WO2019185026A1 - 作为SGLTs抑制剂的葡糖苷类衍生物及其应用 - Google Patents

作为SGLTs抑制剂的葡糖苷类衍生物及其应用 Download PDF

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Publication number
WO2019185026A1
WO2019185026A1 PCT/CN2019/080436 CN2019080436W WO2019185026A1 WO 2019185026 A1 WO2019185026 A1 WO 2019185026A1 CN 2019080436 W CN2019080436 W CN 2019080436W WO 2019185026 A1 WO2019185026 A1 WO 2019185026A1
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group
compound
isomer
pharmaceutically acceptable
acceptable salt
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PCT/CN2019/080436
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English (en)
French (fr)
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吴成德
毛庆华
李翼
于涛
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 CN201980006377.9A priority Critical patent/CN111465598B/zh
Publication of WO2019185026A1 publication Critical patent/WO2019185026A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—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
    • C07D309/04—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a class of glucoside derivatives which are dual inhibitors of SGLT1/SGLT2 and their use in the preparation of a medicament as a dual inhibitor of SGLT1/SGLT2. Specifically, it relates to a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.
  • Diabetes is a metabolic disease characterized by high blood sugar. Hyperglycemia is caused by defects in insulin secretion or its biological effects, or both. In diabetes, long-term abnormal blood glucose levels can lead to serious complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage, and obesity.
  • the treatment of diabetes, early stages, diet control and exercise therapy are the preferred glycemic control programs. When these methods are difficult to control blood sugar, insulin or oral hypoglycemic drugs are needed for treatment.
  • hypoglycemic drugs for clinical treatment including biguanides, sulfonylureas, insulin resistance improvers, levonides, ⁇ -glucosidase inhibitors and dipeptidyl peptidase-IV inhibition.
  • Agents, etc. These drugs have good therapeutic effects, but there are still safety problems in long-term treatment. For example, biguanides are prone to lactic acidosis; sulfonylureas can cause hypoglycemia; insulin resistance improvers cause edema, heart failure and Weight gain; ⁇ -glucosidase inhibitors cause symptoms such as abdominal pain, bloating, and diarrhea. Therefore, there is an urgent need to develop a new safer and more effective hypoglycemic drug to meet the therapeutic needs of diabetes.
  • SGLTs Sodium-glucose cotransporters
  • Family members mainly include SGLT-1 protein and SGLT2 protein. Their functions are It mediates the transmembrane transport of glucose in the gut and kidney and plays a key role in maintaining blood sugar stability in the body.
  • SGLT1 is mainly distributed in intestinal mucosal cells of the small intestine, and is also expressed in a small amount in the myocardium and kidney, which mainly regulates the intestinal absorption process of glucose.
  • SGLT-2 is expressed at high levels in the kidney, it is mainly responsible for the regulation of glucose renal reuptake process, that is, glucose in urine can be actively attached to renal tubular epithelial cells through glomerular filtration and transported through SGLT-2 protein. The inside is reused. In this process, SGLT-2 is responsible for 90% of the reabsorption process, and the remaining 10% is done by SGLT-1. Because the process does not involve the metabolism of glucose, thereby avoiding or reducing the occurrence of adverse reactions of hypoglycemia and reducing the risk of causing cardiovascular diseases, SGLTs have become one of the ideal potential targets for the treatment of diabetes.
  • SGLTs inhibitors especially highly selective SGLT2 inhibitors. They inhibit the reabsorption of glucose by the kidney by inhibiting the activity of SGLT2, thereby increasing the excretion of glucose in the urine and normalizing plasma glucose in diabetic patients.
  • Dapagliflozin Canagliflozin, Luseogliflozin, Ipragliflozin, Tofogliflozin and Engle Six drugs, such as Empagliflozin, have been approved for marketing and become effective drugs for the treatment of diabetes.
  • SGLT1/SGLT2 dual inhibitors have good prospects for development. Therefore, it is urgent to develop a dual inhibitor of SGLT1/SGLT2 with superior efficacy, good pharmacokinetic properties and high safety for the treatment of diabetes and related metabolic disorders.
  • the SGLT1/SGLT2 dual inhibitor Sotagliflozin jointly developed by Lexicon and Sanofi, has completed a clinical phase III study (WO2008042688/WO2012094293).
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • n 1 or 2;
  • n 0, 1 or 2;
  • r is 1, 2, 3 or 4;
  • j is 1, 2 or 3;
  • D is -O- or -C(R 1 )(R 2 )-;
  • Ring A is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein said C 1-3 alkyl group is optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from the group consisting of H, F, Cl, Br, I and C 1-3 alkyl, wherein said C 1-3 alkyl group is optionally substituted by 1, 2 or 3 R b ;
  • R 1 and R 2 are bonded to each other to form a 5- to 6-membered heterocycloalkyl group
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, wherein said C 1-3 alkyl and C 1-3 alkoxy
  • the base is optionally substituted by 1, 2 or 3 R c ;
  • R 4 is selected from C 1-3 alkyl, and the C 1-3 alkyl group is optionally substituted by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein the C 1-3 alkyl group is optionally 1, 2 or 3 R e substitution;
  • R a , R b , R c , R d and R e are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein said C 1-3 alkyl group Optionally substituted by 1, 2 or 3 R;
  • R is selected from the group consisting of F, Cl, Br, I, OH, and NH 2 ;
  • the 5- to 6-membered heteroaryl group and the 5- to 6-membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 hetero atoms or heteroatoms independently selected from the group consisting of -NH-, -O-, -S- and N. .
  • said R a , R b , R c , R d and R e are each independently selected from the group consisting of H, F, Cl, Br, I, OH and NH 2 , and other variables are as defined herein.
  • R 1 above is selected from the group consisting of H, F, Cl, Br, I, OH, and NH 2 , and other variables are as defined herein.
  • R 2 is selected from the group consisting of H, F, Cl, Br, and I, and other variables are as defined herein.
  • R 3 above is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et, and -O-CH 3 , and other variables are as defined herein.
  • R 4 is selected from the group consisting of CH 3 and Et, and other variables are as defined in the present invention.
  • each of said R 5 is independently selected from the group consisting of H, F, Cl, Br, I, OH, and NH 2 , and other variables are as defined herein.
  • Ring A is selected from the group consisting of phenyl and thienyl, and other variables are as defined herein.
  • the ring A is selected from the group consisting of Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention also provides the following compounds, isomers thereof or pharmaceutically acceptable salts thereof,
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a SGLT1/SGLT2-related disease.
  • the above application is characterized in that the medicament is a medicament for treating diabetes.
  • the compounds of the present invention exhibit superior inhibitory activities against Human-SGLT1 and Human-SGLT2 in vitro and exhibit better hypoglycemic effects in animals.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • a double bond structure exists in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is bonded to two different substituents (including a nitrogen atom) Of the double bonds, a pair of lone pairs of electrons on the nitrogen atom are considered as a substituent to which they are attached), if a wavy line is used between the atom on the double bond and the substituent in the compound
  • the linkage means the (Z) isomer, the (E) isomer or a mixture of the two isomers of the compound.
  • the following formula (A) indicates that the compound exists as a single isomer of the formula (A-1) or the formula (A-2) or two isomers of the formula (A-1) and the formula (A-2) The mixture is present;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or two of formula (B-1) and formula (B-2) A mixture of isomers is present.
  • the following formula (C) indicates that the compound exists as a single isomer of the formula (C-1) or the formula (C-2) or two isomers of the formula (C-1) and the formula (C-2) The mixture is present.
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug.
  • Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in AX, the structure is actually A.
  • the substituent When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • “5 to 7-membered ring” means 5 to 7 atoms arranged in a circle.
  • the ring optionally contains from 1 to 3 heteroatoms.
  • the "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • alkyl is used to mean a straight or branched saturated hydrocarbon group, and in some embodiments, the alkyl group is a C 1-12 alkyl group; in other embodiments The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • alkenyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bond may be located at any position of the group.
  • the alkenyl group is a C 2-8 alkenyl group; in other embodiments, the alkenyl group is a C 2-6 alkenyl group; in other embodiments, the alkenyl group is C 2-4 alkenyl. It can be monovalent, divalent or multivalent.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like.
  • alkynyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bond may be located at any position of the group.
  • the alkynyl group is a C 2-8 alkynyl group; in other embodiments, the alkynyl group is a C 2-6 alkynyl group; in other embodiments, the alkynyl group is C 2-4 alkynyl. It can be monovalent, divalent or multivalent. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • heteroalkyl by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the terms “alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) Oxyl) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups. In some embodiments, the alkoxy group is a C 1-3 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S- Pentyloxy.
  • heteroalkenyl by itself or in conjunction with another term, denotes a stable straight or branched alkenyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkenyl group is a C 2-6 heteroalkenyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkenyl group.
  • the hetero atom or heteroatom group may be located at any internal position of the heteroalkenyl group, including the position at which the alkenyl group is attached to the rest of the molecule, but the terms "alkenyloxy”, “alkenylamino” and “alkenylthio” are customary. By expression, it is meant those alkenyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl by itself or in conjunction with another term, denotes a stable straight or branched alkynyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkynyl group is a C 2-6 heteroalkynyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkynyl group.
  • hetero atom or heteroatom group may be located at any internal position of the heteroalkynyl group, including the position at which the alkynyl group is attached to the rest of the molecule, but the terms "alkynyloxy", “alkynylamino” and “alkynylthio” are customary. By expression, it is meant those alkynyl groups attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl groups include, but are not limited to, Up to two heteroatoms can be continuous, for example
  • cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic or tricyclic systems wherein the bicyclic and tricyclic systems include spiro, co and ring.
  • the cycloalkyl group is a C 3-8 cycloalkyl group; in other embodiments, the cycloalkyl group is a C 3-6 cycloalkyl group; in other embodiments, the The cycloalkyl group is a C 5-6 cycloalkyl group. It can be monovalent, divalent or multivalent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane and the like.
  • cycloalkenyl includes any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic
  • the cycloalkenyl group is a C 3-8 cycloalkenyl group; in other embodiments, the cycloalkenyl group is a C 3-6 cycloalkenyl group; in other embodiments, the The cycloalkenyl group is a C 5-6 cycloalkenyl group. It can be monovalent, divalent or multivalent. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkynyl includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position of the group, including monocyclic, bicyclic or tricyclic systems, wherein Bicyclic and tricyclic systems include spiro, parallel and bridging rings. It can be monovalent, divalent or multivalent.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring. Further, in the case of the "heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene) -2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and
  • heterocyclenyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkenyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, Rings and bridge rings, but any ring of this system is non-aromatic.
  • a heteroatom can occupy the position of attachment of the heterocyclenyl group to the rest of the molecule.
  • the heterocycloalkenyl is 4 to 6 membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is 5 to 6 membered heterocycloalkenyl.
  • heterocycloalkenyl groups include, but are not limited to,
  • heterocycloalkynyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkynyl” group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring.
  • a hetero atom may occupy a position where a heterocyclic alkynyl group is bonded to the rest of the molecule.
  • the heterocycloalkynyl group is a 4 to 6 membered heterocycloalkynyl group; in other embodiments, the heterocycloalkynyl group is a 5 to 6 membered heterocycloalkynyl group.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term “haloalkyl” is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • aromatic ring and “aryl” are used interchangeably and the term “aryl ring” or “aryl” means a polyunsaturated carbocyclic ring system which may be monocyclic, bicyclic or poly A ring system in which at least one ring is aromatic, and each ring in the bicyclic and polycyclic ring system is fused together. It may be monovalent, divalent or multivalent, in some embodiments, the aryl group is a C6-12 aryl group; in other embodiments, the aryl group is a C6-10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). Substituents for any of the above aryl ring systems are selected from the group of acceptable substituents described herein.
  • heteroaryl ring and “heteroaryl” are used interchangeably and the term “heteroaryl” means 1, 2, 3 or 4 independently selected from B, N, O and An aryl (or aromatic ring) of a hetero atom of S, which may be a monocyclic, bicyclic or tricyclic system wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl.
  • the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.) , triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- Triazolyl, etc.), tetrazolyl, isoxazolyl (3-
  • aralkyl is intended to include those groups in which an aryl group is attached to an alkyl group.
  • the aralkyl group is a C6-10 aryl- C1-4 alkyl group.
  • the aralkyl group is a C 6-10 aryl-C 1-2 alkyl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like.
  • Aryloxy and "arylthio” mean those groups wherein the carbon atom (e.g., methyl) in the aralkyl group has been replaced by an oxygen or sulfur atom, and in some embodiments, the aryloxy group is C. 6-10 Aryl-OC 1-2 alkyl; in other embodiments, the aryloxy group is C 6-10 aryl-C 1-2 alkyl-O-. In some embodiments, the arylthio group is a C 6-10 aryl-SC 1-2 alkyl group; in other embodiments, the arylthio group is a C 6-10 aryl-C 1-2 alkyl group. -S-. Examples of aryloxy and arylthio groups include, but are not limited to, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, and the like.
  • heteroarylkyl is meant to include those heteroaryl groups attached to an alkyl group, in some embodiments, the heteroaryl group is 5-8 membered heteroaryl, -C 1 -4 alkyl; in other embodiments, the heteroarylalkyl group is a 5-6 membered heteroaryl-C 1-2 alkyl group.
  • heteroarylalkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like.
  • Heteroaryloxy and “heteroarylthio” mean those groups in which the carbon atom (eg, methyl) in the heteroaralkyl group has been replaced by an oxygen or sulfur atom, respectively, and in some embodiments, the heteroaryl The oxy group is a 5-8 membered heteroaryl-OC 1-2 alkyl group; in other embodiments, the heteroaryloxy group is a 5-6 membered heteroaryl-C 1-2 alkyl-O- group. In some embodiments, the heteroarylthio group is a 5-8 membered heteroaryl-SC 1-2 alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C 1 -2 alkyl-S-.
  • heteroaryloxy and heteroarylthio groups include, but are not limited to, pyrroleoxymethyl, pyrazolyloxymethyl, 2-pyridyloxymethyl, pyrrolethiomethyl, pyrazolethiomethyl, 2-pyridinethiomethyl Wait.
  • C n-n+m or C n -C n+m includes any one of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range of n to n+m, for example, C 1-12 includes C 1 - 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-
  • a 10-membered ring, a 11-membered ring, and a 12-membered ring and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Step 1 Synthesis of Compound A-1-3.
  • Step 3 Synthesis of Compound A-1-5.
  • the ZnEt 2 (1M, 180.69mL, 5.25eq ) was dissolved in CH 2 Cl 2 (200mL), the CH 2 I 2 (92.18g, 344.18mmol , 27.77mL, 10eq) was slowly added to the reaction The mixture was stirred at 0 ° C for 30 minutes, then trifluoroacetic acid (20.60 g, 180.69 mmol, 13.38 mL, 5.25 eq) was slowly added to the reaction mixture, and the mixture was stirred at 0 ° C for 30 minutes, and then transferred to the reaction mixture.
  • Step 4 Synthesis of Compound A-1.
  • Step 1 Synthesis of Compound A-9-2.
  • 1,3-acetone dicarboxylic acid was added to the reaction flask dimethyl (12.59g, 72.29mmol, 10.49mL, 2.2eq ) and NaHCO 3 (0.166M, 65.32mL, 0.33eq ), added in one portion with vigorous stirring compound A-9-2 (7 g, 32.86 mmol, 1 eq) was reacted at 25 ° C for 16 hours. The reaction solution was then filtered, and the solid A-9-4 was collected and used directly for the next reaction.
  • compound B-1-1 (30 g, 127.41 mmol, 1 eq) and tetrahydrofuran (600 mL), and borane tetrahydrofuran complex (1M, 382.23 mL, 3 eq) was added while stirring at 25 ° C. The mixture was reacted for 16 hours. After completion of the reaction, methanol (150 mL) was added dropwise to the reaction mixture at 25 ° C, while nitrogen gas was purged, quenched, and concentrated to dryness at 45 ° C to give compound B-1-2.
  • Lithium aluminum hydride (11 g, 289.82 mmol, 1.25 eq) was dissolved in tetrahydrofuran (200 mL) at 0 ° C.
  • Compound B-2-1 (50 g, 232.51 mmol, 1 eq) was slowly dissolved in tetrahydrofuran (200 mL) at 0 ° C. Air bubbles were generated, and the reaction was heated to 25 ° C for 2 hours.
  • Water (11 mL) was slowly added dropwise at 0 ° C, and a 15% aqueous sodium hydroxide solution (11 mL) was added dropwise, and finally water (33 mL) was added. Filter and filter the filter residue twice with ethyl acetate. The filtrate was suspended.
  • the crude compound B-2-2 was obtained.
  • the magnesium alkoxide solution was slowly added to the alkyl lithium solution at -78 °C.
  • the reaction solution was reacted at -78 ° C for 0.5 hour, and then the temperature was raised to 25 ° C, and the reaction was continued for 15.5 hours.
  • an amine chloride solution 50 mL was added to the reaction mixture at 0 ° C, and the mixture was diluted with ethyl acetate (200 mL) and washed with water (50 mL ⁇ 2). After the organic phase was combined, the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated
  • Each of the fragments B-4 in the following table was synthesized by referring to the synthesis methods of the steps 1 to 8 in Reference Example 10.
  • Each of the fragments B-5 in the following table was synthesized by referring to the synthesis methods of the steps 1 to 8 in Reference Example 11.
  • the structures in the table also represent their possible isomers.
  • reaction liquid was concentrated under reduced pressure at 45 ° C with a first water pump to remove ethanol, and then concentrated by an oil pump to remove toluene and water to give a black solid.
  • the crude product was purified by column chromatography to afford the title compound WXD001-1.
  • reaction liquid was concentrated under reduced pressure at 45 ° C with a first water pump to remove ethanol, and then concentrated by an oil pump to remove toluene and water to give a black solid.
  • the crude product was purified by column chromatography to give the object compound WXD0012-1.
  • Example 20 in the following Table 5 was synthesized.
  • the structures in Table 5 also represent their possible isomers.
  • the effect of the compound on the transport of glucose to the SGLT1 transporter was examined by measuring the amount of [ 14C ]-labeled glucose that entered the high-expression Human-SGLT1 cells.
  • the cells stably expressing Human-SGLT1 used in the experiment were constructed by Shanghai WuXi PharmaTech.
  • SGLT1 cells were plated in Cytostar-T (PerkinElmer) 96-well cell culture plates and cultured overnight at 37 ° C in 5% CO 2 .
  • the cells were allowed to act on the cells at 37 ° C for 2 hours with 49 uL of experimental buffer, 1 ⁇ L of the gradient diluted compound and 50 ⁇ L of 3 ⁇ M [ 14 C] isotope-labeled sugar solution.
  • the effect of the compound on the transport of glucose to the SGLT2 transporter was examined by measuring the amount of [ 14C ]-labeled glucose that entered the high-expression Human-SGLT2 cells.
  • the cells stably expressing Human-SGLT2 used in the experiment were constructed by Shanghai WuXi PharmaTech.
  • SGLT2 cells were plated in 96-well cell culture plates (Greiner) and cultured overnight at 37 ° C in 5% CO 2 .
  • Stop buffer 10 mM HEPES, 1.2 mM MgCl 2 , 4.7 mM KCl, 2.2 mM CaCl 2 , 120 mM NaCl and 1 ⁇ M LX4211.
  • the cells were lysed with 50 ⁇ L of 10% sodium hydroxide solution, and the cell lysate was aspirated into a scintillation vial, and 2 mL of scintillation fluid was added.
  • the compounds of the present invention exhibit superior in vitro inhibitory activity against Human-SGLT2 and Human-SGLT1.
  • mice Male Sprague-Dawley rats were used as test animals, and the plasma concentration of the compounds was measured after a single administration and the pharmacokinetic behavior was evaluated.
  • mice Six healthy adult male Sprague-Dawley rats were selected, three were intravenous and three were oral.
  • the test compound was mixed with an appropriate amount of the vehicle (10% N-methylpyrrolidone/10% polyethylene glycol-15 hydroxystearate/80% H 2 O), vortexed and sonicated to prepare 0.2 mg/
  • the clear solution of mL is filtered and the microporous membrane is filtered for use;
  • the oral vehicle is 10% N-methylpyrrolidone/10% polyethylene glycol-15 hydroxystearate/80% H 2 O, and the test compound is mixed with the solvent. Thereafter, vortexing and sonication gave a clear solution of 0.40 mg/mL.
  • Rats were given 1 mg/kg intravenously or 2 mg/kg orally, and whole blood was collected for a certain period of time to prepare plasma.
  • the drug concentration was analyzed by LC-MS/MS method, and the drug was calculated using Phoenix WinNonlin software (Pharsight, USA). Generation parameters.
  • C max is the maximum concentration
  • F% oral bioavailability
  • DNAUC AUC PO /Dose
  • AUC PO oral exposure
  • Dose drug dose
  • Vd ss volume of distribution
  • Cl clearance
  • T 1/2 It It is half life.
  • the compound of the present invention can significantly reduce the blood glucose AUC level in the animal within 2 hours; and can increase the urine glucose excretion level in the animal for 24 hours.
  • mice level SPF animal Ordering weeks 5 weeks old Beginning of the experiment 6 weeks old Weight range ⁇ 25g gender male supplier Nanjing Model Animal Research Institute, Nanjing University supplier address Nanjing, Jiangsu, China
  • the temperature in the rearing room is maintained at 20 to 24 ° C and the humidity is maintained at 40 to 70%.
  • the temperature and humidity of the rearing room were monitored in real time by a thermometer and hygrometer, and the temperature and humidity were recorded twice a day (one in the morning and one in the afternoon).
  • the daylighting of the animal husbandry is controlled by an electronic timed lighting system. The lights are turned on for 12 hours every day for 12 hours (7:00 am and 19:00 pm).
  • the mice were housed in a single cage. During the experiment, the animals were fed ad libitum (large mouse breeding feed 17053113, Beijing Keao Xieli Feed Co., Ltd.) and drinking water.
  • the animals were given the corresponding solvent or test sample according to the group, the administration time was: 16:00, and the administration period was 8 weeks. From the first week to the fourth week, the dose was 5 mg/kg; from the 5th week to the 8th week, the dose was 10 mg/kg.
  • the animals were given a single glucose solution of 2 g/kg, and the sugar supply time was recorded as 0 points, and before the sugar was given, the sugar was given at 15,30.
  • the animals were tested for blood glucose, and the glucose tolerance curve was plotted against the blood glucose data according to the time, and the area under the curve (AUC) was calculated.
  • the administration time is: 16:00.
  • the compounds of the present invention can significantly reduce the blood glucose AUC level within 2 hours.
  • the compounds of the invention significantly reduced animal glycated hemoglobin (HbA1c) levels compared to the vehicle control group.

Abstract

一类作为SGLT1/SGLT2双重抑制剂的葡糖苷类衍生物，及其在制备作为SGLT1/SGLT2双重抑制剂的药物中的应用，所述衍生物为式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。

Description

作为SGLTs抑制剂的葡糖苷类衍生物及其应用
本申请主张如下优先权：
CN201810291288.0，申请日2018.03.30。
技术领域
本发明涉及一类作为SGLT1/SGLT2双重抑制剂的葡糖苷类衍生物，以及在制备作为SGLT1/SGLT2双重抑制剂的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
糖尿病是一种以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时，长期血糖水平异常可导致严重的并发症，包括心血管疾病、慢性肾功能衰竭、视网膜损伤、神经损伤、微血管损伤和肥胖等。糖尿病的治疗，早期阶段，饮食控制和运动疗法是首选的血糖控制方案。当这些方法难以实现对血糖的控制时，则需要使用胰岛素或者口服降糖类药物进行治疗。目前，己有多种降糖药物用于临床治疗，主要包括双胍类、磺酰脲类、胰岛素耐受改善剂、列奈类、α-葡萄糖苷酶抑制剂和二肽基肽酶-IV抑制剂等。这些药物具有良好的治疗效果，但长期治疗仍存在安全性问题，例如，双胍类易引起乳酸性酸中毒；磺酰脲类会导致低血糖症状；胰岛素耐受改善剂会造成水肿、心脏衰竭和体重增加；α-葡萄糖苷酶抑制剂会引起腹痛、腹胀、腹泻等症状。因此，迫切需要开发出一种更安全、优效的新型降糖药物满足糖尿病的治疗需要。
钠-葡萄糖共转运蛋白(sodium-glucose cotransporters,SGLTs)是一类在小肠黏膜和肾近曲小管中发现的葡萄糖转运蛋白家族，家族成员主要包括SGLT-1蛋白和SGLT2蛋白两类，其功能是介导肠道和肾脏中葡萄糖的跨膜转运，在维持人体血糖稳定中起着关键作用。具体而言，SGLT1主要分布于小肠的肠道粘膜细胞，在心肌和肾脏中也有少量表达，它主要调节葡萄糖的肠道吸收过程。而SGLT-2在肾脏中高水平表达，主要负责葡萄糖肾脏重摄取过程的调节，即尿液中的葡萄糖在经过肾小球过滤时可主动附着于肾小管上皮细胞并通过SGLT-2蛋白转运进胞内被重新利用。在这一过程中，SGLT-2负责了90％的重吸收过程，剩余的10％则有由SGLT-1完成。由于该过程不介入葡萄糖的代谢，从而避免或减轻了低血糖不良反应的发生，降低了引起心血管类疾病的风险，因此，SGLTs已成为治疗糖尿病的理想潜在靶点之一。
鉴于此，一些SGLTs抑制剂，尤其是高选择性的SGLT2抑制剂被相继开发。它们通过抑制SGLT2活性，特异性地抑制肾脏对葡萄糖的重吸收，从而增加葡萄糖在尿中的***，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***和肾功能损伤等的风险。因而开发SGLT-1/SGLT2双重抑制剂已成为近年来糖尿病治疗的新靶点和方向。
综上所述，作为新型的糖尿病治疗药物，SGLT1/SGLT2双重抑制剂有着良好的开发前景。因此，急需开发出一种优效、药代性质良好，安全性高的SGLT1/SGLT2双重抑制剂用于糖尿病及相关代谢紊乱疾病的治疗。目前，由Lexicon公司和赛诺菲公司联合开发的SGLT1/SGLT2双抑制剂Sotagliflozin已经完成临床III期研究(WO2008042688/WO2012094293)。
Figure PCTCN2019080436-appb-000001
发明内容
本发明提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019080436-appb-000002
其中，
m为1或2；
n为0、1或2；
r为1、2、3或4；
j为1、2或3；
D为-O-或-C(R 1)(R 2)-；
环A选自苯基和5～6元杂芳基；
R 1选自H、F、Cl、Br、I、OH、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 a取代；
R 2选自H、F、Cl、Br、I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；
或者，R 1和R 2相互连接形成一个5～6元杂环烷基；
R 3选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R c取代；
R 4选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；
每一个R 5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 e取代；
R a、R b、R c、R d和R e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取代；
R选自F、Cl、Br、I、OH和NH 2；
所述5～6元杂芳基和5～6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R a、R b、R c、R d和R e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 1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 2选自H、F、Cl、Br和I，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-O-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述每一个R 5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，上述环A选自苯基和噻吩基，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2019080436-appb-000003
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019080436-appb-000004
选自
Figure PCTCN2019080436-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019080436-appb-000006
选自
Figure PCTCN2019080436-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019080436-appb-000008
选自
Figure PCTCN2019080436-appb-000009
Figure PCTCN2019080436-appb-000010
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019080436-appb-000011
选自
Figure PCTCN2019080436-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019080436-appb-000013
选自
Figure PCTCN2019080436-appb-000014
Figure PCTCN2019080436-appb-000015
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，上述的化合物、其异构体或其药学上可接受的盐，选自
Figure PCTCN2019080436-appb-000016
其中，
R 1、R 2、R 3和R 4如本发明所定义。
本发明还提供了下述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019080436-appb-000017
Figure PCTCN2019080436-appb-000018
本发明的一些方案中，上述的化合物、其异构体或其药学上可接受的盐，选自
Figure PCTCN2019080436-appb-000019
Figure PCTCN2019080436-appb-000020
Figure PCTCN2019080436-appb-000021
本发明还提供了述化合物或其药学上可接受的盐在制备治疗SGLT1/SGLT2相关疾病的药物中的应用。
本发明的一些方案中，上述的应用，其特征在于，所述药物是用于治疗糖尿病的药物。
技术效果
本发明的化合物在体外表现出较优的对Human-SGLT1和Human-SGLT2的抑制活性，在动物体内展现出较好的降糖效果。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
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，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019080436-appb-000022
和楔形虚线键
Figure PCTCN2019080436-appb-000023
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019080436-appb-000024
和直形虚线键
Figure PCTCN2019080436-appb-000025
表示立体中心的相对构型，用波浪线
Figure PCTCN2019080436-appb-000026
表示楔形实线键
Figure PCTCN2019080436-appb-000027
或楔形虚线键
Figure PCTCN2019080436-appb-000028
或用波浪线
Figure PCTCN2019080436-appb-000029
表示直形实线键
Figure PCTCN2019080436-appb-000030
和直形虚线键
Figure PCTCN2019080436-appb-000031
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 PCTCN2019080436-appb-000032
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 PCTCN2019080436-appb-000033
Figure PCTCN2019080436-appb-000034
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“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。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合例如，结构单元
Figure PCTCN2019080436-appb-000035
表示其可在环己基或者环己二烯上的任意一个位置发生取代。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 PCTCN2019080436-appb-000036
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 PCTCN2019080436-appb-000037
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 PCTCN2019080436-appb-000038
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。环上原子的数目通常被定义为环的元数， 例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶基和哌啶基；另一方面，术语“5～7元杂环烷基”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“烯基”用于表示直链或支链的包含一个或多个碳-碳双键的碳氢基团，碳-碳双键可以位于该基团的任何位置上。在一些实施方案中，所述烯基为C 2-8烯基；在另一些实施方案中，所述烯基为C 2-6烯基；在另一些实施方案中，所述烯基为C 2-4烯基。其可以是一价、二价或者多价。烯基的实例包括但不限于乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”用于表示直链或支链的包含一个或多个碳-碳三键的碳氢基团，碳-碳三键可以位于该基团的任何位置上。在一些实施方案中，所述炔基为C 2-8炔基；在另一些实施方案中，所述炔基为C 2-6炔基；在另一些实施方案中，所述炔基为C 2-4炔基。其可以是一价、二价或者多价。炔基的实例包括但不限于乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。在一些实施方案中，所述烷氧基为C 1-3烷氧基。烷氧基的实例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“杂烯基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或 杂原子团组成的，稳定的直链或支链的烯基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烯基为C 2-6杂烯基；在另一些实施方案中，所述杂烷基为C 2-4杂烯基。杂原子或杂原子团可以位于杂烯基的任何内部位置，包括该烯基与分子其余部分的连接位置，但术语“烯基氧基”、“烯基氨基”和“烯基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烯基基团。杂烯基的实例包括但不限于-O-CH＝CH 2、-O-CH＝CHCH 3、-O-CH＝C(CH 3) 2、-CH＝CH-O-CH 3、-O-CH＝CHCH 2CH 3、-CH 2-CH＝CH-OCH 3、-NH-CH＝CH 2、-N(CH＝CH 2)-CH 3、-CH＝CH-NH-CH 3、-CH＝CH-N(CH 3) 2、-S-CH＝CH 2、-S-CH＝CHCH 3、-S-CH＝C(CH 3) 2、-CH 2-S-CH＝CH 2、-S(＝O)-CH＝CH 2和-CH＝CH-S(＝O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH＝CH-NH-OCH 3。
除非另有规定，术语“杂炔基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的炔基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂炔基为C 2-6杂炔基；在另一些实施方案中，所述杂烷基为C 2-4杂炔基。杂原子或杂原子团可以位于杂炔基的任何内部位置，包括该炔基与分子其余部分的连接位置，但术语“炔基氧基”、“炔基氨基”和“炔基硫基”属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些炔基基团。杂炔基的实例包括但不限于
Figure PCTCN2019080436-appb-000039
Figure PCTCN2019080436-appb-000040
Figure PCTCN2019080436-appb-000041
至多两个杂原子可以是连续的，例如
Figure PCTCN2019080436-appb-000042
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“环烯基”包括任何稳定的环状烯基，在该基团的任何位点含有一个或多个不饱和的碳 -碳双键，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。在一些实施方案中，所述环烯基为C 3-8环烯基；在另一些实施方案中，所述环烯基为C 3-6环烯基；在另一些实施方案中，所述环烯基为C 5-6环烯基。其可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，“环炔基”包括任何稳定的环状炔基，在该基团的任何位点含有一个或多个碳-碳三键，其包含单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。其可以是一价、二价或者多价。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷基。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“杂环烯基”本身或者与其他术语联合分别表示环化的“杂烯基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。此外，就该“杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。在一些实施方案中，所述杂环烯基为4～6元杂环烯基；在另一些实施方案中，所述杂环烯基为5～6元杂环烯基。杂环烯基的实例包括但不限于
Figure PCTCN2019080436-appb-000043
Figure PCTCN2019080436-appb-000044
除非另有规定，术语“杂环炔基”本身或者与其他术语联合分别表示环化的“杂炔基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环炔基”而言，杂原子可以占据杂环炔基与分子其余部分的连接位置。在一些实施方案中，所述杂环炔基为4～6元杂环炔基；在另一些实施方案中，所述杂环炔基为5～6元杂环炔基。除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非 另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
除非另有规定，本发明术语“芳环”和“芳基”可以互换使用，术语“芳环”或“芳基”表示多不饱和的碳环体系，它可以是单环、双环或多环体系，其中至少一个环是芳香性的，所述双环和多环体系中的各个环稠合在一起。其可以是一价、二价或者多价，在一些实施方案中，所述芳基为C 6-12芳基；在另一些实施方案中，所述芳基为C 6-10芳基。芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。上述任意一个芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，本发明术语“杂芳环”和“杂芳基”可以互换使用，术语“杂芳基”是指含有1、2、3或4个独立选自B、N、O和S的杂原子的芳基(或芳环)，其可以是单环、双环或三环体系，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。杂芳基可通过杂原子连接到分子的其余部分。在一些实施方案中，所述杂芳基为5-10元杂芳基；在另一些实施方案中，所述杂芳基为5-6元杂芳基。所述杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)、喹啉基(包括3-喹啉基和6-喹啉基等)、吡嗪基、嘌呤基、苯基并噁唑基。上述任意一个杂芳基环系的取代基选自本发明所述的可接受的取代基。
除非另有规定，术语“芳烷基”意在包括芳基附着于烷基的那些基团，在一些实施方案中，所述芳烷基为C 6-10芳基-C 1-4烷基；在另一些实施方案中，所述芳烷基为C 6-10芳基-C 1-2烷基。芳烷基的实例包括但不限于苄基、苯乙基、萘甲基等。“芳氧基”和“芳硫基”分别表示芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述芳氧基为C 6-10芳基-O-C 1-2烷基；在另一些实施方案中，芳氧基为C 6-10芳基-C 1-2烷基-O-。在一些实施方案中，所述芳硫基为C 6-10芳基-S-C 1-2烷基；在另一些实施方案中，芳硫基为C 6-10芳基-C 1-2烷基-S-。芳氧基和芳硫基的实例包括但不限于苯氧基甲基、3-(1-萘氧基)丙基，苯硫基甲基等。
除非另有规定，术语“杂芳烷基”意在包括杂芳基附着于烷基的那些基团，在一些实施方案中，所述杂芳烷基为5-8元杂芳基-C 1-4烷基；在另一些实施方案中，所述杂芳烷基为5-6元杂芳基-C 1-2烷基。杂芳烷基的实例包括但不限于吡咯基甲基、吡唑基甲基、吡啶基甲基、嘧啶基甲基等。“杂芳氧基”和“杂芳硫基”分别表示杂芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述杂 芳氧基为5-8元杂芳基-O-C 1-2烷基；在另一些实施方案中，杂芳氧基为5-6元杂芳基-C 1-2烷基-O-。在一些实施方案中，所述杂芳硫基为5-8元杂芳基-S-C 1-2烷基；在另一些实施方案中，杂芳硫基为5-6元杂芳基-C 1-2烷基-S-。杂芳氧基和杂芳硫基的实例包括但不限于吡咯氧甲基、吡唑氧甲基、2-吡啶氧甲基、吡咯硫甲基、吡唑硫甲基、2-吡啶硫甲基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明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***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过 夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；NMP代表N-甲基吡咯烷酮；IPA代表异丙醇；DEA代表二乙醇胺；HEPES代表4-羟乙基哌嗪乙磺酸。
化合物经手工或者
Figure PCTCN2019080436-appb-000045
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
Figure PCTCN2019080436-appb-000046
合成路线：
Figure PCTCN2019080436-appb-000047
步骤1：化合物A-1-3的合成。
向预先干燥好的三口瓶(500mL)中依次加入化合物A-1-1(20g,84.78mmol,10.87mL,1eq)和四氢呋喃(125mL)，置换氮气，降温至-78℃后缓慢滴加正丁基锂(2.5M,37.64mL,1.11eq)，搅拌0.5小时。最后加入化合物A-1-2(12.5g,93.26mmol,1.1eq)，缓慢升温至0℃搅拌0.5小时。反应完毕后用饱和氯化铵水溶液(200mL)在0～10℃下缓慢淬灭，乙酸乙酯(200mL x 2)萃取，合并有机相，用饱和氯化钠(100mL)洗涤，再用无水硫酸钠干燥，滤去干燥剂后，减压除去溶剂，得到粗品化合物A-1-3，未经纯化直接用于下一步反应。
步骤2：化合物A-1-4的合成。
向预先干燥好的三口瓶(1000mL)中依次加入化合物A-1-3(23.2g,79.82mmol,1eq)和甲苯(600mL)，最后加入一水合对甲苯磺酸(1.82g,9.58mmol,0.12eq)。置换氮气，加热至130℃搅拌10小时(用分水 器)。反应完毕后将反应液降温后减压蒸出溶剂。残余物经过柱层析分离得到化合物A-1-4。 1H NMR(400MHz,CHLOROFORM-d)δ:7.49-7.43(m,2H),7.27-7.22(m,2H),5.91(dt,J＝1.3,2.6Hz,1H),2.80-2.63(m,4H),2.19(tt,J＝6.7,13.7Hz,2H).
步骤3：化合物A-1-5的合成。
在-78℃下，将ZnEt 2(1M,180.69mL,5.25eq)溶于CH 2Cl 2(200mL)中，将CH 2I 2(92.18g,344.18mmol,27.77mL,10eq)缓慢加入到反应液中，并在0℃下搅拌30分钟，然后向反应液中缓慢加入三氟乙酸(20.60g,180.69mmol,13.38mL,5.25eq)，继续在0℃下搅拌30分钟后，再向反应液中缓慢加入化合物A-1-4(9.4g,34.42mmol,1eq)的CH 2Cl 2(100mL)溶液，并升温至25℃下反应12小时。反应完毕后，将反应液冷至0℃下，向反应液中加入30mL水淬灭反应，然后用乙酸乙酯(40mL x 3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，旋干。粗品经过柱层析纯化得到化合物A-1-5。 1H NMR(400MHz,CHLOROFORM-d)δ:7.32(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H),2.43-2.47(m,1H),2.12-2.20(m,2H),1.87-1.98(m,2H),1.55-1.65(m,1H),1.15-1.18(m,1H),0.99-1.03(m,1H),0.67(t,J＝5.2Hz,1H).
步骤4：化合物A-1的合成。
向预先干燥好的单口瓶(100mL)中依次加入化合物A-1-5(3.05g,10.62mmol,1eq)、双联频哪醇硼酸酯(5.39g,21.24mmol,2eq)、乙酸钾(3.13g,31.85mmol,3eq)和1,4-二氧六环(30mL)，置换氮气后加入1,1'-双(二苯基磷)二茂铁氯化钯(776.94mg,1.06mmol,0.1eq)。再次置换氮气，加热至70℃搅拌10小时。反应完毕后将反应液降温，减压蒸出溶剂，残余物经过柱层析纯化得到化合物A-1。 1H NMR(400MHz,CHLOROFORM-d)δ:7.74(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),2.47-2.54(m,1H),2.16-2.37(m,2H),1.90-1.94(m,2H),1.51-1.68(m,1H),1.33(s,12H),1.19-1.21(m,1H),1.04-1.07(m,1H),0.67(t,J＝3.6Hz,1H).
参照参考例1中步骤1～4的合成方法，合成下表中各片段A2-8。表中的结构同时代表其可能的异构体。
Figure PCTCN2019080436-appb-000048
Figure PCTCN2019080436-appb-000049
Figure PCTCN2019080436-appb-000050
参考例9：片段A-9
Figure PCTCN2019080436-appb-000051
合成路线：
Figure PCTCN2019080436-appb-000052
步骤1：化合物A-9-2的合成。
向反应瓶中加入二氧化硒(27.87g,251.20mmol,27.33mL,2eq)、H 2O(17.5mL)和1,4-二氧六环(175mL)，加热至55℃，待溶液变澄清后加入4-溴苯乙酮(25g,125.60mmol,1eq)，109℃下反应16小时。然后将反应液过滤，收集滤液，滤液减压浓缩至干，加入650mL水，加热回流2小时，趁热滤去不溶物，滤液慢慢冷却，析出固体，过滤收集得到A-9-2。 1H NMR(400MHz,DMSO-d6)δ＝9.47(s,1H),8.03-7.96(m,2H),7.82-7.70(m,2H),6.86(br d,J＝7.0Hz,1H),5.62(br t,J＝5.7Hz,1H)。
步骤2：化合物A-9-4的合成。
向反应瓶中加入1,3-丙酮二羧酸二甲酯(12.59g,72.29mmol,10.49mL,2.2eq)和NaHCO 3(0.166M,65.32mL,0.33eq)，剧烈搅拌下一次性加入化合物A-9-2(7g,32.86mmol,1eq)，25℃下反应16小时。然后反应液过滤，收集得到固体A-9-4，直接用于下一步反应。
步骤3：化合物A-9-5的合成。
将A-9-4(3.5g,3.93mmol,1eq)、盐酸(1M,25.81mL,6.57eq)和乙酸(5.42g,90.27mmol,5.16mL,22.96eq)的混合物加热至100℃反应16小时。趁热过滤，滤去不溶物，滤液用二氯甲烷(10mL x3)萃取，合并有机相，无水硫酸钠干燥，过滤，收集滤液，旋干的黄色油状物。粗产物经过柱层析纯化得到化合物A-9-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.52(d,J＝8.3Hz,2H),7.20(d,J＝8.3Hz,2H),3.38-3.23(m,1H),2.86-2.79(m,2H),2.75(dd,J＝8.8,19.3Hz,2H),2.69-2.62(m,2H),2.31(d,J＝5.3Hz,1H),2.26(d,J＝5.3Hz,1H)。
步骤4：化合物A-9-6的合成。
向反应瓶中加入化合物A-9-5(390mg,1.33mmol,1eq)和双(2-甲氧基乙基)氨基三氟化硫(BAST)(2.94g,13.3mmol,971.38uL,10eq)，30℃反应16小时。然后反应液滴加到NaHCO 3水溶液(30mL)淬灭，二氯甲烷(10mLx3)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产物。粗产物经过使用制备薄层色谱纯化得到化合物A-9-6。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.48(d,J＝8.3Hz,2H),7.18(d,J＝8.8Hz,2H),3.18-3.06(m,1H),2.69-2.55(m,4H),2.51(br dd,J＝9.4,13.4Hz,2H),2.23(br dd,J＝5.7,14.0Hz,2H)。
步骤5：化合物A-9的合成。
向预先干燥好的单口瓶(100mL)中依次加入化合物A-9-6(150mg,0.445mmol,1eq)、频哪醇硼酸酯(226mg,0.89mmol,2eq)、乙酸钾(131mg,1.34mmol,3eq)和1,4-二氧六环(10mL)，置换氮气后加入1,1'-双(二苯基磷)二茂铁氯化钯(32.5mg,0.0445mmol,0.1eq)。再次置换氮气，加热至70℃搅拌10小时。反应完毕后将反应液降温，减压蒸出溶剂，残余物经过柱层析纯化得到化合物A-9。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.81(d,J＝8.2Hz,2H),7.31(d,J＝7.4Hz,2H),3.27-3.13(m,1H),2.72-2.58(m,4H),2.57-2.43(m,2H),2.23(br dd,J＝5.7,14.1Hz,2H),1.35(s,12H)。
参考例10：片段B-1
Figure PCTCN2019080436-appb-000053
合成路线：
Figure PCTCN2019080436-appb-000054
步骤1：化合物B-1-2的合成
向3L三口瓶中加入加入化合物B-1-1(30g,127.41mmol,1eq)和四氢呋喃(600mL)，边鼓氮气边加入硼烷四氢呋喃络合物(1M,382.23mL,3eq)，25℃下混合液反应16小时。反应完毕后，25℃向反应液中滴入甲醇(150mL)，同时鼓氮气，淬灭完毕，45℃水泵浓缩干得到化合物B-1-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.68(d,J＝2.4Hz,1H),7.37(dd,J＝2.2,8.6Hz,1H),7.22(d,J＝8.4Hz,1H),4.77(d,J＝5.3Hz,2H).
步骤2：化合物B-1-3的合成
向三口瓶中加入化合物B-1-2(27g,121.91mmol,1eq)和二甲基甲酰胺(150mL)，抽换氮气后0℃加入钠氢(9.75g,243.82mmol,60％纯度,2eq)，半小时后加入烯丙基溴(44.24g,365.73mmol,32.06mL,3eq)，25℃下混合液反应15.5小时。反应完毕后，反应液用饱和氯化铵水溶液(500mL)淬灭，二氯甲烷(100mL x3)萃取，有机相用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机纯化。得到化合物B-1-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.67(d,J＝2.4Hz,1H),7.35(dd,J＝2.4,8.4Hz,1H),7.21(d,J＝8.4Hz,1H),6.08-5.91(m,1H),5.34(q,J＝1.5Hz,1H),5.29-5.24(m,1H),4.57(s,2H),4.13(td,J＝1.3,5.6Hz,2H).
步骤3：化合物B-1-5的合成
向三口瓶中加入化合物B-1-4(9.9g,36.23mmol,1eq)和THF(70.5mL)，抽换氮气后冷却到0℃加入叔丁基格氏试剂(2M,29.70mL,1.64eq)，0℃下混合液反应1小时。此为反应液1。向三口瓶中加入化合物B-1-3(12.32g,47.09mmol,1.3eq)和四氢呋喃(141mL)，抽换氮气后冷却到-78℃加入正丁基锂(2.5M,21.74mL,1.5eq)，-78℃下混合液反应0.5小时。此为反应液2。然后用注射器把反应液1滴加到反应液2中。-78℃反应1小时，25℃反应13.5小时。反应完毕后反应液用饱和氯化铵水溶液(400mL)淬灭，乙酸乙 酯(100mL x 3)萃取，有机相用饱和食盐水(1000mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机纯化得到化合物B-1-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.21(s,1H),7.94(dd,J＝2.0,8.4Hz,1H),7.48(d,J＝8.2Hz,1H),6.10(d,J＝3.5Hz,1H),6.05-5.94(m,1H),5.38(dd,J＝1.5,17.2Hz,1H),5.33(d,J＝2.6Hz,1H),5.28-5.23(m,1H),4.65(s,2H),4.63(br d,J＝3.3Hz,1H),4.61(d,J＝3.5Hz,1H),4.15(d,J＝5.5Hz,2H),2.97(d,J＝4.2Hz,1H),1.59(s,3H),1.38(s,3H).
步骤4：化合物B-1-6的合成
向反应瓶中加入化合物B-1-5(8g,21.69mmol,1eq)、七水合氯化铈(9.70g,26.03mmol,2.47mL,1.2eq)和甲醇(180mL)，抽换氮气后0℃加入硼氢化钠(1.64g,43.38mmol,2eq)，25℃下混合液反应16小时。反应完毕后，反应液先用用饱和氯化铵水溶液(250mL)淬灭，再加入饱和食盐水(250mL)，乙酸乙酯(100mL x3)萃取，(若遇到难以分层现象，可以用硅藻土过滤再分液)，有机相无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干得到化合物B-1-6。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.61-7.56(m,1H),7.42-7.31(m,2H),6.05-5.92(m,2H),5.41-5.32(m,1H),5.28-5.18(m,2H),4.64-4.59(m,2H),4.49(d,J＝3.5Hz,1H),4.16-4.03(m,5H),3.36(br s,1H),1.46(s,3H),1.30(s,3H).
步骤5：化合物B-1-7的合成
向反应瓶加入(7.2g,19.42mmol,1eq)和水(45mL)、醋酸(44.31g,737.82mmol,42.20mL,38eq)，100℃下混合液反应7小时。反应完毕后，反应液在45℃用水泵减压浓缩干。甲苯(100mL x2)共沸带干。得到化合物B-1-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.42(br d,J＝8.6Hz,1H),7.24-7.05(m,2H),5.80(tt,J＝6.0,16.8Hz,1H),5.54-5.08(m,4H),4.58(br d,J＝5.3Hz,1H),4.43(br s,2H),4.14-3.81(m,4H),3.62-3.28(m,3H),2.20(br s,1H).
步骤6：化合物B-1-8的合成
向单口瓶加入化合物B-1-7(6g,18.14mmol,1eq)、三乙胺(12.11g,119.72mmol,16.66mL,6.6eq)和乙腈(110mL)，然后后依次加入醋酸酐(12.22g,119.72mmol,11.21mL,6.6eq)和二甲胺基吡啶(22.16mg,0.18mmol,0.01eq)，25℃下混合液反应16小时。反应完毕后，反应液用饱和硫酸氢钠水溶液(100mL)淬灭，乙酸乙酯(50mL x 3)萃取，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用快速过柱机纯化得到化合物B-1-8。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.49(d,J＝1.9Hz,1H),7.33(d,J＝8.3Hz,1H),7.25-7.21(m,1H),5.99(tdd,J＝5.6,10.4,17.2Hz,1H),5.87(d,J＝8.3Hz,1H),5.41-5.36(m,1H),5.36-5.31(m,1H),5.30-5.23(m,2H),5.17-5.10(m,1H),4.61-4.52(m,3H),4.12-4.08(m,2H),2.11(s,3H),2.07(s,3H),2.04-1.99(m,3H),1.85(s,3H).
步骤7：化合物B-1-9的合成
向反应瓶中加入化合物B-1-8(6.5g,13.03mmol,1eq)、醋酸钠(4.28g,52.11mmol,4eq)、水(13mL)和冰醋酸(117mL)，抽换氮气后冷却到5℃加入二氯化钯(5.08g,28.66mmol,2.2eq)，25℃下混合液反应16小 时。反应完毕后，反应液在45℃用水泵减压浓缩干。粗品用快速过柱机纯化。得到化合物B-1-9。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.53(d,J＝1.8Hz,1H),7.33(d,J＝8.2Hz,1H),7.21(dd,J＝2.1,8.3Hz,1H),5.87(d,J＝8.2Hz,1H),5.41-5.34(m,1H),5.30-5.23(m,1H),5.15(t,J＝9.6Hz,1H),4.77(br d,J＝2.4Hz,2H),4.56(d,J＝9.9Hz,1H),2.11(s,3H),2.07(s,3H),2.02(s,3H),1.85(s,3H).
步骤8：化合物B-1的合成
向反应瓶中加入化合物B-1-9(1g,2.18mmol,14.04μL,1eq)、三苯基膦(857.44mg,3.27mmol,1.5eq)和二氯甲烷(20mL)，抽换氮气后搅拌半小时，0℃加入N-溴代丁二酰亚胺(581.85mg,3.27mmol,1.5eq)，25℃下混合液反应15.5小时。反应完毕后，将反应液25℃浓缩干。粗品用快速过柱机纯化。得到化合物B-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.44-7.36(m,2H),7.29(s,1H),5.87(d,J＝8.2Hz,1H),5.41-5.34(t,1H),5.30-5.23(m,1H),5.15-5.03(m,1H),4.68-4.59(d,1H),4.53(t,J＝9.9Hz,2H),2.22(s,1H),2.13(s,2H),2.08-2.05(m,3H),2.04-2.01(m,3H),1.91-1.86(m,3H).
参考例11：片段B-2
Figure PCTCN2019080436-appb-000055
合成路线：
Figure PCTCN2019080436-appb-000056
步骤1：化合物B-2-2的合成
将氢化铝锂(11g,289.82mmol,1.25eq)于0℃溶于四氢呋喃(200mL)，经氮气置换三次后，充满氮气保护。将化合物B-2-1(50g,232.51mmol,1eq)溶于四氢呋喃(200mL)0℃下缓慢加入反应液中。有气泡产生，将反应升温至25℃下反应2小时。0℃下先缓慢滴加水(11mL)，再滴加15％的氢氧化钠水溶液(11mL)， 最后加水(33mL)。过滤，并用乙酸乙酯清洗滤渣两次。将滤液悬干。得到粗品化合物B-2-2。
步骤2：化合物B-2-3的合成
将化合物B-2-2(47.9g,238.24mmol,1eq)溶于二甲基甲酰胺(120mL)，0℃下加入钠氢(14.29g,357.36mmol,60％纯度,1.5eq)，25℃下搅拌0.5小时，然后向反应液中缓慢加入3-溴丙烯(57.64g,476.47mmol,41.17mL,2eq)，25℃下继续反应2小时。反应完毕后，0℃下加入水(50mL)淬灭，加入乙酸乙酯(500mL x 2)萃取，然后用水(50mL x 2)洗，再用饱和食盐水(50mL x 2)洗，用无水硫酸钠干燥。粗品通过柱层析纯化得到目标化合物B-2-3。
步骤3：化合物B-2-4的合成
将化合物B-2-3(18.5g,76.72mmol,1.2eq)在-78℃溶于四氢呋喃(100mL)，经氮气保护后，加入正丁基锂(2.5M,33.25mL,1.3eq)。在-78℃反应0.5小时。同时将化合物B-1-4(17.47g,63.93mmol,1eq)溶解在四氢呋喃(100mL)中，降温至0℃后，经氮气保护后，滴加叔丁基氯化镁(1.7M,41.37mL,1.1eq)，0℃下反应0.5小时。在-78℃下将镁烷氧溶液缓慢加入到烷基锂溶液。反应液在-78℃下反应0.5小时后，升温至25℃后继续反应15.5小时。反应完毕后，向0℃下向反应液中加入氯化胺溶液(50mL)，加入乙酸乙酯(200mL)稀释反应液后，用水(50mL x 2)洗。合并有机相后用饱和食盐水(50mL x 2)除水，用无水硫酸钠干燥，过滤旋干，粗品用柱层析纯化得到目标化合物B-2-4。
步骤4：化合物B-2-5的合成
将化合物B-2-4(17.80g,51.09mmol,1eq)溶解在甲醇中(100mL)，降温至0℃，依次加入七水合三氯化铈(22.84g,61.31mmol,5.83mL,1.2eq)，硼氢化钠(3.87g,102.18mmol,2eq)，升温至25℃，反应16小时。反应完毕后，向反应液中加入水(30mL)淬灭悬干。再加入乙酸乙酯(100mL)稀释，用水(50mL x 2)洗涤，再用饱和食盐水(50mL x 2)除水，最后用无水硫酸钠干燥，过滤后减压浓缩干。得到目标化合物B-2-5。
步骤5：化合物B-2-6的合成
将化合物B-2-5(10.22g,29.17mmol,1eq)溶于水(100mL)和冰醋酸(100mL)中，100℃下反应16小时。反应完毕后。将溶剂60℃真空旋干，然后用甲苯带干三次。得到化合物B-2-6。
步骤6：化合物B-2-7的合成
将化合物B-2-6(9.52g,30.68mmol,1eq)和乙酸乙酯(25.05g,245.41mmol,22.98mL,8eq)溶解到吡啶(40mL)中，25℃下搅拌16小时。反应完毕后，将反应液用乙酸乙酯(200mL)稀释，用1M稀盐酸(100mL x4)洗涤，有机相再用水(50mL x 2)洗涤，然后用饱和食盐水(50mL x 2)洗涤，最后将有机相用无水硫酸钠干燥，过滤后减压浓缩干。用柱层析进行纯化，得到目标化合物B-2-7。
步骤7：化合物B-2-8的合成
将化合物B-2-7(7g,14.63mmol,1eq)和醋酸钾(5.74g,58.52mmol,4eq)溶解在醋酸(135mL)和水(15mL) 中，经氮气保护后冰浴下加入二氯化钯(5.71g,32.18mmol,2.2eq)。25℃下反应16小时。反应完毕后，将反应液在45℃真空旋干。粗品用柱层析纯化得到产物目标化合物B-2-8。
步骤8：化合物B-2的合成
将化合物B-2-8(2.5g,5.70mmol,1eq)溶解在二氯甲烷(40mL)中，加入三苯基膦(2.24g,8.55mmol,1.5eq)经氮气保护后，搅拌30分钟。降温至0℃，加入N-溴代丁二酰亚胺(1.52g,8.55mmol,1.5eq)，25℃下搅拌2.5小时。反应完毕后，将反应液25℃浓缩干得到粗品。粗品用柱层析法进行纯化得到目标化合物B-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 1.85(s,3H),2.01(s,3H),2.1(s,3H),2.19(s,3H),2.37(s,3H)4.43-4.50(m,2H),4.80-4.83(d,J＝10.4Hz,1H),5.055-5.104(m,1H),5.214-5.249(m,1H),5.553-5.602(m,1H),6.444-6.453(m,1H),7.145-7.165(m,1H),7.209-7.224(m,1H),7.251-7.270(m,1H).
参考例12：片段B-3
Figure PCTCN2019080436-appb-000057
合成路线：
Figure PCTCN2019080436-appb-000058
步骤1：B-3-1的合成
将化合物B-2-7(8.8g,18.39mmol,1eq)溶于1,4-二氧六环(100mL)，加入硫脲(4.20g,55.17mmol,3eq)，置换氮气3次，25℃下加入三氟甲磺酸三甲基硅酯(14.31g,64.37mmol,3.5eq)，升温至60℃反应2小时,降温至25℃，依次加入碘甲烷(13.30g,93.70mmol,5.09eq)，二异丙基乙胺(19.02g,147.13mmol,8eq)，25℃下反应14小时。反应结束后反应液加水(80mL)稀释，用乙酸乙酯(80mL*3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压旋干得到粗产物。粗产物通过柱层析纯化得到目标化合物B-3-1，产物经LCMS确证。
步骤2：B-3-2的合成
向反应瓶中加入B-3-1(2g,4.29mmol,1eq)，巴比妥酸(1.10g,8.57mmol,2eq)，乙醇(20mL)，置换氮气3次后，加入四三苯基膦钯(495.37mg,428.68μmol,0.1eq)，在氮气环境下70℃反应16小时。反应结束后， 反应液加水(20mL)稀释，乙酸乙酯(20mL*3)萃取，合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物经柱层析纯化得到目标化合物B-3-2，产物通过LCMS确证。
步骤3：B-3的合成
向反应瓶中加入B-3-2(1.5g,3.52mmol,1eq)，三苯基膦(1.38g,5.28mmol,1.5eq)，二氯甲烷(20mL)，置换氮气3次，在25℃搅拌0.5小时，随后在0℃下加入N-溴代丁二酰亚胺(938.98mg,5.28mmol,1.5eq)，在25℃下反应1.5小时。反应结束后，反应液加水(20mL)稀释，乙酸乙酯(20mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物用柱层析分离纯化得到目标化合物B-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.25(d,J＝6.4Hz,2H),7.18(d,J＝8.4Hz,1H),5.38(t,J＝9.6Hz,1H),5.25(t,J＝9.6Hz,1H),5.13(t,J＝9.6Hz,1H),4.56(d,J＝9.6Hz,1H),4.53(q,J＝10.4Hz,2H),4.43(d,J＝9.6Hz,1H),2.40(s,3H),2.21(s,3H),2.11(s,3H),2.02(s,3H),1.84(s,3H).
参照参考例10中步骤1～8的合成方法，合成下表中各片段B-4。参照参考例11中步骤1～8的合成方法，合成下表中各片段B-5。表中的结构同时代表其可能的异构体。
Figure PCTCN2019080436-appb-000059
参照参考例12中步骤1～3的合成方法，合成下表中各片段B-6和B-7。表中的结构同时代表其可能的异构体。
Figure PCTCN2019080436-appb-000060
实施例1：WXD001或WXD002
Figure PCTCN2019080436-appb-000061
合成路线：
Figure PCTCN2019080436-appb-000062
步骤1：化合物WXD001-1的合成
向化合物B-1(1g,1.92mmol,1eq)中加入A-1(797.78mg,2.49mmol,1mL,1.3eq)、碳酸钠(2M,1.92mL,2eq)和甲苯(20mL)、乙醇(5mL)、水(5mL)，抽换氮气后加入四三苯基膦钯(221.48mg,191.67μmol,0.1eq)，50℃反应16小时，反应液变黑。反应完毕后，反应液在45℃用先水泵减压浓缩除去乙醇，然后油泵浓缩除去甲苯和水得黑色固体。粗品用柱层析纯化得到目标化合物WXD001-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.36(d,J＝8.2Hz,1H),7.23-7.05(m,6H),6.44(d,J＝3.6Hz,1H),5.84(d,J＝8.2Hz,1H),5.59-5.53(m,1H),5.33(s,1H),5.27-5.19(m,1H),5.12-5.01(m,1H),4.79(d,J＝10.0Hz,1H),4.47(d,J＝9.8Hz,1H),4.15-4.05(m,1H),4.01(d,J＝6.0Hz,1H),3.50(s,5H),2.63-2.46(m,1H),2.31-2.23(m,1H),2.23-1.92(m,3H),1.69(d,J＝5.4Hz,3H),1.09(br dd,J＝4.1,9.2Hz,1H),0.94(br d,J＝3.5Hz,1H),0.75-0.70(m,1H),0.72(t,J＝5.3Hz,1H).
步骤2：化合物WXD001-2的合成
向反应瓶中加入化合物WXD001-1(1g,1.57mmol,1eq)、硫脲(239.73mg,3.15mmol,2eq)和二氧六环(12mL)，抽换氮气后加入三氟甲磺酸三甲基硅酯(874.97mg,3.94mmol,711.35μL,2.5eq)，缓慢升温至80℃反应2小时，冷却至25℃依次加入二异丙基乙胺(1.02g,7.87mmol,1.37mL,5eq)和碘甲烷(670.52mg,4.72mmol,294.09μL,3eq)，25℃混合液反应14小时。反应完毕后反应液用水(5mL)稀释，二氯甲烷(2mL x3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用柱层析纯化得到目标化合物WXD001-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.36(d,J＝8.2Hz,1H),7.24-7.16(m,3H),7.12-7.06(m,3H),5.34-5.28(m,1H),5.23-5.16(m,1H),5.04(t,J＝9.7Hz,1H),4.51(d,J＝9.7Hz,1H),4.38(d,J＝9.9Hz,1H),4.14-4.07(m,1H),4.14-3.97(m,1H),2.59-2.45(m,1H),2.40-2.35(m,1H),2.34-2.19(m,2H),2.16(s,3H),2.11-2.09(m,3H),2.07-2.02(m,1H),2.00(s,3H),1.99-1.91(m,1H),1.74-1.66(s,3H),1.39-1.21(m,1H),1.09(td,J＝4.5,8.9Hz,1H),0.73(t,J＝5.3Hz,1H).
步骤3：化合物WXD001-3的合成
向反应瓶中加入化合物WXD001-2(760mg,1.22mmol,1eq)、甲醇(6mL)和四氢呋喃(3mL)，然后加入一水合氢氧化锂(1.02g,24.39mmol,20eq)和水(6mL)，25℃下混合液反应16小时。反应完毕后，反应液用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，有机相用饱和食盐水(30mL)洗涤，分液，有机相用无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。用制备高效液相色谱法纯化得到目标化合物WXD001-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.39(d,J＝7.9Hz,1H),7.25-7.18(m,4H),7.14-7.09(m,2H),4.39(d,J＝9.5Hz,1H),4.20(d,J＝9.3Hz,1H),4.15-4.02(m,2H),3.77-3.68(m,1H),3.60-3.48(m,2H),2.84(br s,1H),2.61-2.47(m,2H),2.31-2.16(m,5H),2.13-1.91(m,3H),1.79-1.62(m,2H),1.27(br s,1H),1.10(dd,J＝5.1,9.3Hz,1H),0.73(t,J＝5.4Hz,1H).
步骤4：化合物WXD001或WXD002的合成
化合物WX001-3经过超临界流体色谱(分离条件色谱柱：AD-H 250*30mm,5μm)；流动相:[0.1％NH 3H 2O  IPA],B％＝40％；流速：70mL/min)分离，得到两个异构体WX001和WX002，保留时间分别为4.334min和4.500min。
实施例2：WXD003或WXD004
Figure PCTCN2019080436-appb-000063
合成路线：
Figure PCTCN2019080436-appb-000064
步骤1：WXD003-1的合成
向反应瓶中加入B-3(40mg,81.74μmol,1eq)，A-3(41.96mg,122.61μmol,1.5eq)，碳酸钠(17.33mg,163.47μmol,2eq)，甲苯(3mL)，乙醇(0.3mL)，水(0.3mL)，置换氮气3次，加入四三苯基膦钯(9.45mg,8.17μmol,0.1eq)。在氮气环境下50℃反应5小时。反应结束后，反应液加水(5mL)稀释，乙酸乙酯(5mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液经减压旋干得到粗产物。粗产物经制备TLC纯化得到目标化合物WXD003-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.20(d,J＝8.4Hz,2H),7.13-7.11(m,2H),7.03(s,1H),6.99(d,J＝8.0Hz,2H),5.35(t,J＝9.2Hz,1H),5.23(t,J＝9.6Hz,1H),5.13(t,J＝9.6Hz,1H),4.53(d,J＝10.0Hz,1H),4.39(d,J＝9.6Hz,1H),3.96-3.86(m,6H),2.32-2.25(m,1H),2.23-2.19(m,4H),2.16(s,3H),2.09(s,3H),2.05-2.03(m,1H),2.00(s,3H),1.84-1.80(m,1H),1.72(d,J＝0.8Hz,3H),1.66-1.60(m,1H),1.50-1.42(m,1H),1.22-1.18(m,1H),1.01-0.97(m,1H),0.74(t,J＝5.2Hz,1H).
步骤2：WXD003-2的合成
向反应瓶中加入化合物WXD003-1(42mg,67.23μmol,1eq)，甲醇(1mL)，四氢呋喃(0.5mL)，水(1mL)，一水合氢氧化锂(56.42mg,1.34mmol,20eq)，25℃下反应1小时。反应结束后，反应液加水(5mL)稀释，乙酸乙酯(5mL*4)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液旋干得到粗产物。粗产物经过机分纯化得到目标化合物WXD003-2。产物通过LCMS确认。
步骤3：WXD003或WXD004的合成
化合物WX003-2经过超临界流体色谱(分离条件色谱柱：DAICEL CHIRALCEL OJ-H(250mm*30mm,5μm)； 流动相:[0.1％NH 3H 2O EtOH],B％:40％；流速：2.8mL/min)分离，得到两个异构体WXD003和WXD004，保留时间分别为4.283min和4.744min。
实施例3：WXD005
Figure PCTCN2019080436-appb-000065
合成路线：
Figure PCTCN2019080436-appb-000066
步骤1：WXD005-1的合成
向反应瓶中加入A-9(94.21mg,245.21μmol,1.2eq)、B-7(100mg,204.34μmol,1eq)、碳酸钠(43.32mg,408.68μmol,2eq)、甲苯(4mL)、乙醇(1mL)和水(1mL)，氮气置换三次后加入四三苯基膦钯(23.61mg,20.43μmol,0.1eq)，50℃油浴反应16小时。反应完毕后，用注射剂和滤器将反应液过滤，收集滤液，用水(5mL)洗涤，二氯甲烷(2mL x 3)萃取，合并有机相旋干。使用制备薄层色谱纯化得到化合物WXD005-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.37(d,J＝8.4Hz,1H),7.25-7.18(m,3H),7.14(d,J＝8.4Hz,3H),5.35-5.29(m,1H),5.20(s,1H),5.05(s,1H),4.52(d,J＝9.9Hz,1H),4.39(d,J＝9.7Hz,1H),4.07(d,J＝19.6Hz,2H),3.19-3.07(m,1H),2.61(br d,J＝6.8Hz,6H),2.28-2.18(m,2H),2.17(s,3H),2.10(s,3H),2.01(s,3H),1.69(s,3H).
步骤2：WXD005的合成
向反应瓶中加入化合物WXD005-1(140mg,209.98μmol,1eq)、甲醇(1.4mL)、四氢呋喃(0.7mL)和水(1.4mL)，最后加入一水合氢氧化锂(176.23mg,4.20mmol,20eq)，20℃下混合液反应16小时。反应完毕后，反应液用水(5mL)稀释，乙酸乙酯(2mL x3)萃取，有机相用饱和食盐水(10mL)洗涤，无水 硫酸钠干燥，过滤，滤液减压浓缩干得粗品产物。使用高效液相制备色谱法纯化得到WXD005。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.40(d,J＝8.8Hz,1H),7.26-7.15(m,6H),4.39(d,J＝9.5Hz,1H),4.20(d,J＝9.3Hz,1H),4.09(d,J＝15.8Hz,2H),3.69(d,J＝8.9Hz,1H),3.59-3.48(m,2H),3.19-3.08(m,1H),3.03(br s,1H),2.69-2.43(m,7H),2.27-2.14(m,6H).
参照实施例1中步骤1～4的合成方法和表1中手性拆分方法，合成下表2中各实施例4-6。表2中结构同时代表其可能的异构体。
表1实施例4-6的手性拆分条件
Figure PCTCN2019080436-appb-000067
表2实施例4-6的各异构体
Figure PCTCN2019080436-appb-000068
Figure PCTCN2019080436-appb-000069
实施例7：WXD012或WXD013
Figure PCTCN2019080436-appb-000070
步骤1：化合物WXD0012-1的合成
向化合物B-2(962mg,1.92mmol,1eq)中加入A-1(797.78mg,2.49mmol,1mL,1.3eq)、碳酸钠(2M,1.92mL,2eq)和甲苯(20mL)、乙醇(5mL)、水(5mL)，抽换氮气后加入四三苯基膦钯(221.48mg,191.67μmol,0.1eq)，50℃反应16小时，反应液变黑。反应完毕后，反应液在45℃用先水泵减压浓缩除去乙醇，然后油泵浓缩除去甲苯和水得黑色固体。粗品用柱层析纯化得到目标化合物WXD0012-1。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.84(t,J＝5.27Hz,1H)0.82-0.86(m,1H)1.02(br t,J＝6.78Hz,1H)2.14(d,J＝1.51Hz,3H)2.15(s,3H)2.18(s,3H)2.19(s,3H)2.23(d,J＝2.01Hz,3H)2.36(br t,J＝3.01Hz,6H)4.61(dd,J＝9.91,2.13Hz,1H)4.93(d,J＝10.29Hz,1H)5.44(s,2H)5.45-5.52(m,1H)5.66-5.75(m,1H)6.00(dd,J＝8.16,3.64Hz,1H)7.11(d,J＝8.03Hz,3H)7.17-7.23(m,3H)7.29(s,2H)
步骤2：化合物WXD012-2的合成
向反应瓶中加入化合物WXD0012-1(986mg,1.57mmol,1eq)、乙硫醇(580μL,7.85mmol,5eq)和二氧六环(12mL)，抽换氮气后加入三氟甲磺酸三甲基硅酯(874.97mg,3.94mmol,711.35μL,2.5eq)，缓慢升温至50℃反应2小时。反应完毕后反应液用水(5mL)稀释，二氯甲烷(2mL x3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。粗品用柱层析纯化得到目标化合物WXD012-2。 1H NMR(400MHz,CHLOROFORM-d)δppm 0.71(br t,J＝5.02Hz,1H)0.81-0.95(m,1H)1.09(br dd,J＝8.78,4.77Hz,2H)1.63(br s,3H)1.69-1.76(m,3H)2.00(s,3H)2.09(s,3H)2.13-2.18(m,1H)2.21(s,3H)2.19-2.22(m,2H)2.40-2.88(m,4H)3.81-4.02(m,2H)4.35(br d,J＝9.79Hz,1H)4.62(br d,J＝9.79Hz,1H)5.05-5.23(m,2H)5.28-5.37(m,1H)6.99(br d,J＝7.78Hz,2H)7.05(br s,1H)7.10-7.21(m,4H)
步骤3：化合物WXD012-3的合成
向反应瓶中加入化合物WXD012-2(769mg,1.22mmol,1eq)、甲醇(6mL)和四氢呋喃(3mL)，然后加入一水合氢氧化锂(1.02g,24.39mmol,20eq)和水(6mL)，25℃下混合液反应16小时。反应完毕后，反应液用水(10mL)稀释，乙酸乙酯(10mL x 3)萃取，有机相用饱和食盐水(30mL)洗涤，分液，有机相用无水硫酸钠干燥，过滤，滤液在45℃用水泵减压浓缩干。用制备高效液相色谱法纯化得到目标化合物WXD012-3。产物经LCMS确认。
步骤4：化合物WXD012或WXD013的合成
化合物WX012-3经过超临界流体色谱(分离条件色谱柱：AD-H(250mm*30mm,5μm)；流动相：[0.1％NH 3H 2O IPA]；B％:40％；流速：50mL/min)分离，得到两个异构体WX012和WX013，保留时间分别为6.07min和6.202min。
参照实施例2中步骤1～3的合成方法和表3中的手性拆分条件，合成下表4中各实施例8-19。表4中的结构同时代表其可能的异构体。
表3实施例8-19的手性拆分条件
Figure PCTCN2019080436-appb-000071
Figure PCTCN2019080436-appb-000072
表4实施例8-19的各异构体
Figure PCTCN2019080436-appb-000073
Figure PCTCN2019080436-appb-000074
Figure PCTCN2019080436-appb-000075
Figure PCTCN2019080436-appb-000076
参照实施例3中步骤1～2的合成方法，合成下表5中实施例20。表5中的结构同时代表其可能的异构体。
表5实施例20的合成
Figure PCTCN2019080436-appb-000077
各实施例的氢谱和质谱数据如表6所示。
表6各实施例的氢谱和质谱数据
Figure PCTCN2019080436-appb-000078
Figure PCTCN2019080436-appb-000079
Figure PCTCN2019080436-appb-000080
Figure PCTCN2019080436-appb-000081
Figure PCTCN2019080436-appb-000082
Figure PCTCN2019080436-appb-000083
Figure PCTCN2019080436-appb-000084
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 HEPES,1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2and 120mM NaCl.
2)将化合物用100％DMSO以1mM为起始浓度，做8个点5倍连续梯度稀释。
3)用实验缓冲液配制3μM[ 14C]Methyl a-D-glucopyranosid。
4)用49uL实验缓冲液、1μL梯度稀释的化合物和50μL 3μM[ 14C]同位素标记的糖溶液，在37℃作用于 细胞2小时。
5)用同位素检测仪(Micro beta Reader)读数。
6)数据通过GraphPad Prism 5.0软件的计算公式:log(inhibitor)vs.response--Variable slope得到受试化合物的IC 50值。
生物学活性实验2：SGLT2葡萄糖转运试验
1.实验目的：
通过测定进入高表达Human-SGLT2细胞内的带[ 14C]标记葡萄糖的量，检测化合物对SGLT2转运体转运葡萄糖活性的影响。
2.实验方法
2.1.细胞准备
实验所用的稳定表达Human-SGLT2的细胞由上海药明康德构建。将SGLT2细胞铺于96孔细胞培养板(Greiner)中并于5％CO 2，37℃的环境下培养过夜。
2.2.SGLT2葡萄糖转运试验
1)实验缓冲液:10mM HEPES,1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2and 120mM NaCl。
2)终止缓冲液:10mM HEPES,1.2mM MgCl 2,4.7mM KCl,2.2mM CaCl 2,120mM NaCl和1μM LX4211。
3)将化合物用100％DMSO以10uM为起始浓度，做8个点5倍连续梯度稀释。
4)用实验缓冲液配制6μM[ 14C]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7：
表7体外细胞活性测试结果
Figure PCTCN2019080436-appb-000085
Figure PCTCN2019080436-appb-000086
Figure PCTCN2019080436-appb-000087
结论：本发明化合物表现出较优的对Human-SGLT2以及Human-SGLT1的体外抑制活性。
实验例二、体内DMPK研究：
实验目的：以雄性SD大鼠为受试动物，单次给药后测定化合物血药浓度并评估药代动力学行为。
实验操作：选择健康成年雄性SD大鼠6只，3只为静注组，3只为口服组。待测化合物与适量静注组溶媒(10％N-甲基吡咯烷酮/10％聚乙二醇-15羟基硬脂酸酯/80％H 2O)混合，涡旋并超声，制备得到0.2mg/mL澄清溶液，微孔滤膜过滤后备用；口服组溶媒为10％N-甲基吡咯烷酮/10％聚乙二醇-15羟基硬脂酸酯/80％H 2O，待测化合物与溶媒混合后，涡旋并超声，制备得到0.40mg/mL澄清溶液。大鼠1mg/kg静脉给药或2mg/kg口服给药后，收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果见表8：
表8化合物PK测试结果
Figure PCTCN2019080436-appb-000088
备注：C max为最大浓度；F％为口服生物利用度；DNAUC＝AUC PO/Dose，AUC PO为口服暴露量，Dose为药物剂量；Vd ss为分布容积；Cl为清除率；T 1/2为半衰期。
结论：本发明化合物在大鼠中表现出较好的口服暴露量和生物利用度。
实验例三、大鼠口服糖尿受量(OGTT)体内药效研究：
实验概要:
1.动物:
Figure PCTCN2019080436-appb-000089
2.实验分组:
Figure PCTCN2019080436-appb-000090
3.实验流程:
1.动物适应及准备:
实验动物抵达设施后需在动物房适应环境1周。
2.禁食与给药
动物在代谢笼中禁食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著性。
实验结果见表9：
表9大鼠糖耐受量实验结果
Figure PCTCN2019080436-appb-000091
Figure PCTCN2019080436-appb-000092
*表示p<0.05,**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；可增加动物24小时尿糖***水平。
实验例四、糖尿病db/db小鼠体内药效研究：
实验概要:
1.动物信息:
种属 db/db小鼠
级别 SPF动物
订购周龄 5周龄
实验开始周龄 6周龄
体重范围 ～25g
性别 雄性
供应商 南京大学南京模式动物研究所
供应商地址 中国江苏南京
2.动物饲养
动物到达设施后，饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在40～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由电子定时开灯***来控制，每天开灯12小时关灯12小时(上午7：00开，下午19：00关)。小鼠单笼饲养，实验过程中动物自由采食(大小鼠繁殖饲料17053113，北京科澳协力饲料有限公司)和饮水。
3.实验分组:
Figure PCTCN2019080436-appb-000093
实验流程:
1.给药
实验期间，动物按组别相应的给予溶剂或供试品，给药时间为：16:00，给药周期为8周。第1周到第4周，给药剂量为5mg/kg；第5周到第8周，给药剂量为10mg/kg。
2.口服糖耐量(OGTT)实验
于实验末期(给药最后前3天)，动物禁食6小时后，单次给予葡萄糖水溶液2g/kg，并将给糖时间记为0点，在给糖前0min，给糖后15，30，60，90，120min分别对动物进行血糖检测，根据时间对血糖数据绘制糖耐量曲线，计算曲线下面积(AUC)。给药时间为：16:00。
3.生化检测
实验第4周和第8周结束后，动物禁食6h，采血测糖化血红蛋白。
4.数据的处理与分析
所有的数据将被录入到Excel文档中，并以mean±S.E.M的方式表示，多组间差异采用graphpad Prism 6软件比较采用单因素方差分析(One-way analysis of variance(ANOVA)，P值小于0.05时被认为有显著性差异。
第8周口服糖耐量(OGTT)实验结果见表10：
表10第8周口服糖耐量(OGTT)实验结果
Figure PCTCN2019080436-appb-000094
Figure PCTCN2019080436-appb-000095
*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：相比溶媒对照组，本发明化合物均可显著降低动物2小时内血糖AUC水平。
第4周和第8周糖化血红蛋白(HbA1c)实验结果见表11：
表11第4周和第8周糖化血红蛋白(HbA1c)实验结果
Figure PCTCN2019080436-appb-000096
*p<0.05,**p<0.01,**p<0.001,****p<0.0001vs.溶媒对照组。
结论：
相比溶媒对照组，本发明化合物均可显著降低动物糖化血红蛋白(HbA1c)水平。

Claims (19)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019080436-appb-100001
    其中，
    m为1或2；
    n为0、1或2；
    r为1、2、3或4；
    j为1、2或3；
    D为-O-或-C(R 1)(R 2)-；
    环A选自苯基和5～6元杂芳基；
    R 1选自H、F、Cl、Br、I、OH、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 a取代；
    R 2选自H、F、Cl、Br、I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；
    或者，R 1和R 2相互连接形成一个5～6元杂环烷基；
    R 3选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R c取代；
    R 4选自C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代；
    每一个R 5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 e取代；
    R a、R b、R c、R d和R e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取代；
    R选自F、Cl、Br、I、OH和NH 2；
    所述5～6元杂芳基和5～6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所示的化合物、其异构体或其药学上可接受的盐，其中，R a、R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH和NH 2。
  3. 根据权利要求1或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H、F、Cl、Br、I、OH和NH 2。
  4. 根据权利要求1或2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H、F、Cl、Br和I。
  5. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和-O-CH 3。
  6. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，R 4选自CH 3和Et。
  7. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，每一个R 5分别独立地选自H、F、Cl、Br、I、OH和NH 2。
  8. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，环A选自苯基和噻吩基。
  9. 根据权利要求8所述的化合物、其异构体或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2019080436-appb-100002
    Figure PCTCN2019080436-appb-100003
  10. 根据权利要求1或2所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019080436-appb-100004
    选自
    Figure PCTCN2019080436-appb-100005
  11. 根据权利要求10所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019080436-appb-100006
    选自
    Figure PCTCN2019080436-appb-100007
  12. 根据权利要求11所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019080436-appb-100008
    选自
    Figure PCTCN2019080436-appb-100009
  13. 根据权利要求11所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019080436-appb-100010
    选自
    Figure PCTCN2019080436-appb-100011
  14. 根据权利要求12或13所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019080436-appb-100012
    选自
    Figure PCTCN2019080436-appb-100013
  15. 根据权利要求1～7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 PCTCN2019080436-appb-100014
    其中，
    R 1如权利要求1或3所定义；
    R 2如权利要求1或4所定义；
    R 3如权利要求1或5所定义；
    R 4如权利要求1或6所定义。
  16. 下述化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019080436-appb-100015
    Figure PCTCN2019080436-appb-100016
  17. 根据权利要求16所述的化合物、其异构体或其药学上可接受的盐，选自
    Figure PCTCN2019080436-appb-100017
    Figure PCTCN2019080436-appb-100018
    Figure PCTCN2019080436-appb-100019
  18. 根据权利要求1～17任意一项所述化合物或其药学上可接受的盐在制备治疗SGLT1/SGLT2相关疾病的药物中的应用。
  19. 根据权利要求18所述的应用，其特征在于，所述药物是用于治疗糖尿病的药物。
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