WO2021018044A1 - 一种sglt2/dpp4抑制剂及其应用 - Google Patents

一种sglt2/dpp4抑制剂及其应用 Download PDF

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WO2021018044A1
WO2021018044A1 PCT/CN2020/104521 CN2020104521W WO2021018044A1 WO 2021018044 A1 WO2021018044 A1 WO 2021018044A1 CN 2020104521 W CN2020104521 W CN 2020104521W WO 2021018044 A1 WO2021018044 A1 WO 2021018044A1
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compound
reaction
solution
hours
reduced pressure
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PCT/CN2020/104521
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English (en)
French (fr)
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毛庆华
于涛
甘露
李翼
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 MX2022001044A priority Critical patent/MX2022001044A/es
Priority to CA3145678A priority patent/CA3145678C/en
Priority to AU2020320890A priority patent/AU2020320890B2/en
Priority to KR1020227006283A priority patent/KR102471055B1/ko
Priority to CN202080047668.5A priority patent/CN114026079B/zh
Priority to US17/629,527 priority patent/US20220242898A1/en
Priority to JP2022505531A priority patent/JP7227427B2/ja
Priority to EP20848355.2A priority patent/EP4006017A4/en
Publication of WO2021018044A1 publication Critical patent/WO2021018044A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/06—Heterocyclic radicals
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • 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

Definitions

  • the present invention relates to a class of compounds as dual SGLT2/DPP4 inhibitors, and their application in preparing drugs as dual SGLT2/DPP4 inhibitors. Specifically, it relates to a compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof.
  • Diabetes is a metabolic disease characterized by high blood sugar. Hyperglycemia is caused by defective insulin secretion or impaired 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. Diabetes treatment, early stage, diet control and exercise therapy are the first choice for blood sugar control. When these methods are difficult to control blood sugar, insulin or oral hypoglycemic drugs are needed for treatment.
  • hypoglycemic drugs have been used in clinical treatment, mainly including biguanides, sulfonylureas, insulin resistance improvers, glinides, ⁇ -glucosidase inhibitors, dipeptidyl peptidase-IV Inhibitors and sodium-glucose cotransporter (SGLT2) inhibitors, etc. These drugs have good therapeutic effects, but there are still safety problems in long-term treatment.
  • biguanides can easily cause lactic acidosis; sulfonylureas can cause symptoms of hypoglycemia; insulin resistance improvers can cause edema, heart failure and Weight gain; ⁇ -glucosidase inhibitors can cause symptoms such as abdominal pain, bloating, and diarrhea; sodium-glucose cotransporter (SGLT2) inhibitors increase the risk of urinary and reproductive system infections. Therefore, there is an urgent need to develop a safer and more effective new hypoglycemic drug to meet the needs of diabetes treatment.
  • SGLT2 sodium-glucose cotransporter
  • SGLTs Sodium-glucose cotransporters
  • the family members mainly include SGLT-1 protein and SGLT2 protein.
  • SGLT-2 is expressed at a high level in the kidney and is responsible for 90% of kidney glucose reabsorption.
  • Inhibiting SGLT2 can prevent the reabsorption of glucose in the kidneys, promote the excretion of glucose through urine, and lower blood sugar. Since this process does not involve glucose metabolism, the occurrence of adverse reactions of hypoglycemia is avoided or reduced.
  • Dipeptidyl peptidase-IV (Dipeptidyl peptidase 4) is a serine protease on the cell surface that can inactivate a variety of glucagon-like peptide-1 (GLP-1) and glucose-dependent Glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors can inactivate DPP-4, thereby not decomposing GLP-1, and by increasing the level of GLP-1, it can control blood sugar.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent Glucose-dependent insulinotropic polypeptide
  • DPP-4 inhibitors have been marketed worldwide: sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin Linagliptin, gemigliptin and teneligliptin.
  • the marketed DPP4 drug has weak hypoglycemic effect. Although there is no cardiovascular benefit, long-term data show that it is safe and reliable without obvious side effects.
  • the SGLT2/DPP4 dual inhibitor has a good development prospect.
  • the present invention provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is optionally substituted with 1, 2 or 3 R a C 1-3 alkyl group
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is H, F or Cl, and when R 4 is Cl, R 2 , R 3 and R 5 are not H at the same time;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH and NH 2 .
  • the present invention also provides a compound of formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is optionally substituted with 1, 2 or 3 R a C 1-3 alkyl group
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b replace
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is H, F or Cl, and when R 4 is Cl, R 2 , R 3 and R 5 are not H at the same time;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH and NH 2 .
  • R 1 is optionally substituted with 1,2 or 3 substituents R a is CH 3, the other variables are as defined in the present invention.
  • R 1 is selected as CH 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et and -OCH 3 , the CH 3 , Et and- OCH 3 is optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and the CH 3 and Et are optionally selected by 1, 2 Or 3 R b substitutions, other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et and -OCH 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and the CH 3 and Et are optionally substituted by 1, 2 or 3 R c , Other variables are as defined in the present invention.
  • R 5 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • the present invention also provides the following compounds, their isomers or their pharmaceutically acceptable salts,
  • the present invention also provides the application of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of related drugs for dual inhibitors of SGLT2 and DPP4.
  • the compound of the present invention exhibits high selectivity to human SGLT2 and significant in vitro inhibitory activity to human SGLT2 and rhDPP4.
  • the compound of the present invention has good oral bioavailability, significant hypoglycemic effect, kidney and liver protection, and can be used for the treatment of diabetes and related metabolic disorders-derived diseases.
  • 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.
  • a base addition salt can be obtained by contacting 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 amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting 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 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 Isomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the 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 following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of two of formula (B-1) and formula (B-2) A mixture of isomers exists.
  • the following formula (C) represents that the compound exists as a single isomer of formula (C-1) or formula (C-2) or as two isomers of formula (C-1) and formula (C-2) Exist as a mixture.
  • 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 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 lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
  • 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 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
  • 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.
  • 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, a nucleophilic 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 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
  • FIG. 1 Blood glucose change value-time curve
  • Figure 2 The area under the blood glucose change value-time curve
  • FIG. 3 Plasma insulin content when given sugar for 1 hour
  • FIG. 4 DPP4 activity in plasma after 2 hours of sugar administration
  • Figure 5 The content of active GLP-1 in plasma after 2 hours of sugar administration
  • Figure 6 Blood glucose control after 2 and 4 weeks of administration
  • Figure 7 Changes of urine albumin and urine creatinine 24 days after administration
  • Figure 8 Hepatic fatty lesions and liver specific gravity 5 weeks after administration.
  • the aqueous phase was extracted twice with ethyl acetate (100 mL).
  • the organic phases were combined, and the organic phase was washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • Step 8 Synthesis of compound A-1-10.
  • reaction system A Under the protection of nitrogen, at -78°C, add n-butyllithium (2.5M, 27.12mL, 1.1eq) dropwise to compound A-6-2 (14g, 61.65mmol, 1eq) in anhydrous tetrahydrofuran (140mL) In solution. After the addition was completed, the reaction was stirred at -78° C. for 0.5 hours to obtain reaction system A.
  • reaction system B Under the protection of nitrogen, tert-butylmagnesium chloride (1.7M, 47.14mL, 1.3eq) was added dropwise to the anhydrous tetrahydrofuran of compound A-1-4 (18.53g, 67.81mmol, 1.1eq) at 0°C (180 mL), after the dropwise addition is completed, react at 0°C for 0.5 hours to prepare reaction system B. Under the protection of nitrogen, the reaction system B was slowly added to the reaction system A at -78°C. After the reaction was reacted at -78°C for 0.5 hours, the temperature was raised to 25°C and the reaction was continued for 15.5 hours.
  • reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (100mL) was added to the residue, washed with water (50mL*2), then with saturated brine (50mL*2), dried with anhydrous sodium sulfate, filtered and then depressurized Concentrated to obtain the target compound A-6-5.
  • the product was confirmed by LCMS, LC-MS (m/z) 359 [M+Na] + .
  • Compound A-6-6 (9.2g, 31.05mmol, 1eq) was dissolved in 1,4-dioxane (100mL), acetic anhydride (25.36g, 248.38mmol, 23.26mL, 8eq), pyridine ( 24.56g, 310.48mmol, 25.06mL, 10eq), 4-dimethylaminopyridine (1.90g, 15.52mmol, 0.5eq), stirred at 80°C for 16 hours. After the reaction, the solvent was removed by concentration under reduced pressure.
  • phosphorus tribromide (98.44mg, 363.68 ⁇ mol, 34.18 ⁇ l, 0.5eq) was added to a solution of compound A-6-9 (300mg, 727.36 ⁇ mol, 1eq) in anhydrous tetrahydrofuran (3mL) at 0°C, The reaction was stirred at 0°C for 3 hours. After the reaction, the reaction solution was washed with 1N potassium carbonate aqueous solution to separate the layers, and the aqueous phase was extracted with dichloromethane (2 mL). The organic phases were combined and concentrated under reduced pressure.
  • reaction solution was allowed to stand and separate into layers, and the aqueous phase was extracted with ethyl acetate (80 mL*2).
  • the organic phases were combined, washed with brine (80mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a yellow oil, added toluene (50mL) and concentrated under reduced pressure again to obtain compound A-7-3, which was used directly without purification To the next step.
  • tert-butylmagnesium chloride (1.7M, 37.56mL, 1.6eq) was added dropwise to the solution of compound A-1-4 (10.91g, 39.91mmol, 1eq) in dry tetrahydrofuran (200mL) at 0°C. After the addition was completed, the reaction was stirred at 0-5°C for 0.5 hours. Under nitrogen protection, compound A-7-3 (10.5g, 39.91mmol, 1eq) was added to the reaction, the temperature was lowered to -70°C, and n-butyllithium (2.5M, 20.75mL, 1.3eq) was added dropwise.
  • Compound A-7-6 (8 g, 21.48 mmol, 1 eq) was mixed in a mixed solvent of acetic acid (80 mL) and H 2 O (80 mL), and heated to 100° C. and stirred for 16 hours. After the completion of the reaction, the reaction was directly concentrated under reduced pressure and then azeotropically concentrated under reduced pressure with toluene (50mL*2) to obtain compound A-7-7. The product was confirmed by LCMS, LC-MS (m/z) 350.1 [M+H 2 O] + .
  • compound A-7-7 (8g, 24.07mmol, 1eq), triethylamine (19.49g, 192.60mmol, 26.81mL, 8eq), 4-dimethylaminopyridine (294.12mg, 2.41mmol, 0.1eq) and acetonitrile (100mL), then add acetic anhydride (14.75g, 144.45mmol, 13.53mL, 6eq), and stir at 25°C for 16 hours. After the completion of the reaction, it was concentrated under reduced pressure.
  • trimethylsilyl trifluoromethanesulfonate (12.44g, 55.95mmol, 10.11mL, 4eq) was added to compound A-7-8 (7g, 13.99mmol, 1eq) and thiourea (3.73g, 48.96 mmol, 3.5eq) in a mixture of anhydrous dioxane (100mL). The reaction was stirred at 80°C for 0.5 hour.
  • the reaction was cooled to 10°C, and methyl iodide (5.96g, 41.96mmol, 2.61mL, 3eq) and diisopropylethylamine (9.04g, 69.94mmol, 12.18mL, 5eq) were added in sequence, and the temperature was raised to 25°C and stirred for 10 hour.
  • the reaction was quenched by adding water (80 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated brine (150 mL), and concentrated under reduced pressure to obtain a crude product.
  • Triethylamine (27.02g, 267.04mmol, 37.17mL, 2eq) was added to the dichloromethane (110mL) solution of compound B-1-1 (25g, 133.52mmol, 1eq), the temperature was reduced to 0°C, and methane was added dropwise Sulfonyl chloride (15.30 g, 133.52 mmol, 10.33 mL, 1 eq). After the addition was completed, the reaction was raised from 0°C to 15°C, and the reaction was stirred for 3 hours. After the reaction was completed, the temperature was lowered to 0°C, and water (100 mL) was slowly added at 0°C to quench the reaction.
  • compound B-1-6 (24.67g, 75.38mmol, 1.05eq) was dissolved in a mixed solution of anhydrous dichloromethane (200mL) and anhydrous N,N-dimethylformamide (200mL) , Add compound B-1-5 (20g, 71.79mmol, 1eq, HCl) at 20°C and react for 1 hour. After the reaction is cooled to -70°C, continue to stir for 0.5 hours. Below -70°C, slowly add boron acetate within 30 minutes Sodium hydride (30.43g, 143.60mmol, 2eq), control the reaction temperature below -60°C during the feeding process. The reaction was stirred at -70°C for 17.5 hours.
  • reaction was directly concentrated under reduced pressure, and the residue was slowly diluted with water (600 mL), and a large amount of white flocculent solid was precipitated. After stirring for 1 hour, it was filtered and the filter cake was washed with water (100 mL*3). Ethanol (500 mL) was added to the filter cake and stirred for 12 h. The filter cake was collected after filtration, washed with ethanol (100 mL), and the solid was dried under reduced pressure to obtain compound B-1-7.
  • double pinacol borate (4.88g, 19.20mmol, 1.25eq), potassium acetate (4.52g, 46.08mmol, 3eq) and Pd(dppf)Cl 2 .DCM (3.76g, 4.61mmol, 0.3eq) was added to compound B-1-7 (8.5g, 15.36mmol, 1eq) in anhydrous dioxane (170mL) solution.
  • the reaction was heated to 100°C, and the reaction was stirred for 7 hours.
  • the reaction solution was concentrated under reduced pressure and diluted with dichloromethane (500 mL). The organic phase was washed with water (200 mL x 3).
  • compound A-2 and compound B-1 (309.52mg, 515.44 ⁇ mol, 1eq) and tetrakistriphenylphosphine palladium (59.56mg, 51.54 ⁇ mol, 0.1eq) and potassium carbonate (142.47mg, 1.03mmol, 2eq) was suspended in a mixed solution of dioxane (4mL) and water (1mL), and the reaction was stirred at 50°C for 5 hours.
  • WX002-1 (190mg, 207.10 ⁇ mol, 1eq) was dissolved in dichloromethane (2.5mL), trifluoroacetic acid (770.00mg, 6.75mmol, 0.5mL, 32.61eq) was added dropwise, and the reaction was stirred at 25°C for 2 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate (10 mL) and dichloromethane (10 mL) were added to the residue, and the layers were separated after stirring. The organic phase was collected and concentrated under reduced pressure to obtain WX002-2, the product LC-MS m/z) 817.2 [M+H] + .
  • compound A-7 (170 mg, 332.47 ⁇ mol, 1 eq), compound B-1 (199.65 mg, 332.47 ⁇ mol, 1 eq), tetrakistriphenylphosphine palladium (38.42 mg, 33.25 ⁇ mol, 0.1 eq) and sodium carbonate (105.71mg, 997.40 ⁇ mol, 3eq) in a mixture of dioxane (4mL) and water (1mL) was stirred at 50°C for 7 hours. After the completion of the reaction, it was concentrated under reduced pressure to obtain the crude product of WX006-1, which was confirmed by LCMS with LC-MS (m/z) 906.5 [M+H] + .
  • Trifluoroacetic acid (770.00mg, 6.75mmol, 0.5mL, 58.44eq) was added to a solution of WX006-2 (90mg, 115.56 ⁇ mol, 1eq) in dichloromethane (3mL). The reaction was stirred at 20°C for 0.5 hour. After the reaction, it was concentrated under reduced pressure. The residue was dissolved with dichloromethane (20 mL) and washed with 1N potassium carbonate aqueous solution (15 mL). The organic phase was concentrated under reduced pressure to obtain a crude product.
  • A-8 (227mg, 447.41 ⁇ mol, 1eq), B-1 (322.40mg, 536.89 ⁇ mol, 1.2eq), potassium carbonate (123.67mg, 894.82 ⁇ mol, 2eq) and tris(dibenzylideneacetone) Dipalladium (40.97mg, 44.74 ⁇ mol, 0.1eq) was stirred in a mixed solution of water (1.5mL) and dioxane (5mL) at 50°C for 7 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product of WX008-1, which was confirmed by LCMS, LC-MS (m/z) 901.3 [M+H] + .
  • Trifluoroacetic acid (1.26g, 11.02mmol, 815.72 ⁇ L, 40.08eq) was added to a solution of WX008-2 (213mg, 274.88 ⁇ mol, 1eq) in dichloromethane (3mL), and the reaction was stirred at 25°C for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • 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 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), 1.2mM magnesium chloride (MgCl 2 ), 4.7mM potassium chloride (KCl), 2.2mM calcium chloride (CaCl 2 ) and 120mM sodium chloride (NaCl).
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl sodium chloride
  • the compound was diluted with 100% dimethyl sulfoxide (DMSO) with 1 mM as the starting concentration, and made 8 points 5-fold serial dilutions.
  • DMSO dimethyl sulfoxide
  • the data is calculated by GraphPad Prism 5.0 software: log(inhibitor) vs.response--Variable slope to obtain the IC 50 value of the test compound.
  • the experimental results are shown in Table 5.
  • 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.
  • Experimental buffer 10mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), 1.2mM magnesium chloride (MgCl 2 ), 4.7mM potassium chloride (KCl), 2.2mM calcium chloride (CaCl 2 ) and 120mM sodium chloride (NaCl).
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl sodium chloride
  • Stop buffer 10mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), 1.2mM magnesium chloride (MgCl 2 ), 4.7mM potassium chloride (KCl), 2.2mM calcium chloride (CaCl 2 ), 120mM sodium chloride ( NaCl) and 1 ⁇ M LX4211.
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl sodium chloride
  • the compound was diluted with 100% dimethyl sulfoxide (DMSO) with 10uM as the starting concentration, and made 8 points 5-fold serial dilutions.
  • DMSO dimethyl sulfoxide
  • Tricarb isotope detector
  • the data is calculated by GraphPad Prism 5.0 software: log(inhibitor) vs.response--Variable slope to obtain the IC 50 value of the test compound.
  • the experimental results are shown in Table 5.
  • rhDPP4 recombinant human dipeptidyl peptidase 4
  • rhDPP4 is used to catalyze the production of luciferin as a substrate, which is the luminescent precursor glycine-proline-aminofluorescein (Gly-Pro-aminoluciferin), and reacts with luciferase to generate light signals , The intensity of the light signal is directly proportional to the enzyme activity.
  • rhDPP4 was prepared as a 0.2ng/ml working solution with 10mM Tris-HCl (pH8.0) aqueous solution.
  • Inhibitory activity% 100-(compound well signal value-blank control well signal value)/(positive control well signal value-blank control well signal value)*100
  • the compound of the present invention shows high selectivity to human-SGLT2; it has significant in vitro inhibitory activity to human-SGLT2 and rhDPP4.
  • mice 6 healthy adult male C57 mice were selected, 3 for the intravenous injection group and 3 for the oral group.
  • the test compound is mixed with an appropriate amount of intravenous group solvent (20% polyethylene glycol-400 (PEG400)/10% polyethylene glycol-15 hydroxystearate (solutol)/70% H 2 O), vortex and Ultrasound, prepare a clear solution of 1mg/mL, and filter with a microporous membrane for use;
  • the oral group solvent is 20% polyethylene glycol-400 (PEG400)/10% polyethylene glycol-15 hydroxystearate (solutol) /70% H 2 O, after mixing the test compound with the solvent, vortex and sonicate to prepare a 1 mg/mL clear solution.
  • C max is the maximum concentration
  • F% oral bioavailability
  • oral unit exposure is
  • Oral DNAUC AUC PO /Dose
  • AUC PO is oral exposure
  • Dose is drug dose
  • Vd ss volume of distribution
  • Cl clearance Rate
  • T 1/2 is the half-life.
  • the compound of the present invention shows certain oral exposure and bioavailability in mice.
  • 200g BW is the average weight of 200g.
  • the compound of the present invention can significantly reduce the blood glucose AUC level of the animal within 2 hours; the animal's 24-hour urine glucose excretion level is lower than that of the positive compound.
  • Group Compound grouping dose Dosing frequency Mode of administration Number of animals per group 1 Vehicle control group 0 Single dose Gavage 5 2 Test compound 50mg/kg Single dose Gavage 5
  • the animals were fasted for 6 hours and their blood glucose was measured. Drugs or solvents were given according to the above table, and 50% glucose solution (2g/kg, 0.4g/mL) was given 30 minutes later.
  • the time points of -30min, 0min, 15min, 30min, 60min, 90min, and 120min when sugar is collected are used for blood glucose determination.
  • blood was taken to test insulin secretion.
  • sugar was given for 2 hours, the animal was euthanized, and blood was taken to test DPP4 activity and active GLP-1.
  • the compound of the present invention can significantly reduce the blood glucose AUC level of the animal within 2 hours, significantly increase the level of insulin and active GLP-1, and reduce the activity of DPP4.
  • mice After 7-week-old BKS and BKS-db mice completed adaptive breeding, they were fasted for 6 hours to collect blood, and fasting blood glucose and HbA1c were detected. According to the 6h fasting HbA1c group of mice (the main reference index), and fasting blood glucose, body weight grouping (secondary reference index).
  • Figure 6 shows that the compound of the present invention has a significant hypoglycemic effect
  • Figures 7 and 8 show that the compound of the present invention has a renal protective effect.

Abstract

作为SGLT2/DPP4双抑制剂的一类化合物，以及在制备作为SGLT2/DPP4双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。

Description

一种SGLT2/DPP4抑制剂及其应用
本申请主张如下优先权
CN201910683099.2，申请日：2019.07.26；
CN 202010119914.5，申请日：2020.02.26；
CN202010572226.4，申请日：2020.06.22。
技术领域
本发明涉及作为SGLT2/DPP4双抑制剂的一类化合物，以及在制备作为SGLT2/DPP4双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、格列奈类、α-葡萄糖苷酶抑制剂，二肽基肽酶-IV抑制剂和钠-葡萄糖共转运蛋白(SGLT2)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；钠-葡萄糖共转运蛋白(SGLT2)抑制剂增加泌尿，生殖系统感染风险等。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。其中SGLT-2在肾脏中高水平表达，负责90％的肾脏葡萄糖重吸收。抑制SGLT2，可以阻止肾脏葡萄糖的重吸收过程，促使葡萄糖通过尿液排出体外，降低血糖。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。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，并且，达格列净、卡格列净、恩格列净已经在临床中，显示出具有心血管获益或者肾脏保护作用，因此SGLT2已成为治疗糖尿病的理想潜在靶点之一。但SGLT2药物也带来了增加泌尿、生殖系统感染的风险。
二肽基肽酶-IV(Dipeptidyl peptidase 4)是一种细胞表面的丝氨酸蛋白酶，可以灭活多种胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(glucose-dependent insulinotropic polypeptide，GIP)。DPP-4抑制剂可以使DPP-4失活，从而不分解GLP-1，通过提高GLP-1的水平，发挥控 制血糖的作用。迄今，世界范围内已上市多种DPP-4抑制剂：西格列汀(sitagliptin)、维格列汀(vildagliptin)、沙格列汀(saxagliptin)、阿格列汀(alogliptin)、利格列汀(linagliptin)、吉格列汀(gemigliptin)和替格列汀(teneligliptin)等。上市的DPP4药物，降糖效果较弱，虽然没有心血管获益，但长期数据显示安全可靠，无明显的副作用。
综上所述，SGLT2/DPP4双重抑制剂有着良好的开发前景。
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 PCTCN2020104521-appb-000001
其中，
R 1为任选被1、2或3个R a取代的C 1-3烷基；
R 2和R 3分别独立地选自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 b取代；
R 5选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
R 4为H、F或Cl，且当R 4为Cl时，R 2、R 3和R 5不同时为H；
R a、R b和R c分别独立地选自F、Cl、Br、I、OH和NH 2。
本发明还提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020104521-appb-000002
其中，
R 1为任选被1、2或3个R a取代的C 1-3烷基；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
R 5选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
R 4为H、F或Cl，且当R 4为Cl时，R 2、R 3和R 5不同时为H；
R a、R b和R c分别独立地选自F、Cl、Br、I、OH和NH 2。
本发明的一些方案中，上述R 1为任选被1、2或3个R a取代的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 1选为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 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-OCH 3，所述CH 3、Et和-OCH 3任选被1、2或3个R b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 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，所述CH 3和Et任选被1、2或3个R b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 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、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R 5选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，所述CH 3和Et任选被1、2或3个R c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 5选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，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。
本发明还提供了下述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020104521-appb-000003
本发明还提供了上述化合物或其药学上可接受的盐在制备SGLT2和DPP4双抑制剂的相关药物中的 应用。
技术效果
本发明化合物表现出对人SGLT2的高选择性和对人SGLT2和rhDPP4具有显著的体外抑制活性。本发明化合物具有良好的口服生物利用度，降糖效果显著，具有肾脏和肝脏保护作用，可用于糖尿病及相关代谢紊乱衍生疾病的治疗。
定义与说明
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。
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，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020104521-appb-000004
和楔形虚线键
Figure PCTCN2020104521-appb-000005
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020104521-appb-000006
和直形虚线键
Figure PCTCN2020104521-appb-000007
表示立体中心的相对构型，用波浪线
Figure PCTCN2020104521-appb-000008
表示楔形实线键
Figure PCTCN2020104521-appb-000009
或楔形虚线键
Figure PCTCN2020104521-appb-000010
或用波浪线
Figure PCTCN2020104521-appb-000011
表示直形实线键
Figure PCTCN2020104521-appb-000012
和直形虚线键
Figure PCTCN2020104521-appb-000013
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2020104521-appb-000014
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2020104521-appb-000015
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 PCTCN2020104521-appb-000016
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 PCTCN2020104521-appb-000017
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 PCTCN2020104521-appb-000018
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。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020104521-appb-000019
直形虚线键
Figure PCTCN2020104521-appb-000020
或波浪线
Figure PCTCN2020104521-appb-000021
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 PCTCN2020104521-appb-000022
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 PCTCN2020104521-appb-000023
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。
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，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。
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。
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(例如亲核取代反应)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；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；Et代表乙基。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020104521-appb-000024
软件命名，市售化合物采用供应商目录名称。
附图说明
图1：血糖变化值-时间曲线；
图2：血糖变化值-时间曲线下面积；
图3：给糖1h时血浆胰岛素含量；
图4：给糖2h时血浆中DPP4活性；
图5:给糖2h时血浆中活性GLP-1含量；
图6：给药2周和4周后血糖控制情况；
图7：给药24天后尿白蛋白及尿肌酐变化；
图8：给药5周后肝脏脂肪病变及肝脏比重。
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 PCTCN2020104521-appb-000025
合成路线：
Figure PCTCN2020104521-appb-000026
步骤1：化合物A-1-2的合成。
将化合物A-1-1(20g,91.32mmol)加入到盛有无水四氢呋喃(100mL)的反应瓶中，氮气保护下滴加硼烷四氢呋喃溶液(1M,120mL)后，在15℃搅拌16小时。反应完毕后，在氮气保护下缓慢滴加甲醇(70mL)淬灭反应。反应液减压浓缩后得到化合物A-1-2粗品，直接用于下一步反应。MS m/z:229.7[M+23] +。
步骤2：化合物A-1-3的合成。
将化合物A-1-2(19g,92.31mmol)(粗品)加入到盛有无水N,N-二甲基甲酰胺(100mL)的反应瓶中，降温到0℃后加入氢化钠(7.00g,174.88mmol)搅拌0.5小时，反应缓慢升温到15℃后加入烯丙基溴(34g,281.04 mmol)继续搅拌18小时。反应完毕后，反应液滴加饱和氯化铵水溶液(50mL)淬灭后减压浓缩，得到黄色粘稠物，加入二氯甲烷(200mL)和水(200mL)搅拌后分层，有机相用水(100mL*2)洗涤后减压浓缩，得到粗品；粗品经柱层析(石油醚100％体系)纯化得到化合物A-1-3。
步骤3：化合物A-1-5的合成。
将化合物A-1-3(15.00g,61.20mmol)溶于无水四氢呋喃(150mL)中，氮气保护下降温至-70℃，滴加正丁基锂的正己烷溶液(2.5M,33.00mL)，滴加完毕后，反应体系在-70℃下搅拌0.5小时，制备反应体系A。将化合物A-1-4(16.73g,61.20mmol)溶于无水四氢呋喃(150mL)中，氮气保护下降温至0℃，滴加叔丁基氯化镁的四氢呋喃溶液(1.7M,69.00mL)，反应在0℃下搅拌0.5小时后，将反应滴加入前述反应体系A中。滴加完毕后，反应在-70℃下搅拌0.5小时，缓慢升温至20℃，继续搅拌2小时。反应完毕后，滴加饱和氯化铵(100mL)淬灭反应，浓缩除去有机溶剂，剩余物用乙酸乙酯萃取(100mL*3)，合并有机相，有机相用饱和食盐水溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯＝10:1～1:1)纯化得到化合物A-1-5。 1H NMR(400MHz,CHCl 3-d)δppm 1.37(s,3H)1.58(s,3H)3.07(d,J＝4.27Hz,1H)4.06-4.11(m,2H)4.59-4.68(m,4H)5.24(dd,J＝10.42,1.38Hz,1H)5.30-5.33(m,1H)5.35(dd,J＝17.32,1.51Hz,1H)5.90-6.03(m,1H)6.10(d,J＝3.51Hz,1H)7.15(t,J＝9.03Hz,1H)8.05(ddd,J＝8.22,5.33,2.26Hz,1H)8.20(dd,J＝6.90,2.13Hz,1H)。
步骤4：化合物A-1-6的合成。
将化合物A-1-5(6.20g,13.72mmol)，七水合三氯化铈(6.20g,16.64mmol,1.58mL)，无水甲醇(100mL)加入到反应瓶中，0℃下，缓慢分批加入硼氢化钠(1.20g,31.72mmol)，反应体系在20℃下搅拌16小时。反应完毕后，滴加饱和氯化铵溶液(100mL)淬灭反应，浓缩除去有机溶剂，溶液变浑浊，加入柠檬酸调节溶液至澄清，用乙酸乙酯萃取(100mL*3)，合并有机相，有机相用饱和食盐水溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得化合物A-1-6的粗品，直接用于下一步反应。MS m/z:372.0[M+18] +
步骤5：化合物A-1-7的合成。
将化合物A-1-6(8.00g,17.60mmol)，乙酸(42.00g,699.42mmol,40mL)，水(40mL)加入到反应瓶中，100℃下搅拌6小时。反应完毕后，浓缩得粗品黄色固体，加入甲苯(30mL)再浓缩，重复两次，得到化合物A-1-7的粗品，直接用于下一步反应。MS m/z:331.9[M+18] +。
步骤6：化合物A-1-8的合成。
将化合物A-1-7(8.00g,17.94mmol)，三乙胺(13.81g,136.51mmol,19.0mL)，乙腈(100mL)加入到反应瓶中，然后依次加入乙酸酐(16.35g,160.16mmol,15.0mL)，4-二甲氨基吡啶(35mg,286.49μmol)，反应体系在20℃下搅拌8小时。反应完毕后，滴加饱和硫酸氢钠水溶液(10mL)淬灭反应，加入水(100mL)，乙酸乙酯(100mL)，搅拌均匀后分层，水相用乙酸乙酯(100mL)萃取两次，合并有机相，有机相用饱和食盐水溶液(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯 ＝10:1～2:1)纯化得到化合物A-1-8。MS m/z:500.1[M+18] +。
步骤7：化合物A-1-9的合成。
将化合物A-1-8(4.00g,6.50mmol)，硫脲(1.28g,16.82mmol)，无水二氧六环(50mL)加入到反应瓶中，氮气保护下加入三甲硅基三氟甲磺酸酯(4.92g,22.14mmol,4.00mL,)，反应在80℃下搅拌2小时。检测中间体生成后，反应降温至20℃，加入碘甲烷(3.60g,25.36mmol,1.58mL)，二异丙基乙胺(4.20g,32.48mmol,5.66mL)，反应在20℃搅拌16小时。反应加入甲醇(10mL)淬灭反应，减压浓缩，剩余物加入水(50mL)后，用乙酸乙酯萃取(50mL*3)，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，滤液减压浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯＝10:1～3:1)纯化得到化合物A-1-9。MS m/z:493.0[M+23] +。
步骤8：化合物A-1-10的合成。
将化合物A-1-9(3.20g,5.80mmol)，巴比妥酸二水合物(1.50g,11.68mmol,2.01eq)，无水乙醇(40mL)加入到反应瓶中，氮气保护下加入四三苯基磷钯(0.32g,276.92μmol,5％mol当量)，反应在40℃下搅拌14小时。反应完毕后冷却过滤，滤液减压浓缩，剩余物加入水(50mL)，用乙酸乙酯萃取(50mL*3)，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，滤液减压浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯＝10:1～1：1)纯化得到化合物A-1-10。 1H NMR(400MHz,CDCl 3)δppm 7.46(dd,J＝7.03,2.01Hz,1H)7.23-7.27(m,1H)6.97-7.11(m,1H)5.32-5.43(m,1H)5.17-5.28(m,1H)5.12(t,J＝9.66Hz,1H)4.76(br d,J＝5.27Hz,2H)4.55(d,J＝9.79Hz,1H)4.45(d,J＝9.79Hz,1H)2.20(s,3H)2.10(s,3H)2.02(s,3H)1.83(s,3H)1.80-1.86(m,1H)。
步骤9：化合物A-1的合成。
氮气保护下，在0℃条件下，将三溴化磷(34.59mg，127.78μmol，12.14μL)滴加到化合物A-1-10(0.11g，255.55μmol)的无水四氢呋喃(2mL)中。反应搅拌16小时，期间由0℃自然升温至20℃。反应完毕后，在反应中缓慢加入2M的碳酸钾水溶液(5.5mL)，搅拌10分钟淬灭反应。反应液静置分层，水相用乙酸乙酯(10mL*2)萃取，合并有机相，有机相依次用水(20mL)与饱和食盐水(10mL)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品用正己烷(10mL)常温搅拌1小时后，过滤收集固体并用正己烷(2mL×3)洗涤，滤饼减压浓缩，去除残留溶剂后得到化合物A-1。 1H NMR(400MHz，CDCl 3)δ7.39-7.30(m，2H)，7.09-7.03(m，1H)，5.36(t，J＝9.6Hz，1H)，5.22(t，J＝9.6Hz，1H)，5.07(t，J＝9.6Hz，1H)，4.58-4.52(m，2H)，4.48-4.41(m，2H)，2.21(s，3H)，2.11(s，3H)，2.02(s，3H)，1.86(s，3H)。
参照参考例1中步骤1～9的合成方法，合成表1中各片段A-2,A-3,A-4,A-5。
表1
Figure PCTCN2020104521-appb-000027
参考例6：片段A-6
Figure PCTCN2020104521-appb-000028
合成路线：
Figure PCTCN2020104521-appb-000029
步骤1：化合物A-6-2的合成
将化合物A-6-1(25g,133.67mmol,1eq)溶于四氢呋喃(250mL)，0℃下加入氢化钠(10.69g,267.33mmol,2eq)，反应升温至25℃下搅拌0.5小时，然后缓慢加入烯丙基溴(48.51g,401.00mmol,34.65mL,3eq)，25℃下继续反应1.5小时。反应完毕后，0℃下加入饱和氯化铵水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取(250mL×2)。合并有机相，减压浓缩后得到粗品，粗品经柱层析纯化(石油醚)得到目标化合物A-6-2， 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A-6-4的合成
氮气保护下，在-78℃条件下，将正丁基锂(2.5M,27.12mL,1.1eq)滴加到化合物A-6-2(14g,61.65mmol,1eq)的无水四氢呋喃(140mL)溶液中。滴加完毕后，反应在-78℃搅拌0.5小时，得到反应体系A。同时在氮气保护下，在0℃条件下，将叔丁基氯化镁(1.7M,47.14mL,1.3eq)滴加到化合物A-1-4(18.53g,67.81mmol,1.1eq)的无水四氢呋喃(180mL)中，滴加完毕后，在0℃下反应0.5小时，制备反应体系B。氮气保护下，在-78℃下将反应体系B缓慢加入到反应体系A中。反应在-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，0℃下向反应液中加入氯化铵溶液(100mL)淬灭反应，加入乙酸乙酯(200mL)稀释分层，有机相用水(50mL*2)洗涤后，再用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥后减压浓缩，剩余物经柱层析(石油醚：乙酸乙酯＝4:1)纯化得到目标化合物A-6-4，产物经LCMS确证，LC-MS(m/z)357[M+Na] +。
步骤3：化合物A-6-5的合成
将化合物A-6-4(13g,38.88mmol,1eq)溶解在甲醇中(130mL)，降温至0℃，依次加入三氯化铈(9.58g,38.88mmol,2.44mL,1eq)，硼氢化钠(2.94g,77.76mmol,2eq)，反应升温至25℃，反应16小时。反应完 毕后，加入饱和氯化铵水溶液(30mL)淬灭反应。反应液减压浓缩至干，剩余物中加入乙酸乙酯(100mL)后，用水(50mL*2)洗涤，再用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤后减压浓缩，得到目标化合物A-6-5，产物经LCMS确证，LC-MS(m/z)359[M+Na] +。
步骤4：化合物A-6-6的合成
化合物A-6-5(10.8g,32.11mmol,1eq)溶于水(50mL)和冰醋酸(50mL)的混合溶剂中，100℃下反应16小时。反应完毕后，减压浓缩，剩余物中加入甲苯(150mL)，减压浓缩后得到化合物A-6-6，产物经LCMS确证，LC-MS(m/z)319[M+Na] +。
步骤5：化合物A-6-7的合成
将化合物A-6-6(9.2g,31.05mmol,1eq)溶解在1,4-二氧六环中(100mL)中，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，减压浓缩去除溶剂，剩余物用乙酸乙酯(100mL)稀释后依次用1M稀盐酸(100mL*4)，水(50mL*2)，饱和食盐水(50mL*2)洗涤。有机相用无水硫酸钠干燥，过滤后减压浓缩。剩余物用柱层析(石油醚：乙酸乙酯＝3:1)进行纯化，得到目标化合物A-6-7，产物经LCMS确证，LC-MS(m/z)487[M+Na] +。
步骤6：A-6-8的合成
将化合物A-6-7(6.2g,13.35mmol,1eq)溶于1,4-二氧六环(62mL)，加入硫脲(3.56g,46.72mmol,3.5eq)，氮气保护下，在25℃条件下，加入三氟甲磺酸三甲基硅酯(11.87g,53.40mmol,4eq)，反应升温至60℃反应1小时，再降温至25℃，依次加入碘甲烷(9.47g,66.74mmol,5eq)，二异丙基乙胺(17.25g,133.49mmol,10eq)，反应在25℃下继续搅拌15小时。反应结束后，加水(60mL)淬灭反应，用乙酸乙酯(60mL*3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。剩余物经柱层析(石油醚：乙酸乙酯＝4:1)纯化得到目标化合物A-6-8，产物经LCMS确证，LC-MS(m/z)475[M+Na] +。
步骤7：A-6-9的合成
向反应瓶中加入A-6-8(4.4g,9.72mmol,1eq)，巴比妥酸(2.49g,19.45mmol,2eq)，乙醇(44mL)，氮气保护下，加入四三苯基膦钯(516.80mg,486.17μmol,0..05eq)，反应在65℃搅拌16小时。反应结束后，加入饱和碳酸氢钠水溶液调节pH 7至8，过滤，滤液用乙酸乙酯(40mL*2)萃取，合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥后经减压浓缩得到粗产物。粗产物经柱层析(石油醚：乙酸乙酯＝3:2)纯化得到目标化合物A-6-9，产物通过LCMS确证，LC-MS(m/z)435[M+Na] +。
步骤8：A-6的合成
氮气保护下，0℃将三溴化磷(98.44mg，363.68μmol，34.18μl，0.5eq)加入到化合物A-6-9(300mg,727.36μmol,1eq)的无水四氢呋喃(3mL)溶液中，反应在0℃搅拌3小时。反应结束后，反应液用1N碳酸钾水溶液洗涤分层，水相再用二氯甲烷(2mL)萃取。合并有机相，减压浓缩。粗产物用柱层析分离纯化(石 油醚：乙酸乙酯＝4:1)得到目标化合物A-6。 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7：片段A-7
Figure PCTCN2020104521-appb-000030
合成路线：
Figure PCTCN2020104521-appb-000031
步骤1：化合物A-7-2的合成
将反应瓶中用氮气置换后，0℃下将硼氢化钠(7.28g,192.43mmol,3.04eq)分批加入到A-7-1(14g,63.35mmol,1eq)的甲醇(60mL)溶液中。反应在0℃搅拌2小时。反应完毕后，0℃条件下，缓慢加入饱和氯化铵溶液(20mL)淬灭反应，淬灭后，反应继续搅拌30分钟后减压浓缩。剩余物中加入乙酸乙酯(300mL)和饱和氯化钠水溶液(100mL)，搅拌后分层，收集有机相。有机相经无水硫酸钠干燥后减压浓缩。粗品经柱层析(石油醚:乙酸乙酯＝1:0～10:1)纯化得到化合物A-7-2。
步骤2：化合物A-7-3的合成
0℃下将氢氧化钠(20.86g,521.45mmol,5eq)加入到水(60mL)中搅拌溶解，再依次加入甲苯(180mL)，化合物A-7-2(24.4g,104.29mmol,1eq)和四丁基溴化铵(TBAB)(3.36g,10.43mmol,0.1eq)。反应在25℃搅拌0.5小时后再加入烯丙基溴(18.92g,156.43mmol,13.52mL,1.5eq)。反应升温至50℃搅拌10.5小时。反应液静置分层，水相用乙酸乙酯(80mL*2)萃取。合并有机相，用盐水(80mL*2)洗涤后经无水 硫酸钠干燥，减压浓缩得黄色油状物，加入甲苯(50mL)后再次减压浓缩得到化合物A-7-3，不纯化直接用于下一步。
步骤3：化合物A-7-5的合成
氮气保护下，0℃滴加叔丁基氯化镁(1.7M,37.56mL,1.6eq)到化合物A-1-4(10.91g,39.91mmol,1eq)的无水四氢呋喃(200mL)溶液中。滴加完毕后，反应在0-5℃搅拌0.5小时。氮气保护下，向反应中加入化合物A-7-3(10.5g,39.91mmol,1eq)，降温至-70℃，滴加正丁基锂(2.5M,20.75mL,1.3eq)。滴加完后在-70℃搅拌0.5小时后，升温至25℃搅拌反应2小时。反应结束后，在0-10℃下，滴加饱和氯化铵溶液(50mL)淬灭反应，用乙酸乙酯(80mL*2)萃取。有机相合并后，经无水硫酸钠干燥后减压浓缩得到粗品。粗品经柱层析分离(石油醚：乙酸乙酯＝10:1～2:1)得到化合物A-7-5，产物经LCMS确证，LC-MS(m/z)393.2[M+Na] +。
步骤4：化合物A-7-6的合成
向反应瓶中加入化合物A-7-5(6.5g,15.51mmol,1eq)，三氯化铈(4.59g,18.61mmol,1.17mL,1.2eq)和甲醇(80mL)。将硼氢化钠(469.29mg,12.41mmol,0.8eq)溶于氢氧化钠(1M,4.65mL,0.3eq)水溶液中后再加入反应中。反应在25℃搅拌0.5小时。反应完毕后，加入饱和氯化铵水溶液(30mL)淬灭反应，减压浓缩去除溶剂后，加入乙酸乙酯(150mL)和无水硫酸镁(20g)。混合物经硅藻土过滤，用乙酸乙酯(30mL*3)洗涤滤饼。合并滤液减压浓缩得到化合物A-7-6，产物经LCMS确证，LC-MS(m/z)390.2[M+H 2O] +。
步骤5：化合物A-7-7的合成
将化合物A-7-6(8g,21.48mmol,1eq)混合在醋酸(80mL)和H 2O(80mL)的混合溶剂中，升温至100℃下搅拌16小时。反应完毕后，反应直接减压浓缩后再用甲苯(50mL*2)共沸减压浓缩，得到化合物A-7-7，产物经LCMS确证，LC-MS(m/z)350.1[M+H 2O] +。
步骤6：化合物A-7-8的合成
向反应瓶中依次加入化合物A-7-7(8g,24.07mmol,1eq)、三乙胺(19.49g,192.60mmol,26.81mL,8eq)、4-二甲氨基吡啶(294.12mg,2.41mmol,0.1eq)和乙腈(100mL)，然后再加入乙酸酐(14.75g,144.45mmol,13.53mL,6eq)，25℃下搅拌16小时。反应完毕后，减压浓缩，剩余物中加入乙酸乙酯(100mL)稀释，用饱和KHSO 4溶液(80mL*5)洗涤，再用无水硫酸钠干燥后减压浓缩。剩余物经柱层析分离(石油醚：乙酸乙酯＝8:1～2:1)得到黄色油状物。黄色油状物加乙酸乙酯(100mL)溶解后，依次用1N盐酸水溶液(80mL*4)和饱和食盐水(80mL)洗涤。有机相经无水硫酸钠干燥后浓缩，剩余物用甲苯(50mL)共沸减压浓缩两次得到化合物A-7-8，产物经LCMS确证，LC-MS(m/z)523.1[M+Na] +。
步骤7：化合物A-7-9的合成
氮气保护下，将三氟甲磺酸三甲基硅(12.44g,55.95mmol,10.11mL,4eq)加入到化合物A-7-8(7g,13.99mmol,1eq)和硫脲(3.73g,48.96mmol,3.5eq)在无水二氧六环(100mL)的混合液中。反应在80℃搅拌0.5小 时。反应降温至10℃，依次加入碘甲烷(5.96g,41.96mmol,2.61mL,3eq)和二异丙基乙胺(9.04g,69.94mmol,12.18mL,5eq)，再升温至25℃下搅拌10小时。反应中加入水(80mL)淬灭反应，用乙酸乙酯(100mL*3)萃取。有机相合并后用饱和食盐水(150mL)洗涤后，减压浓缩得到粗品。粗品经柱层析分离(石油醚：乙酸乙酯＝10:1～3:1)得到化合物A-7-9，产物经 1H NMR和LCMS确证， 1H NMR(400MHz,CDCl 3)δ1.86(s,3H),2.04(s,3H),2.12(s,3H),2.21(s,3H),4.00-4.09(m,2H),4.50-4.61(m,3H),4.76-4.83(m,1H),5.18-5.46(m,5H),5.89-6.03(m,1H),6.80(t,J＝9.79Hz,1H),7.49-7.57(m,1H)，LC-MS(m/z)534.4[M+2Na] +。
步骤8：化合物A-7-10的合成
氮气保护下，化合物A-7-9(2.5g,5.12mmol,1eq)、巴比妥酸(1.31g,10.24mmol,2eq)和Pd(PPh 3) 4(887.08mg,767.66μmol,0.15eq)在乙醇(60mL)中的混合溶液在50℃下搅拌反应20小时。反应液冷却后减压浓缩。剩余物经柱层析纯化(石油醚：乙酸乙酯＝6:1～2:1)得到化合物A-7-10，产物经LCMS确证，LC-MS(m/z)471.2[M+Na] +。
步骤9：化合物A-7的合成
0℃下，将三溴化磷(271.64mg,1.00mmol,94.32μL,1.5eq)加入到化合物A-7-10(300mg,668.99μmol,1eq)的无水四氢呋喃(5mL)溶液中。反应在20℃搅拌3小时。反应完毕后，将反应液倒入到0℃的1N碳酸钾水溶液(20mL)中淬灭，用乙酸乙酯(20mL*2)进行萃取。有机相合并，经无水硫酸钠干燥后，减压浓缩得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝10:1～3:1)得到化合物A-7。 1H NMR(400MHz,CDCl 3)δppm 1.78(s,3H),1.95(s,3H),2.03(s,3H),2.14(s,3H),4.32-4.44(m,2H),4.49(d,J＝10.01Hz,1H),4.68(d,J＝10.01Hz,1H),5.14(t,J＝9.69Hz,2H),5.26-5.33(m,1H),6.74(t,J＝9.69Hz,1H),7.40(t,J＝7.88Hz,1H)。
参照参考例7中步骤1～9的合成方法，合成表2中片段A-8。
表2
Figure PCTCN2020104521-appb-000032
参考例9：片段B-1
Figure PCTCN2020104521-appb-000033
合成路线：
Figure PCTCN2020104521-appb-000034
步骤1：化合物B-1-2的合成。
将三乙胺(27.02g，267.04mmol，37.17mL，2eq)加到化合物B-1-1(25g，133.52mmol，1eq)的二氯甲烷(110mL)溶液中，降温至0℃，滴加甲烷磺酰氯(15.30g，133.52mmol，10.33mL，1eq)。滴加完毕后，反应由0℃升至15℃，搅拌反应3小时。反应完毕后降温至0℃，于0℃下缓慢加入水(100mL)淬灭反应。混合物用二氯甲烷(100mL*2)萃取，合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥后减压浓缩得到化合物B-1-2，直接用于下一步反应。
步骤2：化合物B-1-4的合成。
将化合物B-1-2(6.00g，22.61mmol，1.00eq)溶于N,N-二甲基甲酰胺(10.00mL)中，依次加入碳酸铯(14.73g，45.22mmol，2.00eq)与化合物B-1-3(3.91g，22.61mmol，1.00eq)，混合物在80℃下搅拌3小时。反应完毕后，加入水(50mL)淬灭反应，用乙酸乙酯(30mL*3)萃取。有机相合并后，依次用水(30mL*3)和饱和食盐水(30mL)洗涤，经无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0～2:1)得到化合物B-1-4。 1H NMR(400MHz，CD 3OD)δ7.41-7.34(m，2H)，6.78-6.74(m，2H)，4.15-4.12(m，1H)，3.64-3.52(m，4H)，2.18-2.07(m，2H)，1.157(s，9H)。
步骤3：化合物B-1-5的合成。
将化合物B-1-4(3.00g，8.77mmol，1.00eq)加到氯化氢的乙酸乙酯溶液(10mL，4M)中，反应在20℃下反应1小时。反应完毕后，加入水(30mL)淬灭反应，混合物用乙酸乙酯(20mL)洗涤后，水相用饱和碳酸氢钠水溶液调节至pH＝7，再用乙酸乙酯(30mL)萃取。有机相用饱和氯化钠水溶液(20mL)洗涤后经无水硫酸钠干燥，减压浓缩得到化合物B-1-5的粗品。该粗品不经进一步纯化直接用于下一步反应。 1H NMR(400MHz，MeOD-d 4)δ7.39-7.35(m，2H)，6.76-6.74(m，2H)，5.30(m，1H)，3.31-3.13(m，4H)，2.15-2.05(m，2H)。
步骤4：化合物B-1-7的合成。
氮气保护下，将化合物B-1-6(24.67g，75.38mmol，1.05eq)溶解在无水二氯甲烷(200mL)和无水N，N-二甲基甲酰胺(200mL)的混合溶液中，20℃下加入化合物B-1-5(20g，71.79mmol，1eq，HCl)反应1小时，反应降温至-70℃后继续搅拌0.5小时，在-70℃以下，30分钟内缓慢加入醋酸硼氢化钠(30.43g，143.60mmol，2eq)，加料过程中控制反应温度在-60℃以下。反应在-70℃搅拌17.5小时。反应完毕后，反应直接减压浓缩，剩余物中缓慢加入水(600mL)稀释，析出大量白色絮状物固体，搅拌1小时后过滤，滤饼用水(100mL*3)洗涤。滤饼中加入乙醇(500mL)后搅拌12h，过滤后收集滤饼，用乙醇(100mL)洗涤后，固体减压干燥后得到化合物B-1-7。 1H NMR(CDCl 3-d)δ7.74(d，J＝8.5Hz，2H)，7.21(br s，1H)，7.02-6.90(m，2H)，6.85-6.82(m，1H)，6.89-6.82(m，2H)，4.88(br dd，J＝7.2，3.1Hz，1H)，4.47(br d，J＝9.5Hz，1H)，4.27(br d，J＝10.0Hz，1H)，4.23-4.18(m，1H)，3.81-3.68(m，1H)，3.38(br t，J＝10.7Hz，1H)，3.02-2.89(m，3H)，2.64-2.51(m，2H)，2.45(br d，J＝11.0Hz，1H)，2.39-2.26(m，1H)，2.07-1.95(m，1H)，1.51(q，J＝11.8Hz，1H)，1.33(s，12H)，1.26(br s，9H)。
步骤5：化合物B-1的合成。
氮气保护下，将依次将双联频那醇硼酸酯(4.88g,19.20mmol,1.25eq)，乙酸钾(4.52g,46.08mmol,3eq)和Pd(dppf)Cl 2.DCM(3.76g,4.61mmol,0.3eq)加入到化合物B-1-7(8.5g,15.36mmol,1eq)的无水二氧六环(170mL)溶液中。反应升温至100℃，搅拌反应7小时。反应液减压浓缩后用二氯甲烷(500mL)稀释。有机相用水(200mL x 3)洗涤。有机相经无水硫酸钠干燥，滤除固体，减压浓缩得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1～0:1)得到化合物B-1。 1H NMR(CDCl 3)δ7.74(d,J＝8.8Hz,2H),7.25-7.15(m,1H),7.00-6.87(m,2H),6.84(d,J＝8.8Hz,2H),4.92-4.82(m,1H),4.48(br d,J＝8Hz,1H),4.27(br d,J＝9.8Hz,1H),4.24-4.18(m,1H),3.78-3.66(m,1H),3.38(br t,J＝10.8Hz,1H),3.07-2.84(m,3H),2.65-2.50(m,2H),2.49-2.39(m,1H),2.37-2.27(br d,J＝7.5Hz,1H),2.04-1.98(m,1H),1.69(s,3H),1.52(q,J＝12Hz,1H),1.33(s,12H),1.26(s,9H)。
实施例1：WX001
Figure PCTCN2020104521-appb-000035
合成路线：
Figure PCTCN2020104521-appb-000036
步骤1：化合物WX001-1的合成
氮气保护下，将B-1(126.59mg，210.81μmol)与A-1(0.104g，210.81μmol)以及碳酸钠(44.69mg，421.62μmol)与四三苯基磷钯(48.72mg，42.16μmol)悬浮于甲苯(2.4mL)与乙醇(0.6mL)以及水(0.6mL)的混合溶剂中。反应在50℃下搅拌16小时。反应完毕后，将反应液减压浓缩后，剩余物用二氯甲烷(30mL)稀释后用水(20mL*2)洗涤。有机相经无水硫酸钠干燥后减压浓缩得到粗品。粗品中加入乙醇(9.50mL)搅拌3小时后过滤。固体用乙醇(2mL*3)洗涤后减压干燥得到化合物WX001-1。MS m/z:887.5[M+1] +
步骤2：化合物WX001-2的合成
将化合物WX001-1(0.128g，144.31μmol)溶于乙酸乙酯(2.5mL)中，再加入氯化氢乙酸乙酯溶液(4M，2.5mL)。反应在20℃搅拌16小时。反应完毕后，减压浓缩，得到化合物WX001-2的粗品。粗品不经进一步纯化直接用于下一步反应。
步骤3：化合物WX001的合成
将碳酸钾(108.28mg，783.42μmol)加到化合物WX001-2(0.129g，156.68μmol)粗品的甲醇(5mL)溶液中。反应在25℃搅拌2小时。反应完毕后过滤，滤液减压浓缩后用二氯甲烷(20mL)稀释。有机相用水(15mL*3)洗涤。水相合并后用二氯甲烷(10mL*2)萃取。合并所有有机相，经无水硫酸钠干燥后，减压浓缩得粗品。粗品经制备高效液相色谱(乙腈/水/碳酸铵/氨水体系)分离纯化。得到目标化合物WX001。 1H NMR(400MHz，CDCl 3)δ7.25-7.17(m，1H)，7.17-7.06(m，4H)，7.06-6.92(m，3H)，6.77(br d，J＝7.6Hz，2H)，4.79(br s，1H)，4.34(br d，J＝8.8Hz，1H)，4.24-4.02(m，3H)，4.01-3.77(m，2H)，3.66-3.52(m，1H)，3.52-3.29(m，3H)，3.14-3.01(m，1H)，2.91-2.82(m，1H)，2.79-2.70(m，2H)，2.62-2.55(m，2H)，2.44-2.30(m，2H)，2.27-2.21(m，1H)，2.16(br s，3H)，2.07-1.89(m，1H)，1.49-1.37(m，1H)。
实施例2：WX002
Figure PCTCN2020104521-appb-000037
合成路线
Figure PCTCN2020104521-appb-000038
步骤1：WX002-1的合成
氮气保护下，将化合物A-2与化合物B-1(309.52mg,515.44μmol,1eq)以及四三苯基膦钯(59.56mg,51.54μmol,0.1eq)与碳酸钾(142.47mg,1.03mmol,2eq)悬浮于二氧六环(4mL)与水(1mL)的混合溶液中，反应在50℃搅拌5小时。粗品经柱层析纯化(二氯甲烷：甲醇＝1:0～4:1)得到WX002-1，产物LC-MS(m/z)917.8[M+H] +。
步骤2：WX002-2的合成
将WX002-1(190mg,207.10μmol,1eq)溶于二氯甲烷(2.5mL)中，滴加三氟乙酸(770.00mg,6.75mmol,0.5mL,32.61eq)，反应在25℃搅拌2小时。反应完毕后，反应液减压浓缩，剩余物中加入饱和碳酸氢钠(10mL)和二氯甲烷(10mL)搅拌后分层，收集有机相并减压浓缩得到WX002-2，产物LC-MS(m/z)817.2[M+H] +。
步骤3：WX002的合成
在25℃下，将碳酸钾(135.28mg,978.79μmol,5eq)加到WX002-2(160mg,195.76μmol,1eq)的甲醇(2mL)溶液中，搅拌2小时。反应完毕后，反应液过滤，滤液减压浓缩得到粗品。粗品通过制备色谱分离纯化得到WX002，产物通过LCMS确证，LC-MS(m/z)691.1[M+H] +， 1H NMR(400MHz,CD 3OD)δppm 1.64(q,J＝11.54Hz,1H),1.95-2.04(m,1H),2.14(s,3H),2.28-2.36(m,1H),2.38(s,3H),2.50(br d,J＝14.31Hz,1H),2.62-2.75(m,2H),2.91-3.09(m,3H),3.21-3.30(m,1H),3.35-3.53(m,4H),3.94-4.07(m,2H),4.21-4.31(m,1H),4.42(d,J＝9.54Hz,1H),4.47(d,J＝9.03Hz,2H),4.59(br s,1H),6.82(d,J＝8.78Hz,2H),7.07-7.38(m,6H),8.47(s,1H)。
参照实施例2中步骤1～3的合成方法，用片段A-3、A-4、A-6替代A-2合成下表3中的实施例3-5。
表3
Figure PCTCN2020104521-appb-000039
实施例6：WX006
Figure PCTCN2020104521-appb-000040
合成路线
Figure PCTCN2020104521-appb-000041
步骤1：WX006-1的合成
氮气保护下，化合物A-7(170mg,332.47μmol,1eq)，化合物B-1(199.65mg,332.47μmol,1eq)，四三苯基膦钯(38.42mg,33.25μmol,0.1eq)和碳酸钠(105.71mg,997.40μmol,3eq)在二氧六环(4mL)和水(1mL)的混合物在50℃下搅拌7小时。反应完毕后减压浓缩得到WX006-1粗品，产物通过LCMS确证，LC-MS(m/z)906.5[M+H] +。
步骤2：WX006-2的合成
将甲醇钠(23.88mg,442.01μmol,2eq)加到WX006-1(200mg,221.00μmol,1eq)粗品与甲醇(5mL)的混合物中。反应在25℃搅拌2小时。反应完毕后减压浓缩，剩余物经硅胶制备板分离纯化两次(展开剂比例依次为二氯甲烷：甲醇＝15:1，二氯甲烷：甲醇＝10:1)得到WX006-2，产物通过LCMS确证，LC-MS(m/z)779.3[M+H] +。
步骤3：WX006的合成
将三氟乙酸(770.00mg,6.75mmol,0.5mL,58.44eq)加到WX006-2(90mg,115.56μmol,1eq)的二氯甲烷(3mL)溶液中。反应在20℃搅拌0.5小时。反应完毕后减压浓缩。剩余物中加如二氯甲烷(20mL)溶解后用1N碳酸钾水溶液(15mL)洗涤。有机相减压浓缩后得到粗品。粗品经硅胶制备板分离(二氯甲烷：甲醇＝8:1，Rf＝0.2)制备分离后，再经超临界手性制备分离(柱型号：DAICEL CHIRALPAK AS(250mm*30mm,10μm)，流动相A相超临界二氧化碳，B相:0.1％氨水-乙醇溶液；比例B％:35％-35％)分离纯化得到WX006，产物通过LCMS确证，LC-MS(m/z)679.4[M+H] +， 1H NMR(400MHz,CD 3OD)δppm 1.45-1.56(m,1H),1.93-2.01(m,1H),2.14(s,3H),2.28-2.38(m,1H),2.39-2.47(m,1H),2.57-2.66(m,2H),2.89-2.97(m,2H),2.97-3.05(m,2H),3.34-3.42(m,3H),3.45-3.52(m,2H),3.93(s,2H),4.18-4.24(m,1H),4.30(d,J＝9.54Hz,1H),4.41(d,J＝9.54Hz,1H),4.46-4.53(m,1H),6.83(d,J＝8.53Hz,2H),6.92(t,J＝10.04Hz,1H),7.06-7.18(m,4H),7.18-7.24(m,1H),7.33(t,J＝8.03Hz,1H)
参照实施例6中步骤1～3的合成方法，用片段A-5替代A-7合成下表4中的实施例7。
表4
Figure PCTCN2020104521-appb-000042
实施例8：WX008
Figure PCTCN2020104521-appb-000043
合成路线
Figure PCTCN2020104521-appb-000044
步骤1：WX008-1的合成
氮气保护下，A-8(227mg,447.41μmol,1eq)，B-1(322.40mg,536.89μmol,1.2eq)，碳酸钾(123.67mg,894.82μmol,2eq)和三(二亚苄基丙酮)二钯(40.97mg,44.74μmol,0.1eq)在水(1.5mL)和二氧六环(5mL)的混合溶液中，50℃下搅拌7小时。反应完毕后，反应液减压浓缩得到WX008-1粗品，产物通过LCMS确证，LC-MS(m/z)901.3[M+H] +。
步骤2：WX008-2的合成
将甲醇钠(53.36mg,987.80μmol,2eq)加到WX008-1(445mg,493.90μmol,1eq)与甲醇(3mL)的混合物中，反应在25℃搅拌2小时。反应完毕后，反应液减压浓缩得粗品。粗品经硅胶制备板分离(二氯甲烷:甲醇＝10:1，Rf＝0.12)分离纯化得到WX008-2，产物通过LCMS确证，LC-MS(m/z)775.3[M+H] +。
步骤3：WX008的合成
将三氟乙酸(1.26g,11.02mmol,815.72μL,40.08eq)加到WX008-2(213mg,274.88μmol,1eq)的二氯甲烷(3mL)溶液中，反应在25℃搅拌1小时。反应完毕后，反应液减压浓缩得到粗品。粗品经制备高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[H 2O(0.2％FA)-ACN]；B(ACN)％:10％-40％,6min)分离纯化得到WX008甲酸盐，产物通过LCMS确证，LC-MS(m/z)675.3[M+H] +， 1H NMR(400MHz,CD 3OD)δppm 1.29-1.34(m,1H),1.59(q,J＝11.67Hz,1H),1.97(br dd,J＝9.51,6.63Hz,1H),2.12(s,3H),2.25-2.35(m,1H),2.36(s,3H),2.43-2.50(m,1H),2.59-2.71(m,2H),2.90-2.96(m,1H),2.97-3.05(m,2H),3.10-3.22(m,1H),3.34-3.43(m,2H),3.45-3.54(m,2H),3.89(s,2H),4.19-4.28(m,1H),4.37-4.46(m,3H),6.79(d,J＝8.75Hz,2H),6.87(d,J＝11.01Hz,1H),7.09-7.21(m,4H),7.23-7.26(m,2H),8.49(s,1H).
各实施例的氢谱和质谱数据如表5所示。
表5各实施例的氢谱和质谱数据
Figure PCTCN2020104521-appb-000045
Figure PCTCN2020104521-appb-000046
Figure PCTCN2020104521-appb-000047
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(人-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
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)。
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。
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)。
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。
用同位素检测仪(Micro beta Reader)读数。
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5。
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
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)。
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。
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。
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)。
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。
吸出孔内液体，用终止缓冲液润洗细胞3遍。
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。
用同位素检测仪(Tricarb)读数。
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5。
生物学活性实验3：rhDPP4抑制剂筛选实验
1.实验目的：
通过测定化合物的半数抑制浓度(IC 50)值来评价化合物对重组人二肽基肽酶4(rhDPP4)的抑制活性。本实验中使用rhDPP4催化底物生成萤光素，该底物为发光前体甘氨酸-脯氨酸-氨基荧光素(Gly-Pro-氨基萤光素)，并与萤光素酶反应产生光信号，该光信号强弱与酶活性成正比。
2.实验方法
1)将梯度稀释的化合物(4倍倍比稀释，10个检测浓度)用非接触式纳升级声波移液系统(ECHO)转移250nl至384孔板中(PerkingElmer-6007299)，最终反应体系二甲基亚砜(DMSO)浓度为0.5％。设置空白对照孔(含DMSO，底物以及10mM三羟甲基氨基甲烷-盐酸盐缓冲液(Tris-HCl)和阳性对照孔(含DMSO，底物以及rhDPP4)。
2)取出预先分装冻存的含萤光素酶的缓冲液恢复到室温，然后加入底物配置成底物浓度为20μM的工作液。rhDPP4用10mM Tris-HCl(pH8.0)水溶液配制成0.2ng/ml的工作液。
3)向已加有化合物的384孔板中分别加入25μl含20μM底物的工作液和25μl含0.2ng/ml rhDPP4的工作液，1000rpm离心30s，用铝箔封板膜封板后置于室温孵育1小时。
4)用多功能酶标检测仪EnVision检测光信号强度。原始数据用于化合物抑制rhDPP4活性计算。
抑制活性％＝100-(化合物孔信号值-空白对照孔信号值)/(阳性对照孔信号值-空白对照孔信号值)*100
将抑制百分数导入GraphPad Prism软件进行数据处理得出对应的剂量-效应曲线并得出测试化合物的IC 50值。实验结果见表6：
表6体外细胞活性测试结果
Figure PCTCN2020104521-appb-000048
Figure PCTCN2020104521-appb-000049
注：“--”表示未做相关检测。
结论：本发明化合物表现出对人-SGLT2的高选择性；对人-SGLT2和rhDPP4具有显著的体外抑制活性。
实验例二、体内DMPK研究：
实验目的：以雄性C57小鼠为受试动物，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C57小鼠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(20％聚乙二醇-400(PEG400)/10％聚乙二醇-15羟基硬脂酸酯(solutol)/70％H 2O)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％H 2O，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。小鼠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。
实验结果见表7：
表7化合物PK测试结果
Figure PCTCN2020104521-appb-000050
备注：C max为最大浓度；F％为口服生物利用度；口服单位暴露量为Oral 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。
结论：本发明化合物在小鼠中表现出具备一定的口服暴露量和生物利用度。
实验例三、大鼠口服糖耐量(OGTT)体内药效研究：
实验概要:
1.动物:
Figure PCTCN2020104521-appb-000051
2.实验分组:
Figure PCTCN2020104521-appb-000052
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16h，按照上表给予药物或溶剂(5mL/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1h，恢复进食，收集0min，20min，40min，60min，90min,120min时间点，用于血糖测定；和0-24h时间段尿分别用于尿糖(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 PCTCN2020104521-appb-000053
*表示p<0.5,**表示p<0.01,***表示p<0.001,****表示p<0.0001vs.溶媒对照组。
备注：200g BW为200g平均体重。
结论：相比溶媒对照组，本发明化合物可显著降低动物2小时内血糖AUC水平；动物24小时尿糖排泄水平低于阳性化合物。
实验例四、dbdb小鼠口服糖耐量(OGTT)体内药效研究：
实验概要:
动物:
Figure PCTCN2020104521-appb-000054
实验分组:
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 0 单次给药 灌胃 5
2 受试化合物 50mg/kg 单次给药 灌胃 5
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，根据血糖和体重进行分组。
2.禁食与给药
动物禁食6h后检测血糖，按照上表给予药物或溶剂，30分钟后给予50％葡萄糖溶液(2g/kg,0.4g/mL)。
3.测试
收集给糖时-30min，0min，15min，30min，60min，90min,120min时间点，用于血糖测定。给糖1h时，取血检测胰岛素分泌，给糖2h时，动物安乐死，取血，检测DPP4活性和active GLP-1。
4.数据分析：
统计学分析使用Graphpad Prism 8 unpaired T-test进行比较，小于0.05的p值被认为具有统计学显著性。
数据表示为平均值±标准误，n＝4～5。实验结果如图1、2、3、4和图5所示。附图中的*表示p<0.5,**表示p<0.01,***表示p<0.001,****表示p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物可显著降低动物2小时内血糖AUC水平，显著升高胰岛素以及活性GLP-1水平，降低DPP4活性。
实验例五、高糖高脂饮食BKS-db小鼠口服糖耐量体内药效研究：
1.实验概要:
动物:
Figure PCTCN2020104521-appb-000055
2.实验分组:
Figure PCTCN2020104521-appb-000056
3.实验流程:
7周龄BKS以及BKS-db小鼠完成适应性饲养后，禁食6h取血，检测空腹血糖和HbA1c。根据小鼠6h禁食HbA1c分组(主要参考指标)，和空腹血糖、体重分组(次要参考指标)。
给药至第2周时禁食6hr，测空腹血糖，恢复进食1hr后测餐后血糖；给药至第4周时禁食6hr，测空腹血糖，恢复进食1hr后餐后糖和HbA1c；收集各组小鼠的尿液。动物安乐死后，取肝脏进行油红染色和脂肪变评分。
4.数据分析：
统计学分析使用Graphpad Prism 8，One Way ANOVA或unpaired T test进行比较，小于0.05的p值被认为具有统计学显著性。
数据表示为平均值±标准误，n＝3～8。实验结果如图6、7和图8所示。附图中的“##”表示p<0.01“###”表示p<0.001vs.正常对照组；“*”表示p<0.5,“**”表示p<0.01,“***”表示p<0.001,“****”表示p<0.0001vs.溶媒对照组。
结论：图6表明，本发明化合物具有显著的降糖效果；图7和8表明，本发明化合物具有肾脏保护作用。

Claims (9)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020104521-appb-100001
    其中，
    R 1为任选被1、2或3个R a取代的C 1-3烷基；
    R 2和R 3分别独立地选自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 b取代；
    R 5选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代；
    R 4为H、F或Cl，且当R 4为Cl时，R 2、R 3和R 5不同时为H；
    R a、R b和R c分别独立地选自F、Cl、Br、I、OH和NH 2。
  2. 根据权利要求1所示的化合物、其异构体或其药学上可接受的盐，其中，R 1为任选被1、2或3个R a取代的CH 3。
  3. 根据权利要求2所示的化合物、其异构体或其药学上可接受的盐，其中，R 1选为CH 3。
  4. 根据权利要求1所示的化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-OCH 3，所述CH 3、Et和-OCH 3任选被1、2或3个R b取代。
  5. 根据权利要求4所示的化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-OCH 3。
  6. 根据权利要求1所示的化合物、其异构体或其药学上可接受的盐，其中，R 5选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，所述CH 3和Et任选被1、2或3个R c取代。
  7. 根据权利要求6所示的化合物、其异构体或其药学上可接受的盐，其中，R 5选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et。
  8. 下述化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020104521-appb-100002
    Figure PCTCN2020104521-appb-100003
  9. 根据权利要求1～8任意一项所述化合物、其异构体或其药学上可接受的盐在制备SGLT2和DPP4双抑制剂的药物中的应用。
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