WXD003能显著降低动物禁食6小时后的糖化血红蛋白水平；
表11.给药4周后动物糖化血红蛋白
Figure PCTCN2020082007-appb-000082
c)如附图3所示，给药4周后，WXD003能有效控制动物体重的增长。
2)给药7周后的实验结果
d)如表12和附图4所示，给药7周后，WXD003能显著降低动物禁食6小时后的血糖水平。相比给药4周，给药7周后，WXD003能进一步降低动物禁食6小时后的血糖水平；
表12.给药7周后动物血糖
Figure PCTCN2020082007-appb-000083
e)如表13和附图5所示，给药7周后，WXD003能显著降低动物禁食6小时后的糖化血红蛋白水平；
表13.给药7周后动物糖化血红蛋白
Figure PCTCN2020082007-appb-000084
f)如附图6所示，给药7周后，WXD003能有效控制动物体重的增长。
注：^^^^表示相对于正常饮食溶媒组p<0.0001，*表示相对于高糖高脂饮食溶媒组p<0.05，**表示相对于高糖高脂饮食溶媒组p<0.01，***表示相对于高糖高脂饮食溶媒组p<0.001，****表示相对于高糖高脂饮食溶媒组p<0.0001。
结论：相比高糖高脂溶媒对照组，给药组可显著降低动物禁食6小时后的血糖和糖化血红蛋白，并能有效控制动物体重的增长。
三、高糖高脂饮食诱导的肥胖小鼠模型体内药效研究
1.实验动物
5周龄雄性C57B/6J小鼠购于江苏集萃药康生物科技有限公司。
2.实验内容
1)动物适应环境后，喂养高糖高脂饲料(Research Diet,HFHS,D12451)20周后，挑选体重大于40克的小鼠开展减重实验。
2)将体重符合标准的动物先进行溶媒给药适应，然后根据体重将所有小鼠分为5组开展减重实验，检测化合物降低动物体重的效果，实验分组如表14所示：
表14.实验分组信息
实验分组 给药剂量 给药方式和给药频率
溶媒组1 正常饮食(Chow Diet)+溶媒 口服，每天一次
溶媒组2 高糖高脂饮食(HFHS)+溶媒 口服，每天一次
给药组3 高糖高脂饮食(HFHS)+WXD003(0.3mg/kg) 口服，每天一次
给药组4 高糖高脂饮食(HFHS)+WXD003(1mg/kg) 口服，每天一次
给药组5 高糖高脂饮食(HFHS)+WXD003(3mg/kg) 口服，每天一次
3)开始给药后，每天监测动物体重变化水平，并在给药3周后，分别检测各组小鼠禁食6小时后的血糖和餐后1小时的血糖水平；
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。
3.实验结果
1)如附图7和附图8所示，给药3周后，WXD003能剂量相关地显著降低动物体重；
2)如表15和附图9所示，给药3周后，WXD003能降低动物禁食6小时后的血糖；
表15.给药3周后动物禁食6小时后的血糖
Figure PCTCN2020082007-appb-000085
3)如表16和图附10所示，给药3周后，WXD003能降低动物餐后1小时的血糖。
表16.给药3周后动物餐后1小时的血糖
Figure PCTCN2020082007-appb-000086
Figure PCTCN2020082007-appb-000087
注：*表示相对于高糖高脂饮食溶媒组p<0.05，**表示相对于高糖高脂饮食溶媒组p<0.01，***表示相对于高糖高脂饮食溶媒组p<0.001，****表示相对于高糖高脂饮食溶媒组p<0.0001。
结论：相比高糖高脂溶媒对照组，给药组可剂量依赖地显著降低动物体重，并同时能降低动物禁食6小时后和餐后1小时的血糖。

Claims (17)

  1. 式(II)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020082007-appb-100001
    其中，
    R 1选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基任选被1、2或3个R a取代；
    R 2选自F、Cl、Br、I、OH、NH 2和C 1-3烷氨基；
    R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
    L选自单键、-O-、-S-、-C(R c) 2-和-N(R d)-；
    m选自0、1和2；
    n选自1、2和3；
    R a、R b和R c分别独立地选自F、Cl、Br、I、OH、NH 2和CH 3；
    R d选自H和CH 3。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
    Figure PCTCN2020082007-appb-100002
    所述CH 3、CH 2CH 3和
    Figure PCTCN2020082007-appb-100003
    任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和
    Figure PCTCN2020082007-appb-100004
  4. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 2选自F、Cl、Br、I、OH、NH 2、NH(CH 3)和N(CH 3) 2。
  5. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代CH 3。
  6. 根据权利要求5所述化合物、其异构体或其药学上可接受的盐，其中，R 3、R 4和R 5分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2和CF 3。
  7. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，L选自单键、-O-和-S-。
  8. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020082007-appb-100005
    选自
    Figure PCTCN2020082007-appb-100006
  9. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020082007-appb-100007
    选自
    Figure PCTCN2020082007-appb-100008
  10. 根据权利要求1～7任意一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020082007-appb-100009
    其中，
    R 1、R 2、R 3、R 4、R 5和L如权利要求1～7任意一项所定义。
  11. 根据权利要求10所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020082007-appb-100010
    Figure PCTCN2020082007-appb-100011
    其中，
    R 2选自F、Cl、Br、I、OH、NH 2、NH(CH 3)和N(CH 3) 2；
    R 1、R 3、R 4、R 5和L如权利要求10所定义。
  12. 根据权利要求11所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020082007-appb-100012
    其中，
    R 1、R 2、R 3、R 4和R 5如权利要求11所定义。
  13. 下式所示化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020082007-appb-100013
  14. 根据权利要求13所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020082007-appb-100014
    Figure PCTCN2020082007-appb-100015
  15. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～14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。
  16. 根据权利要求1～14任意一项所述的化合物、其异构体或其药学上可接受的盐或者权利要求15的组合物在制备SGLT1抑制剂相关药物上的应用。
  17. 根据权利要求16所述的应用，其特征在于，所述SGLT1抑制剂相关药物是用于糖尿病和肥胖症的药物。
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