WO2020211781A1 - 作为XIa因子抑制剂的大环衍生物 - Google Patents

作为XIa因子抑制剂的大环衍生物 Download PDF

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Publication number
WO2020211781A1
WO2020211781A1 PCT/CN2020/084932 CN2020084932W WO2020211781A1 WO 2020211781 A1 WO2020211781 A1 WO 2020211781A1 CN 2020084932 W CN2020084932 W CN 2020084932W WO 2020211781 A1 WO2020211781 A1 WO 2020211781A1
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compound
pharmaceutically acceptable
added
isomers
isomer
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PCT/CN2020/084932
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English (en)
French (fr)
Inventor
蔡亚仙
颜小兵
王廷
吴成德
丁照中
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 JP2021561779A priority Critical patent/JP7270770B2/ja
Priority to AU2020257911A priority patent/AU2020257911B2/en
Priority to US17/604,336 priority patent/US20220204508A1/en
Priority to EP20792125.5A priority patent/EP3957638A4/en
Priority to CN202080028108.5A priority patent/CN113677682B/zh
Priority to KR1020217037317A priority patent/KR20220002966A/ko
Priority to CA3136861A priority patent/CA3136861A1/en
Publication of WO2020211781A1 publication Critical patent/WO2020211781A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a new class of macrocyclic derivatives, their preparation methods and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, especially as factor XIa inhibitors and in drugs for the treatment and prevention of diseases such as thromboembolism the use of.
  • Antithrombotic drugs are mainly divided into antiplatelet drugs (such as clopidogrel, aspirin, ticagrelor, etc.), anticoagulant drugs (such as heparin, low molecular weight heparin, hirudin, warfarin, etc.) and thrombolytic drugs (such as Urokinase, streptokinase, plasmin, etc.).
  • antiplatelet drugs and anticoagulant drugs are mainly used to prevent arterial and venous thrombosis, and thrombolytic drugs are used to dissolve thrombus.
  • Anticoagulant drugs can be widely used in the treatment and prevention of various arterial and venous thrombosis such as acute coronary syndrome, stroke, transient cerebral ischemia, deep vein thrombosis, pulmonary vein thrombosis, and peripheral atherosclerosis obliterans. It has an important position in various authoritative guides. In particular, new oral anticoagulants that have been on the market in recent years have successively entered authoritative guidelines, and they have replaced traditional anticoagulants such as warfarin and heparin as the first-choice drugs recommended by the guidelines due to their good efficacy and safety in clinical trials.
  • the blood coagulation process in the human body consists of two processes: the intrinsic pathway and the extrinsic pathway, and a common pathway.
  • the exogenous pathway means that under injury and various external stimuli, tissue factor and activated factor VII (FVIIa) combine to form a complex, and then the complex reactivates factor X (FX) to form activated FX (FXa).
  • FXa then converts prothrombin into thrombin, and thrombin catalyzes fibrinogen to form fibrin, which plays a role in blood clotting.
  • the endogenous pathway belongs to the body's inherent pathway, and the factors involved in coagulation all come from the blood.
  • Factor XII activated FXII (FXIIa), activated factor XI (FXI), activated FXI (FXIa), activated factor IX (FIX), and activated FIX (FIXa) activate FX through a cascade reaction. Later, thrombin is produced through a common pathway, which in turn can activate FXI.
  • FXI/FXIa The risk of bleeding is a major problem with antithrombotic drugs. Therefore, coagulation factors that target endogenous pathways but have no effect on exogenous and common pathways are ideal antithrombotic drug targets.
  • FXI/FXIa In view of the unique role of FXI/FXIa in the coagulation pathway and the process of coagulation, as well as the important characteristics of FXI gene defects that can prevent thrombosis without significantly increasing the risk of bleeding, FXI/FXIa has become an important target for the development of new anticoagulant drugs.
  • FXI zymogen protein is a 160-kDa dimer with the same subunits connected by disulfide bonds. Each subunit includes 4 "apple domains" and 1 C-terminal catalytic domain. After FXI is activated, it becomes FXIa, which has enzymatic activity, cuts the downstream zymogen protein FIX through the catalytic domain to activate it.
  • Antithrombotic drugs targeting FXI/FXIa include antisense drugs, monoclonal antibodies, and small molecule inhibitors. Some drugs have entered the clinical research phase. Among them, antisense drugs have made the fastest progress and have completed the key phase II clinical trial. A positive result was obtained, which confirmed the effectiveness and safety of antithrombotic drugs targeting FXI/FXIa in humans.
  • the present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • T is -O- or -N(R a )-;
  • R a is H or C 1-3 alkyl
  • R 1 is triazolyl or tetrazolyl, wherein the triazolyl and tetrazolyl are optionally substituted by R b ;
  • R 2 is H or F
  • R 3 is H, F, Cl, Br, CN, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • R 4 and R 5 are each independently H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
  • R 6 is C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ;
  • R b and R c are each independently F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl.
  • the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • T is -O- or -N(R a )-;
  • R a is H or C 1-3 alkyl
  • R 1 is triazolyl or tetrazolyl, wherein the triazolyl and tetrazolyl are optionally substituted by R b ;
  • R 2 is H or F
  • R 3 is H, F, Cl, Br, CN, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • R 4 and R 5 are each independently H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy;
  • R 6 is C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ;
  • R b and R c are each independently F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl.
  • the above-mentioned compound has a structure represented by formula (I-1) or (I-2):
  • R 1, R 2, R 3, R 4, R 5, R 6 , and R a are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-1-a) or (I-2-a):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; R 1 , R 2 , R 3 , R 4 , R 5, R 6, and R a are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-1-b) or (I-2-b):
  • R 1, R 2, R 3, R 4, R 5, R 6 , and R a are as defined in the present invention.
  • R a is H, -CH 3 or -CH 2 CH 3, the other variables are as defined in the present invention.
  • the aforementioned T is -O-, -NH- or -N(CH 3 )-, and other variables are as defined in the present invention. In some aspects of the present invention, the aforementioned T is -O- or -NH-, and other variables are as defined in the present invention.
  • R b and R c are each independently F, Cl, methyl, -CHF 2 , ethoxy or cyclopropyl, and other variables are as defined in the present invention.
  • R b and R c are each independently F, Cl, methyl, ethoxy or cyclopropyl, and other variables are as defined in the present invention.
  • R b is Cl, -CHF 2 , ethoxy or cyclopropyl, and other variables are as defined in the present invention.
  • R c is F, and other variables are as defined in the present invention.
  • R 1 is R b and other variables are as defined in the present invention.
  • R 3 is H, F, Cl, Br, CN, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino, and other variables are as defined in the present invention. definition.
  • R 3 is H, F, Cl, Br, CN, -CH 3 , -OCH 3 , Other variables are as defined in the present invention.
  • R 4 and R 5 are each independently H, F, Cl, Br, I, Other variables are as defined in the present invention.
  • R 6 is -CH 3 optionally substituted with 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • the above R 6 is Other variables are as defined in the present invention. In some aspects of the present invention, the above for Other variables are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-3):
  • R 1 , R 2 , R 3 and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-4):
  • R 1, R 2, R 3, R a and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-3-a):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • R 1 , R 2 , R 3 and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-4-a):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
  • R 1, R 2, R 3 , R a and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-3-b):
  • R 1 , R 2 , R 3 and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-4-b):
  • R 1, R 2, R 3, R a and R 6 are as defined in the present invention.
  • the above-mentioned compound has the structure shown in (I-5) or (I-6):
  • T 1 is N or CR b, R 2, R a , R 6 and R b are as defined herein.
  • the above-mentioned compound is:
  • the above-mentioned compound is:
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound, its isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above-mentioned compound, its isomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of factor XIa inhibitor drugs.
  • the purpose of the present invention is to provide a macrocyclic compound suitable for FXIa enzyme inhibitors, its analogs, and a pharmaceutical combination comprising the macrocyclic compound, which can effectively treat and prevent thromboembolic diseases.
  • Such compounds not only have high FXIa enzyme activity and anticoagulant effects in vitro, but also have good pharmacokinetic properties in vivo.
  • 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 solid 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 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. "Optional" or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • 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.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • 5-membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaromatic composed of 5 ring atoms. base.
  • the ring includes a single ring, as well as a double ring system such as a spiro ring, a fused ring and a bridged ring.
  • the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the term "ring” also includes a ring system containing at least one ring, each of which independently meets the above definition.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-5 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 5 carbon atoms.
  • the C 1-5 alkyl group includes C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 and C 5 alkyl groups, etc.; it may be monovalent (such as methyl) , Divalent (such as methylene) or multivalent (such as methine).
  • C 1-5 alkyl examples 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) and so on.
  • C 1-4 alkyl is used to denote a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 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) and so on.
  • 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) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 haloalkyl means monohaloalkyl and polyhaloalkyl containing 1 to 3 carbon atoms.
  • the C 1-3 haloalkyl group includes C 1-2 , C 2-3 , C 3 , C 2 and C 1 haloalkyl group and the like.
  • Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
  • C 1-4 alkoxy refers to those alkyl groups containing 1 to 4 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy and the like.
  • Examples of C 1-6 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino group Wait.
  • C 1-6 alkylamino examples include, but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-4 alkylamino group includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino group and the like.
  • C 1-4 alkylamino groups include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 and so on.
  • C 1-3 alkylamino means those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
  • C 3-4 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 4 carbon atoms, which is a monocyclic ring system, which may be monovalent, divalent or multivalent.
  • Examples of C 3-4 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and the like.
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means from 6 to A cyclic hydrocarbon group composed of 10 carbon atoms with a conjugated ⁇ -electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It can be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 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 , including any range from 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.; 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
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following acronyms: EtOH stands for ethanol; PE stands for petroleum ether; EA stands for ethyl acetate; MeOH stands for methanol; DCM stands for dichloromethane; CHCl 3 stands for chloroform; THF stands for tetrahydrofuran; PPh 3 stands for triphenyl Phosphine; n-BuLi stands for n-butyl lithium; DMSO stands for dimethyl sulfoxide; LiCl stands for lithium chloride; TBSCl stands for tert-butyldimethyl silicon chloride; DMAP stands for 4-dimethylaminopyridine; Pd(OAc) 2 represents palladium acetate; NH 4 Cl represents ammonium chloride; KOH represents potassium hydroxide; DMA represents N,N-dimethylacetamide; HATU represents O-(7-azabenzotriazol-1-yl)- N,N,N',
  • EtOH (120mL) and sodium metal (3.96g, 172.22mmol) were added to the pre-dried flask, stirred at 25°C for 0.5 hours, and the raw material A1-1 (30g, 172.22mmol) and 5-bromo- 1-pentene (25.67 g, 172.22 mmol). After the nitrogen was pumped three times, the mixture was stirred at 95°C for 5 hours, and the reaction solution was cooled to room temperature. Pour saturated aqueous citric acid solution (200 mL) into the reaction solution, then add ethyl acetate (100 mL), separate the organic phase, and then extract the aqueous phase with ethyl acetate (100 mL ⁇ 3).
  • A1-2 (43g, 177.46mmol) was added to a 500mL three-necked flask, followed by MeOH (120mL) and DCM (240mL), and ozone (8.52g, 177.46mmol) was passed into the reaction solution at -70°C. , Until the color of the solution turns blue.
  • nitrogen was bubbled through the system for 10 minutes, and PPh 3 (51.20 g, 195.20 mmol) was added, and the temperature was raised to 25°C and stirred for 2 hours.
  • reaction solution was poured into a saturated ammonium chloride solution (200 mL), ethyl acetate (200 mL) was added thereto, and the mixture was allowed to stand and separate. After the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined and concentrated under reduced pressure.
  • reaction solution was filtered, and ethyl acetate (50 mL) and water (50 mL) were directly added to the filtrate.
  • the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (50 mL ⁇ 3).
  • the organic phases were combined and concentrated under reduced pressure.
  • A1-8 (8g, 16.11mmol), THF (100mL) and water (50mL) were added to the pre-dried flask, KOH (1.81g, 32.21mmol) was added to the mixture, and then stirred at 30°C for 12 hours .
  • the reaction solution was reduced under reduced pressure to remove most of the organic solvent.
  • the combined organic phases were concentrated under reduced pressure to obtain compound A1-9.
  • A1-11 (1.9 g, 5.65 mmol), DCM (20 mL) and Dess-Martin reagent (2.88 g, 6.78 mmol) were added to a pre-dried flask, and heated to 40° C. and stirred for 12 hours.
  • a saturated sodium thiosulfate solution (50 mL) was added to the reaction solution and stirred for 10 minutes.
  • the organic phase was separated, and the aqueous phase was extracted with DCM (20 mL ⁇ 3). After combining the organic phases, concentrate under reduced pressure.
  • A2-3 (80g, 268.55mmol), 1-difluoromethyl-4-nitropyrazole (43.80g, 268.55mmol), K 2 CO 3 (74.23g, 537.10mmol), n-butyl bis (1 -Adamantyl) phosphine (9.63g, 26.86mmol) and 2,2-dimethylpropionic acid (8.23g, 80.57mmol) were added to 1,4-dioxane (800mL) and replaced with nitrogen 3 times , And then add Pd(OAc) 2 (3.01 g, 13.43 mmol). The reaction mixture was heated to 80°C, stirred for 12 hours, and filtered.
  • A2-5 (46g, 116.59mmol), (2R)-2-methyl-3-butenoic acid (11.67g, 116.59mmol) and pyridine (8.45g, 233.19mmol) were dissolved in THF (500mL), and nitrogen After three replacements, it was cooled to 0°C and T3P (111.29 g, 174.89 mmol, 50% ethyl acetate solution) was added. The reaction mixture was slowly raised to 20°C and stirred for 12 hours. Ethyl acetate (200 mL) was added to the reaction solution, and washed with saturated brine (200 mL ⁇ 3).
  • A2-6 (26.00g, 54.55mmol) was dissolved in ethyl acetate (4L), Hoveyda-Grubbs 2nd generation catalyst (10.25g, 16.36mmol) was added, replaced with nitrogen 3 times, and then heated to 90°C and stirred for 12 hours.
  • A2-8 (20.00 g, 44.39 mmol) was dissolved in 1,4-dioxane (250 mL), and then HCl/1,4-dioxane (263.16 mL, 4M) was added. The reaction mixture was stirred at 15°C for 12 hours and then concentrated under reduced pressure. A saturated aqueous Na 2 CO 3 solution (50 mL) was added to the residue, and it was extracted with ethyl acetate (50 mL ⁇ 4). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound A2-9.
  • A2-10 (8.5g, 25.42mmol) was dissolved in DMF (100mL) and toluene (100mL), cooled to -78°C under nitrogen protection, and LiHMDS (63.56mL, 1M) was added.
  • the reaction mixture was stirred at -78°C for 0.5 hours, and then perfluorobutylsulfonyl fluoride (22.74 g, 76.27 mmol) was added.
  • the temperature was slowly raised to 15°C and stirred for 0.5 hour, then quenched with saturated aqueous NH 4 Cl (100 mL), and extracted with ethyl acetate (100 mL ⁇ 2).
  • 2f-1 (0.04g, 74.08 ⁇ mol) was dissolved in AcOH (3mL), and trimethyl orthoformate (78.61mg, 740.80 ⁇ mol) and NaN 3 (85.35mg, 740.80 ⁇ mol) were added.
  • the reaction mixture was heated to 90°C and stirred for 2 hours, extracted with water (10 mL), and extracted with ethyl acetate (20 mL ⁇ 2). The extracts were combined, washed with saturated brine (20 mL ⁇ 2), and dried over anhydrous sodium sulfate ,filter.
  • 2f-2 (0.045 g, 83.34 ⁇ mol) was dissolved in AcOH (3 mL), and trimethyl orthoformate (88.44 mg, 833.40 ⁇ mol) and TMSN 3 (96.01 mg, 833.40 ⁇ mol) were added.
  • the reaction mixture was heated to 90°C and stirred for 2 hours, extracted with water (10 mL), and extracted with ethyl acetate (20 mL ⁇ 2). The extracts were combined, washed with saturated brine (20 mL ⁇ 2), and dried over anhydrous sodium sulfate ,filter.
  • Component 2 was purified by SFC (separation column: DAICEL CHIRALPAK IC (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [0.1% ammonia, methanol]; gradient: methanol 55%-55%, 2.5min; 50min) Then, it was purified by preparative HPLC (separation column: Phenomenex Synerg
  • Component 2 was purified by SFC (separation column: DAICEL CHIRALPAK IC, 250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [0.1% ammonia, methanol]; gradient: methanol 70%-70%, 3.5min; 40min), After purification by preparative HPLC (separation column: Shim-pack C1825mm ⁇ 150mm, 10 ⁇ m; mobile phase: [water (0
  • Component 1 after purification by SFC (separation column: DAICEL CHIRALPAK IC (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [0.1% ammonia, methanol]; gradient: methanol 70%-70%, 2.7min; 40min)
  • Substrate S-2366 (DiaPharma, catalog number: S821090): 25mg
  • Echo uses 384 shallow hole polypropylene compound version (Labcyte-LP-0200, 2.5-12 ⁇ L)
  • test compound was dissolved in DMSO into a 10 mM solution and stored in a nitrogen cabinet.
  • test compounds were prepared using Echo, serially diluted and transferred 100nL to a 384-well reaction plate.
  • Reference compound and sample to be tested 200 ⁇ M starting (final reaction concentration 1 ⁇ M starting), 3 times dilution, 10 points.
  • the high signal well is DMSO, and the low signal well is 100 ⁇ M reference compound.
  • sample and control distribution see sample distribution.
  • % Inhibition rate 100% ⁇ [1-(sample reading-low signal average)/(high signal average-low signal average)]
  • IC 50 uses 4-factor linear regression analysis:
  • Y is the% inhibition and X is the logarithm of the sample concentration.
  • the compound of the present invention has a good inhibitory activity on the enzyme of human factor XIa.
  • Plasma Fresh human venous blood and 0.109M sodium citrate are mixed uniformly at a ratio of 9:1, centrifuged at 3000 rpm for 15 minutes, and the upper plasma is collected, and the experiment is carried out within 2-5 hours.
  • aPTT reagent activated partial thromboplastin time determination kit, mindray
  • PT reagent prothrombin time determination kit, mindray
  • calcium chloride solution aPTT reagent (activated partial thromboplastin time determination kit, mindray)
  • test compound was dissolved in DMSO to prepare a 10 mM stock solution.
  • 10mM mother liquor compound was added to the plasma and diluted gradually to 400, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.563, 0.781, 0.390, 0.195 ⁇ M, and the blank was a 100% DMSO solution.
  • the compound of the present invention has a significant anticoagulant effect on human plasma in vitro.
  • mice in the first group were given a dose of 0.5 mg/kg and a concentration of 0.2 mg/mL by a single injection through the tail vein, and animals in the second group were given a compound with a dose of 3 mg/kg and a concentration of 0.5 mg/mL by gavage.
  • Plasma samples were collected from the animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
  • the LC-MS/MS method is used to determine the drug concentration in the plasma sample, and the kinetic parameters of the tested drug are shown in Table 3:
  • the compound of the present invention has good pharmacokinetic properties in rats.

Abstract

一类大环衍生物、其制备方法及含有该衍生物的药物组合物，以及它们作为治疗剂，特别是作为XIa因子抑制剂和在治疗和预防血栓栓塞等疾病的药物中的用途，具体公开了式(I)所示化合物、其异构体及其药学上可接受的盐。(I)

Description

作为XIa因子抑制剂的大环衍生物
本申请主张如下优先权：
CN201910303358.4，申请日2019年04月16日；
CN202010200778.2，申请日2020年03月20日。
技术领域
本发明涉及一类新的大环衍生物、其制备方法及含有该衍生物的药物组合物，以及它们作为治疗剂，特别是作为XIa因子抑制剂和在治疗和预防血栓栓塞等疾病的药物中的用途。
背景技术
抗血栓药物主要分为抗血小板药品(如氯吡格雷、阿司匹林、替格瑞洛等)、抗凝血药品(如肝素、低分子肝素、水蛭素、华法林等)和溶血栓药物(如尿激酶、链激酶、纤溶酶等)。在临床应用之中，抗血小板药品和抗凝血药品主要用于预防动脉和静脉血栓，溶血栓药物用于血栓的溶解。由于近年来我国心脑血管疾病发病率持续上升，抗血栓药物的销售额也稳步增长，增速一直维持在15-20％之间，2016年的销售额已经接近200亿元，未来随着老龄化的加剧，预计心脑血管疾病的发病率仍将居高不下，抗血栓药物市场规模仍将持续增长。
抗凝血药物可广泛用于急性冠脉综合症、脑卒中、短暂性脑缺血、深静脉栓塞、肺静脉栓塞、外周动脉粥样硬化闭塞症等多种动脉和静脉血栓的治疗和预防，在各项权威指南中具有重要地位。特别是近年上市的新型口服抗凝药也陆续进入权威指南，并凭借在临床试验中表现出的较好疗效和安全性取代华法林、肝素等传统抗凝药成为指南推荐首选药物。
人体凝血过程包含两个过程：内源性途径和外源性途径及一个共同途径。外源性途径是指在损伤和各种外来刺激下，组织因子和活化的因子VII(FVIIa)结合形成复合物，然后该复合物再激活因子X(FX)形成活化的FX(FXa)。FXa再将凝血酶原转化为凝血酶，凝血酶催化纤维蛋白酶原形成纤维蛋白，起到凝血作用。内源性途径属于机体固有途径，参与凝血的因子全部来自于血液。通过级联反应激活因子XII(FXII)，活化的FXII(FXIIa)激活因子XI(FXI)，活化的FXI(FXIa)激活因子IX(FIX)，活化的FIX(FIXa)进而激活FX。后面通过共同途径产生凝血酶，凝血酶又反过来可以激活FXI。
出血风险是抗血栓药物的主要问题。因此，针对内源性途径，而对外源性和共同途径无影响的凝血因子是理想的抗血栓药物靶点。鉴于FXI/FXIa在凝血途径和凝血过程中的独特作用，以及FXI基因缺陷可防止血栓形成，并不显著增加出血风险的重要特征，FXI/FXIa已成为新型抗凝血药物研发的重要靶点。FXI酶原蛋白是1个160-kDa、通过二硫键连接的具有相同亚基的二聚体，每个亚基包括4个“苹果域”和1个C末端催化域，FXI被激活后成为具有酶活性的FXIa，通过催化域对下游的酶原蛋白FIX进行剪切，使之激活。
以FXI/FXIa为靶点的抗血栓药物包括反义药物、单抗和小分子抑制剂，分别有药物进入临床研究阶段，其中，反义药物进展最快，已完成了关键的临床II期试验并取得阳性结果，在人体中证实了以FXI/FXIa为靶点的抗血栓药物的有效性和安全性。
目前，有多家公司有大环类衍生物做为FXIa抑制剂的专利报道，例如BMS的专利WO2011100401，WO2011100402，WO2013022814，WO2013022818，WO2014022766，WO2014022767，WO2015116882， WO2015116885，WO2015116886和WO2016053455；Merck公司的专利WO2017074832和WO2017074833；东阳光药业有限公司的专利WO2018133793。这些专利报道的大环化合物活性普遍较高，但是由于分子量较大，在体内的药代动力学结果均不理想。
发明内容
一方面，本发明提供了式(I)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020084932-appb-000001
其中，
T为-O-或-N(R a)-；
R a为H或C 1-3烷基；
R 1为三唑基或四唑基，其中所述三唑基和四唑基任选被R b所取代；
R 2为H或F；
R 3为H、F、Cl、Br、CN、C 1-6烷基、C 1-6烷氧基或C 1-6烷氨基；
R 4和R 5各自独立地为H、F、Cl、Br、I、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基；
R 6为任选被1、2或3个R c所取代的C 1-3烷基；
R b和R c各自独立地为F、Cl、Br、I、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-4环烷基。
本发明还提供了式(I)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020084932-appb-000002
其中，
T为-O-或-N(R a)-；
R a为H或C 1-3烷基；
R 1为三唑基或四唑基，其中所述三唑基和四唑基任选被R b所取代；
R 2为H或F；
R 3为H、F、Cl、Br、CN、C 1-6烷基、C 1-6烷氧基或C 1-6烷氨基；
R 4和R 5各自独立地为H、F、Cl、Br、I、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基；
R 6为任选被1、2或3个R c所取代的C 1-3烷基；
R b和R c各自独立地为F、Cl、Br、I、C 1-3烷基、C 1-3烷氧基或C 3-4环烷基。
在本发明的一些方案中，上述化合物具有式(I-1)或(I-2)所示结构：
Figure PCTCN2020084932-appb-000003
其中，R 1、R 2、R 3、R 4、R 5、R 6和R a如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-1-a)或(I-2-a)所示结构：
Figure PCTCN2020084932-appb-000004
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；R 1、R 2、R 3、R 4、R 5、R 6和R a如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-1-b)或(I-2-b)所示结构：
Figure PCTCN2020084932-appb-000005
其中，R 1、R 2、R 3、R 4、R 5、R 6和R a如本发明所定义。
在本发明的一些方案中，上述R a为H、-CH 3或-CH 2CH 3，其他变量如本发明所定义。
在本发明的一些方案中，上述T为-O-、-NH-或-N(CH 3)-，其他变量如本发明所定义。在本发明的一些方案中，上述T为-O-或-NH-，其他变量如本发明所定义。
在本发明的一些方案中，上述R b和R c各自独立地为F、Cl、甲基、-CHF 2、乙氧基或环丙基，其他变量如本发明所定义。
在本发明的一些方案中，上述R b和R c各自独立地为F、Cl、甲基、乙氧基或环丙基，其他变量如本发明所定义。
在本发明的一些方案中，上述R b为Cl、-CHF 2、乙氧基或环丙基，其他变量如本发明所定义。
在本发明的一些方案中，上述R c为F，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1为
Figure PCTCN2020084932-appb-000006
R b及其他变量如本发明所定义。
在本发明的一些方案中，上述R 1为
Figure PCTCN2020084932-appb-000007
Figure PCTCN2020084932-appb-000008
其他变量如本发明所定义。
在本发明的一些方案中，上述R 1为
Figure PCTCN2020084932-appb-000009
Figure PCTCN2020084932-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，上述R 3为H、F、Cl、Br、CN、C 1-3烷基、C 1-3烷氧基或C 1-3烷氨基，其他变量如本发明所定义。
在本发明的一些方案中，上述R 3为H、F、Cl、Br、CN、-CH 3、-OCH 3、
Figure PCTCN2020084932-appb-000011
其他变量如本发明所定义。
在本发明的一些方案中，上述R 4和R 5各自独立地为H、F、Cl、Br、I、
Figure PCTCN2020084932-appb-000012
Figure PCTCN2020084932-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，上述R 6为任选被1、2或3个R c所取代的-CH 3，R c及其他变量如本发明所定义。
在本发明的一些方案中，上述R 6为
Figure PCTCN2020084932-appb-000014
其他变量如本发明所定义。 在本发明的一些方案中，上述
Figure PCTCN2020084932-appb-000015
为
Figure PCTCN2020084932-appb-000016
Figure PCTCN2020084932-appb-000017
其他变量如本发明所定义。
在本发明的一些方案中，上述
Figure PCTCN2020084932-appb-000018
为
Figure PCTCN2020084932-appb-000019
Figure PCTCN2020084932-appb-000020
其他变量如本发明所定义。
在本发明的一些方案中，上述
Figure PCTCN2020084932-appb-000021
为
Figure PCTCN2020084932-appb-000022
Figure PCTCN2020084932-appb-000023
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-3)所示结构：
Figure PCTCN2020084932-appb-000024
其中，R 1、R 2、R 3和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-4)所示结构：
Figure PCTCN2020084932-appb-000025
其中，R 1、R 2、R 3、R a和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-3-a)所示结构：
Figure PCTCN2020084932-appb-000026
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
R 1、R 2、R 3和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-4-a)所示结构：
Figure PCTCN2020084932-appb-000027
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
R 1、R 2、R 3、R a和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-3-b)所示结构：
Figure PCTCN2020084932-appb-000028
其中，R 1、R 2、R 3和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有式(I-4-b)所示结构：
Figure PCTCN2020084932-appb-000029
其中，R 1、R 2、R 3、R a和R 6如本发明所定义。
在本发明的一些方案中，上述化合物具有(I-5)或(I-6)所示结构：
Figure PCTCN2020084932-appb-000030
其中，T 1为N或CR b，R 2、R a、R 6和R b如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
在本发明的一些方案中，上述化合物为：
Figure PCTCN2020084932-appb-000031
Figure PCTCN2020084932-appb-000032
在本发明的一些方案中，上述化合物为：
Figure PCTCN2020084932-appb-000033
Figure PCTCN2020084932-appb-000034
另一方面，本发明提供了一种药物组合物，其含有治疗有效量的上述化合物、其异构体或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物、其异构体或其药学上可接受的盐或上述药物组合物在制备XIa因子抑制剂药物中的应用。
技术效果
本发明的目的在于提供一种适用于FXIa酶抑制剂的大环化合物、其类似物以及包含所述大环化合物的药物组合，该类化合物或药物组合物可以有效治疗和预防血栓栓塞性疾病。该类化合物不仅具有较高的FXIa酶活性和人血体外抗凝血作用，同时具备较好的体内药代动力学性质。
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 PCTCN2020084932-appb-000035
和楔形虚线键
Figure PCTCN2020084932-appb-000036
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020084932-appb-000037
和直形虚线键
Figure PCTCN2020084932-appb-000038
表示立体中心的相对构型，用波浪线
Figure PCTCN2020084932-appb-000039
表示楔形实线键
Figure PCTCN2020084932-appb-000040
或楔形虚线键
Figure PCTCN2020084932-appb-000041
或用波浪线
Figure PCTCN2020084932-appb-000042
表示直形实线键
Figure PCTCN2020084932-appb-000043
和直形虚线键
Figure PCTCN2020084932-appb-000044
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 PCTCN2020084932-appb-000045
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 PCTCN2020084932-appb-000046
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 PCTCN2020084932-appb-000047
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 PCTCN2020084932-appb-000048
直形虚线键
Figure PCTCN2020084932-appb-000049
或波浪线
Figure PCTCN2020084932-appb-000050
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 PCTCN2020084932-appb-000051
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 PCTCN2020084932-appb-000052
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，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个原子的“环”。
除非另有规定，“5元环”表示由5个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。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“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-5烷基”用于表示直链或支链的由1至5个碳原子组成的饱和碳氢基团。所述C 1-5烷基包括C 1-4、C 1-3、C 1-2、C 2-5、C 2-4和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-5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)等。
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3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 1-4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)等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3卤代烷基”表示包含1至3个碳原子的单卤代烷基和多卤代烷基。所述C 1-3卤代烷基包括C 1-2、C 2-3、C 3、C 2和C 1卤代烷基等。C 1-3卤代烷基的实例包括但不限于三氟甲基、三氯甲基、2,2,2-三氟乙基、五氟乙基、五氯乙基、3-溴丙基等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳 原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-4烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C 1-4烷氧基包括C 1-3、C 1-2、C 2-4、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氨基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4、C 3和C 2烷氨基等。C 1-6烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。
除非另有规定，术语“C 1-4烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C 1-4烷氨基包括C 1-3、C 1-2、C 2-4、C 4、C 3和C 2烷氨基等。C 1-4烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，“C 3-4环烷基”表示由3至4个碳原子组成的饱和环状碳氢基团，其为单环体系，可以是一价、二价或者多价。C 3-4环烷基的实例包括，但不限于，环丙基、环丁基等。
除非另有规定，术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10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)。
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：EtOH代表乙醇；PE代表石油醚；EA代表乙酸乙酯；MeOH代表甲醇；DCM代表二氯甲烷；CHCl 3代表三氯甲烷；THF代表四氢呋喃；PPh 3代表三苯基膦；n-BuLi代表正丁基锂；DMSO代表二甲亚砜；LiCl代表氯化锂；TBSCl代表叔丁基二甲基氯化硅；DMAP代表4-二甲氨基吡啶；Pd(OAc) 2代表醋酸钯；NH 4Cl代表氯化铵；KOH代表氢氧化钾；DMA代表N,N-二甲基乙酰胺；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；DIEA代表二异丙基乙基胺；HCl代表盐酸；T3P代表1-丙基磷酸三环酸酐；NCS代表1-氯吡咯烷-2,5-二酮；AcOH代表乙酸；TLC代表薄层色谱；SFC指超临界流体色谱。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体A1的合成
Figure PCTCN2020084932-appb-000053
第一步
在预先干燥过的烧瓶中加入EtOH(120mL)和金属钠(3.96g,172.22mmol)，在25℃下搅拌0.5小时，向混合物中加入原料A1-1(30g,172.22mmol)和5-溴-1-戊烯(25.67g,172.22mmol)。抽换三次氮气后，在95℃下搅拌5小时，将反应液降到室温。往反应液中倒入饱和柠檬酸水溶液(200mL)，再加入乙酸乙酯(100mL)，分出有机相后，水相再用乙酸乙酯(100mL×3)萃取。将有机相合并，用水洗涤(100mL×2)。合并有机相后，减压浓缩，粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝300:1至100:1)，纯化得到化合物A1-2。 1H NMR(400MHz,CDCl 3):δ5.79(tdd,J＝6.6,10.2,17.0Hz,1H),5.06-4.93(m,2H),4.18(q,J＝7.0Hz,4H),2.11-2.03(m,2H),1.91-1.83(m,2H),1.40(s,3H),1.39-1.30(m,2H),1.25(t,J＝7.0Hz,6H)。
第二步
在500mL的三口瓶中加入A1-2(43g,177.46mmol)，随后加入MeOH(120mL)和DCM(240mL)，在-70℃条件下向该反应液中通入臭氧(8.52g,177.46mmol)，直到溶液颜色变蓝。在-70℃条件下搅拌0.5小时后，向体系中通10分钟氮气，并加入PPh 3(51.20g,195.20mmol)升温至25℃搅拌2小时。将反应液减压浓缩，粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝100:1至20:1)，纯化得到化合物A1-3。
第三步
在预先干燥过的烧瓶中加入2-溴-4-氯吡啶(28.60g,148.60mmol)和甲苯(500mL)，并将温度降至 -78℃，向其中加入n-BuLi(59.44mL,2.5M)。在另一个烧瓶中加入A1-3(33g,135.09mmol)和甲苯(500mL)，在-78℃条件下往此溶液中缓慢滴加前面的锂试剂溶液，并在该温度下搅拌0.5小时。将反应液倒入饱和氯化铵溶液(200mL)中，并向其中加入乙酸乙酯(200mL)，静置分层。有机相分离后，水相用乙酸乙酯(100mL×3)萃取，合并有机相，减压浓缩。粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝100:1至3:1)，纯化得到化合物A1-4。LCMS m/z(ESI):358.1(M+1)。
1H NMR(400MHz,CDCl 3):δ8.44(d,J＝5.6Hz,1H),7.32(d,J＝1.6Hz,1H),7.22(dd,J＝2.0,5.5Hz,1H),4.73(td,J＝4.6,8.8Hz,1H),4.23-4.11(m,4H),3.78(d,J＝5.6Hz,1H),2.07-1.80(m,3H),1.68(dt,J＝8.0,14.3Hz,1H),1.46-1.36(m,4H),1.28-1.19(m,6H)。
第四步
在预先干燥过的烧瓶中加入DMSO(120mL)，A1-4(38g,106.20mmol)，LiCl(9.00g,212.39mmol)和水(1.91g,106.20mmol)，抽换三次氮气后，加热至180℃搅拌24小时。将反应液倒入水(200mL)中，并加入乙酸乙酯(200mL)。将有机相分离，用饱和食盐水(200mL×3)洗涤后，减压浓缩得到化合物A1-5。LCMS m/z(ESI):286.1(M+1)。
第五步
在预先干燥的烧瓶中加入A1-5(27g,94.48mmol)和DCM(200mL)，向其中加入TBSCl(28.48g,188.97mmol)，DMAP(8.66g,70.86mmol)和咪唑(16.08g,236.21mmol)，并在20℃下搅拌2小时。将反应液过滤以除掉反应体系中生成的白色固体，滤液减压浓缩。残余物经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝300:1至10:1)，纯化得到化合物A1-6。LCMS m/z(ESI):400.2(M+1)。
1H NMR(400MHz,CDCl 3):δ8.38(d,J＝5.4Hz,1H),7.51-7.47(m,1H),7.16(dd,J＝2.0,5.4Hz,1H),4.78(t,J＝6.0Hz,1H),4.18-4.05(m,2H),2.39(qd,J＝6.8,13.7Hz,1H),1.78-1.58(m,2H),1.49-1.30(m,2H),1.26-1.20(m,5H),1.11(d,J＝7.6Hz,3H),0.99-0.90(m,9H),0.07(s,3H),-0.07(s,3H)。
第六步
在预先干燥过的烧瓶中加入A1-6(11g,27.50mmol)，1-二氟甲基-4-硝基吡唑(4.48g,27.50mmol)，正丁基二(1-金刚烷基)膦(2.96g,8.25mmol)，K 2CO 3(9.50g,68.75mmol)，2,2-二甲基丙酸(842.53mg,8.25mmol)和1,4-二氧六环(220mL)，氮气抽换气三次后加入Pd(OAc) 2(1.23g,5.50mmol)。将反应混合物加热至100℃，搅拌13小时。将反应液过滤，直接向滤液中加入乙酸乙酯(50mL)和水(50mL)。分离有机相，水相再用乙酸乙酯(50mL×3)萃取三次，合并有机相，减压浓缩。粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝300:1至10:1)，纯化得到化合物A1-7。
1H NMR(400MHz,CDCl 3):δ8.71(d,J＝5.0Hz,1H),8.34(s,1H),7.57(s,1H),7.25(s,1H),7.10(t,J＝57.2Hz,1H),4.98-4.86(m,1H),4.21-4.03(m,2H),2.45-2.33(m,1H),1.87-1.74(m,2H),1.47-1.31(m,2H),1.29-1.20(m,5H),1.10(d,J＝7.0Hz,3H),0.88(s,9H),0.08(s,3H),-0.07(s,3H)。
第七步
在预先干燥过的烧瓶中加入A1-7(11g,20.89mmol)，EtOH(110mL)和水(30mL)，氮气抽换气三次之后加入NH 4Cl(5.59g,104.43mmol)和铁粉(5.83g,104.43mmol)，反应在80℃条件下反应1小时。将反应液过滤，滤饼用乙酸乙酯(30mL×3)洗涤。合并滤液，减压浓缩得到化合物A1-8。
1H NMR(400MHz,CDCl 3):δ8.62(d,J＝5.4Hz,1H),7.60(s,1H),7.43(s,1H),7.26-6.95(m,2H),4.94-4.83(m, 1H),4.18-4.03(m,2H),3.18(br s,2H),2.45-2.32(m,1H),1.87-1.73(m,2H),1.71-1.54(m,1H),1.47-1.32(m,3H),1.24-1.17(m,3H),1.10(dd,J＝1.0,6.8Hz,3H),0.91(s,9H),0.09(s,3H),-0.07(s,3H)。
第八步
在预先干燥的烧瓶中加入A1-8(8g,16.11mmol)，THF(100mL)和水(50mL)，向该混合物中加入KOH(1.81g,32.21mmol)，然后在30℃条件下搅拌12小时。将反应液减压除去大部分的有机溶剂。向剩下的水相中加入饱和的氢氧化钠溶液直至pH＝13，再用乙酸乙酯萃取(50mL×3)。合并有机相减压浓缩得到化合物A1-9。LCMS m/z(ESI):469.3(M+1)。
1H NMR(400MHz,CDCl 3):δ8.52-8.45(m,1H),7.57(br d,J＝2.4Hz,1H),7.37-7.31(m,1H),7.26-6.89(m,2H),4.79(br d,J＝2.9Hz,1H),2.14-2.05(m,1H),1.76-1.61(m,2H),1.56-1.41(m,1H),1.32-1.12(m,3H),0.95-0.80(m,12H),0.06--0.02(m,3H),-0.10--0.18(m,3H)。
第九步
在预先干燥的烧瓶中加入A1-9(2.5g,5.33mmol)和DMA(2.5L)，在20℃条件下向其中加入HATU(4.06g,10.67mmol)和DIEA(1.38g,10.67mmol)，反应液在100℃条件下搅拌24小时，将反应液直接减压浓缩。粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝100:1至1:1)，纯化得到化合物A1-10。 1H NMR(400MHz,CD 3OD):δ9.22(s,1H),8.66-8.60(m,1H),7.82-7.61(m,2H),7.54-7.42(m,1H),5.13(td,J＝4.6,11.4Hz,1H),2.59-2.47(m,0.5H),2.36-2.23(m,0.5H),2.14-1.66(m,4H),1.43-1.14(m,2H),1.13-0.95(m,3H),0.92(d,J＝2.4Hz,9H),0.12(d,J＝6.0Hz,3H),0.01(d,J＝13.6Hz,3H)。
第十步
在预先干燥的烧瓶中加入MeOH(35mL)，A1-10(3.8g,8.43mmol)和HCl/MeOH(6.32mL,4M)，在30℃条件下搅拌10小时，然后减压浓缩。将得到的粗品溶于水(20mL)中，向其中加入乙酸乙酯(20mL)，并搅拌5分钟，将有机相分出以除掉杂质。向水相中加入饱和碳酸钠溶液，直至pH＝8，再向其中加入乙酸乙酯(20mL)，分出有机相。水相再用乙酸乙酯萃取(20mL×5)，合并有机相后减压浓缩得到化合物A1-11。LCMS m/z(ESI):337.2(M+1)。
1H NMR(400MHz,CD 3OD):δ8.66(t,J＝5.4Hz,1H),7.81-7.48(m,3H),7.46(d,J＝4.8Hz,1H),5.04-4.93(m,1H),2.53-2.36(m,1H),1.98-1.71(m,3H),1.61-1.45(m,1H),1.34-1.21(m,1H),1.10-1.01(m,3H),0.94-0.72(m,1H)。
第十一步
在预先干燥的烧瓶中加入A1-11(1.9g,5.65mmol)和DCM(20mL)和戴斯-马丁试剂(2.88g,6.78mmol)，加热到40℃搅拌12小时。向反应液中加入饱和硫代硫酸钠溶液(50mL)，并搅拌10分钟。将有机相分离，水相用DCM萃取(20mL×3)。合并有机相后，减压浓缩。粗产品经经自动过柱机COMBI-FLASH分离(梯度淋洗：DCM:MeOH＝100:1至0:1)，纯化得到化合物A1-12。LCMS m/z(ESI):335.1(M+1)。
第十二步
在预先干燥的烧瓶中加入THF(450mL)和A1-12(1.6g,4.79mmol)，将温度降至-70℃后，加入LiHMDS(11.98mL,1M)，搅拌0.5小时，向其中加入N-苯基双(三氟甲磺酰)亚胺(2.05g,5.75mmol)，升温至25℃后搅拌12小时。向反应液中加入水(20mL)淬灭反应，然后减压浓缩掉大部分的THF后向其中加入乙酸乙酯(30mL)，分液得到有机相。水相再用乙酸乙酯(30mL×3)萃取。合并有机相，减压 浓缩。粗产品经自动过柱机COMBI-FLASH分离(梯度淋洗：PE:EA＝20:1至1:1)，纯化得到化合物A1。LCMS m/z(ESI):467.1(M+1)。
1H NMR(400MHz,CD 3OD):δ8.84(d,J＝5.0Hz,1H),7.91-7.66(m,1H),7.57(s,1H),7.42-7.33(m,1H),7.31-7.22(m,1H),6.39-6.28(m,1H),2.59(br s,1H),2.24(br s,1H),2.00-1.77(m,1H),1.38-1.27(m,1H),1.20-1.08(m,3H),0.99-0.76(m,1H)。
中间体A2的合成
Figure PCTCN2020084932-appb-000054
第一步
将化合物A2-1(60g,423.86mmol)溶于THF(600mL)和水(300mL)中，在15℃下加入烯丙基溴(76.92g,635.80mmol)和金属铟(73.00g,635.80mmol)。将反应混合物在15℃搅拌12小时，然后过滤。往滤液中加入乙酸乙酯(1L)，分出有机相，水相再用乙酸乙酯萃取(1L×2)。将有机相合并，用饱和食盐水洗涤(1L×3)，再用无水硫酸钠干燥，过滤。将滤液减压浓缩得到化合物A2-2。LCMS m/z(ESI):184.2(M+1)。
1H NMR(400MHz,CDCl3):δ8.44(d,J＝5.2Hz,1H),7.37(s,1H),7.21(d,J＝4.4Hz,1H),5.86-5.76(m,1H),5.15-5.11(m,2H),4.80-4.78(m,1H),2.68-2.62(m,1H),2.50-2.45(m,1H)。
第二步
将A2-2(62g,337.63mmol)溶于DMF(500mL)，然后加入咪唑(57.46g,844.07mmol)和TBSCl(61.07g,405.15mmol)。将此混合物在15℃搅拌12小时，然后加入水(1.5L)，用乙酸乙酯萃取(1L)。有机相分离后用饱和食盐水洗涤(300mL×4)，再用无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物A2-3。 LCMS m/z(ESI):298.1(M+1)。
第三步
将A2-3(80g,268.55mmol)，1-二氟甲基-4-硝基吡唑(43.80g,268.55mmol)，K 2CO 3(74.23g,537.10mmol)，正丁基二(1-金刚烷基)膦(9.63g,26.86mmol)和2,2-二甲基丙酸(8.23g,80.57mmol)加入到1,4-二氧六环(800mL)中，用氮气置换3次，然后加入Pd(OAc) 2(3.01g,13.43mmol)。将此反应混合物加热到80℃搅拌12小时，过滤。往滤液中加入乙酸乙酯(500mL)，用饱和食盐水洗涤(500mL×2)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经过柱(PE:EA＝3:1)纯化，得到化合物A2-4。LCMS m/z(ESI):425.3(M+1)。
第四步
将A2-4(36g,84.80mmol)溶于MeOH(400mL)，在0℃下加入锌粉(55.45g,848.02mmol)和固体NH 4Cl(45.36g,848.02mmol)，然后搅拌2小时，过滤。将滤饼用MeOH洗涤(100mL×3)，收集滤液，减压浓缩除去大部分有机溶剂，然后用乙酸乙酯萃取(500mL×2)。合并有机相用饱和食盐水洗涤(300mL×3)，用无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物A2-5。LCMS m/z(ESI):395.3(M+1)。
第五步
将A2-5(46g,116.59mmol)，(2R)-2-甲基-3-丁烯酸(11.67g,116.59mmol)和吡啶(8.45g,233.19mmol)溶于THF(500mL)，用氮气置换3次后，冷却到0℃加入T3P(111.29g,174.89mmol，50％的乙酸乙酯溶液)。将反应混合物缓慢升至20℃，搅拌12小时。往反应液中加入乙酸乙酯(200mL)，用饱和食盐水洗涤(200mL×3)。有机相分离后用无水硫酸钠干燥，过滤，滤液减压浓缩。残余物经过柱(PE:EA＝3:1)得到化合物A2-6。LCMS m/z(ESI):477.3(M+1)。
第六步
将A2-6(26.00g,54.55mmol)溶于乙酸乙酯(4L)，加入Hoveyda-Grubbs 2代催化剂(10.25g,16.36mmol)，用氮气置换3次，然后加热到90℃搅拌12小时。将反应液用饱和Na 2CO 3水溶液(500mL)淬灭。有机相分离后，用饱和食盐水洗涤(500mL×2)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经过柱(PE:EA＝1:1(V:V))纯化得到化合物A2-7。LCMS m/z(ESI):449.3(M+1)。
第七步
将A2-7(21.00g,46.81mmol)溶于MeOH(1L)，加入钯碳(10g,46.81mmol,10％含量)，在氢气(15psi)，20℃下搅拌24小时。将反应混合物过滤，滤液减压浓缩得到化合物A2-8。LCMS m/z(ESI):451.3(M+1)。
第八步
将A2-8(20.00g,44.39mmol)溶于1,4-二氧六环(250mL)，然后加入HCl/1,4-二氧六环(263.16mL,4M)。将反应混合物在15℃下搅拌12小时，然后减压浓缩。往残余物中加入饱和Na 2CO 3水溶液(50mL)，用乙酸乙酯萃取(50mL×4)。合并有机相，用无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物A2-9。LCMS m/z(ESI):337.2(M+1)。
第九步
将A2-9(8.5g,25.27mmol)溶于DMSO(50mL)，在20℃下加入IBX(14.15g,50.54mmol)，然后 搅拌2小时。将反应混合物倒入水中(200mL)，用乙酸乙酯萃取(200mL×3)。将有机相合并，用无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物A2-10。LCMS m/z(ESI):335.3(M+1)。
第十步
将A2-10(8.5g,25.42mmol)溶于DMF(100mL)和甲苯(100mL)中，氮气保护下冷却到-78℃，加入LiHMDS(63.56mL,1M)。反应混合物在-78℃下搅拌0.5小时，然后加入全氟丁基磺酰氟(22.74g,76.27mmol)。缓慢升温至15℃搅拌0.5小时，然后用饱和NH 4Cl水溶液(100mL)淬灭，再用乙酸乙酯萃取(100mL×2)。将有机相合并，用无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经过柱(PE:EA＝1:1)纯化得到化合物A2。LCMS m/z(ESI):617.0(M+1)。
实施例1
Figure PCTCN2020084932-appb-000055
第一步
在预先干燥过的1升三口烧瓶中加入1a(100g,630.69mmol)，DMF(400mL)和NaN 3(41.82g,643.30mmol)，加热到55℃搅拌24小时。将反应液倒入水(1L)中，加入乙酸乙酯(1L)，分出有机相。水相再用乙酸乙酯萃取(1L×2)，合并有机相，减压浓缩得到化合物1b。 1H NMR(400MHz,CDCl 3):δ10.29(s, 1H),7.85(d,J＝2.5Hz,1H),7.57(dd,J＝2.5,8.5Hz,1H),7.24(d,J＝8.5Hz,1H)。
第二步
在预先干燥的2升烧瓶中加入1b(110g,605.80mmol)，三甲基硅基乙炔(178.50g,1.82mol)和甲苯(1.1L)，该混合物在110℃搅拌21小时，将反应液减压浓缩。粗产品经过柱(PE:EA＝20:1至2:1)纯化，得到化合物1c。LCMS m/z(ESI):280.0(M+1)。 1H NMR(400MHz,CDCl 3):δ9.86(s,1H),8.08(d,J＝2.4Hz,1H),7.90(s,1H),7.72(dd,J＝2.2,8.4Hz,1H),7.48(d,J＝8.4Hz,1H),0.41(s,9H)。
第三步
在预先干燥过的5升烧瓶中加入1c(130g,464.62mmol)和MeCN(3.5L)，在25℃条件下加入NCS(744.49g,5.58mol)和KF(161.97g,2.79mol)。加热到90℃反应40小时。将反应液直接过滤，并将滤液旋干，得到粗产物。向该粗产物中加入NaOH水溶液直至混合物的pH大于13，再向该混合物中加入乙酸乙酯(1L)，并在25℃搅拌半小时。分离有机相后，水相再用乙酸乙酯萃取(1L×3)。合并有机相后减压浓缩，残余物经过柱(DCM)纯化，得到化合物1d。LCMS m/z(ESI):241.9(M+1)。 1H NMR(400MHz,CDCl 3):δ9.88(s,1H),8.09(d,J＝2.5Hz,1H),7.94(s,1H),7.76(dd,J＝2.5,8.5Hz,1H),7.49(d,J＝8.5Hz,1H)。
第四步
在预先干燥过的烧瓶中加入1d(36.70g,151.61mmol)，三环己基膦(63.78g,227.42mmol)和CHCl 3(1.5L)，向其中滴加2,3-丁二烯酸乙酯(17g,151.61mmol)。密封后，升温到65℃条件下搅拌4小时。将反应液减压浓缩，粗产品过柱(PE:EA＝100:1至2:1)纯化，得到化合物1e。 1H NMR(400MHz,CDCl 3):δ7.83(d,J＝2.3Hz,1H),7.76(s,1H),7.62(dd,J＝2.3,8.4Hz,1H),7.46(d,J＝8.6Hz,1H),7.27(s,1H),6.32-6.27(m,1H),5.94(dd,J＝0.8,6.7Hz,1H)。
第五步
在预先干燥过的烧瓶中加入1e(24g,77.89mmol)，三溴化吡啶鎓(74.73g,233.68mmol)和AcOH(500mL)，该混合物在120℃条件下搅拌24小时。向反应液中加入乙酸乙酯(200mL)和石油醚(200mL)，分层后，将有机相分出。水相再用石油醚和乙酸乙酯的混合液萃取(1:1，400mL×3)。合并有机相，减压浓缩，向残余物中加入石油醚(300mL)并搅拌10分钟，有固体析出。过滤，干燥得到化合物1f。LCMS m/z(ESI):385.9(M+1)。 1H NMR(400MHz,CDCl 3):δ7.83(d,J＝2.3Hz,1H),7.77(s,1H),7.66-7.60(m,2H),7.45(d,J＝8.4Hz,1H),5.85(d,J＝7.2Hz,1H)。
第六步
在预先干燥过的烧瓶中加入1f(3g,7.75mmol)，双联频哪醇硼酸酯(2.95g,11.63mmol)，KOAc(1.52g,15.50mmol)和1,4-二氧六环(90mL)，抽换三次氮气后，向其中加入Pd(dppf)Cl 2(113.44mg,155.03μmol)，并在80℃搅拌5小时。将反应液降至室温后，过滤除掉固体后，将滤液减压浓缩。粗产品经制备HPLC纯化得到化合物1g。LCMS m/z(ESI):352.0(M+1)。 1H NMR(400MHz,DMSO-d 6):δ8.91(s,1H),8.01(d,J＝2.5Hz,1H),7.93-7.86(m,2H),7.82-7.77(m,1H),6.64(d,J＝6.5Hz,1H)。
第七步
将化合物1g(481.44mg,1.37mmol)，中间体A1(0.58g,1.24mmol)和Cs 2CO 3(729.35mg,2.24mmol)溶于1,4-二氧六环(29mL)，在氮气保护下加入Pd(dppf)Cl 2(101.56mg,124.36μmol)。将反应液在30℃反应12小时，然后过滤。往滤液中加入乙酸乙酯(30mL)和水(20mL)。分离有机相，水相再用乙酸乙酯 萃取(20mL×3)。合并有机相，减压浓缩，残余物经过柱(PE:EA＝20:1至0:1)纯化，得到化合物1h。LCMS m/z(ESI):624.1(M+1)。
第八步
在氢化瓶中加入雷尼镍(274.41mg,3.20mmol)，THF(40mL)和1h(0.4g,640.59μmol)，然后在氢气(50psi)氛围下，25℃反应10分钟。将反应液直接过滤，滤液减压浓缩。残余物经薄层层析色谱(PE:EA＝2.5:1)纯化，得到两个非对映异构体。再将每个异构体通过SFC分离(分离柱:DAICEL CHIRALPAK AD(250mm×30mm,10μm)；流动相:异丙醇；梯度:异丙醇50％-50％,7min)得到目标化合物1-1(t R＝1.89min)，化合物1-2(t R＝2.31min)，化合物1-3(t R＝1.93min)和化合物1-4(t R＝2.43min)。
化合物1-1:LCMS m/z(ESI):626.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.70(d,J＝5.0Hz,1H),7.82(d,J＝2.0Hz,1H),7.72(s,1H),7.64(s,1H),7.59(dd,J＝2.4,8.4Hz,1H),7.51-7.37(m,3H),7.30(t,J＝58.8Hz,1H),6.60(s,1H),5.96(d,J＝7.0Hz,1H),4.26(br dd,J＝4.6,12.0Hz,1H),2.57(br dd,J＝3.6,6.6Hz,1H),2.02-1.82(m,3H),1.65-1.57(m,1H),1.78-1.57(m,1H),1.05(d,J＝6.6Hz,3H),0.60(br s,2H)。
化合物1-2:LCMS m/z(ESI):626.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.69(d,J＝5.0Hz,1H),7.81(d,J＝2.0Hz,1H),7.73(s,1H),7.64(s,1H),7.59(dd,J＝2.0,8.6Hz,1H),7.52-7.35(m,3H),7.30(t,J＝58.8Hz,1H),6.66(s,1H),5.96(d,J＝7.0Hz,1H),4.26(br dd,J＝4.4,12.3Hz,1H),2.57(br dd,J＝3.6,6.6Hz,1H),2.02-1.80(m,3H),1.45-1.28(m,2H),1.05(d,J＝7.0Hz,3H),0.59(br s,1H)。
化合物1-3:LCMS m/z(ESI):626.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.66(d,J＝5.0Hz,1H),7.83(d,J＝2.0Hz,1H),7.74(s,1H),7.67(s,1H),7.62-7.57(m,1H),7.47-7.41(m,2H),7.35(br d,J＝5.0Hz,1H),7.29(t,J＝58.8Hz,1H),7.14(s,1H),6.59(s,1H),5.98(d,J＝7.0Hz,1H),4.26(br dd,J＝4.6,12.0Hz,1H),2.29-2.17(m,1H),1.94-1.76(m,3H),1.56-1.37(m,2H),1.28(d,J＝6.6Hz,3H),0.74-0.59(m,1H)。
化合物1-4:LCMS m/z(ESI):626.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.66(d,J＝5.0Hz,1H),7.83(d,J＝2.0Hz,1H),7.73(s,1H),7.67(s,1H),7.63-7.56(m,2H),7.44-7.42(m,2H),7.35(br s,1H),7.29(t,J＝58.8Hz,1H),6.56(s,1H),5.98(d,J＝7.0Hz,1H),4.34-4.18(m,1H),2.33-2.17(m,1H),1.95-1.75(m,3H),1.55-1.39(m,2H),1.29(d,J＝7.0Hz,3H),0.76-0.60(m,1H)。
实施例2
Figure PCTCN2020084932-appb-000056
第一步
将化合物2a(7g,37.72mmol)溶于CHCl 3(70mL)，加入三环己基膦(15.87g,56.58mmol)和2,3-丁二烯酸乙酯(4.65g,41.50mmol)，加热到65℃搅拌3小时。将反应液减压浓缩，往残余物中加入乙酸乙酯(50mL)和水(20mL)。将有机相分离，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤。将滤液减压浓缩，残余物经过柱(PE:EA＝5:1至2:1)纯化得到化合物2b。
第二步
将2b(2g,7.95mmol)溶于AcOH(50mL)中，加入三溴化吡啶鎓(12.71g,39.74mmol)，然后加热到120℃搅拌12小时。将反应混合物减压浓缩，往残余物中加入水(20mL)，用乙酸乙酯萃取(20mL×2)。合并萃取液用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经过柱(PE:EA＝10:1至2:1)纯化得到化合物2c。LCMS m/z(ESI):330.1(M+1)。
第三步
将2c(1.1g,3.33mmol)，六丁基二锡(2.90g,4.99mmol)和Pd(PPh 3) 4(384.58mg,332.81μmol)溶于甲苯(20mL)，用氮气置换3次，然后加热到100℃搅拌12小时。往反应液中加入乙酸乙酯(40mL)，用饱和食盐水洗涤(20mL×3)，用无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经过柱(PE:EA＝5:1)纯化，得到化合物2d。LCMS m/z(ESI):484.2(M-57)。
第四步
将2d(0.4g,739.83μmol)，中间体A2(456.03mg,739.83μmol)，Pd(PPh 3) 4(128.24mg,110.97μmol)，CuCl(732.42mg,7.40mmol)和LiCl(313.64mg,7.40mmol)溶于DMSO(20mL)。将反应混合物用氮 气置换3次，然后加热到80℃搅拌1小时。将反应液用水(50mL)淬灭，再用乙酸乙酯萃取(50mL×2)。合并有机相，用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥后过滤。滤液减压浓缩，残余物经过柱(DCM:EA＝1:1)纯化得到化合物2e。LCMS m/z(ESI):568.2(M+1)。
第五步
将2e(0.14g,246.51μmol)溶于MeOH(15mL)，加入雷尼镍(14.47mg,246.51μmol)，然后在氢气(30psi)氛围下30℃搅拌2小时。将反应混合物过滤，滤液减压浓缩，残余物经制备薄层色谱(PE:EA:MeOH＝4:4:1)纯化得到非对映异构体2f-1(R f＝0.70)和2f-2(R f＝0.63)。LCMS m/z(ESI):540.2(M+1)。
第六步
将2f-1(0.04g,74.08μmol)溶于AcOH(3mL)，加入原甲酸三甲酯(78.61mg,740.80μmol)和NaN 3(85.35mg,740.80μmol)。将反应混合物加热到90℃搅拌2小时，用水(10mL)萃灭，再用乙酸乙酯萃取(20mL×2)，合并萃取液，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经制备HPLC(分离柱:Shim-pack C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈30％-60％,10min)纯化得到化合物2-1。LCMS m/z(ESI):593.0(M+1)。
1H NMR(400MHz,CD 3OD):δ9.52(s,1H),8.61(d,J＝5.2Hz,1H),7.95(d,J＝2.4Hz,1H),7.76-7.73(m,2H),7.69-7.59(m,4H),7.43-7.41(m,1H),6.52(d,J＝5.2Hz,1H),4.21-4.16(m,1H),2.72-2.69(m,1H),2.03-1.54m,3H),1.54(br s,1H),1.35(br s,1H),0.99(d,J＝6.8Hz,3H),0.50(br s,1H)。
第七步
将2f-2(0.045g,83.34μmol)溶于AcOH(3mL)，加入原甲酸三甲酯(88.44mg,833.40μmol)和TMSN 3(96.01mg,833.40μmol)。将反应混合物加热到90℃搅拌2小时，用水(10mL)萃灭，再用乙酸乙酯萃取(20mL×2)，合并萃取液，用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经制备HPLC纯化(分离柱:Shim-pack C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈30％-60％,10min)得到化合物2-2。LCMS m/z(ESI):593.0(M+1)。
1H NMR(400MHz,CD 3OD):δ9.52(s,1H),8.58(d,J＝5.2Hz,1H),7.96(d,J＝2.4Hz,1H),7.82-7.73(m,2H),7.70-7.50(m,4H),7.40(d,J＝5.2Hz,1H),6.51(d,J＝7.1Hz,1H),4.17(br dd,J＝5.6,10.8Hz,1H),2.36-2.25(m,1H),1.94-1.79(m,3H),1.55-1.44(m,1H),1.40-1.28(m,1H),1.23(d,J＝6.8Hz,3H),0.70(m,1H)。
实施例3
Figure PCTCN2020084932-appb-000057
第一步
将化合物1b(10.39g,57.24mmol)，叔丁基二甲基(2-丙炔氧基)硅烷(6.5g,38.16mmol)，CuI(145.36mg,763.25μmol)和三乙胺(77.23mg,763.25μmol)溶于乙腈(200mL)，然后在氮气保护下25℃搅拌反应12小时。将反应混合物减压浓缩，往残余物中加入乙酸乙酯(20mL)，搅拌20分钟，过滤，滤饼真空干燥得到化合物3a。LCMS m/z(ESI):352.3(M+1)。
第二步
将化合物3a(2g,5.68mmol)，2,3-丁二烯酸乙酯(764.71mg,6.82mmol)和三环己基膦(2.39g,8.53mmol)溶于氯仿(200mL)，然后在氮气保护下加热到50℃，搅拌反应12小时。反应混合物减压浓缩，残余物经柱层析(PE:EA＝1:0至3:1)纯化得到化合物3b。LCMS m/z(ESI):418.1(M+1)。
第三步
将化合物3b(1.4g,3.35mmol)溶于1,4-二氧六环(10mL)，加入盐酸/1,4-二氧六环溶液(10mL,1M)，然后在50℃下，搅拌反应20分钟。将反应混合物过滤，滤饼真空干燥得到化合物3c。
第四步
将化合物3c(1g,3.29mmol)溶于二氯甲烷(20mL)，在0℃下加入戴斯-马丁试剂(2.09g,4.94mmol)，然后在0℃下搅拌反应1小时。将反应液过滤，滤液减压浓缩得到化合物3d。LCMS m/z(ESI):301.9(M+1)。
第五步
将化合物3d(2.3g,7.62mmol)溶于二氯甲烷(40mL)，加入二乙氨基三氟化硫(1.84g,11.44mmol)，然后在氮气保护下25℃搅拌反应2小时。将反应液在0℃下倒入饱和碳酸氢钠溶液(60mL)，然后升温至20℃搅拌0.5小时，用二氯甲烷萃取(40mL×2)。合并有机相，用饱和食盐水洗涤(80mL)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经柱层析(PE:EA＝1:0至2:1)纯化得到化合物3e。LCMS m/z(ESI):324.2(M+1)。
第六步
将化合物3e(0.1g,308.95μmol)和三溴化吡啶鎓(296.42mg,926.84μmol)溶于醋酸(2mL)，加热到90℃反应12小时。往反应液中加入水(5mL)，搅拌10分钟，过滤。滤饼真空干燥得到化合物3f。LCMS m/z(ESI):404.2(M+1)。
第七步
将化合物3f(60mg,149.04μmol)，双联频哪醇硼酸酯(45.42mg,178.85μmol)，醋酸钾(29.25mg,298.08μmol)和Pd(dppf)Cl 2(2.18mg,2.98μmol)溶于1,4-二氧六环(2mL)，用氮气置换3次，然后加热到80℃反应1.5小时得到化合物3g。LCMS m/z(ESI):368.1(M+1)。
第八步
将化合物3g(228mg,620.41μmol)，A2(267.70mg,434.29μmol)，Pd(dppf)Cl 2(9.08mg,12.41μmol)和碳酸铯(404.28mg,1.24mmol)加入到1,4-二氧六环(1mL)，用氮气置换3次，然后加热到48℃反应12小时。将反应液过滤，滤液减压浓缩，残余物经柱层析(PE:EA＝1:2至EA:DCM＝2:1)纯化得到化合物3h。LCMS m/z(ESI):640.1(M+1)。
第九步
将化合物3h(290mg,453.13μmol)溶于THF(10mL)，氮气保护下加入雷尼镍(38.82mg)，然后在氢气(50psi)下，25℃下搅拌反应30分钟，过滤。滤液减压浓缩，残余物经制备TLC(EA)纯化得到两个组分。组分1经SFC(分离柱:DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇45％-45％,1.9min；40min)纯化后，再经制备HPLC(分离柱:Phenomenex Synergi C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈36％-66％,10min)纯化得到化合物3-1(t R＝0.901min)；组分2经SFC(分离柱:DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇55％-55％,2.5min；50min)纯化后，再经制备HPLC(分离柱:Phenomenex Synergi C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈36％-66％,10min)纯化得到化合物3-2(t R＝1.403min)。
化合物3-1：LCMS m/z(ESI):642.0(M+1)。 1H NMR(400MHz,CD 3OD):δ8.57-8.65(m,2H),7.92(d,J＝2.40Hz,1H),7.79-7.50(m,6H),7.42(d,J＝4.80Hz,1H),7.12-6.85(m,1H),6.43(d,J＝6.80Hz,1H),4.19(dd,J＝4.00,12.40Hz,1H),2.69(m,1H),1.80-2.08(m,3H),1.49-1.62(m,1H),1.28-1.40(m,1H),0.98(d,J＝6.80Hz,3H),0.50(br s,1H)。
化合物3-2：LCMS m/z(ESI):642.0(M+1)。 1H NMR(400MHz,CD 3OD):δ8.55-8.65(m,2H),7.93(d,J＝2.00Hz,1H),7.72-7.57(m,6H),7.40(d,J＝4.80Hz,1H),7.13-6.85(m,1H),6.44(d,J＝7.20Hz,1H),4.17(dd,J＝4.00,11.20Hz,1H),2.26-2.37(m,1H),1.78-1.94(m,3H),1.49(m,1H),1.27-1.39(m,1H),1.22(d,J＝6.80Hz,3H),0.70(m,1H)。
实施例4
Figure PCTCN2020084932-appb-000058
第一步
将化合物1b(11.83g,65.13mmol)，环丙乙炔(4.1g,43.42mmol)，CuI(165.38mg,868.37μmol)和三乙胺(87.87mg,868.37μmol)溶于乙腈(150mL)，然后在氮气保护下25℃搅拌反应24小时。将反应混合物减压浓缩，残余物经柱层析(PE:EA＝1:0至5:1)纯化得到化合物4a。
第二步
将化合物4a(2.1g,8.48mmol)，2,3-丁二烯酸乙酯(950.68mg,8.48mmol)和三环己基膦(3.57g,12.72mmol)溶于氯仿(20mL)，然后在氮气保护下加热到60℃反应4小时。将反应混合物减压浓缩，残余物经柱层析(PE:EA＝1:0至2:1)纯化得到化合物4b。LCMS m/z(ESI):314.5(M+1)。
第三步
将化合物4b(5g,15.94mmol)和三溴化吡啶鎓(15.29g,47.81mmol)溶于醋酸(50mL)，加热到90℃反应12小时。往反应液中加入乙酸乙酯(100mL)，用水洗涤(600mL×2)。有机相分离后再用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经柱层析(PE:EA＝1:0至3:1)纯化得到化合物4c。LCMS m/z(ESI):393.8(M+1)。
第四步
将化合物4c(0.1g,254.69μmol)，双联频哪醇硼酸酯(77.61mg,305.63μmol)，醋酸钾(49.99mg,509.38μmol)和Pd(dppf)Cl 2(3.73mg,5.09μmol)溶于1,4-二氧六环(1mL)，用氮气置换3次，然后加热到80℃反应2小时得到化合物4d。
第五步
将化合物4d(182mg,509.01μmol)，A2(219.63mg,356.31μmol)，Pd(dppf)Cl 2(7.45mg,10.18μmol)和碳酸铯(331.69mg,1.02mmol)加入到1,4-二氧六环(1mL)，用氮气置换3次，然后加热到48℃反应12小时。将反应液过滤，滤液减压浓缩，残余物经柱层析(PE:EA＝3:1至EA:DCM＝2:1)纯化得到化合物4e。LCMS m/z(ESI):630.1(M+1)。
第六步
将化合物4e(450.00mg,714.24μmol)溶于THF(10mL)，氮气保护下加入雷尼镍(61.19mg)，然后在氢气(50psi)下，25℃搅拌反应30分钟，过滤。滤液减压浓缩，残余物经制备TLC(EA)纯化后得到2个组分。组分1经SFC(分离柱:DAICEL CHIRALPAK IC,250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇60％-60％,2.1min；50min)纯化后，再经制备HPLC(分离柱:Shim-pack C18 25mm×150mm,10μm；[水(0.225％甲酸)-乙腈]；梯度:乙腈40％-70％,10min)纯化得到化合物4-1(t R＝1.231min)；组分2经SFC(分离柱:DAICEL CHIRALPAK IC,250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇70％-70％,3.5min；40min)纯化后，再经制备HPLC(分离柱:Shim-pack C1825mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈38％-68％,10min)纯化得到化合物4-2(t R＝1.875min)。
化合物4-1：LCMS m/z(ESI):632.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.66(d,J＝4.80Hz,1H),7.79(d,J＝2.40Hz,1H),7.59(s,1H),7.54(dd,J＝2.40,8.80Hz,1H),7.39～7.28(m,6H),7.14(s,1H),5.86(d,J＝7.20Hz,1H),4.23(dd,J＝4.00,12.40Hz,1H),2.57(m,1H),1.90-2.03(m,3H),1.83-1.88(m,1H),1.47-1.60(m,1H),1.34(m,1H),0.96-1.04(m,5H),0.82-0.89(m,2H),0.54(br s,1H)。
化合物4-2：LCMS m/z(ESI):632.2(M+1)。 1H NMR(400MHz,CDCl 3):δ8.63(d,J＝5.20Hz,1H),7.80(d,J＝2.00Hz,1H),7.63(s,1H),7.52-7.58(m,2H),7.38～7.13(m,5H),6.97(s,1H),5.86(d,J＝7.20Hz,1H),4.24(dd,J＝4.40,12.40Hz,1H),2.17-2.29(m,1H),1.97-2.01(m,1H),1.79-1.89(m,3H),1.32-1.53(m,2H),1.25(d,J＝6.80Hz,3H),0.95-1.02(m,2H),0.82-0.89(m,2H),0.58-0.71(m,1H)。
实施例5
Figure PCTCN2020084932-appb-000059
第一步
将化合物5a(20g,96.87mmol)溶于乙腈(500mL)，0℃下加入亚硝酸异戊酯(17.02g,145.30mmol)和三甲基硅基叠氮(16.74g,145.30mmol)。将反应混合物在0℃下搅拌反应1小时，然后加入三甲基硅基乙炔(28.54g,290.60mmol)和氧化亚铜(1.39g,9.69mmol)，在0℃下搅拌反应2小时。将反应液用饱和氯化铵淬灭(200mL)，乙酸乙酯萃取(100mL×3)。合并萃取液，用饱和食盐水洗涤，无水硫酸钠干燥，过滤。绿叶减压浓缩，残余物经柱层析(PE:EA＝10:1)纯化得到化合物5b。LCMS m/z(ESI):329.7(M+1)。
第二步
将化合物5b(5g,15.12mmol)和NCS(7.07g,52.92mmol)溶于乙腈(80mL)，加入一水合对甲苯磺酸(431.42mg,2.27mmol)，加热到80℃搅拌反应1小时。将反应混合物减压浓缩，往残余物中加入乙酸乙酯(30mL)，然后用氢氧化钠溶液(30mL,1M)，水(30mL)和饱和食盐水(30mL)洗涤。有机相分离后用无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经柱层析(PE:EA＝20:1至10:1)纯化得到化合物5c。LCMS m/z(ESI):293.9(M+1)。
第三步
将1-甲基-6-(三丁基锡基)吡啶-2(1H)-酮(3.69g,9.27mmol)和化合物5c(2.23g,7.60mmol)溶于甲苯(60mL)，在氮气保护下加入Pd(PPh 3) 2Cl 2(650.48mg,926.74μmol)。将反应液加热到130℃搅拌反应13小时，过滤。滤饼用乙酸乙酯(10mL×3)和二氯甲烷/甲醇的混合溶液(2:1,10mL×3)洗涤。合并滤液和洗涤液，减压浓缩，残余物经柱层析(PE:EA＝10:1至5:1至DCM:EA＝1:1)纯化得到化合物5d。LCMS m/z(ESI):320.9(M+1)。
第四步
将化合物5d(1.42g,3.08mmol)和三溴化吡啶鎓(986.17mg,3.08mmol)溶于醋酸(30mL)，氮气保护下加热到90℃反应4小时。将反应液倒入水中(60mL)，加入乙酸乙酯(20mL)，再用乙酸乙酯萃取(20mL×3)。合并有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物在乙酸乙酯(10mL)中25℃打浆15分钟，过滤，干燥得到化合物5e。LCMS m/z(ESI):401.0(M+1)。
第五步
将化合物5e(0.35g,711.10μmol)，双联频哪醇硼酸酯(361.15mg,1.42mmol)，醋酸钾(139.58mg,1.42mmol)和Pd(dppf)Cl 2(31.22mg,42.67μmol)溶于1,4-二氧六环(2mL)，用氮气置换3次，然后加热到80℃反应0.5小时得到化合物5f。LCMS m/z(ESI):365.3(M+1)。
第六步
将化合物5f(260mg,712.37μmol)，A2(263.46mg,427.42μmol)，Pd(dppf)Cl 2(52.12mg,71.24μmol)和碳酸铯(464.21mg,1.42mmol)加入到1,4-二氧六环(1.5mL)，用氮气置换3次，然后加热到50℃反应12小时。将反应液用乙酸乙酯(30mL)稀释，然后过滤。滤饼再用乙酸乙酯洗涤(10mL×4)，合并滤液和洗涤液，减压浓缩，残余物经柱层析(PE:EA＝2:1至EA:DCM＝1:1)纯化得到化合物5g。LCMS m/z(ESI):637.4(M+1)。
第七步
将化合物5g(0.21g,329.43μmol)溶于THF(20mL)，加入氯仿(0.2mL)。在氮气保护下加入雷尼镍(282.24mg)，然后在氢气(45psi)下，25℃搅拌反应0.5小时，过滤。滤饼用乙酸乙酯洗涤(10mL×4)，合并滤液和洗涤液，减压浓缩，残余物经制备HPLC(分离柱:Phenomenex Synergi C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈31％-61％,10min)纯化后得到化合物5h。LCMS m/z(ESI):639.2(M+1)。
第八步
化合物5h(70mg,167.96μmol)经SFC(分离柱：DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇50％-50％,4.1min)分离后得到化合物5-1(t R＝1.090min)和化合物5-2(t R＝2.538min)。化合物5-1：LCMS m/z(ESI):639.2(M+1)。 1H NMR(400MHz,CD 3OD):δ8.62-8.53(m,1H),8.37-8.17(m,1H),7.82-7.78(m,1H),7.77-7.72(m,3H),7.69-7.61(m,2H),7.59-7.49(m,1H),7.40(br d,J＝3.4Hz,1H),6.29-6.19(m,1H),4.40(ddd,J＝4.2,7.8,12.4Hz,1H),3.20(d,J＝15.4Hz,3H),2.76-2.67(m,1H),2.14-1.98(m,2H),1.92-1.77(m,1H),1.63-1.48(m,1H),1.42-1.31(m,1H),0.99(d,J＝6.8Hz,3H),0.51(br s,1H)。化合物5-2：LCMS m/z(ESI):639.2(M+1)。 1H NMR(400MHz,CD 3OD):δ8.57(br dd,J＝5.0,19.8Hz,1H),8.39-8.17(m,1H),7.82-7.73(m,4H),7.69-7.59(m,3H),7.43(br s,1H),6.35-6.20(m,1H),4.45-4.31(m,1H),3.24-3.13(m,3H),2.38-2.26(m,1H),1.87(br d,J＝9.4Hz,2H),1.51(br d,J＝2.8Hz,1H),1.29(s,2H),1.25(dd,J＝4.0,6.8Hz,3H),0.73(br d,J＝11.2Hz,1H)。
实施例6
Figure PCTCN2020084932-appb-000060
第一步
将化合物1b(8.14g,44.82mmol)，乙氧基乙炔(4.49g,32.02mmol)，CuI(121.95mg,640.32μmol)和三乙胺(64.79mg,640.32μmol)溶于乙腈(100mL)，然后在氮气保护下15℃搅拌反应13小时。将反应混合物减压浓缩，往残余物中加入溶剂PE和EA的混合溶剂(5:1,100mL)，搅拌1小时候后过滤。滤饼用PE洗涤(10mL×3)，干燥得到化合物6a。
第二步
将化合物6a(3.14g,12.48mmol)和三环己基膦(5.25g,18.72mmol)溶于氯仿(100mL)，然后加入2,3-丁二烯酸乙酯(1.68g,14.97mmol)，加热到65℃反应5小时。将反应混合物减压浓缩，残余物经柱层析(PE:EA＝50:1至2:1)纯化得到化合物6b。
第三步
将化合物6b(3.2g,10.07mmol)和三溴化吡啶鎓(6.44g,20.14mmol)溶于醋酸(60mL)，加热到80℃反应8小时。往反应液中加入水(60mL)，用乙酸乙酯萃取(30mL×3)。有机相分离后再用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物经柱层析(PE:EA＝5:1至2:1)纯化得到化合物粗品，再经乙腈(10mL)打浆，过滤，烘干得到化合物6c。LCMS m/z(ESI):396.0(M+1)。
第四步
将化合物6c(165mg,416.01μmol)，双联频哪醇硼酸酯(264.10mg,1.04mmol)，醋酸钾(81.66mg,832.02μmol)和Pd(dppf)Cl 2(18.26mg,24.96μmol)溶于1,4-二氧六环(1mL)，用氮气置换3次，然后 加热到80℃反应1.5小时得到化合物6d。LCMS m/z(ESI):362.0(M+1)。
第五步
将化合物6d(150mg,414.89μmol)，A2(179.60mg,290.42μmol)，Pd(dppf)Cl 2(30.36mg,41.49μmol)和碳酸铯(270.36mg,829.77μmol)加入到1,4-二氧六环(1mL)，用氮气置换3次，然后加热到50℃反应12小时。将反应液过滤，滤饼用乙酸乙酯洗涤(10mL×3)。合并滤液减压浓缩，残余物经柱层析(PE:EA＝3:1至EA:DCM＝1:1)纯化得到化合物6e。LCMS m/z(ESI):634.2(M+1)。
第六步
将化合物6e(210mg,331.21μmol)溶于THF(20mL)，氮气保护下加入雷尼镍(28.38mg)，然后在氢气(45psi)下，25℃搅拌反应30分钟，过滤。滤液减压浓缩，残余物经制备TLC(DCM:EA＝1:1)纯化得到2个组分。组分1，经SFC(分离柱:DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相:[0.1％氨水,甲醇]；梯度:甲醇70％-70％,2.7min；40min)纯化后再经制备HPLC(分离柱:Shim-pack C18 25mm×150mm,10μm；流动相:[水(0.225％甲酸)-乙腈]；梯度:乙腈38％-68％,10min)纯化得到化合物6-1(t R＝1.860min)；组分2经SFC(分离柱:DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相:[0.1％氨水-甲醇]；梯度:甲醇70％-70％,2.8min；40min)纯化后得到化合物6-2(t R＝1.179min)。
化合物6-1：LCMS m/z(ESI):636.3(M+1)。 1H NMR(400MHz,CD 3OD):δ8.58(d,J＝4.8Hz,1H),7.89(d,J＝2.0Hz,1H),7.77(s,1H),7.76(s,1H),7.71～7.56(m,5H),7.42(br s,1H),6.40(d,J＝7.6Hz,1H),4.55(s,1H),4.16-4.21(m,2H),2.31-2.34(m,1H),1.85-1.91(m,3H),1.45-1.55(m,1H),1.27-1.40(m,4H),1.23(d,J＝7.2Hz,3H),0.70(br s,1H)。
化合物6-2：LCMS m/z(ESI):636.3(M+1)。 1H NMR(400MHz,CDCl 3):δ8.61(d,J＝5.6Hz,1H),7.88(d,J＝2.4Hz,1H),7.77(s,1H),7.74(s,1H),7.50～7.79(m,5H),7.44(br s,1H),6.40(d,J＝7.2Hz,1H),4.62(s,1H),4.14-4.22(m,2H),2.68-2.72(m,1H),1.97-2.04(m,2H),1.81-1.92(m,1H),1.36(t,J＝7.2Hz,1H),1.28-1.35(m,1H),0.98(d,J＝6.8Hz,3H),0.49(br s,1H)。
活性测试
1.hFXIa(人XIa因子)酶抑制活性筛选实验
实验目的：
检测本发明化合物对人XIa因子的抑制活性
实验材料：
1)实验缓冲液pH 7.4
100mM Tris–HCl(Sigma,目录号：T2663,批次号：SLBG2775)
200mM NaCl(Sigma,目录号：13423,批次号：SZBB2360V)
0.02％tween20(Sigma-P1379)
2)酶和底物
酶，人凝血十一因子(Human Factor XIa,Abcam,Cat#ab62411):总量:50μg。使用实验缓冲液溶解并分装。
底物S-2366(DiaPharma,目录号：S821090):25mg
3)仪器及耗材
SpectraMax 340PC多功能酶标仪(Molecular Devices)
384-孔黑色透明反应板(Corning Cata#3712)
Echo液体工作站(Labcyte)
Echo使用384孔聚丙烯化合物板(Labcyte-P-05525)
Echo使用384浅孔聚丙烯化合物版(Labcyte-LP-0200，2.5-12μL)
Mutidrop自动分液器(Thermo Scientific)
Mutidrop耗材(Thermo Scientific-24073290)
4)化合物
待测化合物用DMSO溶解成10mM的溶液，储存在氮气柜中。
实验方法：
1)化合物准备
所有测试化合物使用Echo准备，梯度稀释并转移100nL到384孔反应板。参照化合物及待测样品200μM起始(反应终浓度1μM起始)，3倍稀释，10个点。高信号孔为DMSO，低信号孔为100μM的参照化合物。样品及对照分布见样品分布。
2)人XIa因子酶准备
使用实验缓冲液稀释人XIa因子酶到0.5μg/mL。
3)底物S-2306准备
使用实验缓冲液配制S-2306，浓度为1mM。
4)使用Mutidrop自动分液器加10μL 0.5μg/mL的人XIa因子酶到反应板中，终浓度为5ng/孔
5)使用Mutidrop自动分液器加10μL 1mM的S-2306到反应板中，终浓度为0.5mM。
6)离心，1000rpm，10s。
7)反应板放入SpectraMax 340PC中37℃孵育10分钟，在405nm检测吸光值。
8)数据使用GraphPad Prism 5.0分析
％抑制率＝100％×[1-(样品读值–低信号平均值)/(高信号平均值–低信号平均值)]
IC 50使用4因子线性回归分析：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
Y是％抑制率，X是样品浓度的对数。
实验结果：
本发明化合物对hFXIa的酶抑制活性IC 50的数据在下面表1中展示：
表1
化合物 hFXIa IC 50(nM)
1-2 3.9
1-4 34.07
2-1 3.39
2-2 10.69
3-1 3.81
4-1 21.73
5-1 8.22
6-2 20.37
结论：本发明化合物对人XIa因子的酶具有很好的抑制活性。
2.人血浆体外aPTT(活化部分凝血活酶时间)的测定
实验目的：
检测本发明化合物在体外对人血浆的抗凝血作用
实验材料：
1)血浆：人新鲜静脉血与0.109M的枸橼酸钠按9:1混合均匀，以3000rpm离心15分钟，收集上层血浆，在2-5小时内进行实验。
2)试剂：aPTT试剂(活化部分凝血活酶时间测定试剂盒，mindray)、PT试剂(凝血酶原时间测定试剂盒，mindray)、氯化钙溶液。
3)仪器：凝血仪(北京普利生，C2000-4)。
实验检测：
将受试化合物溶于DMSO，配制为10mM母液。在血浆中加入10mM母液化合物，分别梯度稀释至400、200、100、50、25、12.5、6.25、3.125、1.563、0.781、0.390、0.195μM，空白为100％DMSO溶液。将试剂、血浆、化合物放入凝血仪中对应位置，进行化合物aPTT及PT的检测。
数据处理：
通过Prism进行曲线拟合，计算aPTT 2x、PT 2x，即2倍空白对照的aPTT、PT分别所对应的化合物的浓度，结果在下面表2中展示：
表2
化合物 aPTT 2x(μM)
1-2 0.87
2-1 0.65
3-1 1.37
结论：本发明化合物体外对人血浆具有明显的抗凝血作用。
3.大鼠体内药代动力学评价
实验目的：
检测本发明化合物在大鼠体内的药代动力学参数
实验方案：
1)实验药品：化合物1-2；
2)实验动物：4只7-9周龄的雄性SD大鼠，随机分为2组，每组2只；
3)药物配制：称取适量药物，溶于DMAC：slolutol：水＝10:10:80的混合溶剂中，配置成0.2mg/mL和0.5mg/mL的两种溶液；
实验操作：
第1组动物通过尾静脉单次注射给予剂量为0.5mg/kg、浓度为0.2mg/mL的药物，第2组动物通过灌胃给 予剂量为3mg/kg、浓度为0.5mg/mL的化合物。动物于给药后0.0833(仅尾静脉注射组)、0.25、0.5、1、2、4、6、8和24小时采集血浆样品。使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的动力学参数见表3：
表3
Figure PCTCN2020084932-appb-000061
--表示不存在
结论：本发明化合物具有良好的大鼠体内药代动力学性质。

Claims (24)

  1. 式(I)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020084932-appb-100001
    其中，
    T为-O-或-N(R a)-；
    R a为H或C 1-3烷基；
    R 1为三唑基或四唑基，其中所述三唑基和四唑基任选被R b所取代；
    R 2为H或F；
    R 3为H、F、Cl、Br、CN、C 1-6烷基、C 1-6烷氧基或C 1-6烷氨基；
    R 4和R 5各自独立地为H、F、Cl、Br、I、C 1-3烷基、C 1-3卤代烷基或C 1-3烷氧基；
    R 6为任选被1、2或3个R c所取代的C 1-3烷基；
    R b和R c各自独立地为F、Cl、Br、I、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基或C 3-4环烷基。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-1)或(I-2)所示结构：
    Figure PCTCN2020084932-appb-100002
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R a如权利要求1所定义。
  3. 根据权利要求2所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-1-a)或(I-2-a)所示结构：
    Figure PCTCN2020084932-appb-100003
    其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在； R 1、R 2、R 3、R 4、R 5、R 6和R a如权利要求2所定义。
  4. 根据权利要求3所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-1-b)或(I-2-b)所示结构：
    Figure PCTCN2020084932-appb-100004
    其中，R 1、R 2、R 3、R 4、R 5、R 6和R a如权利要求3所定义。
  5. 根据权利要求1～4任一项所述的化合物、其异构体或其药学上可接受的盐，其中R a为H、-CH 3或-CH 2CH 3。
  6. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中T为-O-、-NH-或-N(CH 3)-。
  7. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中R b和R c各自独立地为F、Cl、甲基、-CHF 2、乙氧基或环丙基。
  8. 根据权利要求1～4或7任一项所述的化合物、其异构体或其药学上可接受的盐，其中R 1为
    Figure PCTCN2020084932-appb-100005
    Figure PCTCN2020084932-appb-100006
  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R 1为
    Figure PCTCN2020084932-appb-100007
    Figure PCTCN2020084932-appb-100008
  10. 根据权利要求1～4任一项所述的化合物、其异构体或其药学上可接受的盐，其中R 3为H、F、Cl、Br、CN、C 1-3烷基、C 1-3烷氧基或C 1-3烷氨基。
  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R 3为H、F、Cl、Br、CN、-CH 3、-OCH 3、
    Figure PCTCN2020084932-appb-100009
  12. 根据权利要求1～4任一项所述的化合物、其异构体或其药学上可接受的盐，其中R 4和R 5各自独立地为H、F、Cl、Br、I、
    Figure PCTCN2020084932-appb-100010
  13. 根据权利要求1～4或7任一项所述的化合物、其异构体或其药学上可接受的盐，其中R 6为任选被1、2 或3个R c所取代的-CH 3。
  14. 根据权利要求13所述的化合物、其异构体或其药学上可接受的盐，其中R 6为
    Figure PCTCN2020084932-appb-100011
    Figure PCTCN2020084932-appb-100012
  15. 根据权利要求1～4、6、7、9、11或14任一项所述的化合物、其异构体或其药学上可接受的盐，其中
    Figure PCTCN2020084932-appb-100013
    为
    Figure PCTCN2020084932-appb-100014
    Figure PCTCN2020084932-appb-100015
  16. 根据权利要求1～4、6、7、9、11或14任一项所述的化合物、其异构体或其药学上可接受的盐，其中
    Figure PCTCN2020084932-appb-100016
    为
    Figure PCTCN2020084932-appb-100017
  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，其中所述化合物具有式(I-3)或(I-4)所示结构：
    Figure PCTCN2020084932-appb-100018
    其中，R 1如权利要求1、8或9所定义；R 2如权利要求1所定义；R 3如权利要求1、10或11所定义；R 6如权利要求1、13或14所定义，R a如权利要求1或5所定义。
  18. 根据权利要求17所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-3-a)或(I-4-a)所示结构：
    Figure PCTCN2020084932-appb-100019
    其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    R 1、R 2、R 3、R a和R 6如权利要求17所定义。
  19. 根据权利要求18所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-3-b)或(I-4-b)所示结构：
    Figure PCTCN2020084932-appb-100020
    其中，R 1、R 2、R 3、R a和R 6如权利要求18所定义。
  20. 根据权利要求19所述的化合物、其异构体或其药学上可接受的盐，其中所述化合物具有式(I-5)或(I-6)所示结构：
    Figure PCTCN2020084932-appb-100021
    其中，R 2、R a和R 6如权利要求19所定义，T 1为N或CR b，R b如权利要求1或7所定义。
  21. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020084932-appb-100022
    Figure PCTCN2020084932-appb-100023
  22. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020084932-appb-100024
    Figure PCTCN2020084932-appb-100025
  23. 一种药物组合物，其含有治疗有效量的根据权利要求1～22任一项所述的化合物、其异构体或其药学上可接受的盐和药学上可接受的载体。
  24. 根据权利要求1～22任一项所述的化合物、其异构体或其药学上可接受的盐或根据权利要求23所述的药物组合物在制备XIa因子抑制剂药物中的应用。
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EP3957638A1 (en) 2022-02-23
CA3136861A1 (en) 2020-10-22
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