WO2021018046A1 - 一种SGLTs/DPP4抑制剂及其应用 - Google Patents

一种SGLTs/DPP4抑制剂及其应用 Download PDF

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WO2021018046A1
WO2021018046A1 PCT/CN2020/104534 CN2020104534W WO2021018046A1 WO 2021018046 A1 WO2021018046 A1 WO 2021018046A1 CN 2020104534 W CN2020104534 W CN 2020104534W WO 2021018046 A1 WO2021018046 A1 WO 2021018046A1
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compound
reaction
pharmaceutically acceptable
crude product
isomers
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PCT/CN2020/104534
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English (en)
French (fr)
Inventor
毛庆华
于涛
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 BR112022001314A priority Critical patent/BR112022001314A2/pt
Priority to AU2020323037A priority patent/AU2020323037B2/en
Priority to MX2022001029A priority patent/MX2022001029A/es
Priority to JP2022505233A priority patent/JP7299408B2/ja
Priority to US17/629,618 priority patent/US20220259247A1/en
Priority to CN202080052632.6A priority patent/CN114585358B/zh
Priority to EP20847749.7A priority patent/EP4005568A4/en
Publication of WO2021018046A1 publication Critical patent/WO2021018046A1/zh

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    • 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
    • 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
    • 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
    • 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 class of compounds as triple inhibitors of SGLT1/SGLT2/DPP4, and their application in the preparation of medicines as triple inhibitors of SGLT1/SGLT2/DPP4. 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,
  • hypoglycemic drugs used in clinical treatment, mainly including biguanides, sulfonylureas, insulin resistance improvers, glinides, ⁇ -glucosidase inhibitors and dipeptidyl peptidase-IV 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. Therefore, there is an urgent need to develop a safer and more effective new hypoglycemic drug to meet the needs of diabetes treatment.
  • SGLTs Sodium-glucose cotransporters
  • the family members mainly include SGLT1 protein and SGLT2 protein. Their function is to mediate The transmembrane transport of glucose in the intestines and kidneys plays a key role in maintaining the stability of human blood sugar.
  • SGLT1 is mainly distributed in the intestinal mucosal cells of the small intestine, and is also slightly expressed in the myocardium and kidneys. It mainly regulates 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 kidneys, that is, the glucose in the urine can actively attach to the renal tubular epithelial cells when it is filtered by the glomerulus and be transported into the cell by the SGLT2 protein to be reused. .
  • SGLT2 is responsible for 90% of the reabsorption process, and the remaining 10% is completed by SGLT1. Since this process does not involve glucose metabolism, thereby avoiding or reducing the occurrence of adverse reactions of hypoglycemia and reducing the risk of causing cardiovascular diseases, SGLTs have become one of the ideal potential targets for the treatment of diabetes.
  • SGLTs inhibitors especially highly selective SGLT2 inhibitors 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 plasma glucose of diabetic patients. Since 2012, there have been Dapagliflozin, Canagliflozin, Luseogliflozin, Ipragliflozin, Tofogliflozin and Englegliflozin. Six drugs including Empagliflozin have been approved for marketing and become effective drugs for the treatment of diabetes.
  • 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 plays a role in controlling 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.
  • SGLT1 and DPP4 target inhibitors have a synergistic effect, which can promote and prolong the secretion and concentration of endogenous GLP-1, stimulate the secretion of endogenous insulin and increase the overall application of sugar energy in the body.
  • SGLT2 target inhibition can accelerate the increase The excretion of glucose under the condition of blood sugar level, which runs through the overall pathway of glucose absorption, metabolism and excretion in the body, reduces blood sugar levels in all directions and is not easy to cause the risk of hypoglycemia.
  • the SGLT1/SGLT2/DPP4 triple 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 selected C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R b ;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl Optionally substituted by 1, 2 or 3 R c ;
  • R 8 , R 9 , R 10 and R 11 are each independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally 1, 2 or 3 R d substitutions;
  • E 1 is -(CH 2 ) m -;
  • E 2 is -(CH 2 ) n -;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • R a , R b , R c and Rd 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 selected C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R b ;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl Optionally substituted by 1, 2 or 3 R c ;
  • R 8 , R 9 , R 10 and R 11 are each independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally 1, 2 or 3 R d substitutions;
  • E 1 is -(CH 2 ) m -;
  • E 2 is -(CH 2 ) n -;
  • n 0, 1 or 2;
  • n 1 or 2;
  • R a , R b and R c are each independently selected from F, Cl, Br, I, OH and NH 2 .
  • R 1 is selected Et CH 3, CH 3 and Et are the optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, I, OH, NH 2 , CH 3 and Et, wherein the CH 3 and Et are optionally substituted by 1, 2 or 3 R b , and other variables As defined in the present invention.
  • R 2 is selected from Cl, Br, I, OH, NH 2 , CH 3 , Et and Where the CH 3 , Et and Optionally substituted by 1, 2 or 3 R b , other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, I, OH, NH 2 , CH 3 , Et and Other variables are as defined in the present invention.
  • the aforementioned R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, wherein CH 3 and Et are optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br, I, OH, and NH 2 , and other variables are as defined in the present invention.
  • R 8 , R 9 , R 10 and R 11 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, wherein the CH 3 and Et is optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • R 8 , R 9 , R 10 and R 11 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. definition.
  • E 1 is -CH 2 -or -CH 2 -CH 2 -, and other variables are as defined in the present invention.
  • E 1 is -CH 2 -, and other variables are as defined in the present invention.
  • the above E 2 is a single bond or -CH 2 -, and other variables are as defined in the present invention.
  • E 2 is -CH 2 -, and other variables are as defined in the present invention.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 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 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined in the present invention.
  • the present invention also provides the following compounds, their isomers or their pharmaceutically acceptable salts,
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • the above compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides the application of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of related medicines for SGLT1/SGLT2/DPP4 triple inhibitors.
  • the compound of the present invention exhibits superior in vitro inhibitory activity on Human-SGLT1, Human-SGLT2 and rhDPP4; it shows a certain oral exposure and bioavailability; compared with the vehicle control group, the compound of the present invention can significantly reduce animal 2 The blood glucose AUC level within one hour; the animal's 24-hour urine glucose excretion level was lower than the positive compound.
  • 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
  • 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
  • Reference example 1 Fragment A-1, A-2
  • Step 4 Synthesis of compounds A-1-7 and A-1-8.
  • Reference example 2 Fragment A-3, A-4
  • A-3-1 (8g, 46.19mmol, 1eq), triethylamine (9.35g, 92.37mmol, 12.86mL, 2eq), methanesulfonyl chloride (6.61g, 57.73mmol, 4.47mL, 1.25eq) were added to the two The reaction was carried out at 20°C for 16 hours in methyl chloride (120 mL). After the completion of the reaction, the reactant was slowly poured into 200 mL ice water for quenching. After quenching, stirring was continued for 10 minutes. The layer was separated by standing.
  • A-3-3 (11 g, 33.52 mmol, 1 eq) was put into an ethyl acetate solution of hydrogen chloride (4M, 30 mL, 3.58 eq), and stirred at 20°C for 16 hours. After the reaction was completed, it was filtered, the filter cake was washed with ethyl acetate (30 mL) and dissolved in dichloromethane (40 mL), and then concentrated under reduced pressure to obtain the hydrochloride salt of compound A-3-4.
  • hydrogen chloride 4M, 30 mL, 3.58 eq
  • Step 4 Synthesis of compounds A-3-5 and A-3-6.
  • reaction solution was diluted with water (100 mL), the solid was collected by filtration, the filter cake was washed with water (20 mL), and the filter cake was dissolved with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. , Get crude product.
  • A-5-1 (4g, 13.67mmol, 1eq), A-1-6 (6.71g, 20.51mmol, 1.5eq), triethylamine (1.38g, 13.67mmol, 1.90mL, 1eq), magnesium sulfate ( 16.46g, 136.71mmol, 10eq) was added to N,N-dimethylacetamide (40mL), after reacting at 20°C for 1 hour, sodium cyanoborohydride (3.44g, 54.68mmol, 4eq) was added, and the reaction continued 15 hour.
  • A-5-2 (7g, 12.34mmol, 1eq), double pinacol borate (7.83g, 30.84mmol, 2.5eq), potassium acetate (2.42g, 24.67mmol, 2eq), [1,1 -Bis (diphenylphosphorus) ferrocene] dichloride palladium dichloromethane complex (2.01g, 2.47mmol, 0.2eq) was put into anhydrous dioxane (40mL), under the protection of nitrogen 80 React at °C for 16 hours.
  • reaction solution was concentrated under reduced pressure, and the residue was dissolved by adding dichloromethane (20mL), washed with water (20mL ⁇ 3) three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was passed through column chromatography After separation and purification, the product A-5MS:615.3[M+1]+ was obtained.
  • Step 1 Synthesis of compound A-8-1.
  • Step 3 Synthesis of compounds A-8-3 and A-8-4.
  • Solution B was added to solution A at -78°C, and after the reaction was stirred at -78°C for 0.5 hours, the temperature was raised to 25°C and stirred for 2 hours. After the reaction was completed, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (5 mL) to quench the reaction, and saturated brine (5 mL) was added. After standing for layering, the organic phase was collected. The aqueous phase was extracted three times with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was added with n-heptane (10 mL), stirred for 1 hour and then filtered, and the filter cake was collected to obtain compound B-1-4. MS: 363.2[M+1] +
  • Dissolve B-1-5 (1.4g, 2.84mmol, 1eq), thiourea (757.32mg, 9.95mmol, 3.5eq) in dioxane (14mL), and slowly add trifluoromethanesulfonate at 25°C.
  • Methylsilyl ester (2.53g, 11.37mmol, 2.05mL, 4eq), heated to 60°C and stirred for 1.5 hours.
  • A-1 (3g, 5.96mmol, 1eq) and B-1 (4.29g, 7.15mmol, 1.2eq) and sodium carbonate (1.26g, 11.92mmol, 2eq) and tetrakistriphenylphosphonium palladium (1.38g, 1.19 mmol, 0.2 eq) was suspended in a mixed solvent of toluene (86 mL), ethanol (21.5 mL) and water (21.5 mL). The reaction was stirred at 50°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was diluted with dichloromethane (200 mL) and washed with water (100 mL ⁇ 3).
  • 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 chlorine Sodium (NaCl).
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl 120mM chlorine Sodium
  • 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 chlorine Sodium (NaCl).
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl 120mM chlorine Sodium
  • 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 chlorination Sodium (NaCl) and 1 ⁇ M LX4211.
  • HEPES 4-hydroxyethylpiperazine ethanesulfonic acid
  • MgCl 2 magnesium chloride
  • KCl 4.7mM potassium chloride
  • CaCl 2 calcium chloride
  • NaCl 120mM chlorination Sodium
  • Tricarb isotope detector
  • 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.
  • Inhibition activity% 100-(compound well signal value-blank control well signal value)/(positive control well signal value-blank control well signal value)*100; import the inhibition percentage into GraphPad Prism software for data processing to get the corresponding dose -Effect curve and obtain IC50 value of the test compound.
  • the experimental results are shown in Table 4:
  • the compound of the present invention exhibits excellent in vitro inhibitory activity on Human-SGLT1, 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 solvent # of the intravenous injection group, vortexed and sonicated to prepare a clear solution of 1 mg/mL, which is filtered with a microporous membrane for use; for the oral group, the test compound is mixed with the solvent, vortexed and sonicated to prepare A clear solution of 1 mg/mL was obtained.
  • whole blood was collected for a certain period of time to prepare plasma.
  • the drug concentration was analyzed by LC-MS/MS method, and the drug was calculated by Phoenix WinNonlin software (Pharsight, USA) Generation parameters.
  • C max is the maximum concentration
  • F% is the oral bioavailability
  • Oral 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.
  • the solvent used in WXD001 is 10% N-methylpyrrolidone/10% polyethylene glycol-15 hydroxystearate/80% H 2 O;
  • the solvent used in WXD004 is 20% polyethylene glycol 400/10% polyethylene glycol-15 hydroxystearate/70% H 2 O.
  • the compound of the present invention shows certain oral exposure and bioavailability in mice.
  • the animals were fasted for 18h in the metabolic cage, and were given drugs or solvents (2mL/kg) according to the above table, and then immediately given 50% glucose solution (2g/kg, 4mL/kg).
  • 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.

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Abstract

作为SGLT1/SGLT2/DPP4三重抑制剂的一类化合物，以及在制备作为SGLT1/SGLT2/DPP4三重抑制剂的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。

Description

一种SGLTs/DPP4抑制剂及其应用
本申请主张如下优先权
CN201910683107.3，申请日：2019.07.26；
CN202010105252.6，申请日：2020.02.20。
技术领域
本发明涉及作为SGLT1/SGLT2/DPP4三重抑制剂的一类化合物，以及在制备作为SGLT1/SGLT2/DPP4三重抑制剂的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
糖尿病是一种以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时，长期血糖水平异常可导致严重的并发症，包括心血管疾病、
慢性肾功能衰竭、视网膜损伤、神经损伤、微血管损伤和肥胖等。糖尿病的治疗，早期阶段，饮食控制和运动疗法是首选的血糖控制方案。当这些方法难以实现对血糖的控制时，则需要使用胰岛素或者口服降糖类药物进行治疗。目前，己有多种降糖药物用于临床治疗，主要包括双胍类、磺酰脲类、胰岛素耐受改善剂、格列奈类、α-葡萄糖苷酶抑制剂和二肽基肽酶-IV抑制剂等。这些药物具有良好的治疗效果，但长期治疗仍存在安全性问题，例如，双胍类易引起乳酸性酸中毒；磺酰脲类会导致低血糖症状；胰岛素耐受改善剂会造成水肿、心脏衰竭和体重增加；α-葡萄糖苷酶抑制剂会引起腹痛、腹胀、腹泻等症状。因此，迫切需要开发出一种更安全、优效的新型降糖药物满足糖尿病的治疗需要。
钠-葡萄糖共转运蛋白(sodium-glucose cotransporters,SGLTs)是一类在小肠黏膜和肾近曲小管中发现的葡萄糖转运蛋白家族，家族成员主要包括SGLT1蛋白和SGLT2蛋白两类，其功能是介导肠道和肾脏中葡萄糖的跨膜转运，在维持人体血糖稳定中起着关键作用。具体而言，SGLT1主要分布于小肠的肠道粘膜细胞，在心肌和肾脏中也有少量表达，它主要调节葡萄糖的肠道吸收过程。而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。在这一过程中，SGLT2负责了90％的重吸收过程，剩余的10％则有由SGLT1完成。由于该过程不介入葡萄糖的代谢，从而避免或减轻了低血糖不良反应的发生，降低了引起心血管类疾病的风险，因此，SGLTs已成为治疗糖尿病的理想潜在靶点之一。
鉴于此，一些SGLTs抑制剂，尤其是高选择性的SGLT2抑制剂被相继开发。它们通过抑制SGLT2活性，特异性地抑制肾脏对葡萄糖的重吸收，从而增加葡萄糖在尿中的排泄，使糖尿病患者的血浆葡萄糖正常化。从2012年至今，已有达格列净(Dapagliflozin)，卡格列净(Canagliflozin)，鲁格列净(Luseogliflozin)，伊格列净(Ipragliflozin)，托格列净(Tofogliflozin)和恩格列净(Empagliflozin)等6个药物先后被批准上市，成为治疗糖尿病的有效药物。
除了选择性SGLT2抑制剂，近几年研究发现，抑制SGLT2的同时，对SGLT1部分抑制，既能抑制肾脏 葡萄糖的重摄取，又能实现控制肠道对葡萄糖的吸收而不出现腹泻或者其他胃肠道反应；同时，通过抑制肠道SGLT1减少经胃肠道入血的葡萄糖，能增加餐后GLP-1和PYY水平，从而发挥出较选择性SGLT2抑制剂更佳的降糖作用，并降低了发生尿路感染和肾功能损伤等的风险。因而开发SGLT1/SGLT2双重抑制剂已成为近年来糖尿病治疗的新靶点和方向。目前，由Lexicon公司和赛诺菲公司联合开发的SGLT1/SGLT2双抑制剂Sotagliflozin已经在欧盟上市(WO2008042688/WO2012094293)。
Figure PCTCN2020104534-appb-000001
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。
SGLT1和DPP4靶点抑制协同作用，可促进和延长内源性GLP-1的分泌和浓度，刺激内源性胰岛素的分泌而提高体内整体糖能量的应用，再加上SGLT2靶点抑制，加快高血糖水平条件下葡萄糖的排泄，从而贯穿葡萄糖在体内的吸收，代谢和排泄整体途径，全方位降低血糖水平且不易引发低血糖风险。
综上所述，SGLT1/SGLT2/DPP4三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 PCTCN2020104534-appb-000002
其中，
R 1选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
R 3、R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c取代；
R 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d取代；
E 1为-(CH 2) m-；
E 2为-(CH 2) n-；
m为0、1或2；
n为0、1或2；
R a、R b、R c和R d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 PCTCN2020104534-appb-000003
其中，
R 1选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
R 3、R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c取代；
R 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d取代；
E 1为-(CH 2) m-；
E 2为-(CH 2) n-；
m为0、1或2；
n为1或2；
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选自CH 3和Et，所述CH 3和Et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选自Cl、Br、I、OH、NH 2、CH 3和Et，其中所述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选自Cl、Br、I、OH、NH 2、CH 3、Et和
Figure PCTCN2020104534-appb-000004
其中所述CH 3、Et和
Figure PCTCN2020104534-appb-000005
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选自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 2选自Cl、Br、I、OH、NH 2、CH 3、Et和
Figure PCTCN2020104534-appb-000006
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、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其中所述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 3、R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH和NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其中所述CH 3和Et任选被1、2或3个R d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 8、R 9、R 10和R 11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E 1为-CH 2-或-CH 2-CH 2-，其他变量如本发明所定义。
本发明的一些方案中，上述E 1为-CH 2-，其他变量如本发明所定义。
本发明的一些方案中，上述E 2为单键或-CH 2-，其他变量如本发明所定义。
本发明的一些方案中，上述E 2为-CH 2-，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，其中，化合物选自
Figure PCTCN2020104534-appb-000007
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11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 PCTCN2020104534-appb-000008
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11如本发明所定义。
本发明还提供了下述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020104534-appb-000009
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 PCTCN2020104534-appb-000010
Figure PCTCN2020104534-appb-000011
本发明的一些方案中，上述合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020104534-appb-000012
Figure PCTCN2020104534-appb-000013
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SGLT1/SGLT2/DPP4三重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较优的对Human-SGLT1,Human-SGLT2和rhDPP4的体外抑制活性；表现出具备一定的口服暴露量和生物利用度；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。
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 PCTCN2020104534-appb-000014
和楔形虚线键
Figure PCTCN2020104534-appb-000015
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020104534-appb-000016
和直形虚线键
Figure PCTCN2020104534-appb-000017
表示立体中心的相对构型，用波浪线
Figure PCTCN2020104534-appb-000018
表示楔形实线键
Figure PCTCN2020104534-appb-000019
或楔形虚线键
Figure PCTCN2020104534-appb-000020
或用波浪线
Figure PCTCN2020104534-appb-000021
表示直形实线键
Figure PCTCN2020104534-appb-000022
和直形虚线键
Figure PCTCN2020104534-appb-000023
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 PCTCN2020104534-appb-000024
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 PCTCN2020104534-appb-000025
Figure PCTCN2020104534-appb-000026
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 PCTCN2020104534-appb-000027
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 PCTCN2020104534-appb-000028
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 PCTCN2020104534-appb-000029
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 PCTCN2020104534-appb-000030
直形虚线键
Figure PCTCN2020104534-appb-000031
或波浪线
Figure PCTCN2020104534-appb-000032
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 PCTCN2020104534-appb-000033
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 PCTCN2020104534-appb-000034
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。
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 PCTCN2020104534-appb-000035
软件命名，市售化合物采用供应商目录名称。
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，A-2
Figure PCTCN2020104534-appb-000036
合成路线：
Figure PCTCN2020104534-appb-000037
步骤1：化合物A-1-2的合成。
将化合物A-1-1(25g，133.52mmol，1eq)溶于二氯甲烷(110mL)中，加入三乙胺(27.02g，267.04mmol，37.17mL，2eq)，反应降温至0℃。0℃下，将甲烷磺酰氯(15.30g，133.52mmol，10.33mL，1eq)逐滴加入反应体系。滴加完毕后，反应由0℃升至15℃并于15℃下搅拌反应3小时。反应完毕后降温至0℃，在0℃下缓慢加入水(100mL)淬灭反应。混合物用二氯甲烷(100mL×2)萃取，合并有机相用饱和盐水(100mL)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得到化合物A-1-2。
步骤2：化合物A-1-4的合成。
将化合物A-1-2(6.00g，22.61mmol，1.00eq)，化合物A-1-3(3.91g，22.61mmol，1.00eq)，碳酸铯(14.73g，45.22mmol，2.00eq)加入到N，N-二甲基甲酰胺(10.00mL)中，反应体系加热至80℃，于80℃下搅拌反应3小时。反应完毕后，向反应液中加水(50mL)，用乙酸乙酯(30mL×3)萃取，合并有机相依次用水(30mL×3)饱和盐水(30mL)洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩得粗品。粗品经柱层析纯化得到化合物A-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A-1-5的合成。
将化合物A-1-4(3.00g，8.77mmol，1.00eq)溶于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，反应液加入水(30mL)稀释，混合物用乙酸乙酯(20mL)洗涤。水相用饱和碳酸氢钠水溶液调节至pH＝7。水相用乙酸乙酯(30mL)萃取。有机相用饱和盐水(20mL)洗涤。有机相经无水硫酸钠干燥后减压浓缩，得到化合物A-1-5的粗品。 1H NMR(400MHz，CD 3OD)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A-1-7和A-1-8的合成。
将化合物A-1-5(2g，7.18mmol，1eq)，化合物A-1-6(2.58g，7.90mmol，1.1eq)，溶于二氯甲烷(20mL)和甲醇(4mL)中，向反应液中加入乙酸(43.11mg，717.95μmol，41.06μL，0.1eq)，加入三乙酰氧基硼氢化钠(3.04g，14.36mmol，2eq)，反应在15℃下搅拌2小时。反应完毕后，将反应液减压浓缩，剩余物中加水(50mL)稀释，用二氯甲烷(50mL×2)萃取。合并有机相用饱和盐水(30mL)洗涤。有机相经无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析(石油醚/乙酸乙酯＝3/1)分离纯化，分别得到化合物A-1-7(Rf＝0.5)。 1H NMR(400MHz，CDCl 3)δ7.38(d，J＝9.2Hz，2H)，7.34-7.28(m，1H)，7.03-6.87(m，2H)，6.76(d，J＝8.8Hz，2H)，4.93-4.77(m，1H)，4.49-4.28(m，2H)，4.15(br d，J＝12.4Hz，1H)，4.10-3.97(m，1H)，3.59(d，J＝12.0Hz，1H)，3.50-3.35(m，1H)，3.08-2.89(m，1H)，2.76-2.56(m，2H)，2.50(br s，1H)，2.45-2.37(m，1H)，2.36-2.26(m，1H)，2.12-1.94(m，1H)，1.28(br s，9H)。与化合物A-1-8(Rf＝0.4)。 1H NMR(400MHz，CDCl 3)δ7.37(d，J＝8.8Hz，2H)，7.24-7.17(m，1H)，7.02-6.89(m，2H)，6.74(d，J＝8.8Hz，2H)，4.85-4.74(m，1H)，4.51-4.40(m，1H)，4.31-4.25(m，1H)，4.24-4.18(m，1H)，3.82-3.65(m，1H)，3.45-3.33(m，1H)，3.04-2.83(m，3H)，2.65-2.50(m，2H)，2.50-2.41(m，1H)，2.38-2.23(m，1H)，2.06-1.93(m，1H)，1.26(br s，9H)。
步骤5：化合物A-1的合成。
将化合物A-1-8(15g，27.10mmol，1eq)，化合物A-1-9(13.77g，54.21mmol，2eq)，乙酸钾(7.98g，81.31mmol，3eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯(1.98g，2.71mmol，0.1eq)依次加入到无水二氧六环(20mL)中，氮气保护下于90℃下反应2小时。反应完毕后，反应减压浓缩，剩余物中加水(200mL)稀释，混合物用二氯甲烷(200mL×2)萃取。合并有机相用饱和盐水(100mL×2)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析分离纯化，得到化合物A-1。 1H NMR(400MHz，CDCl 3)δ7.74(d，J＝8.8Hz，2H)，7.24-7.15(m，1H)，7.01-6.90(m，2H)，6.85(d，J＝8.8Hz，2H)，4.93-4.83(m，1H)，4.46(br d，J＝9.6Hz，1H)，4.27(br d，J＝9.6Hz，1H)，4.24-4.18(m，1H)，3.81-3.68(m，1H)，3.38(br t，J＝10.8Hz，1H)，3.05-2.96(m，1H)，2.93(br d，J＝3.2Hz，2H)，2.63-2.49(m，2H)，2.46(br d，J＝11.6Hz，1H)，2.39-2.27(m，1H)，2.05-1.95(m，1H)，1.51(q，J＝12.0Hz，1H)，1.34(s，12H)，1.26(s，9H)。
步骤6：化合物A-2的合成。
将化合物A-1-7(3.20g，5.78mmol，1eq)，化合物A-1-9(2.20g，8.67mmol，1.5eq)，乙酸钾(1.70g，17.35mmol，3eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(472.19mg，578.21μmol，0.1eq)加入到无水二氧六环(30mL)中，氮气保护下反应于90℃下搅拌16小时。反应完毕后，向反应液中加水(50mL)稀释，混合物用二氯甲烷(50mL×2)萃取。合并有机相用饱和盐水(50mL×2)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析分离纯化，得到化合物A-2。 1H NMR(400MHz，CDCl 3)δ7.74(d，J＝8.4Hz，2H)，7.34-7.25(m，1H)，7.00-6.90(m，2H)，6.86(d，J＝8.4Hz，2H)，5.00-4.86(m，1H)，4.50-4.35(m，2H)，4.18-4.07(m，2H)，4.06-9.95(m，1H)，3.57(br d，J＝12.0Hz，1H)，3.54-3.44(m，1H)，3.08-2.93(m，1H)，2.72-2.63(m，1H)，2.62-2.54(m，1H)，2.43-2.36(m，1H)，2.35-2.26(m，1H)，2.04-1.96(m，1H)，1.33(s，12H)，1.23(s，9H)。
参考例2：片段A-3，A-4
Figure PCTCN2020104534-appb-000038
合成路线：
Figure PCTCN2020104534-appb-000039
步骤1：化合物A-3-2的合成。
将A-3-1(8g,46.19mmol,1eq)，三乙胺(9.35g,92.37mmol,12.86mL,2eq)，甲烷磺酰氯(6.61g,57.73mmol,4.47mL,1.25eq)加入到二氯甲烷(120mL)中，20℃下反应16小时。反应完毕后，将反应物缓慢倒入200mL冰水中淬灭，淬灭后继续搅拌10分钟，静置分层，收集有机相并依次用水(50mL)，氢氧化钠水溶液(1M,50mL)，饱和盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩，得到产物A-3-2， 1H NMR(400MHz，CDCl 3)δ5.18(tt,J＝6.7,4.1Hz,1H),4.30-4.22(m,2H),4.09(dd,J＝4.1,0.9Hz,1H),4.07(dd,J＝4.1,0.9Hz,1H),3.05(s,3H),1.38-1.47(s,9H)。
步骤2：化合物A-3-3的合成。
将对溴苯酚(5.78g,33.43mmol,1.2eq)，A-3-2(7g,27.86mmol,1eq)，碳酸铯(18.15g,55.71mmol,2eq)加入到N，N-二甲基甲酰胺(20mL)中，80℃反应16小时，反应结束后，加入水(200mL)淬灭反应，用乙酸乙酯(100mL×2)萃取。合并有机相，用饱和盐水(60mL)洗涤，无水硫酸钠干燥后减压浓缩得到粗品。粗品加入石油醚(60mL)，常温搅拌1小时后过滤，滤饼用二氯甲烷溶解后转移减压浓缩得化合物A-3-3， 1H NMR(400MHz，CDCl 3)δ7.39(d,J＝8.5Hz,2H),6.63(d,J＝8.8Hz,2H),4.89-4.79(m,1H),4.29(dd,J＝9.8,6.3Hz,2H),4.00(d,J＝4.0Hz,1H),3.98(d,J＝4.0Hz,1H),1.40-1.52(s,9H)。
步骤3：化合物A-3-4的合成。
将A-3-3(11g,33.52mmol,1eq)投入到氯化氢的乙酸乙酯溶液(4M,30mL,3.58eq)中，20℃搅拌16小时。反应结束后过滤，滤饼用乙酸乙酯(30mL)洗涤后用二氯甲烷(40mL)溶解，再减压浓缩得到化合物A-3-4的盐酸盐。
步骤4：化合物A-3-5和A-3-6的合成。
将A-3-4的盐酸盐(4.2g,15.88mmol,1eq)，A-1-5(7.79g,23.81mmol,1.5eq)，硫酸镁(19.11g,158.76mmol,10eq)和三乙胺(1.61g,15.88mmol,2.21mL,1eq)加入到N，N-二甲基乙酰胺(90mL)中，20℃反应1小时后，加入氰基硼氢化钠(3.99g,63.50mmol,4eq)继续反应15小时。反应结束后，往反应液中加入水(100mL)稀释，过滤收集固体，滤饼用水(20mL)洗涤，用二氯甲烷(20mL)溶解滤饼，有机相用无水硫酸钠干燥后减压浓缩，得到粗品。粗品经过柱层析分离纯化，分别得到化合物A-3-5(石油醚：乙酸乙酯＝3：1，Rf＝0.31) 1H NMR(400MHz，CDCl 3)δ7.44-7.33(m,2H),7.19(m,1H),6.95(m,2H),6.74-6.60(m,2H),4.77(br t,J＝5.6Hz,1H),4.45(m,1H),4.25(br d,J＝10.0Hz,1H),4.07-3.97(m,1H),3.79(m,3H),3.33-3.15(m,3H),2.63(m,J＝10.8Hz,1H),2.30(br d,J＝13.3Hz,1H),1.34-1.21(s,9H)。
和化合物A-3-6(石油醚：乙酸乙酯＝3：1，Rf＝0.46)。 1H NMR(400MHz，CDCl 3)δ7.38(br d,J＝9.0Hz,3H),6.94(m,2H),6.78-6.61(m,2H),4.78(m,1H),4.37(m,2H),4.07-3.88(m,4H),3.55(br d,J＝12.8Hz,1H),3.07(br s,2H),2.53(br s,1H),2.17(br d,J＝11.5Hz,1H),1.28(s,9H)
步骤5：化合物A-3的合成。
氮气保护下，将化合物A-3-5(200mg,370.78μmol,1eq)，双联频那醇硼酸酯(235.39mg,926.94μmol,2.5eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(60.56mg,74.16μmol,0.2eq)和乙酸钾(109.17mg,1.11mmol,3eq)投入到无水二氧六环(5mL)中，80℃反应16小时。反应完毕后，反应液中加入水(10mL)淬灭稀释，用二氯甲烷(5mL×2)萃取。合并有机相用水(5mL)洗涤后减压浓缩得到粗品。粗品经柱层析分离纯化得到化合物A-3。MS:587.2[M+1] +。
步骤6：化合物A-4的合成。
氮气保护下，将化合物A-3-6(200mg,370.78μmol,1eq),双联频那醇硼酸酯(112.99mg,444.93μmol,1.2eq),[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(60.56mg,74.16μmol,0.2eq),乙酸钾(72.78mg,741.55μmol,2eq)投入到无水二氧六环(4mL)中，80℃反应16小时。反应完毕后，往反应液中加入水(10mL)稀释，加入二氯甲烷(10mL×2)萃取。合并有机相用水(5mL)洗涤后减压浓缩得到粗品。粗品经柱层析分离纯化得到化合物A-4。MS:587.1[M+1] +。
参考例3：片段A-5
Figure PCTCN2020104534-appb-000040
合成路线：
Figure PCTCN2020104534-appb-000041
步骤1：化合物A-5-2的合成。
将A-5-1(4g,13.67mmol,1eq)，A-1-6(6.71g,20.51mmol,1.5eq)，三乙胺(1.38g,13.67mmol,1.90mL,1eq)，硫酸镁(16.46g,136.71mmol,10eq)加入到N，N-二甲基乙酰胺(40mL)中，20℃反应1小时后，加入氰基硼氢化钠(3.44g,54.68mmol,4eq)，继续反应15小时。反应结束后，反应液中加入水(50mL)淬灭稀释，加入二氯甲烷(20mL×2)萃取，合并有机相，用饱和盐水(30mL)洗涤，无水硫酸钠干燥，然后减压浓缩得到粗品。粗品经过柱层析分离纯化，得到产物A-5-2， 1H NMR(400MHz，CDCl 3)δ7.40-7.22(m,2H),7.21(m,1H),7.02-6.89(m,2H),6.83-6.76(m,2H),4.48(br d,J＝8.8Hz,1H),4.27(br dd,J＝7.3,3.0Hz,2H),4.24-4.18(m,1H),3.70(br d,J＝8.0Hz,1H),3.42(t,J＝10.9Hz,1H),2.93-2.71(m,3H),2.56-2.38(m,3H),2.04–1.93(m,2H),1.80(m,4.3Hz,2H),1.70(m,1H),1.50(q,J＝11.9Hz,1H),1.32-1.18(s,9H).
步骤2：化合物A-5的合成。
将A-5-2(7g,12.34mmol,1eq)，双联频哪醇硼酸酯(7.83g,30.84mmol,2.5eq)，乙酸钾(2.42g,24.67mmol,2eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(2.01g,2.47mmol,0.2eq)投入到无水二氧六环(40mL)中，在氮气保护下80℃反应16小时。反应完毕后，反应液减压浓缩，剩余物中加入二氯甲烷(20mL)溶解，用水(20mL×3)洗涤三次后，无水硫酸钠干燥，减压浓缩后得到粗品，粗品通过柱层析分离纯化，得到产物A-5MS:615.3[M+1]+。
参考例4：片段A-6，A-7
Figure PCTCN2020104534-appb-000042
合成路线：
Figure PCTCN2020104534-appb-000043
步骤1：化合物A-6-2的合成。
将化合物A-6-1(10g,53.41mmol,1eq)溶于二氯甲烷(100mL)中，然后将三乙胺(10.81g,106.82mmol,14.87mL,2eq)加入到反应液中，在0℃下向反应中滴加甲烷磺酰氯(6.12g,53.41mmol,4.13mL,1eq)，反应在15℃下搅拌3小时。反应完毕后，在0℃下，向反应中加水(20mL)淬灭反应，再用二氯甲烷(30mL×2)萃取，合并有机相用饱和盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩后得到A-6-2。 1H NMR(400MHz，CDCl 3)δ5.22-5.17(m,1H),3.66-3.39(m,4H),2.99(s,3H),2.27-2.04(m,2H),1.40(s,9H)
步骤2：化合物A-6-3的合成。
将化合物A-6-2(6.5g,24.50mmol,1eq)，对溴苯酚(5.09g,29.40mmol,1.2eq)，碳酸铯(15.96g,49.00mmol,2eq)加入到N，N-二甲基甲酰胺(70mL)中，反应在80℃下搅拌2小时。反应完毕后，加水(500mL)，用乙酸乙酯(500mL×2)萃取，合并有机相用饱和盐水(300mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品经柱层析(石油醚:乙酸乙酯＝3:1)分离纯化得到A-6-3. 1H NMR(400MHz，CDCl 3)δ7.37(br t,J＝8.2Hz,1H),7.31-7.26(m,2H),4.82(br s,1H),3.63-3.43(m,4H),2.21-2.05(m,2H),1.47(br d,J＝3.3Hz,9H)
步骤3：化合物A-6-4的合成。
将化合物A-6-3(15.00g,43.83mmol,1eq)溶于乙酸乙酯(100mL)中，加入氯化氢的乙酸乙酯溶液(4M,21.92mL,2eq)，反应在15℃下搅拌2小时。反应完毕后，反应液减压浓缩，剩余物中加入混合溶液(石油醚:乙酸乙酯＝5:1，100mL)，搅拌2小时后过滤，收集滤饼，得到化合物A-6-4。 1H NMR(400MHz，CD 3OD)δ＝7.48-7.44(m,2H),6.98-6.93(m,2H),5.21(td,J＝2.7,5.8Hz,1H),3.57-3.45(m,4H),2.37-2.29(m,2H)步骤4：化合物A-6-5和A-6-6的合成。
将化合物A-6-4(4g,14.36mmol,1eq)，化合物A-1-6(5.17g,15.79mmol,1.1eq)，溶于二氯甲烷(50mL)和甲醇(20mL)中，向反应液中加入乙酸(86.23mg,1.44mmol,82.12μL,0.1eq)，加入三乙酰氧基硼氢化钠(6.09g,28.72mmol,2eq)，反应在15℃下搅拌2小时。反应完毕后反应液减压浓缩，剩余物中加水(50mL)，用二氯甲烷(50mL×2)萃取。合并有机相用饱和盐水(30mL)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品经过柱层析(石油醚/乙酸乙酯＝3/1-2/1，含千分之一的三乙胺)分离纯化，分别得到化合物A-6-5(Rf＝0.47)。 1H NMR(400MHz，DMSO)δ＝7.44(d,J＝8.9Hz,2H),7.21-7.07(m,3H),6.91(d,J＝8.9Hz,2H),6.83(d,J＝9.8Hz,1H),4.94(br s,1H),4.03(q,J＝7.1Hz,2H),3.95-3.82(m,1H),3.46(br d,J＝12.0Hz,1H),3.00(br dd,J＝6.1,10.0Hz,1H),2.86-2.72(m,2H),2.39-2.28(m,2H),2.07(br d,J＝13.0Hz,1H),1.91-1.82(m,1H),1.77(br t,J＝11.7Hz,1H),1.21-1.17(m,9H)
和化合物A-6-6(Rf＝0.40)。 1H NMR(400MHz,DMSO)δ＝7.43(d,J＝8.9Hz,2H),7.20-7.12(m,3H),6.95-6.85(m,3H),4.84(br s,1H),4.13-4.04(m,1H),3.67-3.56(m,1H),3.33(d,J＝9.5Hz,1H),3.17(br t,J＝10.6Hz,1H),2.88-2.81(m,1H),2.81-2.72(m,1H),2.81-2.71(m,1H),2.48-2.36(m,2H),2.30-2.20(m,1H),2.13(br d,J＝11.9Hz,1H),1.78-1.69(m,1H),1.53(q,J＝11.9Hz,1H),1.30-1.11(m,9H)
步骤5：化合物A-6的合成。
将化合物A-6-5(4.50g,8.13mmol,1eq)，双联频哪醇硼酸酯(3.10g,12.20mmol,1.5eq)，乙酸钾(1.60g,16.26mmol,2eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯(594.96mg,813.10μmol,0.1eq)加入到无水二氧六环(50mL)中，氮气保护下于90℃下反应2小时。反应完毕后，反应液减压浓缩后加水(50mL)稀释，混合物用二氯甲烷(50mL×2)萃取。合并有机相用饱和盐水(30mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得粗品。粗品经柱层析(二氯甲烷/甲醇＝20:1)分离纯化，得到化合物A-6。 1H NMR(400MHz，CDCl 3)δ＝ 7.71-7.54(m,2H),7.24(br s,1H),6.86(br s,2H),6.79(br d,J＝8.4Hz,2H),5.23(s,1H),4.86(br s,1H),4.34(br s,2H),4.09(br d,J＝12.1Hz,1H),3.50(br d,J＝12.3Hz,1H),2.84(br s,1H),2.75-2.59(m,2H),2.41(br s,1H),2.36-2.11(m,3H),1.98(br d,J＝7.3Hz,1H),1.26(s,9H),1.23-1.17(m,12H)
步骤6：化合物A-7的合成。
将化合物A-6-6(3.40g,6.14mmol,1eq)，双联频哪醇硼酸酯(2.34g,9.22mmol,1.5eq)，乙酸钾(1.21g,12.29mmol,2eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(501.70mg,614.35μmol,0.1eq)加入到无水二氧六环(50mL)中，氮气保护下90℃下搅拌2小时。反应完毕后反应液减压浓缩，剩余物中加水(50mL)稀释，混合物用二氯甲烷(50mL×2)萃取。合并有机相用饱和盐水(30mL)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析(二氯甲烷/甲醇＝20:1)分离纯化，得到化合物A-7。 1H NMR(400MHz，CDCl 3)δ＝7.70-7.59(m,2H),7.13(br s,1H),6.87(br s,2H),6.82-6.70(m,2H),5.25-5.20(m,1H),4.79(br s,1H),4.39(br d,J＝8.9Hz,1H),4.17(br d,J＝13.5Hz,1H),3.66(br d,J＝8.3Hz,1H),3.43-3.30(m,1H),2.86(br d,J＝19.4Hz,3H),2.51(br s,2H),2.38(br d,J＝10.9Hz,1H),2.24(br d,J＝6.6Hz,1H),1.95(br d,J＝6.4Hz,1H),1.26(s,9H),1.18(br s,12H)
参考例5：片段A-8，A-9
Figure PCTCN2020104534-appb-000044
合成路线：
Figure PCTCN2020104534-appb-000045
步骤1：化合物A-8-1的合成。
将化合物A-1-2(11.5g，43.34mmol，1.00eq)，邻甲基对溴苯酚(8.11g，43.34mmol，1.00eq)，碳酸钾(11.98g，86.69mmol，2.00eq)加入到N，N-二甲基甲酰胺(100.00mL)中，反应在80℃下搅拌3小时。反应完毕后，向反应液中加水(500mL)，用乙酸乙酯(250mL×2)萃取，有机相依次用1M的氢氧化钠水溶液(200mL×2)，饱和盐水(200mL×2)洗涤，无水硫酸钠干燥后过滤，减压浓缩得粗品。粗品经柱层析纯化得到化合物A-8-1。 1H NMR(400MHz,CDCl3)δ7.22-7.01(m,2H),6.67-6.52(m,1H),4.10-3.97(m,1H),3.57-3.35(m,3H),2.97(s,1H),2.16-2.02(m,3H),2.01-1.82(m,1H),2.02-1.76(m,1H),1.40(s,9H)。
步骤2：化合物A-8-2的合成。
将化合物A-8-1(14.8g，33.57mmol，1.00eq)溶于氯化氢的乙酸乙酯溶液(50mL，4M)中，反应在15℃下反应3小时。反应完毕后减压浓缩，剩余物中加入石油醚10mL和乙酸乙酯1mL，搅拌1小时后，过滤，收集滤饼得到化合物A-8-2。 1H NMR(400MHz,DMSO-d 6)δ7.38-7.29(m,2H),6.96(d,J＝8.8Hz,1H),5.15(s,1H),3.90(br t,J＝5.2Hz,1H),3.44(br s,2H),3.24(br d,J＝10.8Hz,1H),2.24-2.17(m,1H),2.15(s,3H),2.14-2.08(m,1H)。
步骤3：化合物A-8-3和A-8-4的合成。
将化合物A-8-2(1g，3.42mmol，1eq)，化合物A-1-6(1.23g，3.76mmol，1.1eq)，溶于二氯甲烷(20mL)和 甲醇(4mL)中，依次加入乙酸(20.5mg，341.76μmol，20μL，0.1eq)和三乙酰氧基硼氢化钠(1.45g，6.84mmol，2eq)，反应在15℃下搅拌16小时。反应完毕后，反应减压浓缩，剩余物中加水(20mL)稀释，用二氯甲烷(15mL×2)萃取。合并有机相用饱和盐水(15mL)洗涤，经无水硫酸钠干燥后过滤，减压浓缩得粗品。粗品经柱层析(二氯甲烷/乙酸乙酯＝10/1)分离纯化，分别得到化合物A-8-3(Rf＝0.1)： 1H NMR(400MHz,CDCl 3)δ＝7.19-7.18(m,1H),7.15(br dd,J＝2.4,8.4Hz,2H),6.87(br s,2H),6.50(d,J＝8.4Hz,1H),4.70(br t,J＝6.8Hz,1H),4.43-4.33(m,1H),4.22-4.12(m,2H),4.08-4.02(m,1H),3.74-3.65(m,1H),3.06-2.99(m,1H),2.84-2.71(m,2H),2.62-2.50(m,2H),2.38(br d,J＝12.8Hz,1H),2.25-2.17(m,1H),2.11(s,3H),1.67-1.53(m,1H),1.45-1.37(m,1H),1.19(s,9H)。
与化合物A-8-4(Rf＝0.4)： 1H NMR(400MHz,CDCl 3)δ＝7.19(br d,J＝2.4Hz,1H),7.17-7.13(m,1H),7.19-7.12(m,1H),6.89-6.85(m,2H),6.51(d,J＝8.8Hz,1H),4.70(br t,J＝6.8Hz,1H),4.44-4.33(m,1H),4.24-4.18(m,1H),4.14(td,J＝2.4,8.8Hz,1H),3.70-3.63(m,1H),3.30(br t,J＝10.8Hz,1H),3.07-3.00(m,1H),2.85-2.71(m,2H),2.55(br d,J＝11.6Hz,2H),2.39(br d,J＝13.8Hz,1H),2.25-2.16(m,1H),2.11(s,3H),1.60(br s,1H),1.43(br d,J＝11.2Hz,1H),1.19(s,9H)。
步骤4：化合物A-8的合成。
将化合物A-8-4(600mg，1.06mmol，1eq)，双联频哪醇硼酸酯(403mg，1.59mmol，1.5eq)，乙酸钾(156mg，1.59mmol，1.5eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯(173mg，0.211mmol，0.2eq)加入到无水二氧六环(10mL)中，氮气保护下于80℃下反应18小时。反应结束后过滤，滤液中加水(15mL)稀释后再用二氯甲烷(20mL×2)萃取。合并有机相用饱和盐水(20mL)洗涤，经无水硫酸钠干燥后过滤，减压浓缩得粗品。粗品经柱层析分离纯化，得到化合物A-8。 1H NMR(400MHz,CDCl 3)δ＝7.56-7.52(m,2H),7.13(br s,1H),6.87(br s,2H),6.63(d,J＝8.4Hz,1H),4.79(br t,J＝6.8Hz,1H),4.40(br d,J＝9.2Hz,1H),4.25-4.09(m,1H),4.05(q,J＝7.2Hz,2H),4.08-4.02(m,1H),3.29(br t,J＝10.8Hz,1H),3.06-3.00(m,1H),2.83-2.74(m,2H),2.60-2.51(m,2H),2.38(br d,J＝13.3Hz,1H),2.42-2.34(m,1H),2.27-2.20(m,1H),2.13(s,3H),1.26(s,12H),1.19(s,9H),
步骤5：化合物A-9的合成。
将化合物A-8-3(300mg，528.67μmol，1eq)，双联频哪醇硼酸酯(201.4mg，793.01μmol，1.5eq)，溶于无水DMF(5mL)中，氮气保护下，再依次加入乙酸钾(77.8mg，793.01μmol，1.5eq)，[1,1-双(二苯基磷)二茂铁]二氯化钯二氯甲烷络合物(86.4mg，105.73umol，0.2eq)。反应在90℃搅拌16小时。反应完毕后，反应液中加水(15mL)稀释，混合物用乙酸乙酯(20mL×2)萃取。有机相用饱和盐水(20mL)洗涤，无水硫酸钠干燥后减压浓缩得粗品。粗品经柱层析分离纯化，得到化合物A-9。(MS:615.5[M+1] +)
参考例6：片段B-1
Figure PCTCN2020104534-appb-000046
合成路线：
Figure PCTCN2020104534-appb-000047
步骤1：化合物B-1-2的合成。
依次将甲苯(1200mL)，化合物B-1-1(200g,929.86mmol,1eq)，以及四丁基溴化铵(20.00g,62.04mmol,6.67％eq)加入到氢氧化钠(200.00g,5.00mol,5.38eq)的水(400mL)溶液中，搅拌0.5小时。缓慢加入烯丙基溴(157.49g,1.30mol,112.49mL,1.4eq)。反应升至45-50℃搅拌15小时。反应完毕后降温，静置，分层。水相用甲苯(300mL)萃取。合并有机相，用饱和盐水(300mL×3)洗涤后减压浓缩，剩余物中加入甲苯(200mL)后减压浓缩，重复两次后得到化合物B-1-2。 1HNMR(CDCl 3)δ7.52(d，J＝2.0Hz，1H)，7.37(dd，J＝2.4，8.4Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.05-5.87(m，1H)，5.42-5.17(m，2H)，4.57-4.43(m，2H)，4.06(d，J＝5.6Hz，2H)，2.72-2.57(m，2H)，1.21(t，J＝7.6Hz，3H)。
步骤2：化合物B-1-4的合成。
将化合物B-1-2(2.5g，9.80mmol，1eq)溶于无水四氢呋喃(40mL)，氮气保护下降温至-78℃，加入正丁基锂(2.5M，4.31mL，1.1eq)，搅拌0.5小时，得到溶液A；将B-1-3(3.21g，11.76mmol，1.2eq)溶于无水四氢呋喃(30mL)，氮气保护下降温至0℃，加入叔丁基氯化镁(1M，12.74mL，1.3eq)，搅拌0.5小时得到溶液B。在-78℃下将溶液B加入到溶液A中，反应于-78℃搅拌0.5小时后，升温至25℃搅拌2小时。反应完毕后，将反应液缓慢加入到饱和氯化铵水溶液(5mL)中淬灭反应，加入饱和盐水(5mL)，静置分层后，收集有机相。水相用乙酸乙酯(10mL×3)萃取三次。各有机相合并后无水硫酸钠干燥后减压浓缩得到粗品，粗品中加入正庚烷(10mL)，搅拌1小时后过滤，收集滤饼得到化合物B-1-4。MS:363.2[M+1] +
步骤3：化合物B-1-5的合成。
将B-1-4(3.3g，9.11mmol，1eq)溶于甲醇(50mL)，加入三氯化铈七水合物(3.39g，9.11mmol，865.45μL，1eq)，0℃下加入硼氢化钠(1.38g，36.42mmol，4eq)搅拌0.5小时，然后升温至25℃搅拌1.5小时。反应完毕后，反应于0℃下加入饱和氯化铵水溶液(10mL)，搅拌1小时后减压浓缩。剩余物中加入乙酸乙酯(30mL)，水(3mL)，无水硫酸镁(3g)，搅拌0.5小时后过滤，收集滤液，滤饼用乙酸乙酯(15mL×3)洗涤。合并有机相，依次分别用水(10mL×2)和饱和盐水(10mL×2)洗涤，无水硫酸钠干燥后过滤，减压浓缩得到粗品。取2.8g粗品溶于乙酸(14mL)和水(14mL)中，反应加热至95-100℃搅拌16小时。反应完毕后，将反应液减压浓缩，剩余物中加入甲苯(10mL)减压浓缩，重复两次后得到粗品。取粗品2.5g溶于吡啶(12mL)中，0℃下加入乙酸酐(6.29g，61.66mmol，5.77mL，8eq)，反应于10-20℃搅拌16小时。反应完毕后，冰浴下，向反应液中加入水(5mL)淬灭反应。混合物减压浓缩，剩余物中加入1M的盐酸水溶液(5mL)中和剩余吡啶，再加入乙酸乙酯(30mL×2)萃取，合并有机相用饱和盐水(25mL)洗涤，无水硫酸钠干燥后过滤，减压浓缩得粗品。粗品经柱层析纯化得到化合物B-1-5。 1HNMR(CDCl 3)δ7.33(s，1H)，7.30-7.20(m，1H),7.20-7.15(m，1H)，6.05-5.90(m，1H)，5.40-5.05(m，5H)，4.65-4.55(m，1H)，4.52(s，2H)，4.13(q，J＝7.2Hz，1H)，4.05-4.00(m，2H)，2.66(q，J＝7.6Hz，2H),2.15-1.95(m，9H)，1.83(d，J＝12.4Hz，3H)，1.19(t，J＝7.2Hz，3H)。
步骤4：化合物B-1-6的合成。
将B-1-5(1.4g，2.84mmol，1eq)，硫脲(757.32mg，9.95mmol，3.5eq)溶于二氧六环(14mL)中，25℃下缓慢加入三氟甲磺酸三甲基甲硅烷基酯(2.53g，11.37mmol，2.05mL，4eq)，升温至60℃搅拌1.5小时。降温至0℃，加入二异丙基乙胺(2.94g，22.74mmol，3.96mL，8eq)，碘甲烷(2.02g，14.21mmol，884.80μL，5eq)，反应升温至25℃搅拌17小时。反应完毕后，加入水(10mL)淬灭反应，加入乙酸乙酯(15mL×2)萃取，合并有机相，用无水硫酸钠干燥后过滤，滤液减压浓缩后得到粗品。粗品经柱层析纯化得到化合物B-1-6。MS:503.1[M+23] +
步骤5：化合物B-1-7的合成。
向反应瓶中依次加入化合物B-1-6(9.48g,19.73mmol,1eq)，巴比妥酸(5.05g,39.45mmol,2eq)，乙醇(95mL)，以及四三苯基膦钯(2.28g,1.97mmol,0.1eq)。氮气保护下，反应加热至65℃搅拌16小时。反应完毕后，加水(100mL)淬灭反应，混合物减压浓缩，剩余物用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经柱层析分离纯化得到化合物B-1-7。MS:463.2[M+23] +步骤6：化合物B-1的合成。
将B-1-7(14.33g，32.53mmol，1eq)溶于无水四氢呋喃(145mL)。氮气保护下，0℃条件下缓慢滴加三溴化磷(4.40g，16.27mmol，1.54mL，0.5eq)。体系于20℃搅拌16小时。反应完毕后，0℃下，滴加2M的碳酸钾水溶液(75mL)淬灭反应，搅拌10分钟后静置分层。收集有机相，水相用乙酸乙酯(200mL)萃取。合并有机相后，用饱和盐水(100mL)洗涤，经无水硫酸钠干燥后过滤，滤液减压浓缩得到粗品。 粗品中加入甲基叔丁基醚(40mL)和正己烷(60mL)，25℃下搅拌16小时后过滤，滤饼用混合溶剂(甲基叔丁基醚:正己烷＝2:3，50mL)洗涤后，干燥后得到化合物B-1。(15g，27.10mmol，1eq)。 1H NMR(CDCl 3-d)δ7.32-7.28(m，1H)，7.28-7.23(m，1H)，7.23-7.18(m，1H)，5.41-5.29(m，1H)，5.22(t，J＝10.0Hz，1H)，5.11(t，J＝10.0Hz，1H)，4.59-4.47(m，3H)，4.43(br d，J＝9.6Hz，1H)，2.75(q，J＝7.2Hz，2H)，2.20(s，3H)，2.10(s，3H)，2.02(s，3H)，1.84(s，3H)，1.27(t，J＝7.6Hz，3H)。
参照参考例6中步骤1～6的合成方法，合成表1中各片段B-2,B-3,B-4。
表1参考例2-4
Figure PCTCN2020104534-appb-000048
实施例1：WXD001
Figure PCTCN2020104534-appb-000049
合成路线：
Figure PCTCN2020104534-appb-000050
步骤1：化合物WXD001-1的合成
将A-1(3g，5.96mmol，1eq)与B-1(4.29g，7.15mmol，1.2eq)以及碳酸钠(1.26g，11.92mmol，2eq)与四三苯基磷钯(1.38g，1.19mmol，0.2eq)悬浮于甲苯(86mL)与乙醇(21.5mL)以及水(21.5mL)的混合溶剂中。氮气保护下反应于50℃下搅拌16小时。反应完毕后，反应减压浓缩，剩余物用二氯甲烷(200mL)稀释后用水(100mL×3)洗涤。有机相经无水硫酸钠干燥后减压浓缩得粗品。粗品中加入乙醇(80mL)搅拌30分钟后过滤，滤饼用乙醇(10mL×3)洗涤后干燥，得到化合物WXD001-1。
步骤2：化合物WXD001-2的合成
将化合物WXD001-1(3.3g，3.68mmol，1eq)溶于乙酸乙酯(66mL)中，加入氯化氢的乙酸乙酯溶液(4M，66.00mL，71.76eq)。反应于15℃下搅拌16小时。反应完毕后，减压浓缩得到化合物WXD001-2。
步骤3：化合物WXD001的合成
向反应瓶中加入化合物WXD001-2(760mg，0.91mmol，1eq)、甲醇(6mL)和四氢呋喃(3mL)，然后加入一水合氢氧化锂(1.02g，24.39mmol，27eq)和水(6mL)，25℃下搅拌16小时。反应完毕后，反应用水(10mL)稀释，乙酸乙酯(10mL×3)萃取。合并有机相用饱和盐水(30mL)洗涤，用无水硫酸 钠干燥后过滤，滤液减压浓缩得到粗品。粗品用制备高效液相色谱法纯化得到目标化合物WXD001。 1H NMR(400MHz，CDCl 3)δ7.21(s，2H)，7.17-7.11(m，1H)，7.08–6.94(m，5H)，6.77(d，J＝8.8Hz，2H)，4.87-4.79(m，1H)，4.37(d，J＝9.6Hz，1H)，4.25-4.09(m，3H)，3.95(s，2H)，3.68-3.61(m，1H)，3.55-3.46(m，2H)，3.37(br t，J＝10.0Hz，1H)，3.10(br dd，J＝10.0Hz，J＝6.0Hz，1H)，2.88(q，J＝7.6Hz，1H)，2.75(br d，J＝7.6Hz，2H)，2.69-2.51(m，4H)，2.40(br d，J＝11.6Hz，1H)，2.27(br dd，J＝14.0Hz，J＝7.2Hz，1H)，2.18(s，3H)，2.07-1.95(m，1H)，1.42(q，J＝12.0Hz，1H)，1.15(t，J＝7.6Hz，3H)。
参照实施例1中步骤1～3的合成方法，合成下表2中各实施例2-12。表2中结构同时代表其可能的异构体。
表2实施例2-12的各异构体
Figure PCTCN2020104534-appb-000051
Figure PCTCN2020104534-appb-000052
Figure PCTCN2020104534-appb-000053
各实施例的氢谱和质谱数据如表3所示。
表3各实施例的氢谱和质谱数据
Figure PCTCN2020104534-appb-000054
Figure PCTCN2020104534-appb-000055
Figure PCTCN2020104534-appb-000056
Figure PCTCN2020104534-appb-000057
Figure PCTCN2020104534-appb-000058
实验例一、体外细胞活性测试：
实验步骤和方法：
生物学活性实验1：SGLT1葡萄糖转运试验
1.实验目的：
通过测定进入高表达Human-SGLT1细胞内的带[ 14C]标记葡萄糖的量，检测化合物对SGLT1转运体转运葡萄糖活性的影响。
2.实验方法
2.1.细胞准备
实验所用的稳定表达Human-SGLT1的细胞由上海药明康德构建。将SGLT1细胞铺于Cytostar-T(PerkinElmer)96孔细胞培养板中并于5％CO 2，37℃的环境下培养过夜。
2.2.SGLT1葡萄糖转运试验
1)实验缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES),1.2mM氯化镁(MgCl 2),4.7mM氯化钾(KCl),2.2mM氯化钙(CaCl 2)and 120mM氯化钠(NaCl)。
2)将化合物用100％二甲基亚砜(DMSO)以1mM为起始浓度，做8个点5倍连续梯度稀释。
3)用实验缓冲液配制3μM[ 14C]标记甲基α-D-吡喃葡萄糖苷(Methyl a-D-glucopyranosid)。
4)用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，实验结果见表3。
生物学活性实验2：SGLT2葡萄糖转运试验
1.实验目的：
通过测定进入高表达Human-SGLT2细胞内的带[ 14C]标记葡萄糖的量，检测化合物对SGLT2转运体转运葡萄糖活性的影响。
2.实验方法
2.1.细胞准备
实验所用的稳定表达Human-SGLT2的细胞由上海药明康德构建。将SGLT2细胞铺于96孔细胞培养板(Greiner)中并于5％CO 2，37℃的环境下培养过夜。
2.2.SGLT2葡萄糖转运试验
1)实验缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES)，1.2mM氯化镁(MgCl 2)，4.7mM氯化钾(KCl)，2.2mM氯化钙(CaCl 2)and 120mM氯化钠(NaCl)。
2)终止缓冲液:10mM 4-羟乙基哌嗪乙磺酸(HEPES)，1.2mM氯化镁(MgCl 2)，4.7mM氯化钾(KCl)，2.2mM氯化钙(CaCl 2)120mM氯化钠(NaCl)和1μM LX4211。
3)将化合物用100％二甲基亚砜(DMSO)以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]标记甲基α-D-吡喃葡萄糖苷(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3。
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IC50值。实验结果见表4：
表4体外细胞活性测试结果
Figure PCTCN2020104534-appb-000059
注：NA表示无相关数据。
结论：本发明化合物表现出较优的对Human-SGLT1,Human-SGLT2和rhDPP4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 #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，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5：
表5化合物PK测试结果
化合物 C max(nM) F％ Oral DNAUC Vd ss(L/kg) Cl T 1/2(h)
      (nM.h/mpk)   (mL/min/kg)  
WXD001 225 18.2 109 17.8 42.0 8.99
WXD004 171 10.2 113 13.2 20.7 13.4
备注：C max为最大浓度；F％为口服生物利用度；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。
“#”：WXD001采用的溶媒为10％N-甲基吡咯烷酮/10％聚乙二醇-15羟基硬脂酸酯/80％H 2O；
WXD004采用的溶媒为20％聚乙二醇400/10％聚乙二醇-15羟基硬脂酸酯/70％H 2O。
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、大鼠口服糖尿受量(OGTT)体内药效研究：
实验概要:
1.动物:
Figure PCTCN2020104534-appb-000060
2.实验分组:
Figure PCTCN2020104534-appb-000061
实验流程:
1.动物适应及准备:
实验动物抵达设施后需在动物房适应环境1周。
2.禁食与给药
动物在代谢笼中禁食18h，按照上表给予药物或溶剂(2mL/kg)，随后立即给予50％葡萄糖溶液(2g/kg,4mL/kg)。
3.尿糖与血糖测试
动物给糖后2h，恢复进食，收集0min，15min，30min，45min，60min,120min时间点，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6：
表6大鼠糖耐受量实验结果
Figure PCTCN2020104534-appb-000062
*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。

Claims (17)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020104534-appb-100001
    其中，
    R 1选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    R 2选自Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R b取代；
    R 3、R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c取代；
    R 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d取代；
    E 1为-(CH 2) m-；
    E 2为-(CH 2) n-；
    m为0、1或2；
    n为0、1或2；
    R a、R b、R c和R d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选自CH 3和Et，所述CH 3和Et任选被1、2或3个R a取代。
  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选自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选自Cl、Br、I、OH、NH 2、CH 3、Et和
    Figure PCTCN2020104534-appb-100002
    其中所述CH 3、Et和
    Figure PCTCN2020104534-appb-100003
    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选自Cl、Br、I、OH、NH 2、CH 3、Et和
    Figure PCTCN2020104534-appb-100004
  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 3、R 4、R 5、R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其中所述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 3、R 4、R 5、R 6和R 7分别独立 地选自H、F、Cl、Br、I、OH和NH 2。
  8. 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 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其中所述CH 3和Et任选被1、2或3个R d取代。
  9. 根据权利要求8所示的化合物、其异构体或其药学上可接受的盐，其中，R 8、R 9、R 10和R 11分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et。
  10. 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，E 1为-CH 2-或-CH 2-CH 2-。
  11. 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，E 2为单键或-CH 2-。
  12. 根据权利要求1～9任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2020104534-appb-100005
    其中，
    R 1如权利要求1～3任意一项所定义；
    R 2如权利要求1、4或5任意一项所定义；
    R 3、R 4、R 5、R 6和R 7如权利要求1、6或7任意一项所定义；
    R 8、R 9、R 10和R 11如权利要求1、8或9任意一项所定义。
  13. 根据权利要求12所述的化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020104534-appb-100006
    其中，
    R 1如权利要求12所定义；
    R 2如权利要求12所定义；
    R 3、R 4、R 5、R 6和R 7如权利要求12所定义；
    R 8、R 9、R 10和R 11如权利要求12所定义。
  14. 下述化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020104534-appb-100007
  15. 根据权利要求14所述其化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020104534-appb-100008
    Figure PCTCN2020104534-appb-100009
  16. 根据权利要求15所述的化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020104534-appb-100010
    Figure PCTCN2020104534-appb-100011
  17. 根据权利要求1～16任意一项所述化合物或其药学上可接受的盐在制备SGLT1/SGLT2/DPP4三重抑制剂的相关药物中的应用。
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