WO2022017442A1 - 双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途 - Google Patents

双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途 Download PDF

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WO2022017442A1
WO2022017442A1 PCT/CN2021/107804 CN2021107804W WO2022017442A1 WO 2022017442 A1 WO2022017442 A1 WO 2022017442A1 CN 2021107804 W CN2021107804 W CN 2021107804W WO 2022017442 A1 WO2022017442 A1 WO 2022017442A1
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alkyl
alkoxy
cycloalkyl
group
halogen
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French (fr)
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司聚同
姜美锋
张丽云
樊平平
刘涛
刘备
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恩瑞生物医药科技（上海）有限公司
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Priority to CN202180005070.4A priority Critical patent/CN114341128A/zh
Publication of WO2022017442A1 publication Critical patent/WO2022017442A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • 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
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    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and relates to a novel bifunctional protein degradation targeting chimera compound, a preparation method thereof, a pharmaceutical composition containing the same, and the use thereof for degrading and inhibiting FLT3 tyrosine protein kinase, including using Use in the treatment of related diseases caused by abnormal FLT3-mediated signaling pathways, especially in cancer treatment.
  • AML Acute myeloid leukemia
  • AML Acute myeloid leukemia
  • the uncontrolled proliferation and accumulation of dysfunctional cancerous white blood cells in a patient's body results in impaired production of normal blood cells.
  • the 5-year survival rate for AML patients is only about 25%, the lowest of all types of leukemia.
  • the clinical treatment of AML mainly adopts the "7+3" chemotherapy method, and there is no other effective new therapy. It was not until 2017 that several targeted small molecule drugs were approved for clinical practice, but their long-term clinical effects need further clinical verification.
  • the FLT3 gene belongs to the class III receptor tyrosine kinase gene family, which encodes FMS-like Tyrosine Kinase 3 (FLT3/CD135).
  • Human FLT3 protein consists of 993 amino acids with a molecular weight of about 145Kd, and its amino acid sequence is highly homologous to KIT, PDGFRA/B and CSF1R.
  • FLT3 and its ligand bind to the extracellular domain, it induces and forms a homodimer, causing autophosphorylation of the receptor, which in turn activates a series of cellular effector molecules mediated by receptor kinases such as JAK-STAT, PI3K and MAPK signaling pathway, involved in the apoptosis, proliferation and differentiation of bone marrow hematopoietic cells.
  • FLT3L receptor kinases
  • FLT3 is expressed in the cancer cells of most AML patients, and about 30% of AML patients have mutations in the FLT3 gene, mainly including internal tandem repeat mutations (ITD, about 25%) and point mutations in the tyrosine kinase domain (TKD, about 5%). Both FLT3 ITD and TKD mutations can directly activate the FLT3 receptor signaling pathway to transform and promote the proliferation of AML cells.
  • ITD internal tandem repeat mutations
  • TKD tyrosine kinase domain
  • FLT3 As a potential drug target, FLT3 has always been a hot spot in scientific and pharmaceutical industry and drug development. Although dozens of drug molecules targeting FLT3, including macromolecular drugs, have been developed or are in clinical trials, so far only two small-molecule drugs, Midostaurin and Gilteritinib, have been approved by the FDA. It is used in relapsed and refractory AML with positive FLT3-ITD or FLT3-TKD mutation, and midostaurin must be used in combination with chemotherapy.
  • RNAi and CRISPR/Cas9 can significantly reduce protein levels, but pharmacokinetic properties associated with these approaches include metabolic stability and Tissue distribution has so far limited their development as clinical drugs.
  • Ubiquitin a small protein molecule consisting of 76 amino acid residues with a molecular weight of about 8.5kDa, has a highly conserved sequence and is widely present in eukaryotic organisms. Genes encoding ubiquitin in eukaryotes are arranged in tandem repeats, with eight different amino acid residues capable of forming complex polyubiquitin chains on target proteins. Ubiquitination refers to the process in which ubiquitin molecules classify intracellular proteins under the action of a series of special enzymes, select target protein molecules, and specifically modify the target protein to form target protein polyubiquitin chains.
  • Ubiquitination is a three-enzyme cascade, that is, a series of reactions catalyzed by three enzymes are required to occur, and the whole process is also known as the ubiquitination signaling pathway. Ubiquitination plays an important role in protein localization, metabolism, function, regulation and degradation. Protein ubiquitination is a common post-translational modification in organisms and is involved in the regulation of almost all life activities such as cell cycle, proliferation, apoptosis, differentiation, and metastasis.
  • Ubiquitination is closely related to the pathogenesis of tumors, cardiovascular, autoimmunity and other diseases. Ubiquitination has become a new target for research and development of new drugs.
  • E3 ubiquitin ligases (more than 600 species are known in humans) confer specificity to ubiquitinated substrates, which are more attractive than general proteases due to their specificity for certain protein substrates.
  • the development of ligands for E3 ubiquitin ligases has proven challenging, in part because they must disrupt protein-protein interactions.
  • PROTAC Protein degradation targeted chimera
  • PROTAC drugs have affinity for both target protein and E3 ubiquitin ligase binding. After E3 ubiquitin ligase forms a complex with the target protein by binding the selective ligand part in the PROTAC small molecule, it initiates a powerful ubiquitin hydrolysis process to degrade the target protein, so that any protein degradation mechanism of the human body can be used to degrade any protein. Target pathogenic proteins are eliminated.
  • PROTAC small molecule drugs can be repeatedly used in combination with other target proteins after the target protein is degraded, which means that it can work at low doses. PROTAC drugs can not only act on target proteins that traditional small-molecule drugs can inhibit, but also inhibit and degrade target proteins that traditional small-molecule drugs cannot, including acquired drug-resistant mutants.
  • the object of the present invention is to provide a compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • L is selected from the following structures:
  • One of Z 1 and Z 2 is connected to one of Y 1 , Y 2 , Y 3 or Y 4 , and the other is connected to one of X 1 , X 2 , X 3 or X 4 ;
  • One of Z 3 and Z 4 is connected to one of Y 1 , Y 2 , Y 3 or Y 4 , and the other is connected to one of X 1 , X 2 , X 3 or X 4 ;
  • One of Z 5 and Z 6 is connected to one of Y 1 , Y 2 , Y 3 or Y 4 , and the other is connected to one of X 1 , X 2 , X 3 or X 4 ;
  • Z 1 and Z 2 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • Z 3 and Z 4 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • Z 5 and Z 6 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W 7 , W 8 and W 9 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -N(R 3 )-, -C(O)NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O) (CH 2 ) q O-, alkenylene, alkynylene, -S(O) p NH- and -NHS(O) p -;
  • G is selected from single bonds, divalent cycloalkyl groups, divalent heterocyclic groups, divalent aryl groups and divalent heteroaryl groups, the divalent cycloalkyl groups, divalent heterocyclic groups, divalent aryl groups and divalent heteroaryl groups
  • the heteroaryl groups are each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, and haloalkoxy;
  • G 1 , G 2 , G 3 are each independently selected from a single bond, an alkenylene group, an alkynylene group, a divalent cycloalkyl group, a divalent heterocyclic group, a divalent aryl group and a divalent heteroaryl group, the divalent heteroaryl group Heterocyclic, divalent aryl, and divalent heteroaryl are each independently optionally further selected from one or more of hydroxy, halogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, and haloalkoxy substituted by a substituent;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CR b or N;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR c or N;
  • Y and U are each independently selected from N or CR a ;
  • A is selected from heteroaryl or heterocyclyl
  • said heteroaryl or heterocyclyl is optionally further substituted selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, substituted with one or more groups of amino, acyl, ester, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, acyl, ester group, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, substituted with one or more groups of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl
  • a and R 1 are each independently selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, alkyl, alkenyl, , alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkane group, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkene substituted with one or more groups of alkynyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; or
  • a and R 1 are the nitrogen atom to which they are attached form a heterocyclyl group together with the aryl or heteroaryl group, the heterocyclyl or heteroaryl is optionally further substituted selected from halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, substituted with one or more groups of hydroxy, amino, acyl, ester, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, acyl , ester, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo substituted with one or more groups of radical, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, hal
  • R 2 is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl , heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkane substituted with one or more groups of radicals, heterocyclyls, aryls and heteroaryls;
  • R 3 is selected from hydrogen or alkyl
  • R a , R b and R c are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkyne alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, Heterocyclyl, aryl or heteroaryl is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, substituted with one or more groups of alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d and R e or R d1 and R e1 or R d2 and R e2 or R d3 and R e3 or R d4 and R e4 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, Carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl , amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy,
  • Q is selected from hydrogen, hydroxyl, alkyl, cycloalkyl, or the following structures:
  • alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, alkyl, hydroxy, amino and aryl;
  • R 0 is selected from aryl, heterocyclyl, alkyl, cycloalkyl and alkoxy, wherein the aryl, heterocyclyl, alkyl, cycloalkyl and alkoxy being optionally further selected from halogen, Amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and substituted with one or more groups of heteroaryl;
  • R 4 , R 7 , R 8 and R 9 are each independently selected from hydrogen, alkyl, cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are optionally further selected from hydroxy, mercapto, substituted with one or more groups of carboxyl, amido, alkyl, alkoxy and alkylthio;
  • R 5 and R 6 are each independently selected from hydrogen, alkyl, acyl, and aryl ester, wherein the alkyl, acyl, an ester group and an aryl group optionally further substituted selected from halogen, amino, nitro, cyano substituted with one or more groups of radical, hydroxyl, mercapto, ester, acyl, amido, alkyl and alkoxy;
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclyl group optionally further substituted with one or more groups selected from halogen, alkyl, cycloalkyl, heterocyclyl;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • n 1 , n 2 , n 3 , n 4 and n 5 are each independently an integer from 0 to 15;
  • n 1 , m 2 , m 3 , m 4 , m 5 , m 6 and m 7 are each independently an integer from 0 to 15;
  • j 1 , j 2 , j 3 , j 4 , j 5 , j 6 , j 7 , and j 8 are each independently an integer from 0 to 15.
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR c or N;
  • R c is selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl and heterocyclyl, said amino, alkyl, alkoxy, cycloalkyl and heterocyclyl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy , cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl substituted;
  • the Q group is as defined in general formula (I).
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CR c or N;
  • R c is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy;
  • X 1 , X 2 , X 3 and X 4 are each independently selected from CH;
  • Q is selected from hydrogen, hydroxyl, C 1 -C 6 alkyl, preferably methyl,
  • the C 1 -C 6 alkyl group is optionally further substituted by a C 6 -C 10 aryl group, preferably phenyl;
  • R 0 is selected from C 6 -C 10 aryl, preferably phenyl, 5-7 membered heterocyclic group, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl and C 1 -C 10 alkoxy, wherein The C 6 -C 10 aryl, 5-7 membered heterocyclyl, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl and C 1 -C 10 alkoxy groups are optionally further selected from halogen , amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy
  • R 4 , R 7 , R 8 and R 9 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl, preferably phenyl, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl group optionally further substituted selected from hydroxyl, mercapto, carboxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and one or more groups of C 1 -C 6 alkylthio substituted;
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR" wherein R" is C 1 -C 6 alkyl and C 6 -C 10 aryl preferably phenyl, wherein the C 1 -C 6 alkyl and C 6 -C 10 aryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, ester, acyl, amido, C 1 -C 6 alkyl and one or more groups of C 1 -C 6 alkoxy; or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 5-7 membered nitrogen-containing heterocyclic group, optionally further selected from halogen, C 1 -C 6 alkyl, One or more groups of C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl are substituted.
  • L is selected from the following structures:
  • Z 1 is connected to Y 1 , Y 2 , Y 3 or Y 4 groups, and only one of them;
  • Z 2 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 1 and Z 2 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • W 1 , W 2 and W 3 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 -, -C(O )NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, alkenylene, alkynylene, -S(O) p NH- and -NHS(O) p -;
  • R 3 is selected from hydrogen or alkyl
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, alkyl, alkenyl, alkynyl, alkoxy Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • a cycloalkyl or heterocyclyl carbon atom or R d and R e are connected thereto together with the cycloalkyl or heterocyclyl group optionally further substituted selected from halogen, amino, nitro, cyano, hydroxy, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl by one or more groups replace;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d1 and R e1 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R g , R f , Rh and R i are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkene alkynyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, ring Alkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, substituted with one or more groups of alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • n 1 , n 2 , n 3 , n 4 and n 5 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 1 is connected to Y 1 , Y 2 , Y 3 or Y 4 groups, and only one of them;
  • Z 2 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 1 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O )(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH( CH 2 ) q S(O) p -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O(CH 2 ) q C(O
  • Z 2 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O )(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH( CH 2 ) q S(O) p -, C 2 -C 6 C 2 -C 6 alkynyl, -O(CH 2 ) q C(O)NH-,
  • W 1 , W 2 and W 3 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 -, -C(O )NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -S(O) p NH- and -NHS(O) p -; preferably -CH 2 -, -O-, -S-;
  • R 3 is selected from hydrogen or C 1 -C 6 alkyl
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d and R e together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d and R e are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or a 5-7 membered heterocyclyl;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R g, R f, R h and R i are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen, halogen , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy ;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • n 1 , n 2 , n 3 , n 4 and n 5 are each independently an integer of 0 to 15, preferably an integer of 0 to 10, more preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 3 is attached to the Y 1 , Y 2 , Y 3 or Y 4 group, and only one of them;
  • Z 4 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 3 and Z 4 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • W 4 , W 5 and W 6 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 -, -C(O )NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, alkenylene, alkynylene, -S(O) p NH- and -NHS(O) p -;
  • G is selected from the group consisting of divalent cycloalkyl groups, divalent heterocyclic groups, divalent aryl groups and divalent heteroaryl groups, said divalent cycloalkyl groups, divalent heterocyclic groups, divalent aryl groups and divalent heteroaryl groups each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • R 3 is selected from hydrogen or alkyl
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, alkyl, alkenyl, alkynyl, alkoxy Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • a cycloalkyl or heterocyclyl carbon atom or R d and R e are connected thereto together with the cycloalkyl or heterocyclyl group optionally further substituted selected from halogen, amino, nitro, cyano, hydroxy, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d1 and R e1 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d2 and R e2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d3 and R e3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R h and R i are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • n 1 , m 2 , m 3 and m 4 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 3 is attached to the Y 1 , Y 2 , Y 3 or Y 4 group, and only one of them;
  • Z 4 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 3 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O )(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH( CH 2 ) q S(O) p -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O(CH 2 ) q C(O
  • Z 4 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, -NHC( O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH (CH 2 ) q S(O) p -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O(CH 2 ) q C(
  • W 4 , W 5 and W 6 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 -, -C(O )NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, alkenylene, alkynylene, -S(O) p NH- and -NHS(O) p -; preferably -CH 2 -, -O-, -S-;
  • G is selected from C 3 -C 6 divalent cycloalkyl group, 5- to 6-membered divalent heterocyclic group, C 6 -C 10 divalent aryl group and 5-6 membered divalent heteroaryl group, the divalent cycloalkane group, a divalent heterocyclic group, divalent aromatic groups and divalent heteroaryl are each independently optionally further substituted selected from hydroxyl, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy group, C 1 -C 6 halogenated alkyl group and one or more substituents in C 1 -C 6 halogenated alkoxy group; preferably 5- to 6-membered divalent heterocyclic group, divalent phenyl group, 5- to 6-membered divalent heteroaryl group ;
  • R 3 is selected from hydrogen or C 1 -C 6 alkyl
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d and R e together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d and R e are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or a 5-7 membered heterocyclyl;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d2 and R e2 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d3 and R e3 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R h and R i are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen, halogen, C 1 -C 6 Alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • n 1 , m 2 , m 3 and m 4 are each independently an integer of 0 to 15, preferably an integer of 0 to 10, more preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 5 is attached to the Y 1 , Y 2 , Y 3 or Y 4 group, and only one of them;
  • Z 6 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 5 and Z 6 are each independently selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S (CH 2 ) q -, -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O)(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH(CH 2 ) q S(O) p -, alkenylene, alkynylene, -O(CH 2 ) q C(O)NH-, -NHC(
  • W 7 , W 8 and W 9 are each independently selected from each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 - , -C(O)NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, alkenylene, alkynylene, -S(O) p NH- and -NHS(O) p -;
  • G 1 , G 2 , G 3 are each independently selected from a single bond, an alkenylene group, an alkynylene group, a divalent cycloalkyl group, a divalent heterocyclic group, a divalent aryl group and a divalent heteroaryl group, the divalent heteroaryl group Heterocyclic, divalent aryl, and divalent heteroaryl are each independently optionally further selected from one or more of hydroxy, halogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, and haloalkoxy substituted by a substituent;
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, alkyl, alkenyl, alkynyl, alkoxy Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups with one or more groups substituted; form a cycloal
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d1 and R e1 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d2 and R e2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d3 and R e3 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • R d4 and R e4 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, the amino, ester, acyl, amido, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, substituted with one or more groups of alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d4 and R e4 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto , carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more groups of heteroaryl replace;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • j 1 , j 2 , j 3 , j 4 , j 5 , j 6 , j 7 and j 8 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 5 is attached to the Y 1 , Y 2 , Y 3 or Y 4 group, and only one of them;
  • Z 6 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 5 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O )(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH( CH 2 ) q S(O) p -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O(CH 2 ) q C(O
  • Z 6 is selected from a bond, -(CH 2 ) s -, -(CH 2 ) q O-, -O(CH 2 ) q -, -(CH 2 ) q S-, -S(CH 2 ) q - , -(CH 2 ) q N(R 3 )-, -N(R 3 )(CH 2 ) q -, -C(O)-, -C(O)NH(CH 2 ) q -, NHC(O )(CH 2 ) q -, -(CH 2 ) q C(O)NH-, -(CH 2 ) q NHC(O)-, -S(O) p (CH 2 ) q NH-, -NH( CH 2 ) q S(O) p -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -O(CH 2 ) q C(O
  • W 7 , W 8 and W 9 are each independently selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -NR 3 -, -C(O )NH-, -NHC(O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -S(O) p NH- and -NHS(O) p -; preferably -CH 2 -, -O-, -S-;
  • G 1 , G 2 and G 3 are each independently selected from single bond, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 3 -C 6 divalent cycloalkyl, 5-6 membered divalent valent heterocyclic group, C 6 -C 10 divalent aryl group and 5-6 membered divalent heteroaryl group, each of said divalent heterocyclic group, divalent aryl group and divalent heteroaryl group is independently optionally further selected from hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy Substituted by one or more substituents; preferably vinylene, ethynylene, 5-6-membered divalent heterocyclic group, divalent phenyl, 5-6-membered divalent heteroaryl;
  • R d and R e are each independently selected from hydrogen, halo, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, acylamino, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d1 and R e1 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl or a 5-7 membered heterocyclyl;
  • R d1 and R e1 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d2 and R e2 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d2 and R e2 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d3 and R e3 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d3 and R e3 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d4 and R e4 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • R d4 and R e4 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl or 5-7 membered heterocyclyl;
  • R d4 and R e4 are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • s is an integer from 1 to 12;
  • p 0, 1 or 2;
  • q is an integer from 0 to 12;
  • j 1 , j 2 , j 3 , j 4 , j 5 , j 6 , j 7 and j 8 are each independently an integer of 0 to 15, preferably an integer of 0 to 10, more preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • n 5 is selected from an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • n 1 , n 2 , n 3 and n 4 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • R 3 is selected from hydrogen or alkyl
  • n 1 , n 3 and n 4 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • Z 3 is attached to the Y 1 , Y 2 , Y 3 or Y 4 group, and only one of them;
  • Z 4 is attached to X 1 , X 2 , X 3 or X 4 groups, and only one of them;
  • Z 3 and Z 4 are each independently selected from -O-, -S-, -N(R 3 )-, -C(O)NH-, -NHC(O)-, -S(O) p NH-, -NHS (O) p -, C 1 -C 4 alkenylene, C 1 -C 4 alkynylene group, -OCH 2 C (O) NH- and -NHC (O) CH 2 O-;
  • W 4 and W 6 are each independently selected from -O -, - S -, - N (R 3) -, C (O) NH -, - NHC (O) -, - S (O) p NH- and - NHS(O) p -;
  • W 5 is selected from -CH 2 -, -O-, -S-, -S(O) p -, -C(O)-, -N(R 3 )-, -C(O)NH-, -NHC (O)-, -O(CH 2 ) q C(O)-, -C(O)(CH 2 ) q O-, C 1 -C 4 alkenylene, C 1 -C 4 alkynylene, - S(O) p NH- and -NHS(O) p -;
  • G is selected from the following groups:
  • G is optionally further substituted with one or more substituents selected from hydroxy, halo, alkyl, alkoxy, haloalkyl and haloalkoxy;
  • R 3 is selected from hydrogen or alkyl
  • n 1 , m 2 , m 3 , m 4 , m 5 , m 6 and m 7 are each independently an integer of 0 to 15, preferably an integer of 0 to 6.
  • Y and U are each independently selected from CR a ;
  • R a is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 7 cycloalkyl; preferably hydrogen and halogen.
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CR b ;
  • R b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl and heterocyclyl, said amino, alkyl, alkoxy, cycloalkyl or Heterocyclyl is optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, acyl, amido, oxo, alkyl, alkenyl, alkynyl, alkoxy, substituted by one or more groups of cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably R b is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy and C 3 -C 7 cyclo
  • R 1 is hydrogen
  • A is selected from 5- to 7-membered heteroaryl optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkoxy, hydroxyl, amino, acyl, ester, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl , C 6 -C 10 aryl and one or more groups of 5-6 membered heteroaryl.
  • R 1 is hydrogen, and A is selected from the following structures:
  • R is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkoxy, hydroxy, an amino group, an acyl group, an ester group, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl, and 5-6 membered heteroaryl; preferably hydrogen, C 1 -C 6 alkyl .
  • R 1 is an ester group, particularly -C(O)OR', wherein R' is selected from C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; and A is selected from the following structures:
  • R is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkoxy, hydroxy, an amino group, an acyl group, an ester group, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl, and 5-6 membered heteroaryl; preferably hydrogen, C 1 -C 6 alkyl ;
  • A is selected from pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrrolyl; optionally further substituted selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkoxy, hydroxyl, amino, acyl, ester, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl, and 5-6 membered heteroaryl group substituted by an aryl group; preferably substituted C 1 -C 6 alkyl.
  • R 1 is not hydrogen
  • a and R 1 are formed with the nitrogen atom to which they are attached form a 5-7 yuan heteroaryl, said heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, thiazolyl , thiadiazolyl, pyrrolyl;
  • the 5- to 7-membered heteroaryl is optionally further selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkoxy, hydroxyl, amino, acyl, ester, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl and one or more groups of 5-6 membered heteroaryl.
  • Preferred L in the present invention can be selected from the following structures;
  • R 3 is selected from hydrogen or C 1 -C 6 alkyl
  • R d , R e , R d1 , R e1 , R d2 , R e2 , R d3 , R e3 are as defined in general formula (I), preferably R d , R e , R d1 , R e1 , R d2 , R e2 , R d3 , R e3 are each independently selected from C 1 -C 6 alkyl or halogen; s is an integer from 1 to 12;
  • q is an integer from 0 to 12;
  • n 1 , n 2 , n 3 , n 4 and n 5 are each independently an integer from 0 to 15, preferably an integer from 0 to 10, more preferably an integer from 0 to 6;
  • n 1 , m 2 , m 3 , m 4 , m 5 , m 6 and m 7 are each independently an integer from 0 to 15, preferably an integer from 0 to 10, more preferably an integer from 0 to 6;
  • j 1 , j 2 , j 3 , j 4 , j 5 , j 6 , j 7 and j 8 are each independently an integer of 0 to 15, preferably an integer of 0 to 10, more preferably an integer of 0 to 6.
  • L is selected from the following structures:
  • R 3 is selected from hydrogen or C 1 -C 6 alkyl
  • R d5 and R e5 are each independently selected from hydrogen, halogen and C 1 -C 6 alkyl;
  • x1 is an integer from 0 to 5; preferably an integer from 1 to 5;
  • x2 is an integer from 0 to 10, preferably an integer from 0 to 6;
  • x3 is an integer from 1 to 10, preferably an integer from 1 to 6;
  • x4 is an integer from 1 to 4.
  • the compound represented by the general formula (I) according to the present invention is a prodrug compound, and the prodrug refers to a compound that exhibits pharmacological effects after being transformed in vivo, therefore,
  • the prodrug refers to a compound that exhibits pharmacological effects after being transformed in vivo, therefore,
  • Q is selected from hydroxyl, C 1 -C 6 alkyl, preferably methyl,
  • the C 1 -C 6 alkyl group is optionally further substituted by a C 6 -C 10 aryl group, preferably phenyl;
  • R 0 is selected from C 6 -C 10 aryl, preferably phenyl, 5-7 membered heterocyclic group, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl and C 1 -C 10 alkoxy, wherein The C 6 -C 10 aryl, 5-7 membered heterocyclyl, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl and C 1 -C 10 alkoxy groups are optionally further selected from halogen , amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, acyl, amido, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy
  • R 4 , R 7 , R 8 and R 9 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 6 -C 10 aryl, preferably phenyl, wherein the C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and C 6 -C 10 aryl group optionally further substituted selected from hydroxyl, mercapto, carboxyl, amido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and one or more groups of C 1 -C 6 alkylthio substituted;
  • R 5 and R 6 are each independently selected from hydrogen, C 1 -C 6 alkyl, -C(O)OR wherein R is C 1 -C 6 alkyl and C 6 -C 10 aryl, preferably phenyl, wherein The C 1 -C 6 alkyl and C 6 -C 10 aryl groups are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, ester, acyl, amido, C 1 -C 6 alkane substituted with one or more groups of C 1 -C 6 alkoxy; or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, preferably a 5-7 membered nitrogen-containing heterocyclic group, optionally further selected from halogen, C 1 -C 6 alkyl, One or more groups of C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl are substituted.
  • Typical compounds of the present invention include, but are not limited to, the following compounds:
  • the present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof , or its prodrug, or a method for preparing a pharmaceutically acceptable salt thereof, comprising the steps of:
  • Compound M4 and compound M5 obtain the compound of general formula (I) through nucleophilic substitution reaction, coupling reaction, condensation reaction, Suzuki reaction, Buchwald reaction or Mitsunobu reaction;
  • J 1 and J 2 are each independently selected from halogen, hydroxyl, amino, alkynyl and carboxyl;
  • Y, U, Y 1 , Y 2 , Y 3 , Y 4 , A, E, L, R 1 , R 2 are as defined in general formula (I).
  • the present invention further relates to a pharmaceutical composition, which contains a therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, An enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which contains a therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, enantiomer, An enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a bifunctional FLT3 tyrosine kinase degrader and inhibitor.
  • the present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Its prodrug, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is used in the preparation of a medicament for the prevention and/or treatment of related diseases, especially cancer, caused by abnormal FLT3-mediated signaling pathways in mammals including humans
  • the cancer is preferably a non-solid tumor such as leukemia and solid tumor such as skin with abnormal FLT3 tyrosine kinase expression (overexpression, point mutation, insertion or deletion mutation, fusion protein, etc.) or abnormal FLT3-mediated signaling pathway cancer, melanoma, lung cancer, stomach cancer, breast cancer, pancreatic cancer, liver cancer or colon cancer, etc.
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same may be combined with another drug or drugs such as a cancer treatment drug or a method of treatment such as cancer.
  • the treatment methods are used in combination simultaneously, separately or sequentially.
  • the present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a bifunctional FLT3 tyrosine kinase degrader and inhibitor.
  • the present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament preferably for the prevention and/or treatment of FLT3-mediated signaling pathway abnormalities in mammals including humans
  • the related disease caused is especially cancer, and the cancer is preferably a non-solid tumor such as leukemia with abnormal FLT3 tyrosine kinase expression (overexpression, point mutation, insertion or deletion mutation, fusion protein, etc.) or abnormal FLT3-mediated signaling pathway and solid tumors such as skin cancer, melanoma, lung cancer, stomach cancer, breast cancer, pancreatic cancer, liver cancer or colon cancer, etc.
  • the present invention further relates to a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in simultaneous, separate, or sequential combination with another drug or drugs, such as a drug for the treatment of cancer, or a method of treatment, such as a method for the treatment of cancer use.
  • a compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in simultaneous, separate, or sequential combination with another drug or drugs, such as a drug for the treatment of cancer, or a method of treatment, such as a method for the treatment of cancer use.
  • the present invention also relates to a method for degrading and inhibiting FLT3 tyrosine kinase, which comprises administering to a subject in need thereof an effective amount of the compound represented by the general formula (I) according to the present invention or its meso isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same.
  • the present invention also relates to a method for preventing and/or treating related diseases, especially cancer, caused by abnormal FLT3-mediated signaling pathways in mammals including humans, comprising administering to a subject in need thereof an effective amount of The compound represented by the general formula (I) of the invention or its meso, racemate, enantiomer, diastereomer, or its mixture form, or its prodrug, or its A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same; wherein, the cancer is preferably FLT3 tyrosine kinase abnormal expression (overexpression, point mutation, insertion or deletion mutation, fusion protein, etc.) or FLT3-mediated signal Pathway abnormal non-solid tumors such as leukemia and solid tumors such as skin cancer, melanoma, lung, gastric, breast, pancreatic, myeloma, liver or colon cancer.
  • abnormal non-solid tumors such as leukemia and solid tumors such as skin cancer, melanoma, lung, gastric, breast, pancre
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer may be concurrently with another drug or drugs such as a cancer treatment drug or a treatment method such as a cancer treatment method, used separately or in combination in succession.
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group comprising 1 to 20 carbon atoms, preferably 1 to 18 carbon atoms, more preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms carbon atoms, even more preferably 1 to 4 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, Hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group comprising 1 to 20 carbon atoms having 2 hydrogen atoms removed from the same or two different carbon atoms of the parent alkane
  • the resulting residue preferably contains 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1- ethylene (-CH (CH 3) -) , 1,2- ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 - ), 1,4- butylene (-CH 2 CH 2 CH 2 CH 2 -) , and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) Wait.
  • alkenyl refers to a straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms containing at least one carbon-carbon double bond and attached to the rest of the molecule by a single or double bond, preferably having 2 to 10 Carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms.
  • alkenyl groups include vinyl, propenyl, butenyl, pentenyl, pentadienyl, hexenyl, and the like.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • Alkenylene refers to a straight or branched chain hydrocarbon group containing at least one carbon-carbon double bond containing from 1 to 20 carbon atoms, having 2 from the same carbon atom or from two different carbon atoms of the parent alkene
  • the residue derived from the removal of two hydrogen atoms preferably contains 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • alkynyl refers to a straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms containing at least one carbon-carbon triple bond and attached to the rest of the molecule by a single or triple bond, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • Alkynylene refers to a straight or branched chain hydrocarbon group of 1 to 20 carbon atoms containing at least one carbon-carbon triple bond, having 2 on the same or two different carbon atoms from the parent alkyne
  • the residue derived from the removal of two hydrogen atoms preferably contains 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
  • Non-limiting examples of alkynylene groups include, but are not limited to, 1,2-ethynylene (-CH ⁇ CH-), 1,1-propynylene (-CH(C ⁇ CH)-), 1,3- Propylene (-C ⁇ C-CH 2 -), 1,4-butylene (-C ⁇ CCH 2 CH 2 -) and 1,5-butylene (-C ⁇ CCH 2 CH 2 CH 2 -), etc. .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, Most preferably contain 3 to 7 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, Alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Divalent cycloalkyl refers to a cycloalkyl group as defined above having 2 residues derived by removing two hydrogen atoms from the same atom or two different atoms on the parent ring.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2) heteroatoms excluding ring moieties of -OO-, -OS- or -SS- and the remaining ring atoms are carbon.
  • the heterocyclyl ring preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 7 ring atoms , of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl, azepanyl Base et al.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, Alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • groups independently selected from alkyl, Alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl,
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O )m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common
  • the pi-electron system of the yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • a divalent heterocyclyl group refers to a heterocyclyl group as defined above having 2 residues derived by removing two hydrogen atoms from the same atom or two different atoms on the parent ring.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 5 to 10 membered, more preferably 5 to 7 membered , even more preferably phenyl and naphthyl, most preferably phenyl.
  • Aryl groups can be fully aromatic groups such as phenyl, naphthyl, anthracenyl, phenanthryl, and the like.
  • Aryl groups may also contain a combination of aromatic and non-aromatic rings, eg, indene, fluorene, acenaphthene, and the like.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane amino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Thio, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • Divalent aryl refers to an aryl group as defined above having 2 residues derived by removing two hydrogen atoms from the same atom or two different atoms on the parent ring.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, more preferably 5 to 7 membered, even more preferably 5 or 6 membered, eg thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, tri azolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycly
  • Divalent heteroaryl refers to a heteroaryl group as defined above having 2 residues derived by removing two hydrogen atoms from the same atom or two different atoms on the parent ring.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen, wherein alkyl is as defined above.
  • Non-limiting examples include chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2-fluoropropyl, 2-fluoropropan-2-yl, 2, 2,2-trifluoroethyl, 1,1-difluoroethyl, 1,3-difluoro-2-methylpropyl, 2,2-difluorocyclopropyl, (trifluoromethyl)cyclopropyl , 4,4-difluorocyclohexyl and 2,2,2-trifluoro-1,1-dimethyl-ethyl.
  • haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen, wherein alkoxy is as defined above.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • amino means -NH 2.
  • nitro refers to -NO 2.
  • cyano refers to -CN.
  • hydroxy refers to the -OH group.
  • thiol refers to the -SH group.
  • hydroxyalkyl or "hydroxyalkyl” refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxyalkoxy or “hydroxyalkoxy” refers to an alkoxy group substituted with a hydroxy group, wherein alkoxy is as defined above.
  • acyl refers to -C(O)R", wherein R" refers to alkyl, cycloalkyl, alkenyl, alkynyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl are as defined above.
  • R refers to alkyl, cycloalkyl, alkenyl, alkynyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl are as defined above.
  • Non-limiting examples include acetyl, propionyl, butyryl, valeryl, hexanoyl, vinyl, acryloyl.
  • acylamino refers to -NHC (O) R "or -C (O) NH 2, wherein R" refers to an alkyl group, an alkenyl group, an alkynyl group, where the definition of an alkyl group, an alkenyl group, an alkynyl group as described above.
  • R refers to an alkyl group, an alkenyl group, an alkynyl group, where the definition of an alkyl group, an alkenyl group, an alkynyl group as described above.
  • Non-limiting examples include formamido, acetamido, propionamido, butyrylamido, valeramido, hexanoamido, vinylamido, acrylamido.
  • esters refers to -C(O)OR", wherein R" refers to alkyl or cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
  • R refers to alkyl or cycloalkyl, wherein alkyl, cycloalkyl are as defined above.
  • Non-limiting examples include ethyl ester, propyl ester, butyl ester, pentyl ester, cyclopropyl ester, cyclobutyl ester, cyclopentyl ester, cyclohexyl ester.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • Combination medication refers to the simultaneous, sequential or sequential application of two or more drugs used for the purpose of treatment.
  • the present invention mainly adopts the following synthetic route and technical scheme.
  • Step 1 In an appropriate solvent, in the presence of a base, compound M1 is subjected to a nucleophilic substitution reaction with phenyl chloroformate to obtain compound M2; wherein, the solvent is preferably tetrahydrofuran, acetonitrile, dichloromethane, N,N- Dimethylformamide, toluene, N-methylpyrrolidone; the base is preferably triethylamine, N,N-diisopropylethylamine, DMAP and pyridine;
  • Step 2 In an appropriate solvent, compound M2 is formed into an intermediate state of isocyanate under the action of a base, and then reacts with compound M3 to form a urea to obtain compound M4;
  • the solvent is preferably tetrahydrofuran, acetonitrile, dichloromethane, N,N - dimethylformamide, toluene, N-methylpyrrolidone;
  • the base is preferably triethylamine, N,N-diisopropylethylamine, DMAP and pyridine;
  • Step 3 compound M4 and compound M5 obtain the compound of general formula (I) through nucleophilic substitution reaction, coupling reaction, condensation reaction, Suzuki reaction, Buchwald reaction or Mitsunobu reaction;
  • J 1 and J 2 are each independently selected from halogen, hydroxy, amino, alkynyl and carboxyl; Y, U, Y 1 , Y 2 , Y 3 , Y 4 , A, E, L, R 1 , R 2 are as shown in as defined in formula (I).
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention may be an acid addition salt or a base addition salt.
  • the acid may be an inorganic acid, including but not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; or may be an organic acid, including but not limited to: citric acid, maleic acid, oxalic acid, formic acid, acetic acid, propionic acid, valeric acid , glycolic acid, benzoic acid, fumaric acid, trifluoroacetic acid, succinic acid, tartaric acid, lactic acid, glutamic acid, aspartic acid, salicylic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, p-benzenesulfonic acid .
  • the base can be an inorganic base, including but not limited to: sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; or can be an organic base, including but not limited to: ammonium hydroxide, triethylamine, N,N- Dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethyl amine, arginine, or lysine; or can be alkali metal salts, including but not limited to: lithium, potassium, and sodium salts; or can be alkaline earth metal salts, including but not limited to: barium, calcium, and magnesium salts; or can be For transition metal salts, including but not limited to zinc salts; or other metal salts, including but not limited to: sodium hydrogen phosphate and disodium hydrogen phosphate.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is prepared into a clinically usable pharmaceutical composition.
  • its pharmaceutical preparations include but are not limited to oral preparations such as tablets, gels, soft/hard capsules, emulsions, dispersible powders, granules, water/oil suspoemulsions; injections Including intravenous injections, intramuscular injections, intraperitoneal injections, rectal suppositories, intracranial injections, these dosage forms can be aqueous solutions or oily solutions; topical preparations include creams, ointments, gels, water/oil solutions and packs formulations; inhalation dosage forms include fine powders, liquid aerosols, and various dosage forms suitable for implantation in vivo.
  • the pharmaceutical composition of the present invention may be added with a pharmaceutically acceptable carrier, diluent or excipient as required.
  • a pharmaceutically acceptable carrier diluent or excipient as required.
  • Carriers for solid oral formulations include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, cyclodextrin, and vitamin E-PEG1000, a molecular carrier that promotes intestinal absorption.
  • Oral preparations may incorporate suitable coloring, sweetening, flavoring and preservative agents.
  • Carriers for injection include, but are not limited to, cyclodextrin, polyethylene glycol, glycerol and medicinal vegetable oils.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , the patient's diet, administration time, administration mode, excretion rate, combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dose of the compound of the present invention or the type of pharmaceutically acceptable salt can be determined according to traditional treatment options to verify.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt can be used alone in the above-mentioned cancer treatment, or can be used in combination with conventional clinical radiotherapy, chemotherapy, immunotherapy, tumor vaccine, fusion tumor Virus, RNAi, adjuvant cancer therapy, and one or more combination therapy of bone marrow transplantation and stem cell transplantation, including but not limited to the following antitumor drugs and treatments:
  • Alkylating agents such as cisplatin, cisplatin, oxaliplatin, chlorambucil, cyclophosphamide, nitrogen mustard, melphalan, temozolomide, busulfan, nitrosoureas.
  • Anti-tumor antibiotics such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, actinomycin, mitramycin
  • Anti-mitotic drugs such as vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, taxotere, Polo kinase inhibitors.
  • Antimetabolites and antifolates such as fluoropyrimidines, ranmethotrexate, cytarabine, azacitidine, decitabine, tetrexed, hydroxyurea, IDH1/IDH2 mutant inhibitors.
  • Topoisomerase inhibitors such as epipodophyllotoxin, camptothecin, irinotecan.
  • Cytostatic drugs such as anti-estrogen/anti-androgen drugs, such as tamoxifen, fulvestrant, toremifene, raloxifene, dronoxifene, iodoxifene, bicalutamide , flutamide, nilutamide, cyproterone acetate;
  • LHRH antagonists or LHRH agonists such as goserelin, leuprolide, and buserelin, progestins such as megestrol acetate;
  • Aromatase inhibitors such as anastrozole, letrozole, vorozole, exemestane, 5a-reductase inhibitors such as finasteride.
  • Anti-invasive agents such as c-Src kinase family inhibitors, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or heparanase-like antibodies.
  • Inhibitors of growth function such as growth factor antibodies and growth factor receptor antibodies such as anti-HER2 antibody trastuzumab, anti-EGFR antibody panitumumab, anti-EGFR antibody cetuximab, etc.; this inhibitor also Including other tyrosine kinase inhibitors and inhibitors of serine/threonine kinases such as Ras/Raf signaling inhibitors, cell signaling inhibitors of MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors , PI3 kinase inhibitor, JAKs and STAT3 inhibitor, CSF-1R kinase inhibitor, IGF receptor kinase inhibitor, Aurora kinase inhibitor, NTRKA/B/C kinase inhibitor.
  • growth factor antibodies and growth factor receptor antibodies such as anti-HER2 antibody trastuzumab, anti-EGFR antibody panitumumab, anti-EGFR antibody cetuximab, etc.
  • this inhibitor also
  • Anti-angiogenic agents such as bevacizumab, an agent that inhibits the action of vascular endothelial growth factor, and VEGF receptor tyrosine kinase inhibitors.
  • HDACi histone deacetylase inhibitors
  • DNMTi DNA methyltransferase inhibitors
  • histone acetyltransferase inhibitors histone demethylase inhibitors inhibitors
  • histone methyltransferase inhibitors etc.
  • PARPi Poly(ADP-ribose) polymerase inhibitors
  • Tumor immunotherapy methods include any in vitro and in vivo method that increases the immunogenicity of tumor cells in a patient.
  • cytokines IL-2, IL-4 or GM-CSF for transfection methods to reduce T cell inefficiency such as anti-PD-1/PD-L monoclonal antibodies; use of transfected immune cells such as cytokine-transfected trees Methods of dendritic cells; methods of using cytokine-transfected tumor cell lines; reduction of immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, or dendritic cells expressing indoleamine 2,3-deoxygenase Methods of cell function; methods of cancer vaccines composed of agonists that enhance the activity of immune cells such as STING and tumor-associated antigen proteins or peptides.
  • Tumor gene therapy such as CRISPR-Cas 9, RNAi, gene transduction.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured using a liquid chromatography mass spectrometer (Thermo, Ultimate 3000/MSQ).
  • HPLC a high pressure liquid chromatograph (Agilent 1260Infinity, Gemini C18250 ⁇ 4.6mm, 5u chromatographic column).
  • TLC Thin-layer chromatography
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or purchased from Shanghai Darui Fine Chemicals Co., Ltd., Shanghai Titan Technology Co., Ltd., Shanghai Runjie Chemical Reagent Co., Ltd., TCI, Aldrich Chemical Company.
  • the experimental methods that do not specify specific conditions in the examples are usually in accordance with conventional conditions, or in accordance with conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • Step 1 Preparation of 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (1a)
  • reaction solution was poured into 200 ml of saturated brine, acetic acid (1.4 equiv.) was added dropwise, extracted with dichloromethane 200 ml ⁇ 2, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 190 g of crude product were obtained as pale yellow oil.
  • reaction solution was cooled to room temperature, slowly poured into saturated aqueous sodium bicarbonate solution (150ml), extracted with ethyl acetate (100ml ⁇ 2), the organic phase was washed twice with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to obtain 1.8 g of a crude product as a yellow solid.
  • the product was directly used in the next reaction without purification.
  • Step 8 (2- ⁇ 2-[1-(4-Amino-phenyl)-1H-benzimidazol-5-yloxy]-ethoxy ⁇ -ethyl)-carbamic acid tert-butyl ester (1h ) preparation
  • Step 9 (4- ⁇ 5-[2-(2-tert-butoxycarbonylamino-ethoxy)ethoxy]benzimidazol-1-yl ⁇ -phenyl)-carbamic acid phenyl ester (1i) preparation
  • Phenyl chloroformate (3.64 g, 23.25 mmol) (diluted with 10 ml of tetrahydrofuran) was slowly added dropwise to the above solution, and the temperature was controlled at -5°C to 0°C during the process. After the dropwise addition was completed, the ice-salt bath was removed, and the temperature was slowly raised to room temperature and stirred for 1 hour. The reaction solution was poured into 200 ml of water, extracted with 150 ml of ethyl acetate, the organic phase was washed with 150 ml of saturated brine x 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.0 g of crude product.
  • Step 10 ⁇ 2-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazole-5 Preparation of -yloxy)-ethoxy]-ethyl-carbamic acid tert-butyl ester (1j)
  • Step 11 1-(4- ⁇ 5-[2-(2-Amino-ethoxy)-ethoxy]-benzimidazol-1-yl ⁇ -phenyl)-3-(5-tert-butyl Preparation of -2H-pyrazol-3-yl)-urea (1k)
  • Step 12 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 2-[2-(2,6-dioxopiperidine- 3-yl)-1-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ -ethoxy)-benzimidazol-1-yl
  • reaction solution was cooled to room temperature, poured into 60 ml of water, extracted with ethyl acetate 150 ml ⁇ 2, the organic phase was washed with saturated brine 100 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the preparation method is the same as in Example 1, except that ethanolamine is used instead of 2-(2-amino-ethoxy)-ethanol in step 2 to give 1-(5-tert-butyl-2H-pyrazol-3-yl) -3-[4-(5- ⁇ 2-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-iso Indol-4-ylamino]-ethoxy ⁇ benzimidazol-1-yl)-phenyl]-urea.
  • the preparation method was the same as that of Example 1, except that 2-[2-(2-amino-ethoxy)ethoxy]ethanol was used instead of 2-(2-amino-ethoxy)-ethanol in step 2 to obtain 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 2-[2-(2,6-dioxo-piperidine -3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)ethoxy]-benzimidazole-1 -yl ⁇ -phenyl)-urea.
  • the preparation method was the same as that of Example 1, except that 1-amino-3,6,9-trioxa-11-undecanol was used instead of 2-(2-amino-ethoxy)-ethanol in step 2 to obtain 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 2-[2-(2- ⁇ 2-[2-(2,6-dioxo -Piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)ethoxy]-ethoxy yl ⁇ -benzimidazol-1-yl)-phenyl]-urea.
  • the preparation method was the same as in Example 1, except that ethanolamine was used in place of 2-(2-amino-ethoxy)-ethanol in step 2, and 3-amino-5-tert-butylisoxazole was used in place of 5-tert-butylisoxazole in step 10.
  • the preparation method is the same as in Example 1, except that 3-amino-5-tert-butylisoxazole is used instead of 5-tert-butyl-2H-pyrazol-3-ylamine in step 10 to give 1-(5-tert-butylamine yl-isoxazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 2-[2-(2,6-dioxo-piperidin-3-yl)-1,3-di Oxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)benzimidazol-1-yl]-phenyl ⁇ -urea.
  • Example 8 1-(5-tert-Butyl-isoxazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 2-[2-(2,6-dioxo- Piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)ethoxy]benzimidazole- Preparation of 1-yl ⁇ -phenyl)-urea (8)
  • the preparation method is the same as in Example 4, except that 3-amino-5-tert-butylisoxazole is used instead of 5-tert-butyl-2H-pyrazol-3-ylamine in step 10 to give 1-(5-tert-butyl yl-isoxazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 2-[2-(2,6-dioxo-piperidin-3-yl)-1, 3-Dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)ethoxy]benzimidazol-1-yl ⁇ -phenyl)-urea .
  • the preparation method is the same as in Example 5, except that 3-amino-5-tert-butylisoxazole is used instead of 5-tert-butyl-2H-pyrazol-3-ylamine in step 10 to give 1-(5-tert-butyl yl-isoxazol-3-yl)-3-[4-(5- ⁇ 2-[2-(2- ⁇ 2-[2-(2,6-dioxo-piperidin-3-yl) -1,3-Dioxo-2,3-dihydro-1H-isoindol-4-ylamino]ethoxy ⁇ ethoxy)ethoxy]ethoxy ⁇ benzimidazol-1-yl )phenyl]urea.
  • the preparation method is the same as in Example 1, except that 4-fluorophthalic anhydride is used instead of 3-fluorophthalic anhydride in step 1 to give 1-(5-tert-butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 2-[2-(2,6-dioxopiperidin-3-yl)-1-1,3-dioxo-2,3-dihydro-1H-iso Indol-5-ylamino]-ethoxy ⁇ -ethoxy)-benzimidazol-1-yl]-phenyl ⁇ -urea.
  • reaction solution Cool the reaction solution to room temperature, pour the reaction solution into 250ml of saturated brine, adjust the pH to 5-6 with HCl, extract the aqueous phase with 80ml ⁇ 2 of ethyl acetate, combine the organic phases and wash twice with saturated brine, dry Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 5 g of crude product.
  • Step 2 2- ⁇ 2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4- Preparation of amino]-ethoxy ⁇ -ethylmethanesulfonate (11b)
  • Step 3 4-[2-(2-Azidoethoxy)-ethylamino]-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3- Preparation of diketone (11c)
  • Step 4 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 2-[1-(2- ⁇ 2-[2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]-ethoxy ⁇ -ethyl)-1H-[ Preparation of 1,2,3]Triazol-4-ylmethoxy]-ethoxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (11)
  • reaction solution was cooled to room temperature, poured into 100 ml of water, a solid was precipitated, filtered, and the filter cake was washed with 100 ml of water.
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 5-[1-(2- ⁇ 2-[2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]-ethoxy ⁇ -ethyl)-1H-[ Preparation of 1,2,3]Triazol-4-yl]-pentyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (12)
  • reaction solution was cooled to room temperature, poured into 100 ml of water, a solid was precipitated, filtered, and the filter cake was washed with 100 ml of water.
  • the preparation method is the same as in Example 1, except that 5-amino-1-pentanol is used instead of 2-(2-amino-ethoxy)-ethanol in step 2 to give 1-(5-tert-butyl-2H- Pyrazol-3-yl)-3-[4-(5- ⁇ 5-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 -Dihydro-1H-isoindol-4-ylamino]-pentyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea.
  • Example 14 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ [2-(2,6-dioxopiperidine -3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-methyl-amino ⁇ -ethoxy)-ethoxy]-benzo Preparation of imidazol-1-yl ⁇ -phenyl)-urea (14)
  • reaction solution was poured into 50 ml of saturated brine, acetic acid (1.4 equiv.) was added dropwise, extracted with dichloromethane 50 ml ⁇ 2, the organic phase was washed twice with saturated brine, twice with saturated aqueous sodium bicarbonate solution, and anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure to give 1.15 g of product (14c).
  • Step 4 - Step 8 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ [2-(2,6-dioxo (piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-methyl-amino ⁇ -ethoxy)-ethoxy] -Preparation of benzimidazol-1-yl ⁇ -phenyl)-urea (14)
  • the preparation method was the same as that of Example 1, Step 8-Step 12, except that compound 14c was used in place of 2-(2-tert-butoxycarbonylamino-ethoxy)-ethylmethanesulfonate (1c) in Example 1, Step 8.
  • the preparation method was the same as in Example 16 below, except that 5-hexyn-1-ol was used in place of 2-(prop-2-yn-1-yloxy)ethan-1-ol 2-(propion) in step 2 -2-yn-1-yloxy)ethan-1-ol to give 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 6-[2 -(2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-hex-5-ynyloxy ⁇ -Benzimidazol-1-yl)-phenyl]-urea (15).
  • Step 1 Preparation of 4-bromo-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione (16a)
  • reaction solution was poured into 100 ml of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane 100 ml ⁇ 2, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 8.49 g of crude product were obtained as pale red oil. The product was directly used in the next reaction without purification.
  • Step 4 Preparation of ⁇ 4-[5-(2-Prop-2-ynyloxy-ethoxy)-benzimidazol-1-yl]-phenyl ⁇ -carbamic acid phenyl ester (16d)
  • Step 6 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 3-[2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)-benzimidazole-1
  • -yl]-phenyl ⁇ -urea (16)
  • Step 2 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 3-[2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)-ethoxy
  • the preparation method was the same as that of Example 17, except that triethylene glycol was used instead of diethylene glycol in step 1 to give 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5 - ⁇ 2-[2-(2- ⁇ 3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-iso Indol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)-ethoxy]-ethoxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (18).
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 6-[2-(2,6-dioxopiperidin-3-yl) )-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-hexyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (21) preparation
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 3-[2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-propoxy ⁇ -ethoxy)-benzimidazol-1-yl]- Preparation of Phenyl ⁇ -urea (22)
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 3-[2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-propoxy ⁇ -ethoxy)-ethoxy]-benzene
  • 2-(2- ⁇ 3-[2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-propoxy ⁇ -ethoxy)-ethoxy]-benzene Preparation of imidazol-1-yl ⁇ -phenyl)-urea (23)
  • the preparation method was the same as in Example 16, except that 6-heptynol was used instead of 2-(prop-2-yn-1-yloxy)ethan-1-ol in step 2, and 3-(4-bromo- 1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (26b) (prepared as described in Example 26 below) replaces 4- Bromo-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione (16a) to give 1-(5-tert-butyl-2H-pyrazole-3 -yl)-3-[4-(5- ⁇ 7-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindone dol-4-yl]-hept-6-ynyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea
  • the preparation method was the same as that of Example 16, except that 5-hexyn-1-ol was used instead of 2-(prop-2-yn-1-yloxy)ethan-1-ol in step 2, and 3-(4 -Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (26b) in place of 4-bromo-2-(2, 6-Dioxopiperidin-3-yl)-isoindole-1,3-dione (16a) to give 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[ 4-(5- ⁇ 6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]- Hex-5-ynyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (25).
  • Step 2 Preparation of 3-(4-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (26b)
  • Step 3 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 3-[2-(2,6-dioxopiperidine- 3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)-benzimidazol-1-yl] Preparation of -phenyl ⁇ -urea (26)
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[5-(1- ⁇ 5-[2-(2,6-dioxo Piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-pent-4-ynyl ⁇ -1H-[1,2,3]triazole
  • -4-yl)-pentyloxy]-benzimidazol-1-yl ⁇ -phenyl)-urea (29)
  • reaction solution was cooled to room temperature, poured into 100 ml of water, a solid was precipitated, filtered, and the filter cake was washed with 100 ml of water.
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-[4-(5- ⁇ 6-[2-(2,6-dioxopiperidin-3-yl) )-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-hexyloxy ⁇ -benzimidazol-1-yl)-phenyl]-urea (30) preparation
  • the preparation method is the same as that of Example 2, except that Compound (31) is used instead of Compound (1) in Example 2 to obtain 1-[4-(5- ⁇ 7-[2-(1-benzyl-2,6 -Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-heptyloxy ⁇ -benzimidazol-1-yl)-benzene yl]-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea (32).
  • Step 1 1-(5-tert-Butyl-2H-pyrazol-3-yl)-3-(4- ⁇ 5-[2-(2- ⁇ 3-[2-(2,6-dioxo Piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-propoxy ⁇ -ethoxy)-ethoxy]-benzimidazole- Preparation of 1-yl ⁇ -phenyl)-urea (33)
  • Example 34 1-(5-tert-butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 3-[2-(2,6-dioxopiperidine- 3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)-benzimidazol-1-yl] - Preparation of tert-butyl phenyl ⁇ -1-carboxylate-urea (34)
  • Example 35 1-(5-tert-butyl-1-carboxylate tert-butyl-1H-pyrazol-3-yl)-3- ⁇ 4-[5-(2- ⁇ 3-[2-(2, 6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-prop-2-ynyloxy ⁇ -ethoxy)- Preparation of Benzimidazol-1-yl]-phenyl ⁇ -1-carboxylate tert-butyl urea (35)
  • reaction solution was cooled to room temperature, then poured into 100 ml of water, extracted with 50 ml of ethyl acetate ⁇ 2.
  • the organic phase was washed with 100 ml of saturated brine ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 38 1-[4-(5- ⁇ 7-[2-(1-benzyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-Isoindol-4-yl]-hept6-ynyloxy ⁇ -benzimidazol-1-yl)-phenyl]-3-(5-tert-butyl-2H-pyrazol-3-yl) - Preparation of urea (38)
  • Example 2 The same preparation method as in Example 2, except that Compound (24) was used instead of Compound (1) in Example 2 to give 1-[4-(5- ⁇ 7-[2-(1-benzyl-2,6 -Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-hept6-ynyloxy ⁇ -benzimidazol-1-yl )-phenyl]-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea (38).
  • Example 39 Benzoic acid 3-(4- ⁇ 2-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-phenyl]- 1H-benzimidazole-5-(oxy)-ethoxy]-ethylamino ⁇ -1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6- Preparation of dioxo-piperidin-1-ylmethyl ester (39)
  • Step 1 3-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiperidin-1-ylmethylbenzene Preparation of formate (39a)
  • reaction solution was poured into 100 ml of water, extracted with 150 ml of ethyl acetate, the organic phase was washed with 150 ml of saturated brine x 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2 g of crude product.
  • Step 2 Benzoic acid 3-(4- ⁇ 3-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-phenyl]- 2,3-Dihydro-1H-benzimidazol-5-yloxy)-ethoxy]-propyl ⁇ -1,3-dioxo-1,3-dihydro-isoindole-2- yl)-2,6-dioxopiperidin-1-ylmethyl ester (39)
  • reaction solution was cooled to room temperature, poured into 60 ml of water, extracted with ethyl acetate 150 ml ⁇ 2, the organic phase was washed with saturated brine 100 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the preparation method is the same as that of Example 39, except that chloromethyl pivalate is used instead of chloromethyl benzoate in step 1 of Example 39 to obtain 2,2-dimethylpropionic acid 3-(4- ⁇ 2-[2 -(1- ⁇ 4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazol-5-yloxy)-ethoxy (40) .
  • the preparation method is the same as that of Example 39, except that chloromethyl isobutyrate is used instead of chloromethyl benzoate in step 1 of Example 39 to obtain 3-(4- ⁇ 2-[2-(1- ⁇ 4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazole-5-(oxy)-ethoxy]-ethylamino ⁇ -1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo-piperidin-1-ylmethyl ester (41).
  • the preparation method is the same as that of Example 39, except that chloromethyl butyrate is used instead of chloromethyl benzoate in step 1 of Example 39 to obtain 3-(4- ⁇ 2-[2-(1- ⁇ 4-[ 3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazole-5-(oxy)-ethoxy]-ethylamino ⁇ -1 ,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo-piperidin-1-yl methyl ester (42).
  • the preparation method is the same as that of Example 39, except that chloromethyl octoate is used instead of chloromethyl benzoate in step 1 of Example 39 to obtain 3-(4- ⁇ 2-[2-(1- ⁇ 4-[3- (5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazole-5-(oxy)-ethoxy]-ethylamino ⁇ -1,3 -Dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo-piperidin-1-ylmethyl ester (43).
  • the preparation method was the same as that of Example 39, except that chloromethyl benzoate in step 1 of Example 39 was replaced with isopropyl chloromethyl carbonate to obtain 3-(4- ⁇ 2-[2-(1- ⁇ 4-[ 3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazole-5-ethoxy)-ethoxy]-ethylamino ⁇ -1 , 3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiperidin-1-ylmethylisopropyl carbonate (44).
  • Step 2 3-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiperidin-1-ylmethyl ( Preparation of S)-2-tert-butoxycarbonylamino-3-methylbutyrate (45b)
  • reaction solution was poured into 100 ml of water, and extracted with 50 ml x 2 of ethyl acetate.
  • organic phase was washed with saturated brine 100ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 3-(4- ⁇ 2-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-]-phenyl ⁇ - 1H-benzimidazol-5-yloxy)-ethoxy]-ethylamino ⁇ -1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6 - Preparation of dioxopiperidin-1-ylmethyl (S)-2-tert-butoxycarbonylamino-3-methylbutyrate (45)
  • reaction solution was cooled to room temperature, poured into 100 ml of water, and extracted with 50 ml of ethyl acetate ⁇ 2.
  • the organic phase was washed with saturated brine 100ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was poured into 100 ml of water, extracted with 150 ml of dichloromethane, the organic phase was washed with 150 ml of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.75 g of oil.
  • Step 2 3-(4-Fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiperidin-1-ylmethyl[ Preparation of 1,4']bispiperidinyl-1'-carboxylate (48b)
  • reaction solution was poured into 100 ml of water, extracted with 150 ml of ethyl acetate, the organic phase was washed with 150 ml of saturated brine x 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g of crude product.
  • Step 3 3-(4- ⁇ 2-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-]-phenyl ⁇ -1H-benzo Imidazol-5-yloxy)-ethoxy]-ethylamino ⁇ -1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiper
  • reaction solution was cooled to room temperature, poured into 60 ml of water, extracted with ethyl acetate 150 ml ⁇ 2, the organic phase was washed with saturated brine 100 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 3-(4-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxopiperidin-1-ylmethyl 2,2- Preparation of Dimethylpropionate (49a)
  • reaction solution was poured into 100 ml of water, extracted with 150 ml of ethyl acetate, the organic phase was washed with saturated brine 150 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of crude product.
  • Step 2 3- ⁇ 4-[7-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazole -5-yloxy)-heptan-1-yl]-1-oxo-1,3-dihydro-isoindol-2-yl ⁇ -2,6-dioxopiperidin-1-ylmethyl
  • Example 49 The preparation method of Example 49 was the same as that of Example 49, except that 4-bromo-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione (16a) was used instead of Example 49 3-(4-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (26b) from step 1 to give 3- ⁇ 4 -[7-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido]-phenyl]-1H-benzimidazol-5-yloxy) -Hept-1-yl]-1,3-dioxo-1,3-dihydro-isoindol-2-yl ⁇ -2,6-dioxopiperidin-1-ylmethyl 2,2 - Dimethylpropionate (50).
  • Example 49 The preparation method of Example 49 was the same as that of Example 49, except that 4-bromo-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione (16a) was used instead of Example 49 3-(4-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (26b) from step 1 with 1-(5 -tert-Butyl-2H-pyrazol-3-yl)-3- ⁇ 4-[5-(2-prop-2-ynyloxy-ethoxy)-benzimidazol-1-yl]-phenyl ⁇ -urea (16e) in place of 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5-hept-6-ynyloxy-benzimidazole- 1-yl)-phenyl]-urea (49b) to give 3-(4- ⁇
  • Step 1 3-(4- ⁇ 3-[2-(1- ⁇ 4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-ureido-phenyl ⁇ -1H-benzene Zimidazol-5-yloxy)-ethoxy]-prop-1-ynyl ⁇ -1-oxo-1,3-dihydro-isoindol-2-yl)-2,6-dioxo
  • Example 54 7-((1-(4-(3-(3-(tert-butyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-benzo[d]imidazole-5 -yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)heptamide (54)
  • Step 1 Preparation of 7-[1-(4-Amino-phenyl)-1H-benzimidazol-5-yloxy]-heptanoic acid ethyl ester (54a)
  • Step 2 Preparation of 7-[1-(4-phenoxycarbonylamino-phenyl)-1H-benzimidazol-5-yloxy]-heptanoic acid ethyl ester (54b)
  • reaction solution was poured into 200 ml of saturated brine, the aqueous phase was extracted with 50 ml of ethyl acetate ⁇ 2, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3.1 g of a solid crude product product.
  • Step 4 7-(1- ⁇ 4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yloxy Preparation of )-heptanoic acid (54d)
  • Step 5 7-((1-(4-(3-(3-(tert-butyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-benzo[d]imidazole-5 -yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)heptamide (54)
  • the preparation method was the same as that of Example 54, except that ethyl bromoacetate was used instead of ethyl 7-bromoheptanoate in step 1, and 3-amino-5-tert-butylisoxazole was used instead of 5-tert-butyl- 2H-pyrazol-3-ylamine to give 2-(1- ⁇ 4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl ⁇ -1H-benzo Imidazol-5-yloxy)-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl ]-acetamide (57).
  • Step 1 Preparation of (2-benzyloxy-ethoxy)-acetic acid tert-butyl ester (58a)
  • Step 4 Preparation of ⁇ 2-[1-(4-Amino-phenyl)-1H-benzimidazol-5-yloxy]-ethoxy ⁇ -acetic acid tert-butyl ester (58d)
  • Step 5 Preparation of ⁇ 2-[1-(4-Phenoxycarbonylamino-phenyl)-1H-benzimidazol-5-yloxy]-ethoxy ⁇ -acetic acid tert-butyl ester (58e)
  • Step 7 [2-(1- ⁇ 4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yloxy )-ethoxy]-acetic acid (58g) preparation
  • Step 8 2-[2-(1- ⁇ 4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yl Oxy)-ethoxy]-N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4- Preparation of yl]-acetamide (58)
  • reaction solution was poured into 60 ml of water, extracted with ethyl acetate 50 ml ⁇ 2, the organic phase was washed with saturated brine 50 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 3-Hydroxy-2-methyl-benzoic acid methyl ester (5g, 30mmol) was dissolved in 50ml DMF, imidazole (5.1g, 75mmol) was added at room temperature, the reaction system was cooled to 0°C to 5°C, and tertiary Butyldimethylsilyl chloride (5 g, 33 mmol) was dropped, and the mixture was stirred at room temperature for 16 hours.
  • reaction solution was poured into 500 ml of saturated brine, the aqueous phase was extracted with 80 ml of ethyl acetate ⁇ 2, the combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8 g of crude product.
  • Step 3 3-[4-(tert-Butyl-dimethyl-silyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6 - Preparation of diketone (59c)
  • Step 4 Preparation of 3-(4-Hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (59d)
  • reaction solution was poured into 80 ml of saturated brine, extracted with 50 ml of ethyl acetate ⁇ 2, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 583 mg of solid product.
  • Step 6 [2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxy]-acetic acid (59f ) preparation
  • Step 7 Preparation of [1-(4-Amino-phenyl)-1H-benzimidazol-5-yloxy]-acetic acid tert-butyl ester (59 g)
  • Step 8 Preparation of [1-(4-phenoxycarbonylaminophenyl)-1H-benzimidazol-5-yloxy]-acetic acid tert-butyl ester (59h)
  • reaction solution was poured into 80 ml of water, extracted with 80 ml of ethyl acetate, the organic phase was washed with saturated brine 80 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.5 g of crude product.
  • Step 9 (1- ⁇ 4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yloxy)- Preparation of tert-butyl acetate (59i)
  • Step 10 (1- ⁇ 4-[3-(5-tert-Butyl-2H-pyrazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yloxy)- Preparation of acetic acid (59j)
  • Example 60 7-((1-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-1H-benzo[d]imidazol-5-yl )oxy)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)methyl)heptamide (60) preparation
  • Step 1 Preparation of 3-(5-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (60a)
  • Step 2 Preparation of 2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (60b)
  • 3-(5-Bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (60a) (9.6 g, 29.6 mmol), cyanide Zinc (2.1 g, 17.8 mmol) and tetrakistriphenylphosphine palladium (3.4 g, 3 mmol) were placed in 70 ml of DMF, and the temperature was raised to 100° C. for 16 hours.
  • reaction solution was lowered to room temperature, then poured into 400 ml of water, stirred at room temperature for 10 minutes, filtered, washed with water, and the solid was dried by blasting (60° C.) for 12 hours.
  • Step 3 Preparation of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (60c)
  • Step 4 7-(1- ⁇ 4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl ⁇ -1H-benzimidazol-5-yloxy) -Heptanoic acid [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide (60) preparation
  • Step 2 2-(4-Bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-iso Preparation of indol-5-yl)methyl)-2,2-difluoroacetamide (62b)
  • reaction solution was poured into 100 ml of water, and extracted with 150 ml of ethyl acetate ⁇ 2.
  • Step 4 Preparation of [4-(5-Pent-4-ynyloxy-benzimidazol-1-yl)-phenyl]-carbamic acid phenyl ester (62d)
  • Step 6 2-(4-(5-((1-(4-(3-(3-(tert-butyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-benzo [d]Imidazol-5-yl)oxy)pent-1-yn-1-yl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1- Preparation of oxoisoindol-5-yl)methyl)-2,2-difluoroacetamide (62)
  • Example 62 Identical to the preparation of Example 62, except that bromopropyne was used in place of 4-pentyn-1-ol (62a) in step 1 to give 2-(4-(3-((1-(4-(3- (3-(tert-Butyl)-1H-pyrazol-5-yl)ureido)phenyl)-1H-benzo[d]imidazol-5-yl)oxy)prop-1-yn-1-yl )phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)methyl)-2,2-difluoroethyl amide (65).
  • N-(2-chloroethyl)morpholine hydrochloride (14.8g, 0.08mol) and hydrazine hydrate (20g, 0.4mol) were dissolved in ethanol (250ml), and the reaction system was heated to 90 °C for reaction 4 hours. TLC detected that the reaction was complete, concentrated under reduced pressure, the residue was added with 100 ml of water and concentrated under reduced pressure again (repeated three times) to obtain crude (2-morpholin-4-yl-ethyl)-hydrazine.
  • step 1 (2-morpholin-4-yl-ethyl)-hydrazine (0.08 mol) and cyanopinazone (10 g, 0.08 mol) obtained in step 1 were dissolved in 200 ml of ethanol, and 0.2 ml of concentrated hydrochloric acid, and the reaction system was heated to 90°C for 12 hours. The reaction was completed as detected by TLC, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane/methanol) to obtain 8 g of crude product.
  • Step 3 5-((1-(4-(3-(3-(tert-butyl)-1-(2-morpholinoethyl)-1H-pyrazol-5-yl)ureido)phenyl) -1H-Benzo[d]imidazol-5-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl ) preparation of valeramide (66)
  • reaction solution was concentrated, 100 ml of water was added, extracted with ethyl acetate (100 ml ⁇ 3), the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.2 g of oil.
  • 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester.
  • Step 2 Preparation of 4-(5-Amino-3-tert-butyl-pyrazol-1-yl)-piperidine-1-carboxylate tert-butyl ester (67b)
  • tert-butyl 4-hydrazino-piperidine-1-carboxylate obtained in step 1 (11.2 g, 0.052 mol) and cyanopinazone (purchased from TCI) (11.68 g, 0.063 mol) were dissolved in ethanol (150 ml) middle.
  • 1.3 g of concentrated hydrochloric acid was added at room temperature, and the temperature was raised to 90° C. to react for 8 hours. After TLC detected that the reaction was complete, the reaction solution was cooled to 0-5° C., a solid was precipitated, suction filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 4-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-piperidine-1-carboxylate tert-butyl ester ( 67c) Preparation
  • reaction solution was poured into water (50ml), extracted with ethyl acetate (50ml ⁇ 3), the organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 350mg 4-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester as an oil.
  • Step 4 4-(3-tert-Butyl-5- ⁇ 3-[4-(5-methoxy-benzimidazol-1-yl)-phenyl]-ureido ⁇ -pyrazol-1-yl Preparation of )-piperidine-1-carboxylic acid tert-butyl ester (67d)
  • Step 6 5-[4-(3-tert-Butyl-5- ⁇ 3-[4-(5-methoxy-benzimidazol-1-yl)-phenyl]-ureido]-pyrazole- Preparation of 1-yl)-piperidin-1-yl]-pentanoic acid ethyl ester (67f)
  • reaction solution was cooled to room temperature, poured into 100 ml of water, and extracted with 50 ml of ethyl acetate ⁇ 2.
  • the organic phase was washed with saturated brine 100ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 5-[4-(3-tert-Butyl-5- ⁇ 3-[4-(5-methoxy-benzimidazol-1-yl)-phenyl]-ureido]-pyrazole- Preparation of 1-yl)-piperidin-1-yl]-pentanoic acid (67g)
  • reaction solution was poured into 100 ml of water, the pH of the aqueous solution of citric acid was adjusted to 5-6, and the mixture was extracted with 50 ml of ethyl acetate ⁇ 2.
  • the organic phase was washed with saturated brine 100 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 100 mg of yellow solid product.
  • Step 8 5-(4-(3-(tert-butyl)-5-(3-(4-(5-methoxy-1H-benzo[d]imidazol-1-yl)phenyl)ureido )-1H-pyrazol-1-yl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-4- Preparation of yl)valeryl (67)
  • TCFH N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate
  • 62 mg, 0.2 mmol was added at room temperature, the addition was completed, and the reaction was continued at room temperature for 16 hours.
  • the reaction solution was cooled to room temperature, poured into 100 ml of water, and extracted with 50 ml of ethyl acetate ⁇ 2.
  • the organic phase was washed with saturated brine 100ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 68 1-(3-(tert-butyl)-1-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-di oxoisoindol-4-yl)amino)ethoxy)ethyl)piperidin-4-yl)-1H-pyrazol-5-yl)-3-(4-(5-methoxy-1H) - Preparation of benzo[d]imidazol-1-yl)phenyl)urea (68)
  • Step 1 (2- ⁇ 2-[4-(3-tert-butyl-5- ⁇ 3-[4-(5-methoxy-benzimidazol-1-yl)-phenyl]-ureido] Preparation of -pyrazol-1-yl)-piperidin-1-yl]-ethoxy ⁇ -ethyl)-carbamic acid tert-butyl ester (68a)
  • Step 2 1-(2- ⁇ 1-[2-(2-Amino-ethoxy)-ethyl]-piperidin-4-yl ⁇ -5-tert-butyl-2H-pyrazol-3-yl )-3-[4-(5-Methoxy-benzimidazol-1-yl)-phenyl]-urea (68b) Preparation
  • step 1 (190 mg, 0.281 mmol) obtained in step 1 was dissolved in dichloromethane (6 ml), trifluoroacetic acid (3 ml) was added at room temperature, and the reaction was completed at room temperature for 1 hour. After the completion of the reaction was detected by TLC, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 ml of water, the pH was adjusted to 8-9 with ammonia water, and extracted with 50 ml of dichloromethane ⁇ 2. The organic phase was washed with saturated brine 100 ml ⁇ 2, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 60 mg of the product as a yellow solid.
  • Step 3 1-(3-(tert-Butyl)-1-(1-(2-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-di oxoisoindol-4-yl)amino)ethoxy)ethyl)piperidin-4-yl)-1H-pyrazol-5-yl)-3-(4-(5-methoxy-1H) - Preparation of benzo[d]imidazol-1-yl)phenyl)urea (68)

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Abstract

一种双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途。具体而言，涉及一种通式(I)所示的化合物及其制备方法，以及其用于降解和抑制FLT3酪氨酸蛋白激酶的用途，特别是在预防和/或治疗人类疾病包括癌症中的用途。所述化合物一端含有与E3泛素连接酶结合的基团，另一端含有与FLT3酪氨酸蛋白激酶结合的基团，通过连接子相连接，能够使得FLT3位于泛素连接酶的附近，其表现出广泛的药理活性与降解和抑制FLT3酪氨酸蛋白激酶的双功能相一致。其中，通式(I)中各基团的定义与说明书中的定义相同。

Description

双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途 技术领域
本发明属于医药领域，涉及一种新型双功能蛋白降解靶向嵌合体类化合物、其制备方法及含有其的药物组合物，以及其用于降解和抑制FLT3酪氨酸蛋白激酶的用途，包括用于治疗FLT3介导的信号通路异常引起的相关疾病的用途，特别是在癌症治疗中的用途。
背景技术
急性髓系白血病(AML)是一种异质恶性髓系血细胞癌症。患者体内功能失常的癌变白细胞不受控制地增生和积累，导致正常血细胞的生成受到影响。AML患者的5年存活率只有约25％，是所有类型白血病中最低的。过去40年，AML的临床治疗主要采用“7+3”化疗方法，无新的其它有效疗法。直到2017年以后才有几个靶向小分子药物获批应用于临床实践，但其长期临床效果有待进一步的临床验证。
FLT3基因属于III类受体酪氨酸激酶基因家族，其编码FMS样酪氨酸激酶3(FMS-like Tyrosine Kinase 3，FLT3/CD135)。人类FLT3蛋白由993个氨基酸组成，分子量约145Kd，其氨基酸序列与KIT、PDGFRA/B和CSF1R高度同源。当FLT3与其配体(FLT3L)结合到细胞外域时，诱导和形成同源二聚体，引起受体的自动磷酸化，进而激活受体激酶介导的一系列细胞效应分子如JAK-STAT、PI3K和MAPK的信号通路，参与骨髓造血细胞的凋亡、增殖和分化。
FLT3在大多数AML病人的癌细胞中表达，其中约30％的AML病人具有FLT3基因突变，主要包括内部串联重复突变(ITD，约25％)和酪氨酸激酶结构域的点突变(TKD，约5％)。FLT3 ITD和TKD突变都可以直接激活FLT3受体信号通路，转化和促进AML细胞的增殖。临床大数据发现相对于FLT3野生型表达的患者，携带FLT3-ITD/TKD基因突变的患者的预后更为恶劣，复发几率增加和复发后死亡风险升高，即便接受造血干细胞移植，其治疗后的癌症复发几率仍然会提高，这些患者急需有效的治疗来缓解疾病，延长生命。
FLT3作为一个潜在的药物靶点一直是科学界和制药工业界备受关注和药物开发的热点。尽管几十个靶向FLT3的药物分子包括大分子药物进行过或正在进行临床试验开发，但至今为止FDA仅批准米哚妥林(Midostaurin)和吉特替尼(Gilteritinib)两个小分子药物可应用于复发难治的FLT3-ITD或FLT3-TKD突变表达阳性的AML，而且限定米哚妥林必须与化药联用。此外这些传统小分子抑制剂往往在临床应用过程中病人快速产生FLT3耐药突变如N676K、Y842C/H、D835H/Y/V和F691L/I，因此临床上急需更好的靶向FLT3的新型药物。
传统小分子抑制剂药物一方面需要靶向于具有易于控制活性位点的蛋白质； 另一方面还需要高剂量才可达到足够的IC 90浓度，得到显著治疗效果；同时癌细胞可以通过基因突变引起靶蛋白结构变异或构型改变而降低或失去与药物的结合力，产生获得性耐药。为了避免这些问题，已经尝试替代治疗策略来特异性地敲低靶蛋白，诸如RNAi和CRISPR/Cas9的遗传技术可以显著降低蛋白质水平，但与这些方法相关的药代动力学特性包括代谢稳定性和组织分布迄今为止限制了它们作为临床药物的发展。
泛素，一种小蛋白分子，由76个氨基酸残基组成，分子量约8.5kDa，具有高度保守的序列并且广泛存在于真核生物体中。真核生物中编码泛素的基因以串联重复的方式排列，其八个不同的氨基酸残基能够在靶蛋白上形成复杂的多泛素链。泛素化是指泛素分子在一系列特殊的酶作用下，将细胞内的蛋白质分类，从中选出靶蛋白分子，对靶蛋白进行特异性修饰的过程，形成靶蛋白多聚泛素链。这些特殊的酶包括泛素活化酶(E1)、泛素结合酶(E2)、泛素连结酶(E3)等。泛素化是一个三酶级联反应，即，需要有由三个酶催化的一系列反应的发生，整个过程也被称为泛素化信号通路。泛素化在蛋白质的定位、代谢、功能、调节和降解中起重要作用。蛋白质泛素化是生物体内一种常见的翻译后修饰，参与细胞周期、增殖、凋亡、分化、转移等几乎一切生命活动的调控。泛素化与肿瘤、心血管、自身免疫等疾病的发病密切相关。泛素化成为研究和开发新药物的新靶点。E3泛素连接酶(在人类中已知有600多种)赋予泛素化底物特异性，由于其对某些蛋白质底物的特异性，其较一般的蛋白酶更具吸引力。E3泛素连接酶的配体的开发已被证明具有挑战性，部分原因是它们必须破坏蛋白质与蛋白质的相互作用。
蛋白降解靶向嵌合体(PROTAC)技术是近期药物研发领域的一个新兴方向。PROTAC药物具有同时与靶蛋白质和E3泛素连接酶结合的亲和性。E3泛素连接酶通过结合PROTAC小分子中的选择性配体部分与靶蛋白质形成复合物后，启动强大的泛素水解过程，使靶蛋白降解，这样就可以利用人体本身的蛋白质降解机制将任何靶致病蛋白质清除掉。此外PROTAC小分子药物在靶蛋白质降解后可反复与其它靶蛋白质结合进行循环使用，意味着其可以在低剂量下起作用。PROTAC药物不仅能够作用于传统小分子药物可以抑制的靶向蛋白质，还可以抑制和降解传统小分子药物无法成药的靶蛋白包括获得性耐药突变株。
发明内容
本发明人利用PROTAC技术，经过刻苦研究发现了一种新型杂芳环类化合物，其具有选择性降解和抑制FLT3酪氨酸激酶的双功能，可以被开发为治疗FLT3介导的信号通路异常引起的相关疾病的药物，特别是治疗癌症的药物。
因此，本发明的目的是提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，
Figure PCTCN2021107804-appb-000001
其中：
E选自以下结构：
Figure PCTCN2021107804-appb-000002
L选自以下结构：
Figure PCTCN2021107804-appb-000003
其中：
Z 1和Z 2之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
Z 3和Z 4之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
Z 5和Z 6之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
Z 1和Z 2各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、- NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
Z 3和Z 4各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
Z 5和Z 6各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
W 1、W 2、W 3、W 4、W 5、W 6、W 7、W 8和W 9各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-N(R 3)-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；
G选自单键、二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价环烷基、二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、羟基烷基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
G 1、G 2、G 3各自独立地选自单键、亚烯基、亚炔基、二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、羟基烷基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
Y 1、Y 2、Y 3和Y 4各自独立地选自CR b或N；
X 1、X 2、X 3和X 4各自独立地选自CR c或N；
Y和U各自独立地选自N或者CR a；
当R 1为氢时，A选自杂芳基或杂环基，所述杂芳基或杂环基任选进一步被选自卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、酰基、酯基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代，其中所述烷基、烯基、炔基、烷氧基、酰基、酯基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者，
当R 1不为氢时，A和R 1各自独立地选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔 基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者
A和R 1与其所连接的氮原子一起形成杂环基或杂芳基，所述杂环基或杂芳基任选进一步被选自卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、酰基、酯基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代，其中所述烷基、烯基、炔基、烷氧基、酰基、酯基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R 2选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R 3选自氢或烷基；
R a、R b和R c各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d和R e或者R d1和R e1或者R d2和R e2或者R d3和R e3或者R d4和R e4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者，
R d和R e与其相连接的碳原子或者R d1和R e1与其相连接的碳原子或者R d2和R e2与其相连接的碳原子或者R d3和R e3与其相连接的碳原子或者R d4和R e4与其相连接的碳原子，一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；R g、R f、R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟 基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
Q选自氢、羟基、烷基、环烷基、或以下结构：
Figure PCTCN2021107804-appb-000004
其中所述烷基或环烷基任选进一步被选自卤素、烷基、羟基、氨基和芳基的一个或多个基团所取代；
R 0选自芳基、杂环基、烷基、环烷基和烷氧基，其中所述芳基、杂环基、烷基、环烷基和烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R 4、R 7、R 8和R 9各自独立地选自氢、烷基、环烷基和芳基，其中所述烷基、环烷基和芳基任选进一步被选自羟基、巯基、羧基、酰氨基、烷基、烷氧基和烷硫基的一个或多个基团所取代；
R 5和R 6各自独立地选自氢、烷基、酰基、酯基和芳基，其中所述烷基、酰基、酯基和芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、烷基和烷氧基的一个或多个基团所取代；
R 5和R 6与其连接的氮原子一起形成含氮杂环基，所述杂环基任选进一步被选自卤素、烷基、环烷基、杂环基的一个或多个基团取代；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数；
m 1、m 2、m 3、m 4、m 5、m 6和m 7各自独立地为0至15的整数；
j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数。
在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
E选自以下结构：
Figure PCTCN2021107804-appb-000005
X 1、X 2、X 3和X 4各自独立地选自CR c或N；
R c选自氢、卤素、氨基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基和杂环基，所述氨基、烷基、烷氧基、环烷基和杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
Q基团如通式(I)中所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
E选自以下结构：
Figure PCTCN2021107804-appb-000006
X 1、X 2、X 3和X 4各自独立地选自CR c或N；
R c选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基；
优选地，X 1、X 2、X 3和X 4各自独立地选自CH；
Q选自氢、羟基、C 1-C 6烷基优选甲基、
Figure PCTCN2021107804-appb-000007
所述C 1-C 6烷基任选进一步被C 6-C 10芳基优选苯基取代；
R 0选自C 6-C 10芳基优选苯基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基，其中所述C 6-C 10芳基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基、5-7元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代；
R 4、R 7、R 8和R 9各自独立地选自氢、C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基任选进一步被选自 羟基、巯基、羧基、酰氨基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基的一个或多个基团所取代；
R 5和R 6各自独立地选自氢、C 1-C 6烷基、-C(O)OR”其中R”为C 1-C 6烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基和C 6-C 10芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、C 1-C 6烷基和C 1-C 6烷氧基的一个或多个基团所取代；或者
R 5和R 6与其连接的氮原子一起形成含氮杂环基，优选5-7元含氮杂环基，所述杂环基任选进一步被选自卤素、C 1-C 6烷基、C 3-C 7环烷基、5-7元杂环基的一个或多个基团取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000008
Z 1与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 2与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 1和Z 2各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
W 1、W 2和W 3各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；
R 3选自氢或烷基；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d和R e与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、 酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d1和R e1与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R g、R f、R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000009
Z 1与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 2与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 1选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚 烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键或-O(CH 2)C(O)NH-；
Z 2选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚C 2-C 6炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键、-N(R 3)-、亚乙烯基、亚乙炔基、-C(O)NH-、-NHC(O)-、-O(CH 2)C(O)NH-、-(CH 2)NHC(O)-；
W 1、W 2和W 3各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、C 2-C 6亚烯基、C 2-C 6亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
R 3选自氢或C 1-C 6烷基；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d和R e与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d和R e各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R g、R f、R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000010
其中：
Z 3与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 4与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 3和Z 4各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
W 4、W 5和W 6各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；
G选自二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价环烷基、二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
R 3选自氢或烷基；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d和R e与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d1和R e1与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d2和R e2与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d3和R e3与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
m 1、m 2、m 3和m 4各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000011
其中：
Z 3与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 4与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 3选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键；
Z 4选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、-NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键、-NH-、-NHC(O)-；
W 4、W 5和W 6各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
G选自C 3-C 6二价环烷基、5至6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基，所述二价环烷基、二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基中的一个或多个取代基所取代；优选5至6元二价杂环基、二价苯基、5至6元二价杂芳基；
R 3选自氢或C 1-C 6烷基；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d和R e与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d和R e各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d2和R e2与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d2和R e2各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d3和R e3与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d3和R e3各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
m 1、m 2、m 3和m 4各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000012
其中：
Z 5与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 6与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 5和Z 6各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
W 7、W 8和W 9各自独立地选自各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；
G 1、G 2、G 3各自独立地选自单键、亚烯基、亚炔基、二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、羟基烷基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者R d和R e与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d1和R e1与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧 基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d2和R e2与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d3和R e3与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
R d4和R e4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
或者R d4和R e4与其相连接的碳原子一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000013
其中：
Z 5与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 6与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 5选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键；
Z 6选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选自-NH-、-(CH 2)NHC(O)-；
W 7、W 8和W 9各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、C 2-C 6亚烯基、C 2-C 6亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
G 1、G 2、G 3各自独立地选自单键、C 2-C 6亚烯基、C 2-C 6亚炔基、C 3-C 6二价环烷基、5-6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基，所述二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基中的一个或多个取代基所取代；优选亚乙烯基、亚乙炔基、5-6元二价杂环基、二价苯基、5-6元二价杂芳基；
R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d2和R e2与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d2和R e2各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d3和R e3与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d3和R e3各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
R d4和R e4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
或者R d4和R e4与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
优选地R d4和R e4各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
s为1至12的整数；
p为0、1或2；
q为0至12的整数；
j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000014
n 5选自0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000015
n 1、n 2、n 3和n 4各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000016
R 3选自氢或烷基；
n 1、n 3和n 4各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000017
其中：
Z 3与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
Z 4与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
Z 3和Z 4各自独立地选自-O-、-S-、-N(R 3)-、-C(O)NH-、-NHC(O)-、-S(O) pNH-、-NHS(O) p-、C 1-C 4亚烯基、C 1-C 4亚炔基、-OCH 2C(O)NH-和-NHC(O)CH 2O-；
W 4和W 6各自独立地选自-O-、-S-、-N(R 3)-、C(O)NH-、-NHC(O)-、-S(O) pNH-和-NHS(O) p-；
W 5选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-N(R 3)-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、C 1-C 4亚烯基、C 1-C 4亚炔基、-S(O) pNH-和-NHS(O) p-；
G选自以下基团：
Figure PCTCN2021107804-appb-000018
G任选进一步被选自羟基、卤素、烷基、烷氧基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
R 3选自氢或烷基；
m 1、m 2、m 3、m 4、m 5、m 6和m 7各自独立地为0至15的整数，优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
Y和U各自独立地选自CR a；
R a选自氢、卤素、氨基、硝基、氰基、羟基、巯基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、和C 3-C 7环烷基；优选氢和卤素。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
Y 1、Y 2、Y 3和Y 4各自独立地选自CR b；
R b选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、环烷基和杂环基，所述氨基、烷基、烷氧基、环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；优选R b选自氢、卤素、氨基、硝基、氰基、羟基、巯基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基和C 3-C 7环烷基；更优选氢和卤素。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
R 1为氢，且A选自5至7元杂芳基，所述5至7元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
R 1为氢，且A选自以下结构：
Figure PCTCN2021107804-appb-000019
R选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基；优选氢、C 1-C 6烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
R 1为酯基，特别是-C(O)OR’，其中R’选自C 1-C 6烷基或C 3-C 7环烷基；并且A选自以下结构：
Figure PCTCN2021107804-appb-000020
R选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基；优选氢、C 1-C 6烷基；
优选地，A选自吡唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、吡咯基；其任选进一步被选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的基团所取代；优选被C 1-C 6烷基所取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
当R 1不为氢时，A和R 1与其所连接的氮原子一起形成5至7元杂芳基，所述5至7元杂芳基任选进一步被选自卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、酰基、酯基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代，其中所述烷基、烯基、炔基、烷氧基、酰基、酯基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
当R 1不为氢时，A和R 1与其所连接的氮原子一起形成5至7元杂芳基，所述杂芳基选自吡唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、吡咯基；所述5至7元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：R 2选自氢、卤素、羟基、硝基、氨基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基；优选氢和卤素。
在本发明优选的L可以选自以下结构；
Figure PCTCN2021107804-appb-000021
Figure PCTCN2021107804-appb-000022
Figure PCTCN2021107804-appb-000023
Figure PCTCN2021107804-appb-000024
Figure PCTCN2021107804-appb-000025
R 3选自氢或C 1-C 6烷基；
R d、R e、R d1、R e1、R d2、R e2、R d3、R e3如通式(I)所定义，优选R d、R e、R d1、R e1、R d2、R e2、R d3、R e3各自独立地选自C 1-C 6烷基或卤素；s为1至12的整数；
q为0至12的整数；
n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数；
m 1、m 2、m 3、m 4、m 5、m 6和m 7各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数；
j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
L选自以下结构：
Figure PCTCN2021107804-appb-000026
R 3选自氢或C 1-C 6烷基；
R d5和R e5各自独立地选自氢、卤素和C 1-C 6烷基；
x1为0至5的整数；优选1至5的整数；
x2为0至10的整数，优选0至6的整数；
x3为1至10的整数，优选1至6的整数；
x4为1至4的整数。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物为一种前药化合物，所述前药指经过生物体内转化后才呈现药理作用的化合物，因此，在根据本发明所述的通式(I)所示的化合物中，
Q选自羟基、C 1-C 6烷基优选甲基、
Figure PCTCN2021107804-appb-000027
所述C 1-C 6烷基任选进一步被C 6-C 10芳基优选苯基取代；
R 0选自C 6-C 10芳基优选苯基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基，其中所述C 6-C 10芳基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基、5-7元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代；
R 4、R 7、R 8和R 9各自独立地选自氢、C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基任选进一步被选自羟基、巯基、羧基、酰氨基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基的一个或多个基团所取代；
R 5和R 6各自独立地选自氢、C 1-C 6烷基、-C(O)OR其中R为C 1-C 6烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基和C 6-C 10芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、C 1-C 6烷基和C 1-C 6烷氧基的一个或多个基团所取代；或者
R 5和R 6与其连接的氮原子一起形成含氮杂环基，优选5-7元含氮杂环基，所述杂环基任选进一步被选自卤素、C 1-C 6烷基、C 3-C 7环烷基、5-7元杂环基的一个或多个基团取代。
本发明典型的化合物包括但不限于以下化合物：
Figure PCTCN2021107804-appb-000028
Figure PCTCN2021107804-appb-000029
Figure PCTCN2021107804-appb-000030
Figure PCTCN2021107804-appb-000031
Figure PCTCN2021107804-appb-000032
Figure PCTCN2021107804-appb-000033
Figure PCTCN2021107804-appb-000034
Figure PCTCN2021107804-appb-000035
Figure PCTCN2021107804-appb-000036
Figure PCTCN2021107804-appb-000037
Figure PCTCN2021107804-appb-000038
Figure PCTCN2021107804-appb-000039
Figure PCTCN2021107804-appb-000040
Figure PCTCN2021107804-appb-000041
Figure PCTCN2021107804-appb-000042
Figure PCTCN2021107804-appb-000043
Figure PCTCN2021107804-appb-000044
Figure PCTCN2021107804-appb-000045
Figure PCTCN2021107804-appb-000046
Figure PCTCN2021107804-appb-000047
Figure PCTCN2021107804-appb-000048
Figure PCTCN2021107804-appb-000049
Figure PCTCN2021107804-appb-000050
Figure PCTCN2021107804-appb-000051
Figure PCTCN2021107804-appb-000052
Figure PCTCN2021107804-appb-000053
Figure PCTCN2021107804-appb-000054
Figure PCTCN2021107804-appb-000055
Figure PCTCN2021107804-appb-000056
Figure PCTCN2021107804-appb-000057
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐。
本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐的制备方法，其包括以下步骤：
Figure PCTCN2021107804-appb-000058
化合物M4和化合物M5通过亲核取代反应、偶联反应、缩合反应、Suzuki反应、Buchwald反应或Mitsunobu反应等得到通式(I)的化合物；
J 1和J 2各自独立地选自卤素、羟基、氨基、炔基和羧基；
Y、U、Y 1、Y 2、Y 3、Y 4、A、E、L、R 1、R 2如通式(I)中所定义。
本发明进一步涉及一种药物组合物，其含有治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，以及药学上可接受的载体。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物在制备双功能FLT3酪氨酸激酶降解剂和抑制剂中的用途。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物在制备用于预防和/或治疗哺乳动物包括人类中FLT3介导的信号通路异常引起的相关疾病特别是癌症的药物中的用途，所述癌症优选为FLT3酪氨酸激酶表达异常(过表达、点突变、插入或缺失突变、融合蛋白等)或FLT3介导的信号通路异常的非实体瘤如白血病和实体瘤如皮肤癌、黑色素瘤、肺癌、胃癌、乳腺癌、胰腺癌、肝癌或结肠癌等。
在一个优选的实施方案中，根据本发明所述的用途，其中根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物可以与另外一种或多种药物如癌症治疗药物或者治疗方法如癌症治疗方法同时、分别或相继组合使用。
本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其 药学上可接受的盐或者包含其的药物组合物，其用作双功能FLT3酪氨酸激酶降解剂和抑制剂的用途。
本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物，其用作药物，所述药物优选用于预防和/或治疗哺乳动物包括人类中FLT3介导的信号通路异常引起的相关疾病特别是癌症，所述癌症优选为FLT3酪氨酸激酶表达异常(过表达、点突变、插入或缺失突变、融合蛋白等)或FLT3介导的信号通路异常的非实体瘤如白血病和实体瘤如皮肤癌、黑色素瘤、肺癌、胃癌、乳腺癌、胰腺癌、肝癌或结肠癌等。
本发明进一步涉及一种根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物，其用作与另外一种或多种药物如癌症治疗药物或者治疗方法如癌症治疗方法同时、分别或相继组合使用。
本发明还涉及一种降解和抑制FLT3酪氨酸激酶的方法，其包括向有需要的受试者施用有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物。
本发明还涉及一种用于预防和/或治疗哺乳动物包括人类中FLT3介导的信号通路异常引起的相关疾病特别是癌症的方法，其包括向有需要的受试者施用有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物；其中，所述癌症优选为FLT3酪氨酸激酶表达异常(过表达、点突变、插入或缺失突变、融合蛋白等)或FLT3介导的信号通路异常的非实体瘤如白血病和实体瘤如皮肤癌、黑色素瘤、肺癌、胃癌、乳腺癌、胰腺癌、骨髓瘤、肝癌或结肠癌等。
在一个优选的实施方案中，在上述方法中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者包含其的药物组合物可以与另外一种或多种药物如癌症治疗药物或者治疗方法如癌症治疗方法同时、分别或相继组合使用。
具体实施方式
除非另有规定，本文使用的所有技术和科学术语具有与本领域技术人员的通常理解相同含义。所有专利、申请、公开的申请和其他出版物均以全部内容并入作为参考。倘若对于本文使用的术语有多个定义，除非另有说明，以本节中的为准。如果任何给定取代基的数量没有规定，则可以存在一个或多个取代基。例如 “卤代烷基”可以含有一个或多个相同或不同的卤素。在本文的描述中，如果化学结构和化学名称彼此矛盾时，则是以其化学结构为准。当在本文使用时，对于任何保护基团、氨基酸和其他化合物的缩写，除非另有说明，以其常用的公认缩写表示，或根据IUPAC-IUB Commission on Biochemical Nomenclature表示(参见Biochem.1972,77:942-944)。
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
术语“烷基”指包括1至20个碳原子的饱和直链或支链脂族烃基团，优选包含1至18个碳原子，更优选包含1至10个碳原子，更优选包含1至6个碳原子，甚至更优选包含1至4个碳原子。烷基的非限定性实例包括甲基、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、新戊基、己基、异己基、正庚基、异庚基、正辛基、异辛基、正壬基、正癸基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
术语“亚烷基”指包括1至20个碳原子的饱和直链或支链脂肪族烃基团，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，优选含有1至12个碳原子，更优选含有1至6个碳原子。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)和1,5-亚丁基(-CH 2CH 2CH 2CH 2CH 2-)等。
术语“烯基”指由碳和氢原子组成的含有至少一个碳-碳双键的直链或支链烃基团，并通过单键或双键与分子的其余部分连接，优选具有2至10个碳原子，更优选具有2至6个碳原子，甚至更优选具有2至4个碳原子。烯基的非限定性实例包括乙烯基、丙烯基、丁烯基、戊烯基、戊二烯基、己烯基等。烯基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
“亚烯基”指包括1至20个碳原子的含有至少一个碳-碳双键的直链或支链烃基团，其具有2个从母体烯的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，优选含有1至12个碳原子，更优选含有1至6个碳原子。亚烯 基的非限制性实例包括但不限于1,2-亚乙烯基(-CH＝CH-)、1,1-亚丙烯基(-CH(CH＝CH 2)-)、1,2-亚丙烯基(-CH＝C(CH 3)-)、1,3-亚丙烯基(-CH＝CH-CH 2-)、1,4-亚丁基(-CH＝CHCH 2CH 2-)和1,5-亚丁基(-CH＝CHCH 2CH 2CH 2-)等。
术语“炔基”指由碳原子和氢原子组成的含有至少一个碳-碳三键的直链或支链烃基团，并通过单键或三键与分子的其余部分连接，优选具有2至10个碳原子，更优选具有2至6个碳原子，甚至更优选具有2至4个碳原子。炔基的非限定性实例包括乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
“亚炔基”指包括1至20个碳原子的含有至少一个碳-碳三键的直链或支链烃基团，其具有2个从母体炔的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，优选含有1至12个碳原子，更优选含有1至6个碳原子。亚炔基的非限制性实例包括但不限于1,2-亚乙炔基(-CH≡CH-)、1,1-亚丙炔基(-CH(C≡CH)-)、1,3-亚丙烯基(-C≡C-CH 2-)、1,4-亚丁基(-C≡CCH 2CH 2-)和1,5-亚丁基(-C≡CCH 2CH 2CH 2-)等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃基团，其包括3至20个碳原子，优选包括3至12个碳原子，更优选包含3至10个碳原子，最优选包含3至7个碳原子。单环环烷基的非限定性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021107804-appb-000059
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021107804-appb-000060
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021107804-appb-000061
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。
二价环烷基是指如上定义的环烷基，其具有2个从母环上的相同原子或两个不同的原子上除去两个氢原子所衍生的残基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基、或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃基团，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0至2的整 数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。杂环基环优选包含3至12个环原子，其中1至4个是杂原子；更优选包含3至8个环原子，其中1至3个是杂原子；最优选包含5至7个环原子，其中1至2或1至3个是杂原子。单环杂环基的非限定性实例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基、氮杂环庚烷基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021107804-appb-000062
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021107804-appb-000063
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子 系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021107804-appb-000064
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021107804-appb-000065
等。
二价杂环基是指如上定义的杂环基，其具有2个从母环上的相同原子或两个不同的原子上除去两个氢原子所衍生的残基。
术语“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为5至10元，更优选5至7元，甚至更优选苯基和萘基，最优选苯基。芳基可以是完全芳香族的基团，例如苯基、萘基、蒽基、菲基等。芳基也可以含有芳香环与非芳香环的组合，例如，茚、芴和苊等。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限定性实例包含：
Figure PCTCN2021107804-appb-000066
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
二价芳基是指如上定义的芳基，其具有2个从母环上的相同原子或两个不同的原子上除去两个氢原子所衍生的残基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选5至7元，甚至更优选为5元或6元，例如噻二唑基、吡唑基、噁唑基、噁二唑基、咪唑基、三唑基、噻唑基、呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021107804-appb-000067
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基。
二价杂芳基是指如上定义的杂芳基，其具有2个从母环上的相同原子或两个不同的原子上除去两个氢原子所衍生的残基。
术语“卤代烷基”指其中一个或多个氢原子被卤素取代的烷基，其中烷基的定义如上所述。非限定性实例包括氯甲基、三氟甲基、1-氯-2-氟乙基、2,2-二氟乙基、2-氟丙基、2-氟丙-2-基、2,2,2-三氟乙基、1,1-二氟乙基、1,3-二氟-2-甲基丙基、2,2-二氟环丙基、(三氟甲基)环丙基、4,4-二氟环己基和2,2,2-三氟-1,1-二甲基-乙基。
术语“卤代烷氧基”指其中一个或多个氢原子被卤素取代的烷氧基，其中烷氧基的定义如上所述。
术语“卤素”包括氟、氯、溴和碘。
术语“氨基”指-NH 2。
术语“硝基”指-NO 2。
术语“氰基”指-CN。
术语“羟基”指-OH基团。
术语“巯基”指-SH基团。
术语“羟烷基”或“羟基烷基”指被羟基取代的烷基，其中烷基的定义如上所述。
术语“羟烷氧基”或“羟基烷氧基”指被羟基取代的烷氧基，其中烷氧基的定义如上所述。
术语“氧代基”指＝O基团。
术语“羧基”至-COOH基团。
术语“酰基”指-C(O)R”，其中R”指烷基、环烷基、烯基、炔基，其中烷基、环烷基、烯基、炔基的定义如上所述。非限定性实例包括乙酰基、丙酰基、丁酰基、戊酰基、己酰基、乙烯酰基、丙烯酰基。
术语“酰氨基”指-NHC(O)R”或-C(O)NH 2，其中R”指烷基、烯基、炔基，其中烷基、烯基、炔基的定义如上所述。非限定性实例包括甲酰氨基、乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基、己酰氨基、乙烯酰氨基、丙烯酰氨基。
术语“酯基”指-C(O)O R”，其中R”指烷基或环烷基，其中烷基、环烷基的定义如上所述。非限定性实例包括乙酯基、丙酯基、丁酯基、戊酯基、环丙酯基、环丁酯基、环戊酯基、环己酯基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
“联合用药”是指为了达到治疗目的而采用的两种或两种以上药物同时、顺序或相继应用。
本发明化合物的合成方法
本发明通式(I)所示的化合物的制备方法。
为了完成本发明化合物的目的，本发明主要采用如下合成路线与技术方案。
Figure PCTCN2021107804-appb-000068
步骤1：在适当的溶剂中，在碱的存在下，化合物M1与氯甲酸苯酯通过亲核取代反应，得到化合物M2；其中，所述溶剂优选四氢呋喃、乙腈、二氯甲 烷、N,N-二甲基甲酰胺、甲苯、N-甲基吡咯烷酮；所述碱优选三乙胺、N,N-二异丙基乙胺、DMAP和吡啶；
步骤2：在适当溶剂中，化合物M2在碱的作用下生成异氰酸酯中间态，再与化合物M3通过成脲反应，得到化合物M4；其中，所述溶剂优选四氢呋喃、乙腈、二氯甲烷、N,N-二甲基甲酰胺、甲苯、N-甲基吡咯烷酮；所述碱优选三乙胺、N,N-二异丙基乙胺、DMAP和吡啶；
步骤3：化合物M4和化合物M5通过亲核取代反应、偶联反应、缩合反应、Suzuki反应、Buchwald反应或Mitsunobu反应等反应得到通式(I)的化合物；
J 1和J 2各自独立地选自卤素、羟基、氨基、炔基和羧基；Y、U、Y 1、Y 2、Y 3、Y 4、A、E、L、R 1、R 2如通式(I)中所定义。
本发明通式(I)所示的化合物在药学上可接受的盐，可以为酸加成盐或碱加成盐。酸可以为无机酸，包括但不限于：盐酸、硫酸、磷酸、氢溴酸；或可以为有机酸，包括但不限于：柠檬酸、马来酸、草酸，甲酸、乙酸、丙酸、戊酸、乙醇酸、苯甲酸、富马酸、三氟乙酸、琥珀酸、酒石酸、乳酸、谷氨酸、天门冬氨酸、水杨酸、丙酮酸、甲磺酸、苯磺酸、对苯磺酸。碱可以为无机碱，包括但不限于：氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙；或可以为有机碱，包括但不限于：氢氧化铵、三乙胺、N,N-二苄基乙二胺、氯普鲁卡因、胆碱、氨、二乙醇胺和其他羟基烷基胺、乙二胺、N-甲基葡糖胺、普鲁卡因、N-苄基苯乙胺、精氨酸或赖氨酸；或可以为碱金属盐，包括但不限于：锂、钾和钠盐；或可以为碱土金属盐，包括但不限于：钡、钙和镁盐；或可以为过渡金属盐，包括但不限于锌盐；或其他金属盐，包括但不限于：磷酸氢钠和磷酸氢二钠。
本发明另一方面将通式(I)所示的化合物或其药学上可接受的盐制备成临床上可使用的药用组合物。根据临床适应症，给药途径与方式，其药用制剂包括但不限于口服制剂如片剂、凝胶剂、软/硬胶囊、乳剂、分散性粉剂、颗粒剂、水/油悬乳剂；注射剂包括静脉注射剂、肌肉注射剂、腹腔注射剂、直肠给药栓剂、颅内注射剂，这些剂型可为水溶液也可为油类溶液；局部制剂包括霜剂、软膏剂、凝胶剂、水/油溶液以及包合物制剂；吸入剂型包括细粉、液体气溶胶以及适合于体内植入的各种剂型。
本发明的药物组合物可以根据需要加入药学上可接受的载体、稀释剂或赋形剂。这些载体、稀释剂或赋形剂应符合药物制剂制备工艺规则，与活性成分相兼容。固体口服制剂的载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖、环糊精以及促进肠吸收分子载体维生素E-PEG1000。口服制剂可加入适当的着色剂、甜味剂、矫味剂及防腐剂。注射剂的载体包括但不限于环糊精、聚乙二醇、丙三醇和药用植物油。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、本发明化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明通式(I)所示的化合物或药学上可接受的盐，在上述癌症治疗中，可单独使用，或与临床上常规使用的放射疗法、化学疗法、免疫疗法、肿瘤疫苗、融瘤病毒、RNAi、癌症辅助治疗以及骨髓移植和干细胞移植的一个或多个方法联合治疗，其中包括但不限于以下抗肿瘤类药物和治疗方法：
1)烷化剂如顺铂、顺铂、奥沙利铂、苯丁酸氮芥、卡环磷酰胺，氮芥、美法仑、替莫唑胺、白消安、亚硝基脲类。
2)抗肿瘤抗生素类如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光神霉素；抗有丝分裂药如长春新碱、长春碱、长春地辛、长春瑞滨、紫杉醇、泰索帝、Polo激酶抑制剂。
3)抗代谢和抗叶酸剂如氟嘧啶、雷甲氨蝶呤、阿糖胞苷、阿扎胞苷、地西他滨、替曲塞、羟基脲、IDH1/IDH2突变株抑制剂。
4)拓扑异构酶抑制剂如表鬼臼毒素、喜树碱、伊立替康。
5)细胞生长抑制剂如抗雌激素/抗雄激素类药物，如他莫昔芬、氟维司群、托瑞米芬、雷诺昔芬、屈诺昔芬、碘昔芬、比卡鲁胺、氟他胺、尼鲁米特、醋酸环丙孕酮；
LHRH拮抗剂或LHRH激动剂如戈舍瑞林、亮丙瑞林、和布舍瑞林、孕激素类如醋酸甲地孕酮；
芳香酶抑制剂如阿那曲唑、来曲唑、伏罗唑、伊西美坦、5a-还原酶抑制剂如非那雄胺。
6)抗侵袭剂如c-Src激酶家族抑制剂、金属蛋白酶抑制剂、尿激酶纤溶酶原激活物受体功能的抑制剂或者类肝素酶的抗体。
7)生长功能的抑制剂如生长因子抗体和生长因子受体抗体如抗HER2抗体曲妥珠单抗、抗EGFR抗体帕尼单抗、抗EGFR抗体西妥昔单抗等；这种抑制剂还包括其它酪氨酸激酶抑制剂以及丝氨酸/苏氨酸激酶的抑制剂如Ras/Raf信号传导抑制剂，MEK和/或AKT激酶的细胞信号传导抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、JAKs和STAT3抑制剂、CSF-1R激酶抑制剂、IGF受体激酶抑制剂，极光激酶抑制剂，NTRKA/B/C激酶抑制剂。
8)抗血管生成剂如抑制血管内皮生长因子作用的药剂贝伐珠单抗以及VEGF受体酪氨酸激酶抑制剂。
9)表观遗传学(epigenetics)抑制剂如组蛋白去乙酰化酶抑制剂(HDACi)、DNA甲基转移酶抑制剂(DNMTi)、组蛋白乙酰转移酶抑制剂、组蛋白去甲基化酶抑制剂、组蛋白甲基转移酶抑制剂等。
10)聚腺苷二磷酸核糖聚合酶抑制剂(PARPi)如奥拉帕利(Olaparib)、瑞卡帕尼(Rucaparib)和尼拉帕尼(Niraparib)。
11)肿瘤免疫治疗法包括任何提高患者肿瘤细胞的免疫原性的体外和体内方法。如细胞因子IL-2、IL-4或者GM-CSF进行转染；降低T细胞无效能的方法如抗PD-1/PD-L单抗；使用转染的免疫细胞如细胞因子转染的树突状细胞的方法；使用细胞因子转染的肿瘤细胞系的方法；降低免疫抑制性细胞如调节性T细胞、髓源性抑制细胞、或表达吲哚胺2,3-脱氧酶的树突状细胞的功能方法；提高免疫细胞活性的激动剂如STING以及肿瘤相关抗原蛋白类或肽类组成的癌症疫苗的方法。
12)嵌合抗原受体T细胞免疫疗(CART)。
13)肿瘤基因治疗如CRISPR-Cas 9、RNAi、基因转导。
实施例
以下结合实施例进一步描述本发明，但这些实施例并非限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker AVANCE-400)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用液相色谱质谱联用仪(Thermo，Ultimate3000/MSQ)。
HPLC的测定使用高压液相色谱仪(安捷伦1260Infinity，Gemini C18250×4.6mm，5u色谱柱)。
薄层色谱法(TLC)采用烟台黄海硅胶板HSGF245，薄层层析分析产品采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.9mm～1.0mm。
柱层析色谱法一般采用烟台黄海200～300目硅胶为载体。
本发明的已知起始原料可以采用或按照本领域已知的方法来合成，或购买自上海达瑞精细化学品有限公司、上海泰坦科技股份有限公司、上海润捷化学试剂有限公司、TCI、Aldrich Chemical Company。实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例1 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(1)的制备
Figure PCTCN2021107804-appb-000069
步骤1：2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)的制备
于140℃，将3-氟酞酐(28g，168mmol)、3-氨基-2,6-哌啶二酮盐酸盐(27.74g，168mmol)和乙酸钠(16.5g，201.6mml)在420ml乙酸中搅拌14小时。将反应液降温至室温，有固体析出，过滤，滤饼用甲基叔丁基醚洗涤。鼓风干燥(60℃)8小时，得白色固体38g，产品无需纯化，直接用于下一步反应。
步骤2：[2-(2-羟基-乙氧基)乙基]氨基甲酸叔丁酯(1b)的制备
将2-(2-氨基-乙氧基)-乙醇(100g，0.952mol)溶解于1L二氯甲烷中，缓慢滴入BOC酸酐(207g，0.952mol)，于室温搅拌45分钟。将反应液倒入500ml饱和食盐水中，水相用二氯甲烷200ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到190g淡黄色油状粗品产物。
步骤3：2-(2-叔丁氧羰基氨基-乙氧基)-乙基甲磺酸酯(1c)的制备
将[2-(2-羟基-乙氧基)-乙基]氨基甲酸叔丁酯(170g，0.829mol)溶解于1L二氯甲烷中，加入三乙胺(125.5g，1.243mol)，降温至小于-5℃，缓慢滴入用200ml二氯甲烷稀释的甲磺酰氯(113.4g，0.995mol)，保持温度小于-5℃，10分钟后滴毕，保持温度搅拌20分钟。将反应液倒入200ml饱和食盐水中，滴入乙酸(1.4当量)，用二氯甲烷200ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到190g淡黄色油状粗品产物。
步骤4：(4-甲氧基-2-硝基-苯基)-(4-硝基-苯基)-胺(1d)的制备
在氮气氛下，将2-硝基-4-甲氧基苯胺(1.5g，8.92mmol)、对溴硝基苯(3.6g，17mmol)、Xphos(425mg)、Pd 2(dba) 3(408mg)、叔丁醇钠(1.71g,17.8mmol)溶解于30ml甲苯中，并于90℃搅拌3小时。将反应液冷却至室温，加入100ml二氯甲烷，室温搅拌5分钟，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝10:1-1:1)纯化，得2.5g红黑色固体状的(4-甲氧基-2-硝基-苯基)-(4-硝基-苯基)-胺。
步骤5：(4-甲氧基-2-氨基-苯基)-(4-氨基-苯基)-胺(1e)的制备
将(4-甲氧基-2-硝基-苯基)-(4-硝基-苯基)-胺(2.5g，8.65mmol)、还原铁粉(2.91g，52.0mmol)、氯化铵(4.62g，86.5mmol)加入乙醇(50ml)/水(12.5ml)中，并将得到的混合物加热至90℃，搅拌1小时。将反应液冷却至室温后，缓慢倒入饱和碳酸氢钠水溶液中(150ml)，用乙酸乙酯萃取(100ml×2)，有机相用饱和NaCl溶液洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得1.8g黄色固体状的粗品。产品无需纯化，直接用于下一步反应。
步骤6：4-(5-甲氧基-苯并咪唑-1-基)苯胺(1f)的制备
将(4-甲氧基-2-氨基-苯基)-(4-氨基-苯基)-胺(1.8g，7.86mmol)溶解于60ml盐酸中(4mol/L)，于室温加入2ml甲酸，将混合物加热至120℃，搅拌1小时。将反应液冷却，并在冰浴下用氨水调节至PH>9，用乙酸乙酯萃取(80ml×2)，有机相用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，滤液减压 浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-50:1)纯化，得到1.2g黄色固体状的4-(5-甲氧基-苯并咪唑-1-基)-苯胺。
步骤7：1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)的制备
于15ml40％氢溴酸中，将4-(5-甲氧基-苯并咪唑-1-基)-苯胺(875mg，3.66mmol)加热至120℃，搅拌6小时。将反应液冷却至室温，有灰白固体析出。将固体过滤，并溶解于70ml水中。过滤，取滤液用氨水调节至约PH＝7，有白色固体析出，过滤，水洗固体，真空干燥得600mg灰白色固体状1-(4-氨基-苯基)-1H-苯并咪唑-5-醇。
步骤8：(2-{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙基)-氨基甲酸叔丁酯(1h)的制备
将1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(6.75g，30mmol)溶解于90mlDMF中，加入2-(2-叔丁氧羰基氨基-乙氧基)-乙基甲磺酸酯(1c)(12.7g，45mmol)、碳酸钾(12.42g，90mmol)和催化量碘化钾，升温至100℃，搅拌过夜。将反应液降至室温，然后倒入400ml水中，用乙酸乙酯150ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇+＝150:1-60:1)纯化，得到6.38黄色固体状产物。
步骤9：(4-{5-[2-(2-叔丁氧羰基氨基-乙氧基)乙氧基]苯并咪唑-1-基}-苯基)-氨基甲酸苯酯(1i)的制备
于室温将(2-{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙基)-氨基甲酸叔丁酯(1h)(6.38g，15.5mmol)溶解于60ml四氢呋喃中，然后加入吡啶(3.68g，46.5mmol)，冰盐浴降温至-5℃-0℃。将氯甲酸苯酯(3.64g，23.25mmol)(用10ml四氢呋喃稀释)慢慢滴加到上述溶液中，过程中控制温度在-5℃-0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入200ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到10.0g粗品产物。
步骤10：{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙基-氨基甲酸叔丁酯(1j)的制备
将(4-{5-[2-(2-叔丁氧羰基氨基-乙氧基)乙氧基]苯并咪唑-1-基}-苯基)-氨基甲酸苯酯(1i)的粗产品10g溶解于80ml四氢呋喃中，于室温加入5-叔丁基-2H-吡唑-3-基胺(3.24g，23.25mmol)和三乙胺(4.7g，46.5mmol)，升温至70℃搅拌过夜。将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得5.3g黄色固体状产物。
步骤11：1-(4-{5-[2-(2-氨基-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-3-(5-叔丁基-2H-吡唑-3-基)-脲(1k)的制备
将{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙基-氨基甲酸叔丁酯(1j)(5.3g，9.2mmol)溶解于60ml二氯甲烷中，于室温加入12ml三氟乙酸，搅拌1.5小时。将反应液减压浓缩，残余物溶于70ml水中，加氨水调PH至8～9，析出大量固体，过滤，用大量水洗固体，将固体转移至烧瓶中加乙醇带水蒸干，得到5.3g粗产品。
步骤12：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(1)的制备
将1-(4-{5-[2-(2-氨基-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-3-(5-叔丁基-2H-吡唑-3-基)-脲(1k)(250mg，0.53mmol)溶解于10mlDMF中，于室温加入2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(217mg，0.784mmol)和DIPEA(205mg，1.59mmol)，升温至90℃搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯150ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到46mg黄色固体状的产物。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),11.14(s,1H),9.42(s,1H),9.00(s,1H),8.42(s,1H),7.66-7.68(d,2H),7.54-7.59(m,3H),7.42-7.45(d,1H),7.29(d,1H),7.15-7.17(d,1H),7.02-7.04(d,1H),6.92-6.95(dd,1H),6.65-6.68(t,1H),6.02(s,1H),5.03-5.07(m,1H),4.15(m,2H),3.83(m,2H),3.71-3.73(m,2H),3.50-3.53(m,2H),2.84-2.89(m,1H),2.50-2.60(m,2H),1.98-2.01(m,1H),1.26(s,9H)。
LC-MS(ESI):734.3(M+H) +。
实施例2 1-{4-[5-(2-{2-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-3-(5-叔丁基-2H-吡唑-3-基)-脲(2)的制备
Figure PCTCN2021107804-appb-000070
Figure PCTCN2021107804-appb-000071
将1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(1)(300mg，0.41mmol)和苄溴(84mg，0.49mmol)溶解于15ml DMF中，于室温加入碳酸钾(120mg，0.86mmol)和催化量碘化钾，加毕，升温至90℃反应3小时。TLC检测反应完成，将反应液降至室温，然后倒入40ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-40:1)纯化，得到266mg黄色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),9.40(s,1H),8.98(s,1H),8.41(s,1H),7.65-7.68(d,2H),7.53-7.59(m,3H),7.41-7.43(d,2H),7.15-7.29(m,7H),7.03-7.04(d,1H),6.91-6.94(dd,1H),6.65-6.68(t,1H),6.02(s,1H),5.23-5.28(m,1H),4.75-4.91(q,2H),4.16(m,2H),3.83(m,2H),3.72(m,2H),3.52(m,2H),3.02-3.11(m,1H),2.77-2.81(m,1H),2.54-2.65(m,1H),2.02-2.07(m,1H),1.26(s,9H)。
LC-MS(ESI):824.3(M+H) +。
实施例3 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}苯并咪唑-1-基)-苯基]-脲(3)的制备
Figure PCTCN2021107804-appb-000072
与实施例1的制备方法相同，除了用乙醇胺代替步骤2中的2-(2-氨基-乙氧基)-乙醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}苯并咪唑-1-基)-苯基]-脲。
1HNMR(DMSO-d 6,400MHz)δ:12.03(br,1H),11.12(s,1H),9.46(s,1H),9.02(s,1H),8.49(s,1H),7.67-7.69(d,2H),7.55-7.62(m,3H),7.46-7.49(d,1H),7.35(d,1H),7.24-7.26(d,1H),7.05-7.07(d,1H),6.96-6.98(dd,1H),6.80-6.83(t,1H),6.04(s,1H),5.05-5.10(m,1H),4.25-4.27(m,2H),3.74-3.76(m,2H),2.84-2.93(m,1H),2.48-2.61(m,2H),2.01-2.04(m,1H),1.26(s,9H)。
LC-MS(ESI)：690.3(M+H) +。
实施例4 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]-苯并咪唑-1-基}-苯基)-脲(4)的制备
Figure PCTCN2021107804-appb-000073
与实施例1的制备方法相同，除了用2-[2-(2-氨基-乙氧基)乙氧基]乙醇代替步骤2中的2-(2-氨基-乙氧基)-乙醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]-苯并咪唑-1-基}-苯基)-脲。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),11.11(s,1H),9.51(s,1H),9.02(s,1H),8.42(s,1H),7.66-7.68(d,2H),7.54-7.58(m,3H),7.42-7.45(d,1H),7.28(d,1H),7.12-7.14(d,1H),7.01-7.05(d,1H),6.91-6.94(dd,1H),6.60-6.63(t,1H),6.03(s,1H),5.03-5.07(m,1H),4.12-4.14(m,2H),3.77-3.79(m,2H),3.63-3.65(m,6H),3.46-3.49(m,2H),2.84-2.91(m,1H),2.50-2.59(m,2H),1.99-2.02(m,1H),1.26(s,9H)。
LC-MS(ESI)：778.3(M+H) +。
实施例5 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲(5)的制备
Figure PCTCN2021107804-appb-000074
与实施例1的制备方法相同，除了用1-氨基-3,6,9-三氧杂-11-十一醇代替步骤2中的2-(2-氨基-乙氧基)-乙醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),11.10(s,1H),9.43(s,1H),9.00(s,1H),8.50(s,1H),7.66-7.68(d,2H),7.54-7.57(m,3H),7.44-7.46(d,1H),7.29(d,1H), 7.11-7.13(d,1H),7.01-7.03(d,1H),6.94-6.97(dd,1H),6.58-6.61(t,1H),6.02(s,1H),5.03-5.07(m,1H),4.12-4.14(m,2H),3.75-3.77(m,2H),3.56-3.63(m,10H),3.45-3.47(m,2H),2.82-2.91(m,1H),2.50-2.59(m,2H),1.95-2.02(m,1H),1.26(s,9H)。
LC-MS(ESI)：822.3(M+H) +。
实施例6 1-(5-叔丁基-噁唑-2-基)-3-[4-(5-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}苯并咪唑-1-基)苯基]-脲(6)的制备
Figure PCTCN2021107804-appb-000075
与实施例1的制备方法相同，除了用乙醇胺代替步骤2中的2-(2-氨基-乙氧基)-乙醇，并用3-氨基-5-叔丁基异噁唑代替步骤10中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-叔丁基-噁唑-2-基)-3-[4-(5-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}苯并咪唑-1-基)苯基]-脲。
1HNMR(DMSO-d 6,400MHz)δ:11.10(s,1H),9.62(s,1H),9.12(s,1H),8.47(s,1H),7.67-7.69(d,2H),7.57-7.64(m,3H),7.47-7.49(d,1H),7.35(d,1H),7.26-7.28(d,1H),7.05-7.07(d,1H),6.95-6.98(dd,1H),6.80-6.83(t,1H),6.52(s,1H),5.04-5.09(m,1H),4.24-4.27(m,2H),3.75-3.76(m,2H),2.85-2.89(m,1H),2.50-2.59(m,2H),1.99-2.02(m,1H),1.30(s,9H)。
LC-MS(ESI)：691.3(M+H) +。
实施例7 1-(5-叔丁基-异噁唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)苯并咪唑-1-基]-苯基}-脲(7)的制备
Figure PCTCN2021107804-appb-000076
与实施例1的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤10中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-叔丁基-异噁唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)苯并咪唑-1-基]-苯基}-脲。
1HNMR(DMSO-d 6,400MHz)δ:11.12(s,1H),9.61(s,1H),9.10(s,1H),8.46(s,1H),7.67-7.69(d,2H),7.55-7.59(m,3H),7.43-7.45(d,1H),7.29(d,1H),7.15-7.17(d,1H),7.02-7.04(d,1H),6.93-6.95(dd,1H),6.65-6.68(t,1H),6.53(s,1H),5.02-5.07(m,1H),4.15(m,2H),3.82(m,2H),3.70-3.73(m,2H),3.50-3.53(m,2H),2.83-2.92(m,1H),2.50-2.59(m,2H),1.98-2.01(m,1H),1.30(s,9H)。
LC-MS(ESI):735.3(M+H) +。
实施例8 1-(5-叔丁基-异噁唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]苯并咪唑-1-基}-苯基)-脲(8)的制备
Figure PCTCN2021107804-appb-000077
与实施例4的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤10中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-叔丁基-异噁唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]苯并咪唑-1-基}-苯基)-脲。
1HNMR(DMSO-d 6,400MHz)δ:11.11(s,1H),9.61(s,1H),9.11(s,1H),8.46(s,1H),7.67-7.69(d,2H),7.58-7.62(m,3H),7.45-7.47(d,1H),7.29(d,1H),7.16-7.18(d,1H),7.01-7.03(d,1H),6.94-6.96(dd,1H),6.65-6.68(t,1H),6.53(s,1H),5.03-5.06(m,1H),4.12-4.14(m,2H),3.78-3.80(m,2H),3.65-3.69(m,6H),3.48-3.51(m,2H),2.83-2.92(m,1H),2.50-2.59(m,2H),1.98-2.01(m,1H),1.30(s,9H)。
LC-MS(ESI):779.3(M+H) +。
实施例9 1-(5-叔丁基-异噁唑-3-基)-3-[4-(5-{2-[2-(2-{2-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]乙氧基}苯并咪唑-1-基)苯基]脲(9)的制备
Figure PCTCN2021107804-appb-000078
与实施例5的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤10中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-叔丁基-异噁唑-3-基)-3-[4-(5-{2-[2-(2-{2- [2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]乙氧基}乙氧基)乙氧基]乙氧基}苯并咪唑-1-基)苯基]脲。
1HNMR(DMSO-d 6,400MHz)δ:11.10(s,1H),9.60(s,1H),9.07(s,1H),8.44(s,1H),7.66-7.68(d,2H),7.54-7.59(m,3H),7.44-7.46(d,1H),7.29(d,1H),7.11-7.13(d,1H),7.01-7.03(d,1H),6.93-6.96(dd,1H),6.58-6.61(t,1H),6.52(s,1H),5.03-5.07(m,1H),4.12-4.14(m,2H),3.74-3.77(m,2H),3.52-3.63(m,10H),3.43-3.46(m,2H),2.84-2.89(m,1H),2.50-2.59(m,2H),1.98-2.01(m,1H),1.30(s,9H)。
LC-MS(ESI):823.3(M+H) +。
实施例10 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基氨基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(10)的制备
Figure PCTCN2021107804-appb-000079
与实施例1的制备方法相同，除了用4-氟酞酐代替步骤1中的3-氟酞酐，得到1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基氨基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),11.05(s,1H),9.46(s,1H),9.00(s,1H),8.53(s,1H),7.67-7.69(d,2H),7.53-7.57(m,3H),7.45-7.47(d,1H),7.29(d,1H),7.21(m,1H),7.01-7.02(d,1H),6.94-6.97(dd,1H),6.89-6.92(m,1H),6.02(s,1H),5.00-5.04(m,1H),4.16-4.19(m,2H),3.81-3.83(m,2H),3.68-3.71(m,10H),3.40(m,2H),2.83-2.88(m,1H),2.50-2.58(m,2H),1.96-2.03(m,1H),1.26(s,9H)。
LC-MS(ESI):734.3(M+H) +。
实施例11 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[1-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙基)-1H-[1,2,3]三唑-4-基甲氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲(11)的制备
Figure PCTCN2021107804-appb-000080
Figure PCTCN2021107804-appb-000081
步骤1：2-(2,6-二氧代哌啶-3-基)-4-[2-(2-羟基-乙氧基)-乙氨基]-异吲哚-1,3-二酮(11a)的制备
于90℃，将2-(2,6-二氧代哌啶-3-基)-4-氟-异吲哚-1,3-二酮(8.0g，28.98mmol)、2-(2-氨基乙氧基)-乙醇(3g，28.57mmol)和三乙胺(3.5g，34.65mmol)在35ml DMSO中搅拌1小时。将反应液降温至室温，将反应液倒入250ml饱和食盐水中，用HCl调PH为5～6，水相用乙酸乙酯80ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到，5g粗品产物。
步骤2：2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙基甲磺酸酯(11b)的制备
将化合物11a(5g，13.85mmol)、三乙胺(1.39g，13.85mmol)溶解于40ml二氯甲烷中，降温至0℃，缓慢滴入甲磺酰氯(1.58mg，13.85mol)，于室温搅拌30分钟。将反应液倒入100ml饱和食盐水中，水相用二氯甲烷100ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝200:1)纯化，得到3.5g产物。
步骤3：4-[2-(2-叠氮基乙氧基)-乙基氨基]-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(11c)的制备
将化合物11b(3.5g，7.97mmol)溶解于30ml DMF中，加入叠氮化钠(1.0g，15.40mmol)，于65℃搅拌2小时。将反应液倒入100ml饱和食盐水 中，用乙酸乙酯100ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到3g固体产物。
步骤4：1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[1-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙基)-1H-[1,2,3]三唑-4-基甲氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲(11)的制备
在氮气氛下，将化合物11c(60mg，0.14mmol)、1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-脲16e(制备方法参见实施例16)(60mg，0.14mmol)、五水硫酸铜(1M，0.1ml)、抗坏血酸钠(1M，0.1ml)溶解于6ml DMSO和3ml的甲醇中，并于60℃搅拌3小时。将反应液冷却至室温，倒入100ml水中，析出固体，过滤，滤饼用100ml水洗涤。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝30:1～20:1)纯化，得89mg黄色固体状标题产物。
1HNMR(DMSO-d 6,400MHz)12.04(s,1H),11.12(s,1H),9.44(s,1H),8.99(s,1H),8.49(s,1H),8.05(s,1H),7.66-7.68(d,2H),7.53-7.56(m,3H),7.36(d,1H),7.25-7.7.27(d,1H),7.07-7.09(d,1H),7.01-7.03(d,1H),6.93-6.98(d,1H),6.57-6.59(t,1H),6.02(s,1H),5.03-5.07(m,1H),4.61(s,2H),4.52-4.57(m,2H),4.14(m,2H),3.83-3.85(m,2H),3.79(m,2H),3.59-3.60(m,2H),2.83-2.92(m,1H),2.54-2.60(m,2H),2.01-2.03(m,1H),1.26(s,9H)。
LC-MS(ESI):859.8(M+H) +。
实施例12 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{5-[1-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙基)-1H-[1,2,3]三唑-4-基]-戊氧基}-苯并咪唑-1-基)-苯基]-脲(12)的制备
Figure PCTCN2021107804-appb-000082
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{5-[1-(2-{2-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-乙氧基}-乙基)-1H-[1,2,3]三唑-4-基]-戊氧基}-苯并咪唑-1-基)-苯基]-脲(12)的制备
在氮气氛下，将4-[2-(2-叠氮基乙氧基)-乙基氨基]-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮11c(300mg，0.61mmol)、1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-庚-6-炔氧基-苯并咪唑-1-基)-苯基]-脲(制备方法参见实施例49的化合物49b)(240mg，061mmol)、五水硫酸铜(1M，0.2ml)、抗坏血酸钠(1M，0.2ml)溶解于10ml DMSO和5ml的甲醇中，并于60℃搅拌3小时。将反应液冷却至室温，倒入100ml水中，析出固体，过滤，滤饼用100ml水洗涤。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝30:1～20:1)纯化，得20mg黄色固体。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),11.12(s,1H),9.41(s,1H),8.98(s,1H),8.42(s,1H),7.75(s,1H),7.66-7.68(d,2H),7.53-7.56(m,3H),7.43-7.46(d,1H),7.25(s,1H),7.09-7.11(d,1H),7.02-7.04(d,1H),6.92-6.94(m,1H),6.57-6.60(t,1H),6.02(s,1H),5.03-5.08(m,1H),4.47-4.49(m,2H),3.97-4.01(m,2H),3.79-3.83(m,2H),3.58-3.64(m,2H),3.42-3.44(m,2H),2.84-2.93(m,1H),2.54-2.61(m,3H),1.96-2.04(m,2H),1.72-1.77(m,2H),1.58-1.65(m,2H),1.42-1.46(m,2H),1.26(s,9H)。
LC-MS(ESI):871.3(M+H) +。
实施例13 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{5-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-戊氧基}-苯并咪唑-1-基)-苯基]-脲(13)的制备
Figure PCTCN2021107804-appb-000083
与实施例1的制备方法相同，除了用5-氨基-1-戊醇代替步骤2中的2-(2-氨基-乙氧基)-乙醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{5-[2-(2,6-二氧代-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基氨基]-戊氧基}-苯并咪唑-1-基)-苯基]-脲。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.10(s,1H),9.40(s,1H),8.98(s,1H),8.41(s,1H),7.66-7.68(d,2H),7.54-7.59(m,3H),7.43-7.45(d,1H),7.27-7.28(d,1H),7.10-7.13(d,1H),7.00-7.02(d,1H),6.92-6.94(dd,1H),6.57-6.59(m,1H),6.01(s,1H),5.03-5.07(m,1H),4.02-4.05(t,2H),3.33-3.36(m,2H),2.83-2.92(m,1H),2.50-2.60(m,2H),1.97-2.04(m,1H),1.76-1.83(m,2H),1.63-1.70(m,2H),1.50-1.57(m,2H),1.26(s,9H)。
LC-MS(ESI)：732.2(M+H) +。
实施例14 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-甲基-氨基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(14)的制备
Figure PCTCN2021107804-appb-000084
步骤1：[2-(叔丁氧基羰基-甲基-氨基)乙氧基]乙酸乙酯(14a)的制备
将N-BOC-N-甲基氨基乙醇(1g，5.71mmol)溶解于10ml二氯甲烷中，于室温加入二聚醋酸铑(253mg，0.571mmol)，然后加入重氮乙酸乙酯(1.3g，11.43mmol，溶解于20ml二氯甲烷中)，加毕，室温反应15小时。TLC检测反应完成，将反应液倒入50ml饱和食盐水中，二氯甲烷50ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-10:1)纯化，得1.35g产物(14a)。
步骤2：[2-(2-羟基-乙氧基)-乙基]-甲基氨基甲酸叔丁酯(14b)的制备
将化合物14a(1.35g，5.17mol)溶解于60ml甲醇中，于室温慢慢加入硼氢化钠(391mg，10.34mmol)，加毕，继续室温反应15小时。TLC检测反应完成，反应液减压浓缩，残余物加入80ml水，乙酸乙酯(80ml×2)萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩得到989mg产物(14b)。
步骤3：2-[2-(叔丁氧基羰基-甲基氨基)-乙氧基]-乙基甲磺酸酯(14c)的制备
将化合物14b(989mg，4.52mol)溶解于10ml二氯甲烷中，加入三乙胺(685mg，6.78mol)，降温至小于-5℃，缓慢滴入用5ml二氯甲烷稀释的甲磺酰氯(620mg，5.4mmol)，保持温度小于-5℃，3分钟后滴毕，保持温度搅拌1小时。将反应液倒入50ml饱和食盐水中，滴入乙酸(1.4当量)，用二氯甲烷50ml×2萃取，有机相用饱和食盐水洗涤两次，饱和碳酸氢钠水溶液洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.15g产物(14c)。
步骤4-步骤8：1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-甲基-氨基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(14)的制备
与实施例1步骤8-步骤12的制备方法相同，除了用化合物14c代替实施例1步骤8中的2-(2-叔丁氧羰基氨基-乙氧基)-乙基甲磺酸酯(1c)，得到1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-甲基-氨基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(14)。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),11.08(s,1H),9.37-9.40(br,1H),8.98(s,1H),8.42(s,1H),7.66-7.68(d,2H),7.58-7.60(d,1H),7.54-7.57(d,2H),7.43-7.45(d,1H),7.28-7.30(d,1H),7.25(d,1H),7.20-7.21(d,1H),6.90-6.92(dd,1H),6.01(s,1H),5.06-5.10(m,1H),4.07(m,2H),3.75(m,2H),3.72-3.74(m,4H),3.07(s,3H),2.82-2.91(m,1H),2.50.2.59(m,2H),1.99-2.00(m,1H),1.26(s,9H)。
LC-MS(ESI):748.2(M+H) +。
实施例15 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(15)的制备
Figure PCTCN2021107804-appb-000085
与下述实施例16的制备方法相同，除了用5-己炔-1-醇代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇2-(丙-2-炔-1-基氧基)乙-1-醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(15)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.12(s,1H),9.40(br,1H),8.97(s,1H),8.39(s,1H),7.82-7.85(m,1H),7.78-7.80(m,2H),7.65-7.67(d,2H),7.53-7.55(d,2H),7.28-7.44(m,4H),6.93-6.96(dd,1H),6.01(s,1H),5.12-5.17(m,1H),4.08-4.12(t,2H),2.89-2.93(m,1H),2.54-2.67(m,4H),1.94-2.08(m,3H),1.75-1.83(m,2H),1.26(s,9H)。
LC-MS(ESI)：727.2(M+H) +。
实施例16 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16)的制备
Figure PCTCN2021107804-appb-000086
Figure PCTCN2021107804-appb-000087
步骤1：4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)的制备
于140℃，将3-溴酞酐(7g，0.03mol)、3-氨基-2,6-哌啶二酮盐酸盐(6.1g，0.037mol)和乙酸钠(8.6g，0.105mol)在150ml乙酸中搅拌14小时。将反应液降温至室温，有固体析出，过滤，滤饼用甲基叔丁基醚洗涤。鼓风干燥(60℃)8小时，得灰色固体7.5g，产品无需纯化，直接用于下一步反应。
步骤2：2-丙-2-炔氧基乙基甲磺酸酯(16b)的制备
将2-(丙-2-炔-1-基氧基)乙-1-醇(5g，50mmol)溶解于60ml二氯甲烷中，加入三乙胺(10g，0.1mol)，降温至小于-5℃，缓慢滴入甲磺酰氯(6.3g，55mmol)，保持温度小于-5℃，10分钟后滴毕，保持温度搅拌20分钟。TLC检测反应完成，将反应液倒入100ml饱和碳酸氢钠水溶液中，用二氯甲烷100ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到8.49g淡红色油状粗品产物。产品无需纯化，直接用于下一步反应。
步骤3：4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯胺(16c)的制备
将1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)(2.25g，10mmol)溶解于30mlDMF中，加入2-丙-2-炔氧基乙基甲磺酸酯(16b)(2.7g，15mmol)、碳酸铯(9.8g，30mmol)和催化量碘化钾，升温至100℃，搅拌过夜。TLC检测反应完成，将反应液降至室温，然后倒入100ml水中，用乙酸乙酯60ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余 物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-60:1)纯化，得到750mg黄色固体状产物。
步骤4：{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-氨基甲酸苯酯(16d)的制备
于室温将4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯胺(16c)(750mg，2.4mmol)溶解于8ml DMF中，然后加入吡啶(380mg，4.8mmol)，冰盐浴降温至-5℃至0℃。将氯甲酸苯酯(460mg，2.9mmol)(用3ml四氢呋喃稀释)慢慢滴加到上述溶液中，过程中控制温度在-5℃至0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。TLC检测反应完成，将反应液倒入30ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水50ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-60:1)纯化，得到540mg产物。
步骤5：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16e)的制备
将{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-氨基甲酸苯酯(16d)(540mg，1.26mmol)溶解于10ml四氢呋喃中，于室温加入5-叔丁基-2H-吡唑-3-基胺(263mg，1.89mmol)和三乙胺(383g，3.78mmol)，升温至70℃搅拌过夜。TLC检测反应完成，将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得250mg黄色固体状产物。
步骤6：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16)的制备
1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16e)(1.17g，2.5mmol)、4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)(840mg，2.5mmol)和碘化亚铜(95mg，0.5mmol)于20ml三乙胺和20mlDMF的混合溶剂中，氮气置换3次，加入Pd(PPh 3) 2Cl 2(170mg，0.25mmol)，再次氮气置换3次，70℃反应15小时。TLC检测反应完成，降温到室温，将反应液倒入100ml水中，抽滤，固体水洗，所得固体粗品通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得323mg米白色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.01(s,1H),11.14(s,1H),9.42(br,1H),8.97(s,1H),8.40(s,1H),7.82-7.92(m,3H),7.65-7.67(d,2H),7.53-7.55(d,2H),7.43-7.45(d,1H),7.28-7.32(dd,1H),6.93-6.98(m,1H),6.01(s,1H),5.12-5.18(m,1H),4.59(s,2H),4.23-4.26(m,2H),3.98-4.00(m,2H),2.85-2.92(m,1H),2.53-2.62(m,2H),2.04-2.09(m,1H),1.26(s,9H)。
LC-MS(ESI):729.3(M+H) +。
实施例17 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(17)的制备
Figure PCTCN2021107804-appb-000088
步骤1：2-(2-丙-2-炔氧基-乙氧基)-乙醇(17a)的制备
在氮气氛下，向250ml三口瓶中的二甘醇(4.25g，0.04mol)中加入无水四氢呋喃，降温0-5℃，加入叔丁醇钾(2.35g，0.021mol)氮气换气3次。滴加溴丙炔(2.38g，0.02mol)，滴加完毕后升温至室温反应15小时。TLC检测反应完成，抽滤，固体用乙酸乙酯洗涤，滤液浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得2.8g黄色油状产物。
步骤2：1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(17)的制备
与实施例16的制备方法相同，除了用2-(2-丙-2-炔氧基-乙氧基)-乙醇(17a)代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(17)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.14(s,1H),9.40(br,1H),8.98(s,1H),8.41(s,1H),7.82-7.91(m,3H),7.65-7.67(d,2H),7.54-7.56(d,2H),7.43-7.45(d,1H),7.28(d,1H),6.94-6.96(dd,1H),6.02(s,1H),5.13-5.17(m,1H),4.52(s,2H),4.15-4.17(m,2H),3.77-3.82(m,4H),3.69-3.72(m,2H),2.84-2.93(m,1H),2.50-2.61(m,2H),2.01-2.08(m,1H),1.26(s,9H)。
LC-MS(ESI)：773.3(M+H) +。
实施例18 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲(18)的制备
Figure PCTCN2021107804-appb-000089
与实施例17的制备方法相同，除了用三甘醇代替步骤1中的二甘醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{2-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-苯并咪唑-1-基)-苯基]-脲(18)。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.15(s,1H),9.41(br,1H),8.99(s,1H),8.41(s,1H),7.82-7.90(m,3H),7.65-7.67(d,2H),7.54-7.56(d,2H),7.43-7.45(d,1H),7.28-7.29(d,1H),6.93-6.96(dd,1H),6.02(s,1H),5.12-5.19(m,1H),4.50(s,2H),4.13-4.15(t,2H),3.77-3.79(t,2H),3.72-3.74(m,2H),3.60-3.63(m,6H),2.84-2.94(m,1H),2.53-2.61(m,2H),2.01-2.08(m,1H),1.26(s,9H)。
LC-MS(ESI):817.2(M+H)+。
实施例19 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2-{3-[2-(2,6-二氧-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(19)的制备
Figure PCTCN2021107804-appb-000090
与实施例17的制备方法相同，除了用四甘醇代替步骤1中的二甘醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2-{3-[2-(2,6-二氧-哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(19)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.13(s,1H),9.39(br,1H),8.97(s,1H),8.41(s,1H),7.82-7.90(m,3H),7.65-7.67(d,2H),7.53-7.56(d,2H),7.43-7.45(d,1H),7.27-7.28(d,1H),6.93-6.96(dd,1H),6.01(s,1H),5.12-5.16(m,1H),4.49(s, 2H),4.12-4.15(t,2H),3.76-3.78(m,2H),3.70-3.73(m,2H),3.58-3.60(m,4H),3.55-3.57(m,6H),2.84-2.93(m,1H),2.53-2.61(m,2H),1.97-2.07(m,1H),1.26(s,9H)。
LC-MS(ESI):862.2(M+H) +。
实施例20 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(20)的制备
Figure PCTCN2021107804-appb-000091
与实施例17的制备方法相同，除了用五甘醇代替步骤1中的二甘醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{2-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(20)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.13(s,1H),9.40(br,1H),8.94(s,1H),8.44(s,1H),7.84-7.91(m,3H),7.65-7.67(d,2H),7.54-7.56(d,2H),7.46-7.48(d,1H),7.29(m,1H),6.94-6.96(dd,1H),6.01(s,1H),5.10-5.16(m,1H),4.48(s,2H),4.12-4.15(t,2H),3.75-3.77(t,2H),3.70-3.72(m,2H),3.53-3.60(m,14H),2.84-2.93(m,1H),2.53-2.69(m,2H),1.99-2.08(m,1H),1.26(s,9H)。
LC-MS(ESI)：905.3(M+H) +。
实施例21 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-己氧基}-苯并咪唑-1-基)-苯基]-脲(21)的制备
Figure PCTCN2021107804-appb-000092
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-己氧基}-苯并咪唑-1-基)-苯基]-脲(21)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(15)(100mg，0.137mmol)溶解于30ml四氢呋喃中，于室温加入20mg湿Pd/C，氢气氛下，室温反应15小时。TLC检测反应完成，抽滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得50mg米白色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.12(s,1H),9.40(br,1H),8.98(s,1H),8.41(s,1H),7.66-7.76(m,5H),7.54-7.56(d,2H),7.43-7.45(d,1H),7.26(d,1H),6.91-6.94(dd,1H),6.01(s,1H),5.11-5.15(m,1H),3.99-4.03(t,2H),3.05-3.07(t,2H),2.84-2.91(m,1H),2.49-2.61(m,2H),2.03-2.06(m,1H),1.71-1.78(m,2H),1.61-1.29(m,2H),1.47-1.53(m,2H),1.40-1.43(m,2H),1.26(s,9H)。
LC-MS(ESI)：731.3(M+H) +。
实施例22 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(22)的制备
Figure PCTCN2021107804-appb-000093
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(22)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16)(120mg，0.165mmol)溶解于30ml四氢呋喃中，于室温加入20mg湿Pd/C，氢气氛下，室温反应15小时。TLC检测反应完成，抽滤，滤液减压浓 缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得40mg米白色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.11(s,1H),9.40(br,1H),8.98(s,1H),8.41(s,1H),7.65-7.74(m,5H),7.54-7.56(m,2H),7.43-7.47(d,1H),7.30(d,1H),6.94-6.97(dd,1H),6.01(s,1H),5.10-5.15(m,1H),4.15(m,2H),3.74(m,2H),3.49-3.52(m,2H),3.10(m,2H),2.84-2.92(m,1H),2.49-2.61(m,2H),2.03-2.06(m,1H),1.82-1.91(m,2H),1.26(s,9H)。
LC-MS(ESI)：733.2(M+H) +。
实施例23 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(23)的制备
Figure PCTCN2021107804-appb-000094
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(23)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(17)(120mg，0.155mmol)溶解于30ml四氢呋喃中，于室温加入20mg湿Pd/C，氢气氛下，室温反应15小时。TLC检测反应完成，抽滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得45mg米白色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),11.11(s,1H),9.41(br,1H),8.98(s,1H),8.43(s,1H),7.72-7.74(m,2H),7.66-7.69(m,3H),7.53-7.56(d,2H),7.43-7.45(d,1H),7.29-7.30(d,1H),6.93-6.96(dd,1H),6.02(s,1H),5.10-5.15(m,1H),4.14-4.16(m,2H),3.78-3.80(m,2H),3.60-3.62(m,2H),3.52-3.54(m,2H),3.42-3.45(m,2H),3.0 5-3.09(m,2H),2.84-2.93(m,1H),2.54-2.61(m,2H),1.96-2.06(m,1H),1.81-1.88(m,2H),1.27(s,9H)。
LC-MS(ESI)：777.3(M+H) +。
实施例24 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{7-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚-6-炔氧基}-苯并咪唑-1-基)-苯基]-脲(24)的制备
Figure PCTCN2021107804-appb-000095
与实施例16的制备方法相同，除了用6-庚炔醇代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇，并用3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)(制备方法如下实施例26所述)代替步骤6中的4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{7-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚-6-炔氧基}-苯并咪唑-1-基)-苯基]-脲(24)。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),11.00(s,1H),9.44(br,1H),9.00(s,1H),8.44(s,1H),7.45-7.71(m,8H),7.28(m,1H),6.92-6.94(dd,1H),6.03(s,1H),5.10-5.15(m,1H),4.31-4.48(q,2H),4.04-4.07(t,2H),2.84-2.93(m,1H),2.42-2.58(m,4H),1.98-2.01(m,1H),1.79-1.83(m,2H),1.62-1.67(m,4H),1.27(s,9H)。
LC-MS(ESI)：727.3(M+H) +。
实施例25 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(25)的制备
Figure PCTCN2021107804-appb-000096
与实施例16的制备方法相同，除了用5-己炔-1-醇代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇，并用3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮 (26b)代替步骤6中的4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(25)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),10.98(s,1H),9.40(br,1H),8.97(s,1H),8.40(s,1H),7.61-7.76(m,4H),7.48-7.56(m,3H),7.43-7.45(d,1H),7.19-7.30(d,1H),6.91-6.95(dd,1H),6.01(s,1H),5.10-5.15(m,1H),4.43-4.48(d,1H),4.30-4.34(d,1H),4.08-4.11(t,2H),2.85-2.94(m,1H),2.37-2.61(m,4H),1.89-2.02(m,3H),1.74-1.81(m,2H),1.26(s,9H)。
LC-MS(ESI)：713.3(M+H) +。
实施例26 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(26)的制备
Figure PCTCN2021107804-appb-000097
步骤1：3-溴-2-溴甲基-苯甲酸甲酯(26a)的制备
3-溴-2-甲基苯甲酸甲酯(25g，0.109mol)、NBS(21.4g，0.12mol)和AIBN(900mg，5.5mmol)于200ml四氯化碳中80℃反应4小时。TLC检测反应完成，降温至室温，加入100ml石油醚和20ml甲基叔丁基醚室温搅拌1小时。抽滤，滤液减压浓缩，得29g黄色油状产物，产品无需纯化，直接用于下一步反应。
步骤2：3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)的制备
将3-溴-2-溴甲基-苯甲酸甲酯(26a)(2g，6.51mmol)、3-氨基-2,6-哌啶二酮盐酸盐(1.1g，6.51mol)和三乙胺(2g，19.8mmol)溶解于30ml DMF中，外浴70℃反应15小时。TLC检测反应完成，降温至室温，将反应液倒入150ml水 中，抽滤，固体水洗，鼓风干燥(60℃)8小时，得1.8g灰色固体。产品无需纯化，直接用于下一步反应。
步骤3：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(26)的制备
与实施例16步骤6的制备方法相同，除了用3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)代替步骤6中的4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)，得到1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(26)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),10.99(s,1H),9.40(br,1H),8.97(s,1H),8.41(s,1H),7.75-7.77(d,1H),7.65-7.71(m,3H),7.53-7.56(m,3H),7.43-7.46(d,1H),7.31-7.32(d,1H),6.94-6.97(dd,1H),6.01(s,1H),5.11-5.16(m,1H),4.55(s,2H),4.48-4.53(d,1H),4.34-4.38(d,1H),4.22(m,2H),3.92(m,2H),2.85-2.94(m,1H),2.39-2.59(m,2H),1.99-2.02(m,1H),1.26(s,9H)。
LC-MS(ESI)：715.2(M+H) +。
实施例27 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(27)的制备
Figure PCTCN2021107804-appb-000098
与实施例16的制备方法相同，除了用2-(2-丙-2-炔氧基-乙氧基)-乙醇(17a)代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇，并用3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)代替步骤6中的4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)得到1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(27)。
1HNMR(DMSO-d 6,400MHz)δ:12.07(s,1H),11.02(s,1H),9.46(br,1H),9.04(s,1H),8.47(s,1H),7.71-7.82(m,4H),7.58-7.62(m,3H),7.49-7.51(d,1H),7.35(d,1H),6.99-7.02(dd,1H),6.07(s,1H),5.17-5.22(m,1H),4.53-4.58(d,1H),4.54(s,2H),4.39-4.43(d,1H),4.20-4.23(t,2H),3.84-3.87(m,2H),3.75-3.78(m,4H),2.92-2.95(m,1H),2.48-2.65(m,2H),2.03-2.08(m,1H),1.32(s,9H)。
LC-MS(ESI)：759.3(M+H) +。
实施例28 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2-{3-[2-(2,6-二氧-哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(28)的制备
Figure PCTCN2021107804-appb-000099
与实施例17的制备方法相同，除了用四甘醇代替步骤1中的二甘醇，得到1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{2-[2-(2-{3-[2-(2,6-二氧-哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(28)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),10.99(s,1H),9.39(br,1H),8.97(s,1H),8.41(s,1H),7.74-7.76(d,1H),7.69-7.77(d,1H),7.65-7.67(d,2H),7.53-7.56(d,2H),7.52(d,1H),7.43-7.45(d,1H),7.28(d,1H),6.93-6.98(dd,1H),6.01(s,1H),5.11-5.16(m,1H),4.46-4.50(d,1H),4.45(s,2H),4.31-4.36(d,1H),4.12-4.14(t,2H),3.73-3.77(t,2H),3.64-3.66(m,2H),3.58-3.60(m,4H),3.55-3.56(m,6H),2.85-2.95(m,1H),2.54-2.67(m,2H),1.95-2.02(m,1H),1.26(s,9H)。
LC-MS(ESI)：848.3(M+H) +。
实施例29 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[5-(1-{5-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-戊-4-炔基}-1H-[1,2,3]三唑-4-基)-戊氧基]-苯并咪唑-1–基}-苯基)-脲(29)的制备
Figure PCTCN2021107804-appb-000100
Figure PCTCN2021107804-appb-000101
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[5-(1-{5-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-戊-4-炔基}-1H-[1,2,3]三唑-4-基)-戊氧基]-苯并咪唑-1–基}-苯基)-脲(29)的制备
在氮气氛下，将3-[4-(5-叠氮基-戊-1-炔基)-1-氧代-1,3-二氢-异吲哚-2-基]-哌啶-2,6-二酮(根据实施例11的化合物11c的制备方法制备)(75mg，0.21mmo l)、1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-庚6-炔氧基-苯并咪唑-1-基)-苯基]-脲(49b)(100mg，0.20mmol)、五水硫酸铜(1M，0.1ml)、抗坏血酸钠(1M，0.1ml)溶解于12ml DMSO和6ml的甲醇中，并于60℃搅拌3小时。将反应液冷却至室温，倒入100ml水中，析出固体，过滤，滤饼用100ml水洗涤。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝30:1～20:1)纯化，得120mg黄色固体。
1HNMR(DMSO-d 6,400MHz)δ:12.06(br,1H),11.01(s,1H),9.41(br,1H),8.99(s,1H),8.43(s,1H),7.91(s,1H),7.63-7.72(m,4H),7.50-7.56(m,3H),7.44-7.46(d,1H),7.27(s,1H),6.91-6.94(dd,1H),6.02(s,1H),5.12-5.16(m,1H),4.31-4.50(q,2H),4.44-4.48(m,2H),3.99-4.02(t,2H),2.87-2.96(m,1H),2.41-2.67(m,6H),2.07-2.15(m,2H),1.98-2.03(m,1H),1.72-1.79(m,2H),1.67-1.68(m,2H),1.42-1.51(m,2H),1.27(s,9H)。
LC-MS(ESI)：836.3(M+H) +。
实施例30 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-己氧基}-苯并咪唑-1-基)-苯基]-脲(30)的制备
Figure PCTCN2021107804-appb-000102
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-己氧基}-苯并咪唑-1-基)-苯基]-脲(30)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{6-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-己-5-炔氧基}-苯并咪唑-1-基)-苯基]-脲(25)(100mg，0.14mmol)溶解于30ml四氢呋喃中，于室温加入20mg湿Pd/C，氢气氛下，室温反应15小时。TLC检测反应完成，抽滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得65mg米白色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.04(br,1H),11.05(s,1H),9.50(br,1H),9.06(s,1H),8.46(s,1H),7.71-7.74(d,2H),7.59-7.61(m,3H),7.49-7.53(m,3H),7.32(d,1H),6.96-6.99(dd,1H),6.07(s,1H),5.16-5.21(m,1H),4.51-4.55(d,1H),4.35-4.39(d,1H),4.05-4.09(t,2H),2.90-3.02(m,1H),2.70-2.74(t,2H),2.44-2.67(m,2H),2.04-2.08(m,1H),1.79-1.82(m,2H),1.67-1.72(m,2H),1.52-1.60(m,2H),1.45-1.50(m,2H),1.32(s,9H)。
LC-MS(ESI)：717.3(M+H) +。
实施例31 1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{7-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚氧基}-苯并咪唑-1-基)-苯基]-脲(31)的制备
Figure PCTCN2021107804-appb-000103
与实施例30的制备方法相同，除了用化合物(24)代替步骤1中的化合物(25)，得到1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-{7-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚氧基}-苯并咪唑-1-基)-苯基]-脲(31)。
1HNMR(DMSO-d 6,400MHz)δ:12.05(br,1H),11.03(s,1H),9.41(br,1H),9.01(s,1H),8.43(s,1H),7.69-7.72(d,2H),7.58-7.61(m,3H),7.47-7.50(m,3H),7.30(d,1H),6.96-6.98(dd,1H),6.05(s,1H),5.14-5.19(m,1H),4.33-4.53(q,2H),4.04-4.07(t,2H),2.91-3.00(m,1H),2.42-2.71(m,4H),2.03-2.07(m,1H),1.76-1.79(m,2H),1.65-1.72(m,2H),1.43-1.54(m,6H),1.30(s,9H)。
LC-MS(ESI)：731.3(M+H) +。
实施例32 1-[4-(5-{7-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚氧基}-苯并咪唑-1-基)-苯基]-3-(5-叔丁基-2H-吡唑-3-基)-脲(32)的制备
Figure PCTCN2021107804-appb-000104
与实施例2的制备方法相同，除了用化合物(31)代替实施例2中的化合物(1)，得到1-[4-(5-{7-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚氧基}-苯并咪唑-1-基)-苯基]-3-(5-叔丁基-2H-吡唑-3-基)-脲(32)。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),9.42(br,1H),8.99(s,1H),8.41(s,1H),7.66-7.69(d,2H),7.54-7.58(m,3H),7.43-7.46(m,3H),7.20-7.31(m,6H),6.91-6.94(dd,1H),6.03(s,1H),5.27-5.32(m,1H),4.79-4.88(q,2H),4.48-4.52(d,1H),4.26-4.30(d,1H),3.99-4.02(t,2H),3.08-3.16(m,1H),2.79-2.83(m,1H),2.62-2.66(t,2H),2.45-2.56(m,1H),2.02-2.09(m,1H),1.72-1.75(m,2H),1.60-1.63(m,2H),1.37-1.47(m,6H),1.27(s,9H)。
LC-MS(ESI)：821.4(M+H) +。
实施例33 1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(33)的制备
Figure PCTCN2021107804-appb-000105
步骤1：1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(33)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-(4-{5-[2-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-脲(27)(70mg，0.092mmol)溶解于20ml四氢呋喃中，于室温加入10mg 湿Pd/C，氢气氛下，室温反应15小时。TLC检测反应完成，抽滤，滤液浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得6mg米白色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.01(br,1H),10.99(s,1H),9.48(br,1H),9.01(s,1H),8.45(s,1H),7.66-7.68(d,2H),7.53-7.56(m,3H),7.44-7.46(m,3H),7.30(d,1H),6.93-6.96(dd,1H),6.02(s,1H),5.10-5.14(m,1H),4.43-4.48(d,1H),4.28-4.32(d,1H),4.14-4.16(t,2H),3.61-3.63(m,2H),3.51-3.54(m,2H),3.40-3.43(m,2H),2.87-2.91(m,1H),2.66-2.70(t,2H),2.48-2.60(m,2H),1.97-2.01(m,1H),1.82-1.86(m,2H),1.26(s,9H)。
LC-MS(ESI)：763.3(M+H) +。
实施例34 1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-1-甲酸叔丁酯-脲(34)的制备
Figure PCTCN2021107804-appb-000106
将1-(5-叔丁基-1H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代-哌啶-3-基]-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(化合物26)(100mg，0.14mmol)溶解于10ml二氧六环中，加入DMAP(3mg，0.024mmol)和Boc酸酐(45mg，0.206mmol)，升温至50℃，搅拌7个小时。将反应液降至室温，然后倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇+＝80:1-60:1)纯化，得到3mg黄色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.31(s,1H),10.94(s,1H),10.59(s,1H),8.40(s,1H),7.69-7.72(m,3H),7.63-7.65(d,1H),7.55-7.57(d,2H),7.48-7.50(t,1H),7.41-7.43(d,1H),7.26(m,1H),6.89-6.91(d,1H),5.96(s,1H),5.05-5.10(m,1H),4.49(s,2H),4.42-4.46(d,1H),4.27-4.32(d,1H),4.17(m,2H),3.86(m,2H),2.80-2.84(m,1H),2.37-2.53(m,2H),1.92-1.94(m,1H),1.35(s,9H),1.21(s,9H)。
LC-MS(ESI):815.3(M+H) +。
实施例35 1-(5-叔丁基-1-甲酸叔丁酯基-1H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-1-甲酸叔丁酯脲(35)的制备
Figure PCTCN2021107804-appb-000107
将1-(5-叔丁基-1H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代-哌啶-3-基]-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(26)(100mg，0.14mmol)溶解于10ml二氧六环中，加入DMAP(3mg，0.024mmol)和(Boc) 2O(45mg，0.206mmol)，升温至50℃，搅拌7个小时。将反应液降至室温，然后倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇+＝80:1-60:1)纯化，得到6mg黄色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:11.01(s,1H),10.61(s,1H),8.48(s,1H),7.75-7.79(m,3H),7.70-7.72(d,1H),7.64-7.66(d,2H),7.53-7.57(t,1H),7.47-7.50(d,1H),7.32(m,1H),6.96-6.98(d,1H),6.61(s,1H),5.12-5.16(m,1H),4.55(s,2H),4.48-4.53(d,1H),4.34-4.38(d,1H),4.23(m,2H),3.93(m,2H),2.87-2.94(m,1H),2.43-2.59(m,2H),1.99-2.01(m,1H),1.48(s,9H),1.40(s,9H),1.27(s,9H)。
LC-MS(ESI):915.3(M+H) +。
实施例36 1-{4-[5-(2-{3-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-3-(5-叔丁基-2H-吡唑-3-基)-脲(36)的制备
Figure PCTCN2021107804-appb-000108
与实施例2的制备方法相同，除了用化合物(26)代替实施例2中的化合物(1)，得到1-{4-[5-(2-{3-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-3-(5-叔丁基-2H-吡唑-3-基)-脲(36)。
1HNMR(DMSO-d 6,400MHz)δ:11.96(s,1H),9.36(s,1H),8.93(s,1H),8.38(s,1H),7.59-7.71(m,5H),7.47-7.49(m,3H),7.37-7.42(d,1H),7.14-7.26(m,7H),6.89-6.91(d,1H),5.95(s,1H),5.22-5.27(m,1H),4.70-4.79(m,2H),4.49(s,2H),4.25-4.29(d,1H),4.16(m,2H),3.86(m,2H),3.00-3.08(m,1H),2.69-2.80(m,2H),1.99-2.02(m,1H),1.90-1.96(m,1H),1.20(s,9H)。
LC-MS(ESI):805.3(M+H) +。
实施例37 3-{4-[7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)庚基]-1,3-二氧代-1,3-二氢-异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(37)的制备
Figure PCTCN2021107804-appb-000109
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),9.40(br,1H),8.98(s,1H),8.41(s,1H),7.66-7.83(m,5H),7.54-7.56(d,2H),7.43-7.45(d,1H),7.26-7.27(d,1H),6.91-6.94(dd,1H),6.02(s,1H),5.62-5.67(m,2H),5.29-5.33(m,1H),3.99-4.02(t,2H),3.02- 3.05(m,3H),2.80-2.85(m,1H),2.53-2.60(m,1H),2.10-2.13(m,1H),1.30-1.74(m,10H),1.26(s,9H),1.09(s,9H)。
LC-MS(ESI):858.3(M+H) +。
实施例38 1-[4-(5-{7-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚6-炔氧基}-苯并咪唑-1-基)-苯基]-3-(5-叔丁基-2H-吡唑-3-基)-脲(38)的制备
Figure PCTCN2021107804-appb-000110
与实施例2的制备方法相同，除了用化合物(24)代替实施例2中的化合物(1)，得到1-[4-(5-{7-[2-(1-苄基-2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-庚6-炔氧基}-苯并咪唑-1-基)-苯基]-3-(5-叔丁基-2H-吡唑-3-基)-脲(38)。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),9.40(br,1H),8.98(s,1H),8.41(s,1H),7.63-7.71(m,4H),7.49-7.56(m,3H),7.42-7.44(d,1H),7.20-7.30(m,7H),6.91-6.94(dd,1H),6.02(s,1H),5.27-5.31(m,1H),4.77-4.85(q,2H),4.47-4.51(d,1H),4.04-4.07(t,2H),3.04-3.13(m,1H),2.74-2.78(m,1H),2.50-2.55(m,3H),1.97-2.08(m,1H),1.80-1.83(m,2H),1.63-1.67(m,4H),1.27(s,9H)。
LC-MS(ESI)：817.3(M+H) +。
实施例39 苯甲酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基酯(39)的制备
Figure PCTCN2021107804-appb-000111
Figure PCTCN2021107804-appb-000112
步骤1：3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基苯甲酸酯(39a)的制备
将2-(2,6-二氧代哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(1.38g，5mmol)溶解于20ml DMF中，加入碳酸铯(3.26g，10mmol)和催化量碘化钾，降温至0℃至5℃，缓慢滴入苯甲酸氯甲酯(1.02g，6mmol)滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入100ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到2g粗品产物。
步骤2：苯甲酸3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-2,3-二氢-1H-苯并咪唑-5-基氧基)-乙氧基]-丙基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基酯(39)的制备
将1-(4-{5-[2-(2-氨基-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-3-(5-叔丁基-2H-吡唑-3-基)-脲(1k)(300mg，0.629mmol)溶解于20ml DMSO中，于室温加入3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基苯甲酸酯(39a)(387mg，0.943mmol)和TEA(192mg，1.887mmol)，升温至100℃搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯150ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到70mg固体状的产物。
1HNMR(DMSO-d 6,400MHz)δ:12.02(s,1H),9.40(br,1H),8.97(s,1H),8.40(s,1H),7.89-7.94(m,2H),7.66-7.68(m,3H),7.49-7.60(m,5H),7.41-7.43(d,1H),7.29(d,1H),7.16-7.18(d,1H),7.03-7.05(d,1H),6.92-6.95(dd,1H),6.65-6.68(t,1H),6.02(s,1H),5.87-5.93(q,2H),5.26-5.30(m,1H),4.15-4.17(m,2H),3.81-3.83(m,2H),3.71-3.73(t,2H),3.49-3.53(m,2H),3.04-3.11(m,1H),2.83-2.88(m,1H),2.60-2.67(m,1H),2.08-2.11(m,1H),1.80-1.83(m,2H),1.27(s,9H)。
LC-MS(ESI):868.2(M+H) +。
实施例40 2,2-二甲基丙酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基酯(40)的制备
Figure PCTCN2021107804-appb-000113
与实施例39的制备方法相同，除了用特戊酸氯甲酯代替实施例39步骤1中苯甲酸氯甲酯，得到2,2-二甲基丙酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基酯(40)。
1HNMR(DMSO-d 6,400MHz)δ:12.06(s,1H),9.45(br,1H),9.02(br,1H),8.46(s,1H),7.71-7.73(d,2H),7.58-7.65(m,3H),7.46-7.48(d,1H),7.33(d,1H),7.21-7.23(d,1H),7.07-7.10(d,1H),6.96-6.99(dd,1H),6.68-6.71(t,1H),6.06(s,1H),5.68(s,2H),5.26-5.30(m,1H),4.21(m,2H),3.87(m,2H),3.76-3.78(m,2H),3.53-3.57(m,2H),3.05-3.14(m,1H),2.84-2.88(m,1H),2.50-2.66(m,1H),2.00-2.12(m,1H),1.31(s,9H),1.12(s,9H)。
LC-MS(ESI):848.3(M+H) +。
实施例41 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基异丁酸酯(41)的制备
Figure PCTCN2021107804-appb-000114
与实施例39的制备方法相同，除了用异丁酸氯甲基酯代替实施例39步骤1中苯甲酸氯甲酯，得到异丁酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基酯(41)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),9.41(s,1H),8.98(s,1H),8.41(s,1H),7.67-7.69(d,2H),7.54-7.60(m,3H),7.42-7.44(d,1H),7.29-7.30(d,1H),7.16- 7.18(d,1H),7.03-7.05(d,1H),6.92-6.95(m,1H),6.64-6.67(t,1H),6.02(s,1H),5.62-5.67(m,2H),5.21-5.26(m,1H),4.15-4.17(m,2H),3.82-3.84(m,2H),3.71-3.74(m,2H),3.51-3.54(m,2H),3.01-3.10(m,1H),2.79-2.84(m,1H),2.55-2.60(m,1H),2.04-2.08(m,1H),1.27(s,9H),1.01-1.04(m,6H)。
LC-MS(ESI)：834.2(M+H) +。
实施例42 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基丁酸酯(42)的制备
Figure PCTCN2021107804-appb-000115
与实施例39的制备方法相同，除了用丁酸氯甲酯代替实施例39步骤1中苯甲酸氯甲酯，得到丁酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基酯(42)。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),9.43(s,1H),8.99(s,1H),8.41(s,1H),7.67-7.69(d,2H),7.54-7.60(m,3H),7.41-7.44(d,1H),7.29-7.30(d,1H),7.15-7.17(d,1H),7.03-7.05(d,1H),6.92-6.95(m,1H),6.65-6.68(t,1H),6.03(s,1H),5.61-5.26(m,1H),4.15-4.16(m,2H),3.82-3.83(m,2H),3.71-3.73(m,2H),3.51-3.53(m,2H),3.01-3.08(m,1H),2.79-2.84(m,1H),2.53-2.80(m,1H),2.20-2.23(m,2H),2.04-2.07(m,1H),1.44-1.53(m,2H),1.27(s,9H),0.81-0.84(m,3H)。
LC-MS(ESI)：834.3(M+H) +。
实施例43 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基辛酸酯(43)的制备
Figure PCTCN2021107804-appb-000116
与实施例39的制备方法相同，除了用辛酸氯甲酯代替实施例39步骤1中苯甲酸氯甲酯，得到辛酸3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-(氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-基甲基酯(43)。
1HNMR(DMSO-d 6,400MHz)δ:12.01(s,1H),9.41(br,1H),8.97(s,1H),8.41(s,1H),7.66-7.68(d,2H),7.53-7.60(m,3H),7.41-7.43(d,1H),7.29(d,1H),7.16-7.18(d,1H),7.03-7.04(d,1H),6.92-6.95(dd,1H),6.65-6.68(t,1H),6.02(s,1H),5.60-5.66(q,2H),5.20-5.25(m,1H),4.15-4.17(t,2H),3.82-3.84(m,2H),3.71-3.74(t,2H),3.50-3.53(m,2H),3.00-3.10(m,1H),2.79-2.83(m,1H),2.51-2.60(m,1H),2.20-2.24(t,2H),2.06-2.08(m,1H),1.27(s,9H),0.79-1.52(m,13H)。
LC-MS(ESI):890.3(M+H) +。
实施例44 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-乙氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基异丙基碳酸酯(44)的制备
Figure PCTCN2021107804-appb-000117
与实施例39的制备方法相同，除了用氯甲基碳酸异丙酯代替实施例39步骤1中苯甲酸氯甲酯，得到3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-乙氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基异丙基碳酸酯(44)。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),9.41(br,1H),8.99(s,1H),8.43(s,1H),7.66-7.68(d,2H),7.54-7.60(m,3H),7.42-7.44(d,1H),7.29(d,1H),7.17-7.19(d,1H),7.03-7.05(d,1H),6.92-6.94(dd,1H),6.66-6.69(t,1H),6.02(s,1H),5.61-5.68(q,2H),5.22-5.26(m,1H),4.71-4.77(m,1H),4.15-4.17(t,2H),3.82-3.84(m,2H),3.72-3.75(t,2H),3.50-3.54(m,2H),3.01-3.05(m,1H),2.79-2.83(m,1H),2.51-2.59(m,1H),2.03-2.06(m,1H),1.27(s,9H),1.18-1.20(m,6H)。
LC-MS(ESI)：850.3(M+H) +。
实施例45 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙基氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧基羰基氨基-3-甲基丁酸酯(45)的制备
Figure PCTCN2021107804-appb-000118
步骤1：(S)-2-叔丁氧羰基氨基-3-甲基丁酸氯甲基酯(45a)的制备
将BOC-L-缬氨酸(3.0g，10.9mmol)、碳酸氢钠(4.6g，54.7mmol)和四丁基硫酸氢铵(470mg，1.38mmol)溶解于30ml二氯甲烷和30ml的水中，于室温搅5min。冰浴降温至0℃，缓慢滴入氯硫酸氯甲酯(2.0g，9.2mmol)，升至室温，搅拌2小时。将反应液倒入100ml水中，用乙酸乙酯二氯甲烷50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。得到3.6g粗品产物。
步骤2：3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧羰基氨基-3-甲基丁酸酯(45b)的制备
将2-(2,6-二氧代哌啶-3-基)-4-氟-异吲哚-1,3-二酮1a(3.0g，10.8mmol)溶解于20mlDMF中，加入碳酸铯(5.3g，16.25mmol)于室温搅20min。冰浴降温至0℃，缓慢滴入(S)-2-叔丁氧羰基氨基-3-甲基丁酸氯甲基酯(45a)(3.6g，13.5mmol)，升至室温，搅拌2小时。将反应液倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝20:1-10:1)纯化得到1.5g产物。
步骤3：3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙基氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧基羰基氨基-3-甲基丁酸酯(45)的制备
将3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧羰基氨基-3-甲基丁酸酯45b(200mg，0.42mmol)溶解于10ml DMSO中， 加入三乙胺(60mg，0.59mmol)和1-(4-{5-[2-(2-氨基-乙氧基)-乙氧基]-苯并咪唑-1-基}-苯基)-3-(5-叔丁基-2H-吡唑-3-基)-脲1k(212mg，0.42mmol)，升温至90℃，搅拌14小时。将反应液降至室温，然后倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝80:1-40:1)纯化，得到123mg黄色固体状产物。
1HNMR(DMSO-d 6,400MHz)δ:12.08(s,1H),9.47(s,1H),9.04(s,1H),8.47(s,1H),7.72-7.74(d,2H),7.59-7.65(m,3H),7.47-7.49(d,1H),7.34(s,1H),7.18-7.23(m,2H),7.08-7.10(d,1H),6.97-6.99(d,1H),6.70-6.72(d,1H),6.08(s,1H),5.75-5.80(m,1H),5.63-5.66(m,1H),5.26-5.29(m,1H),4.21(m,2H),3.88(m,2H),3.77(m,2H),3.56-3.58(m,2H),3.08-3.15(m,1H),2.85-2.89(m,1H),2.56-2.65(m,1H),2.10-2.13(m,1H),1.97-2.03(m,1H),1.42(s,9H),1.32(s,9H),0.86-0.89(m,6H)。
LC-MS(ESI)：960.3(M+H) +。
实施例46 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-氨基-3-甲基丁酸酯(46)的制备
Figure PCTCN2021107804-appb-000119
将3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙基氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧基羰基氨基-3-甲基丁酸酯(45)(120mg，0.125mmol)溶解于10ml乙酸乙酯中，于室温加入EA/HCl(2M)10ml，加毕继续室温反应2小时。抽滤，固体乙酸乙酯洗涤，所得固体溶解于20ml水中，饱和碳酸氢钠水溶液调节pH＝8-9，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝80:1-40:1)纯化，得到21mg黄色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),9.43(br,1H),8.99(s,1H),8.41(s,1H),7.66-7.68(d,2H),7.54-7.60(m,3H),7.41-7.44(d,1H),7.29(m,1H),7.16-7.18(d,1H),7.03-7.05(d,1H),6.92-6.94(d,1H),6.65(m,1H),6.02(s,1H),5.59-5.73(m,2H),5.20-5.25(m,1H),4.16(m,2H),3.82(m,2H),3.71(m,2H),3.50(m,2H),3.07-3.09(m,1H),3.01-3.05(m,1H),2.79-2.83(m,1H),2.50-2.61(m,1H),2.04-2.07(m,1H),1.74-1.81(m,1H),1.28(s,9H),0.74-0.84(m,6H)。
LC-MS(ESI)：863.3(M+H) +。
实施例47 3-{4-[5-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-戊基氨基]-1,3-二氧代-1,3-二氢异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基异丁酸酯(47)的制备
Figure PCTCN2021107804-appb-000120
将1-{4-[5-(5-(氨基-戊氧基)-苯并咪唑-1-基]-苯基]-3-(5-叔丁基-2H-吡唑-3-基)-脲(与实施例1的化合物1k的制备方法相同，除了用5-氨基-1-戊醇代替步骤2中的2-(2-氨基-乙氧基)-乙醇)(500mg，1.05mmol)溶解于10ml DMF中，于室温加入2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(与实施例39的化合物39a的制备方法相同，除了用异丁酸氯甲基酯代替实施例39步骤1中苯甲酸氯甲酯)(435mg，1.11mmol)和三乙胺(160mg，1.58mmol)，升温至90℃搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯150ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到336mg黄色固体状的产物。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),9.39(br,1H),8.99(s,1H),8.41(s,1H),7.66-7.68(d,2H),7.54-7.60(d,3H),7.43-7.45(d,1H),7.29(m,1H),7.11-7.14(d,1H),7.02-7.04(dd,1H),6.92-6.94(d,1H),6.65(t,1H),6.02(s,1H),5.65(s,2H),5.22-5.27(m,1H),4.02-4.05(t,2H),3.01-3.10(m,1H),2.80-2.85(m,1H),2.54-2.62(m,1H),2.45-2.49(m,1H),2.07-2.11(m,1H),1.78-1.81(m,2H),1.63-1.68(m,2H),1.53-1.57(m,2H),1.27(s,9H),1.03-1.05(m,6H)。
LC-MS(ESI):832.3(M+H) +。
实施例48 3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基[1,4']双哌啶基-1'-羧酸酯(48)的制备
Figure PCTCN2021107804-appb-000121
步骤1：[1,4']双哌啶基-1'-羧酸氯甲酯(48a)的制备
于室温将4-哌啶基哌啶(1g，5.942mmol)、DIEA(2.3g，17.827mmol)溶解于30mlTHF，降温至0℃至5℃，缓慢滴入氯甲酸氯甲酯(0.92g，7.131mmol)，滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入100ml水中，用二氯甲烷150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.75g油状物。
步骤2：3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基[1,4']双哌啶基-1'-羧酸酯(48b)的制备
将2-(2,6-二氧代哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(1.54g，5.598mmol)溶解于20mlDMF中，加入碳酸铯(3.65g，11.964mmol)和催化量碘化钾，降温至0℃至5℃，缓慢滴入[1,4']双哌啶基-1'-羧酸氯甲酯(48a) (1.75g，6.718mmol)，滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入100ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1g粗品产物。
步骤3：3-(4-{2-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙氨基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基[1,4']双哌啶基-1'-羧酸酯(48)的制备
将1-(4-{5-[2-(2-氨基-乙氧基)-乙氧基]-2,3-二氢-苯并咪唑-1-基}-苯基)-3-(5-叔丁基-2H-吡唑-3-基)-脲(1k)(247mg，0.518mmol)溶解于20mlDMSO中，于室温加入3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基[1,4']双哌啶基-1'-羧酸酯(48b)(259mg，0.518mmol)和TEA(157mg，1.554mmol)，升温至90℃搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯150ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到65mg产物。
1HNMR(DMSO-d6,400MHz)δ:12.08(s,1H),9.42(br,1H),9.05(s,1H),8.47(s,1H),7.72-7.74(d,2H),7.59-7.66(d,3H),7.47-7.49(d,1H),7.35-7.36(d,1H),7.22-7.24(d,1H),7.08-7.10(d,1H),6.98-7.00(d,1H),6.70-6.73(t,1H),6.08(s,1H),5.61-5.66(m,2H),5.26-5.30(m,1H),4.21-4.23(t,2H),3.87-3.89(m,2H),3.77-3.79(m,2H),3.57-3.59(m,2H),3.05-3.14(m,1H),2.84-2.88(m,1H),2.70-2.74(m,2H),2.59-2.64(m,1H),2.44(m,4H),2.11-2.13(m,1H),1.66-1.71(m,2H),1.23-1.49(m,11H),1.32(s,9H)。
LC-MS(ESI):958.3(M+H) +。
实施例49 3-{4-[7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-庚-1-基]-1-氧代-1,3-二氢-异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(49)的制备
Figure PCTCN2021107804-appb-000122
Figure PCTCN2021107804-appb-000123
步骤1：3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(49a)的制备
将3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)(1.0g，3mmol)溶解于20mlDMF中，于室温加入碳酸铯(1.96g，6mmol)和催化量碘化钾，降温至0℃至5℃，缓慢滴入特戊酸氯甲酯(542mgg，3.6mmol)，滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入100ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.3g粗品产物。
步骤2：3-{4-[7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-庚-1-基]-1-氧代-1,3-二氢-异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(49)的制备
氮气氛下，向1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-庚-6-炔氧基-苯并咪唑-1-基)-苯基]-脲(49b)(与实施例16的化合物16e制备方法相同，除了用6-庚炔醇代替步骤2中的2-(丙-2-炔-1-基氧基)乙-1-醇)(231mg，0.477mmol)、3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(49a)(250mg，0.57mmol)和碘化亚铜(18mg，0.095mmol)于10ml三乙胺和10mlDMF的混合溶剂中，加入Pd(PPh 3) 2Cl 2(34mg，0.048mmol)，再次氮气置换3次，70℃反应15小时。TLC检测反应完成，降温到室温，将反应液倒入100ml水中，抽滤，固体水洗，所得固体粗品通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得99mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.07(s,1H),9.45(br,1H),9.04(s,1H),8.46(s,1H),7.66-7.77(m,4H),7.54-7.60(m,3H),7.47-7.49(d,1H),7.32(d,1H),6.95-6.99(dd,1H),6.07(s,1H),5.62-5.69(q,2H),5.35-5.39(m,1H),4.51-4.55(d,1H),4.3-4.35(d,1H),4.07-4.10(t,2H),3.08-3.17(m,1H),2.79-2.83(m,1H),2.42-2.58(m,3H),2.08-2.12(m,1H),1.83-1.87(m,2H),1.61-1.70(m,4H),1.31(m,9H),1.13(s,9H)。
LC-MS(ESI)：841.3(M+H) +。
实施例50 3-{4-[7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-庚-1-基]-1,3-二氧代-1,3-二氢-异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(50)的制备
Figure PCTCN2021107804-appb-000124
与实施例49的制备方法相同，除了用4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)代替实施例49步骤1中的3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(26b)，得到3-{4-[7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-庚-1-基]-1,3-二氧代-1,3-二氢-异吲哚-2-基}-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(50)。
1HNMR(DMSO-d 6,400MHz)δ:12.03(s,1H),9.40(br,1H),8.99(s,1H),8.41(s,1H),7.77-7.89(m,3H),766-7.68(d,2H),7.54-7.56(d,2H),7.43-7.45(d,1H),7.29(br,1H),6.92-6.94(dd,1H),6.02(s,1H),5.62-5.67(m,2H),5.31-5.36(m,1H),4.04-4.07(t,2H),3.01-3.06(m,1H),2.80-2.84(m,1H),2.53-2.57(m,3H),2.10-2.14(m,1H),1.79-1.82(m,2H),1.68-1.69(m,4H),1.27(s,9H),1.09(s,9H)。
LC-MS(ESI):855.3(M+H) +。
实施例51 2,2-二甲基丙酸3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基酯(51)的制备
Figure PCTCN2021107804-appb-000125
与实施例49的制备方法相同，除了用4-溴-2-(2,6-二氧代哌啶-3-基)-异吲哚-1,3-二酮(16a)代替实施例49步骤1中的3-(4-溴-1-氧代-1,3-二氢-异吲哚-2-基)- 哌啶-2,6-二酮(26b)，并用1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16e)代替步骤2中的1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-庚-6-炔氧基-苯并咪唑-1-基)-苯基]-脲(49b)，得到3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(51)。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),9.42(br,1H),8.98(s,1H),7.55-7.93(m,10H),6.95-6.97(d,1H),6.02(s,1H),5.65(m,2H),5.32-5.37(m,1H),4.59(s,2H),4.24(m,2H),3.99(m,2H),3.02-3.07(m,1H),282-2.86(m,1H),2.56-2.60(m,1H),2.12-2.15(m,1H),1.26(s,9H),1.08(s,9H)。
LC-MS(ESI)：843.2(M+H) +。
实施例52 3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(52)的制备
Figure PCTCN2021107804-appb-000126
与实施例49的制备方法相同，除了用1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-丙-2-炔氧基-乙氧基)-苯并咪唑-1-基]-苯基}-脲(16e)代替步骤2中的1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-庚-6-炔氧基-苯并咪唑-1-基)-苯基]-脲(49b)，得到3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基2,2-二甲基丙酸酯(52)。
1HNMR(DMSO-d6,400MHz)δ:12.04(s,1H),9.44(br,1H),9.00(s,1H),8.43(s,1H),7.77-7.79(d,1H),7.67-7.72(m,3H),7.53-7.57(m,3H),7.44-7.46(d,1H),7.32(m,1H),6.95-6.97(dd,1H),6.03(s,1H),5.57-5.65(q,2H),5.31-5.37(m,1H),4.54(s,2H),4.47-4.51(d,1H),4.31-4.35(d,1H),4.22(m,2H),3.92(m,2H),3.06-3.15(m,1H),2.78-2.82(m,1H),2.40-2.47(m,1H),2.06-2.09(m,1H),1.26(s,9H),1.08(s,9H)。
LC-MS(ESI):829.2(M+H) +。
实施例53 3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧基羰基氨基-3-甲基丁酸酯(53)的制备
Figure PCTCN2021107804-appb-000127
步骤1：3-(4-{3-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-丙-1-炔基}-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基甲基(S)-2-叔丁氧基羰基氨基-3-甲基丁酸酯(53)的制备
1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-{3-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-丙-2-炔氧基}-乙氧基)-苯并咪唑-1-基]-苯基}-脲(26)(215mg，0.30mmol)、(S)-2-叔丁氧羰基氨基-3-甲基丁酸氯甲基酯(45a)(86mg，0.32mmol)和碳酸铯(190mg，0.58mmol)于10ml DMF中，于40℃反应16小时。TLC检测反应完成，降温到室温，将反应液倒入100ml水中，抽滤，固体水洗，所得固体粗品通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得13mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:11.00(s,1H),9.29(br,1H),8.76(s,1H),8.42(s,1H),7.75-7.77(d,2H),7.68-7.72(m,3H),7.53-7.58(d,1H),7.44(m,1H),7.28-7.32(d,1H),7.21-7.32(d,1H),6.91-6.97(d,1H),6.72-6.74(m,1H),6.22(s,1H),6.05-6.08(d, 1H),5.82-5.85(d,1H),5.12-5.15(m,1H),4.55(m,2H),4.48-4.53(d,1H),4.34-4.39(d,1H),4.23(m,2H),3.93(m,2H),3.80-3.86(m,1H),3.70(m,1H),2.87-2.95(m,1H),2.44-2.60(m,1H),1.88-1.99(m,2H),1.37(s,9H),1.22(s,9H),0.83-0.85(m,6H)。
LC-MS(ESI):944.4(M+H) +。
实施例54 7-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)庚酰胺(54)的制备
Figure PCTCN2021107804-appb-000128
步骤1：7-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-庚酸乙酯(54a)的制备
于70℃，将1-(4-氨基苯基)-1H-苯并咪唑-5-醇(1g)(1.42g，6.31mmol)、7-溴庚酸乙酯(1.8g，7.59mmol)和碳酸铯(6.0g，18.40mml)在20ml DMF中 搅拌1小时。将反应液降温至室，倒入200ml水中，有固体析出，过滤，滤饼用200ml水洗涤。鼓风干燥(60℃)8小时，得固体2.5g，产品无需纯化，直接用于下一步反应。
步骤2：7-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-庚酸乙酯(54b)的制备
将7-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-庚酸乙酯(54a)(2.5g，6.54mmol)、吡啶(670mg，8.48mmol)溶解于30ml DMF中，降温至0℃，缓慢滴入氯甲酸苯酯(1.0g，6.38mmol)，于室温搅拌10分钟。将反应液倒入200ml饱和食盐水中，水相用乙酸乙酯50ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到3.1g固体粗品产物。
步骤3：7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸乙酯(54c)的制备
于70℃，将7-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-庚酸乙酯(54b)(3.1g，6.17mmol)、5-叔丁基-2H-吡唑-3-基胺(1.7g，12.23mmol)和三乙胺(1.8g，17.82mml)在20ml四氢呋喃中搅拌14小时。反应液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝80:1-50:1)纯化，得2.7g固体。
步骤4：7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸(54d)的制备
于50℃，将7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸乙酯(54c)(1.5g，2.74mmol)、氢氧化锂一水合物(230mg，5.47mmol)在20ml四氢呋喃和5ml的水中搅拌14小时。将反应液冷却至室温，加入200ml水，用HCl调PH为5～6，过滤，滤饼用200ml水洗涤。鼓风干燥(60℃)8小时，得固体1.2g。
步骤5：7-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)庚酰胺(54)的制备
于50℃,将7-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸(54d)(100mg，0.19mmol)、3-(7-氨基-3-氧代-1H-异吲哚-2-基)哌啶-2,6-二酮(70mg，0.27mmol)、EDC.HCl(50mg，0.26mmol)、HOBT(40mg，0.29mmol)、TEA(30mg，0.29mmol)在10ml DMF中搅拌14小时。将反应液冷却至室温后，倒入100ml水中，有固体析出，过滤，滤饼用100ml水洗涤。鼓风干燥(60℃)4小时，固体通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝50:1-25:1)纯化，得到18mg黄色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.02(s,1H),9.84(s,1H),8.95(s,1H),8.42(s,1H),7.78-7.80(m,1H),7.43-7.69(m,8H),7.25-7.26(d,1H),6.93-6.94(dd,1H),6.02(s,1H),5.05-5.15(m,1H),4.30-4.39(q,2H),4.00-4.03(t,2H),2.84-2.94(m,1H), 2.55-2.61(m,2H),2.36-2.39(t,2H),2.00-2.04(m,1H),1.73-1.77(m,2H),1.62-1.67(m,2H),1.46-1.51(m,2H),1.36-1.41(m,2H),1.26(s,9H)。
LC-MS(ESI)：815.3(M+H) +。
实施例55 7-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)庚酰胺(55)的制备
Figure PCTCN2021107804-appb-000129
与实施例54的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤3中的5-叔丁基-2H-吡唑-3-基胺，得到7-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)庚酰胺(55)。
1HNMR(DMSO-d6,400MHz)δ:10.81(s,1H),9.59(s,1H),9.38(s,1H),8.87(s,1H),8.24(s,1H),7.58-7.60(d,1H),7.46-7.48(d,2H),7.36-7.38(d,1H),7.22-7.30(m,3H),7.05(m,1H),6.71-6.74(dd,1H),6.30(s,1H),4.89-4.93(m,1H),4.09-4.20(q,2H),3.80-3.83(t,2H),2.64-2.73(m,1H),2.30-2.40(m,2H),2.15-2.19(t,2H),1.77-1.82(m,1H),1.53-1.55(m,2H),1.42-1.46(m,2H),1.18-1.28(m,4H),1.09(s,9H)。
LC-MS(ESI):761.1(M+H) +。
实施例56 5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(56)的制备
Figure PCTCN2021107804-appb-000130
与实施例54的制备方法相同，除了用5-溴戊酸乙酯代替步骤1中的7-溴庚酸乙酯，并用3-氨基-5-叔丁基异噁唑代替步骤3中的5-叔丁基-2H-吡唑-3-基胺，得到5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(56)。
1HNMR(DMSO-d6,400MHz)δ:11.02(s,1H),9.82(s,1H),9.59(s,1H),9.06(s,1H),8.43(s,1H),7.81-7.83(d,1H),7.67-7.69(d,2H),7.57-7.59(d,1H),7.44-7.50(m,3H),7.30(m,1H),6.94-6.96(m,1H),6.52(s,1H),5.11-5.16(m,1H),4.32-4.42(m,2H),4.07(m,2H),2.86-2.94(m,1H),2.56-2.61(m,1H),2.46(m,2H),2.27-2.34(m,1H),1.99-2.03(m,1H),1.81(m,4H),1.30(s,9H)。
LC-MS(ESI)：733.3(M+H) +。
实施例57 2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-N-[2-(2,6-二氧代哌啶-3-基)-1-氧-2,3-二氢-1H-异吲哚-4-基]-乙酰胺(57)的制备
Figure PCTCN2021107804-appb-000131
与实施例54的制备方法相同，除了用溴乙酸乙酯代替步骤1中的7-溴庚酸乙酯，并用3-氨基-5-叔丁基异噁唑代替步骤3中的5-叔丁基-2H-吡唑-3-基胺，得到2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-N-[2-(2,6-二氧代哌啶-3-基)-1-氧-2,3-二氢-1H-异吲哚-4-基]-乙酰胺(57)。
1HNMR(DMSO-d6,400MHz)δ:11.07(s,1H),10.20(s,1H),9.66(s,1H),9.16(s,1H),8.52(s,1H),7.80-7.82(d,1H),7.73-7.75(d,2H),7.57-7.66(m,5H),7.42(m,1H),7.15-7.18(dd,1H),6.58(s,1H),5.17-5.22(m,1H),4.89(s,2H),4.33-4.43(q,2H),2.93-3.02(m,1H),2.63-2.67(m,1H),2.33-2.43(m,1H),2.04-2.06(m,1H),1.35(s,9H)。
LC-MS(ESI)：691.2(M+H) +。
实施例58 2-[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-N-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-乙酰胺(58)的制备
Figure PCTCN2021107804-appb-000132
步骤1：(2-苄氧基-乙氧基)-乙酸叔丁酯(58a)的制备
将2-苄氧基乙醇(10g，65.71mmol)溶解于150ml二氯甲烷中，加入37％的NaOH溶液150ml和四丁基溴化铵(21.22g，65.71mmol)，降温至小于-5℃，搅拌5min，缓慢滴入用20ml二氯甲烷稀释的溴乙酸叔丁酯(19.2g，98.43mmol)，保持温度小于-5℃，6分钟后滴毕，保持温度搅拌10分钟，移去冰浴，搅拌18h。将反应液倒入分液漏斗中分层，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝20:1-5:1)纯化，得到12g油状产物。
步骤2：(2-羟基-乙氧基)-乙酸叔丁酯(58b)的制备
将(2-苄氧基-乙氧基)-乙酸叔丁酯(58a)12g溶解于200ml甲醇中，加入钯碳1.2g，氢气换气三次，升温至60℃，搅拌16h。TLC检测反应完成，过滤，滤液减压浓缩，得到7.8g油状产物。
步骤3：[2-(甲苯-4-磺酰氧基)-乙氧基]-乙酸叔丁酯(58c)的制备
将(2-羟基-乙氧基)-乙酸叔丁酯(58b)(4g，22.73mmol)溶解于40ml二氯甲烷中，加入三乙胺(2.76g，27.3mmol)，降温至小于-5℃，缓慢滴入用10ml二氯甲烷稀释的对甲苯磺酰氯(4.33g，22.73mmol)，保持温度小于-5℃，4分钟后滴毕，保持温度搅拌10分钟，移去冰浴搅拌3h。将反应液倒入40ml饱和食盐水中分层，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝20:1-5:1)纯化，得到4.3g油状产物。
步骤4：{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙酸叔丁酯(58d)的制备
将1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)(2.4g，10.85mmol)溶解于20ml DMF中，加入[2-(甲苯-4-磺酰氧基)-乙氧基]-乙酸叔丁酯(58c)(4.3g，13mmol)、碳酸钾(2g，14mmol)和催化量碘化钾，升温至100℃，搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水50ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得到1.33g固体状产物。
步骤5：{2-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙酸叔丁酯(58e)的制备
于室温将{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙酸叔丁酯(58d)(1.33g，3.48mmol)溶解于15ml DMF中，然后加入吡啶(0.82g，10.44mmol)，冰盐浴降温至-5℃至0℃。将氯甲酸苯酯(818mg，5.2mmol)慢慢滴加到上述溶液中，过程中控制温度在-5℃至0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌0.5小时。将反应液倒入50ml水中，用乙酸乙酯50ml萃取，有机相用饱和食盐水40ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.86g粗品产物。
步骤6：[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙酸叔丁酯(58f)的制备
将{2-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙氧基}-乙酸叔丁酯(58e)的粗产品0.93g溶解于15ml四氢呋喃中，于室温加入5-叔丁基-异噁唑-3-基胺(485mg，3.48mmol)和三乙胺(525mg，5.22mmol)，升温至70℃搅拌过夜。将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得370mg黄色固体状产物。
步骤7：[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙酸(58g)的制备
将[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙酸叔丁酯(58f)370mg溶解于10ml二氯甲烷中，于室温加入5ml三氟乙酸，搅拌3小时。将反应液减压浓缩，得到410mg粗产品。
步骤8：2-[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-N-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基]-乙酰胺(58)的制备
将[2-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙氧基]-乙酸(58g)(410mg，0.67mmol)溶解于10mlDMF中，加入N-甲基吗啉调PH至7-8，加入3-(7-氨基-3-氧代-1H-异吲哚-2-基)哌啶-2,6-二酮(175mg，0.67mmol)室温搅拌20min，加入HATU(305mg,0.804mmol)室温搅拌过夜。将反应液降倒入60ml水中，用乙酸乙酯50ml×2萃取，有机相用饱和食盐水50ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到21mg黄色固体状的产物。
1HNMR(DMSO-d6,400MHz)δ:11.00(s,1H),9.76(s,1H),9.59(s,1H),9.08(s,1H),8.43(s,1H),7.73-7.74(d,1H),7.67-7.69(d,2H),7.44-7.59(m,5H),7.33-7.34(d,1H),6.95-6.97(dd,1H),6.52(s,1H),5.09-5.14(m,1H),4.32-4.41(m,2H),4.24-4.26(m,2H),4.24(s,2H),3.94-3.96(m,2H),2.84-2.92(m,1H),2.54-2.67(m,1H),2.29-2.36(m,1H),1.95-2.20(m,1H),1.30(s,9H)。
LC-MS(ESI)：735.3(M+H) +。
实施例59 2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-N-(4-{2-[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基氧基]-乙酰氨基}-丁基)-乙酰胺(59)的制备
Figure PCTCN2021107804-appb-000133
步骤1：3-(叔丁基-二甲基-硅烷氧基)-2-甲基-苯甲酸甲酯(59a)的制备
将3-羟基-2-甲基-苯甲酸甲酯(5g，30mmol)溶解于50mlDMF中，于室温加入咪唑(5.1g，75mmol)，将反应体系降温至0℃至5℃，缓慢滴入叔丁基二甲基氯硅烷(5g，33mmol)，滴毕，于室温搅拌16小时。将反应液倒入500ml饱和食盐水中，水相用乙酸乙酯80ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到8g粗品产物。
步骤2：2-溴甲基-3-(叔丁基-二甲基-甲硅烷基氧基)-苯甲酸甲酯(59b)的制备
3-(叔丁基-二甲基-硅烷氧基)-2-甲基-苯甲酸甲酯(59a)(8g，28.6mmolmol)、NBS(5.6g，31.43mmol)和AIBN(469mg，2.86mmol)于100ml四氯化碳中回流反应16小时，TLC检测反应，少量原料剩余。降温到室温，浓缩，残余物加入60ml石油醚搅拌30分钟。抽滤，滤液浓缩得9.1g油状物产品。
步骤3：3-[4-(叔丁基-二甲基-甲硅烷氧基)-1-氧代-1,3-二氢-异吲哚-2-基]-哌啶-2,6-二酮(59c)的制备
将2-溴甲基-3-(叔丁基-二甲基-甲硅烷基氧基)-苯甲酸甲酯(9.1g，25.35mol)、3-氨基-2,6-哌啶二酮盐酸盐(4.2g，25.35mmol)和三乙胺(7.7g，76.05mmol)溶解于100mlDMF中，升温至80℃反应3小时。TLC检测反应基本完成，降温至室温。将反应液倒入300ml饱和食盐水中，乙酸乙酯200ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝10:1-1:1)纯化，得1g固体状产物。
步骤4：3-(4-羟基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(59d)的制备
将3-[4-(叔丁基-二甲基-甲硅烷氧基)-1-氧代-1,3-二氢-异吲哚-2-基]-哌啶-2,6-二酮(59c)(1g，2.67mmol)溶解于15ml四氢呋喃中，降温0℃至5℃，滴加四丁基氟化铵四氢呋喃溶液(1M，5ml)，滴毕，缓慢升温室温反应2小时。TLC检测反应完成，将反应液倒入80ml饱和食盐水中，乙酸乙酯50ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得583mg固体状产物。
步骤5：[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基氧基]-乙酸叔丁酯(59e)的制备
将3-(4-羟基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(59d)(583mg，2mmol)和溴乙酸叔丁酯(474mg，2.43mmol)溶解于20mlDMF中，于室温加入碳酸氢钠(420mg，5mmol)和催化量碘化钾，升温60℃反应16小时。TLC检测反应基本完成，降温至室温。将反应液倒入100ml饱和食盐水中，乙酸乙酯80ml×2萃取，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得135mg固体状产物。
步骤6：[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基氧基]-乙酸(59f)的制备
将[2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-4-基氧基]-乙酸叔丁酯(59e)(135mg，0.361mmol)溶解于10ml二氯甲烷中，于室温加入5ml三氟乙 酸，加毕，继续室温反应2小时。TLC检测反应完成，将反应液直接浓缩得150mg粗品，无需纯化，直接用于下一步反应。
步骤7：[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙酸叔丁酯(59g)的制备
将1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)(2.25g，10mmol)溶解于30mlDMF中，加入溴乙酸叔丁酯(2.9g，15mmol)、碳酸铯(9.78g，30mmol)和催化量碘化钾，升温至100℃反应4小时。将反应液降至室温，然后倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇+＝150:1-60:1)纯化，得到910mg黄色固体状产物。
步骤8：[1-(4-苯氧基羰基氨基苯基)-1H-苯并咪唑-5-基氧基]-乙酸叔丁酯(59h)的制备
将[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙酸叔丁酯(59g)(910mg，2.67mmol)溶解于90mlDMF中，然后加入吡啶(633mg，8.01mmol)，冰盐浴降温至-5℃-0℃。将氯甲酸苯酯(3.64g，23.25mmol)慢慢滴加到上述溶液中，过程中控制温度在-5℃至0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。将反应液倒入80ml水中，用乙酸乙酯80ml萃取，有机相用饱和食盐水80ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，1.5g粗品产物。
步骤9：(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙酸叔丁酯(59i)的制备
将[1-(4-苯氧基羰基氨基苯基)-1H-苯并咪唑-5-基氧基]-乙酸叔丁酯(59h)的粗产品1.5g溶解于30ml四氢呋喃中，于室温加入5-叔丁基-2H-吡唑-3-基胺(560mg，4mmol)和三乙胺(810mg，8mmol)，升温至70℃搅拌过夜。将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得800mg黄色固体状产物。
步骤10：(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙酸(59j)的制备
(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-乙酸叔丁酯(59i)(800mg，1.58mmol)溶解于10ml二氯甲烷中，于室温加入5ml三氟乙酸，加毕，继续室温反应2小时。TLC检测反应完成，将反应液直接浓缩得150mg粗品，无需纯化，直接用于下一步反应。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.01(s,1H),9.42(br,1H),8.99(s,1H),8.46(s,1H),8.09-8.16(m,2H),7.66-7.68(d,2H),7.54-7.57(d,2H),7.45-7.51(m,2H),7.29-7.34(m,2H),7.11-7.13(d,1H),7.03-7.06(dd,1H),6.02(s,1H),5.10-5.15(m,1H),4.62(s,2H),4.51(s,2H),4.43-4.47(d,1H),4.32-4.36(d,1H),3.13(m,4H),2.87-2.96(m,1H),2.57-2.61(m,1H),2.35-2.46(m,1H),1.98-2.01(m,1H),1.43(m,4H),1.26(s,9H)。
LC-MS(ESI):819.3(M+H) +。
实施例60 7-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)庚酰胺(60)的制备
Figure PCTCN2021107804-appb-000134
步骤1：3-(5-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(60a)的制备
与实施例26中化合物26b的制备方法相同，除了用4-溴-2-甲基苯甲酸甲酯代替步骤1中的3-溴-2-甲基苯甲酸甲酯，得到3-(5-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(60a)。
步骤2：2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-腈(60b)的制备
3-(5-溴-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(60a)(9.6g，29.6mmol)、氰化锌(2.1g，17.8mmol)和四三苯基膦钯(3.4g，3mmol)于70mlDMF中，氮气换气4次，升温至100℃反应16小时。TLC检测反应完成，将反应液降至室温，然后倒入400ml水中，室温搅拌10分钟，过滤，固体水洗，固体鼓风干燥(60℃)12小时，所得固体于100ml石油醚/乙酸乙酯＝5:1的混合溶剂中，搅拌5小时，过滤，固体鼓风干燥(60℃)2小时，得8g黄色固体状产物。
步骤3：3-(5-氨基甲基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(60c)的制备
2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-腈(60b)(2.3g，8.55mmol)于150ml甲醇中，于室温加入1g雷尼镍(湿)和1ml浓盐酸，氢气置换4次，40℃反应20小时。TLC检测反应基本完成，于室温氨水调节pH＝8-8.5，加入150ml二氯甲烷，搅拌1小时，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝60:1-10:1)纯化，得到600mg黄色固体状的产物。
步骤4：7-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸[2-(2,6-二氧代哌啶-3-基)-1-氧-2,3-二氢-1H-异吲哚-5-基甲基]-酰胺(60)的制备
将7-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-庚酸(与实施例54的化合物54d的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤3中5-叔丁基-2H-吡唑-3-基胺)(100mg，0.19mmol)、3-(5-氨基甲基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(60c)(52mg，0.19mmol)和N-甲基吗啉(100mg，0.99mmol)溶解于10mlDMF中，搅拌下于室温加入HATU(82mg，0.21mmol)，加毕，继续室温反应3小时。TLC检测反应基本完成，将反应液倒入60ml水中，用乙酸乙酯50ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到40mg黄色固体状的产物。
1HNMR(DMSO-d6,400MHz)δ:10.99(s,1H),9.59(s,1H),9.08(s,1H),8.44-8.47(m,2H),7.66-7.68(m,3H),7.57-7.59(d,2H),7.45-7.48(m,2H),7.37-7.39(d,1H),7.27(m,1H),6.93-6.95(m,1H),6.52(s,1H),5.05-5.10(m,1H),4.27-4.44(m,4H),3.99-4.02(t,2H),2.86-2.89(m,1H),2.56-2.60(m,1H),2.34-2.39(m,1H),2.16-2.19(t,2H),1.96-2.01(m,1H),1.69-1.74(m,2H),1.53-1.59(m,2H),1.39-1.48(m,2H),1.33-1.38(m,2H),1.30(s,9H)。
LC-MS(ESI):775.2(M+H) +。
实施例61 5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(61)的制备
Figure PCTCN2021107804-appb-000135
与实施例54的制备方法相同，除了用5-溴戊酸乙酯代替步骤1中的7-溴庚酸乙酯，得到5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(61)。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.03(s,1H),9.84(s,1H),9.41(br,1H),9.00(s,1H),8.42(s,1H),7.81-7.84(m,1H),7.66-7.68(d,2H),7.55-7.57(d,2H),7.44-7.52(m,3H),7.29-7.30(d,1H),6.94-6.97(dd,1H),6.02(s,1H),5.12-5.17(m,1H),4.32-4.43(m,2H),4.08(m,2H),2.87-2.96(m,1H),2.57-2.68(m,1H),2.46-2.48(m,2H),2.30-2.39(m,1H),2.00-2.03(m,1H),1.82(m,4H),1.27(s,9H)。
LC-MS(ESI)：731.6(M+H) +。
实施例62 2-(4-(5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(62)的制备
Figure PCTCN2021107804-appb-000136
步骤1：戊-4-炔-1-基甲磺酸酯(62a)的制备
将4-戊炔-1-醇(8.4g，0.1mol)和三乙胺(15.2g，0.15mol)溶解于100ml二氯甲烷中，降温0-5℃，滴加甲磺酰氯(12.6g，0.11mol)，控制温度小于5℃。滴毕，缓慢升温室温反应12小时。TLC检测反应完成，将反应液倒入200ml饱和氯化铵水溶液中，二氯甲烷萃取100ml×2，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得14.2g油状产物。
步骤2：2-(4-溴苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基)甲基)-2,2-二氟乙酰胺(62b)的制备
(4-溴苯基)-二氟乙酸(1.1g，4.4mmol)溶解于30ml DMF中，加入3-(5-氨基甲基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(1.2g，4.4mmol)和三乙胺(1.3g，13.2mmol)室温搅拌，再加入HATU(2.5g，6.6mmol)，加毕，室温搅拌过夜。TLC检测反应完成，将反应液倒入100ml水中，用乙酸乙酯150ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得到380mg固体产物。
步骤3：4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯胺(62c)的制备
将1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)(10.00g，44mmol)溶解于90ml DMF中，加入戊-4-炔-1-基甲磺酸酯(62a)(8.6g，53mmol)、碳酸钾(18.4g，133mmol)和催化量碘化钾，升温至100℃，搅拌6h。TLC检测反应完成，将反应液降至室温，然后倒入400ml水中，用乙酸乙酯150ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到16g油状产物。
步骤4：[4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯基]-氨基甲酸苯酯(62d)的制备
于室温，将4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯胺(62c)(16g，54.8mmol)溶解于150ml DMF中，然后加入吡啶(13g，164mmol)，冰盐浴降温至-5℃-0℃。将氯甲酸苯酯(12.9g，82.2mmol)(用10ml四氢呋喃稀释)慢慢滴加到上述溶液中，过程中控制温度在-5℃-0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。TLC检测反应完成，将反应液倒入200ml水中，用乙酸乙酯150ml萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到25.6g粗品产物。
步骤5：1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯基]-脲(62e)的制备
将[4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯基]-氨基甲酸苯酯(62c)的粗产品13g溶解于80ml四氢呋喃中，于室温加入5-叔丁基-2H-吡唑-3-基胺(6.6g，47.3mmol)和三乙胺(9.6g，94.7mmol)，升温至70℃搅拌过夜。TLC检测反应 完成，将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得5g固体状产物。
步骤6：2-(4-(5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(62)的制备
2-(4-溴苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代-2,3-二氢-1H-异吲哚-5-基)甲基)-2,2-二氟乙酰胺(62b)(320mg，0.634mmol)、1-(5-叔丁基-2H-吡唑-3-基)-3-[4-(5-戊-4-炔氧基-苯并咪唑-1-基)-苯基]-脲(62e)(289mg，0.634mmol)、碘化亚铜(24mg，0.127mmol)和四三苯基膦钯二氯化钯(45mg,0.063mmol)于20ml(DMF:TEA＝4:1)混合溶剂中，氮气换气4次，升温至70℃搅拌过夜。TLC检测反应完成，将反应液降温至室温，再倒入100ml水中，用乙酸乙酯150ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得到197mg固体产物。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),11.00(s,1H),9.66-9.69(m,1H),9.41(s,1H),8.98(s,1H),8.44(s,1H),7.66-7.69(d,3H),7.55-7.57(m,6H),7.47-7.49(d,1H),7.33-7.39(m,3H),6.97-7.00(m,1H),6.02(s,1H),5.08-5.12(m,1H),4.40-4.45(m,3H),4.26-4.31(d,1H),4.16-4.19(t,2H),2.86-2.95(m,1H),2.58-2.68(m,2H),2.33-2.43(m,1H),1.96-2.07(m,4H),1.26(s,9H)。
LC-MS(ESI):882.3(M+H) +。
实施例63 2-(4-(7-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)己-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(63)的制备
Figure PCTCN2021107804-appb-000137
与实施例62的制备方法相同，除了用6-庚炔醇代替步骤1中的4-戊炔-1-醇，得到2-(4-(7-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)己-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(63)。
1HNMR(DMSO-d6,400MHz)δ:11.94(s,1H),10.92(s,1H),9.58-9.60(t,1H),9.39(br,1H),8.92(s,1H),8.36(s,1H),7.59-7.61(d,3H),7.47-7.49(m,6H),7.37-7.39(d,1H),7.20-7.31(m,4H),6.86-6.89(m,1H),5.95(s,1H),5.01-5.05(m,1H),4.18-4.38(m,4H),3.97-4.00(t,2H),2.79-2.88(m,1H),2.38-2.55(m,2H),2.25-2.34(m,1H),1.92-1.96(m,2H),1.72-1.75(m,2H),1.56(m,4H),1.19(s,9H)。
LC-MS(ESI):910.3(M+H) +。
实施例64 2-(4-(11-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)十一-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)甲基)-2,2-二氟乙酰胺(64)的制备
Figure PCTCN2021107804-appb-000138
与实施例62的制备方法相同，除了用10-十一炔醇代替步骤1中的4-戊炔-1-醇，得到2-(4-(11-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)十一-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)甲基)-2,2-二氟乙酰胺(64)。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),11.00(s,1H),9.66-9.69(m,1H),9.42(s,1H),8.98(s,1H),8.41(s,1H),7.66-7.69(d,3H),7.52-7.57(m,6H),7.44-7.46(d,1H),7.35-7.38(m,2H),7.26-7.27(d,1H),6.92-6.95(dd,1H),6.02(s,1H),5.08-5.12(m,1H),4.39-4.45(m,3H),4.26-4.30(d,1H),3.99-4.02(t,2H),2.86-2.95(m,1H),2.61-2.68(m,1H),2.26-2.45(m,4H),1.96-2.03(m,2H),1.70-1.77(m,2H),1.96-2.03(m,2H),1.52-1.59(m,2H),1.42-1.44(m,4H),1.30-1.33(m,4H),1.26(s,9H)。
LC-MS(ESI):967.3(M+H) +。
实施例65 2-(4-(3-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)丙-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(65)的制备
Figure PCTCN2021107804-appb-000139
与实施例62的制备方法相同，除了用溴丙炔代替步骤1中的4-戊炔-1-醇(62a)，得到2-(4-(3-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)丙-1-炔-1-基)苯基)-N-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)甲基)-2,2-二氟乙酰胺(65)。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),11.00(s,1H),9.69-9.71(m,1H),9.48(s,1H),9.00(s,1H),8.46(s,1H),7.66-7.69(d,3H),7.55-7.64(m,6H),7.50-7.52(d,1H),7.45(d,1H),7.35-7.40(m,2H),7.04-7.07(m,1H),6.02(s,1H),5.08-5.13(m,3H),4.40-4.45(m,3H),4.26-4.31(m,1H),2.86-2.95(m,1H),2.58-2.62(m,1H),2.33-2.44(m,2H),1.97-2.03(m,2H),1.26(s,9H)。
LC-MS(ESI):854.3(M+H) +。
实施例66 5-((1-(4-(3-(3-(叔丁基)-1-(2-吗啉乙基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(66)的制备
Figure PCTCN2021107804-appb-000140
步骤1：(2-吗啉-4-基-乙基)-肼的制备(66a)
于室温，将N-(2-氯乙基)吗啉盐酸盐(14.8g，0.08mol)和水合肼(20g，0.4mol)溶解于乙醇(250ml)中，将反应体系加热至90℃反应4小时。TLC检测反应完全，减压浓缩，残余物加入100ml水再次减压浓缩(重复三次)得粗品(2-吗啉-4-基-乙基)-肼。
步骤2：5-叔丁基-2-(2-吗啉-4-基-乙基)-2H-吡唑-3-基胺的制备(66b)
于室温，将步骤1中得到的(2-吗啉-4-基-乙基)-肼(0.08mol)和氰基频那酮(10g，0.08mol)溶解于200ml乙醇中，加入0.2ml浓盐酸，将反应体系加热至90℃反应12小时。TLC检测反应完全，减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇)纯化，得到8g粗品。所得粗品于40ml甲基叔丁基醚中搅拌4小时，过滤，固体少量甲基叔丁基醚洗涤，鼓风干燥(60℃)1小时，得3g白色固体状的5-叔丁基-2-(2-吗啉-4-基-乙基)-2H-吡唑-3-基胺。
步骤3：5-((1-(4-(3-(3-(叔丁基)-1-(2-吗啉乙基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(66)的制备
与实施例54的制备方法相同，除了用5-溴戊酸乙酯代替步骤1中的7-溴庚酸乙酯，并用5-叔丁基-2-(2-吗啉-4-基乙基)-2H-吡唑-3-基胺(66a)代替步骤3中的5-叔丁基-2H-吡唑-3-基胺，得到5-((1-(4-(3-(3-(叔丁基)-1-(2-吗啉乙基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(66)。
1HNMR(DMSO-d6,400MHz)δ:11.03(s,1H),9.84(s,1H),9.21(s,1H),8.62(s,1H),8.42(s,1H),7.82-7.84(m,1H),7.67-7.70(d,2H),7.56-7.58(d,2H),7.45-7.51(m,3H),7.30-7.31(d,1H),6.94-6.97(dd,1H),6.10(s,1H),5.12-5.17(m,1H),4.32-4.43(m,2H),4.04-4.08(m,4H),3.54-3.56(m,4H),2.87-2.96(m,1H),2.62(m,2H),2.51-2.57(m,1H),2.45-2.47(m,2H),2.42(m,4H),2.28-2.36(m,1H),2.00-2.04(m,1H),1.82(m,4H),1.22(s,9H)。
LC-MS(ESI)：846.3(M+H) +。
实施例67 5-(4-(3-(叔丁基)-5-(3-(4-(5-甲氧基-1H-苯并[d]咪唑-1-基)苯基)脲基)-1H-吡唑-1-基)哌啶-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰胺(67)的制备
Figure PCTCN2021107804-appb-000141
Figure PCTCN2021107804-appb-000142
步骤1：4-肼基-哌啶-1-甲酸叔丁酯(67a)的制备
将1-Boc-4-哌啶酮(20g，0.1mo)溶解于甲醇(200ml)中，于室温加水合肼(5.28g，0.105mmol)，将体系加热到65℃反应2小时。降温到室温，慢慢加入硼氢化钠(10g，0.264mol)，加毕，慢慢滴加1ml乙酸，滴毕将体系加热到60℃反应12小时。TLC检测反应完全后，将反应液浓缩，加入100ml水，乙酸乙酯萃取(100ml×3)，有机相用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到11.2g油状的4-肼基-哌啶-1-甲酸叔丁酯。
步骤2：4-(5-氨基-3-叔丁基-吡唑-1-基)-哌啶-1-羧酸叔丁酯(67b)的制备
将步骤1得到的4-肼基-哌啶-1-甲酸叔丁酯(11.2g，0.052mol)和氰基频那酮(购自TCI)(11.68g，0.063mol)溶解于乙醇(150ml)中。于室温加入1.3g浓盐酸，升温至90℃反应8小时。TLC检测反应完全后，将反应液冷却至0-5℃，有固体析出，抽滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇)纯化，得3g固体状的4-(5-氨基-3-叔丁基-吡唑-1-基)-哌啶-1-羧酸叔丁酯。
步骤3：4-[3-叔丁基-5-(2,2,2-三氯-乙氧基羰基氨基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(67c)的制备
将步骤2得到的4-(5-氨基-3-叔丁基-吡唑-1-基)-哌啶-1-羧酸叔丁酯(210mg，0.652mmol)溶解于乙酸乙酯(3ml)中。于室温加入氢氧化钠(65mg，1.63mmol，溶于2ml水中)，然后滴加氯甲酸-2,2,2-三氯乙酯(207mg，0.978mmol)，滴毕继续室温反应30分钟。TLC检测反应完全后，将反应液倒入水中(50ml)，用乙酸乙酯萃取(50ml×3)，有机相用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到350mg油状的4-[3-叔丁基-5-(2,2,2-三氯-乙氧基羰基氨基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯。
步骤4：4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基}-吡唑-1-基)-哌啶-1-甲酸叔-丁酯(67d)的制备
将步骤3得到的4-[3-叔丁基-5-(2,2,2-三氯-乙氧基羰基氨基)-吡唑-1-基]-哌啶-1-羧酸叔丁酯(3.73g，7.5mmol)、4-(5-甲氧基-苯并咪唑-1-基)苯胺(1f)(1.2g，5mmol)和三乙胺(1.5g，15mmol)溶解于THF(20ml)中。升温至70℃反应6小时。TLC检测反应完全后，将反应液冷却至室温，减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得3g固体状的4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基}-吡唑-1-基)-哌啶-1-甲酸叔-丁酯(67d)。
步骤5：1-(5-叔丁基-2-哌啶-4-基-2H-吡唑-3-基)-3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲(67e)的制备
将步骤4得到的4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基}-吡唑-1-基)-哌啶-1-甲酸叔-丁酯(67d)(3.0g，5.1mmol)溶解于乙酸乙酯(20ml)中。室温加入2M的EA/HCl(20ml)，加毕继续室温反应5个小时，TLC检测反应完成，过滤，乙酸乙酯洗涤，鼓风干燥(60℃)4小时，得2.63g淡紫色固体状产物。
步骤6：5-[4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基]-吡唑-1-基)-哌啶-1-基]-戊酸乙酯(67f)的制备
将步骤5得到的1-(5-叔丁基-2-哌啶-4-基-2H-吡唑-3-基)-3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲(500mg，1.02mmol)溶解于DMF(20ml)中。室温加入碳酸铯(1.33g，4.08mmol)和催化量碘化钾，继续室温反应15分钟。加入5-溴戊酸乙酯(258mg，1.24mmol)，加毕，升温至80℃反应6小时。TLC检测反应完全后，将反应液冷却至室温，倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-60:1)纯化，得到270mg黄色固体状产物。
步骤7：5-[4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基]-吡唑-1-基)-哌啶-1-基]-戊酸(67g)的制备
将步骤6得到的5-[4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基]-吡唑-1-基)-哌啶-1-基]-戊酸乙酯(67f)(130mg，0.211mmol)溶解于乙醇(12ml)中，室温加入4M氢氧化钠水溶液(3ml)，加毕室温反应1小时。TLC检测反应完全后，将反应液倒入100ml水中，柠檬酸水溶液调节pH为5-6，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到100mg黄色固体状产物。
步骤8：5-(4-(3-(叔丁基)-5-(3-(4-(5-甲氧基-1H-苯并[d]咪唑-1-基)苯基)脲基)-1H-吡唑-1-基)哌啶-1-基)-N-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊酰(67)的制备
将步骤7得到的5-[4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基]-吡唑-1-基)-哌啶-1-基]-戊酸(67g)(100mg，0.17mmol)、来那度胺(50mg，0.19mmol)和NMI(42mg，0.52mmol)溶解于DMF(10ml)中。室温加入TCFH(N,N,N',N'-四甲基氯甲脒六氟磷酸盐)(62mg，0.2mmol)，加毕，继续室温反应16小时。TLC检测反应完全后，将反应液冷却至室温，倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-60:1)纯化，得到15mg黄色固体状产物。
1HNMR(DMSO-d6,400MHz)δ:11.04(s,1H),9.89(s,1H),9.36(s,1H),9.37(s,1H),8.54(s,1H),7.83-7.84(d,1H),7.67-7.69(d,2H),7.58-7.59(d,2H),7.47-7.51(m,3H),7.30(d,1H),6.96-6.98(dd,1H),6.08(s,1H),5.14-5.18(m,1H),4.33-4.47(m,2H),3.82(s,3H),3.56-3.59(m,2H),3.10-3.20(m,4H),2.89-2.96(m,1H),2.58-2.62(m,1H),2.43-2.46(m,3H),2.31-2.37(m,4H),2.12-2.14(m,2H),1.99-2.04(m,1H),1.65-1.74(m,4H),1.24(s,9H)。
LC-MS(ESI)：415.2(M/2+H) +。
实施例68 1-(3-(叔丁基)-1-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)乙基)哌啶-4-基)-1H-吡唑-5-基)-3-(4-(5-甲氧基-1H-苯并[d]咪唑-1-基)苯基)脲(68)的制备
Figure PCTCN2021107804-appb-000143
Figure PCTCN2021107804-appb-000144
步骤1：(2-{2-[4-(3-叔丁基-5-{3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲基]-吡唑-1-基)-哌啶-1-基]-乙氧基}-乙基)-氨基甲酸叔丁酯(68a)的制备
1-(5-叔丁基-2-哌啶-4-基-2H-吡唑-3-基)-3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲(67e)(500mg，1.02mmol)溶解于DMF(20ml)中。室温加入碳酸铯(1.33g，4.08mmol)和催化量碘化钾，继续室温反应15分钟。加入2-(2-叔丁氧羰基氨基-乙氧基)-乙基甲磺酸酯(1c)(430mg，1.54mmol)，加毕，升温至80℃反应6小时。TLC检测反应完全后，将反应液冷却至室温，倒入100ml水中，用乙酸乙酯50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝150:1-60:1)纯化，得到200mg黄色固体状产物。
步骤2：1-(2-{1-[2-(2-氨基-乙氧基)-乙基]-哌啶-4-基}-5-叔丁基-2H-吡唑-3-基)-3-[4-(5-甲氧基-苯并咪唑-1-基)-苯基]-脲(68b)的制备
将步骤1得到的(68a)(190mg，0.281mmol)溶解于二氯甲烷(6ml)中，室温加入三氟乙酸(3ml)，加毕室温反应1小时。TLC检测反应完全后，将反应液减压浓缩，残余物加入100ml水溶解，氨水调节pH为8-9，用二氯甲烷50ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到60mg黄色固体状产物。
步骤3：1-(3-(叔丁基)-1-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙氧基)乙基)哌啶-4-基)-1H-吡唑-5-基)-3-(4-(5-甲氧基-1H-苯并[d]咪唑-1-基)苯基)脲(68)的制备
将步骤2得到的(68b)(160mg，0.278mmol)溶解于10ml DMSO中，于室温加入2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(84mg，0.30mmol)和三乙胺(37mg，0.36mmol)，升温至90℃搅拌过夜。将反应液降至室温，然后倒入60ml水中，用乙酸乙酯150ml×2萃取，有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过柱层析色谱 法(洗脱剂：二氯甲烷/氨水甲醇(5％)＝100:1-30:1)纯化，得到11mg黄色固体状的产物。
1HNMR(DMSO-d6,400MHz)δ:11.08(s,1H),9.89(s,1H),9.37(s,1H),8.42(s,1H),7.83-7.84(d,1H),7.67-7.69(d,2H),7.54-7.57(d,2H),7.47-7.47(m,1H),7.29(d,1H),7.18-7.20(m,1H),7.03-7.05(d,1H),6.94-6.95(dd,1H),6.08(s,1H),5.03-5.05(m,1H),3.82(s,3H),3.60-3.65(m,2H),3.45-3.47(m,2H),2.81-2.88(m,1H),2.51-2.62(m,9H),2.36-2.39(m,2H),1.89-2.06(m,5H),1.22(s,9H)。LC-MS(ESI)：416.2(M/2+H) +。
实施例69 1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲69)的制备
Figure PCTCN2021107804-appb-000145
步骤1：4-(2-甲磺酰氧基-乙基)-哌嗪-1-甲酸叔丁酯(69a)的制备
将4-(2-羟乙基)哌嗪-1-羧酸叔丁基酯(1.63g，7.08mmol)溶解于20ml二氯甲烷中，于室温加入三乙胺(1.07g，10.62mmol)，降温至0℃至5℃，缓慢滴入甲磺酰氯(890mg，7.79mmol)，滴加完毕后，移走冰盐浴，慢慢升温至室温搅 拌16小时。TLC检测反应完成，将反应液倒入100ml饱和氯化铵水溶液中，二氯甲烷50ml×2萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到2g粗品产物。
步骤2：4-{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙基}-哌嗪-1-甲酸叔丁酯的制备(69b)的制备
1-(4-氨基-苯基)-1H-苯并咪唑-5-醇(1g)(6g，0.027mol)溶解于于40mlDMF中，室温下加入氢氧化钠(1.38g，0.035mol)，加毕于40℃下搅拌1小时。滴加4-(2-甲磺酰氧基-乙基)-哌嗪-1-甲酸叔丁酯(9.0g，0.029mol)的30mlDMF溶液，滴毕升温70℃反应过夜。将反应液冷却至室温，倒入200ml水中，用乙酸乙酯100ml×2萃取，有机相用饱和食盐水150ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到8.2g粗品产物。
步骤3：4-{2-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙基}-哌嗪-1-甲酸叔丁酯(69c)的制备
于室温4-{2-[1-(4-氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙基}-哌嗪-1-甲酸叔丁酯的制备(69b)(1.2g，2.74mmol)溶解于15mlDMF中，然后加入吡啶(325mg，4.11mmol)，冰盐浴降温至-5℃-0℃。将氯甲酸苯酯(524mg，3.34mmol)慢慢滴加到上述溶液中，过程中控制温度在-5℃-0℃。滴加完毕后，移走冰盐浴，慢慢升温至室温搅拌1小时。TLC检测反应完成，将反应液倒入50ml水中，用乙酸乙酯50ml×2萃取，有机相用饱和食盐水50ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.5g粗品产物。
步骤4：4-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙基]-哌嗪-1-羧酸叔丁酯(69d)的制备
4-{2-[1-(4-苯氧基羰基氨基-苯基)-1H-苯并咪唑-5-基氧基]-乙基}-哌嗪-1-甲酸叔丁酯(69c)的粗产品1.5g溶解于20ml四氢呋喃中，于室温加入5-叔丁基-2H-吡唑-3-基胺(550mg，3.95mmol)和三乙胺(800mg，7.92mmol)，升温至70℃搅拌过夜。TLC检测反应完成，将反应液降温至室温，然后减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝100:1-30:1)纯化，得500mg产物。
步骤5：1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-哌嗪-1-基乙氧基)-苯并咪唑-1-基]-苯基}-脲(69e)的制备
将4-[2-(1-{4-[3-(5-叔丁基-2H-吡唑-3-基)-脲基]-苯基]-1H-苯并咪唑-5-基氧基)-乙基]-哌嗪-1-羧酸叔丁酯(69d)(500mg，9.2mmol)溶解于6ml二氯甲烷中，于室温加入3ml三氟乙酸，搅拌1.5小时。将反应液减压浓缩，残余物溶于70ml水中，加氨水调PH至8～9，析出大量固体，过滤，用大量水洗固体，鼓风干燥(60℃)3小时，得到360mg粗产品。
步骤6：1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(69)的制备
将1-(5-叔丁基-2H-吡唑-3-基)-3-{4-[5-(2-哌嗪-1-基乙氧基)-苯并咪唑-1-基]-苯基}-脲(69e)(360mg，0.71mmol)、2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(217mg，0.78mmol)和三乙胺(85mg，0.84mmol)溶解于15mlDMSO中，90℃过夜反应。TLC检测反应完成，将反应液降至室温，然后倒入100ml水中，过滤得到固体。通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇(5％)＝100:1-30:1)纯化，得到210mg黄色固体。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),11.10(s,1H),9.41(br,1H),9.00(s,1H),8.43(s,1H),7.67-7.73(m,3H),7.56-7.58(d,2H),7.46-7.48(d,1H),7.33-7.37(m,3H),6.96-6.99(dd,1H),6.02(s,1H),5.08-5.12(m,1H),4.19-4.21(m,2H),3.48(m,4H),2.89-2.92(m,1H),2.82(m,2H),2.72(m,4H),2.54-2.57(m,2H),2.01-2.04(m,1H),1.27(s,9H)。
LC-MS(ESI)：758.5(M+H) +。
实施例70 1-(5-(叔丁基)异噁唑-3-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(70)的制备
Figure PCTCN2021107804-appb-000146
与实施例69的制备方法相同，除了用3-氨基-5-叔丁基异噁唑代替步骤4中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-(叔丁基)异噁唑-3-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(70)。
1HNMR(DMSO-d6,400MHz)δ:11.09(s,1H),9.61(s,1H),9.11(s,1H),8.44(s,1H),7.67-7.73(m,3H),7.58-7.60(d,2H),7.46-7.48(d,1H),7.33-7.37(m,3H),6.97-6.99(dd,1H),6.53(s,1H),5.08-5.12(m,1H),4.19-4.21(m,2H),3.38-3.48(m,2H),3.33(m,2H),2.87-2.92(m,1H),2.82(m,2H),2.72(m,4H),2.54-2.57(m,2H),2.01-2.05(m,1H),1.31(s,9H)。
LC-MS(ESI):759.6(M+H)+。
实施例71 1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(71)的制备
Figure PCTCN2021107804-appb-000147
与实施例1步骤1和实施例69的制备方法相同，除了用4-氟酞酐代替实施例1步骤1中的3-氟酞酐，得到1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(71)。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.08(s,1H),9.41(br,1H),8.98(s,1H),8.42(s,1H),7.66(d,3H),7.56(d,2H),7.46-7.47(d,1H),7.26-7.38(m,3H),6.97(dd,1H),6.02(s,1H),5.06-5.07(m,1H),4.20(m,2H),3.47(m,4H),2.82-2.87(m,3H),2.68(m,4H),2.56-2.60(m,2H),2.02(m,1H),1.26(s,9H)。
LC-MS(ESI)：758.5(M+H) +。
实施例72 1-(5-(叔丁基)异噁唑-3-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(72)的制备
Figure PCTCN2021107804-appb-000148
与实施例1步骤1和实施例69的制备方法相同，除了用4-氟酞酐代替实施例1步骤1中的3-氟酞酐；用3-氨基-5-叔丁基异噁唑代替实施例69步骤4中的5-叔丁基-2H-吡唑-3-基胺，得到1-(5-(叔丁基)异噁唑-3-基)-3-(4-(5-(2-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-5-基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(72)。
1HNMR(DMSO-d6,400MHz)δ:11.08(s,1H),9.59(s,1H),9.06(s,1H),8.44(s,1H),7.67-7.69(d,3H),7.58-7.60(d,2H),7.46-7.48(d,1H),7.34-7.36(dd,2H),7.26-7.28(dd,1H),6.53(s,1H),5.06-5.09(m,1H),4.19-4.21(m,2H),3.44-3.47(m,4H),2.88-2.89(m,1H),2.80-2.82(m,2H),2.66-2.68(m,4H),2.54-2.57(m,2H),2.01-2.04(m,1H),1.31(s,9H)。
LC-MS(ESI)：759.6(M+H) +。
实施例73 1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(73)的制备
Figure PCTCN2021107804-appb-000149
与实施例69的制备方法相同，除了用{2-[4-(2-羟基-乙基)-哌嗪-1-基]-乙基}-氨基甲酸叔丁酯(CAS：949528-60-3)代替实施例69步骤1中的4-(2-羟乙基)哌嗪-1-羧酸叔丁基酯，得到1-(3-(叔丁基)-1H-吡唑-5-基)-3-(4-(5-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)乙基)哌嗪-1-基)乙氧基)-1H-苯并[d]咪唑-1-基)苯基)脲(73)。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),11.11(s,1H),9.51(br,1H),9.01(s,1H),8.44(s,1H),7.67-7.69(d,2H),7.54-7.56(d,2H),7.46-7.48(d,1H),7.35(m,1H),6.97-7.06(m,3H),6.73-6.74(dd,1H),6.03(s,1H),5.04-5.09(m,1H),4.16-4.25(m,2H),3.07-3.08(m,4H),2.83-2.91(m,3H),2.54-2.67(m,9H),2.33-2.35(m,1H),2.01-2.04(m,1H),1.27(s,9H)。
LC-MS(ESI)：801.5(M+H) +。
实施例74 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基[1,4'-联哌啶]-1'-羧酸酯(74)的制备
Figure PCTCN2021107804-appb-000150
步骤1：[1,4']双哌啶基-1'-羧酸氯甲酯(74a)的制备
4-哌啶基哌啶(841.4mg，5mmol)溶解于20mL二氯甲烷中，室温加入三乙胺(1.01g，10mmol)，加毕，将反应体系降温0-5℃。慢慢滴加氯甲酸氯甲酯(644.7mg，5mmol，溶解于10ml二氯甲烷中)，加毕，缓慢升温，室温反应3小时。TLC检测反应完成，将反应液倒入100ml饱和氯化铵水溶液中，用二氯甲烷60ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得800mg白色固体产物。
步骤2：(3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基[1,4'-联哌啶]-1'-羧酸酯(74b)的制备
将来那度胺(500mg，1.93mmol)溶解于10ml DMF中，室温加入碳酸铯(940mg，2.88mmol)和催化量碘化钾，加毕，将反应体系降温至0-5℃。慢慢滴加[1,4']双哌啶基-1'-羧酸氯甲酯(74a)(503mg，1.93mmol)，加毕缓慢升温，室温反应过夜。TLC检测反应完成，将反应体系用150ml二氯甲烷稀释，直接湿法上样，通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝30:1-10:1)纯化，得到670mg产物。
步骤3：(3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基[1,4'-联哌啶]-1'-羧酸酯(74)的制备
步骤2中得到的74b(353mg，0.731mmol)和5-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-戊酸(74c)(300mg，0.609mmol，实施例56中制备)于10mL乙腈中室温搅拌，室温依次加入NMI(150mg，1.83mmol)和TCFH(222mg，0.791mmol)，加毕，室温反应16小时。TLC检测反应完成，将反应液倒入100ml水中，有大量固体析出，过滤，固体用水洗涤，残余物(固体)通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝60:1-10:1)纯化，得到264mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:10.01(s,1H),9.85(br,1H),8.97(s,1H),8.46(s,1H),7.80-7.82(d,1H),7.68-7.70(d,2H),7.57-7.61(m,2H),7.45-7.53(m,3H),7.30-7.31(d,1H),6.94-6.97(d,1H),6.54(s,1H),5.54-5.62(m,2H),5.27-5.31(m,1H),4.33-4.48(m,2H),3.86-4.07(m,4H),3.29(m,2H),3.05-3.17(m,2H),2.79-2.83(m,4H),2.33-2.43(m,3H),2.07-2.08(m,3H),1.76-1.81(m,8H),1.46-1.53(m,2H),1.31(s,9H),1.23-1.27(m,2H)。
LC-MS(ESI)：957.5(M+H) +。
实施例75 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(75)的制备
Figure PCTCN2021107804-appb-000151
与实施例74的制备方法相同，除了用4-(4-哌啶基)吗啉代替实施例74步骤1中的4-哌啶基哌啶，得到(3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(75)。
1HNMR(DMSO-d6,400MHz)δ:9.89(s,1H),9.61(s,1H),9.10(s,1H),8.43(s,1H),7.81-7.82(m,1H),7.68-7.70(d,2H),7.57-7.59(d,2H),7.45-7.52(m,3H),7.30-7.31(d,1H),6.94-6.96(dd,1H),6.53(s,1H),5.57(m,2H),5.29-5.34(m,1H),4.32-4.46(m,2H),4.07(m,2H),3.52(m,4H),3.09(m,1H),2.79-2.83(m,1H),2.74(m,2H),2.46-2.48(m,2H),2.41(m,4H),2.28(m,1H),2.07-2.10(m,1H),1.82(m,4H),1.70(m,2H),1.31(s,9H),1.21-1.23(m,2H)。
LC-MS(ESI)：480.2(M/2+H) +。
实施例76 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基吗啉-4-羧酸酯(76)的制备
Figure PCTCN2021107804-appb-000152
与实施例74的制备方法相同，除了用吗啉代替实施例74步骤1中的4-哌啶基哌啶，得到(3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基吗啉-4-羧酸酯(76)。
1HNMR(DMSO-d6,400MHz)δ:9.86(s,1H),9.60(s,1H),9.11(s,1H),8.42(s,1H),7.80-7.81(m,1H),7.67-7.69(d,2H),7.57-7.59(d,2H),7.45-7.52(m,3H),7.30-7.31(d,1H),6.94-6.97(dd,1H),6.53(s,1H),5.57-5.67(m,2H),5.28-5.31(m,1H),4.32-4.45(m,2H),4.08(m,2H),3.52(m,4H),3.30-3.31(m,4H),3.06-3.08(m,1H),2.80-2.83(m,1H),2.46-2.48(m,2H),2.36-2.39(m,1H),2.07-2.10(m,1H),1.82(m,4H),1.31(s,9H)。
LC-MS(ESI)：875.4(M+H) +。
实施例77 3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-羧酸叔丁酯(77)的制备
Figure PCTCN2021107804-appb-000153
步骤1：3-(4-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-甲酸叔丁酯(77a)的制备
3-(4-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-哌啶-2,6-二酮(2.0g，6.9mmol，1.0eq)于20mL二氧六环中室温搅拌，室温加入DMAP(421mg，0.5eq)，加毕，室温搅拌10分钟。滴加(Boc) 2O(4.5g，20.7mmol，3.0eq，溶解于20ml二氧六环中)，加毕，升温至40℃反应2小时。TLC检测反应完成，将反应液降温至室温，再倒入100ml水中，用乙酸乙酯60ml×2萃取。有机相用饱和食盐水100ml×2洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚/乙酸乙酯＝10:1-1:1)纯化，得到2.2g固体产物。
步骤2：3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-甲酸叔丁酯(77b)的制备
将步骤1得到的3-(4-硝基-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代-哌啶-1-甲酸叔丁酯(77a)(2.2g，5.65mmol)溶解于50ml四氢呋喃中，室温加入 300mg湿钯碳，氢气置换3次，室温反应16小时。TLC检测反应完成，过滤，于20mL二氧六环中室温搅拌，室温加入DMAP(421mg，0.5eq)，加毕，滤液减压浓缩得2.0g粗品，无需纯化，直接用于下一步反应。
步骤3：3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-羧酸叔丁酯(77)的制备
步骤2中得到的3-(4-氨基-1-氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-甲酸叔丁酯(77b)(273mg，0.76mmol)和5-(1-{4-[3-(5-叔丁基-异噁唑-3-基)-脲基]-苯基}-1H-苯并咪唑-5-基氧基)-戊酸(77c)(273mg，0.76mmol，实施例56中制备)于10mL乙腈中室温搅拌，室温依次加入NMI(170mg，2.07mmol)和TCFH(233mg，0.82mmol)，加毕，室温反应16小时。TLC检测反应完成，将反应液倒入100ml水中，有大量固体析出，过滤，固体用水洗涤，残余物(固体)通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇＝60:1-20:1)纯化，得到290mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:9.84(s,1H),9.60(s,1H),9.08(s,1H),8.43(s,1H),7.84-7.86(m,1H),7.67-7.69(d,2H),7.57-7.59(d,2H),7.44-7.52(m,3H),7.30-7.31(d,1H),6.94-6.97(dd,1H),6.53(s,1H),5.37-5.41(m,1H),4.35-4.46(m,2H),4.08(m,2H),3.09-3.17(m,1H),2.77-2.81(m,1H),2.41-2.51(m,3H),2.07-2.10(m,1H),1.82(m,4H),1.48(s,9H),1.31(s,9H)。
LC-MS(ESI)：834.1(M+H) +。
实施例78 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基丁酸酯(78)的制备
Figure PCTCN2021107804-appb-000154
与实施例74步骤2-步骤3的制备方法相同，除了用丁酸氯甲酯代替实施例74步骤2中的74a，得到(3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H- 苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基丁酸酯(78)。
1HNMR(DMSO-d6,400MHz)δ:9.86(s,1H),9.60(s,1H),9.07(s,1H),8.44(s,1H),7.80-7.82(m,1H),7.67-7.69(d,2H),7.57-7.59(d,2H),7.45-7.52(m,3H),7.30-7.31(d,1H),6.94-6.97(dd,1H),6.53(s,1H),5.58-5.68(m,2H),5.29-5.34(m,1H),4.31-4.45(m,2H),4.08(m,2H),3.07-3.10(m,1H),2.80-2.84(m,1H),2.47(m,2H),2.34-2.42(m,1H),2.24-2.27(m,2H),2.07-2.10(m,1H),1.78-1.81(m,4H),1.46-1.54(m,3H)1.31(s,9H)。
LC-MS(ESI)：833.0(M+H) +。
实施例79 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基(叔丁氧羰基)-L-缬氨酸酯(79)的制备
Figure PCTCN2021107804-appb-000155
与实施例74步骤2-步骤3的制备方法相同，除了用(S)-2-叔丁氧羰基氨基-3-甲基丁酸氯甲基酯(45a)代替实施例74步骤2中的74a，得到(3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基(叔丁氧羰基)-L-缬氨酸酯(79)。
1HNMR(DMSO-d6,400MHz)δ:9.88-9.89(d,1H),9.60(s,1H),9.07(s,1H),8.43(s,1H),7.77-7.82(m,1H),7.67-7.69(d,2H),7.57-7.59(d,2H),7.44-7.55(m,3H),7.29-7.30(d,1H),7.17-7.20(m,1H),6.93-6.96(dd,1H),6.53(s,1H),5.57-5.71(m,2H),5.30-5.35(m,1H),4.26-4.46(m,2H),4.07(m,2H),3.78-3.83(m,1H),3.07-3.11(m,1H),2.81-2.84(m,1H),2.46(m,2H),2.32-2.38(m,1H),2.08-2.10(m,1H),1.94-1.99(m,1H),1.81(m,4H),1.37(s,9H)1.30(s,9H),0.82-0.86(d,6H)。
LC-MS(ESI)：961.3(M+H) +。
实施例80 二-叔丁基((3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基)磷酸酯(80)的制备
Figure PCTCN2021107804-appb-000156
与实施例74步骤2-步骤3的制备方法相同，除了用二-叔丁基氯甲基磷酸酯代替实施例74步骤2中的74a，得到二-叔丁基((3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基)磷酸酯(80)。
1HNMR(DMSO-d6,400MHz)δ:9.88(s,1H),9.60(s,1H),9.07(s,1H),8.43(s,1H),7.80-7.82(m,1H),7.67-7.69(d,2H),7.57-7.59(d,2H),7.45-7.53(m,3H),7.29-7.30(d,1H),6.94-6.96(dd,1H),6.53(s,1H),5.30-5.44(m,2H),4.30-4.45(m,2H),4.07(m,2H),3.07-3.12(m,1H),2.80-2.84(m,1H),2.46(m,2H),2.29-2.42(m,1H),2.07-2.10(m,1H),1.81(m,4H),1.40(s,18H),1.31(s,9H)。
LC-MS(ESI)：954.5(M+H) +。
实施例81 (3-(4-(5-((1-(4-(3-(5-(叔丁基)异噁唑-3-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基磷酸二氢酯(81)的制备
Figure PCTCN2021107804-appb-000157
Figure PCTCN2021107804-appb-000158
将化合物80(480mg，0.503mmol)溶解于4ml二氯甲烷中，将反应体系降温到0-5℃，加入4ml三氟乙酸，加毕升温至室温反应2小时。TLC检测反应完成，将反应液减压浓缩，残余物加入10ml乙酸乙酯打浆1小时，过滤，固体鼓风干燥(60℃)4小时，得358mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:9.86(s,1H),9.65(s,1H),9.17(s,1H),8.90(s,1H),7.82-7.84(d,1H),7.71-7.73(d,2H),7.62-7.64(d,2H),7.48-7.54(m,3H),7.33-7.34(d,1H),7.04-7.07(dd,1H),6.53(s,1H),5.38-5.46(m,2H),5.27-5.30(m,1H),4.32-4.45(m,2H),4.09-4.10(m,2H),3.04-3.10(m,1H),2.80-2.84(m,1H),2.46-2.48(m,2H),2.33-2.36(m,1H),2.07-2.09(m,1H),1.82-1.83(m,4H),1.31(s,9H)。
LC-MS(ESI)：842.5(M+H) +。
实施例82 (3-(4-(5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基[1,4'-联哌啶]-1'-羧酸酯(82)的制备
Figure PCTCN2021107804-appb-000159
Figure PCTCN2021107804-appb-000160
与实施例74步骤3的制备方法相同，除了用82a(实施例61中制备)代替实施例74步骤3中的74c，得到(3-(4-(5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊酰氨基)-1-氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基[1,4'-联哌啶]-1'-羧酸酯(82)。
1HNMR(DMSO-d6,400MHz)δ:12.01(s,1H),9.90(s,1H),9.44(br,1H),9.00(s,1H),8.42(s,1H),7.80-7.81(d,1H),7.66-7.68(d,2H),7.44-7.56(m,5H),7.30(d,1H),6.93-6.96(d,1H),6.02(s,1H),5.51-5.62(m,2H),5.27-5.31(m,1H),4.31-4.45(m,2H),3.86-4.07(m,4H),3.05-3.17(m,3H),2.58-2.86(m,6H),2.33-2.39(m,2H),1.94-2.12(m,2H),1.81(m,4H),1.53(m,4H),1.32-1.39(m,4H),1.31(s,9H),1.26(m,2H)。
LC-MS(ESI)：478.4(M/2+H) +。
实施例83 (3-(4-((2-(2-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)乙氧基)乙基)氨基)-1,3-二氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(83)的制备
Figure PCTCN2021107804-appb-000161
Figure PCTCN2021107804-appb-000162
步骤1：3-(4-氟-1,3-二氧代-1,3-二氢-异吲哚-2-基)-2,6-二氧代哌啶-1-甲基4-吗啉-4-基-哌啶-1-羧酸酯(83b)的制备
将2-(2,6-二氧代-哌啶-3-基)-4-氟-异吲哚-1,3-二酮(1a)(4.8g，17.6mmol)溶解于40ml DMF中，室温加入碳酸铯(8.6g，26.4mmol)和催化量碘化钾，加毕，将反应体系降温至0-5℃。慢慢滴加83a(4.6g，17.6mmol，实施例75中制备)的12mlDMF溶液，加毕缓慢升温室温反应过夜。TLC检测反应完成，将反应液倒入150ml水中，乙酸乙酯萃取80ml×2萃取，合并有机相用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到5.3g黄色固体状产物。
步骤2：(3-(4-((2-(2-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)乙氧基)乙基)氨基)-1,3-二氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(83)的制备
将化合物83b(210mg，0.418mmol)和化合物1k(200mg，0.418mmol)溶解于10mL DMSO中，室温加入三乙胺(60mg，0.594mmol)，加毕，升温至90℃反应16小时。TLC检测反应基本完成，将反应液加入150ml二氯甲烷稀释，直接湿法上样，通过柱层析色谱法(洗脱剂：二氯甲烷/甲醇(5％氨水)＝30:1-20:1)纯化，得到88mg固体状产物。
1HNMR(DMSO-d6,400MHz)δ:12.02(s,1H),9.49(br,1H),9.01(s,1H),8.42(s,1H),7.67-7.68(d,2H),7.54-7.61(d,3H),7.43-7.44(d,1H),7.30-7.31(d,1H),7.15-7.19(d,1H),7.03-7.05(d,1H),6.92-6.94(dd,1H),6.65-6.67(m,1H),6.03(s,1H),5.57-5.61(m,2H),5.21-5.25(m,1H),4.16-4.17(m,2H),3.96-3.98(m,2H),3.80-3.84(m,2H),3.70-3.74(m,2H),3.51-3.54(m,4H),3.07-3.08(m,4H),3.00-3.04(m,1H),2.74-2.83(m,3H),2.54-2.57(m,1H),2.34-2.43(m,2H),2.05-2.08(m,1H),1.27(s,9H),1.24-1.25(m,5H)。
LC-MS(ESI)：960.5(M+H) +。
实施例84 (3-(4-((5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊基)氨基)-1,3-二氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(84)的制备
Figure PCTCN2021107804-appb-000163
与实施例83的制备方法相同，除了用84a(实施例13中制备)代替实施例83步骤2中的化合物1k，得到(3-(4-((5-((1-(4-(3-(3-(叔丁基)-1H-吡唑-5-基)脲基)苯基)-1H-苯并[d]咪唑-5-基)氧基)戊基)氨基)-1,3-二氧代异吲哚-2-基)-2,6-二氧代哌啶-1-基)甲基4-吗啉基哌啶-1-羧酸酯(84)。
1HNMR(DMSO-d6,400MHz)δ:12.03(s,1H),9.41(br,1H),9.00(s,1H),8.42(s,1H),7.66-7.68(d,2H),7.54-7.61(d,3H),7.43-7.46(d,1H),7.27-7.28(d,1H),7.12-7.14(d,1H),7.01-7.03(d,1H),6.92-6.94(dd,1H),6.56-6.59(m,1H),6.02(s,1H),5.57-5.64(m,2H),5.20-5.25(m,1H),4.02-4.05(m,2H),3.08-3.94(m,2H),3.52(m,4H),3.00-3.09(m,1H),2.67-2.83(m,3H),2.51(m,2H),2.40(m,4H),2.29-2.33(m,1H),2.07-2.10(m,1H),1.76-1.82(m,2H),1.65-1.70(m,4H),1.46-1.57(m,2H),1.35-1.39(m,1H),1.27(s,9H)。
LC-MS(ESI)：957.5(M+H) +。
生物学测试
试验例1本发明化合物对FLT3酪氨酸激酶异常表达细胞系体外生长抑制的测定
实验材料与方法
1、肿瘤细胞系及细胞培养
本发明人选择具有代表性的肿瘤细胞系应用于化合物活性测定。所有使用的细胞系分别来源于ATCC和DSMZ。细胞培养条件与方法按每种细胞系要求进行。每次体外培养不超过3次传代。根据需要，可对细胞系进行单克隆分离与鉴定。
细胞培养基分别选用RPMI1640(Gibco)、IMDM(Gibco)，加入5-20％胎牛血清(Gibco)，100U/mL青霉素(Gibco)和100μg/mL链霉素(Gibco)，2mM谷氨酰胺(Gibco)或者1mM丙酮酸钠(Sigma)。所用细胞系名称、种类、主要基因特征、培养基和细胞来源见下表1，其中“amp”为基因扩增；“+++”为基因过/高表达。细胞主要基因特征分别来源于COSMIC Cell Lines Project和相关研究论文。
表1 本发明使用的细胞系
Figure PCTCN2021107804-appb-000164
2、药物处理
悬浮细胞直接离心收集(1700rpm，3分钟)，弃上清，计数细胞。根据每种细胞生长周期，配制不同的细胞浓度(每毫升5～10×10 4细胞)，接种到96孔板(Corning)，每孔100微升，37℃，5％CO 2培养过夜。第二天，加入待测化合物到培养细胞中，平行2孔。有机溶剂终浓度不超过千分之一，细胞继续培养3-6天，MTT测定。
本发明化合物与对照化合物(见表2)用DMSO(Sigma)溶解，化合物纯度达98％以上。化合物贮存浓度为10mM，-20℃保存，使用前1:3倍系列稀释。
表2 对照化合物
Figure PCTCN2021107804-appb-000165
Figure PCTCN2021107804-appb-000166
3、MTT检测及IC 50计算
MTT检测试剂为Dojindo CCK8试剂盒，酶标测定仪为THERMO MULTISKAN FC仪。
悬浮细胞直接加入CCK8试剂，终浓度为10％，继续培养1～4小时，当溶剂对照孔呈现暗黄色时，测OD450nm光吸收值，按下列公式计算细胞生长率：
细胞生长率％＝100*(T-T 0)/(C-T 0)
T＝药物处理细胞孔光密度值-空白对照孔光密度值；T 0＝药物处理前细胞孔光密度值-空白对照孔光密度值；C＝溶剂对照组细胞孔光密度-空白对照孔光密度值。
通过GraphPad Prism7软件计算细胞生长50％抑制的药物浓度即IC 50。试验重复进行3次以上，并对数据进行生物学统计分析。
4、实验结果
下表3总结本发明化合物对FLT3-ITD表达阳性细胞体外生长抑制(或诱导细胞凋亡)IC 50浓度的测定结果。其中IC 50值越小，化合物活性越强。“*****”代表IC 50<0.1nM；“****”为0.1nM～1nM；“***”为>1nM～10nM；“**”为>10nM～100nM；“*”为>100nM；“-”代表未测定。
表3 本发明化合物细胞体外生长抑制(或诱导细胞凋亡)的IC 50值
Figure PCTCN2021107804-appb-000167
Figure PCTCN2021107804-appb-000168
Figure PCTCN2021107804-appb-000169
ND：未测定
表3结果显示本发明化合物能够抑制FLT3-ITD表达阳性MV4:11和MOLM-13细胞系的生长(诱导细胞凋亡)，其IC 50浓度值可达亚纳摩尔。
试验例2本发明化合物对不同类型肿瘤细胞生长抑制活性的测定
选择具有代表性的不同类型肿瘤细胞系(表4)应用于本发明化合物的体外细胞生长抑制活性的测定。
表4 本发明化合物细胞体外生长抑制活性测定使用的肿瘤细胞系
Figure PCTCN2021107804-appb-000170
Figure PCTCN2021107804-appb-000171
Figure PCTCN2021107804-appb-000172
肿瘤细胞系及细胞培养方法分别依照各种细胞说明书。
药物处理和MTT检测及IC 50计算按照试验例1方法。
结果发现本发明化合物对测试肿瘤细胞系具有不同程度的生长抑制活性。
试验例3本发明化合物体内肿瘤生长抑制活性的测定
人白血病MV4:11裸小鼠肿瘤模型
实验动物：6－8周龄，体重18-22克雌性Balb/c裸小鼠(上海西普尔-必凯实验动物有限公司)，动物到达后在实验环境饲养3天后方开始实验。
细胞培养：人白血病MV4:11(ATCC-CRL95918)细胞株悬浮培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃ 5％CO 2孵箱培养。当细胞饱和度为80％～90％，数量到达要求时，收取细胞，计数，接种。
肿瘤细胞接种：将0.2mL(10×10 6个)MV4:11细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约163mm 3时开始分组给药。
测试药的配制和给药方式：本发明化合物1和阳性对照药物Ara-C分别用20％HP-β-CD(西安天正康源)和生理盐水(0.9％NaCl，由注射用水配制)溶剂体系配制，甲磺酸调PH值(>3.5)。化合物1药物浓度分别为3mg/ml、1mg/ml、0.3mg/ml和0.1mg/ml，Ara-C为6mg/ml。给药方式按表5所示，小鼠每10g尾静脉注射0.1ml，两天一次。
人白血病MOLM-13异种移植瘤小鼠肿瘤模型(i.p给药)
实验动物：NOD/SCID小鼠，雌性，9-10周(肿瘤细胞接种时的小鼠周龄)，96只(批次：20190806B)。购自北京安凯毅博生物技术有限公司，饲养环境：SPF级。
细胞培养：人白血病MOLM-13(DSMZ)细胞株悬浮培养，培养条件为RPMI 1640培养基中加10％胎牛血清、100U/mL青霉素和100μg/mL链霉素，37 ℃ 5％CO 2孵箱培养。当细胞饱和度为80％～90％，数量到达要求时，收取细胞，计数，接种。
肿瘤细胞接种：实验小鼠于右侧皮下接种5×10 6MOLM-13细胞，细胞重悬PBS中(0.1ml/只)。肿瘤细胞接种当天定义为第0天。在第6天，待肿瘤平均体积92mm 3时，根据肿瘤大小随机分组。
测试药的配制和给药方式：本发明化合物1和阳性对照药物Ara-C分别用20％HP-β-CD和生理盐水(0.9％NaCl，由注射用水配制)溶剂体系配制，甲磺酸调PH值(>3.5)。化合物1药物浓度分别为3mg/ml、1mg/ml、0.3mg/ml和0.1mg/ml，Ara-C为6mg/ml。给药方式按表6所示，小鼠每10g腹腔注射0.1ml，每天一次。
人白血病MOLM-13异种移植瘤小鼠肿瘤模型(i.v给药)
实验动物、细胞培养和肿瘤细胞接种同以上人白血病MOLM-13异种移植瘤小鼠肿瘤模型。
测试药的配制和给药方式：本发明化合物70用20％HP-β-CD溶剂体系配制，甲磺酸调PH值(>3.5)。化合物70药物浓度分别为3mg/ml、1mg/ml和0.3mg/ml。给药方式按表7所示，小鼠每10g尾静脉注射0.1ml，每天一次。
肿瘤测量和实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周三次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：
V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。
TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算公式为：
TGI(％)＝(1-(某处理组给药结束时平均瘤体积－该处理组开始给药前平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗前平均瘤体积))×100％。
相对肿瘤增殖率T/C(％)的计算公式如下：
T/C％＝T RTV/C RTV×100％
T RTV：治疗组RTV；C RTV：阴性对照组RTV。根据肿瘤测量的结果计算出相对肿瘤体积(RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d 0)测量所得平均肿瘤体积，V t为某一次测量时的平均肿瘤体积，T RTV与C RTV取同一天数据。
表5 本发明化合物1对MV4:11异种移植瘤模型的抑瘤药效评价
Figure PCTCN2021107804-appb-000173
Figure PCTCN2021107804-appb-000174
注：a.平均值±SEM；b.肿瘤生长抑制TGI(％)＝[1-(T 29-T 0)/(V 29-V 0)]×100)计算；c.p值根据肿瘤体积计算；d.i.v：尾静脉注射；q2d：两天一次。
表6 本发明化合物1对MOLM-13异种移植瘤模型的抑瘤药效评价
Figure PCTCN2021107804-appb-000175
注：a.平均值±SEM；b.肿瘤生长抑制TGI(％)＝[1-(T 13-T 0)/(V 13-V 0)]×100)计算；c.p值根据肿瘤体积计算；d.i.p：腹腔注射,qd：每天一次。
表7 本发明化合物70对MOLM-13异种移植瘤模型的抑瘤药效评价
Figure PCTCN2021107804-appb-000176
注：a.平均值±SEM；b.肿瘤生长抑制TGI(％)＝[1-(T 13-T 0)/(V 13-V 0)]×100)计算；c.p值根据肿瘤体积计算；d.i.v：静脉注射,qd：每天一次。
结果：如表5，表6和表7所示，本发明化合物1和化合物70分别对Balb/c裸小鼠人白血病MV4:11和NOD/SCID小鼠MOLM-13异种移植瘤具有显著的生长抑制作用，对肿瘤的抑制效果呈现有剂量依赖关系，荷瘤鼠对受试化合物1和化合物70在所有剂量下都显示出良好的耐受性，所有治疗组均无明显体重下降，无发病死亡和停药现象。
试验例4免疫印迹试验
将适当浓度MV4:11和MOLM-13细胞接种在6孔板中，过夜培养。本发明化合物分别用DMSO(Sigma)溶解，化合物纯度达98％以上。化合物贮存浓度为10mM，-20℃保存，使用前1:10倍系列稀释。加化合物于每孔培养基中，以使最终浓度为1μM、0.1μM、0.01μM、0.0001μM，DMSO为对照。细胞与化合物一起孵育8或12小时。离心收集细胞，除去培养基，用冰冷1x PBS洗涤细胞一次，加适量裂解缓冲液(25mM Tris.HCl pH 7.5，含1％NP-40(Sigma)和0.25％脱氧胆酸盐(Sigma)，补充有10mM焦磷酸钠(Sigma)、20mMβ-甘油磷酸酯(Sigma)、10mM氟化钠(Sigma)、1mM原钒酸钠(Sigma)、0.1mM苯砷酰氧化物(Sigma)、10μg/ml胃蛋白酶肽(Sigma)、10μg/ml胃抑素A(Sigma)、30μg/ml贝他定(Bestatin，Sigma)、0.3胰蛋白酶抑制剂单位/ml抑肽酶(Sigma)和1mM PMSF(Sigma)，超声裂解(4℃)，将细胞裂解物转移至Eppendorf管中，然后12,000rpm离心10分钟(4℃)，收集上清液。用BCA试剂盒(Thermo Scientific)测定每种裂解物的蛋白质浓度。将每种裂解物的10μg蛋白质上样至SDS/PAGE凝胶(Sigma)，并在120V下运行约2.5小时。转移到PVDF膜(MERCK)之后，用0.1％Tween-20(Sigma)的Tris缓冲盐水(TBS-T)洗涤三次，用5％脱脂奶粉TBST液(Anchor)室温封闭1小时，TBS-T洗涤膜三次，然后在含有3％牛血清白蛋白的TBS-T中用FLT3抗体(CST#3462S)或微管蛋白抗体(Proteintech：60008-1-Ig)(一抗)于4℃孵育过夜。将膜用TBS-T洗涤三次，然后再与含有3％的牛血清白蛋白TBS-T中的HRP标记的羊抗兔IgG(#31460,Thermo Scientific)或羊抗鼠IgG二抗(#31430,Thermo Scientific)一起孵育1小时(室温)。用TBS-T进一步洗涤3次后，使用通过酶联化学发光(ECL，Supersignalwest Dura,Thermo Scientific)检测目标膜蛋白，成像系统为Tanon 4600，用Image Lab v.5.2.1软件(Bio-Rad Laboratories)进行定量和计算50％蛋白降解值(DI 50)。
表8 本发明化合物降解FLT3蛋白的DI 50值
Figure PCTCN2021107804-appb-000177
“****”代表DI 50<10nM；“***”为10nM～100nM；“**”为100nM～1000nM；“*”为>1000nM；“-”代表无蛋白降解活性。
如表8结果显示，本发明化合物能够有效的诱导MV4:11和MOLM-13细胞中表达的FLT3-ITD蛋白的降解。

Claims (21)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，
    Figure PCTCN2021107804-appb-100001
    其中：
    E选自以下结构：
    Figure PCTCN2021107804-appb-100002
    L选自以下结构：
    Figure PCTCN2021107804-appb-100003
    其中：
    Z 1和Z 2之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
    Z 3和Z 4之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
    Z 5和Z 6之一与Y 1、Y 2、Y 3或Y 4之一相连，另一个与X 1、X 2、X 3或X 4之一相连；
    Z 1和Z 2各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
    Z 3和Z 4各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
    Z 5和Z 6各自独立地选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、亚烯基、亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；
    W 1、W 2、W 3、W 4、W 5、W 6、W 7、W 8和W 9各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-N(R 3)-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；
    G选自单键、二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价环烷基、二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、羟基烷基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
    G 1、G 2、G 3各自独立地选自单键、亚烯基、亚炔基、二价环烷基、二价杂环基、二价芳基和二价杂芳基，所述二价杂环基、二价芳基和二价杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、羟基烷基、卤代烷基和卤代烷氧基中的一个或多个取代基所取代；
    Y 1、Y 2、Y 3和Y 4各自独立地选自CR b或N；
    X 1、X 2、X 3和X 4各自独立地选自CR c或N；
    Y和U各自独立地选自N或者CR a；当R 1为氢时，A选自杂芳基或杂环基，所述杂芳基或杂环基任选进一步被选自卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、酰基、酯基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代，其中所述烷基、烯基、炔基、烷氧基、酰基、酯基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯 基、酰基、酰氨基、氧代基、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者，
    当R 1不为氢时，A和R 1各自独立地选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者
    A和R 1与其所连接的氮原子一起形成杂环基或杂芳基，所述杂环基或杂芳基任选进一步被选自卤素、烷基、烯基、炔基、烷氧基、羟基、氨基、酰基、酯基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代，其中所述烷基、烯基、炔基、烷氧基、酰基、酯基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    R 2选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    R 3选自氢或烷基；
    R a、R b和R c各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    R d和R e或者R d1和R e1或者R d2和R e2或者R d3和R e3或者R d4和R e4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；或者
    R d和R e与其相连接的碳原子或者R d1和R e1与其相连接的碳原子或者R d2和R e2与其相连接的碳原子或者R d3和R e3与其相连接的碳原子或者R d4和R e4与其相连接的碳原子，一起形成环烷基或杂环基，所述环烷基或杂环基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    R g、R f、R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基，所述氨基、酯基、酰基、酰氨基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    Q选自氢、羟基、烷基、环烷基、或以下结构：
    Figure PCTCN2021107804-appb-100004
    其中所述烷基或环烷基任选进一步被选自卤素、烷基、羟基、氨基和芳基的一个或多个基团所取代；
    R 0选自芳基、杂环基、烷基、环烷基和烷氧基，其中所述芳基、杂环基、烷基、环烷基和烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基的一个或多个基团所取代；
    R 4、R 7、R 8和R 9各自独立地选自氢、烷基、环烷基和芳基，其中所述烷基、环烷基和芳基任选进一步被选自羟基、巯基、羧基、酰氨基、烷基、烷氧基和烷硫基的一个或多个基团所取代；
    R 5和R 6各自独立地选自氢、烷基、酰基、酯基和芳基，其中所述烷基、酰基、酯基和芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、烷基和烷氧基的一个或多个基团所取代；或者
    R 5和R 6与其连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、烷基、环烷基、杂环基的一个或多个基团取代；
    s为1至12的整数；
    p为0、1或2；
    q为0至12的整数；
    n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数；
    m 1、m 2、m 3、m 4、m 5、m 6和m 7各自独立地为0至15的整数；
    j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    E选自以下结构：
    Figure PCTCN2021107804-appb-100005
    X 1、X 2、X 3和X 4各自独立地选自CR c或N；
    R c选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基；
    优选地，X 1、X 2、X 3和X 4各自独立地选自CH；
    Q选自氢、羟基、C 1-C 6烷基优选甲基、
    Figure PCTCN2021107804-appb-100006
    所述C 1-C 6烷基任选进一步被C 6-C 10芳基优选苯基取代；
    R 0选自C 6-C 10芳基优选苯基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基，其中所述C 6-C 10芳基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基、5-7元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代；
    R 4、R 7、R 8和R 9各自独立地选自氢、C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基任选进一步被选自羟基、巯基、羧基、酰氨基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基的一个或多个基团所取代；
    R 5和R 6各自独立地选自氢、C 1-C 6烷基、-C(O)OR”其中R”为C 1-C 6烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基和C 6-C 10芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、C 1-C 6烷基和C 1-C 6烷氧基的一个或多个基团所取代；或者
    R 5和R 6与其连接的氮原子一起形成含氮杂环基，优选5-7元含氮杂环基，所述含氮杂环基任选进一步被选自卤素、C 1-C 6烷基、C 3-C 7环烷基、5-7元杂环基的一个或多个基团取代。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    L选自以下结构：
    Figure PCTCN2021107804-appb-100007
    Z 1与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
    Z 2与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
    Z 1选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键或-O(CH 2)C(O)NH-；
    Z 2选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键、-N(R 3)-、亚乙烯基、亚乙炔基、-C(O)NH-、-NHC(O)-、-O(CH 2)C(O)NH-、-(CH 2)NHC(O)-；
    W 1、W 2和W 3各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、C 2-C 6亚烯基、C 2-C 6亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
    R 3选自氢或C 1-C 6烷基；
    R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d和R e与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d和R e各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R g、R f、R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    s为1至12的整数；
    p为0、1或2；
    q为0至12的整数；
    n 1、n 2、n 3、n 4和n 5各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
  4. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    L选自以下结构：
    Figure PCTCN2021107804-appb-100008
    其中：
    Z 3与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
    Z 4与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
    Z 3选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键；
    Z 4选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、-NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键、-NH-、-NHC(O)-；
    W 4、W 5和W 6各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、亚烯基、亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
    G选自C 3-C 6二价环烷基、5至6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基，所述C 3-C 6二价环烷基、5至6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基各自独立地任选进一步被选自羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧 基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基中的一个或多个取代基所取代；优选5至6元二价杂环基、二价苯基、5至6元二价杂芳基；
    R 3选自氢或C 1-C 6烷基；
    R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d和R e与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d和R e各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d2和R e2与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d2和R e2各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d3和R e3与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d3和R e3各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R h和R i各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    s为1至12的整数；
    p为0、1或2；
    q为0至12的整数；
    m 1、m 2、m 3、m 4、m 5、m 6、m 7各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
  5. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    L选自以下结构：
    Figure PCTCN2021107804-appb-100009
    其中：
    Z 5与Y 1、Y 2、Y 3或Y 4基团相连，且只与其中一个相连；
    Z 6与X 1、X 2、X 3或X 4基团相连，且只与其中一个相连；
    Z 5选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选一个键；
    Z 6选自一个键、-(CH 2) s-、-(CH 2) qO-、-O(CH 2) q-、-(CH 2) qS-、-S(CH 2) q-、-(CH 2) qN(R 3)-、-N(R 3)(CH 2) q-、-C(O)-、-C(O)NH(CH 2) q-、NHC(O)(CH 2) q-、-(CH 2) qC(O)NH-、-(CH 2) qNHC(O)-、-S(O) p(CH 2) qNH-、-NH(CH 2) qS(O) p-、C 2-C 6亚烯基、C 2-C 6亚炔基、-O(CH 2) qC(O)NH-、-NHC(O)(CH 2) qO-或-O(CH 2) qS(O) p-；优选自-NH-、-(CH 2)NHC(O)-；
    W 7、W 8和W 9各自独立地选自-CH 2-、-O-、-S-、-S(O) p-、-C(O)-、-NR 3-、-C(O)NH-、-NHC(O)-、-O(CH 2) qC(O)-、-C(O)(CH 2) qO-、C 2-C 6亚烯基、C 2-C 6亚炔基、-S(O) pNH-和-NHS(O) p-；优选-CH 2-、-O-、-S-；
    G 1、G 2、G 3各自独立地选自单键、C 2-C 6亚烯基、C 2-C 6亚炔基、C 3-C 6二价环烷基、5-6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基，所述5-6元二价杂环基、C 6-C 10二价芳基和5-6元二价杂芳基各自独立地任选进一步被选自羟基、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6羟基烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基中的一个或多个取代基所取代；优选亚乙烯基、亚乙炔基、5-6元二价杂环基、二价苯基、5-6元二价杂芳基；
    R d和R e各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；优选氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d1和R e1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d1和R e1与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d1和R e1各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d2和R e2各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d2和R e2与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d2和R e2各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d3和R e3各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d3和R e3与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d3和R e3各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    R d4和R e4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    或者R d4和R e4与其相连接的碳原子一起形成C 3-C 6环烷基或5-7元杂环基；
    优选地R d4和R e4各自独立地选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基；
    s为1至12的整数；
    p为0、1或2；
    q为0至12的整数；
    j 1、j 2、j 3、j 4、j 5、j 6、j 7和j 8各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    Y和U各自独立地选自CR a；
    R a选自氢、卤素、氨基、硝基、氰基、羟基、巯基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基和C 3-C 7环烷基；优选氢和卤素。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    Y 1、Y 2、Y 3和Y 4各自独立地选自CR b；
    R b选自氢、卤素、氨基、硝基、氰基、羟基、巯基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基和C 3-C 7环烷基；优选氢和卤素。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    R 1为氢，且A选自5至7元杂芳基，所述5至7元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    R 1为氢，且A选自以下结构：
    Figure PCTCN2021107804-appb-100010
    R选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基；优选氢、C 1-C 6烷基。
  10. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    当R 1不为氢时，A和R 1与其所连接的氮原子一起形成5至7元杂芳基，优选吡唑、噁唑基、异噁唑基、噻唑基、噻二唑基、吡咯基；所述5至7元杂芳基任选进一步被选自卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代。
  11. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    R 1为酯基，特别是-C(O)OR’，其中R’选自C 1-C 6烷基或C 3-C 7环烷基；并且A选自以下结构：
    Figure PCTCN2021107804-appb-100011
    R选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基；优选氢、C 1-C 6烷基；
    优选地，A选自吡唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、吡咯基；其任选进一步被选自氢、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷氧基、羟基、氨基、酰基、酯基、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基和5-6元杂芳基的基团所取代；优选被C 1-C 6烷基所取代。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    R 2选自氢、卤素、羟基、硝基、氨基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基；优选氢和卤素。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    L选自以下结构：
    Figure PCTCN2021107804-appb-100012
    Figure PCTCN2021107804-appb-100013
    Figure PCTCN2021107804-appb-100014
    Figure PCTCN2021107804-appb-100015
    Figure PCTCN2021107804-appb-100016
    R 3选自氢或C 1-C 6烷基；
    R d、R e、R d1、R e1、R d2、R e2、R d3、R e3如权利要求1所定义，优选R d、R e、R d1、R e1、R d2、R e2、R d3、R e3各自独立地选自C 1-C 6烷基或卤素；
    s为1至12的整数；
    q为0至12的整数；
    n 1、n 2、n 3和n 4各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数；
    m 1、m 2、m 3、m 5和m 7各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数；
    j 1、j 4、j 5、j 7和j 8各自独立地为0至15的整数，优选0至10的整数，更优选0至6的整数。
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中：
    L选自以下结构：
    Figure PCTCN2021107804-appb-100017
    Figure PCTCN2021107804-appb-100018
    R 3选自氢或C 1-C 6烷基；
    R d5和R e5各自独立地选自氢、卤素和C 1-C 6烷基；
    x1为0至5的整数；优选1至5的整数；
    x2为0至10的整数，优选0至6的整数；
    x3为1至10的整数，优选1至6的整数；
    x4为1至4的整数。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中所述化合物为前药，所述前药为经过生物体内转化后才呈现药理作用的化合物，并且
    其中，Q选自羟基、C 1-C 6烷基优选甲基、
    Figure PCTCN2021107804-appb-100019
    所述C 1-C 6烷基任选进一步被C 6-C 10芳基优选苯基取代；
    R 0选自C 6-C 10芳基优选苯基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基，其中所述C 6-C 10芳基、5-7元杂环基、C 1-C 10烷基、C 3-C 7环烷基和C 1-C 10烷氧基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、酰基、酰氨基、氧代基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、C 3-C 7环烷基、5-7元杂环基、C 6-C 10芳基和5-6元杂芳基的一个或多个基团所取代；
    R 4、R 7、R 8和R 9各自独立地选自氢、C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基、C 3-C 7环烷基和C 6-C 10芳基任选进一步被选自羟基、巯基、羧基、酰氨基、C 1-C 6烷基、C 1-C 6烷氧基和C 1-C 6烷硫基的一个或多个基团所取代；
    R 5和R 6各自独立地选自氢、C 1-C 6烷基、-C(O)OR其中R为C 1-C 6烷基和C 6-C 10芳基优选苯基，其中所述C 1-C 6烷基和C 6-C 10芳基任选进一步被选自卤素、氨 基、硝基、氰基、羟基、巯基、酯基、酰基、酰氨基、C 1-C 6烷基和C 1-C 6烷氧基的一个或多个基团所取代；或者
    R 5和R 6与其连接的氮原子一起形成含氮杂环基，优选5-7元含氮杂环基，所述杂环基任选进一步被选自卤素、C 1-C 6烷基、C 3-C 7环烷基、5-7元杂环基的一个或多个基团取代。
  16. 一种化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2021107804-appb-100020
    Figure PCTCN2021107804-appb-100021
    Figure PCTCN2021107804-appb-100022
    Figure PCTCN2021107804-appb-100023
    Figure PCTCN2021107804-appb-100024
    Figure PCTCN2021107804-appb-100025
    Figure PCTCN2021107804-appb-100026
    Figure PCTCN2021107804-appb-100027
    Figure PCTCN2021107804-appb-100028
  17. 根据权利要求1至16中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐的制备方法，其包括以下步骤：
    Figure PCTCN2021107804-appb-100029
    化合物M4和化合物M5通过亲核取代反应、偶联反应、缩合反应、Suzuki反应、Buchwald反应或Mitsunobu反应得到通式(I)的化合物；
    J 1和J 2各自独立地选自卤素、羟基、氨基、炔基和羧基；
    Y、U、Y 1、Y 2、Y 3、Y 4、A、E、L、R 1、R 2如权利要求1中所定义。
  18. 一种药物组合物，其含有治疗有效量的根据权利要求1至16中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐，以及药学上可接受的载体。
  19. 根据权利要求1至16中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者根据权利要求18所述的药物组合物在制备双功能FLT3酪氨酸激酶降解剂和抑制剂中的用途。
  20. 根据权利要求1至16中任一项所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者根据权利要求18所述的药物组合物在制备用于预防和/或治疗哺乳动物包括人类中FLT3介导的信号通路异常引起的相关疾病特别是癌症的药物中的用途，所述癌症优选为FLT3酪氨酸激酶表达异常(过表达、点突变、插入或缺失突变、融合蛋白等)或FLT3介导的信号通路异常的非实体瘤如白血病和实体瘤如皮肤癌、黑色素瘤、肺癌、胃癌、乳腺癌、胰腺癌、骨髓瘤、肝癌或结肠癌。
  21. 根据权利要求20所述的用途，其中根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其药学上可接受的盐或者根据权利要求18所述 的药物组合物可以与另外一种或多种药物如癌症治疗药物或者治疗方法如癌症治疗方法同时、分别或相继组合使用。
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