WO2020048547A1 - 三环并呋喃取代哌啶二酮类化合物 - Google Patents

三环并呋喃取代哌啶二酮类化合物 Download PDF

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WO2020048547A1
WO2020048547A1 PCT/CN2019/104992 CN2019104992W WO2020048547A1 WO 2020048547 A1 WO2020048547 A1 WO 2020048547A1 CN 2019104992 W CN2019104992 W CN 2019104992W WO 2020048547 A1 WO2020048547 A1 WO 2020048547A1
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reaction
mmol
ethyl acetate
compound
added
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PCT/CN2019/104992
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English (en)
French (fr)
Inventor
雷茂义
罗云富
徐雨
张国利
董井红
黎健
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 EP19857640.7A priority Critical patent/EP3848371A4/en
Priority to KR1020217010237A priority patent/KR102605291B1/ko
Priority to CN201980058617.XA priority patent/CN112654619B/zh
Priority to JP2021512772A priority patent/JP7323603B2/ja
Priority to US17/274,236 priority patent/US11319330B2/en
Publication of WO2020048547A1 publication Critical patent/WO2020048547A1/zh

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of compounds with tricyclofuran-substituted piperidine dione and its application in preparing medicines for treating diseases related to CRBN protein, and in particular to a derivative compound represented by formula (I) or a pharmaceutically acceptable Of salt.
  • Thalidomide trade name is reaction stop
  • Thalidomide trade name is reaction stop
  • CRBN protein Cereblon
  • DDB1 DNA damage binding protein 1
  • CUL4A Cullin-4A
  • ROC1 Cullins 1 regulator
  • CRBN is a 442 amino acid protein that is conserved from plant to human. It is located on the short arm of p26.3 of human chromosome 3 and has a molecular weight of 51 kDa. In humans, the CRBN gene has been identified as a candidate gene for autosomal recessive non-syndrome mild mental retardation (ARNSMR). CRBN is widely expressed in testes, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocytes, colon, brain, and retina, but in brain tissue (including retina) and testes The expression was significantly higher in other tissues.
  • CRBN as an important target of antitumor and immunomodulator drugs, has been proven in multiple hematological malignancies such as multiple myeloma, chronic lymphocytic leukemia, skin diseases such as leprosy nodular erythema, and systemic lupus erythematosus. Autoimmune diseases have a clear effect. Doxamines have more side effects, especially peripheral neuropathy. There is an urgent need to develop CRBN modulator drugs without teratogenic effects, fewer peripheral neuropathies, stronger immunomodulatory effects, and higher antitumor activity to improve clinical treatment effects, reduce clinical side effects, and facilitate long-term use of patients.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • n is selected from 0, 1, 2 and 3;
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and Wherein said C 1-6 alkyl, C 1-6 alkoxy and Optionally substituted by 1, 2 or 3 R a ;
  • the amino group is optionally substituted with 1, 2 or 3 R;
  • R is independently selected from F, Cl, Br, I, OH, NH 2 , CN, Me, and
  • Ring A is selected from 5- to 6-membered heteroaryl, phenyl, C 4-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 4- to 7-membered heterocycloalkenyl;
  • the 5- to 6-membered heteroaryl group, the 4- to 7-membered heterocycloalkyl group, the 5- to 10-membered heterocycloalkyl group, and the 5- to 10-membered heterocycloalkyl group each include 1, 2, 3, or 4 independently selected from -Atoms or heteroatoms of -NH-, -O-, -S- and N
  • the compound represented by the above formula (I) or a pharmaceutically acceptable salt is selected from
  • n is selected from 0, 1, 2 and 3;
  • R 1 is selected from H, halogen, OH, NH 2 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2 or 3 R a;
  • R a is selected from F, Cl, Br, I, OH, NH 2 and CN;
  • Ring A is selected from 5- to 6-membered heteroaryl, phenyl, C 4-6 cycloalkyl, and 4- to 7-membered heterocycloalkyl;
  • the 5- to 6-membered heteroaryl group and 4- to 7-membered heterocycloalkyl group respectively include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N. .
  • ring A is selected from the group consisting of phenyl, 1,3-dioxocyclopentyl, morpholinyl, tetrahydrofuranyl, furanyl, and oxazolyl.
  • the compound represented by the above formula (I) or a pharmaceutically acceptable salt is selected from
  • n is selected from 0, 1, 2 and 3;
  • R 1 is selected from H, halogen, OH, NH 2 and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2 or 3 R a;
  • R a is selected from F, Cl, Br, I, OH, NH 2 and CN;
  • Ring A is selected from 5- to 6-membered heteroaryl, phenyl, C 4-6 cycloalkyl, and 4- to 7-membered heterocycloalkyl;
  • the 5- to 6-membered heteroaryl group and 4- to 7-membered heterocycloalkyl group respectively include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N. .
  • the aforementioned R a are each independently selected from H, F, Cl, Br, I, OH, NH 2 , Me, Et, Wherein, Me, Et, It is optionally substituted by 1, 2 or 3 R, other variables are as defined in the present invention.
  • R a are each independently selected from H, F, Cl, Br, I, OH, NH 2 , Other variables are as defined in the present invention.
  • R 1 is independently selected from H, F, Cl, Br, I, OH, NH 2 , Me, C 1-6 alkoxy, and Wherein Me, C 1-6 alkoxy and Optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally 1, 2, or 3 R a , other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 and Me, wherein Me is optionally substituted with 1, 2 or 3 R a, of the present invention other variables are as As defined.
  • R 1 is selected from H and Me, and other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a , other variables are as defined in the present invention.
  • R 1 is selected from F, Cl, Br, I, OH, NH 2 and Me, wherein Me is optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • R 1 is selected from H, Me, Other variables are as defined in the present invention.
  • R 1 is selected from Me, and other variables are defined by the present invention.
  • Heteroatoms or heteroatoms independently selected from -NH-, -O-, -S- and N.
  • the ring A is selected from phenyl, 1,3-dioxocyclopentyl, morpholinyl, tetrahydrofuryl, 2,3-dihydrofuryl, furyl, pyrazolyl, Thiazolyl, 4,5-dihydrothiazolyl, oxazolyl, 2,3-dihydrooxazolyl, pyridyl, and 2,3-dihydropyridyl, other variables are as defined in the present invention.
  • the ring A is selected from phenyl, 1,3-dioxocyclopentyl, morpholinyl, oxazolyl, cyclobutyl, oxetanyl, and 1,4-oxo.
  • Azetyl, other variables are as defined in the present invention.
  • the ring A is selected from phenyl, 1,3-dioxocyclopentyl, morpholinyl, and oxazolyl.
  • Other variables are defined by the present invention, and other variables are defined by the present invention .
  • the ring A is selected from phenyl, 1,3-dioxocyclopentyl, morpholinyl, tetrahydrofuryl, furyl and oxazolyl, and other variables are as defined in the present invention.
  • the ring A is selected from the group consisting of phenyl, 1,3-dioxocyclopentyl, morpholinyl, oxazolyl, cyclobutyl, oxethanyl, thienyl, and tetrahydro Thienyl, furyl, tetrahydrofuranyl and 1,4-oxazepine, other variables are as defined in the present invention.
  • the ring A is selected from phenyl, 1,3-dioxocyclopentyl, morpholinyl, tetrahydrofuranyl, and oxazolyl, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • n, R 1 and ring A are as defined in the present invention.
  • the present invention also has some solutions from any combination of the above variables.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof
  • the above compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases related to the CRBN protein.
  • the invention also provides the application of the above composition in the preparation of a medicament for treating diseases related to CRBN protein.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound 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 a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds 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, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, 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 functional groups
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomeric or diastereomeric enriched mixtures, all of which belong to the present invention 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.
  • enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
  • diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
  • wedge solid line key And wedge dashed keys Represents the absolute configuration of a solid center, using straight solid line keys And straight dashed keys
  • the relative configuration of the solid center Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dashed keys
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include recombination of some bonding electrons for mutual conversion.
  • a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content 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, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the 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 enantiomeric 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 an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography that employs a chiral stationary phase and optionally is combined with chemical derivatization (such as the generation of amino groups from amines) Formate).
  • the compounds of the invention may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • compounds such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C) can be labeled with radioisotopes.
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have reduced side effects and increased drug stability. , Enhance efficacy, extend the biological half-life of drugs and other advantages. Transformations 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” refers to events or conditions described later that may, but need not, occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, 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.
  • O oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • 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 such as R
  • its definition in each case is independent.
  • the group may be optionally substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants 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- , the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist.
  • X in A-X indicates that the structure is actually A.
  • substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings. The carbon atom is attached to a substituted group.
  • the number of atoms on a ring is generally defined as the number of rings, for example, a "5-7 member ring” refers to a “ring” arranged around 5-7 atoms.
  • C 1-10 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 10 carbon atoms.
  • the C 1-10 alkyl group includes C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 8 , C 7 , C 6 and C 5 alkyl and the like; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-10 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), hexyl, heptyl, octyl and the like.
  • C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl 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, etc .; it may Is monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 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), hexyl and the like.
  • C 1-3 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and the like; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine).
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-10 alkoxy refers to those alkyl groups containing 1 to 10 carbon atoms that are connected to the rest of the molecule through one oxygen atom.
  • the C 1-10 alkoxy group includes C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-5 , 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 and the like.
  • C 1-10 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutyl (Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through one 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, isobutyl (Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, 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 1-10 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 1-10 alkoxy groups including C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-5 , C 1-4 , C 1- 3 , C 1-2 , C 2-6 , C 2- 4 , C 6 , C 5 , C 4 and C 2 alkylamino.
  • 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 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 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 the like.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom by itself or as part of another substituent.
  • C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic and bicyclic system, wherein the bicyclic system includes a spiro ring, a cyclic ring and Bridged ring, the C 4-6 cycloalkyl includes C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent, or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "5- to 10-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 5 to 10 ring atoms, which has 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, parallel, and bridge rings.
  • the 5-10 membered heterocycloalkyl includes 5-8 members, 5-6 members, 5-7 members, 5-9 members, 4 members, 5 members, 6 members, and the like.
  • Examples of 5- to 10-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithiaalkyl, isoxazolidinyl, isothiazolyl Alkyl, 1,2-oxazinyl, 1,2-thiazinyl
  • the term "5- to 8-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 5 to 8 ring atoms, which has 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 5-8 membered heterocycloalkyl includes 5-6 members, 5-6 members, 5-7 members, 8 members, 5 members, 6 members, and the like.
  • 3- to 8-membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithiaalkyl, isoxazolidinyl, isothiazolyl Alkyl, 1,2-oxazinyl, 1,2-thiazinyl
  • C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic and bicyclic system.
  • the C 4-6 cycloalkyl includes C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent, or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "4- to 7-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 4 to 7 ring atoms, 1, 2, 3 or 4 ring atoms of which Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
  • the 4-7 membered heterocycloalkyl includes 4-5 members, 4-6 members, 5-6 members, 5-7 members, 4 members, 5 members, 6 members, and the like.
  • 4- to 7-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolyl
  • the term "4- to 7-membered heterocycloalkenyl" itself or in combination with other terms, respectively, means a partially unsaturated cyclic group consisting of 4 to 7 ring atoms containing at least one carbon-carbon double bond 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S (O) p , p is 1 or 2).
  • the heteroatom may occupy the connection position of the heterocycloalkenyl group with the rest of the molecule.
  • the 4-7 membered heterocyclenyl includes 5-6 membered, 4-5 membered, 4-membered, 5-membered and 6-membered heterocyclic alkenyl, and the like. Examples of 4-7 membered heterocyclenyl include, but are not limited to
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl group” in the present invention are used interchangeably, and the term “5-6 membered heteroaryl group” means from 5 to 6 ring atoms A single-ring group consisting of a conjugated ⁇ -electron system.
  • One, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • the 5- to 6-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryl.
  • Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyryl) Oxazolyl, 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-triazo
  • 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 , and also include 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.
  • n yuan to n + m means that the number of atoms on the ring is n to n + m.
  • 3-12-membered rings include 3-, 4-, 5-, 6-, 7-, 8-, and 9-membered rings.
  • 10-membered ring, 11-membered ring, and 12-membered ring including any range from n to n + m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring Ring, 5-7 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonic acid. Esters, etc .; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto 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) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of a 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 (such as acetyl); aryl methyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and more.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • aryl methyl groups such as benzyl (Bn), p-formyl Oxybenzyl
  • 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 familiar to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • aq stands for water
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • m-CPBA stands for 3-chloroperoxybenzoic acid
  • eq stands for equivalent, equivalent
  • CDI stands for Carbonyl diimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF stands for N, N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • EtOAc stands for ethyl acetate EtOH for ethanol; MeOH for methanol
  • CBz benzyl
  • the WB test showed that the intracellular IKZF3 protein level was significantly decreased; the lymphoma cell lines OCI-LY10, DOHH2 and Mino showed excellent Inhibition of cell proliferation.
  • the compounds of the invention have higher oral plasma systemic exposures. In rodent mice, the compounds of the invention have superior pharmacokinetic properties.
  • the compound of the present invention exhibits significant tumor shrinking effect in human lymphoma OCI-LY10 in vivo pharmacodynamic model.
  • Figure 1 shows the changes of IKZF3 protein levels detected by WB after treatment of multiple myeloma cells MM.1S with compounds of the present invention at concentrations of 100 nM, 500 nM, and 50 nM.
  • N-butyllithium (2M, 27.23mL, 2.5M in n-hexane) was added dropwise to a solution of WX001-1 (10.16g, 64.22mmol) in tetrahydrofuran (100mL) under the protection of –78 °C and nitrogen, After the reaction mixture was stirred at 20 ° C for 1 hour, the temperature was lowered to -78 ° C, 1,2-dichloroethane (13.27g, 70.65mmol, 28.01mL) was added, and the reaction mixture was stirred at 20 ° C for 14 hours.
  • the intermediate WX001–3 (20.67 g, 92.66 mmol) was dissolved in acetonitrile (250 mL) under nitrogen at 20 ° C, followed by potassium carbonate (25.61 g, 185.33 mmol) and ethyl 4-bromocrotonate (35.78 g). , 185.33 mmol, 25.55 mL), and the reaction mixture was stirred at 20 ° C. for 16 hours. After completion of the reaction, water (300 mL) was added and the mixture was extracted with ethyl acetate (200 mL ⁇ 3).
  • the intermediate WX001-5 (5.24 g, 20.61 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by potassium tert-butoxide (2.31 g, 20.61 mmol), After stirring at 0 ° C for 0.5 hours, acrylamide (1.46 g, 20.61 mmol) was added, and the reaction mixture was stirred at 0 ° C for 1 hour under nitrogen protection. After completion of the reaction, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • the intermediate WX001-2 (0.485 g, 2.20 mmol) was dissolved in a dichloromethane solution (10 mL), and triethylamine (667.26 mg, 6.59 mmol, 917.82 ⁇ L) was added.
  • the reaction mixture was raised under nitrogen protection.
  • the reaction was allowed to reach room temperature and was stirred for 2 hours.
  • water 50 mL was added and the mixture was extracted with dichloromethane (30 mL ⁇ 3).
  • the organic phases were combined, washed with water (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the intermediate WX001-3 (0.332 g, 1.80 mmol) was dissolved in toluene (20 mL), and then ethyl (triphenylphosphine) acetate (753.53 mg, 2.16 mmol) was added and reacted under the protection of nitrogen.
  • the intermediate WX001-4 (0.185 g, 727.54 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), followed by potassium tert-butoxide (81.64 mg, 727.54 ⁇ mol) and acrylamide, respectively. (103.42 mg, 1.46 mmol), the reaction mixture was stirred at 0 ° C for 1.5 hours under the protection of nitrogen. After completion of the reaction, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • the intermediate WX002-2 (0.460 g, 2.14 mmol) was dissolved in a dichloromethane solution (10 mL), and then triethylamine (650.70 mg, 6.43 mmol, 895.05 ⁇ L) was added, and the reaction mixture was protected under nitrogen. The temperature was raised to room temperature and the reaction was stirred for 2 hours. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the intermediate WX003-2 (0.135 g, 543.85 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), followed by potassium tert-butoxide (61.03 mg, 543.85 ⁇ mol), and then propylene was added. Amide (77.31 mg, 1.09 mmol). The reaction mixture was stirred at 0 ° C for 1.5 hours under a nitrogen atmosphere. After completion of the reaction, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • WX003-1 (5.01g, 36.00mmol) was dissolved in N, N-dimethylformamide (80mL) at room temperature, followed by potassium carbonate (14.93g, 108.01mmol) and 1,2-dibromoethane (8.12 g, 43.20 mmol, 3.26 mL), the reaction mixture was heated to 125 ° C and the reaction was stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added, and extraction was performed with ethyl acetate (100 mL ⁇ 3).
  • the intermediate WX003-2 (1.89 g, 11.44 mmol) was dissolved in acetonitrile (40 mL), and potassium carbonate (4.74 g, 34.32 mmol) and benzyl bromide (2.15 g, 12.59 mmol, 1.49 mL), the reaction mixture was heated to 50 ° C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added, and extraction was performed with ethyl acetate (100 mL ⁇ 3).
  • the intermediate WX003-4 (1.11 g, 4.18 mmol, purity: 90.76%) was dissolved in N, N-dimethylformamide (10 mL) under 0 ° C and nitrogen protection, and potassium carbonate (1.15 g, 8.35 mmol), and the reaction was stirred at 0 ° C. for 0.5 hours.
  • Ethyl bromoacetate (697.28 mg, 4.18 mmol, 461.77 ⁇ L) was added.
  • the reaction mixture was warmed to room temperature and the reaction was continued for 12 hours. After completion of the reaction, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL ⁇ 3).
  • the intermediate WX003-5 (1.35 g, 4.01 mmol, purity: 97.23%) was dissolved in tetrahydrofuran (8 mL), ethanol (4 mL), and water (2 mL) at room temperature and under the protection of nitrogen, followed by the addition of sodium hydroxide (160.38 mg , 4.01 mmol), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, tetrahydrofuran and ethanol were removed under reduced pressure. The resulting residue was added with water (50 mL), the pH was adjusted to 2-3 with a 2M dilute aqueous hydrochloric acid solution, and ethyl acetate (30 mL x 3) was extracted.
  • the intermediate WX003-6 (1.01 g, 3.25 mmol, purity: 96.43%) was dissolved in acetonitrile (10 mL), and N, N'-carbonyldiimidazole ( 527.61 mg, 3.25 mmol) and triethylamine (329.26 mg, 3.25 mmol, 452.90 ⁇ L), the reaction mixture was warmed to room temperature and the reaction was stirred for 2 hours.
  • the reaction mixture of the second reaction flask was added dropwise to the first reaction flask under the protection of nitrogen at 0 ° C, and the reaction mixture was warmed to room temperature and the reaction was stirred for 10 hours.
  • the intermediate WX003-8 (0.110 g, 313.04 ⁇ mol) was dissolved in a solution of tetrahydrofuran (1 mL), and wet palladium carbon (30 mg, purity: 10%) was added.
  • the reaction mixture was evacuated and replaced with hydrogen.
  • the reaction mixture was stirred at room temperature under a hydrogen (15 psi) atmosphere for 0.5 hours.
  • the reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure.
  • the intermediate WX003-9 (78 mg, 298.54 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), followed by potassium tert-butoxide (33.50 mg, 298.54 ⁇ mol). And acrylamide (42.44 mg, 597.08 ⁇ mol), the reaction mixture was stirred at 0 ° C. for 2 hours under nitrogen protection. After completion of the reaction, water (50 mL) was added and the mixture was extracted with ethyl acetate (30 mL ⁇ 3).
  • the intermediate WX004-3 (7.87 g, 32.38 mmol) was dissolved in toluene (100 mL), and then ethyl (triphenylphosphine) acetate (16.92 g, 48.57 mmol) was added, and the reaction mixture was heated to 130 The reaction was stirred at 40C for 40 hours. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The obtained residue was slurried with methyl tert-butyl ether (100 mL), filtered, and the solvent was removed from the filtrate under reduced pressure.
  • the intermediate WX004-7 (300 mg, 717.87 ⁇ mol, purity: 65.63%) was dissolved in dichloromethane (10 mL), and after cooling to 0 ° C, boron tribromide (5.20 g, 20.76 mmol, 2 mL) was added. The reaction mixture was naturally warmed to room temperature and stirred for 3 hours. After the reaction, the reaction solution was poured into ice water (50 mL), diluted with ethyl acetate (20 mL), and the organic phase was removed after separation. The aqueous phase was adjusted to pH 6-7 with saturated sodium bicarbonate solution. (20 mL ⁇ 3) extraction.
  • the intermediate WX004-8 (80 mg, 307.40 ⁇ mol) was dissolved in N, N-dimethylformamide (5 mL) at room temperature and under the protection of nitrogen. ⁇ L) and zirconium tetrachloride (7.16 mg, 30.74 ⁇ mol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) and ethyl acetate (20 mL) were added to dilute, the organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure.
  • WX006-1 (15.00g, 73.88mmol) and 1,2-dibromoethane (41.64g, 221.64mmol, 16.72mL) were dissolved in N, N-dimethylformamide (150mL) at room temperature under nitrogen protection. ), Potassium carbonate (20.42 g, 147.76 mmol) was then added, and the reaction mixture was heated to 50 ° C and the reaction was stirred at 50 ° C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was poured into water (300 mL), and extracted with ethyl acetate (200 mL ⁇ 3).
  • the intermediate WX006-3 (2.63 g, 16.39 mmol, purity: 93.61%) was dissolved in dichloromethane (30 mL) at -78 ° C and nitrogen, and boron tribromide (12.32 g, 49.18 mmol, 4.74) was dissolved.
  • the intermediate WX006-4 (1.72 g, 12.63 mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by potassium carbonate (3.49 g, 25.27 mmol), and The reaction was stirred at 0 ° C for 0.5 hours, and then ethyl bromoacetate (2.11 g, 12.63 mmol, 1.40 mL) was added. The reaction mixture was warmed to room temperature and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was added with water (30 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX006-6 (1.28 g, 6.52 mmol, purity: 98.88%) was dissolved in acetonitrile (5 mL), and then N, N-carbonyldiimidazole ( 1.06 g, 6.52 mmol) and triethylamine (659.54 mg, 6.52 mmol, 907.21 ⁇ L), the reaction mixture was warmed to room temperature and the reaction was stirred at room temperature for 2 hours. Finally, the reaction mixture in the second reaction flask was added dropwise to the first reaction flask at 0 ° C. under the protection of nitrogen, and the reaction mixture was warmed to room temperature and the reaction was stirred at room temperature for 10 hours.
  • the intermediate WX006-8 (0.670 g, 2.67 mmol, purity: 98.12%) was dissolved in N, N-dimethylformamide (10 mL), and potassium tert-butoxide (299.55 mg) was added. , 2.67 mmol), then acrylamide (189.75 mg, 2.67 mmol) was added, and the reaction mixture was stirred at 0 ° C for 1 hour under nitrogen protection. After the reaction was completed, the reaction mixture was quenched by adding water (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • MS--ESI m / z 165.0 [M + H] + .
  • the intermediate WX007-3 (5.00 g, 28.86 mmol, purity: 94.77%) was dissolved in dimethylacetamide (3 mL) and water (0.5 mL), and palladium chloride (102.35 mg, 577.16 ⁇ mol) was added. ) And sodium acetate (4.73 g, 57.72 mmol), the reaction mixture was evacuated and replaced with oxygen several times. The reaction mixture was stirred at 25 ° C. for 1 hour under the protection of oxygen (15 psi). Three batches are combined. After the reaction was completed, the reaction mixture was added with water (200 mL), and extracted with ethyl acetate (100 mL ⁇ 3).
  • the intermediate WX007-4 (4.22 g, 25.42 mmol, purity: 97.69%) was dissolved in dichloromethane (40 mL), and boron tribromide (19.10 g, 76.26 mmol, 7.35 was slowly added. mL) of dichloromethane (10 mL), the reaction mixture was warmed to 25 ° C and the reaction was stirred at 25 ° C for 5 hours. After the reaction was completed, the reaction mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL ⁇ 3).
  • the intermediate WX007-5 (3.08 g, 20.48 mmol, purity: 98.53%) was dissolved in N, N-dimethylformamide (30 mL), and potassium carbonate (5.66 g, 40.97 mmol) was added to react. The mixture was stirred at 0 ° C for 0.5 hours, and ethyl 2-bromoacetate (3.42 g, 20.48 mmol, 2.27 mL) was added. The reaction mixture was stirred at 25 ° C for 12 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was added with water (100 mL), and extracted with ethyl acetate (50 mL ⁇ 3).
  • the intermediate WX007-6 (2.10 g, 8.67 mmol, purity: 96.74%) was dissolved in tetrahydrofuran (20 mL), ethanol (10 mL) and water (5 mL), and sodium hydroxide (346.91 mg, 8.67 mmol), and the reaction mixture was stirred at 25 ° C. for 12 hours. Tetrahydrofuran and ethanol were removed under reduced pressure from the reaction mixture, and water (100 mL) was added to the reaction mixture. The reaction mixture was added with 2M dilute hydrochloric acid (10 mL) to adjust the pH to 2-3, and extracted with ethyl acetate (50 mL ⁇ 3).
  • potassium monoethyl malonate (3.29 g, 19.31 mmol) was dissolved in acetonitrile (20 mL), and triethylamine (3.14 g, 31.06 mmol, 4.32 mL) and magnesium chloride (2.16 g, 22.66 mmol, 930.14 ⁇ L) was added to the above reaction solution, and the reaction mixture was raised to 25 ° C. and the reaction was stirred at 25 ° C. for 2 hours.
  • the intermediate WX007-7 (1.77 g, 8.39 mmol, purity: 97.79%) was dissolved in acetonitrile (10 mL), and N, N-carbonyldiimidazole (1.36 g, 8.39 mmol) and three Ethylamine (849.43 mg, 8.39 mmol, 1.17 mL), the reaction mixture was raised to 25 ° C and the reaction was stirred at 25 ° C for 2 hours. The reaction mixture was added dropwise to the above solution at 0 ° C under the protection of nitrogen, the reaction mixture was raised to 25 ° C and the reaction was stirred at 25 ° C for 10 hours.
  • the intermediate WX007-8 (0.821 g, 2.44 mmol, purity: 82.04%) was dissolved in toluene (10 mL), polyphosphoric acid (0.300 g) was added, and the reaction mixture was heated to 110 ° C and 110 ° C. The reaction was stirred at for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the compound WX004-1 (10.00g, 49.25mmol) was dissolved in N, N-dimethylformamide (100mL), and sodium hydrogen (2.17g, 54.18mmol, purity: 60%), and finally bromoacetaldehyde diethanol (12.62 g, 64.03 mmol, 9.63 mL) was added, and the reaction mixture was heated to 110 ° C. and stirred for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water (300 mL) was added to the reaction solution, followed by extraction with methyl tert-butyl ether (100 mL ⁇ 3).
  • the intermediate WX008-2 (2.8g, 12.33mmol) was dissolved in dichloromethane (80mL), and the temperature was lowered to -60 ° C. Boron tribromide (3.71g, 14.80mmol, 1.43mL) was added dropwise ), The reaction mixture was slowly restored to 10 ° C and the reaction was stirred for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (20 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the intermediate WX008-3 (1.45 g, 6.81 mmol) was dissolved in acetonitrile (20 mL), and then potassium carbonate (2.82 g, 20.42 mmol) and ethyl 4-bromocrotonate (2.23 g, 11.57) were added in this order. mmol, 1.60 mL), and the reaction mixture was stirred at 20 ° C. for 12 hours. After completion of the reaction, the reaction solution was directly filtered, and the filter cake was washed with ethyl acetate (20 mL ⁇ 2). The filtrate was collected, and the solvent was removed by concentration under reduced pressure.
  • the intermediate WX008-4 (1.3 g, 4.00 mmol) was dissolved in N, N-dimethylformamide (30 mL) at room temperature and under the protection of nitrogen, and then sodium carbonate (1.06 g, 10.00 mmol) and sodium formate ( 271.91mg, 4.00mmol, 215.80 ⁇ L), palladium acetate (44.88mg, 199.91 ⁇ mol), tetrabutylammonium chloride hydrate (1.22g, 4.40mmol, 1.23mL), the reaction mixture was warmed to 80 ° C and stirred for 8 hours .
  • the intermediate WX008-5 400 mg, 1.64 mmol was dissolved in N, N-dimethylformamide (10 mL), and then acrylamide (116.41 mg, 1.64 mmol) and potassium tert-butoxide ( 183.77 mg, 1.64 mmol), and the reaction mixture was stirred at 20 ° C for 1 hour. After completion of the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the compound WX009-1 (10 g, 44.04 mmol) was dissolved in ethyl acetate (100 mL), and then trimethyloxonium tetrafluoroborate (7.82 g, 52.85 mmol) was added, and the reaction mixture was stirred at room temperature for reaction 12 hour. After completion of the reaction, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the intermediate WX009-2 (6.7g, 27.79mmol) was dissolved in dichloromethane (100mL), cooled to –60 °C ––50 °C, and then boron tribromide (10.44g, 41.69 mmol, 4.02 mL), the reaction mixture was warmed to 20 ° C and the reaction was stirred for 3 hours. After completion of the reaction, the reaction solution was poured into ice water (200 mL), and extracted with ethyl acetate (200 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the intermediate WX009-3 (2.5 g, 11.01 mmol) was dissolved in acetonitrile (30 mL) at room temperature under the protection of nitrogen, and then potassium carbonate (4.57 g, 33.03 mmol) and ethyl 4-bromocrotonate (3.19 g) were sequentially added. , 16.52 mmol, 2.28 mL), the reaction mixture was stirred at room temperature for 12 hours, and then the reaction mixture was heated to 50 ° C. and stirred for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water (200 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL ⁇ 3).
  • the intermediate WX009-5 (600 mg, 2.32 mmol) was dissolved in tetrahydrofuran (20 mL), and then a solution of acrylamide (165.12 mg, 2.32 mmol) and potassium tert-butoxide (1M, 2.32 mL) in tetrahydrofuran was added in order.
  • the reaction mixture was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the intermediate WX010-3 (20 g, 97.00 mmol) was dissolved in ethanol (200 mL), and then concentrated sulfuric acid (5.52 g, 55.16 mmol, 3 mL, purity: 98%) was added.
  • the reaction mixture was heated to 80 ° C and stirred The reaction took 4 hours.
  • the mixture was cooled to room temperature, and concentrated to remove ethanol under reduced pressure.
  • the obtained residue was diluted with water (200 mL) and ethyl acetate (200 mL).
  • the organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3). .
  • the intermediate WX010-4 (14.2g, 60.62mmol) was dissolved in dichloromethane (200mL). After cooling to -60 ° C, boron tribromide (22.78g, 90.93mmol, 8.76) was added dropwise. mL), the reaction mixture was returned to 20 ° C and the reaction was stirred for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (500 mL), and extracted with dichloromethane (200 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • the intermediate WX010-6 (2 g, 5.95 mmol) was dissolved in toluene (50 mL) at room temperature under the protection of nitrogen, and then polyphosphoric acid (3 g) was added. The reaction mixture was heated to 100 ° C. and stirred for 15 minutes. After completion of the reaction, the reaction solution was poured directly and the supernatant was collected, and the solvent was removed by concentration under reduced pressure.
  • the intermediate WX010-7 500 mg, 2.05 mmol was dissolved in N, N-dimethylformamide (10 mL), and then acrylamide (145.51 mg, 2.05 mmol) and potassium tert-butoxide (229.71) were added in this order. mg, 2.05 mmol), and the reaction mixture was stirred at room temperature for hours. After completion of the reaction, water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX011-2 (12.6 g, 52.92 mmol) was dissolved in dichloromethane (1500 mL) at room temperature and under nitrogen protection, cooled to -20 ° C, boron tribromide (66.29 g, 264.62 mmol) was added, and the reaction mixture The reaction was stirred at -20 ° C for 1 hour. The reaction mixture was then stirred at 20 ° C for 12 hours. Additional boron tribromide (13.5 g) was added at 20 ° C, and the reaction mixture was stirred at 20 ° C for 12 hours. Additional boron tribromide (13.5 g) was added at 0 ° C, and the reaction mixture was stirred at room temperature for 12 hours.
  • reaction solution was poured into ice water (2000 mL), filtered, and the filter cake was dissolved in water (4000 mL).
  • the pH was adjusted to 8-9 with a saturated sodium bicarbonate solution, and then 2-methyltetrahydrofuran (1500 mL) was used. ⁇ 3) extraction.
  • the organic phases were combined, washed successively with saturated brine (200 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent.
  • the obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl) to obtain intermediate WX011-3.
  • the intermediate WX011-3 (2.22 g, 9.91 mmol) was dissolved in acetonitrile (50 mL) under nitrogen at 20 ° C, followed by potassium carbonate (6.85 g, 49.54 mmol) and ethyl 4-bromocrotonate (2.42 g). , 9.41 mmol), the reaction mixture was stirred at 20 ° C. for 12 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), diluted with ethyl acetate (80 mL), and the organic phase was collected by liquid separation. The aqueous phase was extracted with ethyl acetate (80 mL ⁇ 3).
  • the intermediate WX011-5 (120 mg, 470.09 ⁇ mol) was dissolved in N, N-dimethylformamide (2 mL), followed by acrylamide (33.41 mg, 470.09 ⁇ mol) and tert-butyl. Potassium alkoxide (79.13 mg, 705.14 ⁇ mol), the reaction mixture was stirred at 20 ° C. for 2 hours. After the reaction, 2N dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 6-7, and the obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; alkaline system: 10mM NH 4 HCO 3 ) to obtain the target compound. WX011.
  • the intermediate WX012-3 (2.9 g, 5.63 mmol) was dissolved in N, N-dimethylformamide (90 mL), followed by sodium formate (585.75 mg, 5.63 mmol), and sodium carbonate (1.49 g). , 14.08 mmol), benzyltriethylammonium chloride (1.41 g, 6.19 mmol) and palladium acetate (63.20 mg, 281.51 ⁇ mol), and the reaction mixture was stirred at 20 ° C. for 3 hours. After completion of the reaction, the reaction solution was poured into ice water (300 mL), and extracted with ethyl acetate (400 mL ⁇ 3).
  • the intermediate WX013-2 (5 g, 20.74 mmol) was dissolved in dichloromethane (100 mL) at room temperature under the protection of nitrogen, and boron tribromide (15.59 g, 62.22 mmol, 6.00 mL) was slowly added dropwise to the above reaction solution. The reaction mixture was stirred at 20 ° C for 12 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the intermediate WX013-4 (0.9 g, 2.23 mmol), palladium acetate (50.04 mg, 222.89 ⁇ mol), tetrabutylammonium chloride (743.33 mg, 2.67 mmol), sodium formate (151.58 mg, 2.23) mmol), sodium carbonate (590.60 mg, 5.57 mmol) was dissolved in N, N-dimethylformamide (50 mL), and the reaction mixture was heated to 80 ° C. and stirred for 2 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL).
  • the intermediate WX013-5 (0.3 g, 1.03 mmol) was dissolved in N, N-dimethylformamide (10 mL) under 0-5 ° C and nitrogen protection, and potassium tert-butoxide (116.00 mg, 1.03 mmol) was sequentially added. ), Acrylamide (73.48 mg, 1.03 mmol), and the reaction mixture was stirred at 0-5 ° C. for 1 hour. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL).
  • the intermediate WX014-1 (0.13 g, 539.23 ⁇ mol) was dissolved in toluene (10 mL), aluminum trichloride (143.80 mg, 1.08 mmol) was added, and the reaction mixture was heated to 110 ° C. and stirred for reaction 12 hour. After completion of the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the intermediate WX014-2 (0.09 g, 396.38 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (109.56 mg, 792.75 ⁇ mol) was added, and 4-bromocroton Acid ethyl ester (114.77 mg, 594.56 ⁇ mol, 81.98 ⁇ L), the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL).
  • the intermediate WX014-3 (0.095 g, 280.08 ⁇ mol), palladium acetate (6.29 mg, 28.01 ⁇ mol), tetrabutylammonium chloride (93.41 mg, 336.10 ⁇ mol), sodium formate (19.05 mg, 280.08) ⁇ mol), sodium carbonate (74.22 mg, 700.21 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), and the reaction mixture was heated to 80 ° C. and stirred for 2 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL).
  • the intermediate WX014-4 (0.07 g, 271.03 ⁇ mol) was dissolved in N, N-dimethylformamide (10 mL), potassium tert-butoxide (30.41 mg, 271.03 ⁇ mol) was added, and acrylamide ( 19.26 mg, 271.03 ⁇ mol), and the reaction mixture was stirred at 0-5 ° C. for 1 hour. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was separated, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate.
  • the intermediate WX015-2 (50 g, 187.18 mmol,) was dissolved in dichloromethane (1000 mL) at room temperature and under the protection of nitrogen, and the reaction mixture was cooled to -78 ° C.
  • Boron tribromide (187.57 g, 748.73 mmol, 72.14 mL ) was slowly added dropwise to the reaction solution, and the reaction mixture was stirred at 20 ° C. for 12 hours.
  • the intermediate WX015-4 (20 g, 50.68 mmol), palladium acetate (3.41 g, 15.21 mmol), tetrabutylammonium chloride (14.09 g, 50.68 mmol), sodium formate (10.34 g, 152.05 mmol) ), Sodium carbonate (16.12 g, 152.05 mmol) was dissolved in N, N-dimethylformamide (500 mL), and the reaction mixture was heated to 80 ° C. and stirred for 5 hours. After completion of the reaction, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL).
  • the intermediate WX016-1 (0.15 g, 393.22 ⁇ mol) was dissolved in N, N-dimethylformamide (30 mL) at room temperature under the protection of nitrogen, potassium tert-butoxide (66.19 mg, 589.83 ⁇ mol) was added, and propylene Amide (27.95 mg, 393.22 ⁇ mol), the reaction mixture was stirred at 0-5 ° C. for 2 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL).
  • the intermediate WX019-1 (360 mg, 1.01 mmol, purity: 92.40%) was dissolved in N, N-dimethylformamide (30 mL), and potassium tert-butoxide (113.67 mg, 1.01 mmol) and acrylamide (72.00 mg, 1.01 mmol), the reaction mixture was stirred at 0 ° C for 2 hours. After the reaction was completed, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX020-1 (101 mg, 299.36 ⁇ mol, purity: 99.09%) was dissolved in N, N-dimethylformamide (30 mL), and potassium tert-butoxide (33.59 mg, 299.36 ⁇ mol) and acrylamide (21.28 mg, 299.36 ⁇ mol), the reaction mixture was stirred at 0 ° C for 2 hours. After completion of the reaction, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • the intermediate WX021-1 (115 mg, 222.80 ⁇ mol, purity: 78.16%) was dissolved in N, N-dimethylformamide (30 mL), and potassium tert-butoxide (25.00 mg, 222.80 ⁇ mol) and acrylamide (15.84 mg, 222.80 ⁇ mol), the reaction mixture was stirred at 0 ° C. for 2 hours. After completion of the reaction, water (50 mL) was added to dilute, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • the intermediate WX022-2 (0.15 g, 421.49 ⁇ mol) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (52.02 mg, 463.63 ⁇ mol), Acrylamide (29.96 mg, 421.49 ⁇ mol) was further added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX023-1 (0.25g, 670.73umol) was dissolved in N, N-dimethylformamide (5mL), followed by potassium tert-butoxide (82.79mg, 737.80 ⁇ mol), Acrylamide (47.67 mg, 670.73 ⁇ mol) was further added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX024-1 (0.12 g, 308.52 ⁇ mol, purity: 98.58%) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (38.08 mg , 339.37 ⁇ mol), acrylamide (21.93 mg, 308.52 ⁇ mol) was added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX025-1 (124 mg, 316.99 ⁇ mol, purity: 97.00%) was dissolved in N, N-dimethylformamide (5 mL), and potassium tert-butoxide (35.57 mg) was then added. 316.99 ⁇ mol) and acrylamide (22.53 mg, 316.99 ⁇ mol), the reaction mixture was stirred for 1.5 hours under the protection of nitrogen at 0 ° C. After completion of the reaction, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL ⁇ 3).
  • the intermediate WX022-1 (150 mg, 394.58 ⁇ mol, purity: 99.23%) was dissolved in acetonitrile (10 mL), and 1-acetylpiperazine (50.57 mg, 394.58 ⁇ mol) and potassium carbonate (109.07 mg, 789.15 ⁇ mol), the reaction mixture was warmed to 80 ° C and the reaction was stirred at 80 ° C for 14 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (30 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL ⁇ 3).
  • the intermediate WX027-1 (72.04 mg, 183.50 ⁇ mol, purity: 97.17%) was dissolved in N, N-dimethylformamide (5 mL), and potassium tert-butoxide (22.65 mg) was then added. , 201.85 ⁇ mol), acrylamide (13.04 mg, 183.50 ⁇ mol) was further added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX028-1 (0.15 g, 360.13 ⁇ mol, purity: 98.32%) was dissolved in N, N-dimethylformamide (10 mL) under nitrogen protection at 25 ° C and cooled to 0 ° C with an ice water bath.
  • Acrylamide 25.60 mg, 360.13 ⁇ mol
  • potassium tert-butoxide 44.45 mg, 396.15 ⁇ mol
  • 2 mL of water was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (5 mL ⁇ 3).
  • the intermediate WX029-1 (0.28 g, 577.56 ⁇ mol, purity: 99.54%) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (71.29 mg (635.32 ⁇ mol), acrylamide (41.05 mg, 577.56 ⁇ mol) was added, and the reaction mixture was stirred at 0 ° C for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX030-2 (0.12 g, 337.62 ⁇ mol) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (41.67 mg, 371.38 ⁇ mol), Acrylamide (24.00 mg, 337.62 ⁇ mol) was further added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX031-1-1 (112 mg, 255.29 ⁇ mol) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (31.51 mg, 280.82 ⁇ mol), and then Acrylamide (18.15 mg, 255.29 ⁇ mol) was added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • the intermediate WX032-1 (0.09 g, 243.02 ⁇ mol, purity: 96.24%) was dissolved in N, N-dimethylformamide (5 mL), followed by potassium tert-butoxide (30.00 mg , 267.32 ⁇ mol), acrylamide (17.27 mg, 243.02 ⁇ mol) was added, and the reaction mixture was stirred at 0 ° C. for 1 hour. After the reaction was completed, water (30 mL) was added to dilute, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • WB method was used to study the regulation of IKZF3 protein in multiple myeloma cells MM.1S by target compounds under different concentration conditions.
  • MM.1S cells are seeded in a 6-well plate with 1 ⁇ 10 6 cells per well, and then treated with a certain concentration of the test intermediate;
  • the tumor cell line was cultured in a 37 ° C, 5% CO 2 incubator under the above-mentioned culture conditions. Passage at regular intervals and take cells in log phase for plating.
  • the culture plate is left at room temperature for 10 minutes to stabilize the luminescence signal.
  • IR (%) (RLU vehicle control-RLU compound) / (RLU vehicle control-RLU blank control) * 100%. Calculate different concentrations in Excel inhibition rate of the compound, and then using GraphPad Prism software for inhibition curves and calculate relevant parameters, including the minimum inhibitory rate, the maximum inhibition rate and IC 50.
  • the compounds of the present invention exhibit excellent inhibitory effects on cell proliferation in the lymphoma cell lines OCI-LY10, DOHH2 and Mino.
  • mice C57BL male mice were selected as the test animals.
  • the LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of the test compound and the reference compound administered at different time points in the mouse to evaluate the test drug's effect in the mouse. Pharmacokinetic characteristics.
  • C57Balb / c mice male, 20-30g, 7-10 weeks of age, Beijing Wetonglihua or Shanghai Slark).
  • mice were given a clear or suspension solution of the test compound by gavage (overnight fasting). Oral administration was performed by oral gavage at 0h (pre-dose) and 0.5,1,2,4,6,8,24h after the administration. Blood was collected from the jugular vein puncture and placed in an anticoagulation tube (Jiangsu Kangjian Medical) with EDTA-K2. Co., Ltd.), the mixture was vortexed and centrifuged at 13000 rpm for 10 minutes.
  • the experimental results show that the oral plasma systemic exposure (AUC 0-inf ) of the hydrochloride salt of WX015 and WX022 is higher. In rodent mice, the pharmacokinetic properties of the hydrochloride salts of WX015 and WX022 are superior.
  • Cell culture human lymphoma OCI–LY10 cells (National Cancer Institute) in vitro monolayer culture, the culture conditions are RPMI 1640 medium plus 10% fetal bovine serum, 100 U / mL penicillin and 100 ⁇ g / mL streptomycin, 37 ° C, 5% CO 2 incubator. Passage with trypsin-EDTA for routine digestion twice a week. When the cell saturation is 80% -90%, when the number reaches the requirements, the cells are collected, counted, and seeded.
  • TGI Tumor Growth Inhibition (tumor growth inhibition rate).
  • TGI (%) [1-(average tumor volume at the end of administration in a treatment group-average tumor volume at the administration of this treatment group) / (average tumor volume at the end of treatment in the solvent control group-average tumor at the start of treatment in the solvent control group Volume)] x 100%.
  • the compound WX001 of the present invention shows a significant tumor shrinking effect on the in vivo pharmacodynamic model of human lymphoma OCI-LY10.

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Abstract

本发明公开了一系列带有三环并呋喃取代哌啶二酮类化合物，及其在制备治疗与CRBN蛋白相关疾病药物中的应用，具体公开了式(I)所示衍生化合物或其药学上可接受的盐。

Description

三环并呋喃取代哌啶二酮类化合物
相关申请的引用
本申请主张如下优先权：
CN201811048512.X，申请日2018-09-07；
CN201811356415.7，申请日2018-11-14；
CN201910225326.7，申请日2019-03-22。
技术领域
本发明涉及一系列带有三环并呋喃取代哌啶二酮类化合物，及其在制备治疗与CRBN蛋白相关疾病药物中的应用，具体涉及式(I)所示衍生化合物或其药学上可接受的盐。
背景技术
沙利度胺，商品名为反应停，首先由德国格兰泰公司合成。20世纪五十年代后半期到六十年代初期间，在40多个国家作为镇静剂销售，也作为孕妇止吐药而广泛应用，最终酿成上万例海豹肢畸形(形态形成障碍)婴儿的惨剧而撤出市场。
自“反应停”事件后，沙利度胺致畸的作用机制引起了广大科研工作者的浓厚兴趣。已经证实蛋白Cereblon(CRBN)是沙利度胺致畸作用的靶蛋白。沙利度胺通过与CRBN、DNA损伤结合蛋白DDB1(Damaged DNA Binding Protein 1)、CUL4A(Cullin-4A)和Cullins 1调控子(ROC1)结合形成E3泛素连接酶复合物，将多种底物蛋白泛素化，形成泛素化链，从而使底物蛋白被蛋白酶体识别、水解。度胺类药物被称为免疫调节药物(Immunomodulatory Drugs，IMiDs)，激活与CRBN形成的E3泛素连接酶复合物对转录因子IKZF1与IKZF3的泛素化，然后被蛋白酶体识别与降解，从而对多发性骨髓瘤(Multiple Myeloma)产生毒性作用。这两种转录因子的缺失会终止骨髓瘤的增长。现在度胺类药物如来那度胺、泊马度胺是治疗多发性骨髓瘤的一线用药。
CRBN是从植物到人均保守的442个氨基酸的蛋白质，其位于人类3号染色体的p26.3短臂上，分子量为51kDa。在人类中，已将CRBN基因鉴别为常染色体隐性遗传非综合征轻型精神发育迟缓(ARNSMR)的候选基因。CRBN广泛地表达在睾丸、脾、前列腺、肝脏、胰腺、胎盘、肾脏、肺、骨骼肌、卵巢、小肠、外周血白细胞、结肠、脑部以及视网膜中，而在脑组织(包括视网膜)以及睾丸中的表达显著高于其他组织。
CRBN作为抗肿瘤和免疫调节剂药物的重要靶点，已被证实在多发性骨髓瘤、慢性淋巴细胞白血病等多种血液性恶性肿瘤、麻风结节性红斑等皮肤病、和系统性红斑狼疮等自免疫性疾病具有明确的疗效。度胺类药物都有较多副作用，尤其是周围神经病变。当前迫切需要开发无致畸作用、更少周围神经病变、更强免疫调节作用和更高抗肿瘤活性的CRBN调节剂药物，来提高临床治疗效果，降低临床副作用，利于患者的长期使用。
发明内容
本发明提供了式(Ⅰ)所示化合物或药学上可接受的盐，
Figure PCTCN2019104992-appb-000001
其中，
n选自0、1、2和3；
R 1选自分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氧基和
Figure PCTCN2019104992-appb-000002
其中所述C 1-6烷基、C 1-6烷氧基和
Figure PCTCN2019104992-appb-000003
任选被1、2或3个R a取代；
R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-10烷基、C 1-10烷氧基、C 1-10烷氨基、-NHC(＝O)-C 1-10烷基、5-10元杂环烷基、5-10元杂环烷基氨基和C 5-10环烷基氨基，其中所述C 1-10烷基、C 1-10烷氧基、C 1- 10烷氨基、-NHC(＝O)-C 1-10烷基、5-10元杂环烷基、5-10元杂环烷基氨基和C 5-10环烷基氨基任选被1、2或3个R取代；
R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、Me和
Figure PCTCN2019104992-appb-000004
环A选自5～6元杂芳基、苯基、C 4-6环烷基、4～7元杂环烷基和4～7元杂环烯基；
所述5～6元杂芳基、4～7元杂环烷基、5-10元杂环烷基和5-10元杂环烷基氨基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团
在本发明的一些方案中，上述式(Ⅰ)所示化合物或药学上可接受的盐选自
Figure PCTCN2019104992-appb-000005
其中，
n选自0、1、2和3；
R 1选自H、卤素、OH、NH 2和C 1-6烷基，其中C 1-6烷基任选被1、2或3个R a取代；
R a选自F、Cl、Br、I、OH、NH 2和CN；
环A选自5～6元杂芳基、苯基、C 4-6环烷基和4～7元杂环烷基；
所述5～6元杂芳基、4～7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。
6.根据权利要求5所述化合物或药学上可接受的盐，其中，环A选自苯基、1,3-二氧环戊烷基、吗啉基、四氢呋喃基、呋喃基和恶唑基。
在本发明的一些方案中，上述式(Ⅰ)所示化合物或药学上可接受的盐选自
Figure PCTCN2019104992-appb-000006
其中，
n选自0、1、2和3；
R 1选自H、卤素、OH、NH 2和C 1-6烷基，其中C 1-6烷基任选被1、2或3个R a取代；
R a选自F、Cl、Br、I、OH、NH 2和CN；
环A选自5～6元杂芳基、苯基、C 4-6环烷基和4～7元杂环烷基；
所述5～6元杂芳基、4～7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。
在本发明的一些方案中，上述R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-NHC(＝O)-C 1-6烷基、5-8元杂环烷基、5-8元杂环烷基氨基和C 5-8环烷基氨基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-NHC(＝O)-C 1-6烷基、5-8元杂环烷基、5-8元杂环烷基氨基和C 5-8环烷基氨基任选被1、2或3个R取代。
在本发明的一些方案中，上述R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、-NHC(＝O)-C 1-3烷基、哌啶基、哌嗪基、吗啉基、吡喃基、吡咯烷基、环己烷基氨基、四氢吡喃基氨基、哌啶基氨基、哌嗪基氨基和3-氮杂双环[3,1,0]己烷基，其中所述C 1-3烷基、C 1-6烷氧基、C 1- 6烷氨基、-NHC(＝O)-C 1-3烷基、哌啶基、哌嗪基、吗啉基、吡喃基、吡咯烷基、环己烷基氨基、四氢吡喃基氨基、哌啶基氨基、哌嗪基氨基和3-氮杂双环[3,1,0]己烷基任选被1、2或3个R取代。
在本发明的一些方案中，上述R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、Et、
Figure PCTCN2019104992-appb-000007
Figure PCTCN2019104992-appb-000008
Figure PCTCN2019104992-appb-000009
其中，所述Me、Et、
Figure PCTCN2019104992-appb-000010
Figure PCTCN2019104992-appb-000011
任选被1、2或3个R取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、
Figure PCTCN2019104992-appb-000012
Figure PCTCN2019104992-appb-000013
Figure PCTCN2019104992-appb-000014
其它变量如本发明所定义。
在本发明的一些方案中，上述R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、C 1-6烷氧基和
Figure PCTCN2019104992-appb-000015
其中所述Me、C 1-6烷氧基和
Figure PCTCN2019104992-appb-000016
任选被1、2或3个R a取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基，其中C 1-3烷基任选被1、2或3个R a取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2和Me，其中Me任选被1、2或3个R a取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H、Me，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自F、Cl、Br、I、OH、NH 2、C 1-3烷基，其中C 1-3烷基任选被1、2或3个R a取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自F、Cl、Br、I、OH、NH 2和Me，其中Me任选被1、2或3个R a取代，其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自H、Me、
Figure PCTCN2019104992-appb-000017
Figure PCTCN2019104992-appb-000018
Figure PCTCN2019104992-appb-000019
其它变量如本发明所定义。
在本发明的一些方案中，上述R 1选自Me，其它变量如本发明所定义。
个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基、四氢呋喃基、2,3-二氢呋喃基、呋喃基、吡唑基、噻唑基、4,5-二氢噻唑基、恶唑基、2,3-二氢恶唑基、吡啶基和2,3-二氢吡啶基，其它变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基、恶唑基、环丁基、氧杂环庚基和1,4-氧氮杂环庚基，其它变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基和恶唑基，其它变量如本发明所定义，其它变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基、四氢呋喃基、呋喃基和恶唑基，其它变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基、恶唑基、环丁基、氧杂环庚基、噻吩基、四氢噻吩基、呋喃基、四氢呋喃基和1,4-氧氮杂环庚基，其它变量如本发明所定义。
在本发明的一些方案中，上述环A选自苯基、1,3-二氧环戊烷基、吗啉基、四氢呋喃基和恶唑基，其它变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019104992-appb-000020
选自
Figure PCTCN2019104992-appb-000021
Figure PCTCN2019104992-appb-000022
Figure PCTCN2019104992-appb-000023
其它变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019104992-appb-000024
选自
Figure PCTCN2019104992-appb-000025
Figure PCTCN2019104992-appb-000026
和
Figure PCTCN2019104992-appb-000027
其它变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019104992-appb-000028
选自
Figure PCTCN2019104992-appb-000029
Figure PCTCN2019104992-appb-000030
其它变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019104992-appb-000031
选自
Figure PCTCN2019104992-appb-000032
Figure PCTCN2019104992-appb-000033
其它变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2019104992-appb-000034
选自
Figure PCTCN2019104992-appb-000035
Figure PCTCN2019104992-appb-000036
其它变量如本发明所定义。
本发明还有一些方案可由上述变量任意组合而来。在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2019104992-appb-000037
其中，n、R 1和环A如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。 本发明还提供下述化合物或其药学上可接受的盐
Figure PCTCN2019104992-appb-000038
Figure PCTCN2019104992-appb-000039
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2019104992-appb-000040
Figure PCTCN2019104992-appb-000041
Figure PCTCN2019104992-appb-000042
本发明还提供一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供上述化合物或其药学上可接受的盐在制备治疗与CRBN蛋白相关疾病药物中的应用。
本发明还提供上述组合物在制备治疗与CRBN蛋白相关疾病药物中的应用。
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“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 PCTCN2019104992-appb-000043
和楔形虚线键
Figure PCTCN2019104992-appb-000044
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019104992-appb-000045
和直形虚线键
Figure PCTCN2019104992-appb-000046
表示立体中心的相对构型，用波浪线
Figure PCTCN2019104992-appb-000047
表示楔形实线键
Figure PCTCN2019104992-appb-000048
或楔形虚线键
Figure PCTCN2019104992-appb-000049
或用波浪线
Figure PCTCN2019104992-appb-000050
表示直形实线键
Figure PCTCN2019104992-appb-000051
和直形虚线键
Figure PCTCN2019104992-appb-000052
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。
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，术语“C 1-10烷基”用于表示直链或支链的由1至10个碳原子组成的饱和碳氢基团。所述C 1-10烷基包括C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 8、C 7、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 1-10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、庚基、辛基等。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-10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10个碳原子的烷基基团。所述C 1-10烷氧基包括C 1-9、C 1-8、C 1-7、C 1-6、C 1-5、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 1-10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 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-10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 1-10烷氧基包括C 1-9、C 1-8、C 1-7、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2- 4、C 6、C 5、C 4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 1-6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“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。
除非另有规定，“C 4-6环烷基”表示由4至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，其中双环体系包括螺环、并环和桥环，所述C 4-6环烷基包括C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，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)。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“5-10元杂环烷基”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。所述5-10元杂环烷基包括5-8元、5-6元、5-7元、5-9元、4元、5元和6元杂环烷基等。5-10元杂环烷基的实例包括但不限于吡咯烷基、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、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“5-8元杂环烷基”本身或者与其他术语联合分别表示由5至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，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)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-8元杂环烷基”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。所述5-8元杂环烷基包括5-6元、5-6元、5-7元、8元、5元和6元杂环烷基等。3-8元杂环烷基的实例包括但不限于吡咯烷基、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、高哌啶基或二氧杂环庚烷基等。
除非另有规定，“C 4-6环烷基”表示由4至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 4-6环烷基包括C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丁基、环戊基、环己基等。
除非另有规定，术语“4-7元杂环烷基”本身或者与其他术语联合分别表示由4至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，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)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-7元杂环烷基”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。所述4-7元杂环烷基包括4-5元、4-6元、5-6元、5-7元、4元、5元和6元杂环烷基等。4-7元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、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“4-7元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由4至7个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，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)。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，此体系的任意环都是非芳香 性的。此外，就该“4-7元杂环烯基”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。所述4-7元杂环烯基包括5-6元、4-5元、4元、5元和6元杂环烯基等。4-7元杂环烯基的实例包括但不限于
Figure PCTCN2019104992-appb-000053
Figure PCTCN2019104992-appb-000054
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。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)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元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)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、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)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
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-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；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；M代表mol/L。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2019104992-appb-000055
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物在100nM或500nM和50nM浓度下处理多发性骨髓瘤细胞MM.1S后，WB检测显示细胞内IKZF3蛋白水平明显下降；在淋巴瘤细胞系OCI–LY10，DOHH2与Mino中均展现出优异细胞增殖的抑制作用。本发明化合物的口服血浆系统暴露量较高。在啮齿动物小鼠中，本发明化合物的药代动力学性质较优。本发明化合物在人淋巴瘤OCI–LY10体内药效模型展示了显著的缩瘤作用。
附图说明
图1为本发明化合物在100nM、500nM、50nM浓度下处理多发性骨髓瘤细胞MM.1S后，WB检测细胞内IKZF3蛋白水平的变化情况。
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。
实施例1：WX001
Figure PCTCN2019104992-appb-000056
步骤1：中间体WX001–2的合成
–78℃和氮气保护下，将正丁基锂(2.5M,27.23mL,2.5M溶于正己烷)逐滴滴加到WX001–1(10.16g,64.22mmol)的四氢呋喃(100mL)溶液中，反应混合物在20℃下搅拌1小时后，降温至–78℃，加入1,2–二氯乙烷(13.27g,70.65mmol,28.01mL)，反应混合液在20℃下搅拌反应14小时。反应完毕后，反应液用饱和氯化铵溶液(100mL)淬灭，用乙酸乙酯(100mL×3)萃取。合并有机相，用食盐水(200mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–100/1，体积比)，得到中间体WX001–2。 1H NMR(400MHz,CDCl 3)δ:8.08(s,1H),7.75–7.69(m,2H),7.50–7.46(m,1H),7.40–7.36(m,1H),7.17–7.15(m,1H),4.02(s,3H).
步骤2：中间体WX001–3的合成
–78℃和氮气保护下，将三溴化硼(63.43g,253.19mmol,24.40mL)逐滴滴加到中间体WX001–2(20.01g,84.40mmol)的二氯甲烷(120mL)溶液中，反应液缓慢升至20℃并在20℃下反应搅拌2小时。反应完毕后，将反应液缓慢滴加到冰水(400mL)中，用二氯甲烷(300mL×3)萃取。合并有机相，用食盐水(300mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–50/1，体积比)，得到中间体WX001–3。 1H NMR(400MHz,CDCl 3)δ:8.04(s,1H),7.70(d,J＝8.8Hz,2H),7.46(td,J＝1.0,7.4Hz,1H),7.40(s,1H),7.36(td,J＝1.2,7.6Hz,1H),5.68(s,1H).
步骤3：中间体WX001–4的合成
20℃和氮气保护下，将中间体WX001–3(20.67g,92.66mmol)溶于乙腈(250mL)中，随后加入碳酸钾(25.61g,185.33mmol)和4–溴巴豆酸乙酯(35.78g,185.33mmol,25.55mL)，反应混合物在20℃下搅拌反应16小时。反应完毕后，加入水(300mL)，用乙酸乙酯(200mL×3)萃取。合并有机相，用饱和食盐水(300mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石 油醚/乙酸乙酯＝100/1–50/1，体积比)，得到中间体WX001–4。MS–ESI m/z:334.8[M+H] +,336.8[M+H+2] +.
步骤4：中间体WX001–5的合成
室温和氮气保护下，将中间体WX001–4(44.87g,116.60mmol，纯度：87.10％)溶于N,N–二甲基甲酰胺(300mL)中，随后依次加入碳酸钠(30.89g,291.49mmol)，甲酸钠(7.93g,116.60mmol,6.29mL)，醋酸钯(1.31g,5.83mmol)和四丁基氯化铵(35.64g,128.25mmol,35.86mL)，反应混合物加热至80℃并搅拌反应14小时。反应完毕后，冷却至室温，加入水(500mL)，用乙酸乙酯(300mL×3)萃取。合并有机相，用饱和食盐水(600mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–50/1，体积比)，得到中间体WX001–5。 1H NMR(400MHz,CDCl 3)δ:8.04(s,1H),7.99–7.92(m,2H),7.90(s,1H),7.76(s,1H),7.47–7.44(m,2H),4.23(q,J＝7.2Hz,2H),3.80(d,J＝1.2Hz,2H),1.30(t,J＝7.2Hz,3H).
步骤5：化合物WX001的合成
0℃和氮气保护下，将中间体WX001–5(5.24g,20.61mmol)溶于N,N–二甲基甲酰胺(40mL)中，随后加入叔丁醇钾(2.31g,20.61mmol)，0℃下搅拌0.5小时后，加入丙烯酰胺(1.46g,20.61mmol)，反应混合物在0℃和氮气保护下继续搅拌反应1小时。反应完毕后，加入水(50mL)，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物用甲醇(20mL)打浆，20℃搅拌2小时后，过滤，滤饼用甲醇(5mL)冲洗，收集滤饼，得到目标化合物WX001。MS–ESI m/z:280.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),8.15(s,1H),8.08(s,1H),8.05(s,1H),8.03–7.99(m,2H),7.50–7.42(m,2H),4.25(dd,J＝4.8,12.0Hz,1H),2.84–2.76(m,1H),2.67–2.59(m,1H),2.48–2.41(m,1H),2.21–2.13(m,1H).
实施例1a：WX001
Figure PCTCN2019104992-appb-000057
步骤1：中间体WX001–2的合成
0℃下，向三氯化硼的二氯甲烷溶液(1M,16.56mL)缓慢滴加WX001–1(1.99g,13.80mmol)的二氯甲烷(20mL)溶液，在氮气保护下反应混合物在0℃下搅拌反应0.5小时，随后缓慢滴加氯乙腈(1.25g,16.56mmol,1.05mL)，反应混合物在0℃下继续搅拌反应0.5小时，最后加入三氯化铝(920.26mg,6.90mmol)，反应混合物升至室温并继续搅拌反应3小时。反应完毕后，反应混合物倒入冰水(50mL)中，用二氯甲烷(30mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝50/1-20/1，体积比)，得到目标中间体WX001–2。 1H NMR(400MHz,CDCl 3)δ:8.69(d,J＝8.4Hz,1H),8.01(d,J＝8.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.60(td,J＝0.8,8.0Hz,1H),7.42(td,J＝1.2,8.0Hz,1H),7.20(d,J＝9.6Hz,1H),4.69(s,2H).
步骤2：中间体WX001–3的合成
0℃下，将中间体WX001–2(0.485g,2.20mmol)溶于二氯甲烷溶液(10mL)中，加入三乙胺(667.26mg,6.59mmol,917.82μL)，在氮气保护下反应混合物升至室温并搅拌反应2小时。反应完毕后，加入水(50mL)，用二氯甲烷(30mL×3)萃取。合并有机相，用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1-10/1，体积比)，得到目标中间体WX001–3。MS–ESI m/z:185.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.70(d,J＝8.0Hz,1H),8.01(d,J＝8.8Hz,1H),7.78(d,J＝8.4Hz,1H),7.61(td,J＝1.2,8.4Hz,1H),7.42(td,J＝1.0,8.0Hz,1H),7.21(d,J＝8.8Hz,1H),4.70(s,2H).
步骤3：中间体WX001–4的合成
室温下，将中间体WX001–3(0.332g,1.80mmol)溶于甲苯(20mL)中，随后加入乙基(三苯基膦)乙酸酯(753.53mg,2.16mmol)，在氮气保护下反应混合物加热至130℃并搅拌反应35小时。反应完毕后，冷却至室温，减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–20/1，体积比)，得到目标中间体WX001–4。MS–ESI m/z 255.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.16(d,J＝8.4Hz,1H),7.89(d,J＝8.4Hz,1H),7.69(s,1H),7.66(d,J＝8.8Hz,1H),7.57(d,J＝8.8Hz,1H),7.51(td,J＝1.2,8.0Hz,1H),7.41(td,J＝0.8,8.0Hz,1H),4.15(q,J＝6.8Hz,2H),4.00(s,2H),1.19(t,J＝7.2Hz,3H).
步骤4：化合物WX001的合成
0℃下，将中间体WX001–4(0.185g,727.54μmol)溶于N,N–二甲基甲酰胺(10mL)中，随后分别加入叔丁醇钾(81.64mg,727.54μmol)和丙烯酰胺(103.42mg,1.46mmol)，氮气保护下反应混合物在0℃下搅拌反应1.5小时。反应完毕后，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离得到化合物WX001。MS–ESI m/z:279.9[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.96(s,1H),8.19(d,J＝8.0Hz,1H),8.06(d,J＝7.6Hz,1H),8.02(s,1H),7.87(d,J＝9.2Hz,1H), 7.80(d,J＝9.2Hz,1H),7.60(t,J＝7.4Hz,1H),7.52(d,J＝7.6Hz,1H),4.69(dd,J＝4.0,12.0Hz,1H),2.96–2.83(m,1H),2.70–2.57(m,1H),2.48–2.36(m,1H),2.34–2.22(m,1H).
实施例2：WX002
Figure PCTCN2019104992-appb-000058
步骤1：中间体WX002–2的合成
0℃下，向三氯化硼的二氯甲烷溶液(1M,8.71mL)中缓慢滴加WX002–1(1.00g,7.25mmol)的二氯甲烷(40mL)溶液，氮气保护下反应混合物在0℃下搅拌反应0.5小时，随后缓慢滴加氯乙腈(657.23mg,8.71mmol,552.30μL)，氮气保护下反应混合物在0℃下继续搅拌反应0.5小时，最后分两批加入三氯化铝(483.66mg,3.63mmol)，反应混合物升至室温并继续搅拌反应3小时。反应完毕后，反应混合物倒入冰水(100mL)中，用二氯甲烷(50mL×3)萃取，合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–4/1，体积比)，得到目标中间体WX002–2。 1H NMR(400MHz,CDCl 3)δ:12.43(s,1H),6.94(s,1H),6.42(s,1H),5.95(s,2H),4.47(s,2H).
步骤2：中间体WX002–3的合成
0℃下，将中间体WX002–2(0.460g,2.14mmol)溶于二氯甲烷溶液(10mL)中，随后加入三乙胺(650.70mg,6.43mmol,895.05μL)，在氮气保护下反应混合物升至室温并搅拌反应2小时。反应完毕后，加入水(20mL)，用二氯甲烷(10mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–3/1，体积比)，得到目标中间体WX002–3。MS–ESI m/z:179.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:6.89(s,1H),6.50(s,1H),6.00(s,2H),4.57(s,2H).
步骤3：中间体WX002–4的合成
室温下，将中间体WX002–3(0.245g,1.38mmol)溶于甲苯(10mL)中，随后加入乙基(三苯基膦)乙酸酯(574.95mg,1.65mmol)，在氮气保护下反应混合物加热至130℃并搅拌反应35小时。反应完毕后，冷却至室温，减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–10/1，体积比)，得到目标中间体WX002–4。MS–ESI m/z:249.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.55(s,1H),6.97(d,J＝11.2Hz,2H),6.01(s,2H),4.21(q,J＝7.0Hz,2H),3.64(d,J＝1.2Hz,2H),1.30(t,J＝7.2Hz,3H).
步骤4：化合物WX002的合成
0℃下，将中间体WX003–2(0.135g,543.85μmol)溶于N,N–二甲基甲酰胺(10mL)中，随后加入叔丁醇钾(61.03mg,543.85μmol)，再加入丙烯酰胺(77.31mg,1.09mmol)，氮气保护下反应混合物在0℃下搅拌反应1.5小时。反应完毕后，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离得到化合物WX002。MS–ESI m/z:274.1.[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.88(s,1H),7.77(s,1H),7.24(s,1H),7.08(s,1H),6.04(s,2H),4.05(dd,J＝4.6,12.2Hz,1H),2.78–2.65(m,1H),2.60–2.52(m,1H),2.30(qd,J＝4.4,12.4Hz,1H),2.13–2.00(m,1H).
实施例3：WX003
Figure PCTCN2019104992-appb-000059
步骤1：中间体WX003–2的合成
室温下，将WX003–1(5.01g,36.00mmol)溶于N,N–二甲基甲酰胺(80mL)中，随后加入碳酸钾(14.93g,108.01mmol)和1,2–二溴乙烷(8.12g,43.20mmol,3.26mL)，反应混合物加热至125℃并搅拌反应12小时。反应完毕后，冷却至室温，加入水(200mL)，用乙酸乙酯(100mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–5/1，体积比)，得到中间体WX003–2。MS–ESI m/z:166.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:6.52(d,J＝8.8Hz,1H),6.13(d,J＝3.2Hz,1H),6.02(dd,J＝2.8,8.8Hz,1H),5.77(s,1H),4.03(t,J＝4.4Hz,2H),3.60(s,3H),3.27–3.20(m,2H).
步骤2：中间体WX003–3的合成
在0℃和氮气保护下，将中间体WX003–2(1.89g,11.44mmol)溶于乙腈(40mL)中，随后加入碳酸钾(4.74g,34.32mmol)和苄溴(2.15g,12.59mmol,1.49mL)，反应混合物加热至50℃并搅拌反应12小时。反应完毕后，冷却至室温，加入水(200mL)，用乙酸乙酯(100mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–20/1，体积比)，得到中间体WX003–3。MS–ESI m/z:256.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.43–7.28(m,5H),6.75(d,J＝8.8Hz,1H),6.28(d,J＝2.8Hz,1H),6.19(dd,J＝2.6,8.6Hz,1H),4.46(s,2H),4.24(t,J＝4.4Hz,2H),3.70(s,3H),3.39(t,J＝4.4Hz,2H).
步骤3：中间体WX003–4的合成
在–78℃和氮气保护下，将中间体WX003–3(1.90g,6.58mmol,纯度：88.42％)和WX003–3(2.22g,8.11mmol,纯度：93.25％)溶于二氯甲烷(30mL)中，随后缓慢滴加三溴化硼(12.19g,48.65mmol,4.69mL)的二氯甲烷(20mL)溶液，反应混合物升至室温并搅拌反应3小时。反应完毕后，加入水(200mL)，用二氯甲烷(100mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–20/1，体积比)，得到中间体WX003–4。MS–ESI m/z:242.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.30–7.19(m,5H),6.59(d,J＝8.4Hz,1H),6.10(d,J＝2.8Hz,1H),6.00(dd,J＝2.6,8.6Hz,1H),4.38(s,1H),4.35(s,2H),4.14(t,J＝4.4Hz,2H),3.30(t,J＝4.4Hz,2H).
步骤4：中间体WX003–5的合成
在0℃和氮气保护下，将中间体WX003–4(1.11g,4.18mmol,纯度：90.76％)溶于N,N–二甲基甲酰胺(10mL)中，随后加入碳酸钾(1.15g,8.35mmol)，并在0℃下搅拌反应0.5小时，再加入溴乙酸乙酯(697.28mg,4.18mmol,461.77μL)，反应混合物升至室温并继续搅拌反应12小时。反应完毕后，加入水(50mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–5/1，体积比)，得到中间体 WX003–5。MS–ESI m/z:328.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.38–7.28(m,5H),6.72(d,J＝8.4Hz,1H),6.36(d,J＝2.8Hz,1H),6.14(dd,J＝2.8,8.4Hz,1H),4.49(s,2H),4.45(s,2H),4.28–4.24(m,2H),4.24–4.20(m,2H),3.38(t,J＝4.6Hz,2H),1.29(t,J＝7.2Hz,3H).
步骤5：中间体WX003–6的合成
室温和氮气保护下，将中间体WX003–5(1.35g,4.01mmol，纯度：97.23％)溶于四氢呋喃(8mL)、乙醇(4mL)和水(2mL)中，随后加入氢氧化钠(160.38mg,4.01mmol)，反应混合物在室温下搅拌反应12小时。反应完毕后，减压除去四氢呋喃和乙醇。所得残余物加入水(50mL)，用2M稀盐酸水溶液调节pH至2–3，乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到中间体WX003–6。MS–ESI m/z:300.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:7.40–7.19(m,5H),6.58(d,J＝8.8Hz,1H),6.22(d,J＝2.4Hz,1H),6.03(dd,J＝2.8,8.8Hz,1H),4.46(s,2H),4.45(s,2H),4.14(t,J＝4.2Hz,2H),3.38(t,J＝4.4Hz,2H).
步骤6：中间体WX003–7的合成
在第一个反应瓶，10℃和氮气保护下，将丙二酸单乙酯钾盐(1.27g,7.48mmol)溶于乙腈(20mL)中，随后加入三乙胺(1.22g,12.04mmol,1.68mL)和氯化镁(836.47mg,8.79mmol)，反应混合物升至室温并搅拌反应2小时。在第二个反应瓶，0℃和氮气保护下，将中间体WX003–6(1.01g,3.25mmol，纯度：96.43％)溶于乙腈(10mL)中，加入N,N’–羰基二咪唑(527.61mg,3.25mmol)和三乙胺(329.26mg,3.25mmol,452.90μL)，反应混合物升至室温并搅拌反应2小时。在0℃和氮气保护下，将第二个反应瓶的反应混合物滴加到第一个反应瓶中，反应混合物升至室温并继续搅拌反应10小时。反应完毕后，加入冰水(60mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–3/1，体积比)，得到目标中间体WX003–7。MS–ESI m/z:370.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.42–7.28(m,5H),6.73(d,J＝8.8Hz,1H),6.27(d,J＝2.8Hz,1H),6.11(dd,J＝2.8,8.8Hz,1H),4.51(s,2H),4.46(s,2H),4.24(t,J＝4.6Hz,2H),4.16(q,J＝7.2Hz,2H),3.57(s,2H),3.40(t,J＝4.4Hz,2H),1.24(t,J＝7.2Hz,3H).
步骤7：中间体WX003–8的合成
室温和氮气保护下，将中间体WX003–7(0.693g,1.60mmol,纯度：85.45％)溶于甲苯(10mL)中，随后加入多聚磷酸(0.500g)，反应混合物加热至110℃并搅拌反应2小时。反应完毕后，冷却至室温，反应混合物加入水(50mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–10/1，体积比)，得到中间体WX003–8。MS–ESI m/z:352.5[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.40(s,1H),7.38–7.28(m,5H),6.97(s,1H),6.74(s,1H),4.52(s,2H),4.30(t,J＝4.6Hz,2H),4.20(q,J＝7.2Hz,2H),3.60(d,J＝0.8 Hz,2H),3.46(t,J＝4.6Hz,2H),1.30(t,J＝7.0Hz,3H).
步骤8：中间体WX003–9的合成
室温和氮气保护下，将中间体WX003–8(0.110g,313.04μmol)溶于四氢呋喃(1mL)溶液中，加入湿钯碳(30mg,纯度：10％)，反应混合物抽真空，并用氢气置换几次，反应混合物在室温和氢气(15psi)氛围下搅拌反应0.5小时。反应完毕后，反应混合物过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5/1–2/1，体积比)，得到中间体WX003–9。MS–ESI m/z:262.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.34(s,1H),6.84(s,1H),6.62(s,1H),4.18(t,J＝4.4Hz,2H),4.10(q,J＝7.4Hz,2H),3.51(s,2H),3.38(t,J＝4.4Hz,2H),1.20(t,J＝7.2Hz,3H).
步骤9：WX003的合成
在0℃和氮气保护下，将中间体WX003–9(78mg,298.54μmol)溶于N,N–二甲基甲酰胺(10mL)中，随后依次加入叔丁醇钾(33.50mg,298.54μmol)和丙烯酰胺(42.44mg,597.08μmol)，反应混合物在0℃和氮气保护下搅拌反应2小时。反应完毕后，加入水(50mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)，得到化合物WX003。MS–ESI m/z:287.0[M+H] +. 1H NMR(400MHz,MeOD_d 4)δ:7.75(s,1H),7.31(s,1H),7.16(s,1H),4.39(t,J＝4.6Hz,2H),4.10(dd,J＝5.2,11.2Hz,1H),3.66(t,J＝4.6Hz,2H),2.88–2.61(m,2H),2.44–2.20(m,2H).
实施例4：WX004
Figure PCTCN2019104992-appb-000060
Figure PCTCN2019104992-appb-000061
步骤1：中间体WX004–2的合成
室温和氮气保护下，将三氯化硼(1M,118.21mL)加入反应瓶中，冷却至0℃后，滴加WX004–1(20g,98.51mmol)的二氯甲烷(40mL)溶液，滴加完毕后在0℃搅拌反应0.5小时，然后滴加氯乙腈(8.92g,118.21mmol,7.50mL)，最后缓慢加入三氯化铝(13.13g,98.51mmol)，反应混合物升至室温并继续搅拌反应4.5小时。反应完毕后，加入水(40mL)，用二氯甲烷(40mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，得到粗品中间体WX004–2的二氯甲烷溶液(160mL)，直接用于下一步反应。
步骤2：中间体WX004–3的合成
室温和氮气保护下，向中间体WX004–2的二氯甲烷溶液(92.35mmol,150mL)加入三乙胺(10.14g,100.17mmol,13.94mL)，反应混合物在室温下搅拌反应2小时。反应完毕后，加入水(200mL)，分液，水相用二氯甲烷(100mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–3/1，体积比)，得到目标中间体WX004–3。 1H NMR(400MHz,CDCl 3)δ:7.44(s,1H),7.08(s,1H),4.63(s,2H),3.90(s,3H).
步骤3：中间体WX004–4的合成
室温下，将中间体WX004–3(7.87g,32.38mmol)溶于甲苯(100mL)中，随后加入乙基(三苯基膦)乙酸酯(16.92g,48.57mmol)，反应混合物加热至130℃并搅拌反应40小时。反应完毕后，冷却至室温，减压除去溶剂，所得残余物用甲基叔丁基醚(100mL)打浆，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–3/1，体积比)，得到目标中间体WX004–4。 1H NMR(400MHz,CDCl 3)δ:7.67(s,1H),7.58(s,1H),7.03(s,1H),4.18(q,J＝7.2Hz,2H),3.92(s,3H),3.65(s,2H),1.26(t,J＝7.2Hz,3H). 步骤4：中间体WX004–5的合成
室温和氮气保护下，将中间体WX004–4(2.8g,8.94mmol)溶于1,4–二氧六环(50mL)中，随后依次加入二苯甲酮亚胺(2.43g,13.41mmol)，三(二亚苄基丙酮)二钯(655.04mg,715.33μmol)，4,5–双二苯基膦–9,9–二甲基氧杂蒽(827.81mg,1.43mmol)和碳酸铯(8.74g,26.82mmol)，反应混合物加热至80℃并搅拌反应4小时。反应完毕后，冷却至室温，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–20/1，体积比)，得到目标中间体WX004–5。 1H NMR(400MHz,CDCl 3)δ:7.86–7.72(m,2H),7.57–7.38(m,4H),7.25–7.10(m,5H),6.85(s,1H),6.72(s,1H),4.18(q,J＝7.2Hz,2H),3.75(s,3H),3.61(s,2H),1.25(t,J＝7.2Hz,3H).
步骤5：中间体WX004–6的合成
室温和氮气保护下，将中间体WX004–5(1.2g,2.90mmol)溶于N,N–二甲基甲酰胺(30mL)中，冷却至0℃，随后依次加入叔丁醇钾(325.67mg,2.90mmol)和丙烯酰胺(206.29mg,2.90mmol)，反应混合物在0℃下搅拌反应0.5小时。反应完毕后，加入水(100mL)和乙酸乙酯(100mL)稀释，分液后收集有机相，水相用乙酸乙酯(50mL×2)萃取。合并有机相，有机相用半饱和食盐水洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–2/3，体积比)，得到中间体WX004–6。 1H NMR(400MHz,DMSO_d 6)δ:10.85(s,1H),7.68–7.61(m,3H),7.55–7.44(m,3H),7.36–7.24(m,3H),7.15(dd,J＝1.7,7.5Hz,2H),7.00(s,1H),6.77(s,1H),4.10–3.97(m,1H),3.68(s,3H),2.76–2.63(m,1H),2.61–2.53(m,1H),2.36–2.22(m,1H),2.13–2.02(m,1H).
步骤6：中间体WX004–7的合成
室温下，向中间体WX004–6(500mg,1.14mmol)中加入盐酸/乙酸乙酯溶液(20mL,4M)和水(0.2mL)，反应混合物在室温下搅拌反应48小时。反应完毕后，加入水(40mL)，分液后除去有机相，水相用饱和碳酸氢钠溶液调节pH至6–7，用乙酸乙酯萃取(20mL×2)。合并有机相，减压除去溶剂，得到目标中间体WX004–7。MS–ESI m/z:275.1[M+H] +.
步骤7：中间体WX004–8的合成
室温下，将中间体WX004–7(300mg,717.87μmol,纯度：65.63％)溶于二氯甲烷(10mL)中，冷却至0℃后，加入三溴化硼(5.20g,20.76mmol,2mL)，反应混合物自然升温至室温并搅拌反应3小时。反应完毕后，将反应液倒入冰水(50mL)中，加乙酸乙酯(20mL)稀释，分液后除去有机相，水相用饱和碳酸氢钠溶液调节pH至6–7，乙酸乙酯(20mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/1–0/1，体积比)，得到目标中间体WX004–8。 1H NMR(400MHz,DMSO_d 6)δ:10.86(s,1H),9.00(s,1H),7.47(s,1H),6.72(s,1H),6.70(s,1H),4.69(br s,2H),3.94(dd,J＝4.8,11.2Hz,1H),2.79–2.65(m,1H),2.61–2.53(m,1H),2.26–2.03(m,2H).
步骤8：WX004的合成
室温和氮气保护下，将中间体WX004–8(60mg,230.55μmol)溶于N,N–二甲基甲酰胺(3mL)中，随后依次加入原甲酸三乙酯(41.00mg,276.66μmol,46.02μL)和四氯化锆(5.37mg,23.06μmol)，反应混合物在室温下搅拌反应2小时。反应完毕后，加入水(20mL)和乙酸乙酯(20mL)稀释，分液后收集有机相，水相用乙酸乙酯(15mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC(流动相：乙腈/水；碱性体系：10mM NH 4HCO 3)分离，得到化合物WX004。MS–ESI m/z:271.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.92(s,1H),8.74(s,1H),8.01(s,1H),8.00(s,1H),7.97(s,1H),4.21(dd,J＝4.8,12.0Hz,1H),2.85–2.70(m,1H),2.69–2.56(m,1H),2.44–2.30(m,1H),2.22–2.09(m,1H).
实施例5：WX005
Figure PCTCN2019104992-appb-000062
室温和氮气保护下，将中间体WX004–8(80mg,307.40μmol)溶于N,N–二甲基甲酰胺(5mL)中，随后依次加入原乙酸三乙酯(59.84mg,368.88μmol,67.62μL)和四氯化锆(7.16mg,30.74μmol)，反应混合物在室温下搅拌反应2小时。反应完毕后，加入水(20mL)和乙酸乙酯(20mL)稀释，分液后收集有机相，水相用乙酸乙酯(20mL×2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC(流动相：乙腈/水；碱性体系：10mM NH 4HCO 3)分离，得到化合物WX005。MS–ESI m/z:285.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.90(s,1H),7.96(s,1H),7.84(s,1H),7.83(s,1H),4.19(dd,J＝4.6,12.2Hz,1H),2.83–2.68(m,1H),2.62(s,3H),2.57–2.50(m,1H),2.46–2.31(m,1H),2.16–2.15(m,1H).
实施例6：WX006
Figure PCTCN2019104992-appb-000063
Figure PCTCN2019104992-appb-000064
步骤1：中间体WX006–2的合成
室温和氮气保护下，将WX006–1(15.00g,73.88mmol)和1,2–-二溴乙烷(41.64g,221.64mmol,16.72mL)溶于N,N–二甲基甲酰胺(150mL)中，随后加入碳酸钾(20.42g,147.76mmol)，反应混合物加热至50℃并在50℃下搅拌反应12小时。反应完毕后，冷却至室温，反应混合物倒入水(300mL)中，用乙酸乙酯(200mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–10/1，体积比)，得到中间体WX006–2。 1H NMR(400MHz,CDCl 3)δ:7.42(d,J＝8.8Hz,1H),6.49(d,J＝2.8Hz,1H),6.45(dd,J＝2.8,8.8Hz,1H),4.32(t,J＝6.8Hz,2H),3.80(s,3H),3.68(t,J＝6.6Hz,2H).
步骤2：中间体WX006–3的合成
在–70℃和氮气保护下，将中间体WX006–2(5.41g,16.97mmol,纯度：97.26％)溶于四氢呋喃(40mL)中，随后缓慢滴加正丁基锂的正己烷溶液(2.5M,20.37mL)，反应混合物在–70℃和氮气保护下搅拌反应2小时。反应完毕后，反应混合物倒入饱和氯化铵溶液(100mL)中，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝50/1–10/1，体积比)，得到中间体WX006–3。MS–ESI m/z:151.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.07(d,J＝4.4Hz,1H),6.43–6.37(m,2H),4.58(t,J＝8.6Hz,2H),3.77(s,3H),3.15(t,J＝8.6Hz,2H).
步骤3：中间体WX006–4的合成
在–78℃和氮气保护下，将中间体WX006–3(2.63g,16.39mmol,纯度：93.61％)溶于二氯甲烷(30mL)中，将三溴化硼(12.32g,49.18mmol,4.74mL)的二氯甲烷(5mL)溶液缓慢滴加到上述反应液中，反应混合物升至室温并在室温下搅拌反应12小时。反应完毕后，冷却至0℃，反应混合物倒入甲醇(5mL)中，再 加入水(50mL)，用二氯甲烷(30mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–3/1，体积比)，得到中间体WX006–4。MS–ESI m/z:137.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.33(s,1H),6.86(d,J＝8.0Hz,1H),6.28(d,J＝2.4Hz,1H),6.14(dd,J＝2.2,8.2Hz,1H),3.55(t,J＝7.8Hz,2H),2.93(t,J＝7.6Hz,2H).
步骤4：中间体WX006–5的合成
在0℃和氮气保护下，将中间体WX006–4(1.72g,12.63mmol)溶于N,N–二甲基甲酰胺(20mL)中，随后加入碳酸钾(3.49g,25.27mmol)，并在0℃下搅拌反应0.5小时，再加入溴乙酸乙酯(2.11g,12.63mmol,1.40mL)，反应混合物升至室温并在室温下继续搅拌反应12小时。反应完毕后，反应混合物加入水(30mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–5/1，体积比)，得到中间体WX006–5。MS–ESI m/z:223.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.07(d,J＝4.4Hz,1H),6.43–6.34(m,2H),4.62–4.54(m,4H),4.27(q,J＝7.0Hz,2H),3.14(t,J＝8.6Hz,2H),1.31(t,J＝7.2Hz,3H).
步骤5：中间体WX006–6的合成
室温和氮气保护下，将中间体WX006–5(2.67g,11.73mmol,纯度:97.64％)溶于四氢呋喃(16mL)、乙醇(8mL)和水(4mL)中，随后加入氢氧化钠(469.23mg,11.73mmol)，反应混合物在室温下搅拌反应12小时。反应完毕后，减压除去四氢呋喃和乙醇。所得残余物加入水(100mL)，用2M稀盐酸水溶液调节pH至2–3，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到中间体WX006–6。MS–ESI m/z:195.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:12.90(s,1H),7.08(d,J＝8.8Hz,1H),6.38–6.30(m,2H),4.60(s,2H),4.52(t,J＝8.8Hz,2H),3.08(t,J＝8.6Hz,2H).
步骤6：中间体WX006–7的合成
10℃和氮气保护下，用第一个反应瓶，将丙二酸单乙酯钾盐(2.55g,14.99mmol)加入到乙腈(20mL)中，随后将三乙胺(2.44g,24.12mmol,3.36mL)和氯化镁(1.68g,17.60mmol)的混合物加入到上述反应液中，反应混合物升至室温并在室温下搅拌反应2小时。0℃和氮气保护下，在另一反应瓶，将中间体WX006–6(1.28g,6.52mmol,纯度:98.88％)溶于乙腈(5mL)中，随后依次加入N,N–羰基二咪唑(1.06g,6.52mmol)和三乙胺(659.54mg,6.52mmol,907.21μL)，反应混合物升至室温并在室温下搅拌反应2小时。最后在0℃和氮气保护下，将第二个反应瓶中的反应混合物滴加到第一个反应瓶中，反应混合物升至室温并在室温下继续搅拌反应10小时。反应完毕后，反应混合物加入冰水(100mL)，用乙酸乙酯(60mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱 层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–5/1，体积比)，得到中间体WX006–7。 1H NMR(400MHz,CDCl 3)δ:7.07(d,J＝8.0Hz,1H),6.41–6.33(m,2H),4.63–4.54(m,4H),4.20(q,J＝7.0Hz,2H),3.62(s,2H),3.15(t,J＝8.4Hz,2H),1.27(t,J＝7.0Hz,3H).
步骤7：中间体WX006–8的合成
室温和氮气保护下，将中间体WX006–7(0.845g,2.73mmol,纯度:85.36％)溶于甲苯(10mL)中，随后加入多聚磷酸(0.400g)，反应混合物加热至110℃并在110℃下搅拌反应1小时。反应完毕后，冷却至室温，反应混合物加入水(30mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–10/1，体积比)，得到中间体WX006–8。MS–ESI m/z:246.6[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.49(s,1H),7.32(s,1H),6.89(s,1H),4.63(t,J＝8.6Hz,2H),4.19(q,J＝7.0Hz,2H),3.64(s,2H),3.28(t,J＝8.4Hz,2H),1.28(t,J＝7.2Hz,3H).
步骤8：WX006的合成
在0℃和氮气保护下，将中间体WX006–8(0.670g,2.67mmol,纯度:98.12％)溶于N,N–二甲基甲酰胺(10mL)中，加入叔丁醇钾(299.55mg,2.67mmol)，随后加入丙烯酰胺(189.75mg,2.67mmol)，反应混合物在0℃和氮气保护下搅拌反应1小时。反应完毕后，反应混合物加入水(50mL)淬灭反应，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到化合物WX006。MS–ESI m/z:272.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.87(s,1H),7.71(s,1H),7.37(s,1H),6.96(s,1H),4.59(t,J＝8.6Hz,2H),4.05(dd,J＝4.8,12.0Hz,1H),3.22(t,J＝8.6Hz,2H),2.78–2.66(m,1H),2.61–2.53(m,1H),2.36–2.23(m,1H),2.15–2.05(m,1H).
实施例7：WX007
Figure PCTCN2019104992-appb-000065
Figure PCTCN2019104992-appb-000066
步骤1：中间体WX007–2的合成
室温氮气保护下，将化合物WX007–1(30.00g,241.67mmol)和3–溴丙–1–烯(35.08g,290.00mmol)溶于丙酮(300mL)中，加入碳酸钾(66.80g,483.34mmol)，反应混合物加热至65℃并在65℃下搅拌反应12小时。反应完毕后，冷却至室温，反应混合物过滤，滤饼丢弃，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–100/1，体积比)，得到中间体WX007–2。MS–ESI m/z:165.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:6.92–6.78(m,4H),6.13–6.00(m,1H),5.41(dq,J＝1.6,17.2Hz,1H),5.28(dq,J＝1.4,10.2Hz,1H),4.51(t,J＝1.6Hz,1H),4.50(t,J＝1.4Hz,1H),3.78(s,3H).
步骤2：中间体WX007–3的合成
在室温氮气保护下，将中间体WX007–2(33.00g,196.63mmol，纯度：97.84％)加入单口烧瓶中，反应混合物加热至180℃并在180℃下搅拌反应6小时。反应完毕后，冷却至室温，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝100/1–10/1，体积比)，得到中间体WX007–3。MS–ESI m/z:165.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:6.79–6.73(m,1H),6.72–6.64(m,2H),6.11–5.92(m,1H),5.23–5.17(m,1H),5.16–5.13(m,1H),4.63(s,1H),3.77(s,3H),3.39(d,J＝6.0Hz,2H).
步骤3：中间体WX007–4的合成
在室温下，将中间体WX007–3(5.00g,28.86mmol，纯度：94.77％)溶于二甲基乙酰胺(3mL)和水(0.5mL)中，加入氯化钯(102.35mg,577.16μmol)和醋酸钠(4.73g,57.72mmol)，反应混合物抽真空，用氧气置换几次。反应混合物在25℃和氧气(15psi)保护下搅拌反应1小时。三个批次合并处理。反应完毕后，反应混合物加入水(200mL)，用乙酸乙酯(100mL×3)萃取。合并有机相，用饱和食盐水(100mL×2) 洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–10/1，体积比)，得到中间体WX007–4。MS–ESI m/z:163.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.29(d,J＝9.2Hz,1H),6.96(d,J＝2.8Hz,1H),6.81(dd,J＝2.6,9.0Hz,1H),6.32(s,1H),3.84(s,3H),2.44(d,J＝0.8Hz,3H).
步骤4：中间体WX007–5的合成
在–78℃氮气保护下，将中间体WX007–4(4.22g,25.42mmol，纯度：97.69％)溶于二氯甲烷(40mL)中，缓慢加入三溴化硼(19.10g,76.26mmol,7.35mL)的二氯甲烷(10mL)溶液，反应混合物升至25℃并在25℃下搅拌反应5小时。反应完毕后，反应混合物倒入水(100mL)，用二氯甲烷(50mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–8/1，体积比)，得到中间体WX007–5。MS–ESI m/z:148.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.24(d,J＝8.4Hz,1H),6.89(d,J＝2.4Hz,1H),6.71(dd,J＝2.4,8.8Hz,1H),6.28(s,1H),4.80(s,1H),2.43(d,J＝0.8Hz,3H).
步骤5：中间体WX007–6的合成
室温氮气保护下，将中间体WX007–5(3.08g,20.48mmol，纯度：98.53％)溶于N,N–二甲基甲酰胺(30mL)，加入碳酸钾(5.66g,40.97mmol)，反应混合物在0℃下搅拌反应0.5小时，加入2–溴乙酸乙酯(3.42g,20.48mmol,2.27mL)，反应混合物在25℃和氮气保护下搅拌反应12小时。反应完毕后，反应混合物加入水(100mL)，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–10/1，体积比)，得到中间体WX007–6。MS–ESI m/z:235.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.30(d,J＝9.2Hz,1H),6.95(d,J＝2.4Hz,1H),6.86(dd,J＝2.4,8.8Hz,1H),6.31(s,1H),4.64(s,2H),4.28(q,J＝7.0Hz,2H),2.43(d,J＝0.8Hz,3H),1.31(t,J＝7.2Hz,3H).
步骤6：中间体WX007–7的合成
在室温氮气保护下，将中间体WX007–6(2.10g,8.67mmol，纯度：96.74％)溶于四氢呋喃(20mL)，乙醇(10mL)和水(5mL)中，加入氢氧化钠(346.91mg,8.67mmol)，反应混合物在25℃下搅拌反应12小时。反应混合物减压除去四氢呋喃和乙醇，反应混合物加入水(100mL)。反应混合物加入2M稀盐酸(10mL)调节pH至2–3，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到中间体WX007–7。MS–ESI m/z:207.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.32(d,J＝8.8Hz,1H),6.98(d,J＝2.8Hz,1H),6.86(dd,J＝2.6,9.0Hz,1H),6.33(s,1H),4.70(s,2H),2.44(d,J＝0.8Hz,3H).
步骤7：中间体WX007–8的合成
在10℃和氮气保护下，将丙二酸单乙酯钾盐(3.29g,19.31mmol)溶于乙腈(20mL)中，将三乙胺(3.14g,31.06mmol,4.32mL)和氯化镁(2.16g,22.66mmol,930.14μL)的混合物加入上述反应液中，反应混合物升至25℃并在25℃下搅拌反应2小时。在0℃和氮气保护下，中间体WX007–7(1.77g,8.39mmol，纯度：97.79％)溶于乙腈(10mL)中，加入N,N–羰基二咪唑(1.36g,8.39mmol)和三乙胺(849.43mg,8.39mmol,1.17mL)，反应混合物升至25℃并在25℃下搅拌反应2小时。在0℃和氮气保护下，反应混合物滴加到上述溶液中，反应混合物升至25℃并在25℃下搅拌反应10小时。反应完毕后，反应混合物加入冰水(100mL)，用乙酸乙酯(60mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1–5/1，体积比)，得到中间体WX007–8。MS–ESI m/z:277.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.31(d,J＝8.8Hz,1H),6.91(d,J＝2.8Hz,1H),6.81(dd,J＝2.8,8.8Hz,1H),6.32(t,J＝0.8Hz,1H),4.66(s,2H),4.20(q,J＝7.0Hz,2H),3.66(s,2H),2.44(d,J＝1.2Hz,3H),1.26(t,J＝7.2Hz,3H).
步骤8：中间体WX007–9的合成
室温和氮气保护下，将中间体WX007–8(0.821g,2.44mmol，纯度：82.04％)溶于甲苯(10mL)中，加入多聚磷酸(0.300g)，反应混合物加热至110℃并在110℃下搅拌反应1小时。反应完毕后，冷却至室温，反应混合物加入水(30mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过超临界流体色谱(分离条件：色谱柱：ChiralPak AD-3 150x 4.6mm I.D.,3um；流动相：A：二氧化碳，B：乙醇(0.05％二乙基胺)；流速：2.5mL/min；柱温：40℃；波长：220nm)分离，收集保留时间为3.066min的样品得到中间体WX007–9。MS–ESI m/z:259.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.62(s,1H),7.52(s,1H),7.49(s,1H),6.43(t,J＝0.8Hz,1H),4.21(q,J＝7.2Hz,2H),3.72(d,J＝0.8Hz,2H),2.48(d,J＝1.2Hz,3H),1.29(t,J＝7.2Hz,3H).
步骤9：WX007的合成
在0℃和氮气保护下，向中间体WX007–9(0.100g,387.19μmol，纯度：100％)的N,N–二甲基甲酰胺(10mL)溶液中加入叔丁醇钾(43.45mg,387.19μmol)，随后加入丙烯酰胺(27.52mg,387.19μmol)，反应混合物在0℃和氮气保护下搅拌反应1小时。反应完毕后，反应混合物加入水(50mL)稀释，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX007。MS–ESI m/z:284.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.90(s,1H),7.86(s,1H),7.65(s,2H),6.63(s,1H),4.16(dd,J＝5.0,11.8Hz,1H),2.83–2.70(m,1H),2.65–2.55(m,1H),2.46(s,3H),2.43–2.31(m,1H),2.20–2.08(m,1H).
实施例8：WX008
Figure PCTCN2019104992-appb-000067
步骤1：中间体WX008–1的合成
0℃和氮气保护下，将化合物WX004–1(10.00g,49.25mmol)溶于N,N–二甲基甲酰胺(100mL)中，之后分批加入钠氢(2.17g,54.18mmol,纯度：60％)，最后加入溴乙醛缩二乙醇(12.62g,64.03mmol,9.63mL)，反应混合物加热至110℃并搅拌反应12小时。反应完毕后，冷却至室温，向反应液加入水(300mL)，用甲基叔丁基醚萃取(100mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–19/1，体积比)，得到中间体WX008–1。 1H NMR(400MHz,CDCl 3)δ:7.18(d,J＝2.8Hz,1H),6.85(d,J＝2.8Hz,1H),6.84(s,1H),4.80(t,J＝5.4Hz,1H),3.95(d,J＝5.2Hz,2H),3.85(s,3H),3.82–3.71(m,2H),3.70–3.57(m,2H),1.25(t,J＝7.0Hz,6H).
步骤2：中间体WX008–2的合成
室温和氮气保护下，将中间体WX008–1(10g,31.33mmol)溶于甲苯(150mL)中，之后加入多聚磷酸(10g)，反应混合物加热至110℃并搅拌反应2小时。反应完毕后，反应液冷却至室温，收集上层清液，减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–49/1，体积比)，得到中间体WX008–2。 1H NMR(400MHz,CDCl 3)δ:7.73(d,J＝0.8Hz,1H),7.59(d,J＝2.0Hz,1H),7.09(s,1H),6.71(d,J＝2.0Hz,1H),3.93(s,3H).
步骤3：中间体WX008–3的合成
10℃和氮气保护下，将中间体WX008–2(2.8g,12.33mmol)溶于二氯甲烷(80mL)中，降温至–60℃滴加三溴化硼(3.71g,14.80mmol,1.43mL)，反应混合物缓慢恢复至10℃并搅拌反应1小时。反应完毕后，将反应液倒入冰水(20mL)，用乙酸乙酯萃取(100mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减 压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–19/1，体积比)，得到中间体WX008–3。 1H NMR(400MHz,CDCl 3)δ:7.65(s,1H),7.59(d,J＝2.4Hz,1H),7.22(s,1H),6.68(dd,J＝0.8,2.0Hz,1H),5.38(s,1H).
步骤4：中间体WX008–4的合成
20℃下，将中间体WX008–3(1.45g,6.81mmol)溶于乙腈(20mL)中，之后依次加入碳酸钾(2.82g,20.42mmol)，4–溴巴豆酸乙酯(2.23g,11.57mmol,1.60mL)，反应混合物在20℃下搅拌反应12小时。反应完毕后，反应液直接过滤，滤饼用乙酸乙酯洗涤(20mL×2)，收集滤液，减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–19/1，体积比)，得到中间体WX008–4。 1H NMR(400MHz,CDCl 3)δ:7.74(s,1H),7.60(d,J＝2.0Hz,1H),7.12(dt,J＝4.0,15.6Hz,1H),7.06(s,1H),6.70(d,J＝1.6Hz,1H),6.35(dt,J＝2.0,15.6Hz,1H),4.77(dd,J＝2.2,3.8Hz,2H),4.24(q,J＝7.0Hz,2H),1.32(t,J＝7.2Hz,3H).
步骤5：中间体WX008–5的合成
室温和氮气保护下，将中间体WX008–4(1.3g,4.00mmol)溶于N,N–二甲基甲酰胺(30mL)中，之后依次加入碳酸钠(1.06g,10.00mmol)，甲酸钠(271.91mg,4.00mmol,215.80μL)，醋酸钯(44.88mg,199.91μmol)，四丁基氯化铵水合物(1.22g,4.40mmol,1.23mL)，反应混合物升温至80℃并搅拌反应8小时。反应完毕后，冷却至室温，加入水(100mL)，用乙酸乙酯萃取(50mL×3)。合并有机相，依次用半饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–19/1，体积比)，得到中间体WX008–5。 1H NMR(399MHz,CDCl 3)δ:7.68–7.65(m,2H),7.63(s,2H),6.83(d,J＝1.6Hz,1H),4.22(q,J＝7.2Hz,2H),3.74(s,2H),1.29(t,J＝7.4Hz,3H).
步骤6：WX008的合成
20℃下，将中间体WX008–5(400mg,1.64mmol)溶于N,N–二甲基甲酰胺(10mL)中，之后依次加入丙烯酰胺(116.41mg,1.64mmol)和叔丁醇钾(183.77mg,1.64mmol)，反应混合物在20℃下搅拌反应1小时。反应完毕后，反应液加入水(30mL)，用乙酸乙酯萃取(30mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝4/1–3/1，体积比)，所得残余物再经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX008。MS–ESI m/z:270.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.91(s,1H),8.00(d,J＝2.4Hz,1H),7.91(s,1H),7.78(d,J＝6.0Hz,2H),7.01(d,J＝1.6Hz,1H),4.18(dd,J＝5.0,11.8Hz,1H),2.82–2.71(m,1H),2.69–2.55(m,1H),2.46–2.32(m,1H),2.19–2.08(m,1H).
实施例9：WX009
Figure PCTCN2019104992-appb-000068
步骤1：中间体WX009–2的合成
室温下，将化合物WX009–1(10g,44.04mmol)溶于乙酸乙酯(100mL)中，之后加入三甲基氧鎓四氟硼酸(7.82g,52.85mmol)，反应混合物在室温下搅拌反应12小时。反应完毕后，向反应液加入水(100mL)，用乙酸乙酯萃取(50mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝4/1–3/2，体积比)，得到中间体WX009–2。 1H NMR(399MHz,CDCl 3)δ:7.94(s,1H),7.75(s,1H),6.92(s,1H),4.15(s,3H),3.89(s,3H).
步骤2：中间体WX009–3的合成
20℃和氮气保护下，将中间体WX009–2(6.7g,27.79mmol)溶于二氯甲烷(100mL)中，冷却至–60℃––50℃后滴加三溴化硼(10.44g,41.69mmol,4.02mL)，反应混合物升温至20℃并搅拌反应3小时。反应完毕后，将反应液倒入冰水(200mL)，用乙酸乙酯萃取(200mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经甲基叔丁基醚(30mL)室温搅拌30分钟，有固体析出，过滤，收集固体，减压浓缩除去溶剂。得到中间体WX009–3。 1H NMR(400MHz,DMSO_d 6)δ:8.11(s,1H),7.83(s,1H),7.06(s,1H),6.45(s,1H),4.08(s,3H).
步骤3：中间体WX009–4的合成
室温和氮气保护下，将中间体WX009–3(2.5g,11.01mmol)溶于乙腈(30mL)中，之后依次加入碳酸钾(4.57g,33.03mmol)，4–溴巴豆酸乙酯(3.19g,16.52mmol,2.28mL)，反应混合物在室温下搅拌反应12小时，然后将反应混合物加热至50℃并搅拌反应6小时。反应完毕后，冷却至室温，反应液加入水(200mL)，用乙酸乙酯萃取(100mL×3)。合并有机相，依次用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝9/1–3/2，体积比)，得到中 间体WX009–4。 1H NMR(400MHz,CDCl 3)δ:7.95(s,1H),7.75(s,1H),7.10(dt,J＝3.8,15.6Hz,1H),6.89(s,1H),6.35(dt,J＝1.8,14.0Hz,1H),4.72(dd,J＝2.0,3.6Hz,2H),4.22(q,J＝7.0Hz,2H),4.15(s,3H),1.31(t,J＝7.2Hz,3H).
步骤4：中间体WX009–5的合成
室温和氮气保护下，将中间体WX009–4(1.6g,4.72mmol)溶于N,N–二甲基甲酰胺(30mL)中，随后依次加入碳酸钠(999.94mg,9.43mmol)，甲酸钠(320.80mg,4.72mmol)，醋酸钯(52.95mg,235.86μmol)，四丁基氯化铵水合物(1.44g,5.19mmol,1.45mL)，反应混合物加热至80℃并搅拌反应6小时。反应完毕后，冷却至室温，反应液加入水(200mL)，用乙酸乙酯萃取(60mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–3/2，体积比)，得到中间体WX009–5。 1H NMR(400MHz,MeOD_d 4)δ:8.23(s,1H),7.69(s,1H),7.67(s,1H),7.63(s,1H),4.23(s,3H),4.18(q,J＝7.2Hz,2H),3.75(s,2H),1.26(t,J＝7.2Hz,3H).
步骤5：WX009的合成
室温下，将中间体WX009–5(600mg,2.32mmol)溶于四氢呋喃(20mL)中，之后依次加入丙烯酰胺(165.12mg,2.32mmol)和叔丁醇钾(1M,2.32mL)的四氢呋喃溶液，反应混合物在室温下搅拌反应2小时。反应完毕后，反应液加入水(50mL)稀释，用乙酸乙酯萃取(50mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物用N,N–二甲基甲酰胺(10mL)室温搅拌15分钟，有淡黄色固体析出，过滤，滤饼用乙腈洗涤(2mL×2)，收集固体。得到目标化合物WX009。MS–ESI m/z:284.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.91(s,1H),8.39(s,1H),7.84(s,1H),7.74(s,1H),7.70(s,1H),4.21(s,3H),4.16(dd,J＝4.8,11.6Hz,1H),2.82–2.69(m,1H),2.68–2.55(m,1H),2.43–2.30(m,1H),2.19–2.09(m,1H).
实施例10：WX010
Figure PCTCN2019104992-appb-000069
Figure PCTCN2019104992-appb-000070
步骤1：中间体WX010–2的合成
室温下，将浓硫酸(220.80g,2.21mol,120mL,纯度：98％)滴加到冰水(40mL)中，之后加入化合物WX010–1(15g,120.83mmol,13.04mL)，反应混合物冷却至5–10℃后滴加4–氯乙酰乙酸乙酯(25.85g,157.08mmol,21.19mL)，反应混合物恢复至室温并搅拌反应12小时。反应完毕后，将反应液倒入冰水(200mL)，有淡黄色固体析出，过滤，收集固体。加入甲苯(50mL)，减压浓缩除去溶剂，得到中间体WX010–2。
步骤2：中间体WX010–3的合成
室温下，将氢氧化钠(16.00g,400mmol)溶于水(200mL)中，之后加入中间体WX010–2(27g,120.19mmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，加入2M稀盐酸调pH至5–6，用乙酸乙酯萃取(100mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得到中间体WX010–3。
步骤3：中间体WX010–4的合成
室温下，将中间体WX010–3(20g,97.00mmol)溶于乙醇(200mL)中，随后加入浓硫酸(5.52g,55.16mmol,3mL,纯度：98％)，反应混合物加热至80℃并搅拌反应4小时。反应完毕后，冷却至室温，减压浓缩除去乙醇，所得残余物经水(200mL)和乙酸乙酯(200mL)稀释，分液后收集有机相，水相用乙酸乙酯萃取(100mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–19/1，体积比)，得到中间体WX010–4。 1H NMR(400MHz,CDCl 3)δ:7.54(s,1H),7.44(d,J＝8.8Hz,1H),7.01(d,J＝2.0Hz,1H),6.90(dd,J＝2.0,8.4Hz,1H),4.19(q,J＝7.2Hz,2H),3.86(s,3H),3.67(s,2H),1.28(t,J＝7.0Hz,3H).
步骤4：中间体WX010–5的合成
20℃和氮气保护下，将中间体WX010–4(14.2g,60.62mmol)溶于二氯甲烷(200mL)中，冷却至–60℃后滴加三溴化硼(22.78g,90.93mmol,8.76mL)，反应混合物恢复至20℃并搅拌反应1小时。反应完毕后，将反应液倒入冰水(500mL)，用二氯甲烷萃取(200mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到残余物。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–9/1，体积比)，得到中间体WX010–5。 1H NMR(400MHz,CDCl 3)δ:7.51(s,1H),7.35(d,J＝8.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.75(dd,J＝1.6,8.4Hz,1H),5.64(s,1H),4.21(q,J＝7.0Hz,2H),3.67(s,2H),1.29(t,J＝7.2Hz,3H).
步骤5：中间体WX010–6的合成
室温和氮气保护下，将中间体WX010–5(5g,22.70mmol)溶于N,N–二甲基甲酰胺(50mL)中，之后加入碳酸钾(6.28g,45.41mmol)和溴乙醛缩二乙醇(6.71g,34.06mmol,5.12mL)，反应混合物加热至100℃并搅拌反应24小时。反应完毕后，冷却至室温，向反应液加入水(300mL)，用乙酸乙酯萃取(100mL×3)。合并有机相，依次用半饱和食盐水洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–9/1，体积比)，得到中间体WX010–6。 1H NMR(400MHz,CDCl 3)δ:7.54(s,1H),7.43(d,J＝8.8Hz,1H),7.03(d,J＝2.4Hz,1H),6.93(dd,J＝2.2,8.6Hz,1H),4.87(t,J＝5.2Hz,1H),4.19(q,J＝7.2Hz,2H),4.05(d,J＝5.2Hz,2H),3.84–3.75(m,2H),3.71–3.59(m,4H),1.33–1.19(m,9H).
步骤6：中间体WX010–7的合成
室温和氮气保护下，将中间体WX010–6(2g,5.95mmol)溶于甲苯(50mL)中，之后加入多聚磷酸(3g)，反应混合物加热至100℃并搅拌反应15分钟。反应完毕后，反应液直接倾倒并收集上层清液，减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–9/1，体积比)，所得残余物经制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，减压浓缩除去乙腈，水相用乙酸乙酯萃取(100mL×3)。合并有机相，用无水硫酸钠干燥，过滤，减压浓缩除去溶剂。得到中间体WX010–7。 1H NMR(399MHz,CDCl 3)δ:7.69(s,1H),7.67–7.63(m,2H),7.61(s,1H),6.84(d,J＝2.0Hz,1H),4.21(q,J＝6.8Hz,2H),3.74(s,2H),1.29(t,J＝7.2Hz,3H).
步骤7：WX010的合成
室温下，将中间体WX010–7(500mg,2.05mmol)溶于N,N–二甲基甲酰胺(10mL)中，之后依次加入丙烯酰胺(145.51mg,2.05mmol)和叔丁醇钾(229.71mg,2.05mmol)，反应混合物在室温下搅拌反应小时。反应完毕后，向反应液加水(20mL)稀释，用乙酸乙酯萃取(20mL×3)。合并有机相，依次用半饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX010。MS–ESI m/z:270.0[M+H] + . 1H NMR(400MHz,DMSO_d 6)δ:10.93(s,1H),7.99(d,J＝2.4Hz,1H),7.91(s,1H),7.85(s,1H),7.77(s,1H),7.01(d,J＝2.4 Hz,1H),4.18(dd,J＝5.0,11.8Hz,1H),2.82–2.70(m,1H),2.69–2.55(m,1H),2.44–2.30(m,1H),2.19–2.10(m,1H).
实施例11：WX011
Figure PCTCN2019104992-appb-000071
步骤1：中间体WX011–2的合成
室温和氮气保护下，将浓硫酸(37.15g,371.20mmol,纯度：98％)溶于水(20mL)中，加入3–硝基苯磺酸水合物(15.99g,78.69mmol)和丙三醇(25.30g,274.69mmol,20.57mL)中，反应混合物升温至110℃后，加入化合物WX011–1(15g,74.24mmol)，水(20mL)，浓硫酸(20mL，纯度：98％)和丙三醇(20mL)，反应混合物升温至140℃并搅拌反应3小时。反应完毕后，将反应液倒入冰水(500mL)中，用2N氢氧化钠水溶液调节pH值至8后，用乙酸乙酯(500mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得到残余物。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–6/1，体积比)，得到中间体WX011–2。 1H NMR(400MHz,CDCl 3)δ:8.85(dd,J＝1.6,4.4Hz,1H),8.04(s,1H),8.01(dd,J＝1.0,8.2Hz,1H),7.46(s,1H),7.30(dd,J＝4.4,8.0Hz,1H),4.04(s,3H).
步骤2：中间体WX011–3的合成
室温和氮气保护下，将中间体WX011–2(12.6g,52.92mmol)溶于二氯甲烷(1500mL)中，冷却至–20℃，加入三溴化硼(66.29g,264.62mmol)，反应混合物在–20℃下搅拌反应1小时。之后反应混合物在20℃下搅拌反应12小时。20℃下补加三溴化硼(13.5g)，反应混合物在20℃下搅拌反应12小时。0℃下补加三溴化硼(13.5g)，反应混合物在室温下搅拌反应12小时。反应完毕后，将反应液倒入冰水(2000mL)中，过滤，滤饼溶于水(4000mL)，用饱和碳酸氢钠溶液调节pH值为8–9，之后用2–甲基四氢呋喃(1500mL×3)萃取。合并有机相，依次用饱和食盐水(200mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到中间体WX011–3。 1H NMR(400MHz,DMSO_d 6)δ:12.53(s,1H),9.07(dd,J＝1.2,5.6Hz,1H),8.86(d,J＝8.4Hz,1H),8.65(s,1H), 7.81–7.74(m,2H).
步骤3：中间体WX011–4的合成
20℃和氮气保护下，将中间体WX011–3(2.22g,9.91mmol)溶于乙腈(50mL)中，随后加入碳酸钾(6.85g,49.54mmol)和4–溴巴豆酸乙酯(2.42g,9.41mmol)，反应混合物在20℃下搅拌反应12小时。反应完毕后，将反应液倒入水(100mL)中，加入乙酸乙酯(80mL)稀释，分液收集有机相，水相用乙酸乙酯(80mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–6/1，体积比)，得到中间体WX011–4。
步骤4：中间体WX011–5的合成
室温和氮气保护下，将中间体WX011–4(1g,2.97mmol)溶于N,N–二甲基甲酰胺(50mL)中，再依次加入碳酸钠(493.78mg,5.95mmol)和氯(2–二环己基膦基-2,4,6-三异丙基–1,1–联苯基)[2-(2–氨基–1,1–联苯)]钯(II)(468.08mg,594.92μmol)，反应混合物升温至80℃并搅拌反应16小时。补加氯(2–二环己基膦基–2,4,6–三异丙基–1,1–联苯基)[2–(2–氨基–1,1–联苯)]钯(II)(60mg)，反应混合物升温至80℃搅拌反应12小时。反应完毕后，反应液冷却至室温，向反应液中加入半饱和食盐水(400mL)和乙酸乙酯(200mL)，分液收集有机相，水相用乙酸乙酯(100mL×3)萃取。合并有机相，用半饱和食盐水(100mL×2)洗涤，再用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物先经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–4/1，体积比)，再经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到中间体WX011–5。 1H NMR(400MHz,DMSO_d 6)δ:9.24(dd,J＝1.2,4.8Hz,1H),9.16(d,J＝8.4Hz,1H),8.58(s,1H),8.47(s,1H),8.34(s,1H),7.93(dd,J＝5.0,8.6Hz,1H),4.16(q,J＝7.2Hz,2H),3.99(s,2H),1.22(t,J＝7.2Hz,3H).
步骤5：WX011的合成
20℃和氮气保护下，将中间体WX011–5(120mg,470.09μmol)溶于N,N–二甲基甲酰胺(2mL)中，随后依次加入丙烯酰胺(33.41mg,470.09μmol)和叔丁醇钾(79.13mg,705.14μmol)，反应混合物在20℃下搅拌反应2小时。反应完毕后，向反应液中滴加2N稀盐酸调节pH值至6–7，所得残余物经过制备HPLC分离(流动相：乙腈/水；碱性体系：10mM NH 4HCO 3)，得到目标化合物WX011。MS–ESI m/z:281.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.98(s,1H),8.90(s,1H),8.46(d,J＝8.0Hz,1H),8.22(s,1H),8.14(d,J＝2.8Hz,2H),7.48(dd,J＝3.6,8.0Hz,1H),4.28(dd,J＝4.2,12.2Hz,1H),2.88–2.74(m,1H),2.69–2.58(m,1H),2.46–2.31(m,1H),2.24–2.12(m,1H).
实施例12：WX012
Figure PCTCN2019104992-appb-000072
步骤1：中间体WX012–2的合成
0℃下，将化合物WX012–1(5g,33.08mmol)溶于二氯甲烷(50mL)中，随后加入N–碘代丁二酰亚胺(14.88g,66.15mmol)，反应混合物恢复至室温并搅拌反应12小时。反应完毕后，反应液过滤，收集滤饼，滤饼减压浓缩除去溶剂，得到WX012–2。 1H NMR(400MHz,DMSO_d 6)δ:10.56(s,1H),9.19–9.06(m,1H),7.96(s,1H),7.08(s,1H),1.98(s,3H).
步骤2：中间体WX012–3的合成
20℃下，将中间体WX012–2(4.7g,11.66mmol)和4–溴巴豆酸乙酯(3.00g,11.66mmol,2.14mL)溶于乙腈(70mL)中，随后加入碳酸钾(4.03g,29.16mmol)，反应混合物在20℃下搅拌反应12小时。反应完毕后，将反应液倒入水(100mL)中，过滤，收集滤饼，用水(100mL)洗涤，减压浓缩除去溶剂。得到中间体WX012–3。
步骤3：中间体WX012–4的合成
20℃下，将中间体WX012–3(2.9g,5.63mmol)溶于N,N–二甲基甲酰胺(90mL)中，随后依次加入甲酸钠(585.75mg,5.63mmol)，碳酸钠(1.49g,14.08mmol)，苄基三乙基氯化铵(1.41g,6.19mmol)和醋酸钯(63.20mg,281.51μmol)，反应混合物在20℃下搅拌反应3小时。反应完毕后，反应液倒入冰水(300mL)中，用乙酸乙酯(400mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–3/1，体积比)，得到中间体WX012–4。
步骤4：中间体WX012–5的合成
室温和氮气保护下，将中间体WX012–4(0.33g,852.34μmol)溶于四氢呋喃(10mL)中，随后加入劳森试剂(344.74mg,852.34μmol)，反应混合物加热至55℃并搅拌反应12小时。反应完毕后，反应液减压浓缩 除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10/1，体积比)，得到中间体WX012–5。
步骤5：中间体WX012–6的合成
室温和氮气保护下，将中间体WX012–5(250mg,619.99μmol)溶于N,N–二甲基甲酰胺(4mL)中，之后加入湿钯/碳(0.25g,纯度：10％)，反应混合物在室温下搅拌反应12小时。反应完毕后，过滤，收集滤液，向滤液中加入水(20mL)，用乙酸乙酯萃取(20mL×3)。合并有机相，依次用半饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0至5/1，体积比)，得到中间体WX012–6。 1H NMR(400MHz,CDCl 3)δ:8.04(s,1H),7.96(s,1H),7.71(s,1H),4.21(q,J＝7.2Hz,2H),3.74(d,J＝0.8Hz,2H),2.86(s,3H),1.28(t,J＝7.0Hz,3H).
步骤6：WX012的合成
室温和氮气保护下，将中间体WX012–6(40mg,145.28μmol)溶于N,N–二甲基甲酰胺(1mL)中，随后依次加入丙烯酰胺(10.33mg,145.28μmol)和叔丁醇钾(16.30mg,145.28μmol)，反应混合物在室温下搅拌反应1小时。反应完毕后，向反应液中加入水(10mL)，用乙酸乙酯萃取(20mL×2)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过制备HPLC分离(流动相：乙腈/水；中性体系：10mM NH 4HCO 3)，得到目标化合物WX012。MS–ESI m/z:301.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.91(s,1H),8.22(s,1H),8.10(s,1H),8.00(s,1H),4.19(dd,J＝5.0,12.2Hz,1H),2.81(s,3H),2.79–2.71(m,1H),2.64–2.57(m,1H),2.44–2.36(m,1H),2.19–2.09(m,1H).
实施例13：WX013
Figure PCTCN2019104992-appb-000073
步骤1：中间体WX013–2的合成
室温和氮气保护下，将化合物WX013–1(10g,44.04mmol)溶于四氢呋喃(100mL)中，叔丁醇钾(7.41g,66.06mmol)分批加入到上述溶液中，随后碘甲烷(17.19g,121.11mmol,7.54mL)滴加到上述反应液中，反应混合物在20℃下搅拌反应2小时。反应完毕后，向反应液加入乙酸乙酯(200mL)，去离子水(200mL)，有机相分离，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5:1，体积比)，得到中间体WX013–2。MS–ESI m/z:240.6[M+H] + ,242.6[M+H+2] +.
步骤2：中间体WX013–3的合成
室温和氮气保护下，将中间体WX013–2(5g,20.74mmol)溶于二氯甲烷(100mL)中，三溴化硼(15.59g,62.22mmol,6.00mL)慢慢滴加到上述反应液中，反应混合物在20℃下搅拌反应12小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(200mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1:1，体积比)，得到中间体WX013–3。MS–ESI m/z:226.7[M+H] + ,228.7[M+H+2] +.
步骤3：中间体WX013–4的合成
室温和氮气保护下，将中间体WX013–3(1.0g,4.40mmol)，4–溴巴豆酸乙酯(1.28g,6.61mmol,910.90μL)，碳酸钾(1.22g,8.81mmol)加入N,N–二甲基甲酰胺(30mL)中，反应混合物在室温下搅拌反应12小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/1，体积比)，得到中间体WX013–4。MS–ESI m/z:338.9[M+H] + ,340.9[M+H+2] +. 1H NMR(400MHz,CDCl 3)δ:7.97(s,1H),7.76(s,1H),7.15–7.10(m,1H),6.92(s,1H),6.39–6.34(m,1H),4.78–4.74(m,2H),4.24(q,J＝14.4Hz,2H),4.18(s,3H),1.32(t,J＝7.2Hz,3H).
步骤4：中间体WX013–5的合成
室温和氮气保护下，将中间体WX013–4(0.9g,2.23mmol)，醋酸钯(50.04mg,222.89μmol)，四丁基氯化铵(743.33mg,2.67mmol)，甲酸钠(151.58mg,2.23mmol)，碳酸钠(590.60mg,5.57mmol)溶于N,N–二甲基甲酰胺(50mL)中，反应混合物加热至80℃并搅拌反应2小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1:1，体积比)，得到中间体WX013–5。MS–ESI m/z:258.9[M+H] +.
步骤5：WX013的合成
0–5℃和氮气保护下，将中间体WX013–5(0.3g,1.03mmol)溶于N,N–二甲基甲酰胺(10mL)中，依次加 入叔丁醇钾(116.00mg,1.03mmol)，丙烯酰胺(73.48mg,1.03mmol)，反应混合物在0–5℃搅拌1小时。反应完毕后，向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX013。 1HNMR(400MHz,DMSO_d 6)δ:10.92(s,1H),8.41(s,1H),7.85(s,1H),7.75(s,1H),7.70(s,1H),4.22(s,3H),4.17(dd,J＝4.6,12.2Hz,1H),2.72–2.50(m,2H),2.34–2.30(m,1H),2.19–2.09(m,1H).
实施例14：WX014
Figure PCTCN2019104992-appb-000074
步骤1：中间体WX014–1的合成
室温和氮气保护下，将化合物WX013–1(10g,44.04mmol)溶于四氢呋喃(100mL)中，叔丁醇钾(7.41g,66.06mmol)分批加入到上述溶液中，随后碘甲烷(17.19g,121.11mmol,7.54mL)滴加到上述反应液中，反应混合物在室温下搅拌反应2小时。反应完毕后，向反应液加入乙酸乙酯(200mL)，去离子水(200mL)，有机相分离，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂。所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5:1，体积比)，得到中间体WX014–1。MS–ESI m/z:240.7[M+H] + ,242.7[M+H+2] +.
步骤2：中间体WX014–2的合成
室温和氮气保护下，将中间体WX014–1(0.13g,539.23μmol)溶于甲苯(10mL)中，加入三氯化铝(143.80mg,1.08mmol)，反应混合物加热到110℃并搅拌反应12小时。反应完毕后，向反应液中加入水(30mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1:1，体积比)，得到中间体 WX014–2。MS–ESI m/z:226.8[M+H] + ,228.8[M+H+2] +. 1H NMR(400MHz,CDCl 3)δ:7.86(s,1H),7.60(s,1H),7.30(s,1H),5.43(s,1H),4.03(s,3H).
步骤3：中间体WX014–3的合成
室温和氮气保护下，将中间体WX014–2(0.09g,396.38μmol)溶于N,N–二甲基甲酰胺(10mL)中，加入碳酸钾(109.56mg,792.75μmol)，4–溴巴豆酸乙酯(114.77mg,594.56μmol,81.98μL)，反应混合物在室温下搅拌反应12小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3:1，体积比)，得到中间体WX014–3。MS–ESI m/z:338.9[M+H] + ,340.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.86(s,1H),7.68(s,1H),7.16–7.09(m,2H),6.38–6.33(m,1H),4.78(t,J＝2.4Hz,2H),4.24(q,J＝14.4Hz,2H),4.04(s,3H),1.32(t,J＝7.2Hz,3H).
步骤4：中间体WX014–4的合成
室温和氮气保护下，将中间体WX014–3(0.095g,280.08μmol)，醋酸钯(6.29mg,28.01μmol)，四丁基氯化铵(93.41mg,336.10μmol)，甲酸钠(19.05mg,280.08μmol)，碳酸钠(74.22mg,700.21μmol)溶于N,N–二甲基甲酰胺(10mL)中，反应混合物加热至80℃并搅拌2小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取。合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1:1，体积比)，得到中间体WX014–4。MS–ESI m/z:258.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:8.06(s,1H),7.73(d,J＝0.8Hz,1H),7.72(s,1H),7.45(s,1H),4.22(q,J＝14.4Hz,2H),4.14(s,3H),3.76(s,2H),1.30(t,J＝7.2Hz,3H).
步骤5：WX014的合成
氮气保护下，将中间体WX014–4(0.07g,271.03μmol)溶于N,N–二甲基甲酰胺(10mL)中，加入叔丁醇钾(30.41mg,271.03μmol)，加入丙烯酰胺(19.26mg,271.03μmol)，反应混合物在0–5℃搅拌1小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取。分离有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX014。 1HNMR(400MHz,DMSO_d 6)δ:10.92(s,1H),8.41(s,1H),7.85(s,1H),7.75(s,1H),7.71(s,1H),4.22(s,3H),4.19(dd,J＝4.6,12.2Hz,1H),2.68–2.57(m,2H),2.34–2.25(m,1H),2.19–2.09(m,1H).
实施例15：WX015的盐酸盐
Figure PCTCN2019104992-appb-000075
步骤1：中间体WX015–2的合成
室温和氮气保护下，将化合物WX015–1(50g,265.64mmol)溶于四氢呋喃(3000mL)中，反应混合物冷却到–65℃，正丁基锂(2.5M,116.88mL)慢慢滴加到上述反应液中，大约需要30分钟，在–65℃下，1,2–二溴乙烷(49.9g,265.64mmol,20.04mL)慢慢滴加到上述溶液中，反应混合物在20℃下搅拌反应12小时。反应完毕后，向反应液加入乙酸乙酯(6000mL)，去离子水(1000mL)，有机相分离，用饱和食盐水(1000mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10:1，体积比)，得到中间体WX015–2。
步骤2：中间体WX015–3的合成
室温和氮气保护下，将中间体WX015–2(50g,187.18mmol,)溶于二氯甲烷(1000mL)中，反应混合物冷却至–78℃，三溴化硼(187.57g,748.73mmol,72.14mL)慢慢滴加到上述反应液中，反应混合物在20℃下搅拌反应12小时。反应完毕后，反应液冷却到0–5℃，甲醇(200mL)慢慢滴加到反应混合物中，在0–5℃下搅拌10分钟，加入去离子水(500mL)，有机相分离，用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3:1，体积比)，得到中间体WX015–3。 1H NMR(400MHz,DMSO_d 6)δ:10.18(s,1H),9.57(s,1H),7.93(s,1H),7.57–7.51(m,1H),7.20(s,1H),7.04–6.97(m,2H).
步骤3：中间体WX015–4的合成
0–5℃和氮气保护下，将中间体WX015–3(25g,104.57mmol)，4–溴巴豆酸乙酯(20.19g,104.57mmol,14.42 mL)，碳酸钾(28.91g,209.15mmol)加入N,N–二甲基甲酰胺(500mL)中，反应混合物在0–5℃下搅拌反应2小时。反应完毕后，向反应液中加入水(2000mL)，用乙酸乙酯(2000mL)萃取。分离有机相，用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3:1，体积比)，得到中间体WX015–4。MS–ESI m/z:351.0[M+H] + ,353.0[M+H+2] +.步骤4：中间体WX015–5的合成
室温和氮气保护下，将中间体WX015–4(20g,50.68mmol)，醋酸钯(3.41g,15.21mmol)，四丁基氯化铵(14.09g,50.68mmol)，甲酸钠(10.34g,152.05mmol)，碳酸钠(16.12g,152.05mmol)溶于N,N–二甲基甲酰胺(500mL)中，反应混合物加热至80℃并搅拌反应5小时。反应完毕后，向反应液中加入水(200mL)，用乙酸乙酯(300mL)萃取。分离有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3:1，体积比)，得到中间体WX015–5。MS–ESI m/z:271.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:9.59(s,1H),7.98(s,1H),7.93(s,1H),7.86(t,J＝3.2Hz,2H),7.21(d,J＝2.0Hz,1H),7.09(dd,J＝2.4,8.8Hz,1H),4.15(q,J＝7.2Hz,2H),3.85(s,2H),1.22(t,J＝7.2Hz,3H).
步骤5：中间体WX015–6的合成
室温和氮气保护下，将中间体WX015–5(0.5g,1.85mmol)，N–(2–羟乙基)吗啡啉(363.99mg,2.77mmol,340.18μL)，三苯基膦(727.82mg,2.77mmol)，偶氮二甲酸二异丙酯(561.11mg,2.77mmol,539.53μL)溶于四氢呋喃(20mL)中，反应混合物加热至70℃并搅拌反应2小时。反应完毕后，向反应液中加入水(20mL)，用乙酸乙酯(50mL)萃取。分离有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到中间体WX015–6。MS–ESI m/z:384.1[M+H] +.
步骤6：WX015的合成
室温和氮气保护下，将中间体WX015–6(0.15g,391.20μmol)溶于N,N–二甲基甲酰胺(30mL)中，加入叔丁醇钾(65.85mg,586.80μmol)，加入丙烯酰胺(27.81mg,391.20μmol)，反应混合物在0–5℃下搅拌反应2小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取。分离有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX015的盐酸盐。MS–ESI m/z:409.1[M+H] +. 1HNMR(400MHz,DMSO_d 6)δ:11.59(s,1H),10.98(s,1H),8.04(t,J＝4.2Hz,3H),7.96(d,J＝8.8Hz,1H),7.48(d,J＝1.6Hz,1H),7.22(dd,J＝2.2,9.0Hz,1H),4.66–4.53(m,2H),4.23(dd,J＝4.8,12.0Hz,1H),4.04–3.81(m,4H),3.67–3.55(m,4H),3.35–3.14(m,2H),2.91–2.75(m,1H),2.69–2.58(m,1H),2.47–2.38(m,1H),2.25–2.11(m,1H).
实施例16：WX016的盐酸盐
Figure PCTCN2019104992-appb-000076
步骤1：中间体WX016–1的合成
室温和氮气保护下，将中间体WX015–5(0.5g,1.85mmol)，1–(2–羟乙基)哌啶(358.52mg,2.77mmol)，三苯基膦(727.83mg,2.77mmol)，偶氮二甲酸二异丙酯(561.11mg,2.77mmol,539.53μL)溶于四氢呋喃(20mL)中，反应混合物加热至70℃并搅拌反应2小时。反应完毕后，向反应液中加入水(20mL)，用乙酸乙酯(50mL)萃取。分离有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到中间体WX016–1。MS–ESI m/z:382.1[M+H] +.
步骤2：WX016的合成
室温和氮气保护下，将中间体WX016–1(0.15g,393.22μmol)溶于N,N–二甲基甲酰胺(30mL)中，加入叔丁醇钾(66.19mg,589.83μmol)，加入丙烯酰胺(27.95mg,393.22μmol)，反应混合物在0–5℃下搅拌反应2小时。反应完毕后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取。分离有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX016的盐酸盐。MS–ESI m/z:407.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.98(s,1H),10.78(s,1H),8.04(d,J＝3.6Hz,2H),8.02(s,1H),7.96(d,J＝9.2Hz,1H),7.48(d,J＝1.6Hz,1H),7.21(dd,J＝2.2,9.0Hz,1H),4.61–4.49(m,2H),4.23(dd,J＝4.8,12.0Hz,1H),3.56–3.51(m,4H),3.11–2.96(m,2H),2.89–2.76(m,1H),2.69–2.58(m,1H),2.47–2.39(m,1H),2.23–2.12(m,1H),1.90–1.78(m,4H),1.75–1.66(m,1H),1.47–1.32(m,1H).
实施例17：WX017
Figure PCTCN2019104992-appb-000077
Figure PCTCN2019104992-appb-000078
步骤1：中间体WX017–1的合成
室温和氮气保护下，将中间体WX015–5(300mg,1.11mmol)溶于二氯甲烷(10mL)中，依次加入醋酸铜(201.60mg,1.11mmol)，吡啶(175.60mg,2.22mmol,179.18μL)，三乙胺(224.63mg,2.22mmol,308.99μL)和4–氟苯硼酸(310.61mg,2.22mmol)，反应混合物在室温下搅拌反应14小时。反应完毕后，向反应液中加入水(30mL)，用二氯甲烷(30mL×3)萃取。合并有机相，用饱和食盐水(60mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–100/1，体积比)，得到中间体WX017–1。 1H NMR(400MHz,CDCl 3)δ:7.92(d,J＝9.2Hz,1H),7.87(d,J＝1.6Hz,2H),7.74(s,1H),7.36(d,J＝2.4Hz,1H),7.25(dd,J＝2.6,9.0Hz,1H),7.07(d,J＝1.6Hz,2H),7.06(s,2H),4.21(q,J＝7.0Hz,2H),3.76(d,J＝1.2Hz,2H),1.28(t,J＝7.2Hz,3H).
步骤2：WX017的合成
0℃和氮气保护下，将中间体WX017–1(180mg,494.01μmol)加入到N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(55.43mg,494.01μmol)和丙烯酰胺(35.11mg,494.01μmol)，反应混合物在0℃氮气保护下继续搅拌反应1.5小时。反应完毕后，加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX017。MS–ESI m/z:390.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.91(s,1H),8.09(s,1H),8.06(t,J＝4.6Hz,2H),8.03(s,1H),7.37(d,J＝2.4Hz,1H),7.32–7.24(m,3H),7.20–7.13(m,2H),4.19(dd,J＝4.6,12.2Hz,1H),2.82–2.71(m,1H),2.62–2.55(m,1H),2.47–2.40(m,1H),2.16–2.09(m,1H).
实施例18：WX018
Figure PCTCN2019104992-appb-000079
步骤1：中间体WX018–1的合成
室温和氮气保护下，将中间体WX015–5(300mg,1.11mmol)溶于二氯甲烷(10mL)中，依次加入醋酸铜(201.60mg,1.11mmol)，吡啶(175.60mg,2.22mmol,179.18μL)，三乙胺(224.63mg,2.22mmol,308.99μL)和3–甲氧基苯硼酸(337.34mg,2.22mmol)，反应混合物在室温下搅拌反应14小时。反应完毕后，向反应液中加入水(30mL)，用二氯甲烷(30mL×3)萃取。合并有机相，用饱和食盐水(60mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–100/1，体积比)，得到中间体WX018–1。MS–ESI m/z:377.0[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.92(d,J＝9.2Hz,1H),7.89(d,J＝4.0Hz,2H),7.75(s,1H),7.47(d,J＝2.0Hz,1H),7.28(d,J＝2.4Hz,1H),7.24(dd,J＝1.6,6.4Hz,1H),6.72–6.68(m,1H),6.67–6.63(m,2H),4.22(q,J＝7.0Hz,2H),3.80(s,3H),3.77(d,J＝0.8Hz,2H),1.29(t,J＝7.0Hz,3H).
步骤2：WX018的合成
0℃和氮气保护下，将中间体WX018–1(250mg,612.11μmol,纯度：92.16％)加入到N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(68.69mg,612.11μmol)和丙烯酰胺(43.51mg,612.11μmol)，反应混合物在0℃氮气保护下继续搅拌反应2小时。反应完毕后，加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX018。MS–ESI m/z:402.0[M+H] +. 1H NMR(400MHz,DMSO _d 6)δ:10.93(s,1H),8.11–8.07(m,2H),8.06–8.02(m,2H),7.46(d,J＝2.4Hz,1H),7.34–7.26(m,2H),6.75(dd,J＝2.4,8.0Hz,1H),6.67(t,J＝2.4Hz,1H),6.62(dd,J＝2.0,8.0Hz,1H),4.20(dd,J＝4.8,12.4Hz,1H),3.74(s,3H),2.83–2.72(m,1H),2.67–2.56(m,1H),2.45–2.31(m,1H),2.17–2.09(m,1H).
实施例19：WX019
Figure PCTCN2019104992-appb-000080
步骤1：中间体WX019–1的合成
室温和氮气保护下，将中间体WX015–5(400mg,1.48mmol)和2–溴乙基甲基醚(205.70mg,1.48mmol)溶于N,N–二甲基甲酰胺(50mL)中，随后加入碳酸钾(613.63mg,4.44mmol)和碘化钾(1.23g,7.40mmol)，反应混合物升至50℃并搅拌反应36小时。反应完毕后，冷却至室温，加入水(50mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(洗脱剂：石油醚/乙酸乙酯＝5/1，体积比)，得到中间体WX019–1。MS–ESI m/z:328.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.89(s,1H),7.82(t,J＝4.6Hz,2H),7.72(s,1H),7.25(d,J＝2.4Hz,1H),7.21(dd,J＝2.6,9.0Hz,1H),4.27(t,J＝4.8Hz,2H),4.22(q,J＝7.6Hz,2H),3.85(t,J＝4.6Hz,2H),3.77(d,J＝0.8Hz,2H),3.50(s,3H),1.29(t,J＝7.0Hz,3H).
步骤2：WX019的合成
0℃和氮气保护下，将中间体WX019–1(360mg,1.01mmol,纯度：92.40％)溶于N,N–二甲基甲酰胺(30mL)中，随后加入叔丁醇钾(113.67mg,1.01mmol)和丙烯酰胺(72.00mg,1.01mmol)，反应混合物在0℃下继续搅拌反应2小时。反应完毕后，加入水(50mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(40mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX019。MS–ESI m/z:354.1.[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.96(s,1H),8.01(s,2H),7.99(s,1H),7.91(d,J＝9.2Hz,1H),7.39(d,J＝2.0Hz,1H),7.15(dd,J＝2.2,9.0Hz,1H),4.22(dd,J＝4.8,12.4Hz,1H),4.20–4.18(m,2H),3.73(t,J＝4.4Hz,2H),3.30(s,3H),2.86–2.74(m,1H),2.69–2.59(m,1H),2.45–2.33(m,1H),2.20–2.11(m,1H).
实施例20：WX020
Figure PCTCN2019104992-appb-000081
步骤1：中间体WX020–1的合成
室温和氮气保护下，将中间体WX015–5(300mg,1.11mmol)和2,2–二氟乙基三氟甲磺酸酯(237.66mg,1.11mmol)溶于N,N–二甲基甲酰胺(30mL)中，随后加入碳酸钾(460.22mg,3.33mmol)，反应混合物在室温下继续搅拌反应36小时。反应完毕后，加入水(50mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层 析分离(洗脱剂：石油醚/乙酸乙酯＝1/0–10/1，体积比)，得到中间体WX020–1。MS–ESI m/z:334.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.92(s,1H),7.88–7.83(m,2H),7.74(s,1H),7.24(d,J＝2.4Hz,1H),7.19(dd,J＝2.6,9.0Hz,1H),6.35–6.03(m,1H),4.33(td,J＝4.2,13.0Hz,2H),4.23(q,J＝7.0Hz,2H),3.78(s,2H),1.30(t,J＝7.2Hz,3H).
步骤2：WX020的合成
0℃和氮气保护下，将中间体WX020–1(101mg,299.36μmol，纯度：99.09％)溶于N,N–二甲基甲酰胺(30mL)中，随后加入叔丁醇钾(33.59mg,299.36μmol)和丙烯酰胺(21.28mg,299.36μmol)，反应混合物在0℃下继续搅拌反应2小时。反应完毕后，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX020。MS–ESI m/z:360.0.[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.98(s,1H),8.04(d,J＝5.6Hz,2H),8.01(s,1H),7.95(d,J＝9.2Hz,1H),7.50(d,J＝2.4Hz,1H),7.21(dd,J＝2.6,9.0Hz,1H),6.66–6.28(m,1H),4.49–4.37(m,2H),4.23(dd,J＝5.0,12.2Hz,1H),2.85–2.76(m,1H),2.69–2.64(m,1H),2.43–2.33(m,1H),2.21–2.13(m,1H).
实施例21：WX021
Figure PCTCN2019104992-appb-000082
步骤1：中间体WX021–1的合成
20℃和氮气保护下，将中间体WX015–5(300mg,1.11mmol)和3–乙酰氨基苯硼酸(397.32mg,2.22mmol)溶于N,N–二甲基甲酰胺(50mL)中，随后加入醋酸铜(201.60mg,1.11mmol)，三乙胺(224.63mg,2.22mmol)和吡啶(175.60mg,2.22mmol)，反应混合物升温至50℃并继续搅拌反应14小时。反应完毕后，冷却至室温，加入水(50mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过板分离(洗脱剂：石油醚/乙酸乙酯＝2/1，体积比)，得到中间体WX021–1。MS–ESI m/z:403.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.92(d,J＝8.8Hz,1H),7.88(d,J＝4.0Hz,2H),7.74(s,1H),7.49(d,J＝7.6Hz,1H),7.46(d,J＝2.4Hz,1H),7.36–7.29(m,3H),7.22–7.17(m,2H),4.21(q,J＝7.2Hz,2H),3.76(d,J＝1.2Hz,2H),2.15(s,3H),1.29(t,J＝7.4Hz,3H).
步骤2：WX021的合成
0℃和氮气保护下，将中间体WX021–1(115mg,222.80μmol，纯度：78.16％)溶于N,N–二甲基甲酰胺(30mL)中，随后加入叔丁醇钾(25.00mg,222.80μmol)和丙烯酰胺(15.84mg,222.80μmol)，反应混合物在0℃下继续搅拌反应2小时。反应完毕后，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX021。MS–ESI m/z:429.1.[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.93(s,1H),10.01(s,1H),8.11(s,1H),8.09–8.02(m,3H),7.47(d,J＝2.4Hz,1H),7.37(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,2H),7.28(dd,J＝2.6,9.0Hz,1H),6.77(dd,J＝1.6,8.0Hz,1H),4.20(dd,J＝4.8,12.0Hz,1H),2.82–2.73(m,1H),2.63–2.56(m,1H),2.47–2.41(m,1H),2.17–2.10(m,1H),1.99(s,3H).
实施例22：WX022的盐酸盐
Figure PCTCN2019104992-appb-000083
步骤1：中间体WX022–1的合成
室温和氮气保护下，将中间体WX015–5(0.5g,1.68mmol,纯度：91％)溶于甲苯(50mL)中，随后加入1,2–二溴乙烷(948.76mg,5.05mmol,381.03μL)，碳酸钾(698.01mg,5.05mmol)和18–冠–6–醚(4.45g,16.83mmol)，反应混合物加热至110℃并搅拌反应12小时。反应完毕后，两批次合并处理，冷却至室温，反应液倒入水(50mL)中稀释，用乙酸乙酯(30mL×3)萃取。合并有机相，用水(50mL×2)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1至5/1，体积比)，得到中间体WX022–1。MS–ESI m/z:376.8[M+H] + ,378.8[M+H+2] +. 1H NMR(400MHz,CDCl 3)δ:7.90(s,1H),7.87–7.83(m,2H),7.73(s,1H),7.25(d,J＝2.4Hz,1H),7.19(dd,J＝2.6,9.0Hz,1H),4.44(t,J＝6.4Hz,2H),4.22(q,J＝7.0Hz,2H),3.78(s,2H),3.74(t,J＝6.4Hz,2H),1.30(t,J＝7.2Hz,3H).
步骤2：中间体WX022–2的合成
室温和氮气保护下，将中间体WX022–1(0.25g,662.73μmol)溶于乙腈(25mL)中，随后加入二甲胺水溶液(283.84mg,2.52mmol,纯度：40％)和碳酸钾(183.19mg,1.33mmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，减压除去溶剂，向残余物中加入水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝30/1，体积比)，得到目标中间体WX022–2。MS–ESI m/z:341.9[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.89(s,1H),7.84–7.79(m,2H),7.72(s,1H),7.25(d,J＝2.0Hz,1H),7.19(dd,J＝2.6,9.0Hz,1H),4.26–4.18(m,4H),3.77(d,J＝0.8Hz,2H),2.83(t,J＝5.6Hz,2H),2.39(s,6H),1.29(t,J＝7.0Hz,3H).
步骤3：WX022的合成
0℃和氮气保护下，将中间体WX022–2(0.15g,421.49μmol)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(52.02mg,463.63μmol)，再加入丙烯酰胺(29.96mg,421.49μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX022的盐酸盐。MS–ESI m/z:367.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.98(s,1H),10.36(s,1H),8.05(s,1H),8.04(s,1H),8.01(s,1H),7.96(d,J＝9.2Hz,1H),7.48(d,J＝2.0Hz,1H),7.21(dd,J＝2.6,9.0Hz,1H),4.47(t,J＝4.8Hz,2H),4.23(dd,J＝4.8,12.4Hz,1H),3.62–3.55(m,2H),2.87(s,6H),2.84–2.75(m,1H),2.66–2.59(m,1H),2.47–2.38(m,1H),2.22–2.13(m,1H).
实施例23：WX023的盐酸盐
Figure PCTCN2019104992-appb-000084
步骤1：中间体WX023–1的合成
室温和氮气保护下，将中间体WX022–1(0.3g,795.28μmol)溶于乙腈(25mL)中，随后加入吡咯烷(216.81mg,3.05mmol)和碳酸钾(219.83mg,1.60mmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，减压除去溶剂，向残余物中加入水(30mL)稀释，用乙酸乙酯(30mL×3)萃取。 合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝30/1，体积比)，得到中间体WX023–1。MS–ESI m/z:368.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.89(s,1H),7.84–7.79(m,2H),7.72(s,1H)7.25(d,J＝2.4Hz,1H),7.19(dd,J＝2.2,9.0Hz,1H),4.28–4.19(m,4H),3.77(d,J＝0.8Hz,2H),3.00(t,J＝5.8Hz,2H),2.73–2.65(m,4H),1.88–1.81(m,4H),1.29(t,J＝7.0Hz,3H).
步骤2：WX023的合成
0℃和氮气保护下，将中间体WX023–1(0.25g,670.73umol)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(82.79mg,737.80μmol)，再加入丙烯酰胺(47.67mg,670.73μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX023的盐酸盐。MS–ESI m/z:393.2[M+H] +. 1H NMR(400MHz,DMSO _d 6)δ:10.97(s,1H),10.86(s,1H),8.04(s,1H),8.03(s,1H),8.01(s,1H),7.96(d,J＝9.2Hz,1H),7.47(d,J＝2.0Hz,1H),7.22(dd,J＝2.2,9.0Hz,1H),4.47(t,J＝4.4Hz,2H),4.23(dd,J＝4.8,12.4Hz,1H),3.69–3.56(m,4H),3.20–3.07(m,2H),2.87–2.75(m,1H),2.69–2.57(m,1H),2.46–2.38(m,1H),2.22–2.11(m,1H),2.08–1.96(m,2H),1.95–1.84(m,2H).
实施例24：WX024的三氟乙酸盐
Figure PCTCN2019104992-appb-000085
步骤1：中间体WX024–1的合成
室温和氮气保护下，将中间体WX022–1(0.15g,385.35μmol,纯度：96.91％)溶于乙腈(25mL)中，随后加入4–氨基四氢吡喃(155.91mg,1.54mmol,455.11μL)和碳酸钾(106.52mg,770.70μmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，减压浓缩除去溶剂，向残余物中加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝30/1，体积比)，得到中间体WX024–1。MS–ESI m/z:384.4[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.88(s,1H),7.82(t,J＝4.6Hz,2H),7.72 (s,1H),7.26(d,J＝2.4Hz,1H),7.16(dd,J＝2.4,9.2Hz,1H),4.23(t,J＝5.2Hz,2H),4.06–3.98(m,2H),3.80(s,2H),3.76(s,3H),3.44(td,J＝1.6,11.6Hz,2H),3.13(t,J＝5.2Hz,2H),2.85–2.77(m,1H),1.93–1.88(m,2H),1.55–1.44(m,2H).
步骤2：WX024的合成
0℃和氮气保护下，将中间体WX024–1(0.12g,308.52μmol,纯度：98.58％)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(38.08mg,339.37μmol)，再加入丙烯酰胺(21.93mg,308.52μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％TFA)分离，得到目标化合物WX024的三氟乙酸盐。MS–ESI m/z:423.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),8.85(s,2H),8.05(s,1H),8.03(s,1H),8.02(s,1H),7.97(d,J＝9.2Hz,1H),7.47(d,J＝2.0Hz,1H),7.22(dd,J＝2.4,9.2Hz,1H),4.36(t,J＝4.4Hz,2H),4.22(dd,J＝4.8,12.4Hz,1H),3.94(dd,J＝3.4,11.4Hz,2H),3.48–3.46(m,2H),3.33–3.28(m,2H),2.85–2.75(m,1H),2.66–2.60(m,1H),2.45–2.32(m,1H),2.24–2.12(m,1H),2.05–1.95(m,2H),1.68–1.55(m,2H),1.25–1.21(m,1H).
实施例25：WX025的盐酸盐
Figure PCTCN2019104992-appb-000086
步骤1：中间体WX025–1的合成
室温和氮气保护下，将中间体WX022–1(145mg,382.04μmol,纯度：99.39％)溶于乙腈(10mL)中，加入3–氮杂双环[3.1.0]己烷(31.76mg,382.04μmol)和碳酸钾(105.60mg,764.08μmol)，反应混合物升温至80℃并在80℃下搅拌反应14小时。反应完毕后，向反应液中加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过板分离(展开剂：石油醚/乙酸乙酯＝1/1，体积比)，得到中间体WX025–1。MS–ESI m/z:379.9[M+H] +.步骤2：WX025的合成
0℃和氮气保护下，将中间体WX025–1(124mg,316.99μmol,纯度：97.00％)溶于N,N–二甲基甲酰胺(5 mL)中，随后加入叔丁醇钾(35.57mg,316.99μmol)和丙烯酰胺(22.53mg,316.99μmol)，反应混合物在0℃氮气保护下继续搅拌反应1.5小时。反应完毕后，加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX025的盐酸盐。MS–ESI m/z:405.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),10.50(s,1H),8.03(d,J＝3.6Hz,2H),8.01(s,1H),7.95(d,J＝9.2Hz,1H),7.45(s,1H),7.20(d,J＝9.2Hz,1H),4.53–4.34(m,2H),4.22(dd,J＝5.0,12.2Hz,1H),3.71–3.53(m,2H),3.52–3.36(m,4H),2.86–2.75(m,1H),2.68–2.59(m,1H),2.47–2.31(m,1H),2.21–2.12(m,1H),1.81–1.60(m,2H),1.06–0.85(m,1H),0.72–0.54(m,1H).
实施例26：WX026的盐酸盐
Figure PCTCN2019104992-appb-000087
步骤1：中间体WX026–1的合成
室温和氮气保护下，将中间体WX022–1(150mg,394.58μmol,纯度：99.23％)溶于乙腈(10mL)中，加入1–乙酰基哌嗪(50.57mg,394.58μmol)和碳酸钾(109.07mg,789.15μmol)，反应混合物升温至80℃并在80℃下搅拌反应14小时。反应完毕后，冷却至室温，向反应液中加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：石油醚/乙酸乙酯＝0/1，体积比)，得到中间体WX026–1。MS–ESI m/z:425.4[M+H] +.
步骤2：WX026的合成
0℃和氮气保护下，将中间体WX026–1(80mg,183.92μmol,纯度：97.59％)加入到N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(20.64mg,183.92μmol)和丙烯酰胺(13.07mg,183.92μmol)，反应混合物在0℃氮气保护下继续搅拌反应1.5小时。反应完毕后，加入水(30mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经制备HPLC分离(流动相：乙腈/水；酸性体系：0.05％HCl)，得到目标化合物WX026的盐酸盐。MS–ESI m/z:450.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),10.90(s,1H),8.04(d,J＝5.2Hz,2H),8.01(s,1H), 7.97(d,J＝9.2Hz,1H),7.48(d,J＝2.0Hz,1H),7.22(dd,J＝2.4,9.2Hz,1H),4.56–4.50(m,2H),4.48–4.41(m,1H),4.23(dd,J＝5.2,12.0Hz,1H),4.08–3.98(m,1H),3.68–3.57(m,4H),3.56–3.49(m,1H),3.27–3.16(m,1H),3.14–3.02(m,2H),2.87–2.76(m,1H),2.69–2.59(m,1H),2.47–2.35(m,1H),2.21–2.13(m,1H),2.05(s,3H).
实施例27：WX027的三氟乙酸盐
Figure PCTCN2019104992-appb-000088
步骤1：中间体WX027–1的合成
室温和氮气保护下，将中间体WX022–1(0.15g,385.35μmol,纯度：96.91％)溶于乙腈(25mL)中，随后加入环己胺(152.87mg,1.54mmol)和碳酸钾(106.52mg,770.70μmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，减压除去溶剂，向残余物中加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝30/1，体积比)，得到中间体WX027–1。MS–ESI m/z:382.4[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.87(s,1H),7.83–7.79(m,2H),7.72(s,1H),7.25(d,J＝2.4Hz,1H),7.16(dd,J＝2.4,9.2Hz,1H),4.22(t,J＝5.2Hz,2H),3.79(s,2H),3.76(s,3H),3.12(t,J＝5.2Hz,2H),2.60–2.52(m,1H),2.01–1.93(m,2H),1.77–1.73(m,1H),1.69–1.60(m,1H),1.36–1.10(m,6H).
步骤2：WX027的合成
0℃和氮气保护下，将中间体WX027–1(72.04mg,183.50μmol,纯度：97.17％)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(22.65mg,201.85μmol)，再加入丙烯酰胺(13.04mg,183.50μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％TFA)分离，得到目标化合物WX027的三氟乙酸盐。MS–ESI m/z:421.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),8.67(s,2H),8.05(s,1H),8.03(s,1H),8.02(s,1H),7.97(d,J＝8.8Hz,1H),7.47(d,J＝2.0Hz,1H),7.21(dd,J＝2.2,9.0Hz,1H),4.35(t,J＝4.8Hz,2H),4.22(dd,J＝4.8,12.4Hz,1H),3.46–3.43(m,2H),3.18–3.07(m,1H),2.87–2.77(m,1H),2.68–2.60(m,1H),2.45–2.31(m,1H),2.22–2.13(m,1H),2.12–2.05(m,2H),1.83–1.74(m,2H),1.68–1.57(m,1H),1.38–1.23(m,5H).
实施例28：WX028的盐酸盐
Figure PCTCN2019104992-appb-000089
步骤1：中间体WX028–1的合成
25℃和氮气保护下，将中间体WX022–1(0.2g,492.80μmol)，N–甲基环己胺(223.14mg,1.97mmol)，碳酸钾(136.22mg,985.61μmol)溶于乙腈(4mL)中，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，向反应液中加入2mL水，用乙酸乙酯(5mL×3)萃取，合并有机相，用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除出溶剂。所得残余物经过硅胶板分离(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到中间体WX028–1。MS–ESI m/z:410.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.88(s,1H),7.83–7.79(m,2H),7.72(s,1H),7.24(d,J＝2.0Hz,1H),7.16(dd,J＝2.4,9.2Hz,1H),4.22(q,J＝7.6Hz,2H),4.19(t,J＝6.0Hz,2H),3.78(s,2H),2.97(t,J＝6.2Hz,2H),2.54–2.47(m,1H),2.44(s,3H),1.94–1.86(m,2H),1.85–1.78(m,2H),1.34–1.30(m,3H),1.29–1.23(m,5H),1.17–1.09(m,1H).
步骤2：WX028的合成
25℃和氮气保护下，将中间体WX028–1(0.15g,360.13μmol，纯度：98.32％)溶于N,N–二甲基甲酰胺(10mL)中，用冰水浴冷却到0℃后，向反应液中加入丙烯酰胺(25.60mg,360.13μmol)，叔丁醇钾(44.45mg,396.15μmol)，反应混合物在0℃下搅拌反应2小时。反应完毕后，向反应液中加入2mL水稀释，用乙酸乙酯(5mL×3)萃取，合并有机相，用饱和食盐水(5mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除出溶剂。所得残余物经过制备HPLC分离(流动相：乙腈/水；酸性体系：HCl)，得到目标化合物WX028的盐酸盐。MS–ESI m/z:435.1[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),10.20(s,1H),8.04(d,J＝4.8Hz,2H),8.01(s,1H),7.96(d,J＝9.2Hz,1H),7.48(s,1H),7.20(dd,J＝2.0,8.8Hz,1H),4.56–4.45(m,2H),4.22(dd,J＝5.0,12.2Hz,1H),3.73–3.63(m,1H),2.94–2.85(m,1H),2.82(d,J＝4.8Hz,4H),2.74–2.57(m,2H),2.42–2.30(m,1H),2.22–2.14(m,1H),2.12–2.03(m,2H),1.89–1.78(m,2H),1.68–1.57(m,1H),1.53–1.40(m,2H),1.35–1.23(m,2H),1.19–1.07(m,1H).
实施例29：WX029的盐酸盐
Figure PCTCN2019104992-appb-000090
步骤1：中间体WX029–1的合成
室温和氮气保护下，将中间体WX022–1(252mg,609.02μmol,纯度：91.16％)溶于乙腈(15mL)中，随后加入N–Boc–哌嗪(567.15mg,3.05mmol)和碳酸钾(168.35mg,1.22mmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，反应混合物倒入水(10mL)中，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过薄层制备板分离(展开剂：石油醚/乙酸乙酯＝1/1，体积比)，得到中间体WX029–1。MS–ESI m/z:483.1[M+H] +. 1H NMR(400MHz,MeOD_d 4)δ:7.63(s,1H),7.55–7.47(m,3H),7.04(d,J＝2.4Hz,1H),6.84(dd,J＝2.6,9.0Hz,1H),3.96(t,J＝5.4Hz,2H),3.90(q,J＝7.0Hz,2H),3.52(s,2H),3.19–3.15(m,4H),2.60(t,J＝5.4Hz,2H),2.30(t,J＝5.0Hz,4H),1.16(s,9H),0.96(t,J＝7.2Hz,3H).
步骤2：WX029的合成
0℃和氮气保护下，将中间体WX029–1(0.28g,577.56μmol,纯度：99.54％)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(71.29mg,635.32μmol)，再加入丙烯酰胺(41.05mg,577.56μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物溶于盐酸乙酸乙酯(5mL)中，随后室温搅拌反应12小时。反应完毕后，减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX029的盐酸盐。MS–ESI m/z:408.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),9.55(s,2H),8.05(s,1H),8.04(s,1H),8.02(s,1H),7.96(d,J＝9.2Hz,1H),7.48(d,J＝2.0Hz,1H),7.23(dd,J＝2.0,8.8Hz,1H),4.58–4.45(m,2H),4.23(dd,J＝4.6,12.2Hz,1H),2.86–2.77(m,1H),2.70–2.64(m,1H),2.63–2.57(m,1H),2.55–2.52(m,8H),2.47–2.43(m,1H),2.42–2.32(m,1H),2.22–2.13(m,1H).
实施例30：WX030的三氟乙酸盐
Figure PCTCN2019104992-appb-000091
步骤1：中间体WX030–1的合成
室温和氮气保护下，将中间体WX015–5(0.5g,1.68mmol,纯度：91％)溶于甲苯(50mL)中，随后加入1,3–二溴丙烷(1.02g,5.05mmol,514.95μL)，碳酸钾(697.99mg,5.05mmol)和18–冠–6醚(4.45g,16.83mmol)，反应混合物加热至在110℃并搅拌反应12小时。反应完毕后，冷却至室温，反应混合物倒入水(50mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水(50mL×2)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–5/1，体积比)，得到中间体WX030–1。 1H NMR(400MHz,CDCl 3)δ:7.90(s,1H),7.86–7.81(m,2H),7.73(s,1H),7.26–7.24(m,1H),7.15(dd,J＝2.2,9.0Hz,1H),4.27–4.19(m,4H),3.78(s,2H),3.68(t,J＝6.4Hz,2H),2.45–2.37(m,2H),1.30(t,J＝7.0Hz,3H).
步骤2：中间体WX030–2的合成
室温和氮气保护下，将中间体WX030–1(0.21g,536.73μmol)溶于乙腈(20mL)中，随后加入二甲胺水溶液(241.98mg,2.15mmol,9.94μL)和碳酸钾(148.36mg,1.07mmol)，反应混合物加热至80℃并搅拌反应12小时。反应完毕后，冷却至室温，减压除去溶剂，向残余物中加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝30/1，体积比)，得到中间体WX030–2。 1H NMR(400MHz,CDCl 3)δ:7.87(s,1H),7.83–7.78(m,2H),7.71(s,1H),7.25(d,J＝2.4Hz,1H),7.15(dd,J＝2.2,9.0Hz,1H),4.22(q,J＝7.2Hz,2H),4.15(t,J＝6.4Hz,2H),3.77(s,2H),2.54(t,J＝7.4Hz,2H),2.30(s,6H),2.09–2.02(m,2H),1.29(t,J＝7.0Hz,3H).
步骤3：WX030的合成
0℃和氮气保护下，将中间体WX030–2(0.12g,337.62μmol)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(41.67mg,371.38μmol)，再加入丙烯酰胺(24.00mg,337.62μmol)，反应混合物在0℃下搅拌 反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％TFA)分离，得到目标化合物WX030的三氟乙酸盐。MS–ESI m/z:381.0[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.97(s,1H),9.53(s,1H),8.02(s,2H),7.98(s,1H),7.93(d,J＝9.2Hz,1H),7.40(d,J＝2.0Hz,1H),7.15(dd,J＝2.0,9.2Hz,1H),4.22(dd,J＝4.6Hz,12.2Hz,1H),4.17(t,J＝6.0Hz,2H),3.29–3.25(m,2H),2.84(s,6H),2.68–2.62(m,2H),2.45–2.38(m,2H),2.20–2.14(m,2H).
实施例31：WX031的盐酸盐
Figure PCTCN2019104992-appb-000092
步骤1：中间体WX031–1的合成
室温和氮气保护下，将1–乙酰哌啶–4–胺(86.84mg,610.71μmol)，碳酸钾(42.20mg,305.35μmol)与WX022–1(0.06g,152.68μmol)溶于乙腈(3mL)中，反应混合物80℃下搅拌12小时。反应完毕后，两批平行反应合并处理，向反应液中加入水(2mL)，用乙酸乙酯(5mL×3)萃取，合并有机相，用饱和食盐水(5mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂。所得残余物经过硅胶板分离(展开剂：二氯甲烷/甲醇＝10/1，体积比)，得到中间体WX031–1。MS–ESI m/z:439.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ:7.89(s,1H),7.85–7.80(m,2H),7.72(s,1H),7.25(d,J＝2.4Hz,1H),7.16(dd,J＝2.4,9.2Hz,1H),4.53–4.45(m,1H),4.27–4.19(m,4H),3.85–3.80(m,1H),3.78(s,2H),3.18–3.10(m,3H),2.86–2.75(m,2H),2.11(s,3H),2.02–1.93(m,2H),1.67–1.61(m,1H),1.57–1.51(m,1H),1.29(t,J＝7.2Hz,3H).
步骤2：WX031的合成
0℃和氮气保护下，将中间体WX031–1(112mg,255.29μmol)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(31.51mg,280.82μmol)，再加入丙烯酰胺(18.15mg,255.29μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX031的盐酸盐。MS–ESI m/z:464.2[M+H] +. 1H NMR(400MHz,DMSO_d 6)δ:10.96(s,1H),9.42(s,2H),8.09–8.00(m,3H),7.96(d,J＝8.8Hz,1H),7.46(d, J＝1.2Hz,1H),7.22(dd,J＝1.6,9.2Hz,1H),4.46–4.40(m,2H),4.22(dd,J＝4.4,12.0Hz,1H),3.48–3.41(m,2H),3.11–3.01(m,1H),2.88–2.73(m,2H),2.68–2.57(m,2H),2.35–2.26(m,2H),2.21–2.08(m,4H),2.02(s,3H),1.63–1.53(m,1H),1.51–1.39(m,1H).
实施例32：WX032
Figure PCTCN2019104992-appb-000093
步骤1：中间体WX032–1的合成
室温和氮气保护下，将中间体WX015–5(200mg,740.72μmol)溶于N,N–二甲基甲酰胺(30mL)中，随后加入2–甲基–4-溴–2–丁醇(494.93mg,2.96mmol,381.03μL)，碳酸钾(307.12mg,2.22mmol)和碘化钾(61.48mg,370.36μmol)，反应混合物在80℃下搅拌反应12小时。反应完毕后，冷却至室温，反应混合物倒入水(50mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，依次用水(50mL×2)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过柱层析分离(洗脱剂：石油醚/乙酸乙酯＝20/1–5/1，体积比)，得到中间体WX032–1。MS–ESI m/z:338.9[M–OH] +. 1H NMR(400MHz,CDCl 3)δ:7.90(s,1H),7.85–7.81(m,2H),7.72(s,1H),7.29(d,J＝2.4Hz,1H),7.15(dd,J＝2.6,9.0Hz,1H),4.33(t,J＝6.4Hz,2H),4.23(q,J＝7.2Hz,2H),3.78(s,2H),2.09(t,J＝6.2Hz,2H),1.37(s,6H),1.30(t,J＝7.2Hz,3H).
步骤2：WX032的合成
0℃和氮气保护下，将中间体WX032–1(0.09g,243.02μmol,纯度：96.24％)溶于N,N–二甲基甲酰胺(5mL)中，随后加入叔丁醇钾(30.00mg,267.32μmol)，再加入丙烯酰胺(17.27mg,243.02μmol)，反应混合物在0℃下搅拌反应1小时。反应完毕后，加入水(30mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂，所得残余物经过制备HPLC(流动相：乙腈/水；酸性体系：0.05％HCl)分离，得到目标化合物WX032。MS–ESI m/z:364.1[M–OH] +. 1H NMR(400MHz,DMSO_d 6)δ:10.95(s,1H),8.05–7.95(m,3H),7.89(d,J＝9.2Hz,1H),7.41(s,1H),7.12(d,J＝8.8Hz,1H),4.25–4.15(m,3H),2.84–2.75(m,1H),2.69–2.63(m,1H),2.35–2.30(m,1H),2.22–2.11(m,1H),1.92(t,J＝6.6Hz,2H),1.20(s,6H).
实验例1：多发性骨髓瘤细胞的IKZF3蛋白水平的体外测试
实验目的：
用WB的方法，研究目标化合物在不同浓度条件下对多发性骨髓瘤细胞MM.1S内IKZF3蛋白水平的调控。
实验方案：
1)将MM.1S细胞解冻并传代2次；
2)将MM.1S细胞以每孔1×10 6个细胞接种在6孔板中，然后用一定浓度的受试中间体处理；
3)处理16小时后，将培养的细胞样品溶解在置于冰上的拥有完整组蛋白酶抑制剂(Roche)的RIPA缓冲液(Sigma–Aldrich)或NETN缓冲液(150mM NaCl，1％NP–40,50mM Tris–HCl,pH＝8.0)中，并静置20分钟；
4)在离心(转速：17950rpm)15分钟后，收集上层清液并进行蛋白定量测试(Pierce BCA蛋白测定试剂盒，Thermo)；
5)通过SDS–PAGE分离等量的20μg蛋白，并转移到PVDF或尼龙膜(Invitrogen)上；
6)加入5％脱脂奶粉，然后在一抗anti–IKZF3(NBP2–24495,Novμs Biologicals)和anti–Actin(1844–1,Epitomics))的5％BSA中4℃孵育过夜；
7)最后用HRP连接的二抗(Goat–anti–rabbit IgG(sc–2004,Santa Cruz))反应1小时后，用化学发光底物(Thermo Scientific)检测膜上的条带。
实验结果如图1所示。
结论：
本发明化合物在100nM或500nM和50nM浓度下处理多发性骨髓瘤细胞MM.1S后，WB检测显示细胞内IKZF3蛋白水平明显下降。
实验例2：在淋巴瘤细胞系OCI–LY10，DOHH2与Mino中的抗增殖作用评估
实验目的：本实验通过检测受试化合物分别在弥漫性大B细胞淋巴瘤细胞系OCI–LY10和DOHH2，以及套细胞淋巴瘤细胞系Mino中对细胞增殖的抑制作用。
实验材料：
1.细胞系及培养方法
细胞系 肿瘤类型 生长特点 培养方法
OCI–LY10 淋巴瘤 悬浮 RPMI 1640+10％FBS
DOHH2 淋巴瘤 悬浮 RPMI 1640+10％FBS
Mino 淋巴瘤 悬浮 RPMI 1640+15％FBS
2.培养基及试剂
培养基及试剂 生产商 货号
RPMI 1640 GIBCO 22400-089
Dulbecco's PBS Hyclone SH30256.01
FBS Hyclone SY30087.03
Antibiotic-antimycotic GIBCO 15240-062
0.25％Trypsin GIBCO 25200072
DMSO SIGMA D2650
2-mercaptoethanol SIGMA 60-24-2
3.多孔板
Greiner
Figure PCTCN2019104992-appb-000094
96–孔板，平底黑板(带盖及透明底),#655090。
4.细胞活性实验所用试剂及仪器
(1)Promega CellTiter–Glo发光法细胞活性检测试剂盒(Promega-G7573)。
(2)2104
Figure PCTCN2019104992-appb-000095
读板器，PerkinElmer。
实验方案：
1.细胞培养
将肿瘤细胞系按上述培养条件在37℃，5％CO 2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。
2.细胞铺板
(1).用台盼兰进行细胞染色并计数活细胞。
(2).将细胞浓度调整至合适浓度。
Cell line Density(per 96-well)
OCI–LY10 5000
DOHH2 5000
Mino 6000
(3).按上图所示在培养板中每孔加入90μL细胞悬液，在空白对照空中加入不含细胞的培养液。
(4).将培养板在37℃,5％CO 2，及100％相对湿度的培养箱中培养过夜。
3.化合物存储板制备
制备400倍化合物存储板：将化合物用DMSO从最高浓度梯度稀释至最低浓度。每次现用现配。
4.10倍化合物工作液的配制及化合物处理细胞
(1).10倍化合物工作液的配制：在V形底的96孔板中加入76μL细胞培养液，从200倍化合物存储板中吸取4μL化合物加入96孔板的细胞培养液中。在溶媒对照和空白对照中加入4μL DMSO。加入化合物或DMSO后用排枪吹打混匀在V形底的96孔板中加入78μL细胞培养液，从400倍化合物存储板中吸取2μL化合物加入96孔板的细胞培养液中。在溶媒对照和空白对照中加入2μL DMSO。加入化合物或DMSO后用排枪吹打混匀。
(2).加药：取10μL的10倍化合物工作液加入到细胞培养板中。在溶媒对照和空白对照中加入10μL DMSO-细胞培养液混合液。
(3).将96孔细胞板放回培养箱中培养OCI–LY10(5倍稀释，加药共孵育5天)，DOHH2(3倍稀释，加药共孵育4天)，Mino(3倍稀释，加药共孵育4天)。
5.CellTiter–Glo发光法细胞活性检测
以下步骤按照Promega CellTiter–Glo发光法细胞活性检测试剂盒(Promega–G7573)的说明书来进行。
(1).将CellTiter–Glo缓冲液融化并放置至室温。
(2).将CellTiter–Glo底物放置至室温。
(3).在一瓶CellTiter–Glo底物中加入10mL CellTiter–Glo缓冲液以溶解底物，从而配制CellTiter–Glo工作液。
(4).缓慢涡旋震荡使充分溶解。
(5).取出细胞培养板放置30分钟使其平衡至室温。
(6).在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter–Glo工作液。用铝箔纸包裹细胞板以避光。
(7).将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。
(8).培养板在室温放置10分钟以稳定发光信号。
(9).在2104EnVision读板器上检测发光信号。
6.数据分析
用下列公式来计算检测化合物的抑制率(Inhibition rate，IR)：IR(％)＝(RLU溶媒对照–RLU化合物)/(RLU溶媒对照–RLU空白对照)*100％.在Excel中计算不同浓度化合物的抑制率，然后用GraphPad Prism软件作抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC 50。
实验结果：测试结果见表1。
表1本发明化合物在OCI–LY10，DOHH2与Mino细胞系中的细胞增殖抑制作用
化合物 OCI-LY10IC 50(nM) DOHH2IC 50(nM) Mino IC 50(nM)
WX001 28 63 72
WX002 86 / /
WX003 83 / /
WX005 6 / /
“/”代表未检测
结论：
本发明化合物在淋巴瘤细胞系OCI-LY10，DOHH2与Mino中均展现出优异细胞增殖的抑制作用。
实验例3：化合物的小鼠药代动力学评价
实验目的：
本研究受试动物选用C57BL雄性小鼠，应用LC/MS/MS法定量测定小鼠口服给予测试化合物和 参比化合物不同时间点的血浆中的药物浓度，以评价受试药物在小鼠体内的药代动力学特征。
实验材料：
C57Balb/c(C57)小鼠(雄性,20–30g,7–10周龄，北京维通利华或上海斯莱克)。
实验操作：
将测试化合物的澄清或悬浮溶液经灌胃给予到C57小鼠(过夜禁食)。口服灌胃给药于0h(给药前)和给药后0.5，1，2，4，6，8，24h从颈静脉穿刺采血，置于添加了EDTA-K2的抗凝管(江苏康健医疗用品有限公司)中，将混合物充分涡旋混合并以13000rpm离心10分钟。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果：测试结果见表2。
表2本发明化合物在小鼠中的药代动力学参数
Figure PCTCN2019104992-appb-000096
结论：
实验结果表明，WX015和WX022的盐酸盐的口服血浆系统暴露量(AUC 0-inf)较高。在啮齿动物小鼠中，WX015和WX022的盐酸盐的药代动力学性质较优。
实验例4：化合物在人淋巴瘤OCI–LY10细胞皮下异种移植肿瘤CB–17SCID模型的体内药效学研究
细胞培养：人淋巴瘤OCI–LY10细胞(National Cancer Institute)体外单层培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃，5％CO 2孵箱培养。一周两次用胰酶–EDTA进行常规消化处理传代。当细胞饱和度为80％–90％，数量到达要求时，收取细胞，计数，接种。
动物：CB–17SCID小鼠，雌性，6–8周龄，体重18–22克。
实验方案：
将0.2mL(10×10 6个)OCI–LY10细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约139mm 3时开始分组给药。七天为一个给药周期，每天给药一次，给药间隔24小时，将实验化合物口服给药，一共给药四个周期。受试化合物WX001给药剂量为60mg/kg，肿瘤体积每周两次用二维卡尺测量，体积以立方毫米计量，通过以下的公式计算：V＝0.5a×b 2，其中a和b分别是肿瘤的长泾和短径。抗肿瘤药效是通过化合物处理过的动物的平均肿瘤增加体积除以未处理过的动物的平均肿瘤增加体积来。
实验结果：
测试结果见表3。
表3本发明化合物在人淋巴瘤OCI–LY10细胞皮下异种移植肿瘤CB–17SCID模型测试结果
Figure PCTCN2019104992-appb-000097
TGI：Tumor Growth Inhibition(肿瘤增长抑制率)。TGI(％)＝[1–(某处理组给药结束时平均瘤体积—该处理组给药时平均瘤体积)/(溶剂对照组结束治疗时平均瘤体积—溶剂对照组开始治疗时平均瘤体积)]×100％。
结论：
本发明化合物WX001在人淋巴瘤OCI–LY10体内药效模型上展示了显著的缩瘤作用。

Claims (15)

  1. 式(Ⅰ)所示化合物或药学上可接受的盐，
    Figure PCTCN2019104992-appb-100001
    其中，
    n选自0、1、2和3；
    R 1选自分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氧基和
    Figure PCTCN2019104992-appb-100002
    其中所述C 1-6烷基、C 1-6烷氧基和
    Figure PCTCN2019104992-appb-100003
    任选被1、2或3个R a取代；
    R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-10烷基、C 1-10烷氧基、C 1-10烷氨基、-NHC(＝O)-C 1-10烷基、5-10元杂环烷基、5-10元杂环烷基氨基和C 5-10环烷基氨基，其中所述C 1-10烷基、C 1-10烷氧基、C 1- 10烷氨基、-NHC(＝O)-C 1-10烷基、5-10元杂环烷基、5-10元杂环烷基氨基和C 5-10环烷基氨基任选被1、2或3个R取代；
    R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、Me和
    Figure PCTCN2019104992-appb-100004
    环A选自5～6元杂芳基、苯基、C 4-6环烷基、4～7元杂环烷基和4～7元杂环烯基；
    所述5～6元杂芳基、4～7元杂环烷基、5-10元杂环烷基和5-10元杂环烷基氨基分别包含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所述化合物或药学上可接受的盐，其中，R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-NHC(＝O)-C 1-6烷基、5-8元杂环烷基、5-8元杂环烷基氨基和C 5-8环烷基氨基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-NHC(＝O)-C 1-6烷基、5-8元杂环烷基、5-8元杂环烷基氨基和C 5-8环烷基氨基任选被1、2或3个R取代。
  3. 根据权利要求2所述化合物或药学上可接受的盐，其中，R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基、-NHC(＝O)-C 1-3烷基、哌啶基、哌嗪基、吗啉基、吡喃基、吡咯烷基、环己烷基氨基、四氢吡喃基氨基、哌啶基氨基、哌嗪基氨基和3-氮杂双环[3,1,0]己烷基，其中所述C 1-3烷基、C 1-6烷氧基、C 1-6烷氨基、-NHC(＝O)-C 1-3烷基、哌啶基、哌嗪基、吗啉基、吡喃基、吡咯烷基、环己烷基氨基、四氢吡喃基氨基、哌啶基氨基、哌嗪基氨基和3-氮杂双环[3,1,0]己烷基任选被1、2或3个 R取代。
  4. 根据权利要求3所述化合物或药学上可接受的盐，其中，R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、Et、
    Figure PCTCN2019104992-appb-100005
    Figure PCTCN2019104992-appb-100006
    其中，所述Me、Et、
    Figure PCTCN2019104992-appb-100007
    Figure PCTCN2019104992-appb-100008
    任选被1、2或3个R取代。
  5. 根据权利要求4所述化合物或药学上可接受的盐，其中，R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、
    Figure PCTCN2019104992-appb-100009
  6. 根据权利要求1～5任意一项所述化合物或药学上可接受的盐，其中，R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、C 1-6烷氧基和
    Figure PCTCN2019104992-appb-100010
    其中所述Me、C 1-6烷氧基和
    Figure PCTCN2019104992-appb-100011
    任选被1、2或3个R a取代。
  7. 根据权利要求6所述化合物或药学上可接受的盐，其中，R 1选自H、Me、
    Figure PCTCN2019104992-appb-100012
    Figure PCTCN2019104992-appb-100013
    Figure PCTCN2019104992-appb-100014
  8. 根据权利要求1～5任意一项所述化合物或药学上可接受的盐，其中，环A选自苯基、1,3-二氧环戊烷基、吗啉基、四氢呋喃基、2,3-二氢呋喃基、呋喃基、吡唑基、噻唑基、4,5-二氢噻唑基、恶唑基、2,3-二氢恶唑基、吡啶基和2,3-二氢吡啶基。
  9. 根据权利要求1～5任意一项所述化合物或药学上可接受的盐，其中，结构单元
    Figure PCTCN2019104992-appb-100015
    选自
    Figure PCTCN2019104992-appb-100016
  10. 根据权利要求1～9任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2019104992-appb-100017
    其中，n、R 1、环A如权利要求1～9所定义。
  11. 下式所示化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2019104992-appb-100018
    Figure PCTCN2019104992-appb-100019
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2019104992-appb-100020
    Figure PCTCN2019104992-appb-100021
    Figure PCTCN2019104992-appb-100022
  13. 一种药物组合物，包括治疗有效量的根据权利要求1～12任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  14. 根据权利要求1～12任意一项所述的化合物或其药学上可接受的盐在制备治疗与CRBN蛋白相关疾病药物中的应用。
  15. 根据权利要求13所述的组合物在制备治疗与CRBN蛋白相关疾病药物中的应用。
PCT/CN2019/104992 2018-09-07 2019-09-09 三环并呋喃取代哌啶二酮类化合物 WO2020048547A1 (zh)

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