WO2022033303A1 - 苄胺类衍生物及其制备方法与用途 - Google Patents

苄胺类衍生物及其制备方法与用途 Download PDF

Info

Publication number
WO2022033303A1
WO2022033303A1 PCT/CN2021/108826 CN2021108826W WO2022033303A1 WO 2022033303 A1 WO2022033303 A1 WO 2022033303A1 CN 2021108826 W CN2021108826 W CN 2021108826W WO 2022033303 A1 WO2022033303 A1 WO 2022033303A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
mmol
amino
alkyl
biphenyl
Prior art date
Application number
PCT/CN2021/108826
Other languages
English (en)
French (fr)
Inventor
肖军海
李松
郭家林
钟武
罗龙龙
郑志兵
周辛波
李行舟
曹瑞源
樊士勇
肖典
谢菲
李微
Original Assignee
中国人民解放军军事科学院军事医学研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国人民解放军军事科学院军事医学研究院 filed Critical 中国人民解放军军事科学院军事医学研究院
Priority to AU2021323754A priority Critical patent/AU2021323754A1/en
Priority to KR1020237007902A priority patent/KR20230050376A/ko
Priority to EP21855356.8A priority patent/EP4198017A1/en
Priority to CA3191714A priority patent/CA3191714A1/en
Priority to JP2023509628A priority patent/JP2023539043A/ja
Priority to US18/020,923 priority patent/US20230303494A1/en
Publication of WO2022033303A1 publication Critical patent/WO2022033303A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • C07D405/02—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of biomedicine, relates to a class of benzylamine derivatives capable of blocking the interaction of PD-1/PD-L1, and also relates to a preparation method of such compounds and their preparation methods for treating and PD-1/PD-L1 compounds. Use in medicine for L1-related disorders.
  • immune checkpoint PD-1/PD-L1 inhibitors are one of the most prominent achievements in tumor immunotherapy.
  • PD-1 programmed cell death protein 1
  • the ligand PD-L1 (programmed cell death protein-ligand 1) is abundantly expressed on the surface of tumor cells and can bind to PD-1 on the surface of T cells.
  • the combination of PD-1 and PD-L1 produces a negative regulatory signal, which inhibits the immune activity of T cells, so that tumor cells can escape the recognition and attack of the immune system, and achieve immune escape and survive.
  • Small-molecule drugs have the advantages of low price, effective oral administration, good stability, low immune side effects, and easy penetration into tumors to improve the efficiency. Compared with monoclonal antibodies, small molecule drugs have wider clinical application value.
  • An object of the present application is to provide a class of benzylamine derivatives that block the interaction of PD-1/PD-L1, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof, and compounds containing the above
  • the present application provides benzylamine derivatives represented by general formula (I), or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof,
  • R is selected from hydrogen and C1-C8 alkyl
  • R 1 is selected from hydrogen, deuterium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy;
  • R 2 is selected from wherein R 6 is selected from halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy, R 7 is located in the meta or ortho position of R 6 and R 7 Selected from hydrogen, -O-(CH 2 ) n -R 0 , -CONH-R 0 and -(CH 2 ) n -R 0 , wherein n is an integer of 1-4, R 0 is cyano, hydroxyl, carboxyl , amino or heteroatom-containing chain or cyclic hydrophilic substituents;
  • R 3 is selected from R 8 -CH 2 -, wherein R 8 is selected from hydrogen, cyano, C1-C4 alkyl, halogenated C1-C4 alkyl, C2-C4 alkenyl, -NR 9 R 10 , -CONR 9 R 10 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, optionally, the C1-C4 alkyl, halogenated C1 -C4 alkyl, C2-C4 alkenyl, -NR 9 R 10 , -CONR 9 R 10 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered aryl
  • the heteroaryl groups are each independently substituted with one or more substituents selected from the group consisting of: cyano, halogen, carboxyl, C1-C
  • R 4 is selected from hydroxyl, carboxyl, fragments of amino acids (preferably hydrophilic amino acids) and -NR 10 R 11 , wherein R 10 and R 11 are each independently selected from hydrogen, deuterium, C1-C6 alkyl and 3-6 membered Cycloalkyl, optionally, the C1-C6 alkyl and 3-6 membered cycloalkyl are each independently substituted with one or more substituents selected from the group consisting of: mercapto, hydroxyl, carboxyl, hydroxyl C1-C6 Alkyl, C1-C6 amido, and 3-6 membered nitrogen-containing heterocycloalkyl; alternatively, R 10 and R 11 and the attached N atom form a 5-6 membered heterocycloalkyl, optionally, the 5- 6-membered heterocycloalkyl substituted with one or more groups selected from the group consisting of amino, hydroxy, carboxyl, mercapto and hydroxy C1-C6 alkyl;
  • R 5 is selected from hydrogen, deuterium, cyano, halogen, C1-C4 alkyl, C2-C4 alkenyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy;
  • Y and Z are each independently selected from carbon and nitrogen.
  • the structure of the benzylamine derivatives is shown in formula (I-A):
  • R, R 1 , R 2 , R 3 , R 4 and R 5 are as described above, and R 5 is located at the para or meta position of -OR 3 . In some preferred embodiments, R5 is in the para position to -OR3 .
  • R, R 1 , R 2 , R 3 , R 4 and R 5 are as described above, at least one of Z and Y is nitrogen, and R 5 is located at the para or meta position of -OR 3 .
  • R, R 1 , R 2 , R 3 , R 4 and R 5 are as described above, and R 5 is located at the para or meta position of -OR 3 .
  • R in any of Formulas I, I-A, I-B, and I-C is selected from hydrogen and methyl.
  • R in any of Formulas I, I-A, I-B, and I-C is hydrogen.
  • R 1 in any of Formulas I, IA, IB, and IC is selected from the group consisting of halogen, C1-C2 alkyl, and haloC1-C2 alkyl.
  • R 1 in any of Formulas I, IA, IB, and IC is bromo, methyl, or trifluoromethyl.
  • R 1 in any of Formulas I, IA, IB, and IC is selected from halogen and C1-C2 alkyl.
  • R1 in any of Formulas I , IA, IB and IC is bromo or methyl.
  • R1 in any of Formulas I , IA, IB, and IC is selected from the group consisting of fluoro, chloro, bromo, iodo, methoxy, methyl, cyano, deuterated methyl, and halomethyl .
  • R in any of Formulas I, IA, IB and IC is selected from wherein R 6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methoxy, methyl, cyano, deuterated methyl and halomethyl, R 7 is located in the meta or ortho position of R 6 and R 7 is selected from hydrogen, -O-(CH 2 ) n -R 0 , -CONH-R 0 , -(CH 2 ) n -R 0 , wherein n is an integer of 1-4, R 0 is cyano, hydroxyl, Carboxyl, amino and heteroatom-containing chain or cyclic hydrophilic substituents.
  • R in any of Formulas I, IA, IB and IC is selected from
  • R3 in any of formulae I, IA, IB and IC is selected from R8 - CH2-, wherein R8 is selected from hydrogen, C1-C2 alkyl, phenyl and 5-6 membered Heteroaryl, optionally, the C1-C2 alkyl, phenyl and 5-6 membered heteroaryl groups are each independently substituted with one cyano group.
  • R in any of Formulas I, IA, IB and IC is selected from methyl, ethyl,
  • R in any of Formulas I, IA, IB and IC is selected from methyl, ethyl,
  • R 4 in any of formulae I, IA, IB and IC is selected from fragments of amino acids and -NR 10 R 11 , wherein R 10 and R 11 are each independently selected from hydrogen, deuterium and C1- C6 alkyl, optionally, the C1-C6 alkyl is substituted with one or more substituents selected from the group consisting of mercapto, hydroxy, carboxyl, hydroxy C1-C4 alkyl, C1-C4 amido, and 5- 6-membered nitrogen-containing heterocycloalkyl; alternatively, R 10 and R 11 and the attached N atom form a 5-6 membered heterocycloalkyl, optionally, the 5-6 membered heterocycloalkyl is replaced by one or more The group is substituted from the group consisting of amino, hydroxyl, carboxyl, mercapto and hydroxyl C1-C4 alkyl; the amino acid fragment is selected from the fragment obtained by losing one hydrogen to the amino group in the amino acid that shares
  • the amino acid is selected from the group consisting of glycine, alanine, proline, hydroxyproline, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine , cysteine, histidine, lysine, arginine, pyroglutamic acid, In some preferred embodiments, the amino acid is selected from serine, hydroxyproline and asparagine.
  • R in any of Formulas I, IA, IB and IC is selected from amino, hydroxyl, carboxyl, and stereoisomers of the above structures.
  • R in any of Formulas I, IA, IB and IC is selected from and stereoisomers of the above structures.
  • R in any of formulae I, IA, IB, and IC is selected from hydrogen, deuterium, halogen, C1-C2 alkyl, and C1-C2 alkoxy, eg, hydrogen, chlorine, methoxy or methyl.
  • R in any of formulae I, IA, IB and IC is selected from fluoro, chloro, bromo, iodo, methoxy, methyl, cyano, deuterated methyl, halomethyl , ethyl, vinyl and ethoxy.
  • R5 in any of formulae I, IA, IB and IC is selected from hydrogen, deuterium, halogen, and C1-C2 alkyl, such as hydrogen, chlorine, or methyl.
  • R is hydrogen ; R5 is selected from hydrogen, chloro and methyl, and R5 is in the para position to -OR3 .
  • R is selected from hydrogen and C1-C8 alkyl
  • R 1 is selected from halogen and C1-C4 alkyl
  • R 2 is selected from wherein R 6 is selected from halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy, R 7 is located in the meta or ortho position of R 6 and R 7 Selected from hydrogen, -O-(CH 2 ) n -R 0 , -CONH-R 0 and -(CH 2 ) n -R 0 , wherein n is an integer of 1-4, R 0 is cyano, hydroxyl, carboxyl , amino or heteroatom-containing chain or cyclic hydrophilic substituents;
  • R3 is selected from R8 - CH2-, wherein R8 is selected from 6-10 membered aryl substituted with one or more cyano groups and 5-10 membered heteroaryl optionally substituted with one or more cyano groups base;
  • R 4 is selected from
  • R 5 is selected from halogen and C1-C4 alkyl, and R 5 is located in the para position of -OR 3 ;
  • Y and Z are each independently selected from carbon and nitrogen.
  • R is selected from hydrogen and methyl
  • R 1 is selected from halogen and C1-C2 alkyl
  • R 2 is selected from
  • R 3 is selected from
  • R 4 is selected from
  • R 5 is selected from halogen and C1-C4 alkyl, and R 5 is in the para position to -OR 3 .
  • R is hydrogen
  • R 1 is bromo or methyl
  • R is selected from methyl
  • R 4 is selected from
  • R 5 is selected from hydrogen, chlorine and methyl, and R 5 is located in the para position to -OR 3 .
  • the benzylamine derivative is selected from:
  • the pharmaceutically acceptable salt of the benzylamine derivative is selected from salts formed with organic or inorganic acids (eg, hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide) , nitrate, bisulfate, oxalate, formate, acetate, citrate, tartrate, sulfonate, benzoate, trifluoroacetate, maleate or citric acid salts, etc.), salts formed with alkali metals and alkaline earth metals (such as lithium, sodium, potassium, magnesium and calcium or ammonium salts, etc.), and salts formed with organic bases (such as methylamine, ethylamine, etc.) salt, triethylamine salt, piperidine salt, morpholine salt, etc.).
  • the pharmaceutically acceptable salt of the benzylamine derivative is its hydrochloride salt.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • C1-C8 alkyl refers to a straight or branched chain alkyl group containing 1-8 carbon atoms, including C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkane base and C1-C2 alkyl, etc.
  • Typical examples thereof are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethylbutyl, 1,2-dimethylpropyl, etc.
  • C1-C4alkoxy refers to a group formed in the form of C1-C4alkyl-O-, wherein "C1-C4alkyl” is as defined above, eg C1 -C3 alkoxy and C1-C2 alkoxy, etc. Typical examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
  • C2-C4 alkenyl refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond and 2-4 carbon atoms. Typical examples thereof are vinyl, propenyl, 2-propenyl, butenyl, 2-butenyl, butadienyl and the like.
  • deuterated refers to a group resulting from the replacement of at least one hydrogen atom in a group with its isotope deuterium, eg, a deuterated C1-C4 alkyl group.
  • halo refers to a group in which at least one hydrogen atom is replaced by a halogen as previously described, eg, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy Wait.
  • a halogen as previously described, eg, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy Wait.
  • a typical example thereof is trifluoromethyl.
  • hydrophilic substituent refers to a group that is prone to affinity with water, the hydrophilic group typically containing at least one hydrophilic functional group, such as hydroxyl, amino, carboxyl, Sulfonic acid group, phosphoric acid group, etc.
  • the hydrophilic substituent is a heteroatom-containing chain or cyclic hydrophilic substituent. Specific examples include but are not limited to Wait.
  • 3-6 membered cycloalkyl refers to a saturated cyclic hydrocarbon group containing 3 to 6 ring-forming carbon atoms.
  • 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl or 6-membered cycloalkyl Typical examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl refers to a saturated cyclic hydrocarbon group containing 3 to 6 ring members, wherein at least 1 (eg 1, 2, 3 or 4) rings Members are heteroatoms selected from N, O and S.
  • 3-6 membered nitrogen-containing heterocycloalkyl For example, 3-6 membered nitrogen-containing heterocycloalkyl.
  • Typical examples include ethylene oxide, butylene oxide, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl , thiomorpholinyl, piperazinyl, piperidinyl, oxazinyl, etc.
  • 6-10 membered aryl refers to an aromatic group containing 6 to 10 ring-forming carbon atoms, such as phenyl or naphthyl.
  • the term "5-10 membered heteroaryl” refers to an aromatic group containing 5-10 ring members, wherein at least 1 (eg, 1, 2, 3, or 4) ring members is a heteroatom selected from N, O and S, the heteroaryl group may be a monocyclic heteroaryl group, a bicyclic heteroaryl group or a polycyclic heteroaryl group. For example, 5-6 membered heteroaryl and the like.
  • Typical examples are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl , 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl Oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl and the like.
  • C1-C4 alkylsulfonyl refers to a group formed in the manner of C1-C4 alkyl- SO2- , wherein "C1-C4 alkyl” is as defined above, For example, C1-C3 alkylsulfonyl and C1-C2 alkylsulfonyl and the like. Typical examples are methanesulfonyl and the like.
  • C1-C6 amido refers to a group formed in the manner of C1-C5 alkyl-CONH-, wherein "C1-C5 alkyl” is as previously defined, eg C1- C4 alkyl amide group and C1-C2 alkyl amide group, etc. Typical examples are formamido, acetamido, and the like.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, and diastereomers isomer.
  • the stereoisomers of the present invention include any of the above-mentioned stereoisomers of the benzylamine derivatives, and mixtures of one or more stereoisomers in any ratio.
  • solvate means that the benzylamine derivatives described herein can interact with solvents (eg, organic solvents such as methanol, ethanol, or water) to form stably existing complexes.
  • solvents eg, organic solvents such as methanol, ethanol, or water
  • the solvent may serve as a structural element of the crystal lattice of the benzylamine derivative.
  • the solvent may be present in a stoichiometric or non-stoichiometric ratio.
  • prodrug refers to a derivative of a benzylamine derivative described herein that contains a bioreactive functional group that yields the benzylamine by cleavage or other biochemical reaction under biochemical reaction conditions
  • derivatives including but not limited to phosphates, esters, amides and ureides of the benzylamine derivatives described herein that are hydrolyzable under biochemical conditions.
  • the present invention provides the preparation method of the compound described in the first aspect, specifically as follows:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the benzylamine derivative according to any one of the first aspect of the present invention, or a pharmaceutically acceptable stereoisomer, salt, solvate or A prodrug, and one or more pharmaceutically acceptable carriers or excipients.
  • the carrier refers to a substance used to improve the selectivity, efficacy and/or safety of the drug during delivery. It is mainly used to control drug release, and can also be used to improve the pharmacokinetic properties of drugs, especially bioavailability.
  • the excipients refer to other substances other than active ingredients in pharmaceutical preparations, which are mainly used for long-term stability, filling solid preparations (thus, also often used to specifically refer to "fillers") or enhancing product efficacy (such as promote absorption, reduce viscosity or increase solubility, etc.). Depending on the route of administration or form of administration, those skilled in the art can select suitable carriers and excipients on the basis of known theory and experience.
  • the carrier or excipient includes, but is not limited to, magnesium stearate, alumina, glycerol, lecithin, serum albumin, cellulosic material, PEG, beeswax, lanolin, potassium sorbate, lactose, Starch, coconut oil and vegetable oil, etc.
  • the pharmaceutical composition of the present invention can be prepared into various forms according to different administration routes.
  • the pharmaceutical composition can be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or administration via an explanted reservoir. Of these, oral, intraperitoneal or intravenous administration is preferred.
  • the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof can be made into any orally acceptable formulations, including but not limited to tablets, Capsules, aqueous solutions or aqueous suspensions.
  • the commonly used carriers for tablets include lactose and corn starch, and lubricants such as magnesium stearate may also be added.
  • Commonly used diluents for capsule formulations include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral formulations.
  • the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof can generally be prepared in the form of suppositories, which are prepared by combining the drug with a suitable non- It is prepared by mixing irritating excipients.
  • the excipient is solid at room temperature, but melts at rectal temperature to release the drug.
  • excipients include cocoa butter, beeswax and polyethylene glycols.
  • benzylamine derivatives or pharmaceutically acceptable stereoisomers thereof, are used for topical administration, especially for the treatment of affected surfaces or organs that are easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases.
  • topical application such as eye, skin or lower intestinal neurological diseases.
  • salts, solvates or prodrugs can be made into different topical preparation forms according to different affected surfaces or organs, the specific instructions are as follows:
  • the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof can be formulated in the form of a micronized suspension or solution, using
  • the carrier is isotonic sterile saline at pH with or without a preservative such as benzyl alkoxide chloride.
  • the compounds can be formulated in the form of an ointment such as petrolatum ointment.
  • the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof can be formulated into a suitable ointment, lotion or cream formulation in which the active The ingredients are suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointments here include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof can be made into rectal suppository formulations or suitable enema formulations as described above , and topical transdermal patches can also be used.
  • benzylamine derivatives, or their pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs can also be administered in the form of sterile injectable preparations, including sterile injectable water or oil suspensions, or sterile injectable solution.
  • sterile injectable preparations including sterile injectable water or oil suspensions, or sterile injectable solution.
  • carriers and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can also be employed as a solvent or suspending medium, such as mono- or diglycerides.
  • the medicines in the above-mentioned various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.
  • the present invention provides the benzylamine derivatives described herein, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof, or pharmaceutical compositions in the preparation of prophylactic or therapeutic and PD- Use of 1/PD-L1-related diseases in medicine.
  • the present invention provides the benzylamine derivatives described herein, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or a pharmaceutical composition for use in the prophylaxis or treatment of a PD-1/PD-L1-related diseases.
  • the present invention provides a method of preventing or treating a disease associated with PD-1/PD-L1, comprising administering to a subject in need thereof an effective amount of a benzylamine derivative described herein , or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or step of a pharmaceutical composition.
  • the present invention provides a method of inhibiting PD-1/PD-L1 interaction, comprising administering to a subject in need thereof an effective amount of a benzylamine derivative described herein, or a pharmacy thereof acceptable stereoisomers, salts, solvates or prodrugs, or pharmaceutical compositions.
  • the present invention provides a method of increasing an immune response comprising administering to a subject in need thereof an effective amount of a benzylamine derivative described herein, or a pharmaceutically acceptable stereoisomer thereof body, salt, solvate or prodrug, or pharmaceutical composition step.
  • Diseases related to PD-1/PD-L1 described herein include tumors, infectious diseases, and autoimmune diseases.
  • the tumor is selected from the group consisting of a tumor of the digestive system, a tumor of the urinary system, a hematological tumor, a tumor of the nervous system, a tumor of the reproductive system, a skin cancer, a lung cancer, a breast cancer, a head and neck cancer, a brain tumor, a glioma, a nasopharyngeal tumor One or more of tumors such as cancer.
  • the infectious disease is selected from one or more infections caused by microorganisms.
  • the infection is an infection caused by bacteria and viruses.
  • the autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritis Syndrome, pemphigus (such as pemphigus vulgaris), pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, acute idiopathic polyneuritis, etc., systemic lupus erythematosus, similar Rheumatoid arthritis, systemic vasculitis, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, Sjogren's syndrome, ankylosing spondylitis, polynodular Arteritis and Wegener's granulomatosis, among others.
  • chronic lymphocytic thyroiditis
  • the term "therapeutically effective amount” or “prophylactically effective amount” refers to an amount sufficient to treat or prevent a patient's disease but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a therapeutically effective amount of a compound will depend on the particular compound selected (eg, taking into account the potency, effectiveness and half-life of the compound), the route of administration selected, the disease being treated, the severity of the disease being treated, the severity of the patient being treated. Factors such as age, size, weight and physical ailment, medical history of the patient being treated, duration of treatment, nature of concurrent therapy, desired therapeutic effect, and the like vary, but can still be routinely determined by those skilled in the art.
  • the specific dosage and method of use of the benzylamine derivatives, or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof for different patients depends on many factors, including the age of the patient. , weight, gender, natural health status, nutritional status, active strength of the drug, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. It is preferred here to use doses between 0.001 and 1000 mg/kg body weight/day.
  • the compounds involved in the present invention have strong binding ability to human PD-L1, have the activity of significantly inhibiting the interaction of PD-1/PD-L1, and have significant antitumor efficacy in vivo.
  • Figure 1 shows the tumor proliferation curve over time after 15 mg/kg compound 5 was administered by intraperitoneal injection to PD-1 humanized mice.
  • Figure 2 shows the proliferation curve of body weight over time after intraperitoneal injection of 15 mg/kg compound 5 in PD-1 humanized mice.
  • Dissolve 16-2 (297 mg, 0.70 mmol) and D-serine (148 mg, 1.41 mmol) in 8 mL of anhydrous DMF and 2 mL of anhydrous methanol, add glacial acetic acid (80 ⁇ L, 1.41 mmol), and react at 35°C for 24 h.
  • Example 22 The by-product isolated in Example 22 was 38 mg.
  • 28-3 (397 mg, 1.38 mmol) was dissolved in 8 mL of MeCN and 2.5 mL of DMF, K 2 CO 3 (229 mg, 1.66 mmol), 28-1 (379 mg, 2.07 mmol) and NaI (42 mg, 0.28 mmol) were added, 30° C. After 24 hours of reaction, water was added, extracted with EA, the organic phase was washed with water until neutral, concentrated and purified by column chromatography to obtain 188 mg of a pale yellow powdery solid with a yield of 31%.
  • Example 39 Activity of Compounds to Inhibit PD-1/PD-L1 Interaction
  • the inhibitory activity of compounds on PD-1/PD-L1 interaction was evaluated at the protein level using PD-1/PD-L1 Binding Assay kits from Cisbio.
  • the evaluation method of the kit is based on the principle of homogeneous time-resolved fluorescence (HTRF), which contains relevant proteins, reagents and buffers required for the experiment.
  • HTRF homogeneous time-resolved fluorescence
  • the positive compound control BMS202 was purchased from MCE Company.
  • Tag1-PD-L1, Tag2-PD-1 and compound solutions were diluted with diluent buffer to form working solutions, and anti-Tag1-Eu 3+ and anti-Tag2-XL665 were diluted with detection buffer to form working solutions.
  • a white 384 shallow-well plate was used for the experiment, and 2 ⁇ L of compound working solution, 4 ⁇ L of Tag1-PD-L1 working solution and 4 ⁇ L of Tag2-PD-1 working solution were added to each well, and incubated at room temperature for 15 min; The mixed solution of 5 ⁇ L of anti-Tag1-Eu 3+ and 5 ⁇ L of anti-Tag2-XL665 working solution was incubated for 2.5h and detected; a control group was also set up in the experiment, and 2 ⁇ L of diluent buffer replaced 2 ⁇ L of compound working solution to form Positive control, 6 ⁇ L Diluent buffer replaces 2 ⁇ L compound and 4 ⁇ L Tag1-PD-L1 working solution to constitute Negative control.
  • HTRF value of each well (665nm fluorescence intensity/620nm fluorescence intensity) ⁇ 10 4
  • compound inhibition rate (%) [1-(HTRF value of compound well-HTRF value of Negative control well)/(HTRF value of Positive control well- Negative control hole HTRF value)] ⁇ 100%
  • the inhibition rate of each compound at 8-10 concentrations was detected, and the IC 50 was calculated using Prism software.
  • the experiment used Fortebio's biofilm interferometry (BLI)-based instrument OctectRED to capture human PD-L1/AVI with SA chips.
  • concentration of antigen PD-L1/AVI was diluted to 10 ⁇ g/mL with running buffer (PBS+0.02%Tween-20+2%DMSO), and the loading time was 300s; the analyte was also diluted to the corresponding concentration with running buffer ( 20nM, 10nM, 5nM, 2.5nM, 1.25nM, 0.625nM, 0.3125nM), and a buffer blank control group was set at the same time.
  • the binding time of human PD-L1/AVI to the analyte was 180 s, and the dissociation time was 300 s; the chip was regenerated with a 5-second pulse of 10 mM glycine HCl, pH 1.7 solution repeated 3 times.
  • the assay data were fitted to a 1:1 binding model to determine the equilibrium dissociation constant KD.
  • the compound has a strong binding ability to human PD-L1, and its affinity KD value is at the level of nM and above.
  • PBMCs Human peripheral blood mononuclear cells
  • TBD sciences human lymphocyte separation medium
  • the cells were washed twice with normal saline and resuspended in buffer (RPMI 1640 complete medium containing 10% FBS, SIGMA) to count the cell density.
  • PBMCs were dispersed in a 96-well plate, 1 ⁇ 10 5 cells per well and 50 ⁇ L of buffer.
  • Anti-CD3 antibody (SIGMA) and anti-CD28 antibody (SIGMA) were mixed at a ratio of 1:1 to obtain an antibody mixture, and the antibody mixture was added to the well to ensure that the final concentration of the antibody was 0.8 ⁇ g/mL.
  • PDL1/FC fusion protein (SINO BIOLOGICAL) was added at a final concentration of 10.0 ⁇ g/mL, and the compound to be tested was diluted with buffer and added to the well to make the final concentration at 0.1 ⁇ M or 1 ⁇ M.
  • the mixed system was incubated at 37°C in 5% CO for 72 hours. The supernatant was collected, and the expression level of IFN- ⁇ was measured by ELISA MAXTM human IFN- ⁇ standard kit (BioLegend), and the increase rate was calculated.
  • Increase rate (%) (expression level of compound treatment-expression level of PDL1 treatment)/expression level of PDL1 treatment ⁇ 100%
  • the raji (ATCC), raw (ATCC) and PBMCs cells were suspended in buffer (RPMI 1640 complete medium containing 10% FBS, SIGMA), respectively, and the cell density was counted. Cells were transferred to wells of a 96-well plate, ensuring a cell density of 1 x 10 4 cells/well in each well, with different concentrations of compounds (100 ⁇ M, 50 ⁇ M, 25 ⁇ M, 12.5 ⁇ M, 6.25 ⁇ M and 3.125 ⁇ M) and buffers, respectively.
  • the control solution (0.2% DMSO) was incubated at 37°C, 5% CO 2 for 24 hours.
  • Cell death rate (%) (1-RLUcompound/RLUcontrol) ⁇ 100%, and IC50 was determined from the inhibition curve.
  • Example 43 Evaluation of antitumor efficacy in vivo
  • the animal models used in in vivo efficacy experiments must be animals with healthy immune systems; in addition, consider There are species differences in PD-1/PD-L1 between animals and humans. Therefore, the in vivo antitumor pharmacodynamics evaluation model of the present invention adopts PD-1 humanized mice, and the inoculated tumors are PD-L1 humanized tumor cells. This evaluation model can more accurately reflect the in vivo efficacy of the compound .
  • PD-1 humanized mice full name of strain: C57BL/6J-Pdcd1 em1(hPDCD1)/Smoc ) about 6 weeks old were purchased from Shanghai Southern Model Animal Center and placed in SPF animal breeding room for observation for 1 to 2 weeks After the animals were adapted to the feeding environment, the genetically engineered colon cancer cell line MC38 (mouse PD - L1 knockout, human PD-L1 knockout) was subcutaneously inoculated to the back of the mice near the groin. . After 7-10 days of observation, when the tumor volume grew to 50-150 mm 3 , animals were randomly divided into vehicle group and test group according to tumor size according to the random number table, with 6 animals in each group.
  • the test group was given 15 mg/kg of compound 5 by intraperitoneal injection.
  • the vehicle group was also intraperitoneally injected with the same volume of buffer as the test group, and the frequency of administration was once a day for three weeks.
  • the tumor size and mouse body weight were measured and recorded, and the mice were sacrificed at the end of the experiment.
  • the mouse body weight and tumor proliferation curve were drawn.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Biotechnology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

涉及苄胺类衍生物及其制备方法与用途。具体涉及通式(Ⅰ)所示的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其与人PD-L1有很强的结合能力，能明显抑制PD-1/PD-L1相互作用，具有显著地体内抗肿瘤药效。因此，还涉及所述苄胺类衍生物的制备方法及其在制备治疗与PD-1/PD-L1相关疾病的药物中的用途，

Description

苄胺类衍生物及其制备方法与用途
本申请是以CN申请号为202010801978.3，申请日为2020年8月11日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本发明属于生物医药技术领域，涉及一类能够阻断PD-1/PD-L1相互作用的苄胺类衍生物，还涉及这类化合物的制备方法及其在制备治疗与PD-1/PD-L1相关疾病的药物中的用途。
背景技术
近些年，肿瘤免疫治疗取得了重大进展，与化放疗及靶向治疗等传统疗法不同，其主要是通过克服患者体内的免疫抑制，重新激活患者自身的免疫细胞来杀伤肿瘤。
目前，免疫检查点PD-1/PD-L1抑制剂是肿瘤免疫治疗最突出的成果之一。PD-1(programmed cell death protein 1)在T细胞、B细胞、NK细胞以及单核细胞中都能表达。肿瘤细胞表面大量表达PD-1的配体PD-L1(programmed cell death protein-ligand 1)，可与T细胞表面的PD-1结合。PD-1与PD-L1结合后产生负调节信号，抑制了T细胞的免疫活性，从而使肿瘤细胞逃过免疫系统的识别和攻击，实现免疫逃逸而存活下来。大量临床前研究以及单抗类药物的上市充分证明，阻断PD-1/PD-L1的相互作用，可以有效地恢复T细胞的免疫功能，从而实现免疫系统对肿瘤细胞的识别和清除，抑制肿瘤的生长。
2014-2017年，国际上先后有Pembrolizumab
Figure PCTCN2021108826-appb-000001
Nivolumab
Figure PCTCN2021108826-appb-000002
Atezolizumab(Tecentriq TM)、Avelumab
Figure PCTCN2021108826-appb-000003
和Durvalumab
Figure PCTCN2021108826-appb-000004
五个单抗类PD-1/PD-L1抑制剂上市。2018年12月，国内药企君实生物的PD-1抑制剂(特瑞普利单抗)及信达生物的PD-1抑制剂(信迪利单抗)相继获CFDA批准上市。2019年12月百济神州的PD-1抑制剂Tislelizumab(替雷利珠单抗)获批上市。FDA临床试验网站(www.clinicaltrials.gov)数据显示，截止2018年9月，全球有2250个单抗类PD-1/PD-L1抑制剂的临床试验，研究其与其它抗肿瘤药物联合用药疗效或拓展其适应症。
但是，抗体类药物生产成本高导致价格昂贵，易产生免疫相关副反应，稳定性差，需要低温存储与运输，给药不便(口服无效需静注)，不适宜的PK(分布容积低、清除半衰期长)，有效率低(多数实体瘤中只有20％-40％有效率)等，严重限制了PD-1/PD-L1抑制剂的临床应用。
而小分子药物具有价格低廉、口服给药有效、稳定性好、免疫副作用低、易渗透到肿瘤中从而提高有效率等优势。相比单抗，小分子药物具有更广泛的临床应用价值。
目前，PD-1/PD-L1小分子抑制剂的研究工作刚刚起步，报道的化合物多处于临床前研究阶段，还没有上市药物。现有化合物能否成功解决单抗类药物临床应用的不足还充满未知。因此，高效、结构新颖的PD-1/PD-L1小分子抑制剂仍需不断地研究和开发。
发明内容
本申请的一个目的是提供一类阻断PD-1/PD-L1相互作用的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，以及含有上述任意成分的药物组合物，所述苄胺类衍生物的制备方法及其在预防或治疗与PD-1/PD-L1相关的疾病中的应用。
在一个方面，本申请提供通式(Ⅰ)所示的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，
Figure PCTCN2021108826-appb-000005
其中，
R选自氢和C1-C8烷基；
R 1选自氢、氘、卤素、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基；
R 2选自
Figure PCTCN2021108826-appb-000006
其中R 6选自卤素、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基，R 7位于R 6的间位或者邻位且R 7选自氢、-O-(CH 2) n-R 0、-CONH-R 0和-(CH 2) n-R 0，其中n为1-4的整数，R 0为氰基、羟基、羧基、氨基或含杂原子的链状或环状亲水性取代基；
R 3选自R 8-CH 2-，其中R 8选自氢、氰基、C1-C4烷基、卤代C1-C4烷基、C2-C4烯基、-NR 9R 10、-CONR 9R 10、3-6元环烷基、3-6元杂环烷基、6-10元芳基和5-10元杂芳基，任选地，所述C1-C4烷基、卤代C1-C4烷基、C2-C4烯基、-NR 9R 10、-CONR 9R 10、3-6元环烷基、3-6元杂环烷基、6-10元芳基和5-10元杂芳基各自独立地被一个或多个选自下述的取代基取代：氰基、卤素、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷基磺酰基、3-6元环烷基、羟基取代的3-6元环烷基、3-6元杂环烷基、羟基取代的3-6元杂环烷基、-CONR 9R 10和-NR 9COR 10，其中R 9和R 10在每次出现时各自独立地选自氢、氘和C1-C4烷基；
R 4选自羟基、羧基、氨基酸(优选亲水性氨基酸)的片段和-NR 10R 11，其中R 10和R 11各自独立地 选自氢、氘、C1-C6烷基和3-6元环烷基，任选地，所述C1-C6烷基和3-6元环烷基各自独立地被一个或多个选自下述的取代基取代：巯基、羟基、羧基、羟基C1-C6烷基、C1-C6酰胺基和3-6元含氮杂环烷基；或者，R 10和R 11与相连的N原子形成5-6元杂环烷基，任选地，所述5-6元杂环烷基被一个或多个选自下述的基团取代：氨基、羟基、羧基、巯基和羟基C1-C6烷基；
R 5选自氢、氘、氰基、卤素、C1-C4烷基、C2-C4烯基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基；
Y和Z各自独立地选自碳和氮。
在一些实施方案中，所述苄胺类衍生物结构如式(Ⅰ-A)所示：
Figure PCTCN2021108826-appb-000007
其中，R、R 1、R 2、R 3、R 4和R 5如前文所述，并且R 5位于-OR 3的对位或者间位。在一些优选的实施方案中，R 5位于-OR 3的对位。
在一些实施方案中，所述苄胺类衍生物结构如式(Ⅰ-B)所示：
Figure PCTCN2021108826-appb-000008
其中，R、R 1、R 2、R 3、R 4和R 5如前文所述，Z和Y中至少一个为氮，并且R 5位于-OR 3的对位或者间位。
在一些实施方案中，上述苄胺类衍生物结构如式(Ⅰ-C)所示：
Figure PCTCN2021108826-appb-000009
其中，R、R 1、R 2、R 3、R 4和R 5如前文所述，并且R 5位于-OR 3的对位或者间位。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R选自氢和甲基。
在一些优选的实施方案中，式I、I-A、I-B和I-C任一通式中的R为氢。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 1选自卤素、C1-C2烷基和卤代C1-C2烷基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 1为溴、甲基或三氟甲基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 1选自卤素和C1-C2烷基。
在一些优选的实施方案中，式I、I-A、I-B和I-C任一通式中的R 1为溴或甲基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 1选自氟、氯、溴、碘、甲氧基、甲基、氰基、氘代甲基和卤代甲基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 2选自
Figure PCTCN2021108826-appb-000010
其中R 6选自氢、氘、氟、氯、溴、碘、甲氧基、甲基、氰基、氘代甲基和卤代甲基，R 7位于R 6的间位或者邻位且R 7选自氢、-O-(CH 2) n-R 0、-CONH-R 0、-(CH 2) n-R 0，其中n为1-4的整数，R 0为氰基、羟基、羧基、氨基和含杂原子的链状或环状亲水性取代基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 2选自
Figure PCTCN2021108826-appb-000011
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 3选自R 8-CH 2-，其中R 8选自氢、C1-C2烷基、苯基和5-6元杂芳基，任选地，所述C1-C2烷基、苯基和5-6元杂芳基各自独立地被一个氰基取代。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 3选自甲基、乙基、
Figure PCTCN2021108826-appb-000012
Figure PCTCN2021108826-appb-000013
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 3选自甲基、乙基、
Figure PCTCN2021108826-appb-000014
Figure PCTCN2021108826-appb-000015
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 4选自氨基酸的片段和-NR 10R 11，其中R 10和R 11各自独立地选自氢、氘和C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自下述的取代基取代：巯基、羟基、羧基、羟基C1-C4烷基、C1-C4酰胺基和5-6元含氮杂环烷基；或者，R 10和R 11与相连的N原子形成5-6元杂环烷基，任选地，所述5-6元杂环烷基被一个或多个选自下述的基 团取代：氨基、羟基、羧基、巯基和羟基C1-C4烷基；所述氨基酸片段选自氨基酸中与羧基共用一个碳原子的氨基失去一个氢得到的片段。在一些优选的实施方案中，所述氨基酸选自甘氨酸、丙氨酸、脯氨酸、羟脯氨酸、丝氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、半胱氨酸、组氨酸、赖氨酸、精氨酸、焦谷氨酸、
Figure PCTCN2021108826-appb-000016
Figure PCTCN2021108826-appb-000017
在一些优选的实施方案中，所述氨基酸选自丝氨酸、羟脯氨酸和天冬酰胺。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 4选自氨基、羟基、羧基、
Figure PCTCN2021108826-appb-000018
Figure PCTCN2021108826-appb-000019
Figure PCTCN2021108826-appb-000020
以及上述结构的立体异构体。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 4选自
Figure PCTCN2021108826-appb-000021
Figure PCTCN2021108826-appb-000022
以及上述结构的立体异构体。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 5选自氢、氘、卤素、C1-C2烷基和C1-C2烷氧基，例如氢、氯、甲氧基或甲基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 5选自氟、氯、溴、碘、甲氧基、甲基、氰基、氘代甲基、卤代甲基、乙基、乙烯基和乙氧基。
在一些实施方案中，式I、I-A、I-B和I-C任一通式中的R 5选自氢、氘、卤素和C1-C2烷基，例如氢、氯或甲基。
在一些实施方案中，在式I、I-A、I-B和I-C任一通式中，R为氢；R 5选自氢、氯和甲基，且R 5位于-OR 3的对位。
在一些实施方案中，在式I、I-A、I-B和I-C任一通式中，
R选自氢和C1-C8烷基；
R 1选自卤素和C1-C4烷基；
R 2选自
Figure PCTCN2021108826-appb-000023
其中R 6选自卤素、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基，R 7位于R 6的间位或者邻位且R 7选自氢、-O-(CH 2) n-R 0、-CONH-R 0和-(CH 2) n-R 0，其中n为1-4的整数，R 0为氰基、羟基、羧基、氨基或含杂原子的链状或环状亲水性取代基；
R 3选自R 8-CH 2-，其中R 8选自被一个或多个氰基取代的6-10元芳基和任选地被一个或多个氰基取代的5-10元杂芳基；
R 4选自
Figure PCTCN2021108826-appb-000024
R 5选自卤素和C1-C4烷基，且R 5位于-OR 3的对位；
Y和Z各自独立地选自碳和氮。
在一些实施方案中，在式I-A中，
R选自氢和甲基；
R 1选自卤素和C1-C2烷基；
R 2选自
Figure PCTCN2021108826-appb-000025
R 3选自
Figure PCTCN2021108826-appb-000026
R 4选自
Figure PCTCN2021108826-appb-000027
R 5选自卤素和C1-C4烷基，且R 5位于-OR 3的对位。
在一些实施方案中，在式I、I-A、I-B和I-C任一通式中，
R为氢；
R 1为溴或甲基；
R 2为
Figure PCTCN2021108826-appb-000028
R 3选自甲基、
Figure PCTCN2021108826-appb-000029
R 4选自
Figure PCTCN2021108826-appb-000030
R 5选自氢、氯和甲基，且R 5位于-OR 3的对位。
在一些实施方案中，所述苄胺类衍生物选自：
Figure PCTCN2021108826-appb-000031
Figure PCTCN2021108826-appb-000032
在一些实施方案中，所述苄胺类衍生物药学上可接受的盐选自与有机或无机酸形成的盐(例如盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸氢盐、草酸盐、甲酸盐、乙酸盐、柠檬酸盐、酒石酸盐、磺酸盐、苯甲酸盐、三氟乙酸盐、马来酸盐或枸橼酸盐等)，与碱金属及碱土金属形成的盐(例如锂盐、钠盐、钾盐、镁盐及钙盐或铵盐等)，以及与有机碱形成的盐(例如甲胺盐、乙胺盐、三乙胺盐、哌啶盐、吗啉盐等)。在一些实施方案中，所述苄胺类衍生物药学上可接受的盐为其盐酸盐。
如本文中所使用的，术语“卤素”是指氟、氯、溴和碘。
如本文中所使用的，术语“C1-C8烷基”表示直链或支链的含有1-8个碳原子的烷基，包括C1-C6烷基、C1-C5烷基、C1-C4烷基和C1-C2烷基等。其典型的实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
如本文中所使用的，术语“C1-C4烷氧基”是指以C1-C4烷基-O-方式形成的基团，其中“C1-C4烷基”的定义如前文所述，例如C1-C3烷氧基和C1-C2烷氧基等。典型的实例为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文中所使用的，术语“C2-C4烯基”是指含有至少一个碳碳双键以及2-4个碳原子的直链或支链烃基。其典型的实例为乙烯基、丙烯基、2-丙烯基、丁烯基、2-丁烯基、丁二烯基等。
如本文中所使用的，术语“氘代”是指基团中至少一个氢原子被其同位素氘取代后得到的基团，例如氘代C1-C4烷基。
如本文中所使用的，术语“卤代”是指基团中至少一个氢原子被如前文描述的卤素取代得到的基团，例如卤代C1-C4烷基、卤代C1-C4烷氧基等。其典型的实例为三氟甲基。
如本文中所使用的，术语“亲水性取代基”是指易于与水亲和的基团，所述亲水性基团中通常含有至少一个亲水性官能团，例如羟基、氨基、羧基、磺酸基、磷酸基等。在一些实施方案中，所述亲水性取代基为含杂原子的链状或环状亲水性取代基。具体的实例包括但不限于
Figure PCTCN2021108826-appb-000033
Figure PCTCN2021108826-appb-000034
Figure PCTCN2021108826-appb-000035
等。
如本文中所使用的，术语“3-6元环烷基”是指含有3至6个成环碳原子的饱和环状烃基。例如3元环烷基、4元环烷基、5元环烷基或6元环烷基。典型的实例包括环丙基、环丁基、环戊基、环己基等。
如本文中所使用的，术语“3-6元杂环烷基”是指含有3至6个环成员的饱和环状烃基，且其中至少1个(例如1、2、3或4个)环成员为选自N、O和S的杂原子。例如3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基。例如3-6元含氮杂环烷基。典型的实例包括环氧乙烷基、环氧丁烷基、吡咯烷基、四氢呋喃基、咪唑啉基、吡唑烷基、噻唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、硫代吗啉基、哌嗪基、哌啶基、噁嗪基等。
如本文中所使用的，术语“6-10元芳基”是指含有6至10个成环碳原子的芳族基团，例如苯基或萘基。
如本文中所使用的，术语“5-10元杂芳基”是指含有5-10个环成员的芳香族基团，且其中至少1个(例如1、2、3或4个)环成员为选自N、O和S的杂原子，所述杂芳基可为单环杂芳基、双环杂芳基或多环杂芳基。例如5-6元杂芳基等。典型的实例为呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基等。
如本文中所使用的，术语“C1-C4烷基磺酰基”是指以C1-C4烷基-SO 2-方式形成的基团，其中“C1-C4烷基”的定义如前文所述，例如C1-C3烷基磺酰基和C1-C2烷基磺酰基等。典型的实例为甲磺酰基等。
如本文中所使用的，术语“C1-C6酰胺基”是指以C1-C5烷基-CONH-方式形成的基团，其中“C1-C5烷基”的定义如前文所述，例如C1-C4烷基酰胺基和C1-C2烷基酰胺基等。典型的实例为 甲酰胺基、乙酰氨基等。
如本文中所使用的，术语“立体异构体”是指由于分子中的原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。本发明所述立体异构体包括所述苄胺类衍生物上述任意立体异构体，以及一种或多种立体异构体以任意比例形成的混合物。
如本文中所使用的，术语“溶剂合物”是指本文中所述苄胺类衍生物可以与溶剂(例如，甲醇、乙醇等有机溶剂或水)交互作用，形成可稳定存在的复合物。在一些实施方案中，所述溶剂可作为所述苄胺类衍生物晶格的结构要素。在一些实施方案中，所述溶剂可以化学计量比或非化学计量比存在。
如本文中所使用的，术语“前药”是指含有生物反应官能团的本文中所述苄胺类衍生物的衍生物，其在生化反应条件下以裂解或其他生化反应方式产生所述苄胺类衍生物，包括但不限于在生化条件下可水解的本文所述苄胺类衍生物的磷酸盐、酯、酰胺及酰脲等。
在另一个方面，本发明提供了第一方面所述化合物的制备方法，具体如下所示：
当通式(Ⅰ)所述苄胺类衍生物为如式(Ⅰ-A)所示结构，其制备方法选自下述的方法一～方法三：
Figure PCTCN2021108826-appb-000036
Figure PCTCN2021108826-appb-000037
当通式(Ⅰ)所述苄胺类衍生物为如式(Ⅰ-B)所示结构，其制备方法选自下述的方法四或方法五：
Figure PCTCN2021108826-appb-000038
当通式(Ⅰ)所述苄胺类衍生物为如式(Ⅰ-C)所示结构，其制备方法选自下述的方法六或方法七：
Figure PCTCN2021108826-appb-000039
除特别说明，上述各化合物中出现的取代基如本发明第一方面任一项所述。
在另一个方面，本发明提供一种药物组合物，其含有本发明第一方面任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，以及一种或多种药学上可接受的载体或赋形剂。
所述载体是指用于提高药物在递送过程中的选择性、有效性和/或安全性的物质。主要用于控制药物释放，也可用于提高药物的药代动力学特性，特别是生物利用度。所述赋形剂是指在药物制剂中除活性成分外的其它物质，主要用于长期稳定性，填充固体制剂(因此，也常被用于特指“填充剂”)或增强产品疗效(例如促进吸收、降低粘度或提高溶解度等)。根据给药途径或给药形式，本领域技术人员可以在已知理论及经验基础上选择合适的载体和赋形剂。在一些实施方案中，所述载体或赋形剂包括但不限于硬脂酸镁、氧化铝、甘油、卵磷脂、血清蛋白、纤维素物质、PEG、蜂蜡、羊毛脂、山梨酸钾、乳糖、淀粉、椰子油及植物油等。
本发明所述药物组合物可以根据不同给药途径而制备成各种形式。
在一些实施方案中，所述药物组合物可以以下面的任意方式施用：口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服、腹膜内或静脉内用药方式。
当口服用药时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂一般使用的载体包括乳糖和玉米淀粉，另外也可加入润滑剂如硬质酸镁。胶囊制剂一般使用的稀释剂包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当直肠用药时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药一般可制成栓剂的形式，其通过将药物与一种适宜的非刺激性赋形剂混合而制得。该赋形剂在室温下呈现固体状态，而在直肠温度下熔化释出药物。该类赋形剂包括可可脂、蜂蜡和聚乙二醇。
当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药可根据不同的患面或器官制成不同的局部用药制剂形式，具体说明如下：
当眼部局部施用时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。此外对于眼用，也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药可制成适当的软膏、洗剂或霜剂制剂形式，其中活性成分悬浮或溶解于一种或多种载体中。这里软膏 即可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
当下肠道局部施用时，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药可制成如上所述的直肠栓剂制剂或适宜的灌肠制剂形式，另外也可使用局部透皮贴剂。
所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液，或无菌注射溶液。其中，可使用的载体和溶剂包括水，林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
上述各种剂型的药物均可以按照药学领域的常规方法制备。
在另一个方面，本发明提供本文所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或药物组合物在制备预防或治疗与PD-1/PD-L1相关的疾病的药物中的用途。
在另一个方面，本发明提供本文所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或药物组合物，其用于预防或治疗与PD-1/PD-L1相关的疾病。
在另一个方面，本发明提供一种预防或治疗与PD-1/PD-L1相关的疾病的方法，其包括向有此需要的受试者施用有效量的本文所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或药物组合物的步骤。
在另一个方面，本发明提供一种抑制PD-1/PD-L1相互作用的方法，其包括向有此需要的受试者施用有效量的本文所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或药物组合物的步骤。
在另一个方面，本发明提供一种提高免疫反应的方法，其包括向有此需要的受试者施用有效量的本文所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或药物组合物的步骤。
本文中所述与PD-1/PD-L1相关的疾病包括肿瘤、感染性疾病和自身免疫性疾病。
在一些实施方案中，所述肿瘤选自消化系统肿瘤、泌尿系统肿瘤、血液肿瘤、神经系统肿瘤、生殖系统肿瘤、皮肤癌、肺癌、乳腺癌、头颈癌、脑瘤、胶质瘤、鼻咽癌等肿瘤中的一种或多种。
在一些实施方案中，所述感染性疾病选自微生物引起的一种或多种感染。在一些实施方案中，所述感染为细菌和病毒引起的感染。
在一些实施方案中，所述自身免疫性疾病选自慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、天疱疮(例如寻常型天疱疮)、类天疱疮、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎等、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、皮肌炎、混合性结缔组织病、自 身免疫性溶血性贫血、甲状腺自身免疫病、口眼干燥综合征、强直性脊柱炎、结节性多动脉炎和Wegener肉芽肿病等。
在本文中，术语“治疗有效量”或“预防有效量”是指在合理的医学判断范围内，足以治疗或预防患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所治疗的疾病、所治疗的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、治疗持续时间、并行疗法的性质、所需的治疗效果等因素发生变化，但仍可以由本领域技术人员常规确定。
另外需要指出，所述苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药针对不同患者的特定使用剂量和使用方法决定于诸多因素，包括患者的年龄，体重，性别，自然健康状况，营养状况，药物的活性强度，服用时间，代谢速率，病症的严重程度以及诊治医师的主观判断。这里优选使用剂量介于0.001-1000mg/kg体重/天。
发明的有益效果
本发明涉及的化合物与人PD-L1有很强的结合能力，具有明显抑制PD-1/PD-L1相互作用的活性，并且具有显著地体内抗肿瘤药效。
附图说明
此处所说明的附图用来提供对本发明的进一步理解，构成本申请的一部分，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1显示了PD-1人源化小鼠腹腔注射给予15mg/kg化合物5后肿瘤随时间增殖曲线。
图2显示了PD-1人源化小鼠腹腔注射给予15mg/kg化合物5后体重随时间增殖曲线。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。以下对至少一个示例性实施例的描述实际上仅仅是说明性的，绝不作为对本发明及其应用或使用的任何限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：
(1)中间体1-1的合成：
Figure PCTCN2021108826-appb-000040
将3-溴-2-甲基苯甲醇(2.51g，12.5mmol)、苯硼酸(2.29g，18.75mmol)、乙酸铯(5.99g，31.25mmol)、PdCl 2(dppf)(0.917g，1.25mmol)在40mL THF中，氩气保护下，回流反应23h，冷却，浓缩，残余物加入水和DCM，萃取三次，有机相水洗三次，浓缩经柱层析纯化得棕色固体2.44g，收率98％。 1H NMR(400MHz,CDCl 3):δ7.44–7.32(m,4H),7.32–7.27(m,2H),7.26–7.23(m,1H),7.20(dd,J＝7.6,1.2Hz,1H),4.77(s,2H),2.24(s,3H),1.70(s,1H).ESI-MS:m/z＝181.11[M-OH] +.
(2)中间体1-2的合成：
Figure PCTCN2021108826-appb-000041
将1-1(1.51g，7.62mmol)溶于30mL DCM中，冰浴降温至0℃，滴加PBr 3(0.36mL，3.81mmol)，滴完继续反应20min后，加入碎冰淬灭反应，DCM萃取三次，饱和碳酸氢钠溶液洗涤有机相一次，有机相水洗至中性，无水Na 2SO 4干燥，抽滤，浓缩至干得无色油状物1.32g，收率66％，无需纯化直接用于下一步。 1H NMR(400MHz,CDCl 3):δ7.44–7.39(m,2H),7.38–7.32(m,2H),7.32–7.27(m,2H),7.22(d,J＝2.8Hz,1H),7.21(s,1H),4.60(s,2H),2.30(s,3H).ESI-MS:m/z＝181.10[M-Br] +.
(3)中间体1-3的合成
Figure PCTCN2021108826-appb-000042
将2-羟基对硝基苯甲醛(4.81g，28.78mmol)溶于40mL DMF中，依次加入K 2CO 3(5.97g，43.20mmol)、间氰基苄溴(6.21g，31.68mmol)、四丁基碘化铵(50mg，0.14mmol)，室温下反应4h后，将反应液倒入900mL冰水中，抽滤，水洗滤饼至中性，滤饼干燥后分散在环己烷中，超声，抽滤，得黄白色粉末状固体8.05g，收率99％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.49(s,1H),8.09(t,J＝1.6Hz,2H),7.98–7.91(m,3H),7.86(d,J＝7.6Hz,1H),7.66(t,J＝7.8Hz,1H),5.51(s,2H).ESI-MS:m/z＝281.06[M-H] -.
(4)中间体1-4的合成
Figure PCTCN2021108826-appb-000043
将1-3(8.05g，28.52mmol)、Fe粉(5.59g，99.82mmol)及NH 4Cl(2.29g，42.81mmol)悬浮于100mL EtOH/H 2O＝4/1的混合溶剂中，升温回流1.5h，冷却，抽滤除去不溶物，滤液蒸干后，加入水超声，抽滤，得橙色粉末状固体6.48g，收率90％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.05(s,1H),8.16–7.34(m,5H),6.60–6.06(m,4H),5.21(s,2H).ESI-MS:m/z＝253.10[M+H] +.
(5)中间体1-5的合成
Figure PCTCN2021108826-appb-000044
将1-2(490mg，1.88mmol)和1-4(567mg，2.25mmol)悬浮于15mL乙腈和2mL DMF中，加入K 2CO 3(392mg，2.84mmol)，回流反应11h后，浓缩，加入水，EA萃取三次，有机相水洗至中性，浓缩，残余物经柱层析纯化得黄白色固体460mg，收率57％。 1H NMR(400MHz,CDCl 3):δ10.23(s,1H),7.75(d,J＝8.4Hz,1H),7.72–7.66(m,2H),7.66–7.60(m,1H),7.51(t,J＝7.6Hz,1H),7.48–7.40(m,2H),7.40–7.35(m,1H),7.33–7.27(m,3H),7.25–7.21(m,2H),6.32(dd,J＝8.8,2.0Hz,1H),6.09(d,J＝2.0Hz,1H),5.14(s,2H),4.67(br,1H),4.40(d,J＝4.8Hz,2H),2.23(s,3H).ESI-MS:m/z＝433.19[M+H] +.
(6)化合物1的合成
Figure PCTCN2021108826-appb-000045
将1-5(100mg，0.23mmol)和N-乙酰基乙二胺(47mg，0.46mmol)溶于2mL DCE和0.5mL DMF中，加入冰醋酸(26μL，0.46mmol)，35℃下反应24h后，加入NaBH(OAc) 3(147mg，0.69mmol)，继续反应14h，加入水，DCM萃取三次，水洗三次，浓缩，经柱层析和重结晶纯化得土黄色粉末42mg， 收率35％。 1H NMR(400MHz,DMSO-d 6):δ7.90(s,1H),7.80–7.76(m,3H),7.60(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,2H),7.39–7.34(m,1H),7.31–7.28(m,3H),7.19(t,J＝7.6Hz,1H),7.10(dd,J＝7.5,1.1Hz,1H),6.97(d,J＝8.0Hz,1H),6.35(d,J＝2.0Hz,1H),6.15(dd,J＝8.0,2.0Hz,1H),6.03(t,J＝5.6Hz,1H),5.10(s,2H),4.23(d,J＝5.6Hz,2H),3.57(s,2H),3.11(q,J＝6.4Hz,2H),2.52–2.50(m,2H),2.18(s,3H),1.81(br,1H),1.76(s,3H).ESI-HRMS:m/z calculated for C 33H 35N 4O 2 +[M+H] +519.2755,found 519.2754.
实施例2：
Figure PCTCN2021108826-appb-000046
将1-5(108mg，0.25mmol)和乙醇胺(31mg，0.5mmol)溶于3mL DCE中，加入冰醋酸(29μL，0.50mmol)，室温下反应12h后，加入NaBH(OAc) 3(159mg，0.75mmol)，继续反应12h，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，浓缩，经柱层析和重结晶纯化得土黄色粉末30mg，收率25％。 1H NMR(400MHz,DMSO-d 6):δ7.90(s,1H),7.79(d,J＝7.6Hz,2H),7.59(t,J＝8.0Hz,1H),7.45(t,J＝7.2Hz,2H),7.38–7.35(m,1H),7.31–7.29(m,3H),7.19(t,J＝7.6Hz,1H),7.10(d,J＝7.2Hz,1H),6.96(d,J＝8.0Hz,1H),6.36(s,1H),6.15(d,J＝7.8Hz,1H),6.03(t,J＝5.6Hz,1H),5.10(s,2H),4.46(br,1H),4.23(d,J＝4.8Hz,2H),3.58(s,2H),3.44(t,J＝5.2Hz,2H),2.53(t,J＝6.0,2H),2.18(s,3H),1.90(br,1H).ESI-HRMS:m/z calculated for C 31H 31N 3NaO 2 +[M+Na] +500.2308,found 500.2307.
实施例3：
Figure PCTCN2021108826-appb-000047
将1-5(108mg，0.25mmol)和2-胺基丙二醇(46mg，0.5mmol)溶于2mL DCE和0.5mLDMF中，加入冰醋酸(29μL，0.50mmol)，35℃下反应24h后，加入NaBH(OAc) 3(159mg，0.75mmol)，继续反应24h，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，浓缩，重结晶纯化得土黄色粉末92mg，收率72％。 1H NMR(400MHz,DMSO-d 6):δ7.92(s,1H),7.82–7.78(m,2H),7.58(t,J＝8.0Hz,1H),7.48–7.42(m,2H),7.40–7.34(m,1H),7.32–7.27(m,3H),7.19(t,J＝7.6Hz,1H),7.10(dd,J＝7.6, 1.2Hz,1H),6.97(d,J＝8.4Hz,1H),6.35(d,J＝2.0Hz,1H),6.15(dd,J＝8.0,1.6Hz,1H),6.02(t,J＝5.2Hz,1H),5.10(s,2H),4.38(br,1H),4.23(d,J＝5.6Hz,2H),3.62(s,2H),3.36(ddd,J＝26.2,10.8,5.6Hz,4H),2.55(p,J＝5.6Hz,1H),2.18(s,3H).ESI-HRMS:m/z calculated for C 32H 33N 3NaO 3 +[M+Na] +530.2414,found 530.2413.
实施例4：
Figure PCTCN2021108826-appb-000048
将1-5(216mg，0.50mmol)和D-丝氨酸(105mg，1.0mmol)悬浮于2mLDMF中，加入冰醋酸(57μL，1.0mmol)，35℃下反应24h后，加入NaBH(OAc) 3(318mg，1.50mmol)，继续反应24h后，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，浓缩，残余物经制备液相纯化得黄白色粉末180mg，收率69％。 1H NMR(400MHz,DMSO-d 6):δ8.31(br,2H),7.99(s,1H),7.88(d,J＝8.0Hz,1H),7.79(d,J＝7.6Hz,1H),7.57(t,J＝8.0Hz,1H),7.47–7.44(m,2H),7.40–7.35(m,1H),7.31(d,J＝1.2Hz,1H),7.29(s,1H),7.26(d,J＝7.6Hz,1H),7.19(t,J＝7.6Hz,1H),7.10(d,J＝7.6Hz,1H),7.07(d,J＝8.4Hz,1H),6.40–6.35(m,2H),6.19(dd,J＝8.0,1.6Hz,1H),5.41(br,1H),5.18–5.11(m,2H),4.25(d,J＝5.2Hz,2H),4.04(dd,J＝43.6,12.8Hz,2H),3.78(dd,J＝11.6,4.0Hz,1H),3.66(dd,J＝11.2,7.2Hz,1H),3.19–3.16(m,1H),2.17(s,3H).ESI-HRMS:m/z calculated for C 32H 31N 3NaO 4 +[M+Na] +544.2207,found 544.2208.
实施例5：
(1)中间体5-1的合成
Figure PCTCN2021108826-appb-000049
将1-1(7.36g，37.14mmol)、邻苯二甲酰亚胺(6.56g，44.57mmol)和PPh 3(13.64g，52.00mmol)置于三口瓶中，在Ar保护下，加入170mL无水THF，降温至0℃，滴加DEAD(9.06g,52.00mmol)，滴完室温下反应24h。蒸干溶剂柱层析纯化得白色固体11.21g，收率92％。 1H NMR(400MHz,CDCl 3):δ7.92–7.86(m,2H),7.77–7.72(m,2H),7.43–7.38(m,2H),7.36–7.31(m,1H),7.30–7.26(m,2H),7.24–7.21(m,1H),7.20–7.12(m,2H),4.94(s,2H),2.34(s,3H).ESI-MS:m/z＝328.13[M+H] +.
(2)中间体5-2的合成
Figure PCTCN2021108826-appb-000050
将5-1(11.21g，34.27mmol)溶于210mL乙醇中，加入85％的水合肼(3.63g，61.68mmol)，回流反应3h，冷却后加入40mL 6N HCl水溶液，继续回流30min后，冷却至0℃，抽滤除去不溶物，滤液浓缩后，饱和NaHCO 3调PH＝8-9，DCM萃取，有机相水洗一次，蒸干溶剂得无色油状物6.5g，收率96％，无需纯化直接用于下一步。 1H NMR(400MHz,CDCl 3):δ7.43–7.37(m,2H),7.36–7.31(m,2H),7.30–7.27(m,2H),7.24(t,J＝7.6Hz,1H),7.15(dd,J＝7.6,1.2Hz,1H),3.93(s,2H),2.22(s,3H),1.79(s,2H).ESI-MS:m/z＝198.13[M+H] +.
(3)中间体5-3的合成
Figure PCTCN2021108826-appb-000051
将4-溴-2-羟基-5-甲基苯甲醛(430mg，2mmol)溶于6mL乙腈，加入K 2CO 3(304mg，2.2mmol)、5-氯甲基烟腈(336mg，2.2mmol)、NaI(30mg，0.2mmol),室温下反应24h，加入18mL水稀释，抽滤不溶物并水洗至中性，得土黄色粉末状固体649mg，收率98％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.37(s,1H),9.03(d,J＝1.6Hz,1H),9.01(d,J＝2.0Hz,1H),8.53(s,1H),7.68(s,1H),7.63(s,1H),5.40(s,2H),2.34(s,3H).ESI-MS:m/z＝331.01[M+H] +.
(4)中间体5-4的合成
Figure PCTCN2021108826-appb-000052
将5-2(296mg，1.5mmol)、5-3(596mg，1.8mmol)、Cs 2CO 3(733mg，2.25mmol)、BINAP(187mg，0.3mmol)及Pd(oAc) 2(34mg，0.15mmol)悬浮于15mL二氧六环中，Ar保护下回流反应20h后，浓缩，加入水，DCM萃取，有机相水洗至中性，经柱层析纯化得黄白色固体300mg，收率45％。 1H NMR(400MHz,CDCl 3):δ10.21(s,1H),8.84(t,J＝1.8Hz,2H),8.05(t,J＝2.0Hz,1H),7.61(s,1H),7.46–7.42(m,2H),7.39–7.35(m,1H),7.33–7.30(m,2H),7.27–7.24(m,3H),6.08(s,1H),5.18(s,2H),4.50(br,1H),4.44(s,2H),2.25(s,3H),2.13(s,3H).ESI-MS:m/z＝448.21[M+H] +.
(5)化合物5的合成
Figure PCTCN2021108826-appb-000053
将5-4(750mg，1.68mmol)和D-丝氨酸(350mg，3.36mmol)悬浮于12mL无水DMF和4mL无水甲醇中，再加入冰醋酸(195μL，3.36mmol)，35℃下反应24h后，加入NaBH(oAc) 3(1.065g，5.04mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体350mg，收率39％。 1H NMR(400MHz,DMSO-d 6):δ8.88(dd,J＝15.6,2.0Hz,2H),8.37(t,J＝2.0Hz,1H),8.34(br,2H),7.48–7.44(m,2H),7.40–7.35(m,1H),7.35–7.34(m,1H),7.33–7.32(m,1H),7.16(dd,J＝7.6,1.8Hz,1H),7.12(t,J＝7.2Hz,1H),7.07(dd,J＝7.2,1.8Hz,1H),7.01(s,1H),6.09(s,1H),5.72(t,J＝5.6Hz,1H),5.38(br,1H),5.14(dd,J＝18.8,13.2Hz,2H),4.35(d,J＝5.6Hz,2H),4.04(dd,J＝44.8,12.8Hz,2H),3.78(dd,J＝11.2,4.4Hz,1H),3.64(dd,J＝11.4,7.2Hz,1H),3.19–3.16(m,1H),2.19(s,3H),2.10(s,3H).ESI-HRMS:m/z calculated for C 32H 32N 4NaO 4 +[M+Na] +559.2316,found 559.2313.
实施例6：
(1)中间体6-1的合成
Figure PCTCN2021108826-appb-000054
将2,4-二羟基-6-甲基苯甲醛(1.52g，10mmol)溶于40mL DCM中，加入2,6-二甲基吡啶(1.13g，10.5mmol)和DMAP(245mg，2mmol)，降温至0℃，滴加15mL Tf 2O(2.96g，10.5mmol)的DCM溶液，滴完室温下反应10h，加入水，DCM萃取，水洗有机相，蒸干溶剂，残余物经柱层析纯化得无色油状物1.7g，收率60％。 1H NMR(400MHz,CDCl 3):δ12.16(s,1H),10.31(s,1H),6.76(d,J＝2.4Hz,1H),6.67(d,J＝2.4Hz,1H),2.67(s,3H).ESI-MS:m/z＝285.00[M+H] +.
(2)中间体6-2的合成
Figure PCTCN2021108826-appb-000055
将6-1(220mg，0.77mmol)溶于8mL乙腈中，加入K 2CO 3(128mg，0.92mmol)、间氰基苄溴(159mg，0.81mmol)和四丁基碘化铵(15mg，0.04mmol)，室温下反应6h，浓缩后加入水，DCM萃取，有机相水洗至中性，有机相浓缩，经柱层析纯化得黄白色固体286mg，收率93％。 1H NMR(400MHz, CDCl 3):δ10.64(s,1H),7.78–7.61(m,3H),7.60–7.52(m,1H),6.80(s,2H),5.20(s,2H),2.63(s,3H),(Isomer ratio＝5:1).ESI-MS:m/z＝400.03[M+H] +.
(3)中间体6-3的合成
Figure PCTCN2021108826-appb-000056
将5-2(99mg，0.5mmol)、6-2(200mg，0.5mmol)、Cs 2CO 3(244mg，0.75mmol)、BINAP(62mg，0.1mmol)及Pd(oAc) 2(11mg，0.05mmol)悬浮于5mL二氧六环中，Ar保护下回流反应24h后，浓缩，加入水，DCM萃取，有机相水洗至中性，经柱层析纯化得黄白色固体131mg，收率59％。 1H NMR(400MHz,CDCl 3):δ10.46(s,1H),7.69–7.64(m,2H),7.63–7.59(m,1H),7.53–7.46(m,1H),7.46–7.40(m,2H),7.39–7.34(m,1H),7.32–7.27(m,3H),7.24(d,J＝2.0Hz,1H),7.23(s,1H),6.10(s,1H),5.99(d,J＝2.0Hz,1H),5.11(s,2H),4.53(br,1H),4.38(d,J＝3.2Hz,2H),2.57(s,3H),2.23(s,3H).ESI-MS:m/z＝447.17[M+H] +.
(4)化合物6的合成
Figure PCTCN2021108826-appb-000057
将6-3(131mg，0.29mmol)和D-丝氨酸(62mg，0.58mmol)悬浮于4mL无水DMF和1mLDCE中，再加入冰醋酸(34μL，0.58mmol)，35℃下反应24h后，加入NaBH(oAc) 3(187mg，0.87mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体48mg，收率31％。 1H NMR(400MHz,DMSO-d 6):δ8.20(br,2H),7.98(s,1H),7.88(d,J＝8.0Hz,1H),7.78(d,J＝7.8Hz,1H),7.56(dt,J＝7.6,1.2Hz,1H),7.49–7.41(m,2H),7.40–7.34(m,1H),7.32–7.28(m,2H),7.27–7.23(m,1H),7.18(t,J＝7.6Hz,1H),7.10(dd,J＝7.6,1.2Hz,1H),6.29(t,J＝5.2Hz,1H),6.24(d,J＝1.6Hz,1H),6.12(d,J＝1.6Hz,1H),5.37(br,1H),5.13(dd,J＝14.8,13.2Hz,2H),4.24(d,J＝5.6Hz,2H),4.10(s,2H),3.84(dd,J＝11.6,4.4Hz,1H),3.61(dd,J＝11.6,8.4Hz,1H),3.19(dd,J＝8.0,4.4Hz,1H),2.21(s,3H),2.17(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 3NaO 4 +[M+Na] +558.2363,found 558.2363.
实施例7：
(1)中间体7-1的合成
Figure PCTCN2021108826-appb-000058
将6-1(852mg，3mmol)溶于24mL乙腈中，加入K 2CO 3(954mg，6.90mmol)、5-氯甲基烟腈盐酸盐(624mg，3.30mmol)和NaI(45mg，0.3mmol)，室温下反应12h，再45℃反应9h，浓缩后加入水，EA萃取，有机相水洗至中性，有机相浓缩后经柱层析纯化得黄白色固体780mg，收率65％。 1H NMR(400MHz,CDCl 3):δ10.61(s,1H),8.93(s,2H),8.10(s,1H),6.85(s,2H),5.25(s,2H),2.64(s,3H).ESI-MS:m/z＝401.03[M+H] +.
(2)中间体7-2的合成
Figure PCTCN2021108826-appb-000059
将5-2(311mg，1.58mmol)、7-1(760mg，1.89mmol)、Cs 2CO 3(772mg，2.37mmol)、BINAP(197mg，0.32mmol)及Pd(oAc) 2(36mg，0.16mmol)悬浮于15mL二氧六环中，Ar保护下，85℃下反应20h后，浓缩，加入水，DCM萃取，有机相水洗至中性，经柱层析纯化得黄白色固体305mg，收率43％。 1H NMR(400MHz,DMSO-d 6):δ10.27(s,1H),9.00(d,J＝2.0Hz,1H),8.96(d,J＝2.0Hz,1H),8.45(t,J＝2.0Hz,1H),7.49–7.42(m,2H),7.42–7.34(m,1H),7.34–7.29(m,2H),7.29–7.18(m,3H),7.14(dd,J＝7.4,1.4Hz,1H),6.27(s,1H),6.16(s,1H),5.26(s,2H),4.39(d,J＝5.2Hz,2H),2.41(s,3H),2.19(s,3H).ESI-MS:m/z＝448.20[M+H] +.
(3)化合物7的合成
Figure PCTCN2021108826-appb-000060
将7-2(269mg，0.60mmol)和D-丝氨酸(126mg，1.20mmol)悬浮于8mL无水DMF和2mLDCE中，再加入冰醋酸(70μL，1.20mmol)，35℃下反应24h后，加入NaBH(oAc) 3(382mg，1.80mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体119mg，收率37％。 1H NMR(400MHz,DMSO-d 6):δ9.02(d,J＝2.4Hz,1H),8.99(d,J＝2.0Hz,1H),8.49(t,J＝2.4Hz,1H),8.17(br,2H),7.48–7.42(m,2H),7.41–7.34(m,1H),7.34–7.28(m,2H),7.26(d,J＝7.6Hz,1H),7.19(t,J＝7.6Hz,1H),7.10(dd,J＝7.6,1.6Hz,1H),6.31(t,J＝5.6Hz, 1H),6.25(d,J＝1.6Hz,1H),6.14(d,J＝1.6Hz,1H),5.38(br,1H),5.18(dd,J＝18.0,13.2Hz,2H),4.25(d,J＝5.2Hz,2H),4.10(s,2H),3.82(dd,J＝11.6,4.4Hz,1H),3.61(dd,J＝11.2,8.4Hz,1H),3.19(dd,J＝8.0,4.4Hz,1H),2.22(s,3H),2.17(s,3H).ESI-HRMS:m/z calculated for C 32H 32N 4NaO 4 +[M+Na] +559.2316,found 559.2317.
实施例8：
(1)中间体8-1的合成
Figure PCTCN2021108826-appb-000061
将2-甲氧基-4-硝基苯甲醛(2.05g，11.32mmol)、2-胺基-4-氯苯甲酸(0.97g，5.66mmol)、1-氟-2,4,6-三甲基吡啶三氟甲烷磺酸盐(4.91g，16.98mmol)、Pd(oAC) 2(249mg，1.11mmol)及对甲苯磺酸(3.89g，22.59mmol)悬浮于80mL冰醋酸中，室温下搅拌10min后，90℃下继续反应24h，冷却，浓缩，残余物经柱层析纯化得淡黄色固体1.50g，收率67％。 1H NMR(400MHz,CDCl 3):δ12.06(s,1H),10.41(s,1H),7.39(dd,J＝2.0,0.8Hz,1H),7.23(d,J＝2.0Hz,1H),4.03(s,3H).ESI-MS:m/z＝198.05[M+H] +.
(2)中间体8-2的合成
Figure PCTCN2021108826-appb-000062
将8-1(684mg，3.47mmol)溶于12mL DMF中，依次加入K 2CO 3(574mg，4.15mmol)、间氰基苄溴(715mg，3.65mmol)、四丁基碘化铵(15mg，0.04mmol)，室温下反应7h后，将反应液倒入300mL冰水中，抽滤，水洗滤饼至中性，滤饼干燥后分散在环己烷中，超声，抽滤，得黄白色粉末状固体1g，收率93％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.42(s,1H),8.00(s,1H),7.91–7.80(m,2H),7.66–7.57(m,3H),5.42(s,2H),3.99(s,3H).
(3)中间体8-3的合成
Figure PCTCN2021108826-appb-000063
将8-2(900mg，2.88mmol)悬浮于30mL EtOH/H 2O＝5/1的混合溶液中，加入Fe(565mg，10.09mmol) 和NH 4Cl(230mg，4.30mmol)，回流反应3.5h后，抽滤除去不溶物，滤液蒸干后柱层析纯化得橙红色粉末状固体790mg，收率97％。 1H NMR(400MHz,DMSO-d 6):δ10.09(s,1H),8.03(s,1H),7.88–7.83(m,1H),7.80(dt,J＝8.0,1.4Hz,1H),7.62(t,J＝7.8Hz,1H),6.39(s,2H),5.87(dd,J＝9.0,1.4Hz,2H),5.13(s,2H),3.74(s,3H).ESI-MS:m/z＝283.11[M+H] +.
(4)中间体8-4的合成
Figure PCTCN2021108826-appb-000064
将1-2(290mg，1.11mmol)溶于5mL DMF中，加入K 2CO 3(184mg，1.33mmol)和8-3(330mg，1.17mmol)，85℃下微波反应35min后，加入水，DCM萃取，有机相水洗至中性，浓缩，残余物经柱层析纯化得黄白色固体150mg，收率29％。 1H NMR(400MHz,CDCl 3):δ10.32(s,1H),7.78(d,J＝7.8Hz,1H),7.70(s,1H),7.59(dt,J＝7.6,1.4Hz,1H),7.48(t,J＝7.8Hz,1H),7.45–7.40(m,2H),7.40–7.34(m,1H),7.32–7.27(m,3H),7.24(d,J＝2.0Hz,1H),7.23(s,1H),5.78(dd,J＝18.2,1.8Hz,2H),5.11(s,2H),4.69(br,1H),4.39(s,2H),3.85(s,3H),2.24(s,3H).ESI-MS:m/z＝463.19[M+H] +.
(5)化合物8的合成
Figure PCTCN2021108826-appb-000065
将8-4(189mg，0.41mmol)和D-丝氨酸(86mg，0.82mmol)悬浮于4mL无水DMF中，再加入冰醋酸(47μL，0.82mmol)，35℃下反应24h后，加入NaBH(oAc) 3(260mg，1.23mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体136mg，收率60％。 1H NMR(400MHz,DMSO-d 6):δ8.16(br,2H),7.95(s,1H),7.84(d,J＝8.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.56(t,J＝7.8Hz,1H),7.48–7.43(m,2H),7.40–7.34(m,1H),7.31–7.28(m,3H),7.20(t,J＝7.6Hz,1H),7.12(dd,J＝7.2,1.2Hz,1H),6.42(t,J＝5.2Hz,1H),6.02(d,J＝3.2Hz,2H),5.31(br,1H),5.13(dd,J＝16.4,13.2Hz,2H),4.28(d,J＝5.2Hz,2H),4.09(dd,J＝26.8,13.2Hz,2H),3.78(dd,J＝11.2,4.4Hz,1H),3.73(s,3H),3.62(dd,J＝11.6,7.6Hz,1H),3.12(dd,J＝7.2,4.4Hz,1H),2.19(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 3NaO 5 +[M+Na] +574.2312,found 574.2313.
实施例9：
(1)中间体9-1的合成
Figure PCTCN2021108826-appb-000066
将5-2(1g，5.07mmol)溶于30mL DCM中，加入DABCO(57mg，0.51mmol)，再加入Boc 2O(553mg，2.54mmol)，室温反应过夜，加入30mL正己烷，抽滤，正己烷：DCM＝1：1混合溶剂洗滤饼，得白色粉末状固体660mg，收率62％。 1H NMR(400MHz,DMSO-d 6):δ7.46–7.34(m,2H)(dd,J＝10.0,4.6Hz,1H),7.40–7.34(m,1H),7.31–7.26(m,3H),7.23(t,J＝7.4Hz,1H),7.09(dd,J＝7.2,1.6Hz,1H),6.39(t,J＝5.8Hz,1H),4.29(d,J＝6.0Hz,2H),2.14(s,3H).ESI-MS:m/z＝421.21[M+H] +.
(2)中间体9-2的合成
Figure PCTCN2021108826-appb-000067
将9-1(907mg，2.16mmol)、6-氯-2-甲氧基-吡啶-3-甲醛(814mg，4.75mmol)、Cs 2CO 3(2.10g，6.48mmol)、Sphos(266mg，0.65mmol)及Pd(oAc) 2(73mg，0.33mmol)悬浮于25mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，DCM萃取，有机相水洗至中性，抽滤除去不溶物，滤液浓缩后经柱层析和制备硅胶板纯化得淡黄色固体364mg，收率25％。 1H NMR(400MHz,CDCl 3):δ10.07(s,1H),7.90(d,J＝8.4Hz,1H),7.45–7.39(m,2H),7.38–7.33(m,1H),7.33–7.27(m,3H),7.25–7.19(m,2H),6.05(d,J＝8.4Hz,1H),5.32(br,1H),4.65(s,2H),3.98(s,3H),2.24(s,3H).ESI-MS:m/z＝333.14[M+H] +.
(3)化合物9的合成
Figure PCTCN2021108826-appb-000068
将9-2(157mg，0.47mmol)和N-乙酰基乙二胺(97mg，0.94mmol)溶于4mL DCE和1mL DMF中，加入冰醋酸(54μL，0.94mmol)，35℃下反应24h后，加入NaBH(OAc) 3(300mg，1.41mmol)，继续反应12h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得黄白色固体85mg，收率43％。 1H NMR(400MHz,CDCl 3):δ7.72(s,1H),7.47–7.39(m,3H),7.39–7.32(m,1H),7.32–7.27(m,3H),7.24–7.16(m,2H),6.54(br,1H),5.94(d,J＝8.0Hz,1H),4.79(t,J＝5.2Hz,1H),4.46(d,J＝5.2Hz,2H),3.93(s,3H),3.88(s,2H),3.54–3.47(m,2H),2.95(t,J＝4.8Hz,2H),2.22(s,3H),2.02(s,3H).ESI-HRMS:m/z calculated for C 25H 30N 4NaO 2 +[M+Na] +441.2261,found  441.2259.
实施例10：
(1)中间体10-1的合成
Figure PCTCN2021108826-appb-000069
将2-羟基对硝基苯甲醛(2.47g，14.78mmol)溶于30mL DMF中，加入K 2CO 3(2.15g，15.56mmol)，室温下搅拌30min后，加入5-氯甲基烟腈(2.48g，16.29mmol)和NaI(222mg，1.48mmol)，室温下反应19h后，将反应液倒入1L水中，抽滤，水洗滤饼至中性，滤饼干燥后得黄白色粉末状固体4.05g，收率97％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.50(s,1H),9.06(d,J＝2.0Hz,1H),9.05(d,J＝2.0Hz,1H),8.59(t,J＝2.0Hz,1H),8.12(d,J＝1.2Hz,1H),8.00–7.93(m,2H),5.57(s,2H).ESI-MS:m/z＝284.07[M+H] +.
(2)中间体10-2的合成
Figure PCTCN2021108826-appb-000070
将10-1(4.75g，16.77mmol)悬浮于185mL EtOH/H 2O＝5/1的混合溶液中，加入Fe(3.29g，58.75mmol)和NH 4Cl(1.36g，25.43mmol)，回流反应1.5h后，抽滤除去不溶物，滤液蒸干后加入水，超声，抽滤得橙黄色粉末状固体4.12g，收率97％。 1H NMR(400MHz,DMSO-d 6):δ10.02(s,1H),9.02(s,1H),9.00(s,1H),8.49(s,1H),7.46(d,J＝8.4Hz,1H),6.43(s,2H),6.26(s,2H),5.24(s,2H).ESI-MS:m/z＝252.09[M-H] -.
(3)中间体10-3的合成
Figure PCTCN2021108826-appb-000071
将1-2(2.48g，9.50mmol)和10-2(2.52g，9.95mmol)溶于51mLMeCN和17mLDMF的混合溶 液中，再加入K 2CO 3(1.58g，11.4mmol)，60℃下反应10h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体1g，收率24％。 1H NMR(400MHz,DMSO-d 6):δ10.06(s,1H),9.00(d,J＝2.0Hz,1H),8.98(d,J＝2.0Hz,1H),8.48(t,J＝2.0Hz,1H),7.51(d,J＝8.8Hz,1H),7.49–7.43(m,2H),7.40–7.35(m,2H),7.33–7.30(m,2H),7.28(dd,J＝7.6,1.2Hz,1H),7.23(t,J＝7.6Hz,1H),7.14(dd,J＝7.4,1.4Hz,1H),6.38(s,1H),6.37(s,1H),5.29(s,2H),4.41(d,J＝5.2Hz,2H),2.20(s,3H).ESI-MS:m/z＝434.19[M+H] +.
(4)化合物10的合成
Figure PCTCN2021108826-appb-000072
将10-3(133mg，0.31mmol)和D-丝氨酸(65mg，0.62mmol)溶于2.5mL无水DMF中，加入冰醋酸(35μL，0.62mmol)，35℃下反应24h后，加入NaBH(OAc) 3(195mg，0.92mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体73mg，收率45％。 1H NMR(400MHz,DMSO-d 6):δ9.00(dd,J＝10.4,2.4Hz,2H),8.51(t,J＝2.0Hz,1H),7.48–7.44(m,2H),7.39–7.35(m,1H),7.32–7.31(m,1H),7.31–7.29(m,1H),7.28–7.25(m,1H),7.19(t,J＝7.6Hz,1H),7.09(t,J＝8.0Hz,2H),6.41–7.25(m,2H),6.21(dd,J＝8.4,1.6Hz,1H),5.32(br,1H),5.20(dd,J＝19.6,12.8Hz,2H),4.26(d,J＝5.2Hz,2H),4.03(dd,J＝46.4,13.2Hz,2H),3.77(dd,J＝11.2,4.4Hz,1H),3.64(dd,J＝11.4,7.2Hz,1H),3.17–3.14(m,1H),2.18(s,3H).ESI-HRMS:m/z calculated for C 31H 30N 4NaO 4 +[M+Na] +545.2159,found 545.2157.
实施例11：
(1)中间体11-1的合成
Figure PCTCN2021108826-appb-000073
将1-2(418mg，1.6mmol)和4-氨基-5-氯-2-甲氧基苯甲醛(312mg，1.68mmol)溶于15mLMeCN中，再加入K 2CO 3(265mg，1.92mmol)，回流反应18h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体277mg，收率47％。 1H NMR(400MHz,CDCl 3):δ10.14(s,1H),7.79(s,1H),7.47–7.40(m,2H),7.40–7.34(m,1H),7.34–7.28(m,3H),7.28–7.23(m,2H),6.14(s,1H),5.22(br,1H),4.48(s,2H),3.87(s,3H),2.26(s,3H).ESI-MS:m/z＝366.13[M+H] +.
(2)化合物11的合成
Figure PCTCN2021108826-appb-000074
将11-1(150mg，0.41mmol)和D-丝氨酸(86mg，0.82mmol)溶于3mL无水DMF中，加入冰醋酸(47μL，0.82mmol)，35℃下反应24h后，加入NaBH(OAc) 3(195mg，0.92mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得黄白色固体110mg，收率59％。 1H NMR(400MHz,DMSO-d 6):δ7.47–7.43(m,2H),7.40–7.34(m,1H),7.30(s,2H),7.29–7.26(m,2H),7.20(t,J＝7.6Hz,1H),7.09(d,J＝8.0Hz,1H),6.23(s,1H),6.05(t,J＝5.6Hz,1H),4.48(d,J＝5.6Hz,2H),3.93(dd,J＝21.6,13.2Hz,2H),3.75(dd,J＝11.6,4.8Hz,1H),3.67(s,3H),3.65–3.60(m,1H),3.15(dd,J＝6.8,4.4Hz,1H),2.23(s,3H).ESI-HRMS:m/z calculated for C 25H 27ClN 2NaO 4 +[M+Na] +477.1552,found 477.1553.
实施例12：
Figure PCTCN2021108826-appb-000075
将9-2(347mg，1.04mmol)和D-丝氨酸(219mg，2.08mmol)溶于6mL无水DMF中，加入冰醋酸(119μL，2.08mmol)，35℃下反应24h后，加入NaBH(OAc) 3(664mg，3.12mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体154mg，收率36％。 1H NMR(400MHz,DMSO-d 6):δ8.17(br,2H),7.46–7.42(m,2H),7.40–7.35(m,2H),7.35–7.30(m,1H),7.31–7.25(m,2H),7.24–7.16(m,2H),7.08(dd,J＝7.6,0.8Hz,1H),6.08(d,J＝8.0Hz,1H),5.46(br,1H),4.50(d,J＝5.6Hz,2H),3.92(dd,J＝20.0,11.2Hz,2H),3.81(s,3H),3.76(dd,J＝11.6,4.4Hz,1H),3.64(dd,J＝11.4,7.0Hz,1H),3.16(dd,J＝6.8,4.4Hz,1H),2.20(s,3H).ESI-HRMS:m/z calculated for C 24H 27N 3NaO 4 +[M+Na] +444.1894,found 444.1892.
实施例13：
(1)中间体13-1的合成
Figure PCTCN2021108826-appb-000076
将4-溴-3-氯苯甲醛(2.53g，11.52mmol)、2-胺基-4-氯苯甲酸(0.99g，5.76mmol)、1-氟-2,4,6-三 甲基吡啶三氟甲烷磺酸盐(5g，17.29mmol)、Pd(oAC) 2(259mg，1.15mmol)及对甲苯磺酸(3.97g，23.05mmol)悬浮于115mL冰醋酸中，室温下搅拌10min后，90℃下继续反应24h，冷却，浓缩，残余物经柱层析纯化得淡黄色固体1.50g，收率55％。 1H NMR(400MHz,DMSO-d 6):δ11.33(s,1H),10.20(s,1H),7.73(s,1H),7.38(s,1H).ESI-MS:m/z＝234.90[M+H] +.
(2)中间体13-2的合成
Figure PCTCN2021108826-appb-000077
将13-1(471mg，2mmol)溶于7mL MeCN中，加入K 2CO 3(304mg，2.2mmol)和5-氯甲基烟腈(336mg，2.2mmol)和NaI(60mg，0.4mmol)，室温下反应22h后，将反应液倒入30mL水中，抽滤，水洗滤饼至中性，滤饼干燥后得淡黄色粉末状固体663mg，收率94％，无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.32(s,1H),9.04(d,J＝2.0Hz,1H),9.01(d,J＝2.0Hz,1H),8.54(t,J＝2.0Hz,1H),7.85(s,1H),7.82(s,1H),5.45(s,2H).ESI-MS:m/z＝350.95[M+H] +.
(3)中间体13-3的合成
Figure PCTCN2021108826-appb-000078
将5-2(354mg，1.80mmol)、13-2(527mg，1.50mmol)、Cs 2CO 3(732mg，2.25mmol)、BINAP(187mg，0.30mmol)及Pd(oAc) 2(34mg，0.15mmol)悬浮于15mL二氧六环中，Ar保护下，85℃下反应24h后，浓缩，加入水，DCM萃取，有机相水洗至中性，经柱层析纯化得黄白色固体345mg，收率49％。 1H NMR(400MHz,DMSO-d 6):δ10.05(s,1H),8.93(d,J＝2.0Hz,1H),8.86(d,J＝2.0Hz,1H),8.37(t,J＝2.0Hz,1H),7.61(s,1H),7.49–7.43(m,2H),7.41–7.35(m,1H),7.35–7.31(m,2H),7.19–7.14(m,1H),7.11(s,1H),7.11–7.08(m,2H),6.29(s,1H),5.27(s,2H),4.58(d,J＝6.0Hz,2H),2.22(s,3H).ESI-MS:m/z＝468.13[M+H] +.
(4)化合物13的合成
Figure PCTCN2021108826-appb-000079
将13-3(436mg，0.93mmol)和D-丝氨酸(196mg，1.86mmol)溶于6mL无水DMF中，加入冰 醋酸(109μL，1.86mmol)，35℃下反应24h后，加入NaBH(OAc) 3(594mg，2.79mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体106mg，收率20％。 1H NMR(400MHz,DMSO-d 6):δ8.91(d,J＝1.6Hz,1H),8.86(d,J＝2.0Hz,1H),8.37(s,1H),8.17(br,2H),7.46(t,J＝7.2Hz,2H),7.40–7.34(m,2H),7.34–7.29(m,2H),7.16–7.03(m,3H),6.24(s,1H),6.09(t,J＝5.8Hz,1H),5.34(br,1H),5.16(dd,J＝18.4,13.2Hz,2H),4.43(d,J＝5.6Hz,2H),4.01(dd,J＝33.6,13.2Hz,2H),3.75(dd,J＝11.2,4.4Hz,1H),3.63(dd,J＝11.2,6.8Hz,1H),3.17(dd,J＝6.6,4.6Hz,1H),2.19(s,3H).ESI-HRMS:m/z calculated for C 31H 29ClN 4NaO 4 +[M+Na] +579.1770,found 579.1766.
实施例14：
(1)中间体14-1的合成
Figure PCTCN2021108826-appb-000080
将5-2(473mg，2.40mmol)、4-溴-2-甲氧基-5-甲基苯甲醛(458mg，2.0mmol)、Cs 2CO 3(977mg，3.0mmol)、BINAP(249mg，0.40mmol)及Pd(oAc) 2(45mg，0.20mmol)悬浮于15mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体405mg，收率59％。 1H NMR(400MHz,DMSO-d 6):δ9.97(s,1H),7.47–7.41(m,2H),7.40–7.32(m,2H),7.33–7.25(m,3H),7.22(t,J＝7.6Hz,1H),7.11(dd,J＝7.2,1.2Hz,1H),6.69(t,J＝5.8Hz,1H),6.05(s,1H),4.54(d,J＝5.6Hz,2H),3.71(s,3H),2.25(s,3H),2.14(s,3H).ESI-MS:m/z＝346.18[M+H] +.
(2)化合物14的合成
Figure PCTCN2021108826-appb-000081
将14-1(257mg，0.74mmol)和D-丝氨酸(156mg，1.48mmol)溶于5mL无水DMF中，加入冰醋酸(85μL，1.48mmol)，35℃下反应24h后，加入NaBH(OAc) 3(473mg，2.23mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体159mg，收率49％。 1H NMR(400MHz,DMSO-d 6):δ8.18(br,2H),7.47–7.43(m,2H),7.40–7.33(m,1H),7.32–7.26(m,3H),7.19(t,J＝7.6Hz,1H),7.08(d,J＝7.5Hz,1H),6.94(s,1H),6.10(s,1H),5.68(t,J＝5.6Hz,1H),5.36(br,1H),4.41(d,J＝5.2Hz,2H),3.95(dd,J＝27.2,13.2Hz,2H),3.77(dd,J＝11.2,4.4Hz,1H),3.65(s,3H),3.63–3.58(m,1H),3.13(dd,J＝7.2,4.4Hz,1H),2.24(s,3H),2.09(s,3H). ESI-HRMS:m/z calculated for C 26H 30N 2NaO 4 +[M+Na] +457.2098,found 457.2096.
实施例15：
(1)中间体15-1的合成
Figure PCTCN2021108826-appb-000082
将9-1(660mg，1.57mmol)、2-氯-4-甲氧基吡啶-5-甲醛(448mg，2.61mmol)、Cs 2CO 3(1.36g，4.18mmol)、Sphos(161mg，0.39mmol)及Pd(oAc) 2(44mg，0.20mmol)悬浮于25mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，DCM萃取，有机相水洗至中性，抽滤除去不溶物，滤液浓缩后经柱层析和制备硅胶板纯化得淡黄色固体143mg，收率16％。 1H NMR(400MHz,CDCl 3):δ10.04(s,1H),8.38(s,1H),7.44–7.39(m,2H),7.38–7.33(m,1H),7.31(dd,J＝6.8,2.4Hz,1H),7.29–7.26(m,2H),7.25–7.20(m,2H),5.81(s,1H),5.77(br,1H),4.59(d,J＝5.2Hz,2H),3.89(s,3H),2.24(s,3H).ESI-MS:m/z＝333.16[M+H] +.
(2)化合物15的合成
Figure PCTCN2021108826-appb-000083
将15-1(203mg，0.61mmol)和D-丝氨酸(160mg，1.52mmol)溶于4mL无水DMF中，加入冰醋酸(87μL，1.52mmol)，35℃下反应24h后，加入NaBH(OAc) 3(388mg，1.83mmol)，继续反应24h后，加入水，正丁醇萃取，有机相浓缩至干，残余物经制备液相纯化得白色固体104mg，收率40％。 1H NMR(400MHz,DMSO-d 6):δ7.81(s,1H),7.45(t,J＝7.4Hz,2H),7.36(t,J＝7.2Hz,1H),7.30–7.26(m,3H),7.19(t,J＝7.4Hz,1H),7.12–7.07(m,2H),6.19(s,1H),5.39(br,1H),4.50(d,J＝5.2Hz,2H),3.93(dd,J＝21.2,13.6Hz,2H),3.81–3.75(m,4H),3.64(dd,J＝11.4,7.0Hz,1H),3.18(dd,J＝6.8,4.4Hz,1H),2.17(s,3H).ESI-HRMS:m/z calculated for C 24H 28N 3O 4 +[M+H] +422.2074,found 422.2074.
实施例16：
(1)中间体16-1的合成
Figure PCTCN2021108826-appb-000084
将4-溴-2-羟基-5-甲基苯甲醛(430mg，2mmol)溶于10mLMeCN中，加入K 2CO 3(304mg，2.2mmol)、苄溴(376mg，2.2mmol)及NaI(30mg，0.2mmol)，室温下反应22h后，加入30mL水，抽滤，滤 饼水洗至中性，干燥得黄白色粉末状固体503mg，收率82％。 1H NMR(400MHz,CDCl 3):δ10.45(s,1H),7.69(s,1H),7.45–7.33(m,5H),7.28(s,1H),5.14(s,2H),2.36(s,3H).ESI-MS:m/z＝327.00[M+Na] +.
(2)中间体16-2的合成
Figure PCTCN2021108826-appb-000085
将5-2(367mg，1.86mmol)、16-1(473mg，1.55mmol)、Cs 2CO 3(758mg，2.33mmol)、BINAP(193mg，0.31mmol)及Pd(oAc) 2(35mg，0.16mmol)悬浮于15mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体337mg，收率52％。 1H NMR(400MHz,CDCl 3):δ10.29(s,1H),7.60(d,J＝0.8Hz,1H),7.45–7.41(m,2H),7.40–7.33(m,5H),7.33–7.29(m,3H),7.29–7.26(m,1H),7.25–7.23(m,2H),6.14(s,1H),5.12(s,2H),4.39(s,2H),4.34(br,1H),2.22(s,3H),2.10(s,3H).ESI-MS:m/z＝422.24[M+H] +.
(2)化合物16的合成
Figure PCTCN2021108826-appb-000086
将16-2(297mg，0.70mmol)和D-丝氨酸(148mg，1.41mmol)溶于8mL无水DMF和2mL无水甲醇中，加入冰醋酸(80μL，1.41mmol)，35℃下反应24h后，加入NaBH(OAc) 3(448mg，2.11mmol)，继续反应24h后，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，有机相浓缩至干，残余物经制备液相纯化得白色固体36mg，收率10％。 1H NMR(400MHz,DMSO-d 6):δ8.16(br,2H),7.46(tt,J＝8.2,1.6Hz,2H),7.41–7.37(m,1H),7.35–7.32(m,3H),7.31(t,J＝1.2Hz,1H),7.30–7.24(m,3H),7.21(dd,J＝7.6,1.6Hz,1H),7.16(t,J＝7.6Hz,1H),7.10(dd,J＝7.4,1.4Hz,1H),6.97(s,1H),6.13(s,1H),5.70(t,J＝5.6Hz,1H),5.38(br,1H),4.98(s,2H),4.32(d,J＝5.2Hz,2H),3.99(dd,J＝36.2,13.0Hz,2H),3.78(dd,J＝11.4,4.4Hz,1H),3.66(dd,J＝11.4,7.0Hz,1H),3.17(dd,J＝7.2,4.4Hz,1H),2.20(s,3H),2.09(s,3H).ESI-HRMS:m/z calculated for C 32H 34N 2NaO 4 +[M+Na] +533.2411,found 533.2408.
实施例17：
(1)中间体17-1的合成
Figure PCTCN2021108826-appb-000087
将4-溴-2-羟基-5-甲基苯甲醛(430mg，2mmol)溶于10mLMeCN中，加入K 2CO 3(608mg，4.4mmol)、3-溴甲基吡啶氢溴酸盐(556mg，2.20mmol)及NaI(30mg，0.2mmol)，室温下避光反应24h后，补加3-溴甲基吡啶氢溴酸盐(303mg，1.20mmol)和K 2CO 3(332mg，2.4mmol)，继续反应12h后，加入50mL水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色粉末状固体180mg，收率29％。 1H NMR(400MHz,CDCl 3):δ10.41(s,1H),8.71(s,1H),8.64(d,J＝4.0Hz,1H),7.83–7.79(m,1H),7.70(s,1H),7.37(dd,J＝8.0,4.8Hz,1H),7.29(s,1H),5.17(s,2H),2.38(s,3H).ESI-MS:m/z＝306.01[M+H] +.
(2)中间体17-2的合成
Figure PCTCN2021108826-appb-000088
将5-2(571mg，2.90mmol)、17-1(740mg，2.42mmol)、Cs 2CO 3(1.18g，3.62mmol)、BINAP(301mg，0.48mmol)及Pd(oAc) 2(55mg，0.24mmol)悬浮于20mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体386mg，收率38％。 1H NMR(400MHz,CDCl 3):δ10.23(s,1H),8.65(s,1H),8.59(d,J＝4.4Hz,1H),7.77(d,J＝8.0Hz,1H),7.60(s,1H),7.44(t,J＝7.4Hz,2H),7.40–7.35(m,1H),7.34–7.27(m,4H),7.27–7.25(m,2H),6.14(s,1H),5.20–5.08(m,2H),4.43(s,2H),4.40(br,1H),2.25(s,3H),2.11(s,3H).ESI-MS:m/z＝423.21[M+H] +.
(3)化合物17的合成
Figure PCTCN2021108826-appb-000089
将17-2(310mg，0.73mmol)和D-丝氨酸(154mg，1.47mmol)溶于8mL无水DMF和2mL无水甲醇中，加入冰醋酸(85μL，1.47mmol)，35℃下反应24h后，加入NaBH(OAc) 3(467mg，2.20mmol)， 继续反应24h后，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，有机相浓缩至干，残余物经制备液相纯化得白色固体51mg，收率14％。 1H NMR(400MHz,DMSO-d 6):δ8.58(d,J＝1.6Hz,1H),8.47(dd,J＝4.8,1.6Hz,1H),8.26(br,2H),7.81(dt,J＝8.0,2.0Hz,1H),7.49–7.42(m,2H),7.40–7.35(m,1H),7.34–7.31(m,2H),7.29(ddd,J＝7.8,4.8,0.4Hz,1H),7.21(dd,J＝7.6,1.2Hz,1H),7.16(t,J＝7.6Hz,1H),7.09(dd,J＝7.4,1.4Hz,1H),6.98(s,1H),6.15(s,1H),5.69(t,J＝5.6Hz,1H),5.38(br,1H),5.04(dd,J＝15.6,13.2Hz,2H),4.35(d,J＝5.2Hz,2H),3.99(dd,J＝40.8,13.2Hz,2H),3.78(dd,J＝11.4,4.4Hz,1H),3.65(dd,J＝11.2,7.2Hz,1H),3.17(dd,J＝7.0,4.6Hz,1H),2.21(s,3H),2.10(s,3H).ESI-HRMS:m/z calculated for C 31H 33N 3NaO 4 +[M+Na] +534.2363,found 534.2360.
实施例18：
Figure PCTCN2021108826-appb-000090
将5-4(313mg，0.7mmol)和(R)-3-氨基-4-羟基丁酸(167mg，1.40mmol)悬浮于6mL无水DMF和2mL无水甲醇中，再加入冰醋酸(80μL，1.40mmol)，35℃下反应24h后，加入NaBH(oAc) 3(445mg，2.10mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体30mg，收率8％。 1H NMR(400MHz,DMSO-d 6):δ10.00(br,2H),8.91–8.80(m,2H),8.32(s,1H),7.45(t,J＝7.4Hz,2H),7.39–7.33(m,3H),7.16–7.04(m,3H),6.97(s,1H),6.08(s,1H),5.66(t,J＝5.4Hz,1H),5.17–5.07(m,2H),4.34(d,J＝4.8Hz,2H),3.91(dd,J＝68.0,12.8Hz,2H),3.58(dd,J＝11.6,4.4Hz,1H),3.47–3.39(m,1H),3.07–3.01(m,1H),2.19(s,3H),2.16–2.13(m,2H),2.11(s,3H).ESI-HRMS:m/z calculated for C 33H 34N 4NaO 4 +[M+Na] +573.2472,found 573.2472.
实施例19：
(1)中间体19-1的合成
Figure PCTCN2021108826-appb-000091
将4-溴-2-羟基-5-甲基苯甲醛(645mg，3mmol)溶于9mLMeCN中，加入K 2CO 3(647mg，4.68mmol)、3-氰基苄溴(647mg，3.3mmol)及NaI(45mg，0.3mmol)，室温下反应24h后，加入40mL水，抽滤， 滤饼水洗至中性，干燥后，滤饼悬浮于环己烷中超声，抽滤得黄白色粉末状固体801mg，收率81％。 1H NMR(400MHz,DMSO-d 6):δ10.36(s,1H),8.01(s,1H),7.85(t,J＝8.6Hz,2H),7.69–7.57(m,3H),5.35(s,2H),2.33(s,3H).ESI-MS:m/z＝330.00[M+H] +.
(2)中间体19-2的合成
Figure PCTCN2021108826-appb-000092
将5-2(548mg，2.78mmol)、19-1(766mg，2.32mmol)、Cs 2CO 3(1.13g，3.46mmol)、BINAP(289mg，0.46mmol)及Pd(oAc) 2(52mg，0.23mmol)悬浮于15mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体382mg，收率37％。 1H NMR(400MHz,CDCl 3):δ10.25(s,1H),7.68(s,1H),7.67–7.58(m,3H),7.48(t,J＝7.6Hz,1H),7.46–7.41(m,2H),7.39–7.35(m,1H),7.34–7.28(m,2H),7.28–7.23(m,3H),6.08(s,1H),5.14(s,2H),4.46(br,1H),4.41(d,J＝4.8Hz,2H),2.24(s,3H),2.12(s,3H).ESI-MS:m/z＝447.21[M+H] +.
(3)化合物19的合成
Figure PCTCN2021108826-appb-000093
将19-2(341mg，0.76mmol)和D-丝氨酸(161mg，1.53mmol)溶于7mL无水DMF中，加入冰醋酸(87μL，1.53mmol)，35℃下反应24h后，加入NaBH(OAc) 3(486mg，2.29mmol)，继续反应24h后，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，有机相浓缩至干，残余物经制备液相纯化得白色固体320mg，收率79％。 1H NMR(400MHz,DMSO-d 6):δ8.29(br,1H),7.87(s,1H),7.74–7.68(m,2H),7.47–7.43(m,3H),7.39–7.35(m,1H),7.33–7.28(m,2H),7.17(dd,J＝7.2,1.2Hz,1H),7.13(t,J＝7.4Hz,1H),7.08(dd,J＝7.2,1.6Hz,1H),6.99(s,1H),6.09(s,1H),5.70(t,J＝5.6Hz,1H),5.38(br,1H),5.12–5.02(m,2H),4.33(d,J＝5.2Hz,2H),4.02(dd,J＝40.4,13.0Hz,2H),3.79(dd,J＝11.6,4.4Hz,1H),3.65(dd,J＝11.2,7.2Hz,1H),3.18(dd,J＝6.9,4.6Hz,1H),2.19(s,3H),2.10(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 3NaO 4 +[M+Na] +558.2363,found 558.2364.
实施例20：
(1)中间体20-1的合成
Figure PCTCN2021108826-appb-000094
将4-溴-2-羟基-5-甲基苯甲醛(660mg，3.07mmol)溶于15mLMeCN中，加入K 2CO 3(467mg，3.38mmol)和碘乙烷(527mg，3.38mmol)，60℃下反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色粉末状固体537mg，收率72％。 1H NMR(400MHz,CDCl 3):δ10.41(s,1H),7.66(s,1H),7.18(s,1H),4.12(q,J＝7.4Hz,2H),2.35(s,3H),1.47(t,J＝7.4Hz,3H).ESI-MS:m/z＝243.01[M+H] +.
(2)中间体20-2的合成
Figure PCTCN2021108826-appb-000095
将5-2(591mg，3.0mmol)、20-1(608mg，2.50mmol)、Cs 2CO 3(1.22g，3.75mmol)、BINAP(311mg，0.50mmol)及Pd(oAc) 2(56mg，0.25mmol)悬浮于15mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体350mg，收率39％。 1H NMR(400MHz,CDCl 3):δ10.22(s,1H),7.58(d,J＝0.8Hz,1H),7.46–7.40(m,2H),7.40–7.34(m,1H),7.34–7.27(m,3H),7.26(d,J＝3.6Hz,1H),7.24(s,1H),6.09(s,1H),4.44(d,J＝4.0Hz,2H),4.39(br,1H),4.09(q,J＝6.8Hz,2H),2.26(s,3H),2.09(s,3H),1.43(t,J＝6.8Hz,3H).ESI-MS:m/z＝360.21[M+H] +.
(3)化合物20的合成
Figure PCTCN2021108826-appb-000096
将20-2(296mg，0.82mmol)和D-丝氨酸(173mg，1.65mmol)溶于5.5mL无水DMF中，加入冰醋酸(94μL，1.65mmol)，35℃下反应24h后，加入NaBH(OAc) 3(523mg，2.47mmol)，继续反应24h后，加入水，DCM/MeOH＝10/1的混合溶剂萃取，水洗，有机相浓缩至干，残余物经制备液相纯化得白色固体290mg，收率79％。 1H NMR(400MHz,DMSO-d 6):δ8.21(br,2H),7.47–7.43(m,2H),7.40–7.34(m,1H),7.30–7.26(m,3H),7.18(t,J＝7.6Hz,1H),7.08(dd,J＝7.6,1.2Hz,1H),6.93(s,1H),6.06(s,1H),5.71(t,J＝5.6Hz,1H),5.41(br,1H),4.40(d,J＝5.6Hz,2H),4.02–3.84(m,4H),3.78 (dd,J＝11.6,4.4Hz,1H),3.63(dd,J＝11.6,7.6Hz,1H),3.14(dd,J＝7.2,4.4Hz,1H),2.23(s,3H),2.09(s,3H),1.24(t,J＝7.0Hz,3H).ESI-HRMS:m/z calculated for C 27H 32N 2NaO 4 +[M+Na] +471.2254,found 471.2254.
实施例21：
Figure PCTCN2021108826-appb-000097
将5-4(339mg，0.76mmol)和L-羟基脯氨酸(199mg，1.52mmol)悬浮于6.5mL无水DMF，再加入冰醋酸(87μL，1.52mmol)，35℃下反应24h后，加入NaBH(oAc) 3(482mg，2.27mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体150mg，收率35％。 1H NMR(400MHz,DMSO-d 6):δ8.91(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.36(t,J＝2.2Hz,1H),7.47–7.43(m,2H),7.40–7.35(m,1H),7.34–7.32(m,1H),7.32–7.31(m,1H),7.20(dd,J＝7.6,1.6Hz,1H),7.14(t,J＝7.6Hz,1H),7.08(dd,J＝7.6,1.6Hz,1H),7.01(s,1H),6.11(s,1H),5.71(t,J＝5.8Hz,1H),5.36(br,1H),5.15(dd,J＝23.2,13.6Hz,2H),4.35(d,J＝5.6Hz,2H),4.28–4.24(m,1H),4.13(dd,J＝63.0,13.0Hz,2H),3.71(t,J＝8.2Hz,1H),3.33(dd,J＝11.6,4.8Hz,1H),2.86(dd,J＝11.6,3.2Hz,1H),2.20(s,3H),2.11(s,3H),2.08–1.98(m,2H).ESI-HRMS:m/z calculated for C 34H 34N 4NaO 4 +[M+Na] +585.2472,found 585.2471.
实施例22：
Figure PCTCN2021108826-appb-000098
将5-4(313mg，0.7mmol)和(S)-(+)-4-氨基-3-羟基丁酸(167mg，1.40mmol)悬浮于6mL无水DMF和2mL无水甲醇中，再加入冰醋酸(80μL，1.40mmol)，35℃下反应24h后，加入NaBH(oAc) 3(445mg,2.10mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体97mg，收率25％。 1H NMR(400MHz,DMSO-d 6):δ8.90(d,J＝2.0Hz,1H),8.83(d,J＝2.0Hz,1H),8.29(t,J＝2.2Hz,1H),7.48–7.42(m,2H),7.40–7.34(m,1H),7.34–7.31(m,2H),7.17(dd,J＝7.6,1.6Hz,1H),7.13(t,J＝7.4Hz,1H),7.07(dd,J＝7.4,1.8Hz,1H),6.96(s, 1H),6.08(s,1H),5.57(t,J＝5.6Hz,1H),5.11(s,2H),4.33(d,J＝5.2Hz,2H),3.88(qui,J＝5.6Hz,1H),3.76(dd,J＝17.0,13.0Hz,2H),2.68(d,J＝5.6Hz,2H),2.29(ddd,J＝32.2,15.2,5.6Hz,2H),2.20(s,3H),2.10(s,3H).ESI-HRMS:m/z calculated for C 29H 26N 3O +[M-C 4H 8NO 3] +432.2070,found 432.2069.
实施例23：
Figure PCTCN2021108826-appb-000099
实施例22中分离到的副产物38mg。 1H NMR(400MHz,CDCl 3):δ8.80(d,J＝1.6Hz,2H),8.08(t,J＝2.0Hz,1H),7.46–7.41(m,2H),7.39–7.34(m,1H),7.34–7.32(m,1H),7.32–7.31(m,1H),7.30–7.27(m,1H),7.24(d,J＝1.6Hz,1H),7.23(s,1H),6.96(s,1H),6.15(s,1H),5.09(s,2H),4.55(d,J＝14.4Hz,1H),4.45(br,1H),4.34(d,J＝14.4Hz,1H),4.32(s,2H),3.86(br,1H),3.50(dd,J＝10.8,5.6Hz,1H),3.20(dd,J＝10.8,2.0Hz,1H),2.69(dd,J＝17.2,6.8Hz,1H),2.44(br,1H),2.39(dd,J＝17.4,2.2Hz,1H),2.25(s,3H),2.08(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 4O 3 +[M+H] +533.2547,found 533.2545.
实施例24：
Figure PCTCN2021108826-appb-000100
将5-4(313mg，0.7mmol)和D-高丝氨酸(167mg，1.40mmol)悬浮于6mL无水DMF和2mL无水甲醇中，再加入冰醋酸(80μL，1.40mmol)，35℃下反应24h后，加入NaBH(oAc) 3(445mg，2.10mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体230mg，收率60％。 1H NMR(400MHz,DMSO-d 6):δ8.90(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.35(t,J＝2.0Hz,1H),8.15(br,2H),7.48–7.42(m,2H),7.40–7.36(m,1H),7.35–7.31(m,2H),7.17–7.10(m,2H),7.07(dd,J＝6.8,2.0Hz,1H),7.01(s,1H),6.08(s,1H),5.73(t,J＝5.6Hz,1H),5.54(br,1H),5.13(dd,J＝18.0,13.2Hz,2H),4.35(d,J＝5.6Hz,2H),4.03–3.89(m,2H),3.56–3.44(m,2H),3.21(t,J＝6.4Hz,1H),2.19(s,3H),2.11(s,3H),1.93–1.67(m,2H).ESI-HRMS:m/z calculated for C 33H 34N 4NaO 4 +[M+Na] +573.2472,found 573.2472.
实施例25：
Figure PCTCN2021108826-appb-000101
将5-4(313mg，0.7mmol)和D-天冬酰胺(185mg，1.40mmol)悬浮于8mL无水DMF中，再加入冰醋酸(80μL，1.40mmol)，35℃下反应24h后，加入NaBH(oAc) 3(445mg，2.10mmol)，继续反应24h，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体180mg，收率46％。 1H NMR(400MHz,DMSO-d 6):δ8.89(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.34(t,J＝2.0Hz,1H),7.78(s,1H),7.49–7.43(m,2H),7.39–7.35(m,1H),7.35–7.34(m,1H),7.33–7.32(m,1H),7.16–7.09(m,3H),7.07(dd,J＝7.0,2.2Hz,1H),6.96(s,1H),6.07(s,1H),5.73(t,J＝5.8Hz,1H),5.16(s,2H),4.34(d,J＝5.2Hz,2H),4.04(dd,J＝21.4,13.0Hz,2H),3.36(dd,J＝9.2,4.0Hz,1H),2.73(dd,J＝16.6,3.8Hz,1H),2.43(dd,J＝16.6,9.0Hz,1H),2.19(s,3H),2.11(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 5NaO 4 +[M+Na] +586.2425,found 586.2422.
实施例26：
(1)中间体26-1的合成
Figure PCTCN2021108826-appb-000102
将1-5(108mg，0.25mmol)和KOH(85％)(20mg，0.30mmol)溶于3mLTHF中，加入苯磺酸甲酯(65mg，0.38mmol)，35℃下反应25h后，补加苯磺酸甲酯(13mg，0.08mmol),继续反应15h，浓缩，加入水，DCM萃取，有机相水洗，经重结晶纯化得黄白色固体70mg，收率63％。 1H NMR(400MHz,CDCl 3):δ10.24(s,1H),7.75(d,J＝8.8Hz,1H),7.69(s,1H),7.67–7.59(m,2H),7.51–7.41(m,3H),7.41–7.35(m,1H),7.34–7.29(m,2H),7.23–7.15(m,2H),6.94(dd,J＝6.4,2.4Hz,1H),6.38(dd,J＝8.8,2.0Hz,1H),6.09(d,J＝2.4Hz,1H),5.14(s,2H),4.59(s,2H),3.19(s,3H),2.18(s,3H).ESI-MS:m/z＝447.22[M+H] +.
(2)化合物26的合成
Figure PCTCN2021108826-appb-000103
将26-1(89mg，0.2mmol)和D-丝氨酸(42mg，0.40mmol)悬浮于2mL无水DMF中，再加入冰醋酸(23μL，0.40mmol)，35℃下反应24h后，加入NaBH(oAc) 3(131mg，0.6mmol)，继续反应14h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得黄白色粉末状固体64mg，收率60％。 1H NMR(400MHz,DMSO-d 6):δ8.33(br,2H),7.98(s,1H),7.85(d,J＝8.0Hz,1H),7.77(d,J＝7.6Hz,1H),7.53(t,J＝7.6Hz,1H),7.46(t,J＝7.6Hz,2H),7.41–7.35(m,1H),7.33–7.29(m,2H),7.17–7.11(m,2H),7.08(d,J＝7.6Hz,1H),6.83(d,J＝7.6Hz,1H),6.37(d,J＝2.0Hz,1H),6.25(dd,J＝8.4,2.0Hz,1H),5.39(br,1H),5.21(dd,J＝17.2,13.2Hz,2H),4.56(s,2H),4.06(dd,J＝42.4,12.8Hz,2H),3.78(dd,J＝11.6,4.4Hz,1H),3.66(dd,J＝11.2,7.2Hz,1H),3.18(dd,J＝6.8,4.4Hz,1H),3.04(s,3H),2.14(s,3H).ESI-HRMS:m/z calculated for C 33H 33N 3NaO 4 +[M+Na] +558.2363,found 558.2361.
实施例27：
Figure PCTCN2021108826-appb-000104
将26-1(70mg，0.16mmol)和乙醇胺(19mg，0.31mmol)溶于于2mLDCE和0.5mL无水DMF中，再加入冰醋酸(18μL，0.31mmol)，35℃下反应24h后，加入NaBH(oAc) 3(103mg，0.49mmol)，继续反应12h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经柱层析纯化后得油状物，油状物溶于DCM中，滴加1N的HCL乙醚溶液3mL，室温下搅拌30min后，抽滤，滤饼再次经制备液相纯化得白色固体34mg，收率38％。 1H NMR(400MHz,DMSO-d 6):δ9.00(s,2H),7.98(s,1H),7.83(d,J＝7.6Hz,1H),7.80–7.74(m,1H),7.55(t,J＝7.8Hz,1H),7.48–7.42(m,2H),7.38–7.34(m,1H),7.32–7.27(m,3H),7.13(t,J＝7.6Hz,1H),7.07(dd,J＝7.4,1.0Hz,1H),6.87(d,J＝7.2Hz,1H),6.47(s,1H),6.35(d,J＝5.6Hz,1H),5.59(br,6H),5.22(s,2H),4.60(s,2H),4.04(t,J＝4.8Hz,2H),3.66(t,J＝5.4Hz,2H),3.07(s,3H),2.96–2.85(m,2H),2.13(s,3H).ESI-HRMS:m/z calculated for C 32H 33N 3NaO 2 +[M+Na] +514.2465,found 514.2460.
实施例28：
(1)中间体28-1的合成
Figure PCTCN2021108826-appb-000105
将3-溴-2-甲基苯胺(2.79g，15mmol)、苯硼酸(2.74g，22.5mmol)、乙酸铯(7.20g，37.51mmol)和PdCl 2(dppf)(1.10g，1.50mmol)悬浮在48mL THF中，氩气保护下，回流反应24h，冷却，浓缩，残余物加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得棕色固体2.61g，收率95％。 1H NMR(400MHz,CDCl 3):δ7.41–7.37(m,2H),7.36–7.27(m,3H),7.07(t,J＝7.8Hz,1H),6.70(d,J＝7.6Hz,2H),3.69(br,2H),2.06(s,3H).ESI-MS:m/z＝184.12[M+H] +.
(2)中间体28-2的合成
Figure PCTCN2021108826-appb-000106
将2-羟基-4-羟甲基苯甲醛(683mg，4.49mmol)溶于20mLMeCN中，加入K 2CO 3(683mg，4.94mmol)和5-氯甲基烟腈(755mg，4.95mmol)，60℃下反应10h后，加入230mL水，抽滤，滤饼经干燥后得黄白色粉末状固体1.01g，收率84％。无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.41(d,J＝0.8Hz,1H),9.04(dd,J＝3.2,2.0Hz,2H),8.55(t,J＝2.0,1H),7.71(d,J＝7.6Hz,1H),7.29(d,J＝0.8Hz,1H),7.08(ddd,J＝8.0,1.2,0.8Hz,1H),5.49(t,J＝5.6Hz,1H),5.39(s,2H),4.59(d,J＝5.6Hz,2H).ESI-MS:m/z＝269.10[M+H] +.
(3)中间体28-3的合成
Figure PCTCN2021108826-appb-000107
将28-2(838mg，3.12mmol)和吡啶(494mg，6.24mmol)溶于20mL无水DCM和2mL无水DMF中，0℃下滴加4mL MsCl(537mg，4.69mmol)的无水DCM溶液，滴完，室温下反应24h后，加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得黄白色固体565mg，收率63％。 1H NMR(400MHz,DMSO-d 6):δ10.42(d,J＝0.4Hz,1H),9.04(dd,J＝3.6,2.0Hz,2H),8.56(t,J＝2.0Hz,1H),7.76(d,J＝7.6Hz,1H),7.44(d,J＝1.6Hz,1H),7.21(d,J＝8.0Hz,1H),5.41(s,2H),4.83(s,2H).ESI-MS: m/z＝287.05[M+H] +.
(4)中间体28-4的合成
Figure PCTCN2021108826-appb-000108
将28-3(397mg，1.38mmol)溶于8mLMeCN和2.5mLDMF中，加入K 2CO 3(229mg，1.66mmol)、28-1(379mg，2.07mmol)及NaI(42mg，0.28mmol)，30℃下反应24h后，加入水，EA萃取，有机相水洗至中性，浓缩后经柱层析纯化得淡黄色粉末状固体188mg，收率31％。 1H NMR(400MHz,CDCl 3):δ10.46(s,1H),8.87(d,J＝2.4Hz,1H),8.85(d,J＝2.0Hz,1H),8.06(t,J＝2.2Hz,1H),7.88(d,J＝7.6Hz,1H),7.44–7.39(m,2H),7.37–7.29(m,3H),7.17(d,J＝8.0Hz,1H),7.09(t,J＝7.8Hz,2H),6.72(d,J＝7.6Hz,1H),6.46(d,J＝8.0Hz,1H),5.24(s,2H),4.50(s,2H),4.19(br,1H),2.11(s,3H).ESI-MS:m/z＝434.19[M+H] +.
(3)化合物28的合成
Figure PCTCN2021108826-appb-000109
将28-4(278mg，0.64mmol)和D-丝氨酸(135mg，1.28mmol)悬浮于6mL无水DMF和2mL无水MeOH中，再加入冰醋酸(73μL，1.28mmol)，35℃下反应24h后，加入NaBH(oAc) 3(408mg，1.93mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体78mg，收率23％。 1H NMR(400MHz,DMSO-d 6):δ9.02(d,J＝2.4Hz,1H),8.98(d,J＝2.0Hz,1H),8.50(t,J＝2.0Hz,1H),7.43–7.38(m,2H),7.38–7.31(m,2H),7.29–7.24(m,2H),7.20(s,1H),7.03(d,J＝7.6Hz,1H),6.91(t,J＝7.8Hz,1H),6.42(dd,J＝7.6,0.8Hz,1H),6.37(d,J＝8.0Hz,1H),5.76(t,J＝6.0Hz,1H),5.27(dd,J＝18.8,12.8Hz,2H),4.37(d,J＝5.6Hz,2H),4.10(dd,J＝20.6,13.4Hz,2H),3.75(dd,J＝11.2,4.4Hz,1H),3.63(dd,J＝11.2,6.8Hz,1H),3.19(dd,J＝6.8,4.4Hz,1H),2.03(s,3H).ESI-HRMS:m/z calculated for C 31H 31N 4O 4 +[M+H] +523.2340,found 523.2338.
实施例29：
(1)中间体29-1的合成
Figure PCTCN2021108826-appb-000110
将1-溴-3-甲基-2-(三氟甲基)苯(10.25g，42.88mmol)、苯硼酸(7.32g，60.03mmol)、乙酸铯(20.58g， 107.22mmol)和PdCl 2(dppf)(3.15g，4.29mmol)悬浮在100mL THF中，氩气保护下，回流反应36h，冷却，浓缩，残余物加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得无色油状5.3g，收率52％。 1H NMR(400MHz,CDCl 3):δ7.41–7.31(m,4H),7.28–7.25(m,3H),7.12–7.08(m,1H),2.57(q,J＝2.8Hz,3H).
(2)中间体29-2的合成
Figure PCTCN2021108826-appb-000111
将29-1(4.48g，18.96mmol)溶于70mLCCl 4中，加入NBS(3.37g，18.96mmol)和75％的BPO(304mg，1.26mmol)，回流反应11h，浓缩至干，加入水，DCM萃取，水洗，饱和食盐水洗，无水Na 2SO 4干燥，抽滤，滤液浓缩至干，残余物溶于50mLDMF中，加入邻苯二甲酰亚胺钾盐(4.05g，21.87mmol)，80℃下反应1.5h后，减压蒸干溶剂，残余物加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得白色固体4.55g，收率60％。 1H NMR(400MHz,CDCl 3):δ7.98–7.91(m,2H),7.82–7.77(m,2H),7.43–7.36(m,4H),7.31–7.27(m,2H),7.19(d,J＝7.6Hz,1H),7.14(d,J＝7.6Hz,1H),5.19(s,2H).ESI-MS:m/z＝382.09[M+H] +.
(4)中间体29-3的合成
Figure PCTCN2021108826-appb-000112
将29-2(450mg，1.18mmol)溶于7mL乙醇中，加入85％的水合肼(125mg，2.12mmol)，回流反应3h，冷却后加入1.38mL 6N HCl水溶液，继续回流30min后，冷却，抽滤除去不溶物，滤液浓缩后，1N NaOH调PH＝10，DCM/MeOH＝10/1萃取，有机相水洗一次，蒸干溶剂得无色油状物290mg，收率98％，无需纯化直接用于下一步。 1H NMR(400MHz,CDCl 3):δ7.57(d,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),7.42–7.33(m,3H),7.29–7.25(m,2H),7.19(d,J＝7.6Hz,1H),4.08(q,J＝1.6Hz,2H).ESI-MS:m/z＝252.09[M+H] +.
(5)中间体29-4的合成
Figure PCTCN2021108826-appb-000113
将29-3(290mg，1.15mmol)、5-3(459mg，1.39mmol)、Cs 2CO 3(564mg，1.73mmol)、BINAP(144mg，0.23mmol)及Pd(oAc) 2(26mg，0.12mmol)悬浮于9mL二氧六环中，Ar保护下，回流反应16h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体388mg，收率67％。 1H NMR(400MHz,CDCl 3):δ10.21(s,1H),8.82(d,J＝1.6Hz,1H),8.79(d,J＝2.0Hz,1H),7.99(t,J＝2.0Hz,1H),7.63(s,1H),7.51–7.46(m,2H),7.46–7.38(m,3H),7.30–7.27(m,3H),5.96(s,1H),5.10(s,2H),4.88(br,1H),4.73(s,2H),2.21(s,3H).ESI-MS:m/z＝502.15[M+H] +.
(6)化合物29的合成
Figure PCTCN2021108826-appb-000114
将29-4(358mg，0.71mmol)和D-丝氨酸(150mg，1.43mmol)悬浮于6mL无水DMF和2mL无水MeOH中，再加入冰醋酸(82μL，1.43mmol)，35℃下反应24h后，加入NaBH(oAc) 3(454mg，2.14mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体181mg，收率43％。 1H NMR(400MHz,DMSO-d 6):δ8.89(d,J＝2.0Hz,1H),8.82(d,J＝2.0Hz,1H),8.34(t,J＝2.0Hz,1H),7.51(t,J＝7.6Hz,1H),7.46–7.38(m,4H),7.31(d,J＝2.0Hz,1H),7.29(d,J＝1.6Hz,1H),7.19(d,J＝7.6Hz,1H),7.05(s,1H),6.09(t,J＝5.6Hz,1H),5.93(s,1H),5.32(br,1H),5.09(dd,J＝17.8,13.2Hz,2H),4.57(d,J＝4.0Hz,2H),4.03(dd,J＝40.4,13.2Hz,2H),3.78(dd,J＝11.4,4.4Hz,1H),3.64(dd,J＝11.6,7.2Hz,1H),3.19–3.16(m,1H),2.14(s,3H).ESI-HRMS:m/z calculated for C 32H 29F 3N 4NaO 4 +[M+Na] +613.2033,found 613.2033.
实施例30：
(1)中间体30-1的合成
Figure PCTCN2021108826-appb-000115
将29-1(473mg，2.0mmol)溶于8mLCCl 4中，加入NBS(356mg，2mmol)和75％的BPO(32mg，0.10mmol)，回流反应10h，浓缩至干，加入水，DCM萃取，水洗，饱和食盐水洗，无水Na 2SO 4干燥，抽滤，滤液经柱层析纯化得白色固体390mg，收率62％。 1H NMR(400MHz,CDCl 3):δ7.61–7.56(m,1H),7.51(t,J＝7.6Hz,1H),7.40–7.36(m,3H),7.27–7.23(m,3H),4.73(q,J＝1.6Hz,2H).
(2)中间体30-2的合成
Figure PCTCN2021108826-appb-000116
将30-1(630mg，2mmol)和10-2(532mg，2.10mmol)溶于10.5mLMeCN和3.5mLDMF的混合溶液中，再加入K 2CO 3(332mg，2.40mmol)，60℃下反应11h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体120mg，收率12％。 1H NMR(400MHz,CDCl 3):δ10.19(s,1H),8.85(d,J＝2.0Hz,2H),8.05(t,J＝2.2Hz,1H),7.74(d,J＝8.4Hz,1H),7.53(d,J＝7.2Hz,1H),7.49(t,J＝7.6Hz,1H),7.44–7.36(m,3H),7.30–7.23(m,3H),6.35(dd,J＝8.4,1.6Hz,1H),6.06(d,J＝2.0Hz,1H),5.16(s,2H),5.04(t,J＝5.8Hz,1H),4.69(d,J＝4.8Hz,2H).ESI-MS:m/z＝488.14[M+H] +.
(3)化合物30的合成
Figure PCTCN2021108826-appb-000117
将30-2(120mg，0.25mmol)和D-丝氨酸(52mg，0.49mmol)悬浮于3mL无水DMF，再加入冰醋酸(28μL，0.49mmol)，35℃下反应24h后，加入NaBH(oAc) 3(157mg，0.74mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体56mg，收率39％。 1H NMR(400MHz,DMSO-d 6):δ9.00(d,J＝2.0Hz,1H),8.99(d,J＝2.0Hz,1H),8.50(t,J＝2.0Hz,1H),8.21(br,2H),7.60–7.55(m,2H),7.47–7.37(m,3H),7.31–7.26(m,2H),7.22(t,J＝4.0Hz,1H),7.10(d,J＝8.0Hz,1H),6.72(t,J＝5.6Hz,1H),6.35(d,J＝1.6Hz,1H),6.13(dd,J＝8.0,1.6Hz,1H),5.34(br,1H),5.19(dd,J＝19.6,13.2Hz,2H),4.49(d,J＝4.0Hz,2H),4.03(dd,J＝44.0,13.2Hz,2H),3.76(dd,J＝11.6,4.4Hz,1H),3.63(dd,J＝11.6,7.2Hz,1H),3.16(dd,J＝7.2,4.4Hz,1H).ESI-HRMS:m/z calculated for C 31H 27F 3N 4NaO 4 +[M+Na] +599.1877,found 599.1876.
实施例31：
(1)中间体31-1的合成
Figure PCTCN2021108826-appb-000118
将2-溴-1-碘-3-甲苯(5g，16.8mmol)、苯硼酸(2.36g，19.35mmol)、乙酸铯(8.08g，42.09mmol) 和PdCl 2(dppf)(1.24g，1.69mmol)悬浮在40mL THF中，氩气保护下，回流反应36h，冷却，浓缩，残余物加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得无色油状3.93g，收率95％。 1H NMR(400MHz,CDCl 3):δ7.61–7.58(m,1H),7.48–7.31(m,6H),7.26–7.23(m,1H),7.16–7.10(m,1H),2.49(s,3H).
(2)中间体31-2的合成
Figure PCTCN2021108826-appb-000119
将31-1(3.93g，15.90mmol)溶于70mLCCl 4中，加入NBS(2.83g，15.90mmol)和75％的BPO(255mg，0.79mmol)，回流反应11h，浓缩至干，加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得白色固体3.36g，收率65％。 1H NMR(400MHz,CDCl 3):δ7.47–7.42(m,2H),7.41–7.39(m,2H),7.38–7.35(m,2H),7.33(t,J＝7.6Hz,1H),7.25(dd,J＝7.6,2.0Hz,1H),4.71(s,2H).
(3)中间体31-3的合成
Figure PCTCN2021108826-appb-000120
将31-2(860mg，2.64mmol)和10-2(668mg，2.64mmol)溶于15mLMeCN和5mLDMF的混合溶液中，再加入K 2CO 3(437mg，3.16mmol)，回流反应11h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体200mg，收率15％。 1H NMR(400MHz,DMSO-d 6):δ10.06(s,1H),9.00(d,J＝1.6Hz,1H),8.97(d,J＝1.6Hz,1H),8.47(s,1H),7.55–7.50(m,2H),7.50–7.44(m,2H),7.43–7.37(m,4H),7.33(dd,J＝7.4,1.4Hz,1H),7.28(dd,J＝7.2,1.6Hz,1H),6.34(d,J＝10.4Hz,2H),5.29(s,2H),4.50(d,J＝5.6Hz,2H).ESI-MS:m/z＝498.08[M+H] +.
(4)化合物31的合成
Figure PCTCN2021108826-appb-000121
将31-3(316mg，0.63mmol)和D-丝氨酸(133mg，1.27mmol)悬浮于6mL无水DMF，再加入冰醋酸(72μL，1.27mmol)，35℃下反应24h后，加入NaBH(oAc) 3(403mg，1.90mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体153mg，收率41％。 1H NMR(400MHz,DMSO-d 6):δ9.00(d,J＝2.0Hz,1H),8.98(d,J＝2.0Hz,1H),8.50(t,J＝2.0Hz,1H),8.22(br,1H),7.50–7.44(m,2H),7.44–7.40(m,1H),7.40–7.34(m, 3H),7.32(dd,J＝7.8,1.8Hz,1H),7.24(dd,J＝7.2,2.0Hz,1H),7.09(d,J＝8.4Hz,1H),6.66(t,J＝5.8Hz,1H),6.37(d,J＝1.6Hz,1H),6.14(dd,J＝8.2,1.8Hz,1H),5.31(br,1H),5.20(dd,J＝19.6,13.2Hz,2H),4.37(d,J＝6.0Hz,2H),4.04(dd,J＝44.4,13.2Hz,2H),3.77(dd,J＝11.2,4.4Hz,1H),3.63(dd,J＝11.6,7.2Hz,1H),3.16(dd,J＝7.2,4.4Hz,1H).ESI-HRMS:m/z calculated for C 30H 27BrN 4NaO 4 +[M+Na] +609.1108,found 609.1111.
实施例32：
(1)中间体32-1的合成
Figure PCTCN2021108826-appb-000122
将3-甲基-4-硝基苯甲醛(1.90g，11.52mmol)、2-胺基-4-氯苯甲酸(0.99g，5.76mmol)、1-氟-2,4,6-三甲基吡啶三氟甲烷磺酸盐(5g，17.29mmol)、Pd(oAC) 2(259mg，1.15mmol)及对甲苯磺酸(3.97g，23.05mmol)悬浮于115mL冰醋酸中，室温下搅拌10min后，90℃下继续反应24h，冷却，浓缩，残余物经柱层析纯化得淡黄色固体942mg，收率45％。 1H NMR(400MHz,DMSO-d 6):δ11.31(s,1H),10.33(s,1H),7.69(s,1H),7.52(s,1H),2.40(s,3H).ESI-MS:m/z＝180.03[M-H] -.
(2)中间体32-2的合成
Figure PCTCN2021108826-appb-000123
将32-1(578mg，3.19mmol)溶于17mLMeCN和3.5mLDMF中，加入K 2CO 3(485mg，3.51mmol)、5-氯甲基烟腈(535mg，3.51mmol)和NaI(96mg，0.64mmol)，室温下反应24h后，加入80mL水，抽滤，滤饼水洗至中性，经干燥后得黄白色粉末状固体939mg，收率99％。无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.44(s,1H),9.04(t,J＝2.0Hz,1H),8.56(t,J＝2.0Hz,1H),7.91(s,1H),7.82(s,1H),5.47(s,2H),2.45(s,3H).ESI-MS:m/z＝296.07[M-H] -.
(3)中间体32-3的合成
Figure PCTCN2021108826-appb-000124
将32-2(1.46g，4.91mmol)悬浮于55mL EtOH/H 2O＝5/1的混合溶液中，加入Fe(963mg，17.20mmol)和NH 4Cl(394mg，7.37mmol)，回流反应4h后，抽滤除去不溶物，滤液蒸干后加入水，DCM/MeOH＝20/1萃取，有机相浓缩至干得橙黄色粉末状固体1.30g，收率99％。无需纯化直接用于下一步。 1H NMR(400MHz,DMSO-d 6):δ10.03(s,1H),9.02(d,J＝2.0Hz,1H),8.99(d,J＝2.0Hz,1H),8.48(t,J＝2.0Hz,1H),7.33(s,1H),6.32(s,1H),6.19(s,2H),5.22(s,2H),2.01(s,3H).ESI-MS:m/z＝268.11[M+H] +.
(4)中间体32-4的合成
Figure PCTCN2021108826-appb-000125
将31-2(815mg，2.50mmol)和32-3(702mg，2.63mmol)溶于12mLMeCN和4mLDMF的混合溶液中，再加入K 2CO 3(415mg，3.0mmol)，回流反应7.5h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体180mg，收率14％。 1H NMR(400MHz,CDCl 3):δ10.20(s,1H),8.82(d,J＝2.0Hz,1H),8.80(d,J＝2.0Hz,1H),7.99(t,J＝2.2Hz,1H),7.62(d,J＝0.4Hz,1H),7.49–7.42(m,3H),7.42–7.37(m,2H),7.36–7.29(m,2H),7.28–7.24(m,1H),5.98(s,1H),5.13(s,2H),4.90(t,J＝5.8Hz,1H),4.61(d,J＝6.0Hz,2H),2.19(s,3H).ESI-MS:m/z＝512.08[M+H] +.
(5)化合物32的合成
Figure PCTCN2021108826-appb-000126
将32-4(180mg，0.35mmol)和D-丝氨酸(74mg，0.70mmol)悬浮于3.5mL无水DMF，再加入冰醋酸(40μL，0.70mmol)，35℃下反应24h后，加入NaBH(oAc) 3(224mg，1.06mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体46mg，收率22％。 1H NMR(400MHz,DMSO-d 6):δ8.89(d,J＝1.6Hz,1H),8.83(d,J＝1.6Hz,1H),8.34(s,1H),8.14(br,2H),7.48–7.39(m,5H),7.30(t,J＝7.6Hz,1H),7.20(t,J＝7.6Hz,2H),7.03(s,1H),6.03–5.96(m,2H),5.29(br,1H),5.12(dd,J＝18.6,13.4Hz,2H),4.44(d,J＝5.6Hz,2H),4.03(dd,J＝40.0,13.0Hz,2H),3.77(dd,J＝11.4,4.2Hz,1H),3.64(dd,J＝11.0,7.4Hz,1H),3.17(dd,J＝6.8,4.4Hz,1H),2.13(s,3H).ESI-HRMS:m/z calculated for C 31H 29BrN 4NaO 4 +[M+Na] +623.1264,found 623.1265.
实施例33：
(1)中间体33-1的合成
Figure PCTCN2021108826-appb-000127
将31-2(400mg，1.23mmol)和1-4(325mg，1.29mmol)溶于4.5mLMeCN和2.5mLDMF的混合溶液中，再加入K 2CO 3(203mg，1.47mmol)，回流反应10h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体155mg，收率25％。 1H NMR(400MHz,CDCl 3):δ10.24(s,1H),7.74(d,J＝8.4Hz,1H),7.69–7.60(m,3H),7.50(t,J＝7.6,1H),7.48–7.40(m,3H),7.41–7.34(m,2H),7.32–7.26(m,3H),6.35–6.30(m,1H),6.06(d,J＝2.0Hz,1H),5.12(s,2H),4.99(br,1H),4.55(s,2H).ESI-MS:m/z＝497.07[M+H] +.
(2)化合物33的合成
Figure PCTCN2021108826-appb-000128
将33-1(152mg，0.31mmol)和D-丝氨酸(64mg，0.61mmol)悬浮于3mL无水DMF，再加入冰醋酸(35μL，0.61mmol)，35℃下反应24h后，加入NaBH(oAc) 3(194mg，0.92mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得黄白色粉末状固体128mg，收率70％。 1H NMR(400MHz,DMSO-d 6):δ8.26(br,2H),7.98(s,1H),7.87(d,J＝8.0Hz,1H),7.79(d,J＝7.6Hz,1H),7.57(t,J＝8.0Hz,1H),7.51–7.29(m,6H),7.24(dd,J＝7.2,1.6Hz,1H),7.08(d,J＝8.4Hz,1H),6.64(t,J＝6.0Hz,1H),6.34(d,J＝1.6Hz,1H),6.12(dd,J＝8.0,1.6Hz,1H),5.33(br,1H),5.18–5.10(m,2H),4.35(d,J＝5.6Hz,2H),4.03(dd,J＝40.4,12.8Hz,2H),3.78(dd,J＝11.6,4.0Hz,1H),3.65(dd,J＝11.2,7.2Hz,1H),3.18–3.15(m,1H).ESI-HRMS:m/z calculated for C 28H 22BrN 2O +[M-C 3H 6NO 3] +481.0910,found 481.0911.
实施例34：
(1)中间体34-1的合成
Figure PCTCN2021108826-appb-000129
将3-溴-2-甲基苯甲醇(3.25g，16.16mmol)、苯并-1,4-二氧六环-6-硼酸(3.64g，20.23mmol)、乙酸铯(7.75g，40.38mmol)和PdCl 2(dppf)(1.19g，1.62mmol)悬浮在50mL THF中，氩气保护下， 回流反应24h，冷却，浓缩，残余物加入水，DCM萃取，有机相水洗，浓缩后经柱层析纯化得无色油状4.05g，收率98％。 1H NMR(400MHz,CDCl 3):δ7.36(dd,J＝7.6,1.2Hz,1H),7.22(t,J＝7.6Hz,1H),7.17(dd,J＝7.6,1.6Hz,1H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝2.0Hz,1H),6.76(dd,J＝8.0,2.0Hz,1H),4.76(s,2H),4.30(s,4H),2.25(s,3H),1.66(s,1H).ESI-MS:m/z＝257.12[M+H] +.
(2)中间体34-2的合成
Figure PCTCN2021108826-appb-000130
将34-1(513mg，2.0mmol)溶于10mL DCM中，冰浴降温至0℃，滴加PBr 3(0.094mL，1.0mmol)，滴完继续反应20min后，加入碎冰淬灭反应，DCM萃取三次，饱和碳酸氢钠溶液洗涤有机相一次，有机相水洗至中性，无水Na 2SO 4干燥，抽滤，浓缩至干得无色油状550mg，收率86％，无需纯化直接用于下一步。 1H NMR(400MHz,CDCl 3):δ7.35–7.29(m,1H),7.22–7.15(m,2H),6.93–6.89(m,1H),6.82–6.80(m,1H),6.78–6.74(m,1H),4.59(s,2H),4.31(s,4H),2.32(s,3H).ESI-MS:m/z＝239.11[M-Br] +.
(3)中间体34-3的合成
Figure PCTCN2021108826-appb-000131
将34-2(550mg，1.72mmol)和1-4(435mg，1.72mmol)溶于10mLMeCN和3mLDMF的混合溶液中，再加入K 2CO 3(262mg，1.90mmol)，回流反应11h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化后得黄白色固体170mg，收率20％。 1H NMR(400MHz,CDCl 3):δ10.23(s,1H),7.74(d,J＝8.4Hz,1H),7.71–7.66(m,2H),7.63(d,J＝7.8Hz,1H),7.51(t,J＝7.8Hz,1H),7.25–7.22(m,1H),7.22–7.17(m,2H),6.91(d,J＝8.4Hz,1H),6.81(d,J＝2.0Hz,1H),6.76(dd,J＝8.2,2.2Hz,1H),6.31(dd,J＝8.6,1.8Hz,1H),6.07(d,J＝1.6Hz,1H),5.14(s,2H),4.64(s,1H),4.38(s,2H),4.31(s,4H),2.24(s,3H).ESI-MS:m/z＝491.20[M+H] +.
(4)化合物34的合成
Figure PCTCN2021108826-appb-000132
将34-3(162mg，0.33mmol)和D-丝氨酸(69mg，0.66mmol)悬浮于3mL无水DMF，再加入冰醋酸(38μL，0.66mmol)，35℃下反应24h后，加入NaBH(oAc) 3(210mg，0.99mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得黄白色粉末状固体91mg，收率48％。 1H NMR(400MHz,DMSO-d 6):δ8.33(br,2H),7.99(s,1H),7.88(d,J＝8.0Hz,1H),7.79(d,J＝7.6Hz,1H),7.57(t,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.15(t,J＝7.6Hz,1H),7.07(d,J＝8.0Hz,2H),6.92(d,J＝8.0Hz,1H),6.80–6.67(m,2H),6.36–6.34(m,2H),6.19(d,J＝8.0Hz,1H),5.36(br,1H),5.18–5.10(m,2H),4.28(br,4H),4.23(d,J＝4.4Hz,2H),4.03(dd,J＝43.6,13.2Hz,2H),3.77(dd,J＝10.8,4.0Hz,1H),3.65(dd,J＝11.2,8.0Hz,1H),3.17–3.14(m,1H),2.18(s,3H).ESI-HRMS:m/z calculated for C 34H 33N 3NaO 6 +[M+Na] +602.2262,found 602.2266.
实施例35：
(1)中间体35-1的合成
Figure PCTCN2021108826-appb-000133
将34-1(3.46g，13.50mmol)、邻苯二甲酰亚胺(2.38g，16.18mmol)和PPh 3(4.96g，18.91mmol)置于三口瓶中，在Ar保护下，加入60mL无水THF，降温至0℃，滴加DEAD(3.29g，18.89mmol)，滴完室温下反应24h。蒸干溶剂柱层析纯化得白色固体5.02g，收率97％。 1H NMR(400MHz,CDCl 3):δ7.89–7.87(m,2H),7.75–7.73(m,2H),7.21–7.16(m,1H),7.14(d,J＝4.0Hz,1H),7.13(s,1H),6.88(d,J＝8.0Hz,1H),6.80(d,J＝2.0Hz,1H),6.74(dd,J＝8.4,2.0Hz,1H),4.93(s,2H),4.30(s,4H),2.35(s,3H).ESI-MS:m/z＝386.14[M+H] +.
(2)中间体35-2的合成
Figure PCTCN2021108826-appb-000134
将35-1(4.88g，12.66mmol)溶于75mL乙醇中，加入85％的水合肼(1.34g，22.75mmol)，回流反应6h，冷却后加入10mL 6N HCl水溶液，继续回流30min后，冷却，抽滤除去不溶物，滤液浓缩后，1N NaOH调PH＝10，DCM/MeOH＝10/1萃取，有机相水洗，蒸干溶剂得无色油状物3.20g，收率99％，无需纯化直接用于下一步。 1H NMR(400MHz,CDCl 3):δ7.31(dd,J＝7.6,1.2Hz,1H),7.21(t,J＝7.6Hz,1H),7.12(dd,J＝7.6,1.2Hz,1H),6.89(d,J＝8.4Hz,1H),6.80(d,J＝2.0Hz,1H),6.75(dd,J＝8.4,2.0Hz,1H),4.30(s,4H),3.91(s,2H),2.23(s,3H),1.56(s,2H).ESI-MS:m/z＝256.13[M+H] +.
(3)中间体35-3的合成
Figure PCTCN2021108826-appb-000135
将35-2(420mg，1.64mmol)、5-3(654mg，1.97mmol)、Cs 2CO 3(804mg，2.47mmol)、BINAP(205mg，0.33mmol)及Pd(oAc) 2(37mg，0.16mmol)悬浮于11mL二氧六环中，Ar保护下，85℃反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体325mg，收率39％。 1H NMR(400MHz,DMSO-d 6):δ10.06(s,1H),8.92(d,J＝2.0Hz,1H),8.83(d,J＝2.4Hz,1H),8.33(t,J＝2.0Hz,1H),7.38(d,J＝0.8Hz,1H),7.13–7.08(m,2H),7.07–7.05(m,1H),6.92(d,J＝8.0Hz,1H),6.81(d,J＝2.0Hz,1H),6.77(dd,J＝8.2,2.2Hz,1H),6.67(t,J＝5.8Hz,1H),6.09(s,1H),5.21(s,2H),4.47(d,J＝5.6Hz,2H),4.29(s,4H),2.23(s,3H),2.14(s,3H).ESI-MS:m/z＝506.20[M+H] +.
(4)化合物35的合成
Figure PCTCN2021108826-appb-000136
将35-3(288mg，0.57mmol)和D-丝氨酸(120mg，1.14mmol)悬浮于6mL无水DMF和2mL无水甲醇，再加入冰醋酸(65μL，1.14mmol)，35℃下反应24h后，加入NaBH(oAc) 3(362mg，1.71mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体98mg，收率29％。 1H NMR(400MHz,DMSO-d 6):δ8.89(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.36(t,J＝2.0Hz,1H),8.22(br,2H),7.11(dd,J＝7.2,1.6Hz,1H),7.08(t,J＝7.2Hz,1H),7.03(dd,J＝7.2,1.6Hz,1H),7.00(s,1H),6.91(d,J＝8.0Hz,1H),6.81(d,J＝2.0Hz,1H),6.77(dd,J＝8.4,2.0Hz,1H),6.07(s,1H),5.69(t,J＝5.6Hz,1H),5.31(br,1H),5.13(dd,J＝18.8,13.2Hz,2H),4.32(d,J＝5.2Hz,2H),4.28(s,4H),4.03(dd,J＝44.0,13.2Hz,2H),3.77(dd,J＝11.2,4.4Hz,1H),3.64(dd,J＝11.6,7.2Hz,1H),3.16(dd,J＝7.2,4.4Hz,1H),2.20(s,3H),2.10(s,3H).ESI-HRMS:m/z calculated for C 34H 34N 4NaO 6 +[M+Na] +617.2371,found 617.2377.
实施例36：
(1)中间体36-1的合成
Figure PCTCN2021108826-appb-000137
将35-2(418mg，1.64mmol)、13-2(480mg，1.37mmol)、Cs 2CO 3(667mg，2.05mmol)、BINAP (170mg，0.27mmol)及Pd(oAc) 2(31mg，0.14mmol)悬浮于14mL二氧六环中，Ar保护下，回流反应24h后，浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄白色固体559mg，收率78％。 1H NMR(400MHz,DMSO-d 6):δ10.04(s,1H),8.93(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.36(t,J＝2.0Hz,1H),7.60(s,1H),7.14–7.03(m,4H),6.92(d,J＝8.2Hz,1H),6.80(d,J＝2.0Hz,1H),6.76(dd,J＝8.2,2.2Hz,1H),6.26(s,1H),5.25(s,2H),4.56(d,J＝6.0Hz,2H),4.29(s,4H),2.22(s,3H).ESI-MS:m/z＝526.19[M+H] +.
(2)化合物36的合成
Figure PCTCN2021108826-appb-000138
将36-1(340mg，0.65mmol)和D-丝氨酸(135mg，1.28mmol)悬浮于6mL无水DMF和2mL无水甲醇，再加入冰醋酸(74μL，1.28mmol)，35℃下反应24h后，加入NaBH(oAc) 3(410mg，1.93mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色粉末状固体135mg，收率34％。 1H NMR(400MHz,DMSO-d 6):δ8.89(d,J＝2.0Hz,1H),8.85(d,J＝2.0Hz,1H),8.36(t,J＝2.0Hz,1H),8.17(br,2H),7.37(s,1H),7.12–7.01(m,3H),6.92(d,J＝8.0Hz,1H),6.80(d,J＝2.0Hz,1H),6.76(dd,J＝8.2,2.2Hz,1H),6.22(s,1H),6.07(t,J＝5.8Hz,1H),5.38(br,1H),5.15(dd,J＝18.0,13.2Hz,2H),4.40(d,J＝5.6Hz,2H),4.28(s,4H),4.01(dd,J＝33.6,13.2Hz,2H),3.75(dd,J＝11.2,4.4Hz,1H),3.64(dd,J＝11.6,6.8Hz,1H),3.18(dd,J＝6.8,4.4Hz,1H),2.20(s,3H).ESI-HRMS:m/z calculated for C 33H 31ClN 4NaO 6 +[M+Na] +637.1824,found 637.1825.
实施例37：(对比实施例1)
(1)中间体37-1的合成
Figure PCTCN2021108826-appb-000139
将1-1(2.18g，11mmol)、2,4-二羟基苯甲醛(1.38g，10mmol)和PPh 3(2.89g，11mmol)置于三口瓶中，在Ar保护下，加入100mL无水THF，降温至0℃，滴加DIAD(2.22g,11mmol)，滴完室温下反应24h。蒸干溶剂柱层析纯化得黄色固体1.75g，收率55％。 1H NMR(400MHz,CDCl 3):δ11.52(s,1H),9.75(s,1H),7.51–7.29(m,11H),6.68(dd,J＝8.5,2.2Hz,1H),6.61(d,J＝2.1Hz,1H),5.16(s, 2H),2.27(s,3H).ESI-MS:m/z＝319.13[M+H] +.
(2)中间体37-2的合成
Figure PCTCN2021108826-appb-000140
将37-1(318mg，1mmol)溶于12mL乙腈中，依次加入K 2CO 3(207mg，1.5mmol)、四正丁基碘化铵(18mg，0.05mmol)和5-氯甲基烟腈(183mg，1.2mmol)，75℃下反应过夜，反应液浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得黄色固体226mg，收率52％。 1H NMR(400MHz,DMSO-d 6):δ10.26(s,1H),9.05–8.97(m,2H),8.56(s,1H),7.72(d,J＝2.0Hz,1H),7.55–7.49(m,3H),7.45–7.38(m,1H),7.35–7.28(m,3H),7.25(d,J＝2.1Hz,1H),7.01(s,1H),6.89(d,J＝2.1Hz,1H),5.45(s,2H),5.31(s,2H),2.25(s,3H).ESI-MS:m/z＝435.16[M+H] +.
(3)化合物37的合成
Figure PCTCN2021108826-appb-000141
将37-2(217mg，0.50mmol)和D-丝氨酸(105mg，1mmol)溶于5mL无水DMF中，加入冰醋酸(58μL，1mmol)，35℃下反应24h后，加入NaBH(OAc) 3(318mg，1.5mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体138mg，收率53％。 1H NMR(400MHz,DMSO-d 6):δ9.05(s,1H),9.01(s,1H),8.35(br,2H),7.49–7.40(m,3H),7.40–7.28(m,5H),7.20(d,J＝2.1Hz,1H),6.88(s,1H),6.75(d,J＝2.1Hz,1H),5.36–5.25(m,2H),5.17(s,2H),4.07(d,J＝5.2Hz,1H),4.00(d,J＝7.2Hz,1H),3.73(d,J＝6.8Hz,1H),3.64(dd,J＝11.4,7.2Hz,1H),3.17–3.14(m,1H),2.21(s,3H),1.93(s,1H).ESI-MS:m/z＝524.25[M+H] +.
实施例38：(对比实施例2)
(1)中间体38-1的合成
Figure PCTCN2021108826-appb-000142
将(5-溴-4-甲基吡啶-3-基)甲醇(308mg，2.5mmol)和CuCN(560mg，6.25mmol)置于反应釜中并悬浮于8mL吡啶中，160℃下反应24h，冷却，反应液加到4mL浓氨水和12mL饱和氯化铵中，室温下搅拌2h。混合物用二氯甲烷/异丙醇(85:15)的混合溶液萃取，萃取液经无水硫酸钠干燥后浓缩至干，得5-羟甲基-4-甲基吡啶-3-甲腈305mg，直接用于下一步。
5-羟甲基-4-甲基吡啶-3-甲腈(305mg，2.06mmol)溶于9mL DCM中，加入氯化亚砜(0.3mL，4.12mmol)，室温下搅拌至反应完全。反应液浓缩至干，加入EA。有机相用饱和碳酸氢钠和氯化钠溶液洗涤，浓缩至干经柱层析纯化得油状物223mg，收率65％。 1H NMR(400MHz,CDCl 3):δ9.08(s,1H),8.75(s,1H),4.52(s,2H),2.45(s,3H).ESI-MS:m/z＝131.08[M-Cl] +.
(2)中间体38-2的合成
Figure PCTCN2021108826-appb-000143
将37-1(337mg，1.06mmol)溶于12mL乙腈中，依次加入K 2CO 3(220mg，1.59mmol)、四正丁基碘化铵(18mg，0.053mmol)和中间体38-1(211mg，1.27mmol)，75℃下反应过夜，反应液浓缩，加入水，EA萃取，有机相水洗至中性，经柱层析纯化得淡黄色固体357mg，收率75％。 1H NMR(400MHz,DMSO-d 6):δ10.26(s,1H),8.97(s,1H),8.92(s,1H),7.87(d,J＝2.3Hz,1H),7.54–7.47(m,3H),7.45–7.34(m,1H),7.35–7.28(m,4H),6.89(d,J＝2.1Hz,1H),6.69(d,J＝2.1Hz,1H),5.45(s,2H),5.31(s,2H),2.55(s,3H),2.25(s,3H).ESI-MS:m/z＝449.21[M+H] +.
(3)化合物38的合成
Figure PCTCN2021108826-appb-000144
将38-2(224mg，0.50mmol)和D-丝氨酸(105mg，1mmol)溶于5mL无水DMF中，加入冰醋 酸(58μL，1mmol)，35℃下反应24h后，加入NaBH(OAc) 3(318mg，1.5mmol)，继续反应24h后，加入水，DCM/MeOH(10:1)混合溶剂萃取，水洗，浓缩至干，残余物经制备液相纯化得白色固体132mg，收率49％。 1H NMR(400MHz,DMSO-d 6):δ9.05(s,1H),9.01(s,1H),8.35(br,2H),7.47–7.39(m,3H),7.41–7.23(m,5H),7.26(d,J＝2.1Hz,1H),6.89(s,1H),6.75(d,J＝2.1Hz,1H),5.36–5.25(m,2H),5.16(s,2H),4.07(d,J＝5.2Hz,1H),4.03(d,J＝7.2Hz,1H),3.71(d,J＝6.8Hz,1H),3.64(dd,J＝11.4,7.2Hz,1H),3.17–3.14(m,1H),2.56(s,3H),2.21(s,3H),1.95(s,1H).ESI-MS:m/z＝538.25[M+H] +.
实施例39：化合物抑制PD-1/PD-L1相互作用的活性
采用Cisbio公司PD-1/PD-L1 Binding Assay kits在蛋白水平上评价化合物对PD-1/PD-L1相互作用的抑制活性。试剂盒的评价方法是基于均相时间分辨荧光(HTRF)的原理，其包含实验所需的相关蛋白、试剂及buffer。阳性化合物对照BMS202购自MCE公司。
(1)实验方法
实验方法和流程按照试剂盒说明书进行，简述如下：
化合物配制成所需浓度的DMSO溶液。Tag1-PD-L1、Tag2-PD-1和化合物溶液用diluent buffer稀释成工作液，anti-Tag1-Eu 3+和anti-Tag2-XL665用detection buffer稀释成工作液。实验使用白色384浅孔板，每孔中依次加入2μL化合物工作液、4μL的Tag1-PD-L1工作液及4μL的Tag2-PD-1工作液，室温下孵育15min；每孔中再加入10μL由5μL的anti-Tag1-Eu 3+和5μL的anti-Tag2-XL665工作液混匀后的溶液，孵育2.5h后检测；实验同时设置对照组，2μL diluent buffer替代2μL化合物工作液构成Positive control，6μL diluent buffer替代2μL化合物和4μL Tag1-PD-L1工作液构成Negative control。使用TECAN公司的Infinite F200PRO在320nm激发光下分别检测发射波长620nm和665nm的荧光强度。每孔的HTRF值＝(665nm荧光强度/620nm荧光强度)×10 4，化合物的抑制率(％)＝[1-(化合物孔HTRF值-Negative control孔HTRF值)/(Positive control孔HTRF值-Negative control孔HTRF值)]×100％，每个化合物检测8-10个浓度下的抑制率，使用Prism软件计算IC 50。
(2)实验结果
化合物对PD-1/PD-L1相互作用的抑制活性评价结果如下表所示。
Figure PCTCN2021108826-appb-000145
Figure PCTCN2021108826-appb-000146
实施例40：化合物与人PD-L1蛋白的相互作用
(1)实验方法
实验使用Fortebio公司基于生物膜干涉技术(BLI)的仪器OctectRED，用SA芯片捕获人PD-L1/AVI。将抗原PD-L1/AVI的浓度用运行buffer(PBS+0.02％Tween-20+2％DMSO)稀释至10μg/mL，上样时间为300s；分析物同样用运行buffer梯度稀释至相应的浓度(20nM、10nM、5nM、2.5nM、1.25nM、0.625nM、0.3125nM)，同时设buffer空白对照组。人PD-L1/AVI与分析物结合时间180s，解离时间300s；芯片用10mM甘氨酸HCl、pH 1.7溶液5秒脉冲重复3次进行再生。测定数据拟合成1:1结合模型，来测定平衡解离常数KD。
(1)实验结果
结果如下表所示，化合物与人PD-L1有很强的结合能力，其亲和力KD值在nM及以上水平。
Figure PCTCN2021108826-appb-000147
实施例41化合物体外促IFN-γ分泌作用评价
(1)实验方法
从10-15ml健康志愿者全血中用实验人淋巴细胞分离液(TBD sciences)分离人外周血单核细胞(PBMCs)。用生理盐水清洗两次，重新悬浮于缓冲液中(RPMI 1640 complete medium containing 10％FBS，SIGMA)计数细胞密度。将PBMCs分散置于96孔板中，每孔1×10 5cells以及50μL缓冲液。将抗CD3抗体(SIGMA)和抗CD28抗体(SIGMA)按1：1的比例混合得抗体混合液，将抗体混合液加入孔中并确保抗体终浓度为0.8μg/mL。同时，加入PDL1/FC融合蛋白(SINO BIOLOGICAL)并使其终浓度10.0μg/mL，将待测化合物用缓冲液稀释后加入孔中，使终浓度在0.1μM或1μM。混合体系在37℃下和5％CO 2中培育72小时。收集上清液，并用ELISA MAXTM人IFN-γ标准试剂盒(BioLegend)测定IFN-γ的表达水平，计算增加率。增加率(％)＝(化合物处理表达量－PDL1处理表达量)/PDL1处理表达量×100％
(2)实验结果
结果如下表所示，化合物5和化合物10在细胞水平具有显著的促IFN-γ分泌作用，优于BMS202。
Figure PCTCN2021108826-appb-000148
实施例42化合物的细胞毒评价
(1)实验方法
分别将raji(ATCC)、raw(ATCC)和PBMCs细胞悬浮于缓冲液中(RPMI 1640 complete medium containing 10％FBS，SIGMA)计数细胞密度。将细胞移至96孔板孔中，确保每个孔的细胞密度为1×10 4cells/孔，分别用不同浓度的化合物(100μM,50μM,25μM,12.5μM,6.25μM and 3.125μM)和缓冲对照液(0.2％DMSO)在37℃,5％CO 2条件下孵育处理24小时。向每个孔中加入100μL of  CellTiter-Glo Luminescent Solution(Promega)并在室温下振摇10分钟，然后用
Figure PCTCN2021108826-appb-000149
Navigator System测定体系荧光并计算细胞死亡率。细胞死亡率(％)＝(1-RLUcompound/RLUcontrol)×100％，并由抑制曲线确定IC50。
(2)实验结果
实验结果如下表所示。结果表明大多数化合物对多种细胞都有较好的安全性，仅少数化合物表现出了一定的毒性。
Figure PCTCN2021108826-appb-000150
实施例43：体内抗肿瘤药效评价
基于PD-1/PD-L1抑制剂是通过干扰PD-1/PD-L1相互作用进而激活免疫系统实现抗肿瘤的机制，体内药效实验所用动物模型必须是免疫系统健全的动物；另外，考虑到动物与人的PD-1/PD-L1存在种属差异。因此，本发明体内抗肿瘤药效学评价模型采用PD-1人源化小鼠，并且接种的肿瘤为PD-L1人源化的肿瘤细胞，此评价模型能够更准确的反映化合物的体内药效。
(1)实验方法
上海南方模式动物中心购置24只6周龄左右PD-1人源化小鼠(品系全名：C57BL/6J-Pdcd1 em1(hPDCD1)/Smoc)并置于SPF级动物饲养房观察1～2周，待动物适应饲养环境，用基因工程改造的结肠癌细胞系MC38(鼠PD-L1敲除，人PD-L1敲入)皮下接种至小鼠后退腹股沟附近，接种细胞量为1x10 6细胞/只。观察7-10天后待肿瘤体积长至50-150mm 3，按照随机数表将动物按照肿瘤大小随机分成vehicle组和测试组，每组6只。测试组采取腹腔注射给予15mg/kg化合物5，vehicle 组同样腹腔注射与测试组等体积的buffer，给药频次每天一次，给药三周。实验过程中测量记录肿瘤大小和小鼠体重，实验终点处死小鼠。绘制小鼠体重及肿瘤增殖曲线图。
(2)实验结果
实验结果如附图1和2所示，化合物5与对照组相比，可以显著地抑制肿瘤的生长。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (20)

  1. 如通式(Ⅰ)所示的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，
    Figure PCTCN2021108826-appb-100001
    其中，
    R选自氢和C1-C8烷基；
    R 1选自氢、氘、卤素、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基；
    R 2选自
    Figure PCTCN2021108826-appb-100002
    其中R 6选自卤素、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基，R 7位于R 6的间位或者邻位且R 7选自氢、-O-(CH 2) n-R 0、-CONH-R 0和-(CH 2) n-R 0，其中n为1-4的整数，R 0为氰基、羟基、羧基、氨基或含杂原子的链状或环状亲水性取代基；
    R 3选自R 8-CH 2-，其中R 8选自氢、氰基、C1-C4烷基、卤代C1-C4烷基、C2-C4烯基、-NR 9R 10、-CONR 9R 10、3-6元环烷基、3-6元杂环烷基、6-10元芳基和5-10元杂芳基，任选地，所述C1-C4烷基、卤代C1-C4烷基、C2-C4烯基、-NR 9R 10、-CONR 9R 10、3-6元环烷基、3-6元杂环烷基、6-10元芳基和5-10元杂芳基各自独立地被一个或多个选自下述的取代基取代：氰基、卤素、羧基、C1-C4烷基、C1-C4烷氧基、C1-C4烷基磺酰基、3-6元环烷基、羟基取代的3-6元环烷基、3-6元杂环烷基、羟基取代的3-6元杂环烷基、-CONR 9R 10和-NR 9COR 10，其中R 9和R 10在每次出现时各自独立地选自氢、氘和C1-C4烷基；
    R 4选自羟基、羧基、氨基酸(优选亲水性氨基酸)的片段和-NR 10R 11，其中R 10和R 11各自独立地选自氢、氘、C1-C6烷基和3-6元环烷基，任选地，所述C1-C6烷基和3-6元环烷基各自独立地被一个或多个选自下述的取代基取代：巯基、羟基、羧基、羟基C1-C6烷基、C1-C6酰胺基和3-6元含氮杂环烷基；或者，R 10和R 11与相连的N原子形成5-6元杂环烷基，任选地，所述5-6元杂环烷基被一个或多个选自下述的基团取代：氨基、羟基、羧基、巯基和羟基C1-C6烷基；
    R 5选自氢、氘、氰基、卤素、C1-C4烷基、C2-C4烯基、氘代C1-C4烷基、卤代C1-C4烷基和C1-C4烷氧基；
    Y和Z各自独立地选自碳和氮。
  2. 权利要求1的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中所 述苄胺类衍生物结构如式(Ⅰ-A)所示：
    Figure PCTCN2021108826-appb-100003
    其中，R、R 1、R 2、R 3、R 4和R 5如权利要求1中所定义，并且R 5位于-OR 3的对位或者间位；优选地，R 5位于-OR 3的对位。
  3. 权利要求1的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中所述苄胺类衍生物结构如式(Ⅰ-B)所示：
    Figure PCTCN2021108826-appb-100004
    其中，R、R 1、R 2、R 3、R 4和R 5如权利要求1中所定义，Z和Y中至少一个为氮，并且R 5位于-OR 3的对位或者间位。
  4. 权利要求1的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中所述苄胺类衍生物如式(Ⅰ-C)所示：
    Figure PCTCN2021108826-appb-100005
    其中，R、R 1、R 2、R 3、R 4和R 5如权利要求1中所定义，并且R 5位于-OR 3的对位或者间位。
  5. 权利要求1-4任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R选自氢和甲基；
    优选地，R为氢。
  6. 权利要求1-5任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R 1选自卤素、C1-C2烷基和卤代C1-C2烷基，例如溴、甲基或三氟甲基；
    优选地，R 1选自卤素和C1-C2烷基，例如溴或甲基。
  7. 权利要求1-6任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R 2选自
    Figure PCTCN2021108826-appb-100006
  8. 权利要求1-7任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R 3选自R 8-CH 2-，其中R 8选自氢、C1-C2烷基、苯基和5-6元杂芳基，任选地，所述C1-C2烷基、苯基和5-6元杂芳基各自独立地被一个氰基取代；
    优选地，R 3选自甲基、乙基、
    Figure PCTCN2021108826-appb-100007
  9. 权利要求1-8任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R 4选自氨基酸的片段和-NR 10R 11，其中R 10和R 11各自独立地选自氢、氘和C1-C6烷基，任选地，所述C1-C6烷基被一个或多个选自下述的取代基取代：巯基、羟基、羧基、羟基C1-C4烷基、C1-C4酰胺基和5-6元含氮杂环烷基；或者，R 10和R 11与相连的N原子形成5-6元杂环烷基，任选地，所述5-6元杂环烷基被一个或多个选自下述的基团取代：氨基、羟基、羧基、巯基和羟基C1-C4烷基；所述氨基酸片段选自氨基酸中与羧基共用一个碳原子的氨基失去一个氢得到的片段；优选地，所述氨基酸选自甘氨酸、丙氨酸、脯氨酸、羟脯氨酸、丝氨酸、苏氨酸、天冬氨酸、天冬酰胺、谷氨酸、谷氨酰胺、半胱氨酸、组氨酸、赖氨酸、精氨酸、焦谷氨酸、
    Figure PCTCN2021108826-appb-100008
    Figure PCTCN2021108826-appb-100009
    优选地，R 4选自
    Figure PCTCN2021108826-appb-100010
    Figure PCTCN2021108826-appb-100011
    以及上述结构的立体异构体。
  10. 权利要求1-9任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中，R 5选自氢、氘、卤素、C1-C2烷基和C1-C2烷氧基，例如氢、氯、甲氧基或甲基；
    优选地，R 5选自氢、氘、卤素和C1-C2烷基，例如氢、氯或甲基。
  11. 权利要求1-10任一项的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，其中所述苄胺类衍生物选自：
    N-(2-((2-((3-氰基苄基)氧基)-4-(((2-甲基-[1,1'联苯基]-3-基)甲基)胺基)苄基)胺基)乙基)乙酰胺，
    3-((2-(((2-羟乙基)胺基)甲基)-5-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苯氧基)甲基)苯甲腈，
    3-((2-(((1,3-二羟丙基-2-基)胺基)甲基)-5-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苯氧基)甲基)苯甲腈，
    (2-((3-氰基苄基)氧基)-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-((3-氰基苄基)氧基)-6-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-6-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-((3-氰基苄基)氧基)-6-甲氧基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    N-(2-(((2-甲氧基-6-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)吡啶-3-基)甲基)胺基)乙基)乙酰胺，
    (2-((5-氰基吡啶-3-基)甲氧基)-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (5-氯-2-甲氧基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    ((2-甲氧基-6-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)吡啶-3-基)甲基)-D-丝氨酸，
    (5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-甲氧基-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    ((4-甲氧基-6-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)吡啶-3-基)甲基)-D-丝氨酸，
    (2-(苄氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)-2-(吡啶-3-基甲氧基)苄基)-D-丝氨酸，
    (R)-3-((2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)胺基)-4-羟基丁酸，
    (2-((3-氰基苄基)氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-乙氧基-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2S，4R)-1-(2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-4-羟基吡咯烷-2-羧酸，
    (S)-4-((2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)胺基)-3-羟基丁酸，
    (S)-5-((2-((4-羟基-2-氧吡咯烷-1-基)甲基)-4-甲基-5-(((2-甲基-[1,1'-联苯基]-3-基)甲基) 胺基)苯氧基)甲基)烟腈，
    (2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-高丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-天冬酰胺，
    (2-((3-氰基苄基)氧基)-4-(甲基((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    3-((2-(((2-羟乙基)胺基)甲基)-5-(甲基((2-甲基-[1,1'-联苯基]-3-基)甲基)胺基)苯氧基)甲基)苯甲腈二盐酸盐，
    (2-((5-氰基吡啶-3-基)甲氧基)-4-(((2-甲基-[1,1'-联苯基]-3-基)胺基)甲基)苄基)-D-丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-5-甲基-4-(((2-(三氟甲基)-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-4-(((2-(三氟甲基)-[1,1'-联苯基]-3-基)甲基)胺基)苄基)-D-丝氨酸，
    (4-(((2-溴-[1,1'-联苯基]-3-基)甲基)胺基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)-D-丝氨酸，
    (4-(((2-溴-[1,1'-联苯基]-3-基)甲基)胺基)-2-((5-氰基吡啶-3-基)甲氧基)-5-甲基苄基)-D-丝氨酸，
    (4-(((2-溴-[1,1'-联苯基]-3-基)甲基)胺基)-2-((3-氰基苄基)氧基)苄基)-D-丝氨酸，
    (2-((3-氰基苄基)氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)胺基)苄基)-D-丝氨酸，
    (2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)胺基)-5-甲基苄基)-D-丝氨酸和
    (5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3-(2,3-二氢苯并[b][1,4]二恶英-6-基)-2-甲基苄基)胺基)苄基)-D-丝氨酸。
  12. 权利要求2所述苄胺类衍生物的制备方法，其选自下述方法：
    Figure PCTCN2021108826-appb-100012
  13. 权利要求3所述苄胺类化合物的制备方法，其选自下述方法：
    Figure PCTCN2021108826-appb-100013
    Figure PCTCN2021108826-appb-100014
  14. 权利要求4所述苄胺类化合物的制备方法，其选自下述方法：
    Figure PCTCN2021108826-appb-100015
  15. 药物组合物，其含有权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，以及一种或多种药学上可接受的载体或赋形剂。
  16. 权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或权利要求15的药物组合物在制备预防或治疗与PD-1/PD-L1相关的疾病的药物中的用途；
    优选地，所述与PD-1/PD-L1相关的疾病包括肿瘤、感染性疾病和自身免疫性疾病；
    优选地，所述肿瘤选自消化系统肿瘤、泌尿系统肿瘤、血液肿瘤、神经系统肿瘤、生殖系统肿瘤、皮肤癌、肺癌、乳腺癌、头颈癌、脑瘤、胶质瘤和鼻咽癌；
    优选地，所述感染性疾病选自微生物(例如细菌或病毒)引起的一种或多种感染；
    优选地，所述自身免疫性疾病选自慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、天疱疮(例如寻常型天疱疮)、类天疱疮、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、口眼干燥综合征、强直性脊柱炎、结节性多动脉炎和Wegener肉芽肿病。
  17. 权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或权利要求15的药物组合物，其用于预防或治疗与PD-1/PD-L1相关的疾病；
    优选地，所述与PD-1/PD-L1相关的疾病包括肿瘤、感染性疾病和自身免疫性疾病；
    优选地，所述肿瘤选自消化系统肿瘤、泌尿系统肿瘤、血液肿瘤、神经系统肿瘤、生殖系统肿瘤、皮肤癌、肺癌、乳腺癌、头颈癌、脑瘤、胶质瘤和鼻咽癌；
    优选地，所述感染性疾病选自微生物(例如细菌或病毒)引起的一种或多种感染；
    优选地，所述自身免疫性疾病选自慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖 尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、天疱疮(例如寻常型天疱疮)、类天疱疮、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、口眼干燥综合征、强直性脊柱炎、结节性多动脉炎和Wegener肉芽肿病。
  18. 一种预防或治疗与PD-1/PD-L1相关的疾病的方法，其包括向有此需要的受试者施用有效量的权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或权利要求15的药物组合物的步骤；
    优选地，所述与PD-1/PD-L1相关的疾病包括肿瘤、感染性疾病和自身免疫性疾病；
    优选地，所述肿瘤选自消化系统肿瘤、泌尿系统肿瘤、血液肿瘤、神经系统肿瘤、生殖系统肿瘤、皮肤癌、肺癌、乳腺癌、头颈癌、脑瘤、胶质瘤和鼻咽癌；
    优选地，所述感染性疾病选自微生物(例如细菌或病毒)引起的一种或多种感染；
    优选地，所述自身免疫性疾病选自慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、天疱疮(例如寻常型天疱疮)、类天疱疮、原发性胆汁性肝硬化、多发性脑脊髓硬化症、急性特发性多神经炎、系统性红斑狼疮、类风湿关节炎、系统性血管炎、硬皮病、皮肌炎、混合性结缔组织病、自身免疫性溶血性贫血、甲状腺自身免疫病、口眼干燥综合征、强直性脊柱炎、结节性多动脉炎和Wegener肉芽肿病。
  19. 一种抑制PD-1/PD-L1相互作用的方法，其包括向有此需要的受试者施用有效量的权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或权利要求15的药物组合物的步骤。
  20. 一种提高免疫反应的方法，其包括向有此需要的受试者施用有效量的权利要求1-11任一项所述的苄胺类衍生物，或其药学上可接受的立体异构体、盐、溶剂化物或前药，或权利要求15的药物组合物的步骤。
PCT/CN2021/108826 2020-08-11 2021-07-28 苄胺类衍生物及其制备方法与用途 WO2022033303A1 (zh)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2021323754A AU2021323754A1 (en) 2020-08-11 2021-07-28 Benzylamine derivative, preparation method therefor and use thereof
KR1020237007902A KR20230050376A (ko) 2020-08-11 2021-07-28 벤질아민 유도체, 이의 제조 방법, 및 이의 용도
EP21855356.8A EP4198017A1 (en) 2020-08-11 2021-07-28 Benzylamine derivative, preparation method therefor and use thereof
CA3191714A CA3191714A1 (en) 2020-08-11 2021-07-28 Benzylamine derivative, preparation method therefor and use thereof
JP2023509628A JP2023539043A (ja) 2020-08-11 2021-07-28 ベンジルアミン誘導体、その調製方法およびその用途
US18/020,923 US20230303494A1 (en) 2020-08-11 2021-07-28 Benzylamine derivative, preparation method therefor and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010801978.3 2020-08-11
CN202010801978.3A CN114075123B (zh) 2020-08-11 2020-08-11 苄胺类衍生物及其制备方法与用途

Publications (1)

Publication Number Publication Date
WO2022033303A1 true WO2022033303A1 (zh) 2022-02-17

Family

ID=80247637

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/108826 WO2022033303A1 (zh) 2020-08-11 2021-07-28 苄胺类衍生物及其制备方法与用途

Country Status (8)

Country Link
US (1) US20230303494A1 (zh)
EP (1) EP4198017A1 (zh)
JP (1) JP2023539043A (zh)
KR (1) KR20230050376A (zh)
CN (1) CN114075123B (zh)
AU (1) AU2021323754A1 (zh)
CA (1) CA3191714A1 (zh)
WO (1) WO2022033303A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024088036A1 (zh) * 2022-10-26 2024-05-02 西安新通药物研究股份有限公司 一种非对称性联苯衍生物及其制备方法与医药用途

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170174671A1 (en) * 2015-12-17 2017-06-22 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018119221A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Pyridine derivatives as immunomodulators
CN108698995A (zh) * 2016-01-08 2018-10-23 格罗宁根大学 Pd-1/pd-l1蛋白/蛋白相互作用的抑制剂
WO2018195321A1 (en) * 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
CN109721527A (zh) * 2017-10-27 2019-05-07 广州丹康医药生物有限公司 一种新型抗pd-l1化合物、其应用及含其的组合物
CN110092745A (zh) * 2018-01-29 2019-08-06 广州丹康医药生物有限公司 一种含芳环的化合物及其应用
WO2019149183A1 (zh) * 2018-02-05 2019-08-08 上海和誉生物医药科技有限公司 一种联芳基衍生物、其制备方法和在药学上的应用
WO2019191624A1 (en) * 2018-03-29 2019-10-03 Arbutus Biopharma, Inc. Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
WO2020011209A1 (zh) * 2018-07-11 2020-01-16 上海和誉生物医药科技有限公司 免疫抑制剂及其制备方法和在药学上的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3459925B1 (en) * 2016-05-23 2021-08-11 Tianjin Chase Sun Pharmaceutical Co., Ltd. Method for preparing 2-hydroxyl-4-(2, 3-disubstituted benzyloxy)-5-substituted benzaldehyde derivative

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170174671A1 (en) * 2015-12-17 2017-06-22 Incyte Corporation Heterocyclic compounds as immunomodulators
US20180273519A1 (en) * 2015-12-17 2018-09-27 Incyte Corporation Heterocyclic compounds as immunomodulators
CN108698995A (zh) * 2016-01-08 2018-10-23 格罗宁根大学 Pd-1/pd-l1蛋白/蛋白相互作用的抑制剂
WO2018119221A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Pyridine derivatives as immunomodulators
WO2018195321A1 (en) * 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
CN109721527A (zh) * 2017-10-27 2019-05-07 广州丹康医药生物有限公司 一种新型抗pd-l1化合物、其应用及含其的组合物
CN110092745A (zh) * 2018-01-29 2019-08-06 广州丹康医药生物有限公司 一种含芳环的化合物及其应用
WO2019149183A1 (zh) * 2018-02-05 2019-08-08 上海和誉生物医药科技有限公司 一种联芳基衍生物、其制备方法和在药学上的应用
WO2019191624A1 (en) * 2018-03-29 2019-10-03 Arbutus Biopharma, Inc. Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
WO2020011209A1 (zh) * 2018-07-11 2020-01-16 上海和誉生物医药科技有限公司 免疫抑制剂及其制备方法和在药学上的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHENG BINBIN, REN YICHANG, NIU XIAOGE, WANG WEI, WANG SHUANGHU, TU YINGFENG, LIU SHUWEN, WANG JIN, YANG DEYING, LIAO GUOCHAO, CHEN: "Discovery of Novel Resorcinol Dibenzyl Ethers Targeting the Programmed Cell Death-1/Programmed Cell Death–Ligand 1 Interaction as Potential Anticancer Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 15, 13 August 2020 (2020-08-13), US , pages 8338 - 8358, XP055900174, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c00574 *
GUO JIALIN, LUO LONGLONG, WANG ZHIHONG, HU NAIJING, WANG WEI, XIE FEI, LIANG ERGUANG, YAN XINLIN, XIAO JUNHAI, LI SONG: "Design, Synthesis, and Biological Evaluation of Linear Aliphatic Amine-Linked Triaryl Derivatives as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction with Promising Antitumor Effects In Vivo", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 22, 25 November 2020 (2020-11-25), US , pages 13825 - 13850, XP055900171, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c01329 *
KATARZYNA GUZIK, KRZYSZTOF M. ZAK, PRZEMYSLAW GRUDNIK, KATARZYNA MAGIERA, BOGDAN MUSIELAK, RICARDA TÖRNER, LUKASZ SKALNIAK, ALEXAN: "Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 13, 13 July 2017 (2017-07-13), US , pages 5857 - 5867, XP055401481, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b00293 *

Also Published As

Publication number Publication date
CN114075123B (zh) 2023-06-06
JP2023539043A (ja) 2023-09-13
AU2021323754A1 (en) 2023-03-09
CA3191714A1 (en) 2022-02-17
EP4198017A1 (en) 2023-06-21
US20230303494A1 (en) 2023-09-28
CN114075123A (zh) 2022-02-22
KR20230050376A (ko) 2023-04-14

Similar Documents

Publication Publication Date Title
JP7033079B2 (ja) 芳香族スルホンアミド誘導体
TWI534144B (zh) 甲狀腺荷爾蒙β受體作動藥
JP5913400B2 (ja) 核内受容体結合剤
CN102883607B (zh) 用于治疗癌的化合物
CA3093851A1 (en) Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
TW200403210A (en) Benzamide derivatives
CN111356456A (zh) 2-芳基磺酰胺基-iV-芳基乙酰胺衍生的Stat3抑制剂
CN107660202B (zh) 水溶性前药
JP6380777B2 (ja) ＰＩ３Ｋ、ｍＴＯＲ阻害薬としての縮合キノリン化合物
WO2021121210A1 (zh) 并环类衍生物、其制备方法及其在医药上的应用
CN115413279A (zh) P2x3调节剂
EP3412664A1 (en) Heterocyclic sulfonamide derivative and medicine containing same
CN105980349A (zh) 苯甲酰胺和烟酰胺化合物及其使用方法
TW202227430A (zh) 含氮雜環類衍生物、其製備方法及其在醫藥上的應用
TW201609734A (zh) 用於治療寄生蟲疾病之化合物及組合物
WO2022033303A1 (zh) 苄胺类衍生物及其制备方法与用途
CN111315734A (zh) 作为食欲素受体拮抗剂的经取代的2-氮杂双环[3.1.1]庚烷和2-氮杂双环[3.2.1]辛烷衍生物
KR20210065944A (ko) Dp 길항제
WO2022166860A1 (zh) Pim激酶抑制剂
KR0164437B1 (ko) 1-(피리디닐아미노)-2-피롤리디논, 이의 제조방법 및 이를 포함하는 약제학적 조성물
TW201136922A (en) New oxadiazole derivatives
EP3130588A1 (en) Polysubstituted pyridine compound, preparation method, use and pharmaceutical composition
KR20200123184A (ko) 증식이상 장애를 치료하기 위한 물질 및 방법
US6037357A (en) N-benzoyl-α-alkylated azatyrosines as anticancer agents
CN114181277A (zh) 一种用于雄激素受体蛋白靶向降解的嵌合体化合物、其制备方法及其在医药上的应用

Legal Events

Date Code Title Description
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2023509628

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3191714

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 20237007902

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2021323754

Country of ref document: AU

Date of ref document: 20210728

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021855356

Country of ref document: EP

Effective date: 20230313