WO2021023233A1 - Egfr蛋白降解剂及其抗肿瘤应用 - Google Patents

Egfr蛋白降解剂及其抗肿瘤应用 Download PDF

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WO2021023233A1
WO2021023233A1 PCT/CN2020/107177 CN2020107177W WO2021023233A1 WO 2021023233 A1 WO2021023233 A1 WO 2021023233A1 CN 2020107177 W CN2020107177 W CN 2020107177W WO 2021023233 A1 WO2021023233 A1 WO 2021023233A1
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amino
dioxopiperidin
fluorophenyl
chloro
piperazin
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French (fr)
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杨小宝
姜标
宋肖玲
孙宁
任超伟
孙仁红
屈小娟
刘海霞
仇星
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上海科技大学
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/54—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
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/54—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a bifunctional compound and its preparation method and use.
  • the bifunctional compound can be used for the prevention or treatment of cancer.
  • the use can be specifically antitumor use, especially for EGFR, Her2, Her3, Her4 and other protein-related tumors.
  • Lung cancer is the leading cause of cancer deaths worldwide. In my country and the world, the incidence of lung cancer exceeds the incidence of other malignant tumors, occupying the first place in cancer incidence. According to the latest epidemiological data of Chinese Oncology in 2019, the total number of new lung cancer cases in China each year is 572,600, and 458,700 people die from lung cancer each year. At present, the five-year survival rate of lung cancer is very low, only 17%, and this survival rate has not changed much since the 1970s. This is largely due to the fact that conventional radiotherapy and chemotherapy kill cancer cells as well as normal cells in the patient's body, which have great toxic side effects and cannot effectively control the progression of lung cancer. Clinical treatment urgently needs new treatment methods to improve the quality of life of patients and increase the survival rate of lung cancer patients.
  • Targeted therapy for patients with specific driver gene mutations can greatly reduce the side effects of conventional radiotherapy and chemotherapy.
  • the use of tyrosine kinase inhibitor drugs for patients with lung cancer with epidermal growth factor receptor (EGFR) mutations can increase the therapeutic effect from 40% to 70% of the effect of conventional chemotherapy, and reduce the patient’s progression-free survival. From about 5 months to about 10 months.
  • EGFR is an epidermal growth factor receptor tyrosine kinase.
  • Patients with EGFR mutations have a higher incidence in Eastern populations. The number of patients with this disease accounts for about 15% of the total number of lung adenocarcinomas in the West, while EGFR mutations in Asian populations Up to about 50% of the total number of lung adenocarcinomas.
  • Targeted drugs developed for EGFR will greatly benefit Asian patients. However, almost all patients treated with targeted drugs will develop secondary drug resistance to the drug within a year or so after using the drug, and the tumor will recur. Research on the mechanism of tumor drug resistance found that almost 60% of the first and second generation EGFR inhibitor resistance is due to the secondary mutation T790M of EGFR. This promotes the development and clinical application of subsequent second and third generation targeted drugs for EGFR mutations, and improves the quality of life of patients.
  • the main EGFR-targeting drugs used in clinical practice are the small molecule drugs approved by the FDA for EGFR-mutant lung cancer, including the first-generation reversible tyrosine kinase inhibitor (TKI) and Erlotinib (Erlotinib). , Trade name Tarceva) or Gefitinib (Gefitinib, trade name Iressa) and second generation irreversible tyrosine kinase inhibitor Afatinib (Afatinib, FDA approved in July 2013 ).
  • the FDA approved the third-generation EGFR targeted drug Ositinib AZD9291.
  • AZD9291 can specifically kill cells with EGFR activating mutations and drug-resistant mutations T790M, and can prolong the disease-free survival of patients with acquired EGFR T790M mutations by about one year.
  • Dacomtinib the second-generation EGFR drug
  • NSCLC metastatic non-small cell lung cancer
  • studies have found that tumors can also develop secondary drug resistance to third-generation AZD9291 drugs, such as C797S mutations.
  • PROTAD PROteolysis TArgeting Drug
  • the protein degradation targeted chimera technology hopes to use the ubiquitin-proteasome degradation mechanism to change the fate of disease-causing proteins.
  • the PROTAD molecule is designed to be a small molecule with two active ends. One active end can be combined with the target protein, and the other active end can be combined with the protein of E3 ubiquitin ligase, and the middle is through the linking chain. connection. This bifunctional small molecule can force ubiquitin to bind to the target protein and transport them to the cell’s waste disposal station.
  • PROTAD mobilizes the whole cell as the drug effect unit.
  • This mode of drug action only requires small molecule drugs to temporarily bind to the target protein and label the target protein as "need to be cleaned up". Therefore, a low-concentration drug dose can meet the requirements, and these drugs can be recycled.
  • nanomolar concentrations are required to work, which greatly reduces the risk of off-target effects, and may fundamentally eliminate tumor progression caused by driver gene expression and drug resistance caused by driver gene acquired mutations . This technique can potentially overcome or delay the development of drug resistance in tumors.
  • the purpose of the present invention is to provide a bifunctional compound and a preparation method and application thereof to solve the problems in the prior art.
  • one aspect of the present invention provides a bifunctional compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and the chemistry of the bifunctional compound
  • the structural formula is shown in formula I:
  • EGFR Binders can bind to EGFR protein
  • B, X, Y, and Z are each independently selected from CH and N;
  • ULM means:
  • ULM means:
  • D 1 , D 2 , D 3 , D 4 , D 5 , D 6 , D 7 , D 8 are each independently selected from F, Cl, Br, OH, Me, Et, iPr, H and D;
  • LIN represents a linking group connected to EGFR Binders and ULM through covalent bonds.
  • Another aspect of the present invention provides the use of the bifunctional compound in the preparation of medicines.
  • Another aspect of the present invention provides a pharmaceutical composition, including the bifunctional compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and at least one pharmaceutically acceptable Accepted carriers, additives, adjuvants or excipients.
  • Figure 1 shows a compound study of the present invention based on dacomitinib derivative A (lung cancer HCC827 cell line).
  • Figure 2 shows a compound study based on dacomitinib derivative B of the present invention (lung cancer H1975 cell line).
  • Figure 3 shows a compound study of the present invention based on Canetinib derivatives A and B (lung cancer PC9 and H1975 cell lines).
  • Figure 4 shows that the inhibitory activity of the compounds of the present invention on the phosphorylation level of EGFR is better than small molecule inhibitors (lung cancer H1975 cell line and PC9Brc1 cell line).
  • Figure 5 shows the degradation ability of the compound of the present invention on the EGFR protein with three mutations (PC9DCT (Del19+T790M+C797S) cell line).
  • Figure 6 shows the study of the compounds of the present invention on breast cancer cell lines (BT474 cell line).
  • the inventors of the present invention have gone through a lot of practical research based on different EGFR-related drugs (for example, EGFR inhibitors, dacomitinib, poziotinib, gefitinib, afatinib ( afatinib), sapitinib, canertinib (canertinib), Osimertinib (Osimertinib), EAI045, etc.) provide a class of bifunctional compounds.
  • EGFR inhibitors for example, EGFR inhibitors, dacomitinib, poziotinib, gefitinib, afatinib ( afatinib), sapitinib, canertinib (canertinib), Osimertinib (Osimertinib), EAI045, etc.
  • the bifunctional compound provided by the present invention has varying degrees of regulatory effects on EGFR protein, and can not only promote the degradation of EGFR protein, but also inhibit the activity of EGFR kinase, and can also inhibit the proliferation of EGFR mutation-positive cells, and can develop into tumor patients On this basis, the present invention has been completed.
  • Designing degradants that target specific proteins is a new mode of drug development.
  • the inventors used the Proteolysis Targeting Drug (PROTAD) technology platform and specially designed bispecific protein modulators to achieve The target protein is labeled for "degradation", and the target protein is degraded by activating the protein degradation pathway inside the cell.
  • the targeted protein modulator small molecule provided by the present invention can induce the degradation of the target protein, which is essentially different in mechanism from the traditional small molecule inhibitor.
  • One aspect of the present invention provides a bifunctional compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and the chemical structural formula of the bifunctional compound is shown in Formula I:
  • EGFR Binders can bind to EGFR protein
  • B, X, Y, and Z are each independently selected from CH and N;
  • ULM means:
  • ULM means:
  • D 1 , D 2 , D 3 , D 4 , D 5 , D 6 , D 7 , D 8 are each independently selected from F, Cl, Br, OH, Me, Et, iPr, H and D;
  • LIN represents a linking group connected to EGFR Binders and ULM through covalent bonds.
  • the isotopically labeled form of the compound of the present invention is also included in the protection scope of the present invention.
  • at least one hydrogen atom is replaced by deuterium or tritium, or at least one carbon is replaced by 13 C- or 14 C-rich carbon, or at least one nitrogen is replaced by 15 N-rich nitrogen substitution.
  • salt should be understood as any form of active compound used by the present invention, wherein the compound can be in ionic form or charged or coupled to a counterion (cation or anion) or in solution.
  • This definition can also include quaternary ammonium salts and complexes of active molecules with other molecules and ions, especially complexes through ionic interaction.
  • This definition especially includes physiologically acceptable salts, and this term can be understood to be equivalent to "pharmacologically acceptable salts”.
  • the term "pharmaceutically acceptable salt” generally refers to any salt that is physiologically tolerable when used in treatment in an appropriate manner (especially when applied or used in humans and/or mammals) ( Generally speaking, this means that it is non-toxic, especially as a result of counter-ion is non-toxic).
  • physiologically acceptable salts may be formed with cations or bases, and in the context of the present invention, especially when administered in humans and/or mammals, they should be understood to be at least provided by the present invention.
  • a compound usually an acid (deprotonated), such as a salt of an anion and at least one physiologically tolerable cation (preferably an inorganic cation).
  • salts formed with alkali metals and alkaline earth metals may specifically include salts formed with ammonium cations (NH 4 + ), specifically including but not limited to (mono) or (di) sodium , (Single) or (two) potassium, magnesium or calcium salts.
  • NH 4 + ammonium cations
  • physiologically acceptable salts may also be formed with anions or acids, and in the context of the present invention, especially when administered in humans and/or mammals, they should be understood as those provided by the present invention
  • a salt formed by a physiologically tolerable acid that is, a salt formed by a specific active compound and a physiologically tolerable organic or inorganic acid, specifically including but not limited to Salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • the compound of the present invention represented by the above formula I may include an enantiomer depending on the presence of a chiral center or an isomer depending on the presence of a double bond (for example, Z, E).
  • a double bond for example, Z, E.
  • Single isomers, enantiomers, diastereomers or cis-trans isomers and their mixtures fall within the scope of the present invention.
  • prodrug in the present invention is used in its broadest sense and includes those derivatives that can be converted into the compounds of the present invention in vivo.
  • the methods for preparing prodrugs of the designated functional compounds should be known to those skilled in the art. For example, you can refer to Krogsgaard-Larsen et al., "Textbook of Drug design and Discovery” (Textbook of Drug design and Discovery) Relevant content disclosed in Taylor & Francis (April 2002).
  • solvate generally refers to any form of the active compound according to the present invention combined with another molecule (usually a polar solvent) through a non-covalent bond, and the obtained substance may specifically include but not Limited to hydrates and alcoholates, such as methanolate.
  • the bifunctional compound provided by the present invention may include an EGFR Binders part, the EGFR Binders part is usually connected to LIN by a covalent bond, and the EGFR Binders can usually bind to EGFR protein.
  • the EGFR Binders can be any molecule that can bind to EGFR protein, and more specifically can be EGFR TKIs.
  • the EGFR TKIs epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
  • EGFR TKIs epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
  • Inner protein tyrosine kinase region; the epidermal growth factor receptor tyrosine kinase inhibitor usually binds to the tyrosine kinase functional domain competitively with ATP, and can reversibly or irreversibly inhibit tyrosine kinase phosphorylation.
  • the EGFR TKIs part is usually used as the protein target binding part (PTM, protein target moiety), which can be connected to the ULM part (E3 ubiquitin ligase binding moiety, E3 ubiquitin ligase binding part) through LIN, which can cause the target protein to be ubiquitinated.
  • PTM protein target binding part
  • ULM part E3 ubiquitin ligase binding moiety, E3 ubiquitin ligase binding part
  • the ubiquitinated degradation pathway can degrade most of the ubiquitinated proteins in the cell, for example, it can degrade 80% to 90% or a higher proportion of ubiquitinated proteins in the cell. If this system can be activated to specifically clean up carcinogens Protein, which restores the protein homeostasis in the cell to normal, is likely to alleviate or treat cancer.
  • the PROTAD technology takes advantage of this point by using a specially designed bispecific degradation agent to "ubiquitin" the target protein to achieve targeted degradation.
  • the EGFR TKIs can specifically represent the groups shown in the chemical structural formula as follows:
  • R1, R2, R3, R4 are each independently selected from H, halogen, Cl, F, C1-10 alkyl, C1-10 haloalkyl, C1-10 alkynyl, C1-10 alkoxy, arylmethyl Oxy, heteroaryl methoxy, in the aryl methoxy and heteroaryl methoxy, the aryl and heteroaryl are unsubstituted or are selected from 1-2 C 1-10 alkanes Substituents substituted by groups, halogen and C 1-10 haloalkyl;
  • R 5 and R 6 are connected to LIN by a covalent bond, and forms a group selected from -NR"-, the chemical structural formula is as shown below, R" is selected from H, linear or branched C 1 -C 10 alkyl or C 3 -C 9 cycloalkyl:
  • R 5 and R 6 is selected from H, N, halogen, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy, amino, amido, alkylamino, C 1- 10 Dialkylamino, cyano, aryl, heteroaryl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, C 3-9 cycloalkyl, C 3-9 Cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, -NHC(O)R 14 , wherein the aryl and heteroaryl are unsubstituted or are selected from 1-2 C 1- 10 Alkyl, halogen, C 1-10 haloalkyl, cyano, R 7 SO 2 (CH 2 )sNHCH 2 -, -OR 8 , -NHC(O)R 9 substituents substituted, wherein R 7 is selected from C 1-10 alkyl and
  • R 10 and R 11 are each independently selected from H, C 1-10 alkyl
  • R 12 and R 13 are each independently selected from H, C 1-10 alkyl, or together with the adjacent nitrogen atom to form a heterocycloalkyl;
  • R 14 is selected from C 1-10 alkyl and alkenyl.
  • halogen or halo generally refers to fluorine, chlorine, bromine or iodine.
  • alkyl generally refers to saturated aliphatic groups, and they can be straight or branched.
  • C 1-10 alkyl generally refers to an alkyl group including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the alkyl group may specifically include, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • C 1-30 alkylene generally refers to including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 1, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
  • An alkylene group with 30 carbon atoms the alkylene group may specifically include but not limited to methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene , Octyl group, nonyl group, and decyl group.
  • haloalkyl generally refers to a halogenated saturated aliphatic group, which can be linear or branched, and is optionally monosubstituted or polysubstituted independently selected from fluorine, chlorine, bromine or iodine .
  • C 1-10 haloalkyl generally refers to a haloalkyl group including 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the halogenated alkyl group can specifically include, but are not limited to, halogenated methyl, halogenated ethyl, halogenated propyl, halogenated butyl, halogenated pentyl, halogenated hexyl, halogenated heptyl, halogenated octyl, Halogenated nonyl, halogenated decyl, etc.
  • C 3-9 cycloalkyl generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon having 3 to 9 carbon atoms.
  • the cycloalkyl group may specifically include, but are not limited to, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl , Cyclooctyl, adamantyl, noradamantyl, etc.
  • heterocycloalkyl generally refers to a saturated or unsaturated (but not aromatic) cyclic hydrocarbon, and has at least one heteroatom selected from N, O or S in its structure.
  • the heterocycloalkyl group may specifically include, but are not limited to, pyrroline, pyrrolidine, pyrazoline, aziridine, azetidine, tetrahydropyrrole, ethylene oxide, oxetane, dioxane Etidine, tetrahydropyran, tetrahydrofuran, dioxane, dioxolane, oxazolidine, piperidine, piperazine, morpholine, azepane or diazepane, etc.
  • the heterocycloalkyl group in the present invention is usually a 5- or 6-membered ring system.
  • aryl generally refers to a group having at least one aromatic ring but no heteroatoms.
  • the aryl group may optionally be independently selected from alkyl, halogen, haloalkyl, cyano, R 7 SO 2 (CH 2 )sNHCH 2 -, -OR 8 , -NHC(O)R 9 Substituents are single or multiple substituted.
  • the aryl group may specifically include, but is not limited to, phenyl, naphthyl, fluoranthene, fluorenyl, tetrahydronaphthyl, indanyl, anthracenyl and the like.
  • the aryl group in the present invention is a 5- or 6-membered ring system that is optionally at least monosubstituted.
  • heteroaryl generally refers to a heterocyclic ring system having at least one aromatic ring and may optionally contain one or more heteroatoms selected from N and O, and may optionally be independently selected from Alkyl, halogen, haloalkyl, cyano, R 7 SO 2 (CH 2 )sNHCH 2 -, -OR 8 , -NHC(O)R 9 substituents are mono- or poly-substituted.
  • the heteroaryl group may specifically include but not limited to furan, benzofuran, pyrrole, pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine, triazole, pyrazole, isoxazole, Indole, benzotriazole, benzodioxolane, benzodioxane, benzimidazole, carbazole, quinazoline, etc.
  • the heteroaryl group in the present invention is a 5- or 6-membered ring system optionally at least monosubstituted.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H, halogen, Cl, and F.
  • R 1 is selected from Cl
  • R 2 is selected from F
  • R 3 , and R 4 are each independently selected from H; or, R 1 is selected from H, R 2 It is selected from Cl, R 3 is selected from Cl, and R 4 is selected from F.
  • one of R 5 and R 6 can be covalently bonded to LIN and form a formula selected from -NR"-, or one of the following chemical structural formulas: Group:
  • R c represents vinylidene or absent
  • R" is selected from H, linear or branched C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
  • R 5 and R 6 is selected from C 1 -C 10 alkoxy, heterocycloalkyloxy, -NHC(O)R 14 , and R 14 is selected from C 1 -C 10 alkyl and alkenyl.
  • R 5 can be connected to LIN via a covalent bond and form a group selected from -NH- or a group represented by one of the following chemical structural formulas:
  • R 6 may be selected from a methoxy group or a group having the following structural formula:
  • R 5 may be selected from —NHC(O)R 14
  • R 14 may be selected from vinyl
  • R 6 can be connected to LIN by a covalent bond, and the chemical structural formula is one of the following groups:
  • the EGFR TKIs represents a group represented by one of the following chemical structural formulas:
  • the EGFR TKIs can also specifically represent the groups shown in the chemical structural formula as follows:
  • R 16 , R 17 , R 18 , R 19 , and R 20 are each independently selected from H, OH, F, Br, Cl, OMe;
  • R 15 and LIN are connected by a covalent bond and form a group selected from one of the following chemical structural formulas:
  • P 2 is selected from CHR d , wherein R d is selected from -NH- and piperazinylene.
  • R 16 , R 17 , R 18 , R 19 , and R 20 are each independently selected from H, OH, and F;
  • R 16 is selected from H and OH;
  • R 17 is selected from H;
  • R 18 is selected from H;
  • R 19 is selected from H and F;
  • R 20 is selected from H;
  • R 15 and LIN are connected by a covalent bond and form a group selected from one of the following chemical structural formulas:
  • P 2 is selected from CHR d , wherein R d is selected from -NH- and piperazinylene.
  • the EGFR TKIs represents a group represented by one of the following chemical structural formulas:
  • the EGFR TKIs can also specifically represent the groups shown in the chemical structural formula as follows:
  • R 21 and R 22 are connected to LIN by a covalent bond, and forms a group selected from -NR"'-, the chemical structural formula is as follows, R" is selected from H, linear or branched C 1- C 10 alkyl or C 3 -C 9 cycloalkyl:
  • R 21 and R 22 is selected from H, N, halogen, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy, amino, amido, alkylamino, C 1- 10 Dialkylamino, cyano, aryl, heteroaryl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, C 3-9 cycloalkyl, C 3-9 Cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, -NHC(O)R 31 , wherein the aryl and heteroaryl are unsubstituted or are selected from 1-2 C 1- 10 Alkyl, halogen, C 1-10 haloalkyl, cyano, R 24 SO 2 (CH 2 )sNHCH 2 -, -OR 25 , -NHC(O)R 26 substituent substituted, wherein R 24 is selected from C 1-10 alkyl and s
  • R 27 and R 28 are each independently selected from H, C 1-10 alkyl
  • R 29 and R 30 are each independently selected from H, C 1-10 alkyl, or together with the adjacent nitrogen atom to form a heterocycloalkyl;
  • R 31 is selected from C 1-10 alkyl and alkenyl.
  • one of R 21 and R 22 is covalently bonded to LIN, and forms a group selected from -NR"'- with the chemical structural formula shown below, R" is selected from H, linear or branched C 1 -C 10 alkyl or C 3 -C 9 cycloalkyl:
  • the EGFR TKIs represents a group represented by one of the following chemical structural formulas:
  • the bifunctional compound provided by the present invention may include a ULM part, which is usually connected to LIN by a covalent bond, and the ULM part is mainly used to connect E3 ubiquitin ligase and is a ligand of E3 ubiquitin ligase.
  • ULM can represent a group whose chemical structural formula is as follows:
  • B, X, Y, and Z are each independently selected from CH and N;
  • ULM can represent a group whose chemical structural formula is as follows:
  • ULM can represent a group whose chemical structural formula is as follows:
  • ULM can represent a group whose chemical structural formula is as follows:
  • ULM can represent a group whose chemical structural formula is as follows:
  • D 1 , D 2 , D 3 , D 4 , D 5 , D 6 , D 7 , D 8 are each independently selected from F, Cl, Br, OH, Me, Et, iPr, H, and D.
  • the bifunctional compound provided by the present invention may include a LIN part.
  • the LIN is usually connected to the EGFR TKIs part and the ULM part by covalent bonds.
  • the LIN part is mainly used to connect two key parts, namely the target protein and E3.
  • the length, type, and hydrophobicity of the ligase ligand and LIN part usually have an impact on the stability of the final target protein-PROTAD-E3 ligase ternary complex, which in turn affects its inhibitory and degradation activities.
  • Suitable for connecting PTM (protein target binding portion) and ULM (E3 ubiquitin ligase binding moiety, E3 ubiquitin ligase binding portion) of LIN should be known to those skilled in the art, for example, specific reference to Org. Lett. 2019, 21, 3838-3841, Bioorg. Med. Chem. Lett. 2016; 26: 5260-5262 and other documents.
  • the LIN can specifically mean:
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from: -O-, -CONH-, -NHCO-, -NH-, -NHCONH-, -S-, sulfinyl, sulfonyl, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene or any combination thereof , Wherein the linear or branched alkylene group is optionally substituted with one or more substituents;
  • the substituents of the linear or branched alkylene are each independently selected from hydroxyl, amino, mercapto and halogen.
  • the alkylene group is a C 1-30 alkylene group.
  • the LIN means :
  • R a1, R a2, R a3 , R a4, R a5, R a6, R a7, R a8, R a9, R a10, R a11, R a12, R a13, R a14, R a15, R a16, R a17 , R a18, R a19, R a20, R a21, R a22, R a23, R a24, R a25, R a26, R a27, R a28 are each independently selected from H, linear or branched a C 1 -C 10 alkyl group or C 3 -C 10 cycloalkyl group, wherein when in the same LIN, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10, R a11, R a12 , R
  • n1, n2, n3, n4, n5, n6, m1, m2 are independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, or 20.
  • the LIN means :
  • the LIN means :
  • the LIN represents: -W-(CH 2 ) 3 CH(OH)CH(OH)(CH 2 ) 4 -.
  • the LIN means :
  • n1, n2, n3, n4, n5, n6, m1, m2 are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, An integer of 15, 16, 17, 18, 19, or 20.
  • the LIN represents: -W-(CH 2 ) 3 -triazolylidene-(CH 2 ) 5 -, -W-(CH 2 ) 2 -triazolylidene- (CH 2 ) 5 -, -W-CH 2 -triazolylidene-(CH 2 ) 5 -, -W-(CH 2 ) 2 -triazolylidene-(CH 2 ) 4 -, -W-( CH 2 ) 3 -triazolylidene-(CH 2 ) 3 -, -W-(CH 2 ) 5 -triazolylidene-(CH 2 ) 5 -, -W-(CH 2 ) 5 -triazole Group -(CH 2 ) 8 -, -W-(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -O(CH 2 ) 2 -, -W-(CH 2 ) 2
  • the LIN means :
  • -W-CH 2 CONHCH 2 -, -W-(CH 2 ) 2 CONH(CH 2 ) 2 -, -W-(CH 2 ) 3 CONH(CH 2 ) 3 -, -W-(CH 2 ) 3 CONH (CH 2 ) 4 -, -W-(CH 2 ) 4 CONH(CH 2 ) 4 -, -W-(CH 2 ) 5 CONH(CH 2 ) 5 -, -W-(CH 2 ) 6 CONH(CH 2 ) 7 -, -W-(CH 2 ) 6 CONH(CH 2 ) 6 -, -W-(CH 2 ) 7 CONH(CH 2 ) 7 -, -W-(CH 2 ) 8 CONH(CH 2 ) 8 , W-(CH 2 ) 9 CONH(CH 2 ) 9 -, -W-(CH 2 ) 10 CONH(CH 2 ) 10 -, -W-(CH 2 ) 2 CONH(
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN means :
  • the LIN represents -W-piperazinylidene-, -W-spirocyclylene, -W-phenylene-, -WC ⁇ CC ⁇ C-, which can be specifically structured One of the following groups:
  • the bifunctional compound is selected from the compounds shown in Table 1 or Table 2:
  • the second aspect of the present invention provides the use of the bifunctional compound provided in the first aspect of the present invention in the preparation of medicines.
  • the bifunctional compound provided by the present invention includes the EGFR TKIs part and the ULM part.
  • the EGFR TKIs part and the ULM part can be covalently linked to LIN respectively.
  • the EGFR TKIs part is usually used as a protein target binding part (PTM, protein target moiety), the EGFR TKIs (epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors) can act on the intracellular protein tyrosine kinase region of EGFR, and the ULM part can cause the target protein to be ubiquitinated , Thereby activating the proteasome system inside the cell for targeted degradation of the target protein.
  • the ubiquitinated degradation pathway can degrade most of the ubiquitinated proteins in the cell, for example, it can degrade 80% to 90% or a higher proportion of ubiquitinated proteins in the cell.
  • this system can be activated to specifically clean up carcinogens Protein, which restores the protein homeostasis in the cell to normal, is likely to alleviate or treat cancer.
  • the PROTAD technology takes advantage of this point by using a specially designed bispecific degradation agent to "ubiquitin" the target protein to achieve targeted degradation.
  • the bifunctional compound exhibits a good inhibitory effect on EGFR, is a good EGFR inhibitor, can be used to modulate epidermal growth factor receptor (EGFR) and/or its mutants, and is applicable
  • the diseases can be specifically selected from tumors, myeloid tumors or solid tumors, cancer, leukemia, lymphoma, colorectal Cancer, brain cancer, bone cancer, epithelial cell-derived tumors (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small bowel cancer, gastric cancer, colon cancer, liver cancer, bladder Cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and/or basal cell carcinoma, prostate cancer, glioma, glioblastoma, renal cell carcinoma and
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the bifunctional compound provided in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and at least A pharmaceutically acceptable carrier.
  • the composition may include one or more pharmaceutically acceptable carriers, which generally refer to carriers used for the administration of therapeutic agents, which themselves do not induce the production of antibodies harmful to the individual receiving the composition, And there is no excessive toxicity after administration.
  • pharmaceutically acceptable carriers are well-known to those skilled in the art.
  • Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991) discloses related content about pharmaceutically acceptable carriers.
  • the carrier may be a combination of one or more including but not limited to saline, buffer, glucose, water, glycerol, ethanol, adjuvant and the like.
  • the bifunctional compound in the pharmaceutical composition provided by the present invention, can be a single active ingredient, or can be combined with other active ingredients to form a combined preparation.
  • the other active ingredients can be various other drugs that can be used to treat tumors, myeloma or solid tumors, and cancer.
  • the content of the active ingredient in the composition is usually a safe and effective amount, and the safe and effective amount should be adjustable for those skilled in the art.
  • the application amount of the bifunctional compound and the active ingredient of the pharmaceutical composition is usually Depending on the weight of the patient, the type of application, the condition and severity of the disease, for example, the administration amount of the bifunctional compound as an active ingredient can usually be 1 to 1000 mg/kg/day, 20 to 200 mg/kg/day, 1 ⁇ 3mg/kg/day, 3 ⁇ 5mg/kg/day, 5 ⁇ 10mg/kg/day, 10 ⁇ 20mg/kg/day, 20 ⁇ 30mg/kg/day, 30 ⁇ 40mg/kg/day, 40 ⁇ 60mg/kg/day, 60 ⁇ 80mg/kg/day, 80 ⁇ 100mg/kg/day, 100 ⁇ 150mg/kg/day, 150 ⁇ 200mg/kg/day, 200 ⁇ 300mg/kg/day, 300 ⁇ 500mg/ kg/day, or 500 ⁇ 1000mg/kg/day.
  • the bifunctional compound provided by the present invention can be adapted to any form of administration, which can be oral or parenteral administration, for example, it can be pulmonary, nasal, rectal and/or intravenous injection, and more specifically can be Intradermal, subcutaneous, intramuscular, intraarticular, intraperitoneal, lung, oral, sublingual, nasal, transdermal, vaginal, oral or parenteral administration.
  • Those skilled in the art can choose a suitable formulation form according to the mode of administration.
  • the formulation form suitable for oral administration may include but not limited to pills, tablets, chews, capsules, granules, drops or syrups.
  • the preparation form suitable for parenteral administration may include, but is not limited to, solution, suspension, reconstituted dry preparation or spray, etc.
  • the preparation suitable for rectal administration may usually be suppository. .
  • the fourth aspect of the present invention provides a treatment method comprising: administering to an individual a therapeutically effective amount of the bifunctional compound provided in the first aspect of the present invention or the pharmaceutical composition provided in the third aspect of the present invention.
  • mammals generally include humans and non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cows, etc., which can be treated with the preparations, kits or combination preparations. And benefit.
  • therapeutically effective amount generally refers to an amount that can achieve the effect of treating the diseases listed above after a proper administration period.
  • the bifunctional compound provided by the present invention is a bifunctional compound based on an epidermal growth factor receptor tyrosine kinase inhibitor.
  • the bifunctional compound based on an epidermal growth factor receptor tyrosine kinase inhibitor can not only promote the EGFR protein Degradation can also inhibit the activity of EGFR kinase and have a significant inhibitory effect on the proliferation of EGFR mutation-positive cells.
  • the one or more method steps mentioned in the present invention does not exclude that there may be other method steps before and after the combined steps or other method steps may be inserted between these explicitly mentioned steps, unless otherwise.
  • the number of each method step is only a convenient tool for identifying each method step, and is not intended to limit the sequence of each method step or limit the scope of implementation of the present invention. The change or adjustment of the relative relationship is If there is no substantial change in the technical content, it shall be regarded as the scope of the present invention.
  • Solvent and reagent treatment are as follows:
  • HPLC preparation uses preparative CH 3 CN and deionized water
  • n an integer of 1-10, as shown in Scheme 6.
  • n 1-5 integer, as shown in scheme 7.
  • n 1-10 integer, as shown in scheme 8.
  • n 1-5 integer, as shown in Scheme 9.
  • n 1-10 integer, as shown in scheme 10.
  • n 1-10 integer, as shown in scheme 11.
  • n 1-10 integer, as shown in scheme 12.
  • dacomitinib derivative B Using a method similar to that of dacomitinib derivative A in Example 1, dacomitinib derivative B was prepared according to Scheme 1.
  • the intermediate synthesis data and structural characterization data are as follows :
  • Bozitinib Derivative A (SIAIS219149B): According to Scheme 2, Bozitinib Derivative A (SIAIS219149B) was prepared.
  • 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4(3H)-one (468.4mg, 2mmol) was dissolved in 4mL of thionyl chloride and added A drop of DMF initiates the reaction. Stir at 90°C for 4 hours. Rotate at low temperature to remove excess thionyl chloride and put it directly into the next step; add the product of the previous step (2mmol), 10mL DMF, 3,4-dichloro to a clean 100mL egg-shaped flask. -2-fluoroaniline (432mg, 2.4mmol), stirred at 80°C for 1h.
  • the yellow solid was dissolved in 6 mL DCM, 2 mL CF 3 COOH was added, and then reacted at room temperature for 2 h. After the reaction is detected by LC-MS, spin off most of the CF 3 COOH, add saturated sodium bicarbonate solution to adjust the pH of the solution to alkaline, extract with dichloromethane, dry with anhydrous sodium sulfate, spin to dry, and separate on reversed-phase C18 column.
  • the eluent was methanol and water to obtain 320 mg of yellow solid SIAIS184161, and the total yield of the two steps was 81%.
  • Gefitinib Derivative B Using a method similar to that of Gefitinib Derivative A of Intermediate Preparation Example 4, Gefitinib Derivative B was prepared according to Scheme 3, and its intermediate synthesis data and structure The characterization data are as follows:
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine 400mg, 0.8mmol
  • NMP 3-( tert-butoxy)-3-oxopropanoic acid (234mg, 1.2mmol)
  • NaI 240mg, 1.6mmol
  • DIPEA 310mg, 2.4mmol
  • linker intermediate SIAIS1213061 please refer to patent WO2020103878(A1) for the specific synthesis method and data of SIAIS1213011.
  • the intermediate compound SIAIS151014 (0.724mmol, 1equiv) was added to a 50mL egg-shaped flask, followed by the addition of anhydrous N,N-dimethylformamide (10mL) and anhydrous potassium carbonate (1.448mmol, 2equiv) ), slowly drop the corresponding p-toluenesulfonate substitution substrate (0.869 mmol, 1.2 equiv) as a linker under stirring at room temperature, and stir for 0.5h at room temperature after dropping. After the reaction of the raw materials, filter to remove the insoluble materials and directly load the sample on a C18 reversed phase column for separation.
  • SIAIS1204139 was prepared. The difference is that the raw material p-toluenesulfonate substitution substrate is tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate.
  • the target compound SIAIS1204139 (light yellow solid, 190 mg, yield 63%) was obtained.
  • SIAIS1204141 Refer to the method of Intermediate Preparation Example 10 to prepare SIAIS1204141.
  • the difference is that the p-toluenesulfonate used as the raw material to replace the substrate is tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy )ethoxy)acetate.
  • the target compound SIAIS1204141 (light yellow solid, 246 mg, yield 74%) was obtained.
  • SIAIS1204147 was prepared. The difference is that the raw material p-toluenesulfonate substituted substrate is tert-butyl 14-(tosyloxy)-3,6,9,12-tetraoxatetradecanoate.
  • the target compound SIAIS1204147 (light yellow solid, 228 mg, yield 63%) was obtained.
  • SIAIS1204149 Refer to the method of Intermediate Preparation Example 10 to prepare SIAIS1204149.
  • the difference is that the raw material used is tert-butyl 17-(tosyloxy)-3,6,9,12,15-pentaoxaheptadecanoate. .
  • the target compound SIAIS1204149 (light yellow solid, 259 mg, yield 66%) was obtained.
  • the compound SIAIS151045 was prepared according to the method described in Scheme 6, except that the brominated substrate used as the linker was tert-butyl 2-bromoacetate.
  • the target compound SIAIS151045 (light yellow solid, 0.69 g, yield 80%) was obtained.
  • HRMS(ESI)m/z calculated value C 16 H 15 N 2 O 6 S + [M+H] + ,363.0645; actual measurement Value, 363.0802.
  • the compound SIAIS151139B was prepared according to the method of Intermediate Preparation Example 15, except that the brominated substrate used as the linker was tert-butyl 4-bromobutyrate.
  • the target compound SIAIS151139B (light yellow solid, 0.71 g, yield 82%) was obtained.
  • the compound SIAIS151140B was prepared according to the method of Intermediate Preparation Example 15, except that the brominated substrate used as the linker was tert-butyl 5-bromopentanoate.
  • the target compound SIAIS151140B (light yellow solid, 0.9g, yield 74%) was obtained.
  • the compound SIAIS151141B was prepared according to the method of intermediate preparation example 15, except that the brominated substrate used as the linker was tert-butyl 6-bromohexanoate.
  • the target compound SIAIS151141B (light yellow solid, 0.71 g, yield 74%) was obtained.
  • the compound SIAIS151142B was prepared according to the method of intermediate preparation example 15, except that the brominated substrate used as the linker was tert-butyl 7-bromoheptanoate.
  • the target compound SIAIS151142B (light yellow solid, 0.7g, yield 80%) was obtained.
  • the intermediate compound SIAIS171095 (0.724mmol, 1equiv) was added to a 50mL egg-shaped flask, followed by the addition of anhydrous N,N-dimethylformamide (10mL) and anhydrous potassium carbonate (1.448mmol, 2equiv) ), slowly drop the corresponding p-toluenesulfonate substitution substrate (0.869 mmol, 1.2 equiv) as a linker under stirring at room temperature, and stir for 0.5h at room temperature after dropping. After the reaction of the raw materials, filter to remove the insoluble materials and directly load the sample on a C18 reversed phase column for separation.
  • SIAIS1213131 was prepared. The difference is that the raw material p-toluenesulfonate substituted for the substrate was tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate.
  • the target compound SIAIS1213131 pale yellow oil, 158 mg, yield 52%) was obtained.
  • SIAIS1213133 Refer to the method of Intermediate Preparation Example 21 to prepare SIAIS1213133.
  • the difference is that the raw material p-toluenesulfonate substituted substrate is tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy )ethoxy)acetate.
  • the target compound SIAIS1213133 (light yellow oil, 149 mg, yield 44%) was obtained.
  • SIAIS1213135 was prepared. The difference is that the raw material p-toluenesulfonate substituted substrate is tert-butyl 14-(tosyloxy)-3,6,9,12-tetraoxatetradecanoate.
  • the target compound SIAIS1213135 (light yellow oil, 181 mg, yield 49%) was obtained.
  • SIAIS1213133 Refer to the method of intermediate preparation example 21 to prepare SIAIS1213133.
  • the difference is that the raw material p-toluenesulfonate substituted substrate is tert-butyl 17-(tosyloxy)-3,6,9,12,15-pentaoxaheptadecanoate .
  • the target compound SIAIS1213137 pale yellow oil, 209 mg, yield 52%) was obtained.
  • the compound SIAIS171090 was prepared according to the method described in Scheme 8, except that the brominated substrate used as the linker was tert-butyl 2-bromoacetate.
  • the target compound SIAIS171090 (white solid, 77 mg, total yield of step 3 64%) was obtained.
  • the compound SIAIS171086 was prepared according to the method of Intermediate Preparation Example 26, except that the brominated substrate used as the linker was tert-butyl 3-bromopropionate.
  • the target compound SIAIS171086 (white solid, 40 mg, total yield of step 3 32%) was obtained.
  • the compound SIAIS171089 was prepared by referring to the method of Intermediate Preparation Example 26, except that the brominated substrate used as the linker was tert-butyl 4-bromobutyrate.
  • the target compound SIAIS171089 (white solid, 50 mg, step 3 total yield 38%) was obtained.
  • the compound SIAIS171079 was prepared according to the method of Intermediate Preparation Example 26, except that the brominated substrate used as the linker was tert-butyl 5-bromopentanoate.
  • the target compound SIAIS171079 was obtained (white solid, 30 mg, total yield of step 3 was 22%).
  • the compound SIAIS171091 was prepared by referring to the method of Intermediate Preparation Example 26, except that the brominated substrate used as the linker was tert-butyl 6-bromohexanoate.
  • the target compound SIAIS171091 was obtained (white solid, 75 mg, the total yield of step 3 was 53%).
  • the compound SIAIS171092 was prepared according to the method of intermediate preparation example 26, except that the brominated substrate used as the linker was tert-butyl 7-bromoheptanoate.
  • the target compound SIAIS171092 (white solid, 79 mg, step 3 total yield 54%) was obtained.
  • step 1 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.50g, 1.5 mmol) was dissolved in 5mL DMF, and Ar gas was bubbled for 5min , Add 3-alkynylbutanol (0.21g, 3.0mmol), Pd(PPh 3 ) 2 Cl 2 (0.10g, 0.15mmol) and CuI (57mg, 0.30mmol) in sequence. Stir for 5min, add 2.5mL triethylamine, heat to 80°C, and react overnight.
  • SIAIS255121 was prepared, except that 4-ynylpentanol was used as the starting material.
  • HRMS(ESI) C 19 H 21 N 2 O 6 S + [M+H] + the calculated value is 405.1115; the measured value, 405.1111.
  • SIAIS255119 was prepared, except that 5-alkynylhexanol was used as the starting material.
  • step 1 the compound SIAIS171095 (0.36mmol, 1equiv) was added to a 10mL reaction flask, and then anhydrous DMF (2mL) and anhydrous potassium carbonate (0.72mmol, 2equiv) were added, and slowly under stirring at room temperature Add the corresponding tert-butyl (2-bromoethyl) carbamate (0.43 mmol, 1.2 equiv), and stir at room temperature for 1 h after dropping.
  • step 1 The corresponding product obtained in step 1 was added to a 10 mL reaction flask, followed by adding anhydrous dichloromethane (2 mL) and trifluoroacetic acid (2 mL), stirring at room temperature for 12 hours.
  • SIAIS171124 was prepared. The difference is that the brominated substrate used as the linker is tert-butyl (3-bromobutyl) carbamate. (White solid, 68mg, total yield of two steps 56%).
  • SIAIS171131 was prepared, except that the brominated substrate used as the linker was tert-butyl (4-bromobutyl) carbamate. (Light yellow solid, 76mg, total yield of two steps 60%).
  • SIAIS171132 was prepared, except that the brominated substrate used as the linker was tert-butyl (5-bromopentyl) carbamate. (Light yellow solid, 95mg, the total yield of the two steps is 73%).
  • SIAIS171134 was prepared, except that the brominated substrate used as the linker was tert-butyl (6-bromohexyl) carbamate. (Light yellow solid, 78mg, total yield of two steps 57%).
  • SIAIS171135 was prepared, except that the brominated substrate used as the linker was tert-butyl (7-bromoheptyl) carbamate. (White solid, 100mg, total yield of two steps 71%).
  • SIAIS171136 was prepared, except that the brominated substrate used as the linker was tert-butyl (8-bromooctyl) carbamate. (White solid, 100mg, total yield of two steps 68%).
  • step 1 dissolve 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (16.8mmol, 1equiv) Add 6-aminohexan-1-ol (16.8 mmol, 1.0 equiv) and DMF (25.2 mmol, 1.5 equiv) to 25 mL of NMP, and heat the reaction at 90° C. for 4 hours, and the reaction is complete.
  • reaction solution was cooled to room temperature, poured into saturated brine, extracted with ethyl acetate (4x 50mL), combined the organic phases, washed with water (2x 30mL), washed with saturated brine (50mL), dried with anhydrous Na 2 SO 4 and evaporated under reduced pressure
  • the intermediate was dissolved in 50 mL of tetrahydrofuran, tetrabutylammonium fluoride (16.8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was complete.
  • DCM/Pyridine 3/1
  • triethylamine 0.52 mL, 3.8 mmol
  • methanesulfonyl chloride 0.30 mL, 3.8 mmol
  • step 3 the compound of the previous step was dissolved in 10 mL of acetone, sodium iodide (3.0 equiv) was added, and the reaction was heated to 60° C. for 24 hours to complete the conversion. It was cooled to room temperature, diluted with 40 mL ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent to obtain the product SIAIS264018 as a yellow solid, which was directly put into use.
  • Ositinib derivative (SIAIS337051) was prepared according to Scheme 16.
  • Steps 1 and 2 Add N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl) in an egg-shaped flask under room temperature open conditions pyrimidin-2-amine (1.18g, 3mmol), 6mL DMF, tert-butyl methyl(2-(methylamino)ethyl)carbamate (677.8mg, 3.6mmol), potassium carbonate (621.9mg, 4.5mmol), then change the argon React at 80°C for 12h. After the reaction is detected by TLC, it is quenched with water, extracted with ethyl acetate, spin-dried, and separated on a silica gel column.
  • the yellow solid was dissolved in 20 mL of 75% ethanol, iron powder (268.8 mg, 4.8 mmol) and ammonium chloride (342 mg, 6.4 mmol) were added, and then argon was pumped and reacted at 80°C for 3 hours.
  • After the reaction is detected by LC-MS, filter on Buchner funnel, wash with dichloromethane: methanol 10:1, spin dry, and separate on silica gel column.
  • HRMS(ESI) C 29 H 36 N 7 O 5 + [M+H] + , calculated value 562.2772; measured value, 562.2771.
  • Steps 3 and 4 Add the yellow solid (300mg, 0.565mmol) from the previous step to a clean 100mL egg-shaped flask, 5mL DCM, add 3-chloropropanoyl chloride (60 ⁇ L, 0.633mmol) at 0°C, return to room temperature, stir, and react at room temperature 1h. After the reaction, it was quenched with water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and proceed directly to the next step.
  • 3-chloropropanoyl chloride 60 ⁇ L, 0.633mmol
  • Step 5 Dissolve the above-mentioned yellow solid in 2 mL of MeOH, add 4 mL of hydrochloric acid dioxane solution (4M), and then react at room temperature for 2 hours. After the reaction was detected by LC-MS, it was spin-dried and separated by reversed-phase C18 column. The eluent was methanol and water to obtain 228 mg of yellow solid SIAIS337051, with a yield of 99%.
  • dacomitinib derivative C using a method similar to that of the dacomitinib derivative A of intermediate example 1, prepared according to scheme 1 to obtain dacomitinib derivative B, its intermediate synthesis data and structural characterization Data are as follows:
  • SIAIS255127 was prepared, except that 8-alkynylnonanol was used as the starting material.
  • Nalidomide (1mmol, 1equiv) will be added to a 50mL egg-shaped flask, and then anhydrous N,N-dimethylformamide (10mL) and DIPEA (3mmol, 3equiv) will be added.
  • N,N-dimethylformamide 10mL
  • DIPEA 3mmol, 3equiv
  • SIAIS1222125 was prepared, except that the brominated substrate used as the linker was tert-butyl 5-bromopentanoate.
  • the target compound SIAIS1222125 (light yellow solid, 418 mg, yield 59%) was obtained.
  • SIAIS1222149 was prepared. The difference is that the brominated substrate used as the linker is tert-butyl 6-bromohexanoate.
  • the target compound SIAIS1222149 (light yellow solid, 313 mg, yield 42%) was obtained.
  • SIAIS1222151 was prepared, except that the brominated substrate used as the linker was tert-butyl 7-bromoheptanoate.
  • the target compound SIAIS1222151 (light yellow solid, 250 mg, yield 32%) was obtained.
  • hydroxylenalidomide (CAS: 1061604-41-8, 2mmol, 1equiv) into a 50mL egg-shaped flask, then add acetonitrile (10mL) and potassium carbonate (4mmol, 2equiv), add 1,6 under stirring at room temperature -Dibromohexane (4mmol, 2equiv), react at 80°C overnight.
  • the target compound (SIAIS262013) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151004). (yellow solid, 8.2mg, 44%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249047) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151005). (yellow solid, 9.9mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262014) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151006). (yellow solid, 10.1mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219194) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151025). (yellow solid, 8.2mg, 50%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262016) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151026). (yellow solid, 6.6 mg, 39%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249062) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151019). (yellow solid, 8.2mg, 48%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249048) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151020). (yellow solid, 8.1mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249049) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151027). (yellow solid, 8.3mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262015) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151086). (yellow solid, 8.9mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249056) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204057). (yellow solid, 7.1mg, 44%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249057) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204085). (yellow solid, 8.2mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249058) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1210133). (yellow solid, 8.5mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249059) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204061). (yellow solid, 8.7mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249060) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204063). (yellow solid, 8.3mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249034) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151045). (yellow solid, 8.2mg, 49%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS249035) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151138B). (yellow solid, 9.1mg, 53%) 1 H NMR (500MHz, DMSO) ⁇ 8.
  • the target compound (SIAIS249036) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151139B). (yellow solid, 7.4mg, 42%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS249037) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151140B). (yellow solid, 8.5mg, 48%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS249038) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151141B). (yellow solid, 8.9mg, 49%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS249039) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151142B). (yellow solid, 9.1mg, 50%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS219192) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204137). (yellow solid, 9.5mg, 54%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262005) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204139). (yellow solid, 9.1mg, 49%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262006) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204141). (yellow solid, 9.7mg, 49%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262007) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204147). (yellow solid, 10.1mg, 49%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262008) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1204149). (yellow solid, 11.5mg, 54%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS219185) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171090). (yellow solid, 8.1mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219186) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171086). (yellow solid, 8.5mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219187) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171089). (yellow solid, 9.0mg, 53%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219188) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171079). (yellow solid, 8.8mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219189) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171091). (yellow solid, 9.1mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219190) was prepared using dacomitinib derivative A and intermediate LM (SIAIS171092). (yellow solid, 8.9mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS219193) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1213129). (yellow solid, 9.1mg, 52%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262001) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1213131). (yellow solid, 9.2mg, 50%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262002) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1213133). (yellow solid, 10.2mg, 53%) 1 H NMR (500MHz, DMSO) ⁇ 10.
  • the target compound (SIAIS262003) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1213135). (yellow solid, 10.3mg, 51%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS262004) was prepared using dacomitinib derivative A and intermediate LM (SIAIS1213137). (yellow solid, 11.2mg, 53%) 1 H NMR (500MHz, DMSO) ⁇ 11.
  • the target compound (SIAIS249045) was prepared using dacomitinib derivative A and intermediate LM (SIAIS151002). (white solid, 11.1mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249041) was prepared using dacomitinib derivative A and intermediate LM (SIAIS074011). (white solid, 10.2mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249042) was prepared using dacomitinib derivative A and intermediate LM (SIAIS074013). (white solid, 10.8mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249043) was prepared using dacomitinib derivative A and intermediate LM (SIAIS074015). (white solid, 10.8mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262032) was prepared using dacomitinib derivative B and intermediate LM (SIAIS151141B). (yellow solid, 8.1mg, 48%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262033) was prepared using dacomitinib derivative B and intermediate LM (SIAIS151142B). (yellow solid, 8.4mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262034) was prepared using dacomitinib derivative B and intermediate LM (SIAIS171090). (yellow solid, 6.5mg, 42%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262035) was prepared using dacomitinib derivative B and intermediate LM (SIAIS171091). (yellow solid, 8.3mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262036) was prepared using dacomitinib derivative B and intermediate LM (SIAIS151025). (yellow solid, 7.4mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262037) was prepared using dacomitinib derivative B and intermediate LM (SIAIS151086). (yellow solid, 9.1mg, 54%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS262052) was prepared using dacomitinib derivative B and intermediate LM (SIAIS172147). (yellow solid, 8.6mg, 55%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249029) was prepared using bozitinib derivative A and intermediate LM (SIAIS151001). (yellow solid, 9.7mg, 52%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249030) was prepared using bozitinib derivative A and intermediate LM (SIAIS151004). (yellow solid, 9.5mg, 48%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249031) was prepared using bozitinib derivative A and intermediate LM (SIAIS151005). (yellow solid, 11.0mg, 53%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249032) was prepared using bozitinib derivative A and intermediate LM (SIAIS151006). (yellow solid, 11.2mg, 52%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249033) was prepared using bozitinib derivative A and intermediate LM (SIAIS151007). (yellow solid, 11.4mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219179) was prepared using bozitinib derivative A and intermediate LM (SIAIS151019). (yellow solid, 9.2mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • SIAIS219181 4-((6-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexyl)amino )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS219181) was prepared by referring to the method in Example 1, using bozitinib derivative A and intermediate LM (SIAIS151027) Obtain the target compound (SIAIS219181).
  • the target compound (SIAIS249014) was prepared using bozitinib derivative A and intermediate LM (SIAIS151045). (yellow solid, 6.7mg, 38%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249015) was prepared using bozitinib derivative A and intermediate LM (SIAIS151138B). (yellow solid, 6.9mg, 38%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249016) was prepared using bozitinib derivative A and intermediate LM (SIAIS151139B). (yellow solid, 5.7mg, 31%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249017) was prepared using bozitinib derivative A and intermediate LM (SIAIS151140B). (yellow solid, 8.5mg, 46%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249018) was prepared using bozitinib derivative A and intermediate LM (SIAIS151141B). (yellow solid, 6.5mg, 34%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249019) was prepared using bozitinib derivative A and intermediate LM (SIAIS151142B). (yellow solid, 9.0mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219164) was prepared using bozitinib derivative A and intermediate LM (SIAIS171090). (yellow solid, 8.4mg, 48%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219165) was prepared using bozitinib derivative A and intermediate LM (SIAIS171086). (yellow solid, 9.4mg, 53%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219166) was prepared using bozitinib derivative A and intermediate LM (SIAIS171089). (yellow solid, 9.7mg, 54%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219167) was prepared using bozitinib derivative A and intermediate LM (SIAIS171079). (yellow solid, 9.2mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219168) was prepared using bozitinib derivative A and intermediate LM (SIAIS171091). (yellow solid, 10.1mg, 54%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS219169) was prepared using bozitinib derivative A and intermediate LM (SIAIS171092). (yellow solid, 9.8mg, 52%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS249024) was prepared using bozitinib derivative A and intermediate LM (SIAIS151010). (white solid, 11.2mg, 48%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249025) was prepared using bozitinib derivative A and intermediate LM (SIAIS151002). (white solid, 12.1mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249026) was prepared using bozitinib derivative A and intermediate LM (SIAIS151003). (white solid, 12.4mg, 50%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249027) was prepared using bozitinib derivative A and intermediate LM (SIAIS151008). (white solid, 12.1mg, 47%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249028) was prepared using bozitinib derivative A and intermediate LM (SIAIS151009). (white solid, 13.1mg, 49%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249020) was prepared using bozitinib derivative A and intermediate LM (SIAIS074011). (white solid, 7.7mg, 35%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249021) was prepared using bozitinib derivative A and intermediate LM (SIAIS074013). (white solid, 8.1mg, 36%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249022) was prepared using bozitinib derivative A and intermediate LM (SIAIS074015). (white solid, 9.7mg, 42%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS249023) was prepared using bozitinib derivative A and intermediate LM (SIAIS074019). (white solid, 10.8mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 9.
  • the target compound (SIAIS184164) was prepared using gefitinib derivative A and intermediate LM (SIAIS151045). (yellow solid, 6.9mg, 40%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • SIAIS184165 4-((4-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-4- oxobutyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (SIAIS184165) was prepared referring to the method in Example 1, using gefitinib derivative A and intermediate LM ( SIAIS151139B) was prepared to obtain the target compound (SIAIS184165).
  • the target compound (SIAIS184166) was prepared using gefitinib derivative A and intermediate LM (SIAIS151141B). (yellow solid, 9.5mg, 51%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184168) was prepared using gefitinib derivative A and intermediate LM (SIAIS1204137). (yellow solid, 8.2mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184169) was prepared using gefitinib derivative A and intermediate LM (SIAIS1204141). (yellow solid, 9.1mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184170) was prepared using gefitinib derivative A and intermediate LM (SIAIS1204149). (yellow solid, 9.2mg, 41%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184185) was prepared using gefitinib derivative A and intermediate LM (SIAIS171089). (yellow solid, 7.2mg, 41%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184186) was prepared using gefitinib derivative A and intermediate LM (SIAIS171091). (yellow solid, 8.2mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS262085) was prepared using gefitinib derivative B and intermediate LM (SIAIS171090). (yellow solid, 10.1 mg, 43%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS262086) was prepared using gefitinib derivative B and intermediate LM (SIAIS171079). (yellow solid, 11.2mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS262087) was prepared using gefitinib derivative B and intermediate LM (SIAIS171091). (yellow solid, 11.3mg, 45%) 1 H NMR (500MHz, MeOD) ⁇ 8.
  • the target compound (SIAIS184093) was prepared using afatinib derivative A and intermediate LM (SIAIS151045). (white solid, 12.2mg, 43%) 1 H NMR (500MHz, MeOD) ⁇ 9.

Abstract

一种双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，双功能化合物的化学结构式如式I所示，双功能化合物可以用于预防或治疗癌症。

Description

EGFR蛋白降解剂及其抗肿瘤应用 技术领域
本发明涉及药物化学领域，特别是涉及一种双功能化合物及其制备方法和用途，所述双功能化合物可以用于预防或治疗癌症，所述用途具体可以为抗肿瘤的用途，尤其可以针对与EGFR、Her2、Her3、Her4等蛋白相关的肿瘤。
背景技术
肺癌是世界范围内癌症致死的首要原因。在我国以及世界范围内，肺癌的发病率超过其它恶性肿瘤的发病率,占据癌症发病之首位。据2019年中国肿瘤学最新流行病学数据显示，中国每年新发肺癌总数为57.26万例，每年有45.87万人死于肺癌。目前，肺癌的五年存活率很低，仅有17％，而且这个存活率从上世纪七十年代至今未有多大变化。这很大原因上是由于常规的放疗和化疗疗法在杀死癌症细胞的同时也杀死患者体内的正常细胞，具有很大的毒副作用，不能对肺癌进程进行有效的控制。临床治疗迫切需要新的治疗方法来改善患者的生存质量，提高肺癌患者的生存率。
对带有特定驱动基因突变的患者进行靶向治疗可大大减少常规放疗和化疗的毒副作用。比如，对肺癌具有表皮生长因子受体(EGFR)突变的患者使用酪氨酸激酶抑制剂类药物可以将治疗效果从常规化疗效果的40％提高至70％，并将病人的无进展生存期从约5个月提高至10个月左右。EGFR是一种表皮生长因子受体酪氨酸激酶，EGFR突变的患者在东方人群发病率较高，该病患者人数在西方占肺腺癌总数的15％左右，而在亚洲人群中EGFR突变患者高达肺腺癌总数的50％左右。针对EGFR开发的靶向药物会使亚洲患者大大受益。然而，几乎所有使用靶向药物治疗的患者在使用药物后一年左右的时间会对药物产生继发耐药性，肿瘤会复发。对肿瘤耐药性机制的研究发现几乎60％的第一代和第二代EGFR抑制剂耐药是由于EGFR获得了继发性突变T790M。这推动了后续第二代和第三代针对EGFR突变的靶向药物的研发和临床应用，提高了患者的生存质量。目前临床上主要使用的EGFR靶向药物为FDA已经批准的针对EGFR突变肺癌的小分子药物包括第一代的可逆性酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)、厄洛替尼(Erlotinib，商品名为特罗凯)或吉非替尼(Gefitinib，商品名为易瑞沙)和第二代不可逆性酪氨酸激酶抑制剂阿法替尼(Afatinib，FDA获批于2013年7月)。2015年年底，FDA批准了第三代EGFR靶向药物奥西替尼AZD9291。AZD9291可特异性杀死具有EGFR激活突变以及耐药性突变T790M的细胞，可延长获得性EGFR T790M突变 肿瘤患者的无病生存期一年左右的时间。2018年FDA批准EGFR二代药物达克替尼(Dacomtinib)用于携带EGFR激活突变的局部晚期或转移性非小细胞肺癌(NSCLC)患者的一线治疗。然而，研究发现肿瘤对第三代AZD9291药物也会产生继发耐药性，如C797S突变等。肿瘤的复发并对靶向药物耐药性的产生是阻碍小分子药物长期药效的一大绊脚石，这严重影响了患者的生存及社会发展的需求。具有EGFR突变的肺癌患者在中国肺癌患者中占有很高比例，而且中国肺癌患者还在逐年上升。克服肺癌治疗中肿瘤对靶向药物小分子化合物的耐药性也成为刻不容缓的问题。所以，开发新的治疗措施和新的药物对肺癌患者很有必要。
我们发展的蛋白降解技术(PROTAD:PROteolysis TArgeting Drug)平台是一种全新的药物开发技术，蛋白降解靶向嵌合体技术希望利用泛素-蛋白酶体的降解机制来改变导致疾病的蛋白的命运。为了达成以上目标，设计PROTAD分子成为拥有两个活性端的小分子，一个活性端可以与靶向的蛋白相结合，而另一个活性端可以与E3泛素连接酶的蛋白相结合，中间通过连接链连接。这种双功能小分子能够强迫泛素与靶蛋白相结合，将它们运送到细胞的垃圾处理站中。与传统的小分子药物设计相比，PROTAD最大的不同在于调动了整个细胞作为药物效应单元。这种药物作用模式只需要小分子药物短暂地与靶蛋白结合，给靶蛋白打上“需要清理”的标签就可以了，因此低浓度的药物剂量就可以满足要求，而且这些药物是可以循环使用的，很多情况下只需纳摩尔级别的浓度即可发挥作用，大大降低了脱靶效应的风险，可能可以从根本上消除由于驱动基因的表达造成的肿瘤进展和驱动基因获得性突变造成的耐药性。该技术可以潜在地克服或推迟肿瘤中耐药性的产生。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供一种双功能化合物及其制备方法和用途，用于解决现有技术中的问题。
为实现上述目的及其他相关目的，本发明一方面提供一种双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述双功能化合物的化学结构式如式I所示：
Figure PCTCN2020107177-appb-000001
其中，EGFR Binders可以结合EGFR蛋白；
ULM表示：
Figure PCTCN2020107177-appb-000002
其中，A选自-CH 2-、-(C＝O)-；
B、X、Y、Z各自独立地选自CH、N；
R选自-S-、-SO-、-SO 2-、
Figure PCTCN2020107177-appb-000003
-CH 2-、-(C＝O)-、-NH-、-O-、亚乙炔基、或者不存在；
D选自-(C＝O)-、或D不存在；
或者，ULM表示：
Figure PCTCN2020107177-appb-000004
其中，Z选自-(C＝O)-、或Z不存在；
或者，ULM表示：
Figure PCTCN2020107177-appb-000005
其中，A选自-CH 2-、-NR’-、-O-、-S-、-(C＝O)-，其中，R’选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
B选自-(C＝O)-、或B不存在；
D 1、D 2、D 3、D 4、D 5、D 6、D 7、D 8各自独立地选自F、Cl、Br、OH、Me、Et、iPr、H和D；
LIN表示分别与EGFR Binders和ULM通过共价键连接的连接基团。
本发明另一方面提供所述双功能化合物在制备药物中的用途。
本发明另一方面提供一种药物组合物，包括所述的双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体、添加剂、助剂或赋形剂。
附图说明
图1显示为本发明基于达克替尼衍生物A的化合物研究(肺癌HCC827细胞系)。
图2显示为本发明基于达克替尼衍生物B的化合物研究(肺癌H1975细胞系)。
图3显示为本发明基于卡奈替尼衍生物A和B的化合物研究(肺癌PC9和H1975细胞系)。
图4显示为本发明化合物对EGFR磷酸化水平的抑制活性优于小分子抑制剂(肺癌H1975细胞系和PC9Brc1细胞系)。
图5显示为本发明化合物对具有三突变EGFR蛋白的降解能力研究(PC9DCT(Del19+T790M+C797S)细胞系)。
图6显示为本发明化合物对乳腺癌细胞系的研究(BT474细胞系)。
具体实施方式
本发明发明人经过大量实践研究，基于不同EGFR相关药物(例如，EGFR抑制剂，达克替尼(dacomitinib)、波齐替尼(poziotinib)、吉非替尼(gefitinib)、阿法替尼(afatinib)、sapitinib、卡奈替尼(canertinib)、奥西替尼(Osimertinib)、EAI045等)提供了一类双功能化合物。本发明所提供的双功能化合物对于EGFR蛋白均有不同程度的调节效果，不仅能够促进EGFR蛋白的降解，也能抑制EGFR激酶的活性，还可抑制EGFR突变阳性细胞的增殖，可以发展成为肿瘤病人的治疗药物，在此基础上完成了本发明。
设计具有靶向特定蛋白的降解剂是药物开发的新模式，本发明中发明人通过利用蛋白降解靶向药物(Proteolysis Targeting Drug,PROTAD)技术平台，通过特殊设计的双特异性蛋白调节剂，可对靶蛋白进行“降解”标记，通过激活细胞内部的蛋白降解途径对靶蛋白进行定向降解。和传统药物设计相比，本发明所提供的靶向蛋白调节剂小分子能诱导靶蛋白的降解，与传统的小分子抑制剂在机理上有本质不同。
本发明一方面提供一种双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述双功能化合物的化学结构式如式I所示：
Figure PCTCN2020107177-appb-000006
其中，EGFR Binders可以结合于EGFR蛋白；
ULM表示：
Figure PCTCN2020107177-appb-000007
其中，A选自-CH 2-、-(C＝O)-；
B、X、Y、Z各自独立地选自CH、N；
R选自-S-、-SO-、-SO 2-、
Figure PCTCN2020107177-appb-000008
-CH 2-、-(C＝O)-、-NH-、-O-、亚乙炔基；
D选自-(C＝O)-、或D不存在；
或者，ULM表示：
Figure PCTCN2020107177-appb-000009
其中，Z选自-(C＝O)-、或Z不存在；
或者，ULM表示：
Figure PCTCN2020107177-appb-000010
其中，A选自-CH 2-、-NR’-、-O-、-S-、-(C＝O)-，其中，R’选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
B选自-(C＝O)-、或B不存在；
D 1、D 2、D 3、D 4、D 5、D 6、D 7、D 8各自独立地选自F、Cl、Br、OH、Me、Et、iPr、H和D；
LIN表示分别与EGFR Binders和ULM通过共价键连接的连接基团。
除非另外指明，本发明的化合物的同位素标记的形式也包括在本发明的保护范围以内。例如，具有上述所给出的具有本发明结构的化合物中，至少一个氢原子被氘或氚替代，或至少一个碳被 13C-或 14C-富集的碳替代，或至少一个氮被 15N-富集的氮替代。
本发明中，术语“盐”应当被理解为由本发明使用的任何形式的活性化合物，其中所述化合物可以为离子形式或带电荷或被偶联到反离子(阳离子或阴离子)或在溶液中。这个定义还可以包括活性分子与其它分子和离子的季铵盐和络合物，特别是通过离子相互作用的络合物。该定义尤其包括生理上可接受的盐，该术语可以被理解为与“药理学上可接受的盐”等同。
本发明中，术语“药学上可接受的盐”通常指当以适当的方式用于治疗时(特别是在人类和/或哺乳动物中应用或使用时)在生理学上可耐受的任何盐(通常来说，这意味着它是无毒的，特别是作为抗衡离子的结果是无毒的)。这些生理上可接受的盐可以是与阳离子或碱形成的，并且在本发明的上下文中，尤其是在人类和/或哺乳动物中施用时，它们应该被理解为由按照本发明所提供的至少一种化合物，通常为酸(去质子化的)，如阴离子和至少一种生理学上耐受的阳离子(优选无机阳离子)形成的盐。在本发明的上下文中，具体地可以包括与碱金属和碱土金属形成的盐、以及与铵阳离子(NH 4 +)形成的盐，具体可以是包括但不限于与(单)或(二)钠、(单)或(二)钾、镁或钙形成的盐。这些生理上可接受的盐也可以是与阴离子或酸形成的，并且在本发明的上下文中，特别是在人类和/或哺乳动物中施用时，它们应该被理解为由按照本发明所提供的至少一种化合物，通常质子化的(例如在氮上)，如阳离子和至少一种生理上可耐受的阴离子形成的盐。在本发明的上下文中，具体地可以包括由生理上可耐受的酸形成的盐，即特定的活性化合物与生理上可耐受的有机或无机酸形成的盐，具体可以是包括但不限于与盐 酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、苹果酸、酒石酸、扁桃酸、富马酸、乳酸或柠檬酸形成的盐。
由上述式I表示的本发明化合物可以包括取决于存在的手性中心的对映体或取决于存在的双键的异构体(例如Z,E)。单一异构体、对映异构体、非对映异构体或顺反异构体和它们的混合物均落入本发明的范围之内。
本发明中术语“前药”以其最广泛的意义使用，并且包括在体内可以转化为本发明的化合物的那些衍生物。制备指定的起作用化合物的前药的方法对于本领域技术人员来说应该是已知的，例如，可以参阅如Krogsgaard-Larsen等人，“药物设计和发现教科书”(Textbook of Drug design and Discovery)泰勒弗朗西斯出版社Taylor&Francis(2002年4月)中所公开的相关内容。
本发明中，术语“溶剂化物”通常指任何形式的根据本发明的活性化合物通过非共价键与另一分子(通常为极性溶剂)相结合，所获得的物质，具体可以是包括但不限于水化物和醇化物，例如甲醇化物。
本发明所提供的双功能化合物中，可以包括EGFR Binders部分，所述EGFR Binders部分通常与LIN通过共价键连接，所述EGFR Binders通常可以结合EGFR蛋白。本发明中，所述EGFR Binders可以是任何可以结合EGFR蛋白的分子，更具体可以是EGFR TKIs，所述EGFR TKIs(表皮生长因子受体(EGFR)酪氨酸激酶抑制剂)可以作用于EGFR胞内蛋白酪氨酸激酶区；所述表皮生长因子受体酪氨酸激酶抑制剂通常可以与ATP竞争性结合于酪氨酸激酶功能域，可逆或不可逆抑制酪氨酸激酶磷酸化。所述EGFR TKIs部分通常作为蛋白质靶标结合部分(PTM，protein target moiety)，可以通过LIN与ULM部分(E3 ubiquitin ligase binding moiety，E3泛素连接酶结合部分)连接，从而可以导致靶标蛋白被泛素化，从而激活细胞内部的蛋白酶体系统对靶蛋白进行定向降解。泛素化降解途径可以降解细胞内大部分的泛素化的蛋白质，例如，可以降解细胞内80％～90％或更高比例的泛素化的蛋白质，如果能够激活这个系统特异性地清理致癌蛋白，使细胞内的蛋白质稳态恢复正常，就很有可能缓解或治疗癌症。PROTAD技术正是利用了这一点，通过特殊设计的双特异性降解剂，对靶蛋白进行“泛素”标记，从而实现定向降解。
本发明所提供的双功能化合物中，所述EGFR TKIs可以具体表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000011
其中，R1、R2、R3、R4各自独立地选自H、卤素、Cl、F、C1-10烷基、C1-10卤代烷基、C1-10炔基、C1-10烷氧基、芳基甲氧基、杂芳基甲氧基，所述芳基甲氧基和杂芳基甲氧基中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素和C 1-10卤代烷基的取代基取代；
R 5和R 6其中之一与LIN通过共价键连接、且形成选自-NR”-、化学结构式如下所示的基团，R”选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
Figure PCTCN2020107177-appb-000012
其中，P 1选自
Figure PCTCN2020107177-appb-000013
CHR b，其中，R b选自-NH-、亚哌嗪基，n＝0～3、0、1、2、3，R c表示亚乙烯基或不存在；
R 5、R 6其中之一选自H、N、卤素、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基、氨基、酰氨基、烷基氨基、C 1-10二烷基氨基、氰基、芳基、杂芳基、呋喃基、吡咯基、咪唑基、恶唑基、异恶唑基、三唑基、C 3-9环烷基、C 3-9环烷基氧基、杂环烷基、杂环烷基氧基、-NHC(O)R 14，其中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素、C 1-10卤代烷基、氰基、R 7SO 2(CH 2)sNHCH 2-、-OR 8、-NHC(O)R 9的取代基取代，其中，R 7选自C 1-10烷基且s为0、1、2、3，R 8选自任选地被独立地选自羟基、C 1-10烷氧基、氨基、C 1-10烷基氨基、C 1-10二烷基氨基单取代或多取代的C 1-10烷基，R 9选自如下所示的基团：
Figure PCTCN2020107177-appb-000014
R 10、R 11各自独立地选自H、C 1-10烷基；
R 12、R 13各自独立地选自H、C 1-10烷基，或者与相邻的氮原子一起形成杂环烷基；
R 14选自C 1-10烷基、烯基。
本发明中，所述“卤素”或“卤代”通常指氟、氯、溴或碘。
本发明中，所述“烷基”通常指饱和脂肪族基团，它们可以是直链或支链。例如，C 1-10烷基通常指包括1个、2个、3个、4个、5个、6个、7个、8个、9个、10个碳原子的烷基基团，所述烷基基团具体可以是包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、葵基等。再例如，C 1-30亚烷基通常指包括1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个、25个、26个、27个、28个、29个、30个碳原子的亚烷基基团，所述亚烷基基团具体可以是包括但不限于亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、亚庚基、亚辛基、亚壬基、亚葵基等。
本发明中，“卤代烷基”通常指卤代的饱和脂肪族基团，它们可以是直链或支链的、并且任选被被独立地选自氟、氯、溴或碘单取代或多取代。例如，C 1-10卤代烷基通常指包括1个、2个、3个、4个、5个、6个、7个、8个、9个、10个碳原子的卤代烷基基团，所述卤代烷基基团具体可以是包括但不限于卤代甲基、卤代乙基、卤代丙基、卤代丁基、卤代戊基、卤代己基、卤代庚基、卤代辛基、卤代壬基、卤代葵基等。
本发明中，“C 3-9环烷基”通常指具有3个至9个碳原子的饱和或不饱和(但不是芳族)环烃。所述环烷基具体可以是包括但不限于环丙基、2-甲基环丙基、环丙基甲基、环丁基、环戊基、环戊基甲基、环己基、环庚基、环辛基、金刚烷基、降金刚烷基等。
本发明中，“杂环烷基”通常指饱和或不饱和(但不是芳族)环烃，并且在其结构中具有至少一个选自N、O或S的杂原子。所述杂环烷基具体可以是包括但不限于吡咯啉、吡咯烷、吡唑啉、氮丙啶、氮杂环丁烷、四氢吡咯、环氧乙烷、氧杂环丁烷、二氧杂环丁烷、四氢吡喃、四氢呋喃、二恶烷、二氧戊环、恶唑烷、哌啶、哌嗪、吗啉、氮杂环庚烷或二氮杂环庚烷等。优选的，本发明中的杂环烷基通常是5或6元环体系。
本发明中，“芳基”通常指具有至少一个芳环但没有杂原子的基团。所述芳基基团可以任选地被独立地选自烷基、卤素、卤代烷基、氰基、R 7SO 2(CH 2)sNHCH 2-、-OR 8、-NHC(O)R 9的取代基单取代或多取代。所述芳基基团具体可以是包括但不限于苯基、萘基、荧蒽基、芴基、四氢萘基、茚满基或蒽基等。优选的，本发明中的芳基是任选地至少单取代的5或6元环体系。
本发明中，“杂芳基”通常指具有至少一个芳族环并且可以任选地含有一个或多个选自N、O的杂原子的杂环体系，并且可以任选地被独立地选自烷基、卤素、卤代烷基、氰基、R 7SO 2(CH 2)sNHCH 2-、-OR 8、-NHC(O)R 9的取代基单取代或多取代。所述杂芳基具体可以是包括但不限于呋喃、苯并呋喃、吡咯、吡啶、嘧啶、哒嗪、吡嗪、喹啉、异喹啉、酞嗪、三唑、 吡唑、异恶唑、吲哚、苯并三唑、苯并二氧戊环、苯并二恶烷、苯并咪唑、咔唑和喹唑啉等。优选的，本发明中的杂芳基是任选至少单取代的5或6元环体系。
本发明中，“烯基”通常指包括至少一个C＝C双键的不饱和脂肪族基团，所述烯基基团具体可以是包括但不限于乙烯基、丙烯基、丁烯基等。
在本发明一些优选实施例中，所述式V中，R 1、R 2、R 3、R 4各自独立地选自H、卤素、Cl、F。
在本发明更加优选的实施例中，所述式V中，R 1选自Cl，R 2选自F，R 3、R 4各自独立地选自H；或，R 1选自H，R 2选自Cl，R 3选自Cl，R 4选自F。
在本发明一些优选实施例中，所述式V中，R 5和R 6其中之一可以与LIN通过共价键连接、且形成选自-NR”-、或化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000015
其中，P 1选自
Figure PCTCN2020107177-appb-000016
CHR b，其中，R b选自-NH-、亚哌嗪基，n＝0～3、0、1、2、3，
R c表示亚乙烯基或不存在；
R”选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
R 5、R 6其中之一选自C 1-C 10烷氧基、杂环烷基氧基、-NHC(O)R 14，R 14选自C 1-C 10烷基、烯基。
在本发明更加优选的实施例中，所述式V中，R 5可以与LIN通过共价键连接、且形成选自-NH-、或化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000017
Figure PCTCN2020107177-appb-000018
在本发明更加优选的实施例中，所述式V中，R 6可以选自甲氧基、或结构式如下所示的基团：
Figure PCTCN2020107177-appb-000019
在本发明更加优选的实施例中，所述式V中，R 5可以选自-NHC(O)R 14，R 14选自乙烯基。
在本发明更加优选的实施例中，所述式V中，R 6可以与LIN通过共价键连接、且化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000020
在本发明进一步优选的实施例中，所述EGFR TKIs表示化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000021
本发明所提供的双功能化合物中，所述EGFR TKIs也可以具体表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000022
其中，R 16、R 17、R 18、R 19、R 20各自独立地选自H、OH、F、Br、Cl、OMe；
R 15与LIN通过共价键连接、且形成选自化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000023
其中，P 2选自
Figure PCTCN2020107177-appb-000024
CHR d，其中，R d选自-NH-、亚哌嗪基。
在本发明一些优选实施例中，所述式VI中，R 16、R 17、R 18、R 19、R 20各自独立地选自H、OH、F；
在本发明更加优选的实施例中，所述式VI中，R 16选自H、OH；R 17选自H；R 18选自H；R 19选自H、F；R 20选自H；
在本发明一些优选实施例中，R 15与LIN通过共价键连接、且形成选自化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000025
其中，P 2选自
Figure PCTCN2020107177-appb-000026
CHR d，其中，R d选自-NH-、亚哌嗪基。
在本发明进一步优选的实施例中，所述EGFR TKIs表示化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000027
本发明所提供的双功能化合物中，所述EGFR TKIs也可以具体表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000028
R 21和R 22其中之一与LIN通过共价键连接、且形成选自-NR”’-、化学结构式如下所示的基团，R”选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
Figure PCTCN2020107177-appb-000029
其中，P 3选自
Figure PCTCN2020107177-appb-000030
CHR e，其中，R e选自-NH-、亚哌嗪基，n＝0、1、2、或3，R c’表示亚乙烯基或不存在；
R 21、R 22其中之一选自H、N、卤素、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基、氨基、酰 氨基、烷基氨基、C 1-10二烷基氨基、氰基、芳基、杂芳基、呋喃基、吡咯基、咪唑基、恶唑基、异恶唑基、三唑基、C 3-9环烷基、C 3-9环烷基氧基、杂环烷基、杂环烷基氧基、-NHC(O)R 31，其中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素、C 1-10卤代烷基、氰基、R 24SO 2(CH 2)sNHCH 2-、-OR 25、-NHC(O)R 26的取代基取代，其中，R 24选自C 1-10烷基且s为0、1、2、3，R 25选自任选地被独立地选自羟基、C 1-10烷氧基、氨基、C 1-10烷基氨基、C 1-10二烷基氨基单取代或多取代的C 1-10烷基，R 26选自如下所示的基团：
Figure PCTCN2020107177-appb-000031
R 27、R 28各自独立地选自H、C 1-10烷基；
R 29、R 30各自独立地选自H、C 1-10烷基，或者与相邻的氮原子一起形成杂环烷基；
R 31选自C 1-10烷基、烯基。
在本发明一些优选实施例中，所述式VII中，R 21和R 22其中之一与LIN通过共价键连接、且形成选自-NR”’-、化学结构式如下所示的基团，R”选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
Figure PCTCN2020107177-appb-000032
其中，P 3选自
Figure PCTCN2020107177-appb-000033
CHR e，其中，R e选自-NH-、亚哌嗪基，n＝0、1、2、或3，R c’表示亚乙烯基或不存在；
R 21、R 22其中之一选自C 1-C 10烷氧基、杂环烷基氧基、-NHC(O)R 23，R 23选自C 1-C 10烷基、烯基、
Figure PCTCN2020107177-appb-000034
其中，n＝0、1、2、或3。
在本发明进一步优选的实施例中，所述EGFR TKIs表示化学结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000035
本发明所提供的双功能化合物中，可以包括ULM部分，ULM部分通常与LIN通过共价键连接，所述ULM部分主要用于连接E3泛素连接酶，是E3泛素连接酶的配体。
在本发明一些优选实施例中，ULM可以表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000036
其中，A选自-CH 2-、-(C＝O)-；
B、X、Y、Z各自独立地选自CH、N；
R选自-S-、-SO-、-SO 2-、
Figure PCTCN2020107177-appb-000037
-CH 2-、-(C＝O)-、-NH-、-O-、亚乙炔基；
D选自-(C＝O)-、或D不存在。
在本发明更加优选的实施例中，所述式II中，A选自-CH 2-、-(C＝O)-；B选自C、N；，X、 Y、Z各自独立地选自CH、N；
在本发明更加优选的实施例中，所述式II中，R选自-S-、-NH-、亚乙炔基、或者不存在；D选自-(C＝O)-、或者不存在。
在本发明进一步优选的实施例中，ULM可以表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000038
在本发明一些优选实施例中，ULM可以表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000039
其中，Z选自-(C＝O)-、或Z不存在；
在本发明更加优选的实施例中，所述式III中，Z选自-(C＝O)-。
在本发明进一步优选的实施例中，ULM可以表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000040
在本发明一些优选实施例中，ULM可以表示化学结构式如下所示的基团：
Figure PCTCN2020107177-appb-000041
其中，A选自-CH 2-、-NR’-、-O-、-S-、-(C＝O)-，其中，R’选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
B选自-(C＝O)-、或B不存在；
D 1、D 2、D 3、D 4、D 5、D 6、D 7、D 8各自独立地选自F、Cl、Br、OH、Me、Et、iPr、H和D。
本发明所提供的双功能化合物中，可以包括LIN部分，所述LIN通常分别与EGFR TKIs部分和ULM部分通过共价键连接，所述LIN部分主要用于连接两个关键部分即靶蛋白和E3连接酶配体，LIN部分的长度、种类、疏水性通常对最终形成的靶蛋白-PROTAD-E3连接酶三元复合物的稳定性具有影响，进而影响其抑制和降解活性。适合用于连接PTM(蛋白质靶标结合部分)和ULM(E3 ubiquitin ligase binding moiety，E3泛素连接酶结合部分)的LIN对于本领域技术人员来说应该是已知的，例如，具体可以参照Org.Lett.2019,21,3838-3841，Bioorg.Med.Chem.Lett.2016；26:5260-5262等文献中所公开的内容。本发明中，所述LIN具体可以表示：
-W-亚烷基-；
其中，所述亚烷基是可选地被一或多个选自以下的基团中断一次或多次的直链或支链的亚 烷基：-O-、-CONH-、-NHCO-、-NH-、-NHCONH-、-S-、亚磺酰基、磺酰基、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一个或多个取代基取代；
W选自-(C＝O)-、-(C＝O)O-、-NR””-、或不存在，其中R””选自H、直链或支链的C 1-C 10亚烷基或C 3-C 10亚环烷基。
在本发明更加优选的实施例中，所述直链或支链的亚烷基的取代基各自独立地选自羟基、氨基、巯基和卤素。
在本发明更加优选的实施例中，所述亚烷基为C 1-30亚烷基。
在本发明更加优选的实施例中，所述LIN表示：
-W-C 1-30亚烷基-、-W-(CH 2) n1-(O(CH 2) n2) m1-、-W-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-、-W-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-(CH 2) n3-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-W-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-、-W-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-、-W-(CH 2) n1-(NHCO-(CH 2) n2) m1-、-W-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CH 2) n1-CONH-(O(CR a27R a28) n2) m1-、-(CH 2) n1-NHCONH-(CH 2) n2-、-(CH 2) n1-S-(CH 2) n2-、-(CH 2) n1-SO-(CH 2) n2-、-(CH 2) n1-SO 2-(CH 2) n2-、-(CH 2) n1-CH＝CH-(CH 2) n2-、-(CH 2) n1-C≡C-(CH 2) n2-、-(CH 2) n1-C≡C-C≡C-(CH 2) n2-、-(CH 2) n1-哌嗪亚基-(CH 2) n2-、-(CH 2) n1-亚苯基-(CH 2) n2-、和其碳链被一个或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一次或多次的-W-(CH 2) n1-(O(CH 2) n2) m1-；
R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26、R a27、R a28分别独立地选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26、R a27、R a28不同时为H；
n1、n2、n3、n4、n5、n6、m1、m2分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2-、-W-(CH 2) 2-、-W-(CH 2) 3-、-W-(CH 2) 4-、-W-(CH 2) 5-、-W-(CH 2) 6-、-W-(CH 2) 7-、 -W-(CH 2) 8-、-W-(CH 2) 9-、-W-(CH 2) 10-、-W-(CH 2) 11-、-W-(CH 2) 12-、-W-(CH 2) 13-、-W-(CH 2) 14-、-W-(CH 2) 15-、-W-(CH 2) 16-、-W-(CH 2) 17-、-W-(CH 2) 18-、-W-(CH 2) 19-；-W-(CH 2) 20-；-W-(CH 2) 21-；-W-(CH 2) 22-；-W-(CH 2) 23-、-W-(CH 2) 24-、-W-(CH 2) 25-、-W-(CH 2) 26-、-W-(CH 2) 27-、-W-(CH 2) 28-、-W-(CH 2) 29-、或-W-(CH 2) 30-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2-O-(CH 2) 2-、-W-CH 2-(O(CH 2) 2) 2-、-W-CH 2-(O(CH 2) 2) 3-、-W-CH 2-(O(CH 2) 2) 4-、-W-CH 2-(O(CH 2) 2) 5-、-W-CH 2-(O(CH 2) 2) 6-、-W-CH 2-(O(CH 2) 2) 7-、-W-CH 2-(O(CH 2) 2) 8-、-W-CH 2-(O(CH 2) 2) 9-、-W-CH 2-(O(CH 2) 2) 10-、-W-(CH 2) 2-O-(CH 2) 2-、-W-(CH 2) 2-(O(CH 2) 2) 2-、-W-(CH 2) 2-(O(CH 2) 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-、-W-(CH 2) 2-(O(CH 2) 2) 5-、-W-(CH 2) 2-(O(CH 2) 2) 6-、-W-(CH 2) 2-(O(CH 2) 2) 7-、-W-(CH 2) 2-(O(CH 2) 2) 8-、-W-(CH 2) 2-(O(CH 2) 2) 9-、-W-(CH 2) 2-(O(CH 2) 2) 10-、-W-(CH 2) 3-O-(CH 2) 2-、-W-(CH 2) 3-(O(CH 2) 2) 2-、-W-(CH 2) 3-(O(CH 2) 2) 3-、-W-(CH 2) 3-(O(CH 2) 2) 4-、-W-(CH 2) 3-(O(CH 2) 2) 5-、-W-(CH 2) 3-(O(CH 2) 2) 6-、-W-(CH 2) 3-(O(CH 2) 2) 7-、-W-(CH 2) 3-(O(CH 2) 2) 8-、-W-(CH 2) 3-(O(CH 2) 2) 9-、-W-(CH 2) 3-(O(CH 2) 2) 10-、-W-(CH 2) 4-O-(CH 2) 2-、-W-(CH 2) 4-(O(CH 2) 2) 2-、-W-(CH 2) 4-(O(CH 2) 2) 3-、-W-(CH 2) 4-(O(CH 2) 2) 4-、-W-(CH 2) 4-(O(CH 2) 2) 5-、-W-(CH 2) 4-(O(CH 2) 2) 6-、-W-(CH 2) 4-(O(CH 2) 2) 7-、-W-(CH 2) 4-(O(CH 2) 2) 8-、-W-(CH 2) 4-(O(CH 2) 2) 9-、-W-(CH 2) 4-(O(CH 2) 2) 10-、-W-CH 2-O-(CH 2) 3-、-W-CH 2-(O(CH 2) 3) 2-、-W-CH 2-(O(CH 2) 3) 3-、-W-CH 2-(O(CH 2) 3) 4-、-W-CH 2-(O(CH 2) 3) 5-、-W-CH 2-(O(CH 2) 3) 6-、-W-CH 2-(O(CH 2) 3) 7-、-W-CH 2-(O(CH 2) 3) 8-、-W-CH 2-(O(CH 2) 3) 9-、-W-CH 2-(O(CH 2) 3) 10-、-W-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 2-(O(CH 2) 3) 3-、-W-(CH 2) 2-(O(CH 2) 3) 4-、-W-(CH 2) 2-(O(CH 2) 3) 5-、-W-(CH 2) 2-(O(CH 2) 3) 6-、-W-(CH 2) 2-(O(CH 2) 3) 7-、-W-(CH 2) 2-(O(CH 2) 3) 8-、-W-(CH 2) 2-(O(CH 2) 3) 9-、-W-(CH 2) 2-(O(CH 2) 3) 10-、-W-(CH 2) 3-O-(CH 2) 3-、-W-(CH 2) 3-(O(CH 2) 3) 2-、-W-(CH 2) 3-(O(CH 2) 3) 3-、-W-(CH 2) 3-(O(CH 2) 3) 4-、-W-(CH 2) 3-(O(CH 2) 3) 5-、-W-(CH 2) 3-(O(CH 2) 3) 6-、-W-(CH 2) 3-(O(CH 2) 3) 7-、-W-(CH 2) 3-(O(CH 2) 3) 8-、-W-(CH 2) 3-(O(CH 2) 3) 9-、-W-(CH 2) 3-(O(CH 2) 3) 10-、-W-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-W-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-W-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、 -W-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-W-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-W-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-W-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-CH 2-O-(CH 2) 2-O-CH 2-、-W-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-W-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-。
在本发明进一步优选的实施例中，所述LIN表示：-W-(CH 2) 3CH(OH)CH(OH)(CH 2) 4-。
在本发明更加优选的实施例中，所述LIN表示：
-W-(CH 2) n1-三唑亚基-(CH 2) n2-、-W-(CH 2) n1-亚三唑基-(CH 2) n2-(O(CH 2) n3) m1-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-三唑亚基-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-W-(CH 2) n1-三唑亚基-(CH 2) n2-(O(CH 2) n3) m1-O-(CH 2) n4-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-三唑亚基-(CH 2) n4-；
其中，n1、n2、n3、n4、n5、n6、m1、m2分别独立地选自1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
在本发明进一步优选的实施例中，所述LIN表示：-W-(CH 2) 3-亚三唑基-(CH 2) 5-、-W-(CH 2) 2-亚三唑基-(CH 2) 5-、-W-CH 2-亚三唑基-(CH 2) 5-、-W-(CH 2) 2-亚三唑基-(CH 2) 4-、-W-(CH 2) 3-亚三唑基-(CH 2) 3-、-W-(CH 2) 5-亚三唑基-(CH 2) 5-、-W-(CH 2) 5-亚三唑基-(CH 2) 8-、-W-(CH 2) 3-亚三唑基-(CH 2) 2-O(CH 2) 2-、-W-(CH 2) 2-亚三唑基-(CH 2) 2-O(CH 2) 2-、W-CH 2-亚三唑基-(CH 2) 2-O(CH 2) 2。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2CONHCH 2-、-W-(CH 2) 2CONH(CH 2) 2-、-W-(CH 2) 3CONH(CH 2) 3-、-W-(CH 2) 3CONH(CH 2) 4-、-W-(CH 2) 4CONH(CH 2) 4-、-W-(CH 2) 5CONH(CH 2) 5-、-W-(CH 2) 6CONH(CH 2) 7-、-W-(CH 2) 6CONH(CH 2) 6-、-W-(CH 2) 7CONH(CH 2) 7-、-W-(CH 2) 8CONH(CH 2) 8、W-(CH 2) 9CONH(CH 2) 9-、-W-(CH 2) 10CONH(CH 2) 10-、-W-(CH 2) 2CONH(CH 2) 5-、 -W-(CH 2) 2CONH(CH 2) 3-、-W-(CH 2) 2CONH(CH 2) 4-、-W-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2NHCOCH 2-、-W-(CH 2) 2NHCO(CH 2) 2-、-W-(CH 2) 3NHCO(CH 2) 3-、-W-(CH 2) 3NHCO(CH 2) 4-、-W-(CH 2) 4NHCO(CH 2) 4-、-W-(CH 2) 5NHCO(CH 2) 5-、-W-(CH 2) 6NHCO(CH 2) 7-、-W-(CH 2) 6NHCO(CH 2) 6-、-W-(CH 2) 7NHCO(CH 2) 7-、-W-(CH 2) 8NHCO(CH 2) 8、-W-(CH 2) 9NHCO(CH 2) 9-、-W-(CH 2) 10NHCO(CH 2) 10-、-W-(CH 2) 2NHCO(CH 2) 5-、-W-(CH 2) 2NHCO(CH 2) 3-、-W-(CH 2) 2NHCO(CH 2) 4-、-W-(CH 2) 4NHCO(CH 2) 8-、-W-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-、-W-(CH 2) 4NHCOCH 2-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 4NHCONH(CH 2) 4-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 5S(CH 2) 5-、-W-(CH 2) 6S(CH 2) 5-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 5SO(CH 2) 5-、-W-(CH 2) 6SO(CH 2) 5-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 5SO 2(CH 2) 5-、-W-(CH 2) 6SO 2(CH 2) 5-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 4CH＝CH(CH 2) 3-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-(CH 2) 2C≡C(CH 2) 2-、-W-(CH 2) 5C≡C(CH 2) 4-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2-哌嗪亚基-CH 2-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 2-、-W-(CH 2) 3-哌嗪亚基-(CH 2) 3-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 3-、-W-CH 2-哌嗪亚基-(CH 2) 2-、-W-CH 2-哌嗪亚基-(CH 2) 3-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 3-。
在本发明进一步优选的实施例中，所述LIN表示：
-W-CH 2-亚苯基-CH 2-、-W-(CH 2) 2-亚苯基-(CH 2) 2-、-W-CH 2-亚苯基-(CH 2) 2-、-W-(CH 2) 2-亚苯基-CH 2-、-W-(CH 2) 3-亚苯基-(CH 2) 3-、-W-CH 2-亚苯基-(CH 2) 3-、-W-(CH 2) 2-亚苯基-(CH 2) 3-、-W-(CH 2) 3-亚苯基-(CH 2) 2-、-W-(CH 2) 3-亚苯基-CH 2-、-W-(CH 2) 2-O-CH 2-亚苯基-CH 2-O-(CH 2) 2-。
在本发明进一步优选的实施例中，所述LIN表示-W-哌嗪亚基-、-W-亚螺环基、-W-亚苯基-、-W-C≡C-C≡C-，具体可以结构式如下之一所示的基团：
Figure PCTCN2020107177-appb-000042
在本发明进一步优选的具体实施例中，所述双功能化合物选自如表1或表2中所示的化合物：
Figure PCTCN2020107177-appb-000043
Figure PCTCN2020107177-appb-000044
Figure PCTCN2020107177-appb-000045
Figure PCTCN2020107177-appb-000046
Figure PCTCN2020107177-appb-000047
Figure PCTCN2020107177-appb-000048
Figure PCTCN2020107177-appb-000049
Figure PCTCN2020107177-appb-000050
Figure PCTCN2020107177-appb-000051
Figure PCTCN2020107177-appb-000052
Figure PCTCN2020107177-appb-000053
Figure PCTCN2020107177-appb-000054
Figure PCTCN2020107177-appb-000055
Figure PCTCN2020107177-appb-000056
Figure PCTCN2020107177-appb-000057
Figure PCTCN2020107177-appb-000058
Figure PCTCN2020107177-appb-000059
Figure PCTCN2020107177-appb-000060
Figure PCTCN2020107177-appb-000061
Figure PCTCN2020107177-appb-000062
Figure PCTCN2020107177-appb-000063
Figure PCTCN2020107177-appb-000064
Figure PCTCN2020107177-appb-000065
Figure PCTCN2020107177-appb-000066
Figure PCTCN2020107177-appb-000067
Figure PCTCN2020107177-appb-000068
Figure PCTCN2020107177-appb-000069
Figure PCTCN2020107177-appb-000070
Figure PCTCN2020107177-appb-000071
Figure PCTCN2020107177-appb-000072
Figure PCTCN2020107177-appb-000073
Figure PCTCN2020107177-appb-000074
Figure PCTCN2020107177-appb-000075
Figure PCTCN2020107177-appb-000076
Figure PCTCN2020107177-appb-000077
Figure PCTCN2020107177-appb-000078
Figure PCTCN2020107177-appb-000079
Figure PCTCN2020107177-appb-000080
Figure PCTCN2020107177-appb-000081
Figure PCTCN2020107177-appb-000082
Figure PCTCN2020107177-appb-000083
Figure PCTCN2020107177-appb-000084
Figure PCTCN2020107177-appb-000085
Figure PCTCN2020107177-appb-000086
Figure PCTCN2020107177-appb-000087
Figure PCTCN2020107177-appb-000088
Figure PCTCN2020107177-appb-000089
Figure PCTCN2020107177-appb-000090
Figure PCTCN2020107177-appb-000091
Figure PCTCN2020107177-appb-000092
Figure PCTCN2020107177-appb-000093
Figure PCTCN2020107177-appb-000094
Figure PCTCN2020107177-appb-000095
Figure PCTCN2020107177-appb-000096
Figure PCTCN2020107177-appb-000097
Figure PCTCN2020107177-appb-000098
Figure PCTCN2020107177-appb-000099
Figure PCTCN2020107177-appb-000100
Figure PCTCN2020107177-appb-000101
Figure PCTCN2020107177-appb-000102
Figure PCTCN2020107177-appb-000103
Figure PCTCN2020107177-appb-000104
Figure PCTCN2020107177-appb-000105
Figure PCTCN2020107177-appb-000106
Figure PCTCN2020107177-appb-000107
Figure PCTCN2020107177-appb-000108
Figure PCTCN2020107177-appb-000109
Figure PCTCN2020107177-appb-000110
Figure PCTCN2020107177-appb-000111
Figure PCTCN2020107177-appb-000112
Figure PCTCN2020107177-appb-000113
Figure PCTCN2020107177-appb-000114
Figure PCTCN2020107177-appb-000115
Figure PCTCN2020107177-appb-000116
Figure PCTCN2020107177-appb-000117
Figure PCTCN2020107177-appb-000118
Figure PCTCN2020107177-appb-000119
Figure PCTCN2020107177-appb-000120
Figure PCTCN2020107177-appb-000121
Figure PCTCN2020107177-appb-000122
Figure PCTCN2020107177-appb-000123
Figure PCTCN2020107177-appb-000124
Figure PCTCN2020107177-appb-000125
Figure PCTCN2020107177-appb-000126
Figure PCTCN2020107177-appb-000127
Figure PCTCN2020107177-appb-000128
Figure PCTCN2020107177-appb-000129
本发明第二方面提供本发明第一方面所提供的双功能化合物在制备药物中的用途。如上所述，本发明所提供的双功能化合物包括EGFR TKIs部分和ULM部分，EGFR TKIs部分和ULM部分可以分别与LIN通过共价键连接，所述EGFR TKIs部分通常作为蛋白质靶标结合部分(PTM，protein target moiety)，所述EGFR TKIs(表皮生长因子受体(EGFR)酪氨酸激酶 抑制剂)可以作用于EGFR胞内蛋白酪氨酸激酶区，而ULM部分则可以导致靶标蛋白被泛素化，从而激活细胞内部的蛋白酶体系统对靶蛋白进行定向降解。泛素化降解途径可以降解细胞内大部分的泛素化的蛋白质，例如，可以降解细胞内80％～90％或更高比例的泛素化的蛋白质，如果能够激活这个系统特异性地清理致癌蛋白，使细胞内的蛋白质稳态恢复正常，就很有可能缓解或治疗癌症。PROTAD技术正是利用了这一点，通过特殊设计的双特异性降解剂，对靶蛋白进行“泛素”标记，从而实现定向降解。从而使所述双功能化合物对EGFR表现出很好的抑制效果，是一种良好的EGFR抑制剂，可以用于调节表皮生长因子受体(EGFR)和/或其突变体，并且表现出可以适用于治疗受体酪氨酸激酶(RTK)相关疾病、或与EGFR过表达或高活性相关的疾病，所述疾病具体可以选自肿瘤、髓瘤或实体瘤，癌症，白血病，淋巴瘤，结肠直肠癌，脑癌，骨癌，上皮细胞-来源的肿瘤(上皮癌)，基底细胞癌，腺癌，胃肠癌，唇癌，口腔癌，食道癌，小肠癌，胃癌，结肠癌，肝癌，膀胱癌，胰腺癌，卵巢癌，宫颈癌，肺癌，乳腺癌，皮肤癌，鳞状细胞和/或基底细胞癌，前列腺癌，神经胶质瘤，胶质母细胞瘤，肾细胞癌和其他已知影响全身上皮细胞的癌症，慢性粒细胞白血病(CML)，急性髓性白血病(AML)和急性早幼粒细胞白血病(APL)等。
本发明第三方面提供一种药物组合物，包括本发明第一方面所提供的双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体。
本发明中，所述组合物可以包括一种或多种药学上可接受的载体，其通常指用于治疗剂给药的载体，它们本身不诱导产生对接受该组合物的个体有害的抗体，且给药后没有过分的毒性。这些载体是本领域技术人员所熟知的，例如，在Remington’s Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中公开了关于药学上可接受的载体的相关内容。具体来说，所述载体可以是包括但不限于盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂等中的一种或多种的组合。
本发明所提供的药物组合物中，所述双功能化合物可以是单一有效成分，也可以与其他活性组分进行组合，构成联合制剂。所述其他活性组分可以是其他各种可以用于治疗肿瘤、髓瘤或实体瘤、癌症的药物。组合物中活性组分的含量通常为安全有效量，所述安全有效量对于本领域技术人员来说应该是可以调整的，例如，所述双功能化合物和药物组合物的活性成分的施用量通常依赖于患者的体重、应用的类型、疾病的病情和严重程度，例如，作为活性成分的所述双功能化合物的施用量通常可以为1～1000mg/kg/day、20～200mg/kg/day、1～3mg/kg/day、3～5mg/kg/day、5～10mg/kg/day、10～20mg/kg/day、20～30mg/kg/day、30～40mg/kg/day、40～60mg/kg/day、60～80mg/kg/day、80～100mg/kg/day、100～150mg/kg/day、150～200mg/kg/day、200～300mg/kg/day、300～500mg/kg/day、或500～1000mg/kg/day。
本发明所提供的双功能化合物可以适应于任何形式的给药方式，可以是口服或胃肠外给药，例如，可以是经肺、经鼻、经直肠和/或静脉注射，更具体可以是真皮内、皮下、肌内、关节内、腹膜内、肺部、口腔、舌下含服、经鼻、经皮、阴道、口服或胃肠外给药。本领域技术人员可根据给药方式，选择合适的制剂形式，例如，适合于口服给药的制剂形式可以是包括但不限于丸剂、片剂、咀嚼剂、胶囊剂、颗粒剂、滴剂或糖浆等，再例如，适合于胃肠外给药的制剂形式可以是包括但不限于溶液、悬浮液、可复水的干制剂或喷雾剂等，再例如，适合于直肠给药的通常可以是栓剂。
本发明第四方面提供一种治疗方法包括：向个体施用治疗有效量的本发明第一方面所提供的双功能化合物、或本发明第三方面所提供的药物组合物。
本发明中，“个体”通常包括人类、非人类的灵长类，如哺乳动物、狗、猫、马、羊、猪、牛等，其可因利用所述制剂、试剂盒或联合制剂进行治疗而获益。
本发明中，“治疗有效量”通常指一用量在经过适当的给药期间后，能够达到治疗如上所列出的疾病的效果。
本发明所提供的双功能化合物是基于表皮生长因子受体酪氨酸激酶抑制剂的双功能化合物，所述基于表皮生长因子受体酪氨酸激酶抑制剂的双功能化合物不仅能够促进EGFR蛋白的降解，还可抑制EGFR激酶的活性，并对EGFR突变阳性细胞的增殖起到明显的抑制效果。
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
须知，下列实施例中未具体注明的工艺设备或装置均采用本领域内的常规设备或装置。
此外应理解，本发明中提到的一个或多个方法步骤并不排斥在所述组合步骤前后还可以存在其他方法步骤或在这些明确提到的步骤之间还可以插入其他方法步骤，除非另有说明；还应理解，本发明中提到的一个或多个设备/装置之间的组合连接关系并不排斥在所述组合设备/装置前后还可以存在其他设备/装置或在这些明确提到的两个设备/装置之间还可以插入其他设备/装置，除非另有说明。而且，除非另有说明，各方法步骤的编号仅为鉴别各方法步骤的便利工具，而非为限制各方法步骤的排列次序或限定本发明可实施的范围，其相对关系的改变或调整，在无实质变更技术内容的情况下，当亦视为本发明可实施的范畴。
实施例中所涉及的各缩写的具体含义如下表所示：
Boc                叔丁氧基羰基
Con.               浓度
DCM                二氯甲烷
DMF                N,N-二甲基甲酰胺
DMSO               二甲基亚砜
DIPEA              N,N-二异丙基乙胺
EDCI               碳化二亚胺
ESI                电喷雾离子化
equiv              当量
EtOH               乙醇
HOAT               1-羟基-7-偶氮苯并三氮唑
HPLC               高效液相层析
HRMS               高分辨率质谱
LC-MS              液相色谱-质谱联用
LRMS               低分辨率质谱
LC                 液相层析
Me                 甲基
MeCN               乙腈
MeOH               甲醇
MS                 质谱
MW                 微波
NMM                N-甲基吗啡啉
NMP                N-甲基吡咯烷酮
1H NMR             核磁共振氢谱
rt                 室温
TFA                三氟乙酸
TLC                薄层层析
TMS                三甲基硅烷基
Xantphos；或X-phos 4,5-双(二苯基膦)-9,9-二甲基氧杂蒽
在本发明中， 1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS的CD 3OD做溶剂，其中 1H NMR谱以CD 3OD(δ＝3.31ppm)作为内标；或用含0.1％TMS的CDCl 3做溶剂，其中 1H NMR谱以CDCl 3(δ＝7.26ppm)作为内标；或使用含0.03％TMS的DMSO-d 6做溶剂，其中 1H NMR谱以DMSO-d 6(δ＝2.50ppm)作为内标；LRMS谱在AB Triple 4600型质谱仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下：
反应所用溶剂DCM、DMF、无水EtOH、无水MeOH均购自国药集团；
HPLC制备所用的是制备级CH 3CN及去离子水；
除非另有说明，达克替尼、艾乐替尼衍生物A、克唑替尼、色瑞替尼、布加替尼、TAE684(NVP-TAE684)、ASP3026、GSK1838705A、AZD3463、Entrectinib(RXDX-101)、Ensartinib(X-396))以及各种不同长度碳链链接单元linker(即，用于形成LIN所表示的基团的化合物)、以及其他试剂和药品均通过市售渠道直接购买获得。
实施例中所使用的通用合成方法概述如下：
达克替尼衍生物A、B(EGFR抑制剂)的通用制备方法：
Figure PCTCN2020107177-appb-000130
其中基团U和V如方案1中所示。
波齐替尼衍生物(EGFR抑制剂)的通用制备方法：
Figure PCTCN2020107177-appb-000131
吉非替尼衍生物(EGFR抑制剂)的通用制备方法：
Figure PCTCN2020107177-appb-000132
卡奈替尼衍生物(EGFR抑制剂)的通用制备方法：
Figure PCTCN2020107177-appb-000133
Sapitinib衍生物及吉非替尼衍生物D(EGFR抑制剂)的通用制备方法：
Figure PCTCN2020107177-appb-000134
中间体LM(硫取代泊马度胺碳链羧酸linker)的通用制备方法：
Figure PCTCN2020107177-appb-000135
其中，n＝1-10的整数，如方案6中所示。
中间体LM(硫取代泊马度胺PEG链羧酸linker)的通用制备方法：
Figure PCTCN2020107177-appb-000136
其中，n＝1-5整数，如方案7中所示。
中间体LM(硫基取代来那度胺碳链羧酸linker)的通用制备方法：
Figure PCTCN2020107177-appb-000137
其中，n＝1-10整数，如方案8中所示。
中间体LM(硫基取代来那度胺PEG链羧酸linker)的通用制备方法：
Figure PCTCN2020107177-appb-000138
其中，n＝1-5整数，如方案9中所示。
中间体LM(来那度胺炔基烷基碳链linker)的通用制备方法：
Figure PCTCN2020107177-appb-000139
Figure PCTCN2020107177-appb-000140
其中，n＝1-10整数，如方案10中所示。
中间体LM(硫基取代来那度胺碳链胺基linker)的通用制备方法：
Figure PCTCN2020107177-appb-000141
其中，n＝1-10整数，如方案11中所示。
中间体LM(末端溴取代的硫代来那度胺碳链linker)的通用制备方法：
Figure PCTCN2020107177-appb-000142
其中，n＝1-10整数，如方案12中所示。
中间体LM(末端碘取代的泊马度胺碳链linker)的通用制备方法：
Figure PCTCN2020107177-appb-000143
本发明化合物通用的合成方法：
Figure PCTCN2020107177-appb-000144
本发明化合物特殊的合成方法(烷基化反应)
Figure PCTCN2020107177-appb-000145
中间体制备实施例1
达克替尼衍生物A(SIAIS219183)的制备：根据方案1制备达克替尼衍生物A(SIAIS219183)。
Figure PCTCN2020107177-appb-000146
制备(E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide(SIAIS219176)：
氩气条件下，4-溴-巴豆酸(825mg,5mmol)溶于4mL的草酰氯中，加入一滴DMF引发反应，室温搅拌2h，低温旋蒸除去多余的草酰氯，干净的100mL蛋形瓶中依次加入N-(3-氯-4-氟苯基)-7-甲氧基-6-氨基喹唑啉-4-胺(636mg,2mmol)，4mL THF,三乙胺(417mg,3mmol)，室温搅拌，随后将现场制备的酰氯溶于4mL THF滴加进入该反应液中，室温反应1h。反应结束后，水淬灭，乙酸乙酯萃取，有机相水洗，饱和食盐水洗涤，无水硫酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色目标固体SIAIS219176 754mg,收率为81％。 1H NMR(500MHz,MeOD)δ9.25(s,1H),8.77(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69-7.64(m,1H),7.38(t,J＝8.9Hz,1H),7.34(s,1H),7.07-7.01(m,1H),6.69(d,J＝15.3Hz,1H),4.18(s,3H),3.53–3.48(m,2H).HRMS(ESI)C 19H 16BrClFN 4O 2 +[M+H] +,计算值465.0124；实测值,465.0121.
制备(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperazin-1-yl)but-2-enamide(SIAIS219183)：
室温敞口条件下，在蛋形瓶中，依次加入SIAIS219176(200mg,0.43mmol)，4mL DMF，N-叔丁氧羰基哌嗪(160.2mg,0.86mmol)，碳酸钾(356.6mg,1.29mmol)，随后抽换氩气40℃反应2h。TLC检测反应结束后，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体，直接进行下一步反应。将该黄色固体溶于6mL DCM，加入2mL CF 3COOH，随后室温反应2h。LC-MS检测反应结束后，旋去大部分CF 3COOH，加入饱和碳酸氢钠溶液调节溶液PH值至碱性，二氯甲烷萃取，无水硫酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS219183 178mg，两步总收率为88％。 1H NMR(500MHz,MeOD)δ9.24(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.66(ddd,J＝8.9,4.1,2.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.33(s,1H),7.03(dt,J＝15.3,6.2Hz,1H),6.68(d,J＝15.3Hz,1H),4.17(s,3H),3.51–3.48(m,2H),3.36–3.33(m,4H),2.93(s,4H).HRMS(ESI)C 23H 25ClFN 6O 2 +[M+H] +,计算值471.1706；实测值,471.1706.
中间体制备实施例2
达克替尼衍生物B的制备：采用与实施例1的达克替尼衍生物A相似的方法，根据方案1制备得到达克替尼衍生物B，其中间体合成数据以及结构表征数据如下：
Figure PCTCN2020107177-appb-000147
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262021).(黄色固体,166.3mg,两步总收率79％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.67-7.63(m,1H),7.40–7.34(m,2H),7.05-7.01(m,1H),6.84(d,J＝15.2Hz,1H),4.17(s,3H),4.03(d,J＝7.0Hz,2H),3.66(s,1H),3.29–3.26(m,4H),3.22–3.09(m,2H),3.01–2.80(m,6H),2.16(s,2H),2.01–1.85(m,2H).HRMS(ESI)C 28H 34ClFN 7O 2 +[M+H] +:计算值554.2441,实测值554.2433.
中间体制备实施例3
波齐替尼衍生物A(SIAIS219149B)的制备：根据方案2制备波齐替尼衍生物A(SIAIS219149B)。
Figure PCTCN2020107177-appb-000148
制备4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol(SIAIS219148)：
氩气条件下，6-乙酰氧基-7-甲氧基-3,4-二氢喹唑啉-4(3H)-酮(468.4mg,2mmol)溶于4mL的氯化亚砜中，加入一滴DMF引发反应，90℃搅拌4h，低温旋蒸除去多余的氯化亚砜，直接投入下一步；干净的100mL蛋形瓶中依次加入上一步产物(2mmol)，10mL DMF,3,4-dichloro-2-fluoroaniline(432mg,2.4mmol)，80℃搅拌1h。反应结束后，冰水淬灭，过滤得到粗产物，直接进行下一步；干净的100mL蛋形瓶中依次加入上一步产物(2mmol)，10mL甲醇，2mL氨水，70℃回流搅拌2h，冷却过滤，少量冷甲醇洗涤，得到黄色目标固体SIAIS219148 310mg,三步收率为44％。 1H NMR(500MHz,MeOD)δ8.38(s,1H),7.78(s,1H),7.61(t,J＝8.2Hz,1H),7.40(dd,J＝8.8,1.9Hz,1H),7.21(s,1H).HRMS(ESI)C 15H 11Cl 2FN 3O 2 +[M+H] +,计算值354.0207；实测值,354.0202.
制备N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine(SIAIS219149B)：
室温敞口条件下，在蛋形瓶中，依次加入SIAIS219148(177.1mg,0.5mmol)，4mL DMF，tert-butyl 4-(tosyloxy)piperidine-1-carboxylate(213.3mg,0.6mmol)，碳酸钾(207.3mg,1.5mmol)，随后抽换氩气70℃反应5h。TLC检测反应结束后，反相C18柱分离，洗脱剂为甲 醇和水，得黄色固体，直接进行下一步反应。将该黄色固体溶于6mL DCM，加入2mL CF 3COOH，随后室温反应2h。LC-MS检测反应结束后，旋去大部分CF 3COOH，加入饱和碳酸氢钠溶液调节溶液PH值至碱性，二氯甲烷萃取，无水硫酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS219149B 196.8mg，两步总收率为90％。 1H NMR(500MHz,MeOD)δ8.37(s,1H),7.79(s,1H),7.59(t,J＝8.2Hz,1H),7.42(dd,J＝8.8,1.9Hz,1H),7.20(s,1H),4.85-4.80(m,1H),4.00(s,3H),3.98–3.89(m,2H),3.71–3.59(m,2H),2.08(dd,J＝8.4,3.7Hz,2H),1.90(dd,J＝10.1,6.6Hz,2H).HRMS(ESI)C 20H 20Cl 2FN 4O 2 +[M+H] +,计算值437.0942；实测值,437.0942.
中间体制备实施例4
吉非替尼衍生物A(SIAIS219161)的制备：根据方案3制备吉非替尼衍生物A(SIAIS219161)。
Figure PCTCN2020107177-appb-000149
制备N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine(SIAIS184151)：
氩气条件下，4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol(639.4mg,2mmol)，5mL DMF，1-bromo-3-chloropropane(630mg,4mmol)，碳酸钾(829.3mg,6mmol)，室温反应12h。反应结束后，反相C18柱分离，洗脱剂为甲醇和水，得黄色目标固体SIAIS184151350mg,收率为44％。 1H NMR(500MHz,MeOD)δ8.44(s,1H),8.00(dd,J＝6.7,2.6Hz,1H),7.75(s,1H),7.67(ddd,J＝8.8,4.0,2.7Hz,1H),7.25(t,J＝9.0Hz,1H),7.17(s,1H),4.33(t,J＝5.9Hz,2H),4.00(s,3H),3.84(t,J＝6.3Hz,2H),2.34(p,J＝6.1Hz,2H).HRMS(ESI)C 18H 17Cl 2FN 3O 2 +[M+H] +,计算值396.0676；实测值,396.0676.
制备N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(piperazin-1-yl)propoxy)quinazolin-4-amine(SIAIS184161)：
室温敞口条件下，在蛋形瓶中，依次加入SIAIS184151(350mg,0.883mmol)，4mL NMP，N-叔丁氧羰基哌嗪(328.9mg,1.766mmol)，DIPEA(456.5mg,3.532mmol)，NaI(264.7mg,1.766mmol)，随后抽换氩气90℃反应2h。TLC检测反应结束后，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体，直接进行下一步反应。将该黄色固体溶于6mL DCM，加入2mL CF 3COOH，随后室温反应2h。LC-MS检测反应结束后，旋去大部分CF 3COOH，加入饱和碳酸氢钠溶液调节溶液PH值至碱性，二氯甲烷萃取，无水硫酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS184161 320mg，两步总收率为81％。 1H NMR(500 MHz,MeOD)δ8.74(s,1H),7.98(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69-7.63(m,1H),7.37(t,J＝8.9Hz,1H),7.27(s,1H),4.37(t,J＝5.6Hz,2H),4.09(s,3H),3.57-3.52(m,4H),3.48–3.40(m,4H),3.32(d,J＝4.4Hz,2H),2.41–2.32(m,2H).HRMS(ESI)C 22H 26ClFN 5O 2 +[M+H] +,计算值446.1754；实测值,446.1754.
中间体制备实施例5
吉非替尼衍生物B的制备：采用与中间体制备实施例4的吉非替尼衍生物A相似的方法，根据方案3制备得到吉非替尼衍生物B，其中间体合成数据以及结构表征数据如下：
Figure PCTCN2020107177-appb-000150
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-(piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-4-amine(SIAIS262080).(黄色固体,401mg,两步总收率76％) 1H NMR(500MHz,MeOD)δ8.75(s,1H),7.99(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.71-7.62(m,1H),7.38(t,J＝8.9Hz,1H),7.29(s,1H),4.38(t,J＝5.6Hz,2H),4.08(s,3H),3.58-3.52(m,8H),3.49–3.40(m,9H),3.34(d,J＝4.4Hz,2H),2.41–2.31(m,2H).HRMS(ESI)C 27H 35ClFN 6O 2 +[M+H] +:计算值529.2489,实测值529.2489.
中间体制备实施例6
卡奈替尼衍生物A(SIAIS293064)的制备：根据方案4制备卡奈替尼衍生物A(SIAIS293064)。
Figure PCTCN2020107177-appb-000151
制备N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS293064)：
氩气条件下，tert-butyl4-(3-((6-amino-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazine-1-carboxylate(531mg,1mmol)，5mL THF，零度冰水浴下加入acryloyl chloride(362mg,4mmol)，恢复至室温反应1h。反应结束后，水淬灭，二氯甲烷萃取，无水硫酸钠干燥，旋干，硅胶过柱，洗脱剂二氯甲烷：甲醇＝20：1到10：1，得黄色目标固体，直接进行下一步反应。将该黄色固体溶于6mL DCM，加入2mL CF 3COOH，随后室温反应2h。LC-MS检测反应结束后，旋去大部分CF 3COOH，加入饱和碳酸氢钠溶液调节溶液PH值至碱性，二氯甲烷萃取，无水硫 酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS293064 341mg，两步总收率为70％。 1H NMR(500MHz,MeOD)δ9.20(s,1H),8.76(s,1H),7.95–7.91(m,1H),7.66(ddd,J＝8.9,4.2,2.6Hz,1H),7.37(d,J＝5.5Hz,1H),6.89(dd,J＝16.9,10.3Hz,1H),6.52(dd,J＝16.9,1.5Hz,1H),5.90(dd,J＝10.3,1.6Hz,1H),4.51(t,J＝5.8Hz,2H),3.72(dd,J＝21.9,11.5Hz,6H),3.61–3.56(m,2H),2.54(td,J＝11.7,5.8Hz,2H).HRMS(ESI)C 24H 27ClFN 6O 2 +[M+H] +,计算值485.1863；实测值,485.1861.
中间体制备实施例7
卡奈替尼衍生物B的制备：采用与中间体制备实施例6的卡奈替尼衍生物A相似的方法，根据方案4制备得到卡奈替尼衍生物B，其合成数据以及结构表征数据如下：
Figure PCTCN2020107177-appb-000152
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS249183).(黄色固体,200mg,两步总收率62％) 1H NMR(500MHz,MeOD)δ9.22(s,1H),8.78(s,1H),7.96–7.91(m,1H),7.67-7.62(m,1H),7.38(d,J＝5.5Hz,1H),6.89-6.83(m,1H),6.55-6.51(m,1H),5.91(dd,J＝10.3,1.6Hz,1H),4.52(t,J＝5.8Hz,2H),3.79-3.68(m,10H),3.64–3.56(m,3H),2.54-2.43(m,6H).HRMS(ESI)C 29H 36ClFN 7O 2 +[M+H] +:计算值568.2598,实测值568.2591.
中间体制备实施例8
吉非替尼衍生物C(SIAIS293033)的制备：根据方案5制备吉非替尼衍生物C(SIAIS293033)。
Figure PCTCN2020107177-appb-000153
制备2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetic acid(SIAIS293033)：
空气条件下，N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine(400mg,0.8mmol)溶于5mL NMP，依次加入3-(tert-butoxy)-3-oxopropanoic acid(234mg,1.2mmol)，NaI(240mg,1.6mmol)，DIPEA(310mg,2.4mmol)，80℃反应2h。反应结束后，水淬灭，二氯甲烷萃取，无水硫酸钠干燥，旋干，硅胶过柱，洗脱剂二氯甲烷：甲醇＝20：1到10：1，得黄色目标固体，直接进行下一步反应。将该黄色固体溶于6mL DCM，加入2mL  CF 3COOH，随后室温反应2h。LC-MS检测反应结束后，旋去大部分CF 3COOH，加入饱和碳酸氢钠溶液调节溶液PH值至碱性，二氯甲烷萃取，无水硫酸钠干燥，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS293033 320mg，两步总收率为87％。 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.11(s,1H),7.93(d,J＝4.5Hz,1H),7.66(d,J＝8.8Hz,1H),7.37(t,J＝8.9Hz,1H),7.30(s,1H),4.95(s,2H),4.12(s,1H),4.10(s,3H),3.57(d,J＝15.2Hz,4H),2.34(s,4H).HRMS(ESI)C 22H 23ClFN 4O 4 +[M+H] +:计算值461.1386,实测值461.1385.
中间体制备实施例9
Sapitinib衍生物A的制备：采用与中间体制备实施例8的吉非替尼衍生物C相似的方法，根据方案5制备得到Sapitinib衍生物A，其合成数据以及结构表征数据如下：
Figure PCTCN2020107177-appb-000154
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetic acid(SIAIS293061).(黄色固体,335mg,两步总收率61％) 1H NMR(500MHz,MeOD)δ8.67(s,1H),8.21(s,1H),7.62(d,J＝7.6Hz,2H),7.53-7.48(m,3H),7.33–7.27(m,2H),4.94(s,2H),4.14(s,1H),4.11(s,3H),3.58(d,J＝15.2Hz,4H),2.34(s,4H).HRMS(ESI)C 22H 23ClFN 4O 4 +[M+H] +:计算值461.1386,实测值461.1381.
充当连接物的中间体SIAIS151001，SIAIS151004，SIAIS151005，SIAIS151006，SIAIS151007，SIAIS151025，SIAIS151026，SIAIS151019，SIAIS151020，SIAIS151027，SIAIS151086，SIAIS1204057，SIAIS1204085，SIAIS1210133，SIAIS1204061，SIAIS1204063，SIAIS151010，SIAIS151002，SIAIS151003，SIAIS151008，SIAIS151009，SIAIS074011，SIAIS074012，SIAIS074013，SIAIS074014，SIAIS074015，SIAIS074016，SIAIS074019，SIAIS074020，SIAIS172147具体的合成方法和数据请参照专利CN109912655A。
充当连接物的中间体SIAIS1220099,SIAIS299138,SIAIS299135,SIAIS213132,SIAIS213135,SIAIS1216135,SIAIS1216137,SIAIS1220059,SIAIS1220013,SIAIS1220015,SIAIS1220141具体的合成方法和数据请参照中国专利申请201910279248.9。
充当连接物的中间体SIAIS164118,SIAIS164119具体的合成方法和数据请参照专利WO2019170150(A1)。
充当连接物的中间体SIAIS1213061,SIAIS1213011具体的合成方法和数据请参照专利WO2020103878(A1)。
中间体制备实施例10
2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)acetic acid的制备(SIAIS1204137)
Figure PCTCN2020107177-appb-000155
根据方案7，将中间体化合物SIAIS151014(0.724mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(1.448mmol,2equiv)，室温搅拌下缓慢滴入相应的作为linker的对甲苯磺酸酯取代底物(0.869mmol,1.2equiv),滴完室温搅拌0.5h。原料反应完后，过滤除去不溶物后直接上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应的叔丁醇酯中间产物；将该相应的叔丁醇酯中间化合物加入25mL的蛋形瓶中，随后加入二氯甲烷(1mL)和三氟乙酸(3mL),室温搅拌反应1h。减压蒸去溶剂，加水冻干得相应的目标产物。得到目标化合物SIAIS1204137(淡黄色固体，185mg，收率69％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.73(m,2H),7.64(d,J＝6.6Hz,1H),5.12(dd,J＝12.8,5.4Hz,1H),4.08(s,2H),3.77(t,J＝6.4Hz,2H),3.14-3.07(m,2H),2.94–2.82(m,1H),2.66–2.55(m,2H),2.09-2.01(m,1H).HRMS(ESI)m/z:calcd for C 17H 17N 2O 7S +[M+H] +,393.0751；found,393.0763.
中间体制备实施例11
2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetic acid的制备(SIAIS1204139)
Figure PCTCN2020107177-appb-000156
参照中间体制备实施例10的方法，制备得到SIAIS1204139，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate。得到目标化合物SIAIS1204139(淡黄色固体，190mg，收率63％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83-7.76(m,2H),7.63(dd,J＝6.4,1.3Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.02(s,2H),3.72(t,J＝6.3Hz,2H),3.59(s,4H),3.39–3.30(m,2H),3.13-3.06(m,1H),2.64-2.52(m,2H),2.09-2.02(m,1H).HRMS(ESI)m/z:calcd for C 19H 21BN 2O 8S +[M+H] +,437.1013；found,437.1032.
中间体制备实施例12
2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetic acid的制备(SIAIS1204141)
Figure PCTCN2020107177-appb-000157
参照中间体制备实施例10的方法，制备得到SIAIS1204141，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate。得到目标化合物SIAIS1204141(淡黄色固体，246mg，收率74％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.85–7.73(m,2H),7.63(dd,J＝6.1,1.9Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.02(s,2H),3.71(t,J＝6.3Hz,2H),3.62–3.48(m,8H),3.35(t,J＝6.3Hz,2H),2.94-2.84(m,1H),2.63-2.52(m,2H),2.11–1.99(m,1H).HRMS(ESI)m/z:calcd for C 21H 25N 2O 9S +[M+H] +,481.1275；found,481.1273.
中间体制备实施例13
14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecanoic acid的制备(SIAIS1204147)
Figure PCTCN2020107177-appb-000158
参照中间体制备实施例10的方法，制备得到SIAIS1204147，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 14-(tosyloxy)-3,6,9,12-tetraoxatetradecanoate。得到目标化合物SIAIS1204147(淡黄色固体，228mg，收率63％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.73(m,2H),7.63(dd,J＝6.2,1.7Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.01(s,2H),3.71(t,J＝6.3Hz,2H),3.59–3.54(m,4H),3.54–3.49(m,8H),3.35(t,J＝6.3Hz,2H),2.94–2.84(m,1H),2.64–2.56(m,1H),2.55–2.51(m,1H),2.08-2.02(m,1H).HRMS(ESI)m/z:calcd for C 23H 29N 2O 10S +[M+H] +,525.1537；found,525.1536.
中间体制备实施例14
17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecanoic acid的制备(SIAIS1204149)
Figure PCTCN2020107177-appb-000159
参照中间体制备实施例10的方法，制备得到SIAIS1204149，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 17-(tosyloxy)-3,6,9,12,15-pentaoxaheptadecanoate。得到目标化合物SIAIS1204149(淡黄色固体，259mg，收率66％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H), 7.83–7.74(m,2H),7.63(dd,J＝6.2,1.8Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.01(s,2H),3.71(t,J＝6.3Hz,2H),3.60–3.55(m,4H),3.55–3.47(m,12H),3.35(t,J＝6.3Hz,2H),2.93-2.84(m,1H),2.64–2.56(m,1H),2.55–2.51(m,1H),2.08-2.02(m,1H).HRMS(ESI)m/z:calcd for C 25H 33N 2O 11S +[M+H] +,569.1800；found,569.1814.
中间体制备例15
制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酸(SIAIS151045)
Figure PCTCN2020107177-appb-000160
根据所述的方案6的方法制备化合物SIAIS151045，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151045(淡黄色固体,0.69g,收率80％)。 1H NMR(500MHz,DMSO)δ13.06(s,1H),11.15(s,1H),7.80(dd,J＝8.1,7.3Hz,1H),7.66(t,J＝7.9Hz,2H),5.13(dd,J＝12.9,5.4Hz,1H),4.09(s,2H),2.92–2.85(m,1H),2.66–2.51(m,2H),2.08–2.03(m,1H).HRMS(ESI)m/z:计算值C 15H 13N 2O 6S +[M+H] +,349.0489；实测值,349.0297.
中间体制备例16
制备3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酸(SIAIS151138B)
Figure PCTCN2020107177-appb-000161
根据中间体制备实施例15的方法制备化合物SIAIS151138B，不同之处在于采用的作为linker的溴代底物是叔丁基3-溴丙酸酯。得到目标化合物SIAIS151138B(淡黄色固体,0.64g,收率74％) 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.81–7.76(m,2H),7.64(d,J＝6.7Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.32(t,J＝7.0Hz,2H),2.92–2.84(m,1H),2.66(t,J＝7.0Hz,2H),2.62–2.51(m,2H),2.07–2.00(m,1H).HRMS(ESI)m/z:计算值C 16H 15N 2O 6S +[M+H] +,363.0645；实测值,363.0802.
中间体制备例17
制备4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酸(SIAIS151139B)
Figure PCTCN2020107177-appb-000162
根据中间体制备实施例15的方法制备化合物SIAIS151139B，不同之处在于采用的作为linker 的溴代底物是叔丁基4-溴丁酸酯。得到目标化合物SIAIS151139B(淡黄色固体,0.71g,收率82％)。 1H NMR(500MHz,DMSO)δ12.24(s,1H),11.12(s,1H),7.86–7.74(m,2H),7.63(d,J＝6.2Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.15(t,J＝7.2Hz,2H),2.92–2.84(m,1H),2.64–2.51(m,2H),2.42(t,J＝7.2Hz,2H),2.09–2.02(m,1H),1.93–1.83(m,2H).HRMS(ESI)m/z:计算值C 17H 17N 2O 6S +[M+H] +,377.0802；实测值,377.0962.
中间体制备例18
制备5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酸(SIAIS151140B)
Figure PCTCN2020107177-appb-000163
根据中间体制备实施例15的方法制备化合物SIAIS151140B，不同之处在于采用的作为linker的溴代底物是叔丁基5-溴戊酸酯。得到目标化合物SIAIS151140B(淡黄色固体,0.9g,收率74％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.71(m,2H),7.62(d,J＝6.9Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.13(t,J＝6.6Hz,2H),2.92–2.85(m,1H),2.64–2.52(m,2H),2.28(t,J＝6.6Hz,2H),2.08–2.02(m,1H),1.72–1.65(m,4H).HRMS(ESI)m/z:计算值C 18H 19N 2O 6S +[M+H] +,391.0958；实测值,391.1109.
中间体制备例19
制备6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酸(SIAIS151141B)
Figure PCTCN2020107177-appb-000164
根据中间体制备实施例15的方法制备化合物SIAIS151141B，不同之处在于采用的作为linker的溴代底物是叔丁基6-溴己酸酯。得到目标化合物SIAIS151141B(淡黄色固体,0.71g,收率74％)。 1H NMR(500MHz,DMSO)δ12.01(s,1H),11.12(s,1H),7.82–7.70(m,2H),7.62(d,J＝7.1Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.12(t,J＝7.2Hz,2H),2.92–2.85(m,1H),2.62–2.48(m,2H),2.22(t,J＝7.2Hz,2H),2.08–2.03(m,1H),1.71–1.63(m,2H),1.59–1.51(m,2H),1.49–1.40(m,2H).HRMS(ESI)m/z:计算值C 19H 21N 2O 6S +[M+H] +,405.1115；实测值,405.1268.
中间体制备例20
制备7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酸(SIAIS151142B)
Figure PCTCN2020107177-appb-000165
根据中间体制备实施例15的方法制备化合物SIAIS151142B，不同之处在于采用的作为linker的溴代底物是叔丁基7-溴庚酸酯。得到目标化合物SIAIS151142B(淡黄色固体,0.7g,收率80％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.80–7.71(m,2H),7.62(d,J＝6.9Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.12(t,J＝7.3Hz,2H),2.92–2.85(m,1H),2.62–2.52(m,2H),2.20(t,J＝7.3Hz,2H),2.07–2.00(m,1H),1.69–1.62(m,2H),1.53–1.47(m,2H),1.46–1.41(m,2H),1.36–1.27(m,2H).HRMS(ESI)m/z:计算值C 20H 23N 2O 6S +[M+H] +,419.1271；实测值,419.1432.
中间体制备例21
2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)acetic acid的制备(SIAIS1213129)
Figure PCTCN2020107177-appb-000166
根据方案9，将中间体化合物SIAIS171095(0.724mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(1.448mmol,2equiv)，室温搅拌下缓慢滴入相应的作为linker的对甲苯磺酸酯取代底物(0.869mmol,1.2equiv),滴完室温搅拌0.5h。原料反应完后，过滤除去不溶物后直接上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应的叔丁醇酯中间产物；将该相应的叔丁醇酯中间化合物加入25mL的蛋形瓶中，随后加入二氯甲烷(1mL)和三氟乙酸(3mL),室温搅拌反应1h。减压蒸去溶剂，加水冻干得相应的目标产物。得到目标化合物SIAIS1213129(淡黄色固体，148mg，收率54％)。 1H NMR(500MHz,CDCl 3)δ8.90(s,1H),7.81(d,J＝7.5Hz,1H),7.68(d,J＝7.7Hz,1H),7.54(t,J＝7.7Hz,1H),5.33(dd,J＝13.4,5.1Hz,1H),4.60(d,J＝17.2Hz,1H),4.47(d,J＝17.2Hz,1H),4.11(s,2H),3.78-3.73(m,1H),3.72-3.66(m,1H),3.22(t,J＝6.2Hz,2H),2.98-2.93(m,1H),2.90–2.82(m,1H),2.53-2.43(m,1H),2.32-2.25(m,1H).HRMS(ESI)m/z:calcd for C 17H 19N 2O 6S +[M+H] +,379.0958；found,379.0963.
中间体制备例22
2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetic acid的制备(SIAIS1213131)
Figure PCTCN2020107177-appb-000167
参照中间体制备实施例21的方法，制备得到SIAIS1213131，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate。得到目标化合物SIAIS1213131(淡黄色油状物，158mg，收率52％)。 1H NMR(500MHz,CDCl 3)δ8.77(s,1H),7.68(d,J＝7.5Hz,1H),7.53(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),5.21(dd,J＝13.4,5.1Hz,1H),4.41(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),4.06(s,2H),3.65–3.59(m,4H),3.54(t,J＝4.1Hz,2H),3.11(t,J＝6.1Hz,2H),2.88–2.83(m,1H),2.81–2.76(m,1H),2.42–2.34(m,1H),2.20–2.14(m,1H).HRMS(ESI)m/z:calcd for C 19H 23BN 2O 7S +[M+H] +,423.1200；found,423.1205.
中间体制备例23
2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetic acid的制备(SIAIS1213133)
Figure PCTCN2020107177-appb-000168
参照中间体制备实施例21的方法，制备得到SIAIS1213133，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate。得到目标化合物SIAIS1213133(淡黄色油状物，149mg，收率44％)。 1H NMR(500MHz,CDCl 3)δ8.91(s,1H),7.75(d,J＝7.5Hz,1H),7.61(d,J＝7.6Hz,1H),7.50(t,J＝7.7Hz,1H),5.29(dd,J＝13.4,5.1Hz,1H),4.49(d,J＝17.0Hz,1H),4.39(d,J＝17.1Hz,1H),4.17–4.15(m,2H),3.72–3.63(m,10H),3.20(t,J＝6.3Hz,2H),2.96-2.90(m,1H),2.90–2.82(m,1H),2.50-2.44(m,1H),2.28–2.22(m,1H).HRMS(ESI)m/z:calcd for C 21H 27N 2O 8S +[M+H] +,467.1483；found,467.1467.
中间体制备例24
14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecanoic acid(SIAIS1213135)
Figure PCTCN2020107177-appb-000169
参照中间体制备实施例21的方法，制备得到SIAIS1213135，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 14-(tosyloxy)-3,6,9,12-tetraoxatetradecanoate。得到目标化合物SIAIS1213135(淡黄色油状物，181mg，收率49％)。 1H NMR(500MHz,CDCl 3)δ8.61(s,1H), 7.78(dd,J＝7.6,0.7Hz,1H),7.63(dd,J＝7.8,0.8Hz,1H),7.50(t,J＝7.0Hz,1H),5.29(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝17.0Hz,1H),4.40(d,J＝16.9Hz,1H),4.15(s,2H),3.72–3.66(m,14H),3.19(t,J＝6.6Hz,2H),2.95-2.93(m,1H),2.91–2.86(m,1H),2.52–2.46(m,1H),2.28–2.24(m,1H).HRMS(ESI)m/z:calcd for C 23H 31N 2O 9S +[M+H] +,511.1745；found,511.1749.
中间体制备例25
17-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecanoic acid的制备(SIAIS1213137)
Figure PCTCN2020107177-appb-000170
参照中间体制备实施例21的方法，制备得到SIAIS1213133，不同之处在于采用的原料对甲苯磺酸酯取代底物是tert-butyl 17-(tosyloxy)-3,6,9,12,15-pentaoxaheptadecanoate。得到目标化合物SIAIS1213137(淡黄色油状物，209mg，收率52％)。 1H NMR(500MHz,CDCl 3)δ8.71(s,1H),7.77(d,J＝7.0Hz,1H),7.64(dd,J＝7.7,0.7Hz,1H),7.54–7.49(m,1H),5.31(dd,J＝13.4,5.1Hz,1H),4.50(d,J＝17.0Hz,1H),4.40(d,J＝17.0Hz,1H),4.17(s,2H),3.76–3.74(m,2H),3.70–3.66(m,12H),3.64–3.61(m,4H),3.20(t,J＝6.5Hz,2H),2.98–2.94(m,1H),2.90–2.85(m,1H),2.53-2.43(m,1H),2.30–2.25(m,1H).HRMS(ESI)m/z:calcd for C 25H 35N 2O 10S +[M+H] +,569.1800；found,569.1814.
中间体制备例26
制备2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酸(SIAIS171090)
Figure PCTCN2020107177-appb-000171
根据所述的方案8的方法制备化合物SIAIS171090，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS171090(白色固体,77mg,步骤3总收率64％)。 1H NMR(500MHz,DMSO)δ12.88(s,1H),11.00(s,1H),7.68–7.45(m,3H),5.15–5.13(m,1H),4.32(dd,J＝56.2,17.3Hz,2H),3.94(s,2H),2.95–2.91(m,1H),2.63–2.59(m,1H),2.49–2.39(m,1H),2.08–1.92(m,1H).HRMS(ESI)m/z:计算值C 15H 15N 2O 5S +[M+H] +,335.0696；实测值,334.8134.
中间体制备例27
制备3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酸(SIAIS171086)
Figure PCTCN2020107177-appb-000172
参照中间体制备实施例26的方法制备化合物SIAIS171086，不同之处在于采用的作为linker的溴代底物是叔丁基3-溴丙酸酯。得到目标化合物SIAIS171086(白色固体,40mg,步骤3总收率32％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.70–7.55(m,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.40–4.18(m,2H),3.24(t,J＝7.0Hz,2H),2.95–2.87(m,1H),2.63–2.53(m,3H),2.47–2.34(m,1H),2.05–1.95(m,1H).HRMS(ESI)m/z:计算值C 16H 17N 2O 5S +[M+H] +,349.0853；实测值,348.8166.
中间体制备例28
制备4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酸(SIAIS171089)
Figure PCTCN2020107177-appb-000173
参照中间体制备实施例26的方法制备化合物SIAIS171089，不同之处在于采用的作为linker的溴代底物是叔丁基4-溴丁酸酯。得到目标化合物SIAIS171089(白色固体,50mg,步骤3总收率38％)。 1H NMR(500MHz,DMSO)δ12.15(s,1H),10.99(s,1H),7.71–7.49(m,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.41–4.18(m,2H),3.10(t,J＝7.3Hz,2H),2.92–2.88(m,1H),2.61–2.59(m,1H),2.49–2.42(m,1H),2.38(t,J＝7.2Hz,2H),2.05–1.96(m,1H),1.84–1.74(m,2H).HRMS(ESI)m/z:计算值C 17H 19N 2O 5S +[M+H] +,363.1009；实测值,362.8160.
中间体制备例29
制备5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酸(SIAIS171079)
Figure PCTCN2020107177-appb-000174
参照中间体制备实施例26的方法制备化合物SIAIS171079，不同之处在于采用的作为linker的溴代底物是叔丁基5-溴戊酸酯。得到目标化合物SIAIS171079(白色固体,30mg,步骤3总收率22％)。 1H NMR(500MHz,DMSO)δ12.01(s,1H),10.98(s,1H),7.66–7.55(m,3H),5.12(dd,J＝13.3,5.1Hz,1H),4.37–4.18(m,2H),3.10–3.05(m,2H),2.95–2.84(m,1H),2.65–2.61 (m,1H),2.48–2.38(m,1H),2.27–2.20(m,3H),1.63–1.59(m,4H).HRMS(ESI)m/z:计算值C 18H 21N 2O 5S +[M+H] +,377.1166；实测值,376.8981.
中间体制备例30
制备6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酸(SIAIS171091)
Figure PCTCN2020107177-appb-000175
参照中间体制备实施例26的方法制备化合物SIAIS171091，不同之处在于采用的作为linker的溴代底物是叔丁基6-溴己酸酯。得到目标化合物SIAIS171091(白色固体,75mg,步骤3总收率53％)。 1H NMR(500MHz,DMSO)δ11.98(s,1H),10.98(s,1H),7.59–7.52(m,3H),5.12(dd,J＝13.4,5.1Hz,1H),4.26(dd,J＝40.9,20.5Hz,2H),3.07(t,J＝7.3Hz,2H),2.96–2.84(m,1H),2.64–2.60(m,1H),2.48–2.39(m,1H),2.19–2.15(m,2H),2.02–2.00(m,1H),1.70–1.35(m,6H).HRMS(ESI)m/z:计算值C 19H 23N 2O 5S +[M+H] +,391.1322；实测值,390.8150.
中间体制备例31
制备7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酸(SIAIS171092)
Figure PCTCN2020107177-appb-000176
参照中间体制备实施例26的方法制备化合物SIAIS171092，不同之处在于采用的作为linker的溴代底物是叔丁基7-溴庚酸酯。得到目标化合物SIAIS171092(白色固体,79mg,步骤3总收率54％)。 1H NMR(500MHz,DMSO)δ11.99(s,1H),10.98(s,1H),7.66–7.45(m,3H),5.12(dd,J＝13.3,5.1Hz,1H),4.26(dd,J＝40.9,20.5Hz,2H),3.07(t,J＝7.3Hz,2H),2.97–2.83(m,1H),2.63–2.60(m,1H),2.47–2.35(m,1H),2.18(t,J＝7.3Hz,2H),2.06–1.93(m,1H),1.65–1.20(m,8H).HRMS(ESI)m/z:计算值C 20H 25N 2O 5S +[M+H] +,405.1479；实测值,404.8155.
中间体制备实施例32
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl methanesulfonate(SIAIS255120)的制备
Figure PCTCN2020107177-appb-000177
根据方案10，在步骤1中，将3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.50g,1.5 mmol)溶于5mL DMF中，Ar气鼓泡5min，依次加入3-炔基丁醇(0.21g,3.0mmol)、Pd(PPh 3) 2Cl 2(0.10g,0.15mmol)和CuI(57mg,0.30mmol)。搅拌5min，加入2.5mL三乙胺，加热到80℃，反应过夜。冷却到室温，用50mL水淬灭反应，乙酸乙酯萃取(3x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(DCM/MeOH＝5/1)得到醇中间体。淡黄色固体，0.50g。
在步骤2中，将上述中间体溶于15mL DCM中，依次加入三乙胺(0.44g,4.4mmol)和甲基磺酰氯(0.25g,2.2mmol)，体系变澄清，反应过夜。将反应液用饱和食盐水洗涤，减压蒸去溶剂，柱层析(DCM/MeOH＝5/1)得到SIAIS255120。淡黄色固体，0.35g。 1H NMR(500MHz,DMSO-d6)δ11.01(s,1H),7.74(dd,J＝7.6,1.0Hz,1H),7.67(dd,J＝7.6,1.0Hz,1H),7.54(t,J＝7.6Hz,1H),5.16(dd,J＝13.4,5.1Hz,1H),4.52–4.27(m,4H),3.24(s,3H),3.02–2.87(m,3H),2.67–2.57(m,1H),2.42(qd,J＝13.3,4.4Hz,1H),2.03(m,1H).HRMS(ESI)C 18H 19N 2O 6S +[M+H] +,计算值391.0958；实测值,391.0952.
中间体制备实施例33
5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl methanesulfonate(SIAIS255121)的制备
Figure PCTCN2020107177-appb-000178
参照中间体制备实施例32的方法，制备得到SIAIS255121，不同之处在于以4-炔基戊醇为起始原料。 1H NMR(500MHz,DMSO-d 6)δ11.00(s,1H),7.72(dd,J＝7.6,1.0Hz,1H),7.66(dd,J＝7.8,1.0Hz,1H),7.53(t,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.8Hz,1H),4.38–4.28(m,3H),3.20(s,3H),3.00–2.86(m,1H),2.61m,3H),2.45(dd,J＝13.1,4.5Hz,1H),2.00(m,3H).HRMS(ESI)C 19H 21N 2O 6S +[M+H] +,计算值405.1115；实测值,405.1111.
中间体制备实施例34
6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl methanesulfonate(SIAIS255119)的制备
Figure PCTCN2020107177-appb-000179
参照中间体制备实施例32的方法，制备得到SIAIS255119，不同之处在于以5-炔基己醇为起始原料。 1H NMR(500MHz,DMSO-d 6)δ10.99(s,1H),7.71(dd,J＝7.6,1.1Hz,1H),7.65(dd,J＝7.7,1.0Hz,1H),7.52(t,J＝7.6Hz,1H),5.14(dd,J＝13.4,5.1Hz,1H),4.46(d,J＝17.7Hz,1H), 4.31(d,J＝17.7Hz,1H),4.27(t,J＝6.4Hz,2H),3.17(s,3H),2.91(m,1H),2.55(m,3H),2.48–2.42(m,1H),2.01(m,1H),1.88–1.80(m,2H),1.67(m,2H).HRMS(ESI)C 20H 23N 2O 6S +[M+H] +,计算值419.1271；实测值,419.1270.
中间体制备实施例35
3-(4-((2-氨基乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171123)的制备
根据方案11，在步骤1中，将化合物SIAIS171095(0.36mmol,1equiv)加入一个10mL的反应瓶中，随后加入无水DMF(2mL)和无水碳酸钾(0.72mmol,2equiv)，室温搅拌下缓慢加入相应的叔丁基(2-溴乙基)氨基甲酸酯(0.43mmol,1.2equiv),滴完室温搅拌1h。原料反应完后，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得到Boc保护的烷基化中间体产物。
将步骤1得到的相应产物加入10mL的反应瓶中，随后加入无水二氯甲烷(2mL)和三氟乙酸(2mL)，室温搅拌12h.减压蒸去反应溶剂，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得相应的目标化合物SIAIS171123(白色固体,68mg,两步反应的总收率59％)。 1H NMR(500MHz,DMSO)δ11.02(s,1H),7.88(s,3H),7.73(dd,J＝7.7,0.8Hz,1H),7.66(dd,J＝7.5,0.7Hz,1H),7.59(t,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.45–4.25(m,2H),3.32–3.26(m,2H),3.05–3.00(m,2H),2.96–2.87(m,1H),2.64–2.60(m,1H),2.48–2.41(m,1H),2.05–2.00(m,1H).HRMS(ESI)m/z:计算值C 15H 18N 3O 3S +[M+H] +,320.1063；实测值,320.1082.
中间体制备实施例36：
3-(4-((3-氨基丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171124)的制备
参照中间体制备实施例35的方法，制备得到SIAIS171124，不同之处在于采用的作为linker的溴代底物是叔丁基(3-溴丁基)氨基甲酸酯。(白色固体,68mg,两步总收率56％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.75–7.67(m,4H),7.63–7.49(m,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.43–4.16(m,2H),3.22–3.11(m,2H),2.97–2.85(m,3H),2.67–2.56(m,1H),2.48–2.40(m,1H),2.05–1.95(m,1H),1.91–1.77(m,2H).HRMS(ESI)m/z:计算值C 16H 20N 3O 3S +[M+H] +,334.1220；实测值,334.1213.
中间体制备实施例37：
3-(4-((4-氨基丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171131)的制备
参照中间体制备实施例35的方法，制备得到SIAIS171131，不同之处在于采用的作为linker的溴代底物是叔丁基(4-溴丁基)氨基甲酸酯。(淡黄色固体,76mg,两步总收率60％)。 1H NMR (500MHz,DMSO)δ10.99(s,1H),7.81–7.47(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.25(dd,J＝31.3,15.7Hz,2H),3.20–3.03(m,2H),2.96–2.85(m,1H),2.85–2.80(m,2H),2.63–2.60(m,1H),2.46–2.30(m,1H),2.06–1.94(m,1H),1.71–1.56(m,4H).HRMS(ESI)m/z:计算值C 17H 22N 3O 3S +[M+H] +,348.1376；实测值,348.1381.
中间体制备实施例38：
制备3-(4-((5-氨基戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171132)
参照中间体制备实施例35的方法，制备得到SIAIS171132，不同之处在于采用的作为linker的溴代底物是叔丁基(5-溴戊基)氨基甲酸酯。(淡黄色固体,95mg,两步总收率73％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.85–7.45(m,6H),5.21–5.07(m,1H),4.42–4.16(m,2H),3.16–3.05(m,2H),2.92–2.85(m,1H),2.84–2.71(m,2H),2.64–2.60(m,1H),2.45–2.40(m,1H),2.07–1.93(m,1H),1.66–1.58(m,2H),1.54–1.50(m,2H),1.49–1.44(m,2H).HRMS(ESI)m/z:计算值C 18H 24N 3O 3S +[M+H] +,362.1533；实测值,362.1537.
中间体制备实施例39：
制备3-(4-((6-氨基己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171134)
参照中间体制备实施例35的方法，制备得到SIAIS171134，不同之处在于采用的作为linker的溴代底物是叔丁基(6-溴己基)氨基甲酸酯。(淡黄色固体,78mg,两步总收率57％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.84–7.43(m,6H),5.16–5.13(m,1H),4.30–4.15(m,2H),3.14–3.03(m,2H),2.97–2.88(m,1H),2.82–2.72(m,2H),2.62(t,J＝14.7Hz,1H),2.49–2.39(m,1H),2.06–1.96(m,1H),1.68–1.56(m,2H),1.51–1.46(m,2H),1.45–1.37(m,2H),1.36–1.28(m,2H).HRMS(ESI)m/z:计算值C 19H 26N 3O 3S +[M+H] +,376.1689；实测值,376.1702.
中间体制备实施例40：
制备3-(4-((7-氨基庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171135)
参照中间体制备实施例35的方法，制备得到SIAIS171135，不同之处在于采用的作为linker的溴代底物是叔丁基(7-溴庚基)氨基甲酸酯。(白色固体,100mg,两步总收率71％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.84–7.42(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.37–4.18(m,2H),3.15–3.02(m,2H),2.92–2.88(m,1H),2.81–2.71(m,2H),2.61(t,J＝14.8Hz,1H),2.48–2.40(m,1H),2.05–1.98(m,1H),1.65–1.56(m,2H),1.54–1.46(m,2H),1.44–1.36(m,2H),1.33–1.23(m,4H).HRMS(ESI)m/z:计算值C 20H 28N 3O 3S +[M+H] +,390.1846；实测值,390.1846.
中间体制备实施例41：
制备3-(4-((8-氨基辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171136)
参照中间体制备实施例35的方法，制备得到SIAIS171136，不同之处在于采用的作为linker的溴代底物是叔丁基(8-溴辛基)氨基甲酸酯。(白色固体,100mg,两步总收率68％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.75–7.47(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.28(dd,J＝70.1,17.4Hz,2H),3.13–3.00(m,2H),2.98–2.84(m,1H),2.78–2.74(m,2H),2.64–2.59(m,1H),2.47–2.38(m,1H),2.06–1.93(m,1H),1.68–1.54(m,2H),1.52–1.48(m,2H),1.45–1.34(m,2H),1.30–1.20(m,6H).HRMS(ESI)m/z:计算值C 21H 30N 3O 3S +[M+H] +,404.2002；实测值,404.1996.
中间体制备实施例42：
制备3-(4-((6-溴己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1216133)
根据方案12，将化合物SIAIS171095(0.344mmol,1equiv),碳酸钾(0.688mmol，2equiv)和DMF(5mL)加入50mL两口瓶中，抽换氩气保护后，加入相应的1,6-二溴己烷(0.413mmol，1.2equiv)，然后室温搅拌反应1h。反应结束后，过滤除去不溶物后，C18反相柱分离，洗脱剂(v/v)：乙腈/(水)＝10％-100％，减压除去溶剂得到相应的目标化合物。SIAIS1216133(白色固体,339mg，收率38％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.63(dd,J＝7.5,1.2Hz,1H),7.58–7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.52(t,J＝6.7Hz,2H),3.08(t,J＝7.2Hz,2H),2.96-2.87(m,1H),2.59(d,J＝17.4Hz,1H),2.49–2.41(m,1H),2.04–1.97(m,1H),1.82–1.74(m,2H),1.63–1.56(m,2H),1.46–1.36(m,4H).HRMS(ESI)m/z:calcd for C 19H 24BrN 2O 3S +[M+H] +,439.0686；found,439.0680。
中间体制备实施例43：
制备2-(2,6-dioxopiperidin-3-yl)-4-((6-iodohexyl)amino)isoindoline-1,3-dione(SIAIS264018)
Figure PCTCN2020107177-appb-000180
根据方案13，在步骤1中，将2-(2,6-二氧代基哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(16.8mmol,1equiv)溶于25mL NMP中，依次加入6-aminohexan-1-ol(16.8mmol,1.0equiv)和DMF(25.2mmol,1.5equiv)，90℃加热反应4h，反应完全。将反应液降至室温，倾入饱和食盐水中，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到中间体。将中间体溶于50mL四氢呋喃中，加入四丁基氟化铵(16.8mmol)，室温下搅拌2h，反应完全。加入饱和食盐水200mL，乙酸乙酯萃取(4x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水Na 2SO 4干燥，减压蒸去溶剂，得到粗品1.0g，投入到下一步。
在步骤2中，将上步粗品溶于40mL混合溶剂(DCM/Pyridine＝3/1)中，依次加入三乙胺(0.52mL,3.8mmol)和甲烷磺酰氯(0.30mL,3.8mmol)，加热到40℃，反应2h，反应完全。饱和食盐水洗涤，减压蒸去溶剂，柱层析，得到黄色粉末，m＝0.80g。
在步骤3中，上步化合物溶于10mL丙酮中，加入碘化钠(3.0equiv)，加热到60℃反应24h，转化完全。冷却到室温，用40mL乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸去溶剂，得到产物SIAIS264018，黄色固体，直接投入使用。 1H NMR(500MHz,DMSO-d 6)δ11.09(s,1H),7.58(dd,J＝8.5,7.0Hz,1H),7.10(d,J＝8.6Hz,1H),7.02(d,J＝7.0Hz,1H),6.54(t,J＝5.9Hz,1H),5.05(dd,J＝12.7,5.4Hz,1H),3.28(q,J＝6.7Hz,4H),2.95–2.83(m,1H),2.63–2.55(m,1H),2.08(d,J＝4.9Hz,1H),2.06–1.99(m,1H),1.77(t,J＝7.0Hz,2H),1.57(t,J＝7.1Hz,2H),1.38(p,J＝5.0Hz,4H).
中间体制备实施例44：
奥西替尼衍生物SIAIS337051的制备：根据方案16制备奥西替尼衍生物(SIAIS337051)。
Figure PCTCN2020107177-appb-000181
制备N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337051)
步骤1和2：室温敞口条件下，在蛋形瓶中，依次加入N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(1.18g,3mmol)，6mL DMF，tert-butyl methyl(2-(methylamino)ethyl)carbamate(677.8mg,3.6mmol)，碳酸钾(621.9mg,4.5mmol)，随后抽换氩气80℃反应12h。TLC检测反应结束后，水淬灭，乙酸乙酯萃取，旋干，硅胶柱分离，洗脱剂为二氯甲烷：甲醇＝30：1，得黄色固体，900mg，直接进行下一步反应。将该黄色固体溶于20mL 75％的乙醇中，加入铁粉(268.8mg,4.8mmol),氯化铵(342mg,6.4mmol)，随后抽换氩气80℃反应3h。LC-MS检测反应结束后，布氏漏斗过滤，二氯甲烷：甲醇＝10：1洗涤，旋干，硅胶柱分离，洗脱剂为二氯甲烷：甲醇＝30：1， 得黄色固体780mg，两步总收率为49％。HRMS(ESI)C 29H 36N 7O 5 +[M+H] +,计算值562.2772；实测值,562.2771.
步骤3和4：干净的100mL蛋形瓶中依次加入上一步的黄色固体(300mg,0.565mmol)，5mL DCM,0℃下加入3-chloropropanoyl chloride(60μL,0.633mmol)，恢复室温搅拌，室温反应1h。反应结束后，水淬灭，DCM萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，直接下一步。上一步产物(0.565mmol)溶于5mL乙腈,随后加入三乙胺(171.2mg,1.695mmol)，80℃反应12h。LC-MS检测反应结束后，旋干，硅胶柱分离，洗脱剂为二氯甲烷：甲醇＝30：1，得黄色固体280mg，两步总收率为82％。HRMS(ESI)C 32H 40N 7O 4 +[M+H] +,计算值586.3136；实测值,586.3133.
步骤5：将上述黄色固体溶于2mL MeOH，加入4mL盐酸二氧六环溶液(4M)，随后室温反应2h。LC-MS检测反应结束后，旋干，反相C18柱分离，洗脱剂为甲醇和水，得黄色固体SIAIS337051 228mg，收率为99％。 1H NMR(500MHz,DMSO-d 6)δ9.83(s,1H),9.13(s,2H),8.80(s,1H),8.32(d,J＝89.5Hz,2H),7.59(d,J＝8.2Hz,1H),7.40(d,J＝6.6Hz,1H),7.27(dt,J＝31.2,7.7Hz,2H),7.13(dd,J＝16.9,10.2Hz,1H),7.00(s,1H),6.21(d,J＝16.9Hz,1H),5.71(d,J＝10.3Hz,1H),3.93(s,3H),3.84(s,3H),3.32(d,J＝5.6Hz,2H),3.15(q,J＝6.0,5.6Hz,2H),2.64(s,3H),2.58(t,J＝5.5Hz,3H).HRMS(ESI)m/z:计算值C 27H 32N 7O 2 +[M+H] +,486.2612；实测值,486.2614.
中间体制备实施例45
达克替尼衍生物C的制备：采用与中间体实施例1的达克替尼衍生物A相似的方法，根据方案1制备得到达克替尼衍生物B，其中间体合成数据以及结构表征数据如下：
Figure PCTCN2020107177-appb-000182
(E)-4-(4-aminopiperidin-1-yl)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)but-2-enamide(SIAIS249077).(黄色固体,310mg,两步总收率73％) 1H NMR(500MHz,MeOD)δ9.19(s,1H),8.70(s,1H),7.94(dd,J＝6.7,2.6Hz,1H),7.69-7.63(m,1H),7.36(d,J＝8.9Hz,1H),7.32(d,J＝13.5Hz,1H),7.06(dt,J＝14.7,7.0Hz,1H),6.81(d,J＝15.2Hz,1H),4.16(s,3H),3.92(s,1H),3.59(s,1H),3.08–2.99(m,1H),2.26(d,J＝13.7Hz,2H),2.19(t,J＝7.5Hz,1H),2.09-1.98(m,2H),1.65-1.58(m,1H),1.32(s,2H).HRMS(ESI)C 24H 27ClFN 6O 2 +[M+H] +:计算值485.1863,实测值485.1869.
中间体制备实施例46
9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)non-8-yn-1-yl methanesulfonate(SIAIS255127)的制备
Figure PCTCN2020107177-appb-000183
参照中间体制备实施例32的方法，制备得到SIAIS255127，不同之处在于以8-炔基壬醇为起始原料。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.70(d,J＝7.4Hz,1H),7.63(d,J＝7.0Hz,1H),7.52(t,J＝7.6Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.6Hz,1H),4.30(d,J＝17.6Hz,1H),4.18(t,J＝6.5Hz,2H),3.15(s,3H),2.91(ddd,J＝17.5,13.7,5.4Hz,1H),2.63–2.57(m,1H),2.47(d,J＝7.1Hz,2H),2.46–2.40(m,1H),2.02(ddd,J＝10.3,5.1,3.1Hz,1H),1.66(dd,J＝13.5,6.6Hz,2H),1.61–1.53(m,2H),1.47–1.40(m,2H),1.40–1.33(m,4H).HRMS(ESI)C 23H 29N 2O 6S +[M+H] +,计算值461.1741；实测值,461.1740.
中间体制备实施例47
Figure PCTCN2020107177-appb-000184
3-(4-((4-(bromomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS1221131)的制备
将来那度胺(1mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和DIPEA(3mmol,3equiv)，室温搅拌下加入1,4-二(溴甲基)苯(2mmol,2equiv),40℃搅拌3h。反应结束后，过滤除去不溶物，直接上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应的产物SIAIS1221131(黄色固体,235mg,收率53％). 1H NMR(500MHz,DMSO)δ11.02(s,1H),7.38(q,J＝8.3Hz,4H),7.20(t,J＝7.7Hz,2H),6.93(d,J＝7.3Hz,1H),6.62(d,J＝8.1Hz,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.68(s,2H),4.39(s,2H),4.32(d,J＝17.2Hz,1H),4.20(d,J＝17.1Hz,1H),2.97–2.89(m,1H),2.63(d,J＝16.1Hz,1H),2.38–2.27(m,1H),2.09–2.01(m,1H).HRMS(ESI)C 21H 21BrN 3O 3 +[M+H] +,计算值442.0761；实测值,442.0766.
中间体制备例48
制备2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid(SIAIS1222121)
Figure PCTCN2020107177-appb-000185
将羟基来那度胺(CAS:1061604-41-8,2mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入乙腈(10mL)和碳酸钾(4mmol,2equiv)，室温搅拌下加入叔丁基2-溴乙酸酯(2.4mmol,1.2equiv),80℃反应4h。反应结束后，减压除去乙腈，少量DMSO溶解后上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应的叔丁酯中间体，将该相应的叔丁醇酯中间化合物加入25mL的蛋形瓶中，随后加入二氯甲烷(1mL)和三氟乙酸(3mL),室温搅拌反应1h。减压蒸去溶剂，加水冻干得相应的目标产物SIAIS1222121(淡黄色固体,371mg,收率58％). 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.48(t,J＝7.6Hz,1H),7.35(d,J＝7.6Hz,1H),7.17(d,J＝8.2Hz,1H),5.12(dd,J＝13.5,4.9Hz,1H),4.86(s,2H),4.41(d,J＝17.5Hz,1H),4.27(d,J＝17.4Hz,1H),2.96–2.88(m,1H),2.60(d,J＝17.1Hz,1H),2.48-2.42(m,1H),2.04-1.97(m,1H).HRMS(ESI)C 15H 15N 2O 6 +[M+H] +,计算值319.0925；实测值,319.0928.中间体制备例49
制备5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)pentanoic acid(SIAIS1222125)
Figure PCTCN2020107177-appb-000186
参照中间体制备实施例48的方法，制备得到SIAIS1222125，不同之处在于采用的作为linker的溴代底物是叔丁基5-溴戊酸酯。得到目标化合物SIAIS1222125(淡黄色固体,418mg,收率59％)。 1H NMR(500MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.6Hz,1H),7.31(d,J＝7.5Hz,1H),7.24(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.37(d,J＝17.3Hz,1H),4.23(d,J＝17.3Hz,1H),4.13(t,J＝5.9Hz,2H),2.96–2.87(m,1H),2.59(d,J＝17.2Hz,1H),2.49–2.42(m,1H),2.30(t,J＝7.1Hz,2H),2.02–1.95(m,1H),1.79–1.75(m,2H),1.73-1.64(m,2H).HRMS(ESI)C 18H 21N 2O 6 +[M+H] +,计算值361.1394；实测值,361.1391.
中间体制备例50
制备6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoic acid(SIAIS1222149)
Figure PCTCN2020107177-appb-000187
参照中间体制备实施例48的方法，制备得到SIAIS1222149，不同之处在于采用的作为linker的溴代底物是叔丁基6-溴己酸酯。得到目标化合物SIAIS1222149(淡黄色固体,313mg,收率 42％)。 1H NMR(500MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.7Hz,1H),7.31(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,4.9Hz,1H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.3Hz,1H),4.11(t,J＝6.2Hz,2H),2.97–2.87(m,1H),2.59(d,J＝17.6Hz,1H),2.49–2.40(m,1H),2.24(t,J＝7.3Hz,2H),2.03–1.96(m,1H),1.79–1.72(m,2H),1.61–1.54(m,2H),1.50-1.41(m,2H).HRMS(ESI)C 19H 23N 2O 6 +[M+H] +,计算值375.1551；实测值,375.1535.
中间体制备例51
制备7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoic acid(SIAIS1222151)
Figure PCTCN2020107177-appb-000188
参照中间体制备实施例48的方法，制备得到SIAIS1222151，不同之处在于采用的作为linker的溴代底物是叔丁基7-溴庚酸酯。得到目标化合物SIAIS1222151(淡黄色固体,250mg,收率32％)。 1H NMR(500MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.2,4.9Hz,1H),4.38(d,J＝17.3Hz,1H),4.23(d,J＝17.3Hz,1H),4.11(t,J＝6.2Hz,2H),2.95–2.87(m,1H),2.59(d,J＝18.3Hz,1H),2.49–2.41(m,1H),2.22(t,J＝7.3Hz,2H),2.03–1.96(m,1H),1.77-1.70(m,2H),1.56–1.49(m,2H),1.48-1.40(m,2H),1.38-1.30(m,2H).HRMS(ESI)C 20H 25N 2O 6 +[M+H] +,计算值389.1707；实测值,389.1702.
中间体制备例52
制备3-(4-((6-bromohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS1222127)
Figure PCTCN2020107177-appb-000189
将羟基来那度胺(CAS:1061604-41-8,2mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入乙腈(10mL)和碳酸钾(4mmol,2equiv)，室温搅拌下加入1,6-二溴己烷(4mmol,2equiv),80℃反应过夜。反应结束后，减压除去乙腈，少量DMSO溶解后上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应目标化合物SIAIS1222127(淡黄色固体,318mg,收率38％)。 1H NMR(500MHz,DMSO)δ10.91(s,1H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.3Hz,1H),4.12(t,J＝6.2Hz,2H),3.54(t,J＝6.6Hz,2H),2.96–2.86(m,1H),2.59(d,J＝17.4Hz,1H),2.47–2.40(m,1H),2.03–1.96(m,1H),1.88–1.79(m,2H),1.78-1.72(m,2H),1.46(s,4H).HRMS(ESI)C 19H 24BrN 2O 4 +[M+H] +,计算值423.0914；实测值, 423.0913.
本发明化合物制备实施例
实施例1
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS249046)的制备
根据方案14，室温下，在反应瓶中，依次加入相应的EGFR抑制剂，即达克替尼衍生物A(0.02mmol,1equiv)，中间体LM(SIAIS151001)(0.02mmol,1equiv),HOAt(0.04mmol,2equiv),EDCI(0.04mmol,2equiv),2mL DMF，NMM(0.2mmol,10equiv)，室温反应过夜。LC-MS检测反应结束后，过滤，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得到最终目标化合物(SIAIS249046).(黄色固体,8.9mg,50％) 1H NMR(500MHz,MeOD)δ9.23(s,1H),8.76(s,1H),7.95(dd,J＝6.6,2.5Hz,1H),7.70-7.65(m,1H),7.47(s,1H),7.39(t,J＝8.9Hz,1H),7.30(s,1H),7.08–6.99(m,2H),6.94(d,J＝6.9Hz,1H),6.79(d,J＝15.2Hz,1H),5.09(dd,J＝12.7,5.5Hz,1H),4.16(s,3H),4.04(d,J＝6.5Hz,2H),3.81(s,2H),3.74(d,J＝5.1Hz,1H),3.72(d,J＝5.2Hz,1H),3.71–3.32(m,8H),2.94–2.84(m,1H),2.75–2.68(m,2H),2.17–2.13(m,1H).HRMS(ESI)C 41H 42ClFN 9O 8 +[M+H] +,计算值842.2823；实测值,842.2820.
实施例2
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS262013)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151004)制备得到目标化合物(SIAIS262013).(黄色固体,8.2mg,44％) 1H NMR(500MHz,MeOD)δ9.24(s,1H),8.78(s,1H),7.96(dd,J＝6.6,2.5Hz,1H),7.72-7.65(m,1H),7.49(s,1H),7.41(t,J＝8.9Hz,1H),7.32(s,1H),7.09–6.99(m,2H),6.95(d,J＝6.9Hz,1H),6.81(d,J＝15.2Hz,1H),5.09(dd,J＝12.7,5.5Hz,1H),4.18(s,3H),4.03(d,J＝6.5Hz,2H),3.84(s,2H),3.74(d,J＝5.1Hz,1H),3.71(d,J＝5.2Hz,1H),3.72–3.34(m,8H),3.31-3.23(m,4H),2.96–2.85(m,1H),2.75–2.68(m,2H),2.17–2.13(m,1H).HRMS(ESI)C 43H 46ClFN 9O 9 +[M+H] +,计算值886.3086；实测值,886.3083.
实施例3
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-(2-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS249047)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151005)制备得到目标化合物(SIAIS249047).(黄色固体,9.9mg,51％) 1H NMR(500MHz,MeOD)δ9.22(s,1H),8.75(s,1H),7.94(dd,J＝6.6,2.5Hz,1H),7.71–7.62(m,1H),7.50–7.42(m,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.09–7.01(m,2H),6.94(d,J＝7.0Hz,1H),6.83(d,J＝15.2Hz,1H),5.06(dd,J＝12.8,5.5Hz,1H),4.17(s,3H),4.08(d,J＝7.1Hz,2H),3.78–3.71(m,4H),3.69-3.65(m,6H),3.60(d,J＝3.3Hz,4H),3.48(t,J＝5.0Hz,2H),3.22–3.00(m,2H),2.91–2.84(m,1H),2.73-2.68(m,2H),2.17–2.08(m,1H).HRMS(ESI)C 45H 50ClFN 9O 10 +[M+H] +,计算值930.3348；实测值,930.3344.
实施例4
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-oyl)piperazin-1-yl)but-2-enamide(SIAIS262014)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151006)制备得到目标化合物(SIAIS262014).(黄色固体,10.1mg,49％) 1H NMR(500MHz,MeOD)δ9.19(s,1H),8.73(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.64(m,1H),7.43(dd,J＝8.5,7.2Hz,1H),7.37(t,J＝8.9Hz,1H),7.30(s,1H),7.04(dd,J＝15.1,7.4Hz,1H),6.98(d,J＝8.6Hz,1H),6.90(d,J＝7.0Hz,1H),6.85(d,J＝15.2Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.16(s,3H),4.12–4.04(m,2H),3.73(t,J＝5.8Hz,6H),3.67(s,2H),3.65–3.57(m,8H),3.46–3.43(m,2H),2.91-2.86(m,2H),2.79–2.72(m,2H),2.72–2.63(m,1H),2.14-2.10(m,1H).HRMS(ESI)C 47H 54ClFN 9O 11 +[M+H] +,计算值974.3610；实测值,974.3612.
实施例5
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetyl)piperazin-1-yl)but-2-enamide(SIAIS219194)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151025)制备得到目标化合物(SIAIS219194).(黄色固体,8.2mg,50％) 1H NMR(500MHz,DMSO)δ11.10(s,1H),9.81(s,1H),9.72(s,1H),8.92(s,1H),8.53(s,1H),8.15-8.09(m,1H),7.83–7.76(m,1H),7.64–7.58(m,1H),7.42(t,J＝9.1Hz,1H),7.29(s,1H),7.09(d,J＝4.2Hz,2H),6.85-6.80(m,1H),6.62(d,J＝15.3Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.20(d,J＝4.1Hz,2H),4.02(s,3H),3.55(d,J＝16.3Hz,8H),3.21(d,J＝5.8Hz,2H),2.65–2.57(m,1H),2.42(s,2H),2.07–2.00(m,1H).HRMS (ESI)C 38H 35ClFN 9O 7 +[M+H] +,计算值783.2332；实测值,783.2330.
实施例6
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS262016)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151026)制备得到目标化合物(SIAIS262016).(黄色固体,6.6mg,39％) 1H NMR(500MHz,MeOD)δ9.25(s,1H),8.74(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.58(dd,J＝8.5,7.2Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.13(d,J＝8.6Hz,1H),7.08–7.00(m,2H),6.83(d,J＝15.3Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.17(d,J＝5.4Hz,3H),4.01(d,J＝7.1Hz,2H),3.74–3.66(m,2H),3.30(s,8H),2.92–2.69(m,5H),2.16–2.08(m,1H).HRMS(ESI)C 39H 37ClFN 9O 7 +[M+H] +,计算值797.2489；实测值,797.2485.
实施例7
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)but-2-enamide(SIAIS249062)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151019)制备得到目标化合物(SIAIS249062).(黄色固体,8.2mg,48％) 1H NMR(500MHz,MeOD)δ9.29(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.66(dd,J＝4.8,2.7Hz,1H),7.57(dd,J＝8.5,7.2Hz,1H),7.38(t,J＝8.9Hz,1H),7.34(s,1H),7.13(d,J＝8.5Hz,1H),7.07(dt,J＝11.1,5.7Hz,2H),6.87(d,J＝15.2Hz,1H),5.07(dd,J＝12.6,5.4Hz,1H),4.19(s,3H),4.07(d,J＝7.1Hz,2H),3.43(t,J＝6.2Hz,2H),3.32-3.30(m,8H),2.90–2.80(m,1H),2.77-2.72(m,2H),2.57(s,2H),2.12(d,J＝5.2Hz,1H),2.01(d,J＝10.9Hz,2H).HRMS(ESI)C 40H 39ClFN 9O 7 +[M+H] +,计算值811.2645；实测值,811.2642.
实施例8
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)but-2-enamide(SIAIS249048)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151020)制备得到目标化合物(SIAIS249048).(黄色固体,8.1mg,47％) 1H NMR(500MHz,MeOD)δ9.22(s,1H),8.70(s,1H),7.88(dd,J＝6.6,2.5Hz,1H),7.65–7.58(m,1H),7.55–7.46(m,1H),7.32(t,J＝8.9Hz,1H), 7.28(s,1H),7.04–6.95(m,3H),6.82(d,J＝15.2Hz,1H),5.02(dd,J＝12.3,5.0Hz,1H),4.13(s,3H),4.03(d,J＝7.0Hz,2H),3.33(d,J＝8.4Hz,8H),3.25–3.08(m,2H),2.84-2.80(m,1H),2.74–2.65(m,2H),2.48(s,2H),2.12–2.03(m,1H),1.69(s,4H).HRMS(ESI)C 41H 41ClFN 9O 7 +[M+H] +,计算值825.2802；实测值,825.2800.
实施例9
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)but-2-enamide(SIAIS249049)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151027)制备得到目标化合物(SIAIS249049).(黄色固体,8.3mg,47％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.53(dd,J＝8.5,7.2Hz,1H),7.37(t,J＝8.9Hz,1H),7.33(s,1H),7.07-7.02(m,3H),6.88(d,J＝15.2Hz,1H),5.06(dd,J＝12.6,5.5Hz,1H),4.18(s,3H),4.10(d,J＝7.2Hz,2H),3.92–3.32(m,8H),3.18(d,J＝12.6Hz,2H),2.89-2.85(m,1H),2.76–2.67(m,2H),2.48(t,J＝7.2Hz,2H),2.13-2.08(m,1H),1.74–1.65(m,4H),1.49-1.46(m,2H).HRMS(ESI)C 42H 43ClFN 9O 7 +[M+H] +,计算值839.2958；实测值,839.2955.
实施例10
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)but-2-enamide(SIAIS262015)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151086)制备得到目标化合物(SIAIS262015).(黄色固体,8.9mg,50％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.09–7.01(m,3H),6.87(d,J＝15.2Hz,1H),5.06(dd,J＝12.5,5.5Hz,1H),4.18(s,3H),4.07(d,J＝7.0Hz,2H),3.38–3.31(m,8H),2.88-2.84(m,1H),2.77–2.68(m,2H),2.44(t,J＝7.5Hz,2H),2.16–2.07(m,1H),1.68-1.63(m,4H),1.51–1.42(m,4H),1.33-1.28(m,2H).HRMS(ESI)C 43H 45ClFN 9O 7 +[M+H] +,计算值853.3115；实测值,853.3111.
实施例11
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetyl)piperazin-1-yl)but-2-enamide(SIAIS249056)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204057)制备得到目标化合 物(SIAIS249056).(黄色固体,7.1mg,44％) 1H NMR(500MHz,MeOD)δ9.28(d,J＝6.8Hz,1H),8.76(s,1H),7.95-7.91(m,1H),7.68–7.63(m,1H),7.43–7.31(m,3H),7.15(dd,J＝7.5,4.7Hz,1H),7.07-7.02(m,1H),6.93–6.82(m,2H),5.21(dd,J＝13.3,5.2Hz,1H),4.82–4.29(m,4H),4.19(s,3H),4.12(t,J＝7.7Hz,2H),3.73–3.32(m,8H),3.23–3.08(m,2H),2.98–2.89(m,1H),2.80(d,J＝18.4Hz,1H),2.58–2.44(m,1H),2.21(d,J＝10.3Hz,1H).HRMS(ESI)C 38H 37ClFN 9O 6 +[M+H] +,计算值769.2539；实测值,769.2535.
实施例12
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanoyl)piperazin-1-yl)but-2-enamide(SIAIS249057)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204085)制备得到目标化合物(SIAIS249057).(黄色固体,8.2mg,49％) 1H NMR(500MHz,MeOD)δ9.27(d,J＝5.4Hz,1H),8.75(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.67-7.63(m,1H),7.53(dd,J＝9.7,5.7Hz,1H),7.47(d,J＝7.4Hz,1H),7.37(t,J＝8.9Hz,1H),7.34(d,J＝11.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.08–6.98(m,1H),6.85(d,J＝15.2Hz,1H),5.17(d,J＝8.6Hz,1H),4.74–4.46(m,2H),4.19(s,3H),4.03(d,J＝6.5Hz,2H),3.62(d,J＝45.4Hz,2H),3.46(t,J＝6.0Hz,2H),3.34–3.31(m,8H),3.14(d,J＝29.1Hz,2H),2.98–2.84(m,1H),2.79(d,J＝15.3Hz,1H),2.68–2.47(m,2H),2.29–2.17(m,1H),2.05(d,J＝6.0Hz,1H).HRMS(ESI)C 40H 41ClFN 9O 6 +[M+H] +,计算值797.2852；实测值,797.2851.
实施例13
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoyl)piperazin-1-yl)but-2-enamide(SIAIS249058)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1210133)制备得到目标化合物(SIAIS249058).(黄色固体,8.5mg,50％) 1H NMR(500MHz,MeOD)δ9.29(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.66(ddd,J＝8.9,4.1,2.7Hz,1H),7.58(d,J＝4.4Hz,2H),7.38(dd,J＝12.1,5.7Hz,2H),7.34(s,1H),7.06(dt,J＝14.3,7.1Hz,1H),6.88(d,J＝15.2Hz,1H),5.20(dd,J＝13.1,5.0Hz,1H),4.62(d,J＝17.2Hz,1H),4.55(d,J＝17.2Hz,1H),4.19(s,3H),4.09(d,J＝7.1Hz,2H),3.60(s,2H),3.44(t,J＝6.9Hz,2H),3.31(d,J＝1.6Hz,8H),2.97–2.86(m,1H),2.80(d,J＝17.5Hz,1H),2.54(d,J＝8.6Hz,2H),2.22(d,J＝10.6Hz,1H),1.87–1.71(m,4H).HRMS(ESI)C 41H 43ClFN 9O 6 +[M+H] +,计算值811.3009；实测值,811.3007.
实施例14
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)but-2-enamide(SIAIS249059)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204061)制备得到目标化合物(SIAIS249059).(黄色固体,8.7mg,50％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.68–7.57(m,3H),7.44(d,J＝7.4Hz,1H),7.36(dd,J＝17.4,8.5Hz,2H),7.12–7.02(m,1H),6.89(d,J＝15.2Hz,1H),5.20(dd,J＝13.2,4.8Hz,1H),4.64(d,J＝17.2Hz,1H),4.57(d,J＝17.2Hz,1H),4.18(s,3H),4.10(d,J＝7.0Hz,2H),3.63(d,J＝37.0Hz,2H),3.42(t,J＝7.3Hz,2H),3.31–3.11(m,8H),2.98–2.76(m,2H),2.60–2.44(m,3H),2.27–2.17(m,1H),1.88–1.63(m,4H),1.58–1.45(m,2H).HRMS(ESI)C 42H 45ClFN 9O 6 +[M+H] +,计算值825.3165；实测值,825.3163.
实施例15
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)but-2-enamide(SIAIS249060)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204063)制备得到目标化合物(SIAIS249060).(黄色固体,8.3mg,47％) 1H NMR(500MHz,MeOD)δ9.28(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.64(m,1H),7.40(dt,J＝17.8,8.3Hz,2H),7.33(s,1H),7.26(d,J＝7.5Hz,1H),7.09–7.02(m,2H),6.88(d,J＝15.2Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.43(d,J＝17.0Hz,1H),4.37(d,J＝17.0Hz,1H),4.09(d,J＝7.2Hz,2H),3.57(s,2H),3.31(d,J＝1.6Hz,8H),2.95-2.88(m,1H),2.83–2.75(m,1H),2.59–2.38(m,3H),2.23-2.18(m,1H),1.69-1.64(m,4H),1.52–1.39(m,4H).HRMS(ESI)C 43H 47ClFN 9O 6 +[M+H] +,计算值839.3322；实测值,839.3322.
实施例16
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)but-2-enamide(SIAIS249034)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151045)制备得到目标化合物(SIAIS249034).(黄色固体,8.2mg,49％) 1H NMR(500MHz,DMSO)δ11.13(s,1H),10.13(s,1H),9.10(s,1H),8.80(s,1H),8.02(d,J＝4.9Hz,1H),7.82-7.77(m,2H),7.74–7.62(m,3H),7.52(t,J＝9.0Hz,1H),7.38(s,1H),6.94(s,1H),6.80(d,J＝15.8Hz,1H),5.14–5.09(m,1H),4.35(s, 2H),4.07(s,3H),3.55-3.50(m,4H),3.25–3.11(m,4H),2.92-2.86(m,2H),2.60(d,J＝17.4Hz,2H),2.10–1.96(m,2H).HRMS(ESI)C 38H 35ClFN 8O 7S +[M+H] +,计算值801.2016；实测值,801.2013.
实施例17
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS249035)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151138B)制备得到目标化合物(SIAIS249035).(黄色固体,9.1mg,53％) 1H NMR(500MHz,DMSO)δ8.43(s,1H),7.94(s,1H),7.12(s,1H),6.92(d,J＝17.4Hz,4H),6.83(d,J＝25.9Hz,2H),6.56(t,J＝8.8Hz,1H),6.50(s,1H),6.31–6.20(m,1H),6.04(d,J＝15.5Hz,1H),4.35-4.29(m,1H),3.37(s,3H),3.26(s,2H),2.62-2.55(m,8H),2.09-2.05(m,4H),1.96-1.91(m,4H).HRMS(ESI)C 39H 37ClFN 8O 7S +[M+H] +,计算值815.2173；实测值,815.2170.
实施例18
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)butanoyl)piperazin-1-yl)but-2-enamide(SIAIS249036)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151139B)制备得到目标化合物(SIAIS249036).(黄色固体,7.4mg,42％) 1H NMR(500MHz,DMSO)δ11.61(s,1H),11.12(s,1H),10.16(s,1H),9.13(s,1H),8.84(s,1H),8.00(dd,J＝6.6,2.3Hz,1H),7.86(d,J＝8.2Hz,1H),7.80(t,J＝7.7Hz,1H),7.72–7.66(m,1H),7.64(d,J＝7.2Hz,1H),7.53(t,J＝9.1Hz,1H),7.41(s,1H),6.96(dd,J＝14.7,7.4Hz,1H),6.80(d,J＝15.3Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.07(s,3H),3.99(s,2H),3.16-3.11(m,8H),2.99–2.83(m,2H),2.65–2.53(m,4H),2.07-1.96(m,2H),1.91(s,2H).HRMS(ESI)C 40H 39ClFN 8O 7S +[M+H] +,计算值829.2329；实测值,829.2329.
实施例19
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)pentanoyl)piperazin-1-yl)but-2-enamide(SIAIS249037)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151140B)制备得到目标化合物(SIAIS249037).(黄色固体,8.5mg,48％) 1H NMR(500MHz,DMSO)δ11.75(s,1H),11.12(s,1H),10.16(s,1H),9.13(s,1H),8.84(s,1H),8.00(dd,J＝6.7,2.4Hz,1H),7.82–7.73(m,2H),7.73–7.66(m,1H),7.63(d,J＝6.9Hz,1H),7.53(t,J＝9.0Hz,1H),7.43(s,1H),7.03–6.93(m, 1H),6.79(d,J＝15.4Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.07(s,3H),3.98(s,2H),3.27–3.00(m,8H),2.95–2.83(m,2H),2.65–2.55(m,2H),2.44(s,2H),2.09–1.95(m,2H),1.70(s,4H).HRMS(ESI)C 41H 41ClFN 8O 7S +[M+H] +,计算值843.2486；实测值,843.2483.
实施例20
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)but-2-enamide(SIAIS249038)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151141B)制备得到目标化合物(SIAIS249038).(黄色固体,8.9mg,49％) 1H NMR(500MHz,DMSO)δ11.62(s,1H),11.12(s,1H),10.15(s,1H),9.12(s,1H),8.83(s,1H),8.00(dd,J＝6.8,2.4Hz,1H),7.81–7.73(m,2H),7.73–7.66(m,1H),7.63(d,J＝7.0Hz,1H),7.52(t,J＝9.1Hz,1H),7.41(s,1H),6.98-6.84(m,1H),6.79(d,J＝15.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.07(s,3H),3.99(s,2H),3.16-3.09(m,8H),2.97–2.82(m,2H),2.60-2.53(m,2H),2.38(t,J＝7.2Hz,2H),2.04-1.99(m,2H),1.71-1.66(m,2H),1.55(d,J＝7.2Hz,2H),1.49-1.44(m,2H).HRMS(ESI)C 42H 43ClFN 8O 7S +[M+H] +,计算值857.2642；实测值,857.2640.
实施例21
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)heptanoyl)piperazin-1-yl)but-2-enamide(SIAIS249039)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151142B)制备得到目标化合物(SIAIS249039).(黄色固体,9.1mg,50％) 1H NMR(500MHz,DMSO)δ11.79–11.41(m,1H),11.12(s,1H),10.12(s,1H),9.09(s,1H),8.79(s,1H),8.03(s,1H),7.81–7.70(m,3H),7.63(d,J＝7.0Hz,1H),7.51(t,J＝9.0Hz,1H),7.41(s,1H),6.94(s,1H),6.78(d,J＝14.9Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.06(s,3H),3.97(s,2H),3.14-3.08(m,8H),2.94–2.83(m,2H),2.66–2.54(m,2H),2.36(t,J＝7.0Hz,2H),2.05-1.99(m,2H),1.67(dd,J＝14.6,7.2Hz,2H),1.54–1.42(m,4H),1.36-1.32(m,2H).HRMS(ESI)C 43H 45ClFN 8O 7S +[M+H] +,计算值871.2799；实测值,871.2797.
实施例22
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS219192)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204137)制备得到目标化合 物(SIAIS219192).(黄色固体,9.5mg,54％) 1H NMR(500MHz,MeOD)δ9.20(s,1H),8.76(d,J＝4.8Hz,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.72(dd,J＝12.5,7.9Hz,2H),7.69–7.64(m,1H),7.55(t,J＝5.4Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.17–7.10(m,1H),6.88(d,J＝15.2Hz,1H),5.11(dd,J＝12.8,5.5Hz,1H),4.40-4.36(m,2H),4.22–4.07(m,8H),3.89-3.84(m,2H),3.66(s,2H),3.19-3.17(m,2H),2.91–2.85(m,1H),2.75-2.70(m,2H),2.16–2.09(m,1H).HRMS(ESI)C 40H 39ClFN 8O 8S +[M+H] +,计算值845.2279；实测值,845.2275.
实施例23
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS262005)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204139)制备得到目标化合物(SIAIS262005).(黄色固体,9.1mg,49％) 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.12(s,1H),9.11(s,1H),8.83(s,1H),8.01(s,1H),7.80–7.74(m,2H),7.70(s,1H),7.61(d,J＝6.0Hz,1H),7.53(s,1H),7.36(s,1H),6.94(s,1H),6.79(d,J＝14.0Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.22(d,J＝15.0Hz,2H),4.07(s,3H),4.02(s,2H),3.73(t,J＝6.3Hz,2H),3.55-3.50(m,10H),3.09(s,4H),2.92-2.86(m,1H),2.64–2.55(m,2H),2.09–2.01(m,1H).HRMS(ESI)C 42H 43ClFN 8O 9S +[M+H] +,计算值889.2541；实测值,889.2543.
实施例24
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS262006)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204141)制备得到目标化合物(SIAIS262006).(黄色固体,9.7mg,49％) 1H NMR(500MHz,DMSO)δ11.44–11.23(m,1H),11.12(s,1H),10.13(s,1H),9.10(s,1H),8.82(s,1H),8.01(s,1H),7.80–7.74(m,2H),7.69(s,1H),7.62(dd,J＝5.9,2.0Hz,1H),7.52(t,J＝8.9Hz,1H),7.37(s,1H),6.93(s,1H),6.79(d,J＝14.8Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.20(d,J＝16.9Hz,2H),4.07(s,3H),4.01(s,2H),3.71(t,J＝6.3Hz,2H),3.58–3.53(m,8H),3.34(t,J＝6.3Hz,6H),3.07(s,4H),2.93–2.84(m,1H),2.66–2.57(m,2H),2.09–2.02(m,1H).HRMS(ESI)C 44H 47ClFN 8O 10S +[M+H] +,计算值933.2803；实测值,933.2800.
实施例25
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecanoyl)piperazin-1-yl)but-2 -enamide(SIAIS262007)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204147)制备得到目标化合物(SIAIS262007).(黄色固体,10.1mg,49％) 1H NMR(500MHz,DMSO)δ11.72–11.32(m,1H),11.12(s,1H),10.16(s,1H),9.14(s,1H),8.85(s,1H),8.00(s,1H),7.79–7.74(m,2H),7.68(s,1H),7.62(dd,J＝5.5,2.4Hz,1H),7.53(t,J＝9.1Hz,1H),7.39(s,1H),6.96(s,1H),6.80(d,J＝15.1Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.20(d,J＝20.5Hz,2H),4.07(s,3H),4.01(s,2H),3.70(t,J＝6.3Hz,2H),3.59–3.50(m,14H),3.34(t,J＝6.3Hz,4H),3.03(d,J＝50.8Hz,4H),2.92-2.88(m,1H),2.64–2.53(m,2H),2.09–2.01(m,1H).HRMS(ESI)C 46H 51ClFN 8O 11S +[M+H] +,计算值977.3065；实测值,977.3061.
实施例26
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecanoyl)piperazin-1-yl)but-2-enamide(SIAIS262008)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1204149)制备得到目标化合物(SIAIS262008).(黄色固体,11.5mg,54％) 1H NMR(500MHz,DMSO)δ11.89(s,1H),11.12(s,1H),10.17(s,1H),9.15(s,1H),8.86(s,1H),7.99(dd,J＝6.8,2.5Hz,1H),7.79–7.74(m,2H),7.69-7.66(m,1H),7.65–7.60(m,1H),7.53(td,J＝9.0,3.2Hz,1H),7.45(s,1H),7.02–6.94(m,1H),6.80(d,J＝15.3Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.21(s,2H),4.07(s,3H),4.00(d,J＝9.4Hz,2H),3.70(t,J＝6.3Hz,2H),3.61–3.51(m,18H),3.33(t,J＝6.3Hz,4H),3.06(d,J＝41.3Hz,4H),2.91-2.86(m,1H),2.62–2.52(m,2H),2.08–1.99(m,1H).HRMS(ESI)C 48H 55ClFN 8O 12S +[M+H] +,计算值1021.3327；实测值,1021.3324.
实施例27
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)but-2-enamide(SIAIS219185)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS219185).(黄色固体,8.1mg,49％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.82–7.77(m,2H),7.74(d,J＝7.5Hz,1H),7.68-7.62(m,1H),7.56(t,J＝7.7Hz,1H),7.44(d,J＝8.1Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.05-7.00(m,1H),6.86(d,J＝15.2Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.56(d,J＝17.5Hz,1H),4.49(d,J＝17.4Hz,1H),4.18(s,3H),4.16–4.12(m,2H),4.08(d,J＝5.9Hz,2H),4.03(d,J＝5.4Hz,2H),3.77–3.53(m,6H),2.94–2.87(m,1H),2.82–2.76(m,1H),2.58-2.52(m,1H),2.21-2.17(m,1H). HRMS(ESI)C 38H 37ClFN 8O 6S +[M+H] +,计算值787.2224；实测值,787.2221.
实施例28
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)propanoyl)piperazin-1-yl)but-2-enamide(SIAIS219186)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171086)制备得到目标化合物(SIAIS219186).(黄色固体,8.5mg,51％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.74-7.68(m,2H),7.69-7.64(m,1H),7.56(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.08–7.00(m,1H),6.84(d,J＝15.2Hz,1H),5.19(dd,J＝13.4,5.1Hz,1H),4.49(d,J＝17.4Hz,1H),4.43(d,J＝17.4Hz,1H),4.18(s,3H),4.02(d,J＝6.8Hz,2H),3.96–3.32(m,8H),3.17(s,2H),2.95-2.90(m,1H),2.83–2.76(m,3H),2.56-2.52(m,1H),2.21-2.18(m,1H).HRMS(ESI)C 39H 39ClFN 8O 6S +[M+H] +,计算值801.2380；实测值,801.2381.
实施例29
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)butanoyl)piperazin-1-yl)but-2-enamide(SIAIS219187)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171089)制备得到目标化合物(SIAIS219187).(黄色固体,9.0mg,53％) 1H NMR(500MHz,MeOD)δ9.29(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.72(d,J＝7.7Hz,1H),7.70–7.64(m,2H),7.55(t,J＝7.7Hz,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.07-7.02(m,1H),6.87(d,J＝15.2Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.4Hz,1H),4.46–4.40(m,1H),4.19(s,3H),4.06(d,J＝7.0Hz,2H),3.72–3.62(m,2H),3.59–3.49(m,2H),3.25–3.08(m,5H),2.94–2.86(m,2H),2.83–2.74(m,1H),2.62–2.50(m,3H),2.21–2.14(m,1H),1.97-1.93(m,2H).HRMS(ESI)C 40H 41ClFN 8O 6S +[M+H] +,计算值815.2537；实测值,815.2535.
实施例30
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentanoyl)piperazin-1-yl)but-2-enamide(SIAIS219188)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS219188).(黄色固体,8.8mg,51％) 1H NMR(500MHz,MeOD)δ9.28(s,1H),8.75(s, 1H),7.94(dd,J＝6.6,2.6Hz,1H),7.68–7.63(m,3H),7.53(t,J＝7.7Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.09-7.03(m,1H),6.85(d,J＝15.2Hz,1H),5.17(dd,J＝13.4,5.1Hz,1H),4.48(d,J＝17.4Hz,1H),4.43(d,J＝17.4Hz,1H),4.18(s,3H),4.02(s,2H),3.15-3.10(m,8H),2.96–2.85(m,1H),2.82–2.76(m,1H),2.57-2.52(m,1H),2.45(t,J＝7.1Hz,2H),2.22–2.15(m,2H),2.04(s,1H),1.77–1.68(m,4H).HRMS(ESI)C 41H 43ClFN 8O 6S +[M+H] +,计算值829.2693；实测值,829.2690.
实施例31
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)but-2-enamide(SIAIS219189)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS219189).(黄色固体,9.1mg,51％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68–7.63(m,3H),7.53(t,J＝7.7Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.09-7.03(m,1H),6.87(d,J＝15.3Hz,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.50–4.44(m,1H),4.42(d,J＝17.3Hz,1H),4.18(s,3H),4.05(d,J＝7.2Hz,2H),3.34-3.30(m,8H),3.09-3.05(m,2H),2.95-2.88(m,1H),2.79-2.74(m,1H),2.57-2.52(m,1H),2.38(t,J＝7.3Hz,2H),2.22–2.14(m,1H),1.66-1.62(m,4H),1.53-1.49(m,2H).HRMS(ESI)C 42H 45ClFN 8O 6S +[M+H] +,计算值843.2850；实测值,843.2852.
实施例32
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)heptanoyl)piperazin-1-yl)but-2-enamide(SIAIS219190)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS171092)制备得到目标化合物(SIAIS219190).(黄色固体,8.9mg,49％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.74(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.67–7.62(m,3H),7.52(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.05(dd,J＝14.9,7.4Hz,1H),6.86(d,J＝15.2Hz,1H),5.17(dd,J＝13.4,5.2Hz,1H),4.49–4.43(m,1H),4.40(d,J＝17.3Hz,1H),4.18(s,3H),4.04(d,J＝7.0Hz,2H),3.31(d,J＝1.6Hz,8H),3.10–3.02(m,2H),2.92-2.88(m,1H),2.82–2.74(m,1H),2.57-2.52(m,1H),2.39(t,J＝7.5Hz,2H),2.22–2.14(m,1H),1.71–1.63(m,2H),1.59-1.55(m,2H),1.49-1.44(m,2H),1.39-1.34(m,2H).HRMS(ESI)C 43H 47ClFN 8O 6S +[M+H] +,计算值857.3006；实测值,857.3003.
实施例33
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS219193)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1213129)制备得到目标化合物(SIAIS219193).(黄色固体,9.1mg,52％) 1H NMR(500MHz,MeOD)δ9.29(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.72(d,J＝7.7Hz,1H),7.70–7.61(m,2H),7.52(dd,J＝10.0,5.3Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.07(dt,J＝14.8,7.2Hz,1H),6.86(d,J＝15.2Hz,1H),5.17(dd,J＝13.1,5.1Hz,1H),4.51(d,J＝17.5Hz,1H),4.47(d,J＝8.0Hz,1H),4.21(d,J＝5.0Hz,2H),4.18(s,3H),4.09–4.05(m,2H),3.74(dd,J＝10.6,4.8Hz,2H),3.35–3.31(m,8H),3.26(dd,J＝13.1,6.9Hz,2H),2.91–2.86(m,1H),2.83–2.76(m,1H),2.58-2.54(m,1H),2.25–2.17(m,1H).HRMS(ESI)C 40H 41ClFN 8O 7S +[M+H] +,计算值831.2486；实测值,831.2482.
实施例34
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS262001)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1213131)制备得到目标化合物(SIAIS262001).(黄色固体,9.2mg,50％) 1H NMR(500MHz,DMSO)δ11.50(s,1H),10.99(s,1H),10.15(s,1H),9.13(s,1H),8.85(s,1H),8.00(d,J＝6.8Hz,1H),7.69(d,J＝7.7Hz,2H),7.59–7.51(m,3H),7.39(s,1H),7.00–6.92(m,1H),6.80(d,J＝15.4Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.37(d,J＝17.4Hz,1H),4.24(d,J＝17.5Hz,1H),4.20(d,J＝9.9Hz,2H),4.07(s,3H),4.01(s,2H),3.63(t,J＝6.4Hz,2H),3.52(d,J＝34.2Hz,8H),3.26(t,J＝6.1Hz,2H),3.17–2.92(m,4H),2.93-2.88(m,1H),2.65–2.58(m,1H),2.47-2.43(m,1H),2.05–1.99(m,1H).HRMS(ESI)C 42H 45ClFN 8O 8S +[M+H] +,计算值875.2748；实测值,875.2744.
实施例35
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetyl)piperazin-1-yl)but-2-enamide(SIAIS262002)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1213133)制备得到目标化合物(SIAIS262002).(黄色固体,10.2mg,53％) 1H NMR(500MHz,DMSO)δ10.99(s,1H),10.15(s,1H),9.13(s,1H),8.85(s,1H),8.00(dd,J＝6.8,2.5Hz,1H),7.71–7.65(m,2H),7.59–7.51(m,3H),7.41(s,1H),7.03–6.93(m,1H),6.80(d,J＝15.4Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.25–4.21(m,1H),4.21(s,2H),4.07(s,3H),4.02–3.95(m,2H),3.61 (d,J＝6.3Hz,2H),3.57–3.52(m,8H),3.25(t,J＝6.0Hz,2H),3.05(s,4H),2.95–2.88(m,1H),2.60(t,J＝15.9Hz,1H),2.48–2.42(m,1H),2.05-1.98(m,1H).HRMS(ESI)C 44H 49ClFN 8O 9S +[M+H] +,计算值919.3010；实测值,919.3012.
实施例36
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecan-1-oyl)piperazin-1-yl)but-2-enamide(SIAIS262003)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1213135)制备得到目标化合物(SIAIS262003).(黄色固体,10.3mg,51％) 1H NMR(500MHz,DMSO)δ11.54(s,1H),10.99(s,1H),10.15(s,1H),9.13(s,1H),8.84(s,1H),8.00(d,J＝7.0Hz,1H),7.70–7.67(m,2H),7.56(ddd,J＝18.6,5.8,2.8Hz,3H),6.96(dd,J＝15.1,7.0Hz,1H),6.80(d,J＝15.3Hz,1H),5.15–5.11(m,1H),4.37(d,J＝12.5Hz,1H),4.23(d,J＝13.4Hz,1H),4.19(d,J＝14.0Hz,2H),4.07(s,3H),4.01(s,2H),3.63–3.61(m,2H),3.54–3.51(m,8H),3.26–3.25(m,2H),3.08(s,4H),2.93-2.88(m,1H),2.59(d,J＝16.1Hz,1H),2.45-2.41(m,1H),2.02–2.00(m,1H).HRMS(ESI)C 46H 53ClFN 8O 10S +[M+H] +,计算值963.3272；实测值,963.3270.
实施例37
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(17-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecan-1-oyl)piperazin-1-yl)but-2-enamide(SIAIS262004)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS1213137)制备得到目标化合物(SIAIS262004).(黄色固体,11.2mg,53％) 1H NMR(500MHz,DMSO)δ11.25(s,1H),10.99(s,1H),10.18(s,1H),9.16(s,1H),8.87(s,1H),8.02–7.96(m,1H),7.70–7.66(m,2H),7.55(tdd,J＝12.9,7.0,3.5Hz,3H),7.45(d,J＝2.0Hz,1H),6.99(dt,J＝14.4,7.1Hz,1H),6.80(d,J＝15.3Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.37(dd,J＝17.4,4.1Hz,1H),4.26–4.22(m,1H),4.23–4.16(m,2H),4.08(d,J＝1.9Hz,3H),4.01(t,J＝5.5Hz,2H),3.73–3.69(m,1H),3.69–3.64(m,1H),3.64-3.60(m,2H),3.58–3.52(m,10H),3.28–3.24(m,2H),3.23–2.95(m,4H),2.91(ddd,J＝13.6,11.1,5.5Hz,1H),2.65–2.56(m,1H),2.44(d,J＝13.1Hz,1H),2.03-1.98(m,1H).HRMS(ESI)C 48H 57ClFN 8O 11S +[M+H] +,计算值1007.3535；实测值,1007.3533.
实施例38
(2S,4R)-1-((S)-2-(3-(2-(3-(4-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (SIAIS249045)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS151002)制备得到目标化合物(SIAIS249045).(白色固体,11.1mg,49％) 1H NMR(500MHz,MeOD)δ9.84(s,1H),9.27(s,1H),8.76(s,1H),7.92(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.53(dt,J＝16.8,6.5Hz,5H),7.37(dd,J＝15.8,6.9Hz,2H),7.08(dd,J＝14.9,7.4Hz,1H),6.89(d,J＝15.2Hz,1H),4.65(s,1H),4.61–4.55(m,2H),4.51(d,J＝12.2Hz,2H),4.43(s,1H),4.18(s,3H),4.12(d,J＝7.1Hz,2H),3.90(d,J＝11.1Hz,1H),3.83–3.72(m,7H),3.62(t,J＝9.1Hz,7H),2.62–2.51(m,8H),2.26-2.22(m,1H),2.09-2.05(m,1H),1.34-1.29(m,2H),1.04(s,9H).HRMS(ESI)C 53H 65ClFN 10O 9S +[M+H] +,计算值1071.4324；实测值,1071.4321.
实施例39
(2S,4R)-1-((S)-2-(4-(4-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249041)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS074011)制备得到目标化合物(SIAIS249041).(白色固体,10.2mg,49％) 1H NMR(500MHz,MeOD)δ9.83(s,1H),9.27(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.68–7.63(m,1H),7.54(dt,J＝8.2,3.5Hz,5H),7.38(d,J＝8.9Hz,1H),7.12–7.05(m,1H),6.90(d,J＝15.0Hz,1H),4.62–4.48(m,6H),4.39(dd,J＝15.8,6.1Hz,2H),4.19(s,3H),4.12(d,J＝6.9Hz,2H),3.89(d,J＝11.0Hz,1H),3.80(dd,J＝10.9,3.7Hz,1H),3.69–3.55(m,3H),2.78–2.48(m,10H),2.29–2.20(m,2H),2.12–1.97(m,2H),1.03(s,9H).HRMS(ESI)C 49H 57ClFN 10O 7S +[M+H] +,计算值983.3799；实测值,983.3795.
实施例40
(2S,4R)-1-((S)-2-(6-(4-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249042)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS074013)制备得到目标化合物(SIAIS249042).(白色固体,10.8mg,51％) 1H NMR(500MHz,MeOD)δ9.61(s,1H),9.27(s,1H),8.76(s,1H),7.92(dd,J＝6.6,2.6Hz,1H),7.65(ddd,J＝8.8,4.1,2.6Hz,1H),7.56–7.48(m,4H),7.38(t,J＝8.9Hz,1H),7.34(s,1H),7.07(dd,J＝14.9,7.4Hz,1H),6.89(d,J＝15.3Hz,1H),4.63(s,1H),4.57(dd,J＝14.8,6.0Hz,2H),4.51(d,J＝12.2Hz,2H),4.41(d,J＝15.7Hz,1H),4.19(s,3H),4.10(d,J＝7.2Hz,2H),3.91(d,J＝11.0Hz,1H),3.80(dd,J＝10.9,3.8Hz,1H),3.75–3.48(m,3H),2.56(s,3H),2.48(d,J＝3.1Hz,2H),2.36-2.31(m,2H),2.25-2.20(m,1H),2.09-2.05(m,1H),1.69–1.62(m,4H),1.04(s,9H).HRMS(ESI)C 51H 61ClFN 10O 7S +[M+H] +,计 算值1011.4112；实测值,1011.4110.
实施例41
(2S,4R)-1-((S)-2-(8-(4-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249043)的制备
参照实施例1的方法，采用达克替尼衍生物A和中间体LM(SIAIS074015)制备得到目标化合物(SIAIS249043).(白色固体,10.8mg,49％) 1H NMR(500MHz,MeOD)δ9.86(s,1H),9.27(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.66(ddd,J＝8.9,4.1,2.7Hz,1H),7.54(dd,J＝23.3,8.2Hz,4H),7.39(d,J＝8.9Hz,1H),7.35(d,J＝6.7Hz,1H),7.10-7.06(m,1H),6.89(d,J＝15.2Hz,1H),4.64(s,1H),4.59–4.48(m,3H),4.41(d,J＝15.7Hz,1H),4.19(s,3H),4.11(d,J＝7.1Hz,2H),3.91(d,J＝11.0Hz,1H),3.82-3.78(m,1H),2.59(s,3H),2.46(t,J＝7.5Hz,2H),2.33–2.20(m,3H),2.09-2.05(m,1H),1.66–1.57(m,4H),1.03(s,9H).HRMS(ESI)C 53H 65ClFN 10O 7S +[M+H] +,计算值1039.4425；实测值,1039.4423.
实施例42
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262032)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151141B)制备得到目标化合物(SIAIS262032).(黄色固体,8.1mg,48％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.5,2.5Hz,1H),7.76–7.69(m,2H),7.67–7.63(m,1H),7.63–7.57(m,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.05(dd,J＝14.8,7.3Hz,1H),6.87(d,J＝15.2Hz,1H),5.13(dd,J＝12.7,5.4Hz,1H),4.18(s,3H),4.07(d,J＝6.4Hz,2H),3.92(s,2H),3.77(d,J＝12.3Hz,2H),3.60(s,2H),3.41-3.36(m,5H),3.22(s,2H),3.15(t,J＝7.1Hz,2H),2.87(t,J＝8.7Hz,1H),2.80–2.68(m,2H),2.55–2.42(m,4H),2.22(d,J＝10.3Hz,2H),2.18–2.10(m,1H),1.85–1.76(m,2H),1.74–1.64(m,2H),1.58(d,J＝6.9Hz,2H).HRMS(ESI)C 47H 52ClFN 9O 7S +[M+H] +,计算值940.3377；实测值,940.3374.
实施例43
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)heptanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262033)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151142B)制备得到目标化合 物(SIAIS262033).(黄色固体,8.4mg,49％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.74–7.68(m,2H),7.68–7.64(m,1H),7.60(dd,J＝6.8,1.0Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.10–7.02(m,1H),6.87(d,J＝15.1Hz,1H),5.16–5.12(m,1H),4.18(d,J＝6.0Hz,3H),4.08(d,J＝6.4Hz,2H),3.92(s,2H),3.77(d,J＝11.9Hz,2H),3.61(s,2H),3.45-3.42(m,5H),3.22(s,2H),3.13(t,J＝7.1Hz,2H),2.90-2.86(m,1H),2.76-2.72(m,2H),2.52–2.42(m,4H),2.22(d,J＝12.3Hz,2H),2.18–2.11(m,1H),1.81–1.73(m,2H),1.66-1.62(m,2H),1.58-1.53(m,2H),1.47-1.42(m,2H).HRMS(ESI)C 48H 54ClFN 9O 7S +[M+H] +,计算值954.3534；实测值,954.3532.
实施例44
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262034)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS262034).(黄色固体,6.5mg,42％) 1H NMR(500MHz,MeOD)δ9.28(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.83(d,J＝7.7Hz,1H),7.76(d,J＝7.5Hz,1H),7.70–7.63(m,1H),7.58(t,J＝7.7Hz,1H),7.38(t,J＝8.9Hz,1H),7.32(s,1H),7.07(dt,J＝14.6,7.1Hz,1H),6.88(d,J＝15.3Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.57(d,J＝17.6Hz,1H),4.50(d,J＝11.6Hz,1H),4.18(s,3H),4.12–3.98(m,4H),3.78(d,J＝11.7Hz,2H),3.58(s,2H),3.38(d,J＝65.5Hz,5H),3.20(d,J＝27.5Hz,4H),2.93–2.87(m,1H),2.82-2.78(m,1H),2.59-2,54(m,1H),2.42(s,1H),2.21-2.18(m,4H).HRMS(ESI)C 43H 46ClFN 9O 6S +[M+H] +,计算值870.2959；实测值,870.2955.
实施例45
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262035)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS262035).(黄色固体,8.3mg,50％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.69–7.63(m,3H),7.54(t,J＝7.6Hz,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.11–7.01(m,1H),6.88(d,J＝15.1Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.3Hz,1H),4.42(d,J＝17.4Hz,1H),4.19(s,3H),4.09(s,2H),3.79(d,J＝10.9Hz,2H),3.63(d,J＝12.1Hz,2H),3.50–3.32(m,5H),3.27–3.21(m,2H),3.20–3.01(m,4H),2.94-2.90(m,1H),2.84–2.77(m,1H),2.62–2.54(m,1H),2.50(d,J＝10.6Hz,2H),2.39(t,J＝7.2Hz,2H), 2.30–2.15(m,3H),1.69-1.65(m,2H),1.65–1.58(m,2H),1.56–1.47(m,2H).HRMS(ESI)C 47H 54ClFN 9O 6S +[M+H] +,计算值926.3585；实测值,926.3581.
实施例46
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262036)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151025)制备得到目标化合物(SIAIS262036).(黄色固体,7.4mg,47％) 1H NMR(500MHz,MeOD)δ9.25(s,1H),8.74(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.68–7.63(m,1H),7.55–7.49(m,1H),7.37(t,J＝8.9Hz,1H),7.29(s,1H),7.09(dd,J＝18.4,7.4Hz,2H),6.99(d,J＝8.5Hz,1H),6.88(d,J＝15.1Hz,1H),5.08(dd,J＝12.7,5.5Hz,1H),4.26(s,2H),4.18(s,3H),4.10(s,2H),3.81(d,J＝11.7Hz,2H),3.68(s,1H),3.39-3.36(m,8H),3.26(d,J＝12.3Hz,2H),2.88(m,1H),2.75-2.70(m,2H),2.54-2.51(s,2H),2.30(s,2H),2.17–2.07(m,1H).HRMS(ESI)C 43H 45ClFN 10O 7 +[M+H] +,计算值867.3140；实测值,867.3141.
实施例47
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262037)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151086)制备得到目标化合物(SIAIS262037).(黄色固体,9.1mg,54％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(d,J＝2.4Hz,1H),7.96–7.90(m,1H),7.68–7.61(m,1H),7.56(dd,J＝10.9,4.7Hz,1H),7.38(dd,J＝10.1,7.7Hz,1H),7.32(d,J＝2.1Hz,1H),7.05(t,J＝7.4Hz,3H),6.88(d,J＝15.6Hz,1H),5.09–5.05(m,1H),4.18(d,J＝2.1Hz,3H),4.09(s,2H),3.79(d,J＝10.9Hz,2H),3.65(s,2H),3.35(d,J＝5.0Hz,9H),3.24(s,2H),2.85(dd,J＝13.3,4.7Hz,1H),2.73(t,J＝13.9Hz,2H),2.49-2.44(m,4H),2.24(s,2H),2.17–2.07(m,1H),1.68-1.65(m,4H),1.46(s,4H).HRMS(ESI)C 48H 55ClFN 10O 7 +[M+H] +,计算值937.3922；实测值,937.3920.
实施例48
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262052)的制备
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS172147)制备得到目标化合物 (SIAIS262052).(黄色固体,8.6mg,55％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(d,J＝2.4Hz,1H),7.96–7.90(m,1H),7.68–7.61(m,1H),7.56(dd,J＝10.9,4.7Hz,1H),7.38(dd,J＝10.1,7.7Hz,1H),7.32(d,J＝2.1Hz,1H),7.05(t,J＝7.4Hz,3H),6.88(d,J＝15.6Hz,1H),5.09–5.05(m,1H),4.18(d,J＝2.1Hz,3H),4.09(s,2H),3.79(d,J＝10.9Hz,2H),3.65(s,2H),3.35(d,J＝5.0Hz,9H),3.24(s,2H),2.85(dd,J＝13.3,4.7Hz,1H),2.73(t,J＝13.9Hz,2H),2.49-2.44(m,4H),2.24(s,2H),2.17–2.07(m,1H),1.68-1.65(m,4H),1.46(s,4H).HRMS(ESI)C 44H 48ClFN 9O 6 +[M+H] +,计算值852.3395；实测值,852.3391.
实施例49
4-((2-(3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249029)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151001)制备得到目标化合物(SIAIS249029).(黄色固体,9.7mg,52％) 1H NMR(500MHz,MeOD)δ8.72(s,1H),7.98(s,1H),7.57–7.51(m,3H),7.21(s,1H),7.06(d,J＝8.6Hz,1H),6.94(d,J＝7.1Hz,1H),4.99(dd,J＝12.6,5.5Hz,1H),4.06(s,3H),3.86-3.81(m,2H),3.75-3.70(m,2H),3.59–3.39(m,5H),2.90–2.55(m,6H),2.15–2.00(m,4H),1.84-1.78(m,2H).HRMS(ESI)C 38H 37Cl 2FN 7O 8 +[M+H] +,计算值808.2059；实测值,808.2059.
实施例50
4-((2-(2-(3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249030)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151004)制备得到目标化合物(SIAIS249030).(黄色固体,9.5mg,48％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),7.95(d,J＝6.9Hz,1H),7.59–7.52(m,2H),7.47–7.42(m,1H),7.22(d,J＝2.0Hz,1H),7.00(t,J＝8.5Hz,1H),6.91(d,J＝7.1Hz,1H),5.03(dd,J＝8.3,4.3Hz,1H),4.07(d,J＝2.1Hz,3H),3.99(d,J＝8.6Hz,1H),3.93–3.86(m,1H),3.78(t,J＝5.8Hz,2H),3.71(t,J＝5.3Hz,2H),3.67–3.63(m,4H),3.57–3.43(m,5H),2.88–2.58(m,6H),2.18–2.02(m,4H).HRMS(ESI)C 40H 41Cl 2FN 7O 9 +[M+H] +,计算值852.2321；实测值,852.2317.
实施例51
4-((2-(2-(2-(3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249031)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151005)制备得到目标化合物(SIAIS249031).(黄色固体,11.0mg,53％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),7.98(d,J＝3.5Hz,1H),7.55(q,J＝9.0Hz,2H),7.48(t,J＝7.8Hz,1H),7.24(s,1H),7.02(dd,J＝8.6,3.9Hz,1H),6.96(d,J＝7.1Hz,1H),5.04(dd,J＝12.8,5.3Hz,1H),4.09(d,J＝6.5Hz,3H),3.97–3.85(m,2H),3.76(t,J＝5.4Hz,2H),3.71(t,J＝5.2Hz,2H),3.65(s,1H),3.62–3.54(m,4H),3.46(dd,J＝8.1,5.0Hz,2H),2.90–2.80(m,1H),2.77–2.62(m,5H),2.18–2.03(m,4H),1.94(s,1H),1.81(d,J＝8.9Hz,1H).HRMS(ESI)C 42H 45Cl 2FN 7O 10 +[M+H] +,计算值896.2584；实测值,896.2581.
实施例52
4-((15-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249032)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151006)制备得到目标化合物(SIAIS249032).(黄色固体,11.2mg,52％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.00(d,J＝3.8Hz,1H),7.58–7.54(m,2H),7.54–7.47(m,1H),7.25(s,1H),7.07–7.02(m,1H),7.03–6.96(m,1H),5.03(dd,J＝12.7,5.4Hz,1H),4.09(s,3H),3.97–3.87(m,2H),3.76(t,J＝6.2Hz,2H),3.71(t,J＝5.0Hz,2H),3.62–3.56(m,15H),3.46(t,J＝4.1Hz,2H),2.90–2.80(m,1H),2.78–2.66(m,4H),2.19–2.05(m,3H),1.94(s,1H),1.83(d,J＝8.8Hz,1H).HRMS(ESI)C 44H 49Cl 2FN 7O 11 +[M+H] +,计算值940.2846；实测值,940.2841.
实施例53
4-((18-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-18-oxo-3,6,9,12,15-pentaoxaoctadecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249033)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151007)制备得到目标化合物(SIAIS249033).(黄色固体,11.4mg,50％) 1H NMR(500MHz,MeOD)δ8.69(s,1H),7.98(d,J＝11.8Hz,1H),7.59–7.53(m,2H),7.49(dd,J＝15.6,8.2Hz,1H),7.24(d,J＝4.0Hz,1H),7.04–6.95(m,2H),5.03(dd,J＝12.9,5.4,Hz,1H),4.08(s,3H),3.89(d,J＝4.1Hz,2H),3.76(t,J＝6.2Hz,2H),3.71(t,J＝5.1Hz,2H),3.69–3.48(m,19H),3.47-3.42(m,2H),2.91–2.80(m,1H),2.77–2.66(m,4H),2.19–2.06(m,3H),1.97(d,J＝19.9Hz,1H),1.84(s,1H).HRMS(ESI)C 46H 53Cl 2FN 7O 12 +[M+H] +,计算值984.3108；实测值,984.3102.
实施例54
4-((2-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) -2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS219177)的制备参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151025)制备得到目标化合物(SIAIS219177).(黄色固体,8.6mg,50％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.05(s,1H),7.63(t,J＝8.7Hz,2H),7.58–7.50(m,3H),7.28(s,1H),5.15(dd,J＝13.2,4.6Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.09(s,3H),3.95–3.79(m,2H),3.54(d,J＝9.3Hz,2H),3.36(s,1H),3.11–3.04(m,2H),2.94–2.84(m,1H),2.77(dd,J＝15.4,2.2Hz,1H),2.58–2.46(m,1H),2.42(t,J＝7.6Hz,2H),2.18(dt,J＝12.8,6.5Hz,1H),2.14–2.02(m,2H),1.93–1.79(m,2H),1.68(dt,J＝14.7,7.2Hz,2H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.42-1.38(m,2H).HRMS(ESI)C 35H 31Cl 2FN 7O 7 +[M+H] +,计算值750.1641；实测值,750.1638.
实施例55
4-((4-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-4-oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS219179)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151019)制备得到目标化合物(SIAIS219179).(黄色固体,9.2mg,51％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.05(s,1H),7.63(t,J＝8.7Hz,2H),7.58–7.50(m,3H),7.28(s,1H),5.15(dd,J＝13.2,4.6Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.09(s,3H),3.95–3.79(m,2H),3.54(d,J＝9.3Hz,2H),3.36(s,1H),3.11–3.04(m,2H),2.94–2.84(m,1H),2.77(dd,J＝15.4,2.2Hz,1H),2.58–2.46(m,1H),2.42(t,J＝7.6Hz,2H),2.18(dt,J＝12.8,6.5Hz,1H),2.14–2.02(m,2H),1.93–1.79(m,2H),1.68(dt,J＝14.7,7.2Hz,2H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.42-1.38(m,2H).HRMS(ESI)C 37H 35Cl 2FN 7O 7 +[M+H] +,计算值778.1954；实测值,778.1950.
实施例56
4-((5-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-5-oxopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS219180)的制备参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151020)制备得到目标化合物(SIAIS219180).(黄色固体,9.7mg,53％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.05(s,1H),7.63(t,J＝8.7Hz,2H),7.58–7.50(m,3H),7.28(s,1H),5.15(dd,J＝13.2,4.6Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.09(s,3H),3.95–3.79(m,2H),3.54(d,J＝9.3Hz,2H),3.36(s,1H),3.11–3.04(m,2H),2.94–2.84(m,1H),2.77(dd,J＝15.4,2.2Hz,1H),2.58–2.46(m,1H),2.42(t,J＝7.6Hz,2H),2.18(dt,J＝12.8,6.5Hz,1H),2.14–2.02(m,2H),1.93–1.79(m,2H),1.68(dt,J＝14.7,7.2Hz,2H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.42-1.38(m,2H).HRMS(ESI)C 38H 37Cl 2FN 7O 7 +[M+H] +,计算值792.2110；实测值,792.2113.
实施例57
4-((6-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS219181)的制备参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151027)制备得到目标化合物(SIAIS219181).(黄色固体,9.3mg,50％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.05(s,1H),7.63(t,J＝8.7Hz,2H),7.58–7.50(m,3H),7.28(s,1H),5.15(dd,J＝13.2,4.6Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.09(s,3H),3.95–3.79(m,2H),3.54(d,J＝9.3Hz,2H),3.36(s,1H),3.11–3.04(m,2H),2.94–2.84(m,1H),2.77(dd,J＝15.4,2.2Hz,1H),2.58–2.46(m,1H),2.42(t,J＝7.6Hz,2H),2.18(dt,J＝12.8,6.5Hz,1H),2.14–2.02(m,2H),1.93–1.79(m,2H),1.68(dt,J＝14.7,7.2Hz,2H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.42-1.38(m,2H).HRMS(ESI)C 39H 39Cl 2FN 7O 7 +[M+H] +,计算值806.2267；实测值,806.2262.
实施例58
4-((2-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-oxoethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249014)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151045)制备得到目标化合物(SIAIS249014).(黄色固体,6.7mg,38％) 1H NMR(500MHz,MeOD)δ8.69(s,1H),8.06(s,1H),7.87(d,J＝8.1Hz,1H),7.75(t,J＝7.7Hz,1H),7.67(d,J＝7.3Hz,1H),7.58–7.52(m,2H),7.29(s,1H),5.13(dd,J＝12.7,5.5Hz,1H),4.20(s,2H),4.10(s,3H),4.00–3.87(m,2H),3.73–3.60(m,2H),3.33(s,1H),2.89-2.85(m,1H),2.78–2.69(m,2H),2.29–2.20(m,1H),2.17–1.99(m,3H),1.88-1.83(m,1H).HRMS(ESI)C 35H 30Cl 2FN 6O 7S +[M+H] +,计算值767.1252；实测值,767.1250.
实施例59
4-((3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249015)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151138B)制备得到目标化合物(SIAIS249015).(黄色固体,6.9mg,38％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.05(s,1H),7.76(d,J＝6.0Hz,2H),7.66–7.61(m,1H),7.58-7.52(m,2H),7.28(s,1H),5.12(dd,J＝9.0,3.7Hz,1H),4.09(s,3H),3.94–3.87(m,1H),3.82(d,J＝3.8Hz,1H),3.66–3.59(m,1H),3.59–3.50(m,1H),3.43(t,J＝7.0Hz,2H),3.33(s,1H),2.91(t,J＝6.9Hz,2H),2.89–2.81(m,1H),2.76-2.72(m,2H),2.16–2.05(m,3H),1.92–1.82(m,2H).HRMS(ESI)C 36H 32Cl 2FN 6O 7S +[M+H] +,计算值781.1409；实测值,781.1405.
实施例60
4-((4-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) -4-oxobutyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249016)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151139B)制备得到目标化合物(SIAIS249016).(黄色固体,5.7mg,31％) 1H NMR(500MHz,MeOD)δ8.71(d,J＝1.9Hz,1H),8.03(d,J＝2.8Hz,1H),7.83(d,J＝8.2Hz,1H),7.75(t,J＝7.7Hz,1H),7.60(t,J＝7.5Hz,1H),7.56–7.52(m,2H),7.29(s,1H),5.11(dd,J＝8.7,3.9Hz,1H),5.08(dd,J＝8.8,4.0Hz,1H),4.10(s,3H),3.94(d,J＝12.9Hz,1H),3.83(s,1H),3.58-3.54(m,2H),3.28–3.15(m,2H),2.92–2.82(m,1H),2.80–2.61(m,4H),2.19–2.01(m,5H),1.84(s,2H).HRMS(ESI)C 37H 34Cl 2FN 6O 7S +[M+H] +,计算值795.1565；实测值,795.1561.
实施例61
4-((5-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-5-oxopentyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249017)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151140B)制备得到目标化合物(SIAIS249017).(黄色固体,8.5mg,46％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.04(s,1H),7.76–7.71(m,2H),7.60(dd,J＝6.0,1.8Hz,1H),7.58–7.51(m,2H),7.28(s,1H),5.10(dd,J＝12.6,5.5Hz,1H),4.10(s,3H),3.95–3.83(m,2H),3.63–3.53(m,2H),3.33(s,1H),3.18(t,J＝6.5Hz,2H),2.92–2.79(m,1H),2.78–2.64(m,2H),2.53(t,J＝6.8Hz,2H),2.22–2.02(m,4H),1.92(d,J＝17.1Hz,1H),1.85–1.82(m,4H).HRMS(ESI)C 38H 36Cl 2FN 6O 7S +[M+H] +,计算值809.1722；实测值,809.1720.
实施例62
4-((6-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249018)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151141B)制备得到目标化合物(SIAIS249018).(黄色固体,6.5mg,34％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.03(s,1H),7.75–7.69(m,2H),7.59(d,J＝6.6Hz,1H),7.58–7.53(m,2H),7.28(s,1H),5.12–5.08(m,1H),4.10(s,3H),3.95–3.83(m,2H),3.61–3.52(m,2H),3.29–3.25(m,1H),3.15(t,J＝7.2Hz,2H),2.87–2.82(m,1H),2.77–2.69(m,2H),2.48(t,J＝7.4Hz,2H),2.18–2.00(m,4H),1.92(d,J＝18.2Hz,1H),1.83–1.79(m,2H),1.71-1.67(m,2H),1.62–1.57(m,2H).HRMS(ESI)C 39H 38Cl 2FN 6O 7S +[M+H] +,计算值823.1878；实测值,823.1870.
实施例63
4-((7-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-7-oxoheptyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS249019)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151142B)制备得到目标化合物(SIAIS249019).(黄色固体,9.0mg,47％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.03(s,1H),7.75–7.68(m,3H),7.58(d,J＝7.3Hz,1H),7.55(s,1H),7.28(s,1H),5.12–5.09(m,1H),4.09(s,3H),3.92-3.88(m,2H),3.60–3.53(m,2H),3.15-3.11(m,3H),2.91–2.80(m,2H),2.75–2.68(m,2H),2.48-2.44(m,2H),2.30(t,J＝7.4Hz,1H),2.18–2.03(m,4H),1.91(s,1H),1.79–1.75(m,2H),1.68-1.63(m,2H),1.59–1.55(m,2H),1.47-1.43(m,2H).HRMS(ESI)C 40H 40Cl 2FN 6O 7S +[M+H] +,计算值837.2035；实测值,837.2031.
实施例64
3-(4-((2-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-oxoethyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219164)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS219164).(黄色固体,8.4mg,48％) 1H NMR(500MHz,MeOD)δ8.69(s,1H),8.02(d,J＝2.3Hz,1H),7.80(dd,J＝7.7,2.1Hz,1H),7.74(d,J＝7.5Hz,1H),7.55(q,J＝8.9Hz,3H),7.27(s,1H),5.20–5.15(m,1H),4.57(dd,J＝17.5,2.7Hz,1H),4.50(dd,J＝17.3,3.7Hz,1H),4.10(s,3H),4.00(t,J＝9.9Hz,2H),3.85-3.81(m,2H),3.62–3.51(m,2H),3.35(s,1H),2.97–2.87(m,1H),2.78(d,J＝17.5Hz,1H),2.55-2.51(m,1H),2.23–2.16(m,1H),2.06(s,2H),1.88-1.84(m,2H).HRMS(ESI)C 35H 32Cl 2FN 6O 6S +[M+H] +,计算值753.1460；实测值,753.1455.
实施例65
3-(4-((3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219165)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171086)制备得到目标化合物(SIAIS219165).(黄色固体,9.4mg,53％) 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.01(d,J＝3.1Hz,1H),7.75–7.70(m,1H),7.68(d,J＝7.5Hz,1H),7.58–7.53(m,3H),7.27(s,1H),5.17(dd,J＝13.2,5.0Hz,1H),4.49(d,J＝16.9Hz,1H),4.44(d,J＝16.8Hz,1H),4.09(s,3H),3.88(s,1H),3.78-3.75(m,1H),3.57-3.53(m,1H),3.46(d,J＝10.0Hz,1H),3.40–3.33(m,3H),2.94–2.86(m,1H),2.81-2.76(m,3H),2.60–2.47(m,1H),2.23–2.15(m,1H),2.05(s,2H),1.83(s,2H).HRMS(ESI)C 36H 34Cl 2FN 6O 6S +[M+H] +,计算值767.1616；实测值,767.1611.
实施例66
3-(4-((4-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-4-oxobutyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219166)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171089)制备得到目标化合 物(SIAIS219166).(黄色固体,9.7mg,54％) 1H NMR(500MHz,MeOD)δ8.71(d,J＝2.4Hz,1H),7.99(d,J＝4.3Hz,1H),7.71(d,J＝8.3Hz,1H),7.69–7.63(m,1H),7.60–7.53(m,3H),7.27(d,J＝3.4Hz,1H),5.13(dd,J＝14.7,5.1Hz,1H),4.48(d,J＝12.8Hz,1H),4.42(d,J＝12.8Hz,1H),4.10(d,J＝1.6Hz,3H),3.88(s,1H),3.73(t,J＝20.2Hz,1H),3.58–3.41(m,2H),3.18-3.15(m,3H),2.95–2.84(m,1H),2.81–2.74(m,1H),2.64–2.50(m,3H),2.19-2.15(m,1H),2.05–1.94(m,4H),1.81(s,2H).HRMS(ESI)C 37H 36Cl 2FN 6O 6S +[M+H] +,计算值781.1773；实测值,781.1770.
实施例67
3-(4-((5-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-5-oxopentyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219167)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS219167).(黄色固体,9.2mg,50％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.01(d,J＝6.7Hz,1H),7.65(dd,J＝14.9,6.9Hz,2H),7.58-7.54(m,3H),7.28(s,1H),5.14(dd,J＝13.4,5.1Hz,1H),4.48(d,J＝17.3Hz,1H),4.41(d,J＝17.3Hz,1H),4.10(s,3H),3.92–3.76(m,2H),3.59–3.47(m,2H),3.34(s,1H),3.19–3.04(m,2H),2.94–2.82(m,1H),2.81-2.77(m,1H),2.57–2.42(m,3H),2.22–2.14(m,1H),2.08–1.72(m,8H).HRMS(ESI)C 38H 38Cl 2FN 6O 6S +[M+H] +,计算值795.1929；实测值,795.1925.
实施例68
3-(4-((6-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219168)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS219168).(黄色固体,10.1mg,54％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.04(s,1H),7.68–7.62(m,2H),7.59–7.50(m,3H),7.28(s,1H),5.18–5.11(m,1H),4.47(d,J＝17.3Hz,1H),4.41(d,J＝17.4Hz,1H),4.09(s,3H),3.87-3.81(m,2H),3.53-3.50(m,2H),3.33(s,1H),3.12–3.04(m,2H),2.93–2.83(m,1H),2.79-2.75(m,1H),2.55-2.50(m,1H),2.41(t,J＝7.3Hz,2H),2.23–2.14(m,1H),2.07(s,2H),1.87-1.81(m,2H),1.69-1.65(m,4H),1.55-1.49(m,2H).HRMS(ESI)C 39H 40Cl 2FN 6O 6S +[M+H] +,计算值809.2086；实测值,809.2084.
实施例69
3-(4-((7-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-7-oxoheptyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS219169)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS171092)制备得到目标化合 物(SIAIS219169).(黄色固体,9.8mg,52％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.05(s,1H),7.63(t,J＝8.7Hz,2H),7.58–7.50(m,3H),7.28(s,1H),5.15(dd,J＝13.2,4.6Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.09(s,3H),3.95–3.79(m,2H),3.54(d,J＝9.3Hz,2H),3.36(s,1H),3.11–3.04(m,2H),2.94–2.84(m,1H),2.77(dd,J＝15.4,2.2Hz,1H),2.58–2.46(m,1H),2.42(t,J＝7.6Hz,2H),2.18(dt,J＝12.8,6.5Hz,1H),2.14–2.02(m,2H),1.93–1.79(m,2H),1.68(dt,J＝14.7,7.2Hz,2H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.42-1.38(m,2H).HRMS(ESI)C 40H 41Cl 2FN 6O 6S +[M+H] +,计算值823.2242；实测值,823.2238.
实施例70
(2S,4R)-1-((S)-2-(2-(2-(2-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-oxoethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249024)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151010)制备得到目标化合物(SIAIS249024).(白色固体,11.2mg,48％) 1H NMR(500MHz,MeOD)δ9.65(s,1H),8.70(s,1H),8.16(d,J＝18.4Hz,1H),7.56–7.48(m,6H),7.29(d,J＝4.3Hz,1H),4.96(s,1H),4.69(s,1H),4.56(dd,J＝19.5,11.0Hz,2H),4.49(s,2H),4.44–4.35(m,3H),4.23–4.05(m,6H),3.94–3.74(m,8H),3.57(d,J＝7.5Hz,2H),2.59–2.56(m,1H),2.55(s,3H),2.28–2.16(m,2H),2.13–2.02(m,2H),1.89-1.84(m,2H),1.03(s,9H).HRMS(ESI)C 48H 56Cl 2FN 8O 9S +[M+H] +,计算值1009.3247；实测值,1009.3243.
实施例71
(2S,4R)-1-((S)-2-(3-(2-(3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropoxy)ethoxy)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249025)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151002)制备得到目标化合物(SIAIS249025).(白色固体,12.1mg,51％) 1H NMR(500MHz,MeOD)δ9.50(s,1H),8.70(s,1H),8.14(d,J＝3.5Hz,1H),7.55–7.46(m,6H),7.30(s,1H),4.96(d,J＝3.3Hz,1H),4.64(s,1H),4.56(dd,J＝18.3,11.0Hz,3H),4.49(s,1H),4.38(d,J＝15.7Hz,1H),4.09(s,3H),3.92(dd,J＝33.3,9.7Hz,3H),3.78-3.73(m,6H),3.65–3.50(m,8H),2.73(dd,J＝13.3,6.6Hz,2H),2.61–2.49(m,6H),2.24-2.18(m,2H),2.15–2.03(m,2H),1.97–1.77(m,2H),1.03(s,9H).HRMS(ESI)C 50H 60Cl 2FN 8O 9S +[M+H] +,计算值1037.3560；实测值,1037.3555.
实施例72
(2S,4R)-1-((S)-2-(tert-butyl)-16-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-4,16-dioxo-7,10,13-trioxa-3-azahexadecan-1-oyl)-4-hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249026)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151003)制备得到目标化合物(SIAIS249026).(白色固体,12.4mg,50％) 1H NMR(500MHz,MeOD)δ9.47(s,1H),8.71(s,1H),8.14(s,1H),7.55–7.46(m,6H),7.30(s,1H),4.95(s,1H),4.64(s,1H),4.60–4.51(m,3H),4.49(s,1H),4.38(d,J＝15.7Hz,1H),4.09(s,3H),3.96(d,J＝3.9Hz,1H),3.89(d,J＝10.9Hz,2H),3.82–3.70(m,6H),3.67–3.57(m,12H),2.77–2.69(m,2H),2.61–2.48(m,6H),2.25–2.15(m,2H),2.14–2.05(m,2H),1.91-1.86(m,2H),1.03(s,9H).HRMS(ESI)C 52H 64Cl 2FN 8O 10S +[M+H] +,计算值1081.3822；实测值,1081.3820.
实施例73
(2S,4R)-1-((S)-2-(tert-butyl)-19-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249027)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151008)制备得到目标化合物(SIAIS249027).(白色固体,12.1mg,47％) 1H NMR(500MHz,MeOD)δ9.53(s,1H),8.71(s,1H),8.15(s,1H),7.55–7.46(m,6H),7.31(s,1H),4.99–4.93(m,1H),4.64(s,1H),4.60–4.52(m,2H),4.49(s,1H),4.38(d,J＝15.7Hz,1H),4.09(s,3H),3.98(s,1H),3.88(d,J＝10.7Hz,2H),3.82–3.70(m,6H),3.62(d,J＝6.3Hz,16H),2.78–2.65(m,2H),2.62–2.53(m,5H),2.51-2.45(m,1H),2.28–2.15(m,2H),2.15–2.05(m,2H),1.98–1.78(m,2H),1.03(s,9H).HRMS(ESI)C 54H 68Cl 2FN 8O 11S +[M+H] +,计算值1125.4084；实测值,1125.4081.
实施例74
(2S,4R)-1-((S)-2-(tert-butyl)-22-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-4,22-dioxo-7,10,13,16,19-pentaoxa-3-azadocosan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249028)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS151009)制备得到目标化合物(SIAIS249028).(白色固体,13.1mg,49％) 1H NMR(500MHz,MeOD)δ9.23(s,1H),8.71(s,1H),8.16(s,1H),7.57–7.43(m,6H),7.31(s,1H),5.00–4.94(m,1H),4.64(s,1H),4.61–4.47(m,4H),4.37(d,J＝15.6Hz,1H),4.10(d,J＝9.6Hz,3H),4.01-3.95(m,1H),3.88(d,J＝11.0Hz,2H),3.83–3.70(m,6H),3.66–3.56(m,22H),2.75-2.69(m,2H),2.61–2.54(m,1H),2.52–2.45(m,5H),2.24-2.16(m,2H),2.09-2.04(m,2H),1.96-1.90(m,1H),1.84-1.79(m,1H).HRMS(ESI)C 56H 72Cl 2FN 8O 12S +[M+H] +,计算值1169.4346；实测值,1169.4341.
实施例75
(2S,4R)-1-((S)-2-(4-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) piperidin-1-yl)-4-oxobutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249020)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS074011)制备得到目标化合物(SIAIS249020).(白色固体,7.7mg,35％) 1H NMR(500MHz,MeOD)δ9.24(d,J＝3.2Hz,1H),8.71(d,J＝2.6Hz,1H),8.05(s,1H),7.58–7.54(m,2H),7.50(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),7.28(s,1H),4.91(s,1H),4.61(d,J＝2.0Hz,1H),4.56(dd,J＝18.6,10.6Hz,2H),4.49(s,1H),4.38(d,J＝15.5Hz,1H),4.09(t,J＝5.2Hz,3H),3.89(d,J＝10.2Hz,3H),3.80(dd,J＝11.0,3.9Hz,1H),3.59(d,J＝9.8Hz,2H),2.79–2.70(m,2H),2.69–2.61(m,1H),2.57(dd,J＝14.1,7.4Hz,1H),2.52(d,J＝8.1Hz,3H),2.26–2.14(m,2H),2.12–2.05(m,2H),1.94(s,1H),1.84(s,1H),1.04(s,9H).HRMS(ESI)C 46H 52Cl 2FN 8O 7S +[M+H] +,计算值949.3035；实测值,949.3032.
实施例76
(2S,4R)-1-((S)-2-(6-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-6-oxohexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249021)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS074013)制备得到目标化合物(SIAIS249021).(白色固体,8.1mg,36％) 1H NMR(500MHz,MeOD)δ9.32(s,1H),8.71(s,1H),8.05(s,1H),7.58–7.53(m,2H),7.50(d,J＝8.4Hz,2H),7.46(dd,J＝10.9,5.8Hz,2H),7.28(s,1H),4.91(s,1H),4.63(d,J＝3.9Hz,1H),4.60–4.52(m,2H),4.49(s,1H),4.37(d,J＝15.6Hz,1H),4.09(s,3H),3.90(d,J＝11.1Hz,3H),3.80(dd,J＝10.9,3.9Hz,1H),3.62–3.53(m,2H),2.53(d,J＝9.0Hz,3H),2.48(d,J＝6.7Hz,2H),2.38-2.32(m,2H),2.23-2.18(m,2H),2.09-2.06(m,2H),1.90(d,J＝51.0Hz,2H),1.69-1.64(m,4H),1.04(s,9H).HRMS(ESI)C 48H 56Cl 2FN 8O 7S +[M+H] +,计算值977.3348；实测值,977.3343.
实施例77
(2S,4R)-1-((S)-2-(8-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-8-oxooctanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249022)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS074015)制备得到目标化合物(SIAIS249022).(白色固体,9.7mg,42％) 1H NMR(500MHz,MeOD)δ9.36(s,1H),8.71(s,1H),8.07(s,1H),7.58–7.53(m,2H),7.53–7.49(m,2H),7.46(t,J＝6.5Hz,2H),7.28(s,1H),4.92(s,1H),4.63(s,1H),4.60–4.47(m,3H),4.38(d,J＝15.6Hz,1H),4.09(s,3H),3.90(q,J＝17.7Hz,3H),3.80(dd,J＝11.0,3.9Hz,1H),3.57(dd,J＝11.1,6.7Hz,2H),2.52(s,3H),2.47–2.42(m,2H),2.34–2.14(m,4H),2.12–2.05(m,2H),1.96–1.80(m,2H),1.69–1.60(m,4H), 1.43–1.35(m,4H),1.03(s,9H).HRMS(ESI)C 50H 60Cl 2FN 8O 7S +[M+H] +,计算值1005.3661；实测值,1005.3656.
实施例78
(2S,4R)-1-((S)-2-(10-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-10-oxodecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249023)的制备
参照实施例1的方法，采用波齐替尼衍生物A和中间体LM(SIAIS074019)制备得到目标化合物(SIAIS249023).(白色固体,10.8mg,45％) 1H NMR(500MHz,MeOD)δ9.31(s,1H),8.71(s,1H),8.08(d,J＝3.8Hz,1H),7.59–7.54(m,2H),7.51(q,J＝5.6Hz,2H),7.46(t,J＝7.0Hz,2H),7.29(s,1H),4.92(dd,J＝6.9,3.5Hz,1H),4.64(s,1H),4.61–4.48(m,3H),4.42–4.35(m,1H),4.10(s,3H),3.95–3.84(m,3H),3.80(dd,J＝10.9,3.8Hz,1H),3.62–3.52(m,2H),2.56–2.52(m,3H),2.49–2.41(m,2H),2.33–2.15(m,4H),2.11-2.07(m,2H),1.94–1.77(m,2H),1.61(d,J＝6.2Hz,4H),1.35(s,8H),1.03(s,9H).HRMS(ESI)C 52H 64Cl 2FN 8O 7S +[M+H] +,计算值1033.3974；实测值,1033.3971.
实施例79
4-((2-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184164)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS151045)制备得到目标化合物(SIAIS184164).(黄色固体,6.9mg,40％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.08(d,J＝3.5Hz,1H),8.00–7.96(m,1H),7.96(s,1H),7.80–7.75(m,1H),7.73(s,1H),7.72–7.67(m,1H),7.38(t,J＝8.9Hz,1H),7.27(s,1H),5.14(dd,J＝12.6,5.6Hz,1H),4.42(d,J＝5.6Hz,2H),4.10(t,J＝3.4Hz,3H),3.74(s,2H),3.50(s,2H),3.29–2.95(m,8H),2.89–2.82(m,1H),2.76-2.71(m,2H),2.45(s,2H),2.15(s,1H).HRMS(ESI)C 37H 36ClFN 7O 7S +[M+H] +,计算值776.2064；实测值,776.2061.
实施例80
4-((4-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-4-oxobutyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184165)的制备参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS151139B)制备得到目标化合物(SIAIS184165).(黄色固体,7.8mg,43％) 1H NMR(500MHz,MeOD)δ8.73(s,1H),8.09(s,1H),7.98(dd,J＝6.6,2.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.77–7.74(m,1H),7.70(ddd,J＝9.0,4.1,2.6Hz,1H),7.62(d,J＝7.0Hz,1H),7.37(t,J＝8.9Hz,1H),7.26(s,1H),5.11(dd,J＝12.6, 5.4Hz,1H),4.42(t,J＝5.6Hz,2H),4.09(s,3H),3.82–3.58(m,2H),3.49(t,J＝7.5Hz,2H),3.30–3.20(m,8H),2.88-2.82(m,1H),2.75–2.64(m,4H),2.49–2.41(m,2H),2.17–2.06(m,3H).HRMS(ESI)C 39H 40ClFN 7O 7S +[M+H] +,计算值804.2377；实测值,804.2374.
实施例81
4-((6-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-6-oxohexyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184166)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS151141B)制备得到目标化合物(SIAIS184166).(黄色固体,9.5mg,51％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.11(s,1H),7.98(dd,J＝6.6,2.6Hz,1H),7.75–7.68(m,3H),7.59(dd,J＝6.7,1.3Hz,1H),7.37(t,J＝8.9Hz,1H),7.26(s,1H),5.11(dd,J＝12.7,5.5Hz,1H),4.43(t,J＝5.5Hz,2H),4.09(s,3H),3.73(d,J＝40.0Hz,2H),3.50(t,J＝7.3Hz,2H),3.31–3.01(m,8H),2.89-2.83(m,1H),2.78–2.67(m,2H),2.48-2.43(m,4H),2.18–2.09(m,1H),1.86–1.78(m,2H),1.77–1.67(m,2H),1.61-1.58(m,2H).HRMS(ESI)C 41H 44ClFN 7O 7S +[M+H] +,计算值832.2690；实测值,832.2687.
实施例82
4-((2-(2-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethoxy)ethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184168)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS1204137)制备得到目标化合物(SIAIS184168).(黄色固体,8.2mg,45％) 1H NMR(500MHz,MeOD)δ8.73(s,1H),8.05(s,1H),8.02-7.97(m,1H),7.71(dd,J＝10.3,3.7Hz,3H),7.57(s,1H),7.39–7.35(m,1H),7.22(s,1H),5.08(dd,J＝12.6,5.4Hz,1H),4.45-4.41(m,4H),4.08(s,3H),3.93–3.90(m,2H),3.56-3.53(m,4H),3.38-3.34(m,8H),2.84–2.75(m,1H),2.69-2.65(m,2H),2.46(s,2H),2.11(d,J＝5.2Hz,1H).HRMS(ESI)C 39H 40ClFN 7O 8S +[M+H] +,计算值820.2326；实测值,820.2321.
实施例83
4-((2-(2-(2-(2-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethoxy)ethyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184169)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS1204141)制备得到目标化合物(SIAIS184169).(黄色固体,9.1mg,45％) 1H NMR(500MHz,MeOD)δ8.71(s,1H),8.01–7.95(m,2H),7.73–7.67(m,2H),7.64(s,1H),7.48(dd,J＝6.0,2.0Hz,1H),7.37(dd,J＝8.9,3.4Hz,1H),7.20(s,1H),5.12–5.08(m,1H),4.41–4.37(m,2H),4.37–4.25(m,2H),4.07(s,3H),3.84(t,J＝6.0Hz,2H),3.72–3.61(m,14H),3.56–3.47(m,4H),3.05(s,1H),2.89-2.83(m,1H), 2.78–2.60(m,3H),2.45(s,2H),2.15–2.08(m,1H).HRMS(ESI)C 43H 48ClFN 7O 10S +[M+H] +,计算值908.2850；实测值,908.2846.
实施例84
4-((17-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-17-oxo-3,6,9,12,15-pentaoxaheptadecyl)thio)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(SIAIS184170)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS1204149)制备得到目标化合物(SIAIS184170).(黄色固体,9.2mg,41％) 1H NMR(500MHz,MeOD)δ8.72(s,1H),8.06(s,1H),7.98(dt,J＝6.0,3.0Hz,1H),7.73–7.70(m,1H),7.68(dd,J＝7.1,4.7Hz,2H),7.56–7.51(m,1H),7.39-7.33(m,1H),7.23(s,1H),5.10(dd,J＝12.7,5.5Hz,1H),4.41(dd,J＝11.5,5.9Hz,2H),4.39–4.27(m,2H),4.08(s,3H),3.80(t,J＝6.1Hz,2H),3.69–3.60(m,18H),3.57–3.41(m,4H),3.37–3.32(m,2H),3.29(s,2H),3.26–3.04(m,2H),2.89-2.83(m,1H),2.79–2.63(m,2H),2.50–2.42(m,2H),2.17–2.09(m,1H).HRMS(ESI)C 47H 56ClFN 7O 12S +[M+H] +,计算值996.3375；实测值,996.3371.
实施例85
3-(4-((2-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-2-oxoethyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS184184)的制备参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS184184).(黄色固体,6.7mg,39％) 1H NMR(500MHz,MeOD)δ8.44(s,1H),8.00(dd,J＝6.7,2.5Hz,1H),7.78(d,J＝7.8Hz,1H),7.75–7.73(m,2H),7.69–7.64(m,1H),7.55(t,J＝7.6Hz,1H),7.26(t,J＝8.9Hz,1H),7.18(s,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.55(d,J＝17.6Hz,1H),4.48(d,J＝17.3Hz,1H),4.25(d,J＝6.0Hz,2H),4.00(s,3H),3.57(d,J＝5.4Hz,2H),3.53(d,J＝3.7Hz,2H),3.35-3.30(m,8H),2.92-2.88(m,1H),2.81–2.76(m,1H),2.58–2.51(m,1H),2.21–2.17(m,1H),2.08(d,J＝7.2Hz,2H).HRMS(ESI)C 37H 38ClFN 7O 6S +[M+H] +,计算值762.2271；实测值,762.2268.
实施例86
3-(4-((4-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-4-oxobutyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS184185)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS171089)制备得到目标化合物(SIAIS184185).(黄色固体,7.2mg,41％) 1H NMR(500MHz,MeOD)δ8.46(s,1H),8.02–7.98(m,1H),7.75(s,1H),7.68(dd,J＝19.3,7.6Hz,3H),7.54(t,J＝7.7Hz,1H),7.27(t,J＝8.9 Hz,1H),7.19(s,1H),5.18–5.14(m,1H),4.48(d,J＝17.3Hz,1H),4.42(d,J＝17.2Hz,1H),4.25(t,J＝5.8Hz,2H),4.01(s,3H),3.69-3.65(m,2H),3.60–3.36(m,8H),3.15–3.10(m,2H),2.89-2.84(m,1H),2.79-2.75(m,1H),2.65(s,2H),2.55(d,J＝7.0Hz,1H),2.19(s,1H),2.11(s,2H),1.95(t,J＝7.1Hz,2H).HRMS(ESI)C 39H 42ClFN 7O 6S +[M+H] +,计算值790.2584；实测值,790.2581.
实施例87
3-(4-((6-(4-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperazin-1-yl)-6-oxohexyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS184186)的制备
参照实施例1的方法，采用吉非替尼衍生物A和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS184186).(黄色固体,8.2mg,45％) 1H NMR(500MHz,MeOD)δ8.45(s,1H),8.00(d,J＝6.7Hz,1H),7.74(s,1H),7.65(dd,J＝19.0,8.2Hz,3H),7.52(t,J＝7.7Hz,1H),7.26(t,J＝8.9Hz,1H),7.18(s,1H),5.17–5.13(m,1H),4.46(d,J＝17.6Hz,1H),4.40(d,J＝17.2Hz,1H),4.24(t,J＝5.9Hz,2H),4.00(s,3H),3.79–3.65(m,2H),3.63–3.33(m,8H),3.07(d,J＝3.5Hz,2H),2.92–2.86(m,1H),2.79-2.75(m,1H),2.60(t,J＝7.3Hz,2H),2.38(d,J＝7.2Hz,1H),2.22–2.08(m,3H),1.71-1.67(m,2H),1.65–1.59(m,2H),1.58–1.49(m,2H).HRMS(ESI)C 41H 46ClFN 7O 6S +[M+H] +,计算值818.2897；实测值,818.2893.
实施例88
3-(4-((2-(4-(1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS262085)的制备
参照实施例1的方法，采用吉非替尼衍生物B和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS262085).(黄色固体,10.1mg,43％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.12(s,1H),7.98(dd,J＝6.6,2.6Hz,1H),7.83(d,J＝7.7Hz,1H),7.78(d,J＝7.5Hz,1H),7.75-7.68(m,1H),7.58(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.26(s,1H),5.18(dd,J＝13.4,5.1Hz,1H),4.57(d,J＝17.5Hz,1H),4.50(dd,J＝14.7,4.1Hz,1H),4.43(t,J＝5.5Hz,2H),4.11(s,3H),3.99-3.91(m,5H),3.58-3.52(m,4H),3.30–3.13(m,8H),2.94–2.87(m,1H),2.81-2.77(m,1H),2.61–2.51(m,1H),2.45(s,3H),2.29–2.14(m,4H).HRMS(ESI)C 42H 47ClFN 8O 6S +[M+H] +,计算值845.3006；实测值,845.3001.
实施例89
3-(4-((5-(4-(1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperidin-4-yl)piperazin-1-yl)-5-oxopentyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS262086)的制备
参照实施例1的方法，采用吉非替尼衍生物B和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS262086).(黄色固体,11.2mg,45％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.11(s,1H),7.98(dd,J＝6.6,2.6Hz,1H),7.75-7.68(m,1H),7.66(t,J＝7.0Hz,2H),7.54(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.26(s,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.3Hz,1H),4.46–4.39(m,3H),4.11(s,3H),3.92(d,J＝12.6Hz,2H),3.60(s,2H),3.45-3.41(m,5H),3.18-3.11(m,8H),2.94-2.89(m,1H),2.81-2.76(m,1H),2.57–2.43(m,7H),2.24-2.18(m,3H),1.79-1.71(m,4H).HRMS(ESI)C 45H 53ClFN 8O 6S +[M+H] +,计算值887.3476；实测值,887.3471.
实施例90
3-(4-((6-(4-(1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperidin-4-yl)piperazin-1-yl)-6-oxohexyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS262087)的制备
参照实施例1的方法，采用吉非替尼衍生物B和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS262087).(黄色固体,11.3mg,45％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.02(s,1H),7.96–7.93(m,1H),7.69–7.64(m,3H),7.54(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.27(s,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.48(d,J＝17.4Hz,1H),4.42(d,J＝14.3Hz,1H),4.39(t,J＝3.9Hz,2H),4.10(s,3H),3.85(d,J＝49.3Hz,6H),3.45(d,J＝7.2Hz,2H),3.30–3.12(m,6H),3.11–3.02(m,2H),2.96–2.86(m,1H),2.82-2.77(m,1H),2.59–2.50(m,1H),2.49–2.36(m,6H),2.22–2.13(m,3H),1.71–1.58(m,4H),1.55-1.51(m,2H).HRMS(ESI)C 46H 55ClFN 8O 6S +[M+H] +,计算值901.3632；实测值,901.3632.
实施例91
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)acetamide(SIAIS184093)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS151045)制备得到目标化合物(SIAIS184093).(白色固体,12.2mg,43％) 1H NMR(500MHz,MeOD)δ9.16(s,1H),8.72(s,1H),7.90(dd,J＝6.6,2.6Hz,1H),7.80(d,J＝7.9Hz,1H),7.75(t,J＝7.6Hz,1H),7.68(d,J＝7.2Hz,1H),7.66–7.60(m,1H),7.36(t,J＝8.9Hz,1H),7.21(s,1H),5.29(s,1H),5.16(dd,J＝12.5,5.5Hz,1H),4.26(s,2H),4.02(qd,J＝10.7,4.1Hz,2H),3.89–3.82(m,2H),2.92–2.85(m,1H),2.79–2.70(m,2H),2.37(dd,J＝14.0,8.0Hz,1H),2.14(dd,J＝13.1,6.1Hz,2H).HRMS(ESI)C 33H 27ClFN 6O 7S +[M+H] +,计算值705.1329；实测值,705.1326.
实施例92
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)butanamide(SIAIS184094)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS151139B)制备得到目标化合物(SIAIS184094).(白色固体,13.6mg,46％) 1H NMR(500MHz,MeOD)δ9.07(s,1H),8.73(s,1H),7.94(dd,J＝6.6,2.4Hz,1H),7.79(d,J＝8.3Hz,1H),7.74(t,J＝7.6Hz,1H),7.68–7.63(m,1H),7.62(d,J＝7.0Hz,1H),7.37(t,J＝8.9Hz,1H),7.22(s,1H),5.32(s,1H),5.08(dd,J＝12.7,5.3Hz,1H),4.18(d,J＝10.3Hz,1H),4.04(dd,J＝13.3,7.3Hz,2H),3.91(dt,J＝13.2,6.6Hz,1H),2.85-2.78(m,3H),2.76–2.66(m,2H),2.48-242(m,1H),2.29(s,1H),2.25–2.17(m,2H),2.10(s,1H).HRMS(ESI)C 35H 31ClFN 6O 7S +[M+H] +,计算值733.1642；实测值,733.1640.
实施例93
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)hexanamide(SIAIS184095)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS151141B)制备得到目标化合物(SIAIS184095).(白色固体,14.1mg,46％) 1H NMR(500MHz,MeOD)δ9.05(s,1H),8.72(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.71–7.67(m,2H),7.67-7.64(m,1H),7.56–7.52(m,1H),7.37(t,J＝8.9Hz,1H),7.23(s,1H),5.33(d,J＝4.6Hz,1H),5.09(dd,J＝12.8,5.4Hz,1H),4.19(d,J＝10.6Hz,1H),4.11–4.02(m,2H),3.94-3.88(m,1H),3.16(t,J＝7.0Hz,2H),2.87-2.83(m,1H),2.77–2.66(m,2H),2.64–2.59(m,2H),2.47-2.43(m,1H),2.33–2.24(m,1H),2.15–2.08(m,1H),1.87–1.82(m,4H),1.69-1.64(m,2H).HRMS(ESI)C 37H 35ClFN 6O 7S +[M+H] +,计算值761.1955；实测值,761.1952.
实施例94
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)acetamide(SIAIS184152)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS1204137)制备得到目标化合物(SIAIS184152).(白色固体,8.8mg,44％) 1H NMR(500MHz,CDCl 3)δ9.34(d,J＝5.8Hz,2H),9.08(s,1H),8.73(d,J＝24.1Hz,1H),8.64(s,1H),7.97(s,1H),7.86(s,1H),7.55(s,3H),7.42(d,J＝10.7Hz,1H),7.21(t,J＝8.4Hz,1H),5.31(s,1H),4.97(s,1H),4.18-4.12(m,2H),4.06(s,2H),3.93–3.74(m,2H),3.29(s,2H),2.85-2.78(m,3H),2.63-2.57(m,1H),2.21-2.15(m,3H),1.47-1.42(m,1H).HRMS(ESI)C 35H 31ClFN 6O 8S +[M+H] +,计算值749.1591；实测值,749.1588.
实施例95
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)acetamide (SIAIS184153)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS1204139)制备得到目标化合物(SIAIS184153).(白色固体,10.5mg,50％) 1H NMR(500MHz,CDCl 3)δ9.33(d,J＝5.8Hz,2H),9.07(s,1H),8.71(d,J＝24.1Hz,1H),8.62(s,1H),7.96(s,1H),7.85(s,1H),7.53(s,3H),7.40(d,J＝10.7Hz,1H),7.20(t,J＝8.4Hz,1H),5.29(s,1H),4.96(s,1H),4.14(d,J＝15.7Hz,2H),4.04(s,2H),3.90–3.72(m,6H),3.28(s,2H),2.83-2.78(m,3H),2.61-2.55(m,1H),2.19-2.14(m,3H),1.45-1.40(m,1H).HRMS(ESI)C 37H 35ClFN 6O 9S +[M+H] +,计算值793.1853；实测值,793.1851.
实施例96
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)ethoxy)ethoxy)ethoxy)acetamide(SIAIS184154)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS1204141)制备得到目标化合物(SIAIS184154).(白色固体,9.9mg,44％) 1H NMR(500MHz,CDCl 3)δ9.78(s,1H),9.41(d,J＝2.7Hz,1H),9.20(s,1H),9.09(s,1H),8.57(s,1H),8.02(s,1H),7.86–7.77(m,1H),7.61–7.49(m,2H),7.46-7.43(m,2H),7.17(dd,J＝14.7,8.5Hz,1H),5.25(s,1H),5.05–4.93(m,1H),4.23(s,2H),4.09(dd,J＝31.1,9.7Hz,2H),3.94–3.74(m,8H),3.69(d,J＝8.8Hz,4H),3.21(s,2H),2.88-2.83(m,1H),2.83–2.72(m,2H),2.54(s,1H),2.17-2.12(m,2H).HRMS(ESI)C 39H 39ClFN 6O 10S +[M+H] +,计算值837.2115；实测值,837.2112.
实施例97
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12-tetraoxatetradecan-1-amide(SIAIS184155)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS1204147)制备得到目标化合物(SIAIS184155).(白色固体,9.8mg,42％) 1H NMR(500MHz,CDCl 3)δ9.66(s,1H),9.41(s,1H),9.23(s,1H),9.09(s,1H),8.59(s,1H),8.05(s,1H),7.83(s,1H),7.57(d,J＝4.7Hz,2H),7.53–7.46(m,2H),7.18(td,J＝8.6,3.9Hz,1H),5.25(s,1H),5.04–4.93(m,1H),4.24(s,2H),4.09(dd,J＝24.2,12.7Hz,2H),3.95–3.76(m,8H),3.71–3.64(m,8H),3.24(s,2H),2.88-2.84(m,1H),2.83–2.71(m,2H),2.53(s,1H),2.19-2.14(m,2H).HRMS(ESI)C 41H 43ClFN 6O 11S +[M+H] +,计算值881.2378；实测值,881.2375.
实施例98
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-17-((2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)thio)-3,6,9,12,15-pentaoxaheptadecan-1-ami de(SIAIS184156)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS1204149)制备得到目标化合物(SIAIS184156).(白色固体,10.2mg,41％) 1H NMR(500MHz,CDCl 3)δ9.66(s,1H),9.41(s,1H),9.33(s,1H),9.13(s,1H),8.59(s,1H),8.02(s,1H),7.82(d,J＝5.2Hz,1H),7.66–7.49(m,4H),7.15(t,J＝8.6Hz,1H),5.26(s,1H),5.05–4.93(m,1H),4.24(s,2H),4.09–4.03(m,2H),3.91–3.72(m,8H),3.70–3.59(m,12H),3.24(d,J＝5.7Hz,2H),2.90–2.78(m,2H),2.54(s,1H),2.18-2.13(m,2H).HRMS(ESI)C 43H 47ClFN 6O 12S +[M+H] +,计算值925.2640；实测值,925.2636.
实施例99
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)propanamide(SIAIS1210085)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS171086)制备得到目标化合物(SIAIS1210085).(黄色固体,9.9mg,53％) 1H NMR(500MHz,MeOD)δ9.02(s,1H),8.70(s,1H),7.91(dd,J＝6.6,2.5Hz,1H),7.67(t,J＝6.7Hz,1H),7.63–7.60(m,2H),7.54–7.50(m,1H),7.33(dd,J＝11.1,6.7Hz,1H),7.23(s,1H),5.35-5.30(m,1H),5.17-5.13(m,1H),4.45(d,J＝17.2Hz,1H),4.41(d,J＝17.2Hz,1H),4.14(dd,J＝10.5,4.0Hz,1H),4.05-4.01(m,2H),3.91-3.88(m,1H),3.18(t,J＝7.2Hz,2H),2.95–2.83(m,2H),2.77–2.74(m,2H),2.51–2.46(m,2H),2.29–2.21(m,1H),2.17-2.12(m,1H).HRMS(ESI)C 34H 31ClFN 6O 6S +[M+H] +,计算值705.1693；实测值,705.1691.
实施例100
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)butanamide(SIAIS1210087)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS171089)制备得到目标化合物(SIAIS1210087).(黄色固体,10.3mg,54％) 1H NMR(500MHz,MeOD)δ9.04(s,1H),8.71(s,1H),7.93(dd,J＝6.6,2.5Hz,1H),7.69(t,J＝6.7Hz,1H),7.65–7.62(m,2H),7.56–7.50(m,1H),7.35(dd,J＝11.1,6.7Hz,1H),7.24(s,1H),5.36-5.31(m,1H),5.18-5.14(m,1H),4.46(d,J＝17.2Hz,1H),4.42(d,J＝17.2Hz,1H),4.16(dd,J＝10.5,4.0Hz,1H),4.06-4.01(m,2H),3.93-3.90(m,1H),3.20(t,J＝7.2Hz,2H),2.96–2.84(m,2H),2.78–2.75(m,2H),2.52–2.47(m,2H),2.30–2.22(m,1H),2.19-2.14(m,1H),2.13–2.07(m,2H).HRMS(ESI)C 35H 33ClFN 6O 6S +[M+H] +,计算值719.1849；实测值,719.1846.
实施例101
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanamide(SIAIS1210089)的制备
参照实施例1的方法，采用阿法替尼衍生物A和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS1210089).(黄色固体,11.1mg,56％) 1H NMR(500MHz,MeOD)δ8.95(d,J＝8.6Hz,1H),8.68(s,1H),7.95(dd,J＝6.6,2.6Hz,1H),7.67–7.62(m,2H),7.58(dd,J＝6.8,5.4Hz,1H),7.48(dd,J＝10.0,4.5Hz,1H),7.34(dd,J＝9.2,8.6Hz,1H),7.22(d,J＝1.0Hz,1H),5.31(d,J＝4.6Hz,1H),5.16(dd,J＝9.5,3.9Hz,1H),4.46–4.41(m,1H),4.38(d,J＝17.3Hz,1H),4.17(t,J＝10.6Hz,1H),4.08–4.00(m,2H),3.92-3.88(m,1H),3.09(dt,J＝7.0,4.5Hz,2H),2.91-2.87(m,1H),2.79–2.73(m,1H),2.57–2.53(m,2H),2.51-2.46(m,2H),2.27-2.23(m,1H),2.21–2.11(m,1H),1.80–1.70(m,4H),1.62-1.57(m,2H).HRMS(ESI)C 37H 37ClFN 6O 6S +[M+H] +,计算值747.2162；实测值,747.2161.
实施例102
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262050)的制备
根据方案9，将达克替尼衍生物B(20mg,0.036mmol)溶于2mL DMF中，依次加入SIAIS255121(17.5mg,0.0432mmol)、NaI(10.8mg,0.072mmol)和K 2CO 3(10mg,0.072mmol)，加热到50℃，反应过夜。加入0.10mL水淬灭反应，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，减压蒸去乙腈大部分水，冻干后得到最终目标化合物(SIAIS262050)(黄色固体,12.1mg,39％) 1H NMR(500MHz,MeOD)δ9.26(s,1H),8.74(s,1H),7.91(dd,J＝6.6,2.6Hz,1H),7.74(d,J＝7.4Hz,1H),7.67–7.62(m,2H),7.50(t,J＝7.6Hz,1H),7.36(t,J＝8.9Hz,1H),7.32(s,1H),7.11–7.02(m,1H),6.86(d,J＝15.5Hz,1H),5.20(dd,J＝13.2,5.2Hz,1H),4.57(d,J＝17.6Hz,1H),4.51(d,J＝17.6Hz,1H),4.19(s,3H),4.06(s,2H),3.72(s,5H),3.60–3.37(m,8H),3.16(d,J＝13.9Hz,2H),2.97–2.88(m,1H),2.77(d,J＝15.6Hz,1H),2.63-2.58(m,3H),2.38(s,2H),2.24–2.16(m,1H),2.11–1.99(m,2H),1.77–1.71(m,2H).HRMS(ESI)C 46H 50ClFN 9O 5 +[M+H] +,计算值862.3602；实测值,862.3601.
实施例103
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262051)的制备
参照实施例102的方法，采用达克替尼衍生物B和中间体LM(SIAIS255119)制备得到目标化合 物(SIAIS262051).(黄色固体,12.8mg,41％) 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.75(d,J＝7.4Hz,1H),7.68–7.62(m,2H),7.51(t,J＝7.6Hz,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.10–7.02(m,1H),6.87(d,J＝15.5Hz,1H),5.21(dd,J＝13.2,5.2Hz,1H),4.58(d,J＝17.6Hz,1H),4.52(d,J＝17.6Hz,1H),4.19(s,3H),4.08(s,2H),3.74(s,5H),3.61–3.37(m,8H),3.18(d,J＝13.9Hz,2H),2.98–2.88(m,1H),2.79(d,J＝15.6Hz,1H),2.63-2.59(m,3H),2.39(s,2H),2.25–2.16(m,1H),2.12–1.99(m,4H),1.79–1.71(m,2H).HRMS(ESI)C 47H 52ClFN 9O 5 +[M+H] +,计算值876.3758；实测值,876.3755.
实施例104
3-(4-(5-(4-(1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS262089)的制备
参照实施例102的方法，采用吉非替尼衍生物B和中间体LM(SIAIS255121)制备得到目标化合物(SIAIS262089).(黄色固体,13.1mg,41％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.12(s,1H),7.98(s,1H),7.77(d,J＝8.0Hz,1H),7.70(s,1H),7.65(d,J＝7.2Hz,1H),7.53(d,J＝7.5Hz,1H),7.37(t,J＝8.5Hz,1H),7.26(s,1H),5.20(d,J＝7.1Hz,1H),4.56(s,1H),4.51(d,J＝17.5Hz,1H),4.42(s,2H),4.10(s,3H),3.83(d,J＝11.2Hz,2H),3.75–3.32(m,13H),3.15(d,J＝12.9Hz,2H),2.93(s,1H),2.81-2.77(m,1H),2.68(s,2H),2.55(s,1H),2.44(s,2H),2.28(s,2H),2.18-2.13(m,3H),2.02(s,2H).HRMS(ESI)C 45H 51ClFN 8O 5 +[M+H] +,计算值837.3649；实测值,837.3644.
实施例105
3-(4-(6-(4-(1-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(SIAIS262090)的制备
参照实施例102的方法，采用吉非替尼衍生物B和中间体LM(SIAIS255119)制备得到目标化合物(SIAIS262090).(黄色固体,13.1mg,41％) 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.11(s,1H),7.97(dd,J＝6.6,2.6Hz,1H),7.76(d,J＝7.9Hz,1H),7.71(dd,J＝7.9,3.7Hz,1H),7.64(d,J＝6.9Hz,1H),7.51(t,J＝7.7Hz,1H),7.37(t,J＝8.9Hz,1H),7.26(s,1H),5.20(dd,J＝13.3,5.2Hz,1H),4.56(d,J＝17.4Hz,1H),4.50(d,J＝17.4Hz,1H),4.42(t,J＝5.7Hz,2H),4.10(s,3H),3.85(d,J＝11.7Hz,2H),3.55–3.40(m,5H),3.28–3.04(m,8H),2.95-2.90(m,1H),2.79(d,J＝15.6Hz,1H),2.64–2.51(m,3H),2.43(s,2H),2.29(d,J＝7.1Hz,2H),2.20(s,1H),1.99(s,4H),1.75(d,J＝7.7Hz,2H),1.60(s,2H).HRMS(ESI)C 46H 53ClFN 8O 5 +[M+H] +,计算值851.3806；实测值,851.3802.
实施例106
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262065)的制备
参照实施例102的方法，采用达克替尼衍生物B和中间体LM(SIAIS1216133)制备得到目标化合物(SIAIS262065)(黄色固体,11.2mg,收率45％)。 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.76(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.66(dt,J＝8.7,4.3Hz,3H),7.54(t,J＝7.7Hz,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.06(dt,J＝14.7,7.2Hz,1H),6.88(d,J＝15.4Hz,1H),5.18(dd,J＝13.4,5.2Hz,1H),4.47(d,J＝17.3Hz,1H),4.45–4.39(m,1H),4.18(d,J＝5.9Hz,3H),4.08(d,J＝6.0Hz,2H),3.76(s,2H),3.75–3.35(m,8H),3.18(s,4H),3.08(dq,J＝13.2,6.3Hz,3H),2.97–2.88(m,1H),2.80(ddd,J＝17.7,4.6,2.4Hz,1H),2.60–2.51(m,1H),2.43(s,2H),2.23–2.07(m,3H),1.79–1.66(m,4H),1.57–1.51(m,2H),1.42(dd,J＝14.7,7.3Hz,2H).HRMS(ESI)m/z:计算值C 47H 56ClFN 9O 5S +[M+H] +,912.3792；实测值,912.3790.
实施例107
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262072)的制备
参照实施例102的方法，采用达克替尼衍生物B和中间体LM(SIAIS264018)制备得到目标化合物(SIAIS262072)(黄色固体,10.8mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.27(s,1H),8.75(s,1H),7.92(dd,J＝6.6,2.6Hz,1H),7.67-7.63(m,1H),7.58–7.54(m,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.05(q,J＝8.3Hz,3H),6.87(d,J＝15.1Hz,1H),5.07(dd,J＝12.6,5.7Hz,1H),4.18(s,3H),4.07(s,2H),3.74(s,4H),3.39(dd,J＝26.0,19.4Hz,5H),3.19(s,4H),2.85(dd,J＝13.0,4.4Hz,1H),2.78–2.69(m,2H),2.38(s,2H),2.13–2.03(m,3H),1.80(s,2H),1.71(dd,J＝14.0,6.7Hz,2H),1.49(d,J＝9.3Hz,4H).HRMS(ESI)m/z:计算值C 47H 55ClFN 10O 6 +[M+H] +,909.3973；实测值,909.3971.
实施例108
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262121)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS262121)(黄色固体,6.8mg,收率40％)。 1H NMR(500MHz,MeOD)δ9.14(s,1H),8.75(s,1H),7.95(dd,J＝6.6,2.5Hz,1H),7.83(d,J＝7.7Hz,1H),7.76(d,J＝7.6Hz,1H),7.68–7.63(m,1H),7.58(t,J＝7.6Hz,1H),7.39–7.33(m,2H),6.79(dd,J＝17.0,10.3Hz,1H),6.51(d,J＝16.9Hz,1H),5.90(d,J＝11.0Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.55(s,1H),4.48(dd,J＝ 14.6,8.9Hz,4H),4.02(d,J＝17.2Hz,2H),3.60(s,4H),3.45(s,4H),2.93–2.88(m,1H),2.78(s,1H),2.58–2.51(m,1H),2.46(s,2H),2.19(d,J＝7.7Hz,1H).HRMS(ESI)m/z:计算值C 39H 39ClFN 8O 6S +[M+H] +,801.2380；实测值,801.2381.
实施例109
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentanoyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262122)的制备参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS262122)(黄色固体,7.1mg,收率40％)。 1H NMR(500MHz,MeOD)δ9.11(s,1H),8.74(s,1H),7.95(dd,J＝6.6,2.6Hz,1H),7.69–7.64(m,3H),7.53(d,J＝7.6Hz,1H),7.37(t,J＝8.9Hz,1H),7.34(s,1H),6.75(dd,J＝16.9,10.3Hz,1H),6.51(dd,J＝16.9,1.5Hz,1H),5.90(dd,J＝10.2,1.5Hz,1H),5.15(dd,J＝13.4,5.1Hz,1H),4.48(dd,J＝11.5,5.8Hz,3H),4.41(d,J＝17.3Hz,1H),3.64(s,4H),3.45(s,2H),3.23–2.97(m,6H),2.93–2.86(m,1H),2.79(dd,J＝10.0,7.6Hz,1H),2.54(dd,J＝13.1,4.8Hz,1H),2.46(t,J＝7.1Hz,4H),2.21–2.16(m,1H),1.74(dd,J＝23.6,6.9Hz,4H).HRMS(ESI)m/z:计算值C 42H 45ClFN 8O 6S +[M+H] +,843.2850；实测值,843.2853.
实施例110
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-
4-yl)thio)hexanoyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262123)的制备参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS262123)(黄色固体,8.2mg,收率46％)。 1H NMR(500MHz,MeOD)δ9.14(s,1H),8.75(s,1H),7.95(dd,J＝6.6,2.6Hz,1H),7.69–7.63(m,3H),7.54(t,J＝7.6Hz,1H),7.38(t,J＝8.9Hz,1H),7.35(s,1H),6.78(dd,J＝17.0,10.2Hz,1H),6.51(d,J＝16.8Hz,1H),5.91(d,J＝10.4Hz,1H),5.18–5.13(m,1H),4.47(dd,J＝11.2,5.3Hz,3H),4.42(d,J＝17.3Hz,1H),3.63(d,J＝30.6Hz,4H),3.46(s,2H),3.09(ddd,J＝22.7,18.4,16.1Hz,6H),2.95–2.85(m,1H),2.78(d,J＝15.2Hz,1H),2.55(dd,J＝13.2,4.7Hz,1H),2.50(d,J＝9.4Hz,2H),2.40(t,J＝7.2Hz,2H),2.19(d,J＝7.9Hz,1H),1.68(dd,J＝14.5,7.1Hz,2H),1.61(dd,J＝14.6,7.4Hz,2H),1.52(d,J＝7.3Hz,2H).HRMS(ESI)m/z:计算值C 43H 47ClFN 8O 6S +[M+H] +,857.3006；实测值,857.3002.
实施例111
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262124)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS151025)制备得到目标化合 物(SIAIS262124)(黄色固体,7.3mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.10(s,1H),8.73(s,1H),7.95(dd,J＝6.5,2.5Hz,1H),7.68–7.63(m,1H),7.57(d,J＝8.5Hz,1H),7.39–7.33(m,2H),7.11(d,J＝7.0Hz,1H),7.03(d,J＝8.4Hz,1H),6.76(dd,J＝17.0,10.3Hz,1H),6.51(dd,J＝16.9,1.5Hz,1H),5.91(dd,J＝10.3,1.5Hz,1H),5.10–5.06(m,1H),4.48(t,J＝5.8Hz,2H),4.29(s,2H),3.62(d,J＝21.2Hz,4H),3.47(d,J＝18.1Hz,4H),3.17(s,2H),2.84(dd,J＝13.0,7.8Hz,1H),2.74(dd,J＝18.5,5.6Hz,3H),2.50–2.47(m,1H),2.13(d,J＝5.1Hz,1H).HRMS(ESI)m/z:计算值C 39H 38ClFN 9O 7 +[M+H] +,798.2561；实测值,798.2564.
实施例112
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262125)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS151027)制备得到目标化合物(SIAIS262125)(黄色固体,7.9mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.08(s,1H),8.73(s,1H),7.95(d,J＝3.9Hz,1H),7.65(s,1H),7.55(d,J＝8.2Hz,1H),7.37(t,J＝8.9Hz,1H),7.33(s,1H),7.08–7.02(m,2H),6.72(dd,J＝16.9,10.7Hz,1H),6.51(d,J＝16.9Hz,1H),5.90(d,J＝10.6Hz,1H),5.05(d,J＝11.9Hz,1H),4.46(s,2H),4.28–4.08(m,2H),3.58(s,4H),3.45(s,4H),3.14–3.02(m,2H),2.84(d,J＝13.8Hz,1H),2.72–2.68(m,2H),2.48(d,J＝6.9Hz,4H),2.11(s,1H),1.70(s,4H),1.50(s,2H).HRMS(ESI)m/z:计算值C 43H 46ClFN 9O 7 +[M+H] +,854.3187；实测值,854.3182.
实施例113
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262126)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS151086)制备得到目标化合物(SIAIS262126)(黄色固体,7.6mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.12(s,1H),8.74(s,1H),7.95(dd,J＝6.6,2.4Hz,1H),7.68–7.63(m,1H),7.59–7.53(m,1H),7.37(t,J＝8.8Hz,1H),7.34(s,1H),7.05(t,J＝8.0Hz,2H),6.75(dd,J＝16.9,10.2Hz,1H),6.51(d,J＝17.7Hz,1H),5.91(d,J＝10.5Hz,1H),5.07–5.03(m,1H),4.47(t,J＝5.5Hz,2H),3.60(s,4H),3.45(s,4H),3.17(s,4H),2.85(d,J＝13.4Hz,1H),2.72(t,J＝13.1Hz,2H),2.52–2.42(m,4H),2.13–2.08(m,1H),1.73–1.62(m,4H),1.46(s,4H).HRMS(ESI)m/z:计算值C 44H 48ClFN 9O 7 +[M+H] +,868.3344；实测值,868.3341.
实施例114
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262127)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS151004)制备得到目标化合物(SIAIS262127)(黄色固体,8.5mg,收率45％)。 1H NMR(500MHz,MeOD)δ9.06(s,1H),8.70(s,1H),7.95(dd,J＝6.7,2.6Hz,1H),7.67(dd,J＝7.2,4.5Hz,1H),7.48–7.43(m,1H),7.38(t,J＝8.9Hz,1H),7.27(s,1H),7.00(d,J＝8.5Hz,1H),6.91(d,J＝7.2Hz,1H),6.73(dd,J＝16.9,10.3Hz,1H),6.55–6.48(m,1H),5.93–5.89(m,1H),5.06(dd,J＝12.8,5.5Hz,3H),4.38(s,2H),3.81–3.56(m,12H),3.44(d,J＝11.5Hz,8H),2.89–2.81(m,2H),2.75(d,J＝7.4Hz,2H),2.67(d,J＝13.4Hz,1H),2.44(s,2H),2.11(s,1H).HRMS(ESI)m/z:计算值C 44H 48ClFN 9O 9 +[M+H] +,900.3242；实测值,900.3241.
实施例115
(2S,4R)-1-((S)-2-(5-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-5-oxopentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS262128)的制备
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS074012)制备得到目标化合物(SIAIS262128)(黄色固体,10.3mg,收率48％)。 1H NMR(500MHz,MeOD)δ9.40(d,J＝10.0Hz,1H),9.17(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.51(t,J＝7.7Hz,2H),7.46(d,J＝8.3Hz,2H),7.39–7.35(m,2H),6.85(dd,J＝16.9,10.3Hz,1H),6.51(dd,J＝16.9,1.5Hz,1H),5.90(dd,J＝10.3,1.5Hz,1H),4.58(dd,J＝13.6,5.6Hz,2H),4.50(dd,J＝12.6,7.2Hz,4H),4.41–4.36(m,1H),4.22(s,1H),3.91(d,J＝11.0Hz,1H),3.81(dd,J＝11.0,3.8Hz,1H),3.66(d,J＝35.5Hz,3H),3.51(s,2H),3.18(d,J＝12.4Hz,2H),2.55–2.49(m,5H),2.46(t,J＝7.5Hz,2H),2.29-2.23(m,3H),2.11–2.05(m,1H),1.66–1.59(m,4H),1.41–1.35(m,4H),1.04(s,9H).HRMS(ESI)m/z:计算值C 51H 61ClFN 10O 7S +[M+H] +,1011.4112；实测值,1011.4114.
实施例116
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-1-yl)hex-5-yn-1-yl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262131)的制备
参照实施例102的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS255119)制备得到目标化合物(SIAIS262131)(黄色固体,9.4mg,收率38％)。 1H NMR(500MHz,MeOD)δ9.18(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.76(d,J＝7.1Hz,1H),7.68–7.62(m,2H),7.51(t,J＝ 7.6Hz,1H),7.38(t,J＝8.9Hz,1H),7.35(s,1H),6.81(dd,J＝16.8,10.4Hz,1H),6.51(dd,J＝16.9,1.5Hz,1H),5.90(dd,J＝10.2,1.5Hz,1H),5.21(dd,J＝13.3,5.2Hz,1H),4.56(s,1H),4.52(d,J＝12.1Hz,1H),4.49(d,J＝5.9Hz,2H),3.75(s,4H),3.65–3.38(m,8H),2.95–2.87(m,1H),2.80(dd,J＝15.3,12.9Hz,1H),2.63(t,J＝6.7Hz,2H),2.60–2.53(m,1H),2.46(s,2H),2.22–2.15(m,1H),2.03(d,J＝7.9Hz,2H),1.76(dd,J＝14.7,7.3Hz,2H).HRMS(ESI)m/z:计算值C 43H 45ClFN 8O 5 +[M+H] +,807.3180；实测值,807.3177.
实施例117
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262182)的制备
参照实施例102的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS264018)制备得到目标化合物(SIAIS262182)(黄色固体,12.1mg,收率46％)。 1H NMR(500MHz,DMSO)δ11.09(s,1H),9.94(s,1H),9.16(s,1H),8.87(s,1H),7.99(d,J＝5.9Hz,1H),7.68(dd,J＝7.5,4.2Hz,1H),7.59(dd,J＝8.4,7.2Hz,1H),7.54(t,J＝9.0Hz,1H),7.43(s,1H),7.11(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.94(s,1H),6.55(s,1H),6.37(d,J＝16.9Hz,1H),5.86(d,J＝11.1Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),4.38(s,2H),3.73(d,J＝47.0Hz,6H),3.22(d,J＝102.4Hz,10H),2.89-2.83(m,1H),2.64–2.52(m,2H),2.36(s,2H),2.07–1.98(m,1H),1.72(s,2H),1.67–1.56(m,2H),1.38(s,4H).HRMS(ESI)m/z:计算值C 43H 48ClFN 9O 6 +[M+H] +,840.3395；实测值,840.3392.
实施例118
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262174)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS262174)(黄色固体,6.8mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.69–7.64(m,2H),7.53(t,J＝7.6Hz,1H),7.34(dd,J＝11.7,6.0Hz,2H),6.85-6.82(m,1H),6.50(d,J＝16.9Hz,1H),5.91(d,J＝10.3Hz,1H),5.16(dd,J＝13.4,5.1Hz,1H),4.46(dd,J＝11.5,5.9Hz,3H),4.41(d,J＝17.3Hz,1H),3.87(d,J＝12.0Hz,2H),3.66(s,2H),3.56–3.43(m,4H),3.25(t,J＝12.5Hz,4H),3.17–3.06(m,3H),2.95–2.85(m,1H),2.76(d,J＝15.5Hz,1H),2.60–2.44(m,7H),2.26(d,J＝12.5Hz,2H),2.21–2.16(m,1H).HRMS(ESI)m/z:计算值C 44H 48ClFN 9O 6S +[M+H] +,884.3115；实测值,884.3119.
实施例119
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoli n-4-yl)thio)pentanoyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262175)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS262175)(黄色固体,7.1mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.18(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69–7.65(m,2H),7.54(t,J＝7.6Hz,1H),7.37(dd,J＝11.7,6.0Hz,2H),6.85(dd,J＝16.8,10.3Hz,1H),6.51(d,J＝16.9Hz,1H),5.91(d,J＝10.3Hz,1H),5.17(dd,J＝13.4,5.1Hz,1H),4.48(dd,J＝11.5,5.9Hz,3H),4.42(d,J＝17.3Hz,1H),3.87(d,J＝12.0Hz,2H),3.68(s,2H),3.56–3.40(m,4H),3.24(t,J＝12.5Hz,4H),3.17–3.04(m,3H),2.97–2.87(m,1H),2.79(d,J＝15.5Hz,1H),2.60–2.44(m,7H),2.28(d,J＝12.5Hz,2H),2.22–2.16(m,1H),1.83–1.68(m,4H),1.45–1.32(m,2H).HRMS(ESI)m/z:计算值C 47H 54ClFN 9O 6S +[M+H] +,926.3585；实测值,926.3583.
实施例120
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanoyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262176)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS262176)(黄色固体,7.5mg,收率45％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.67(dd,J＝7.7,2.9Hz,2H),7.54(t,J＝7.6Hz,1H),7.38(t,J＝8.9Hz,1H),7.34(s,1H),6.82(dd,J＝16.9,10.3Hz,1H),6.52(dd,J＝16.9,1.4Hz,1H),5.95–5.88(m,1H),5.18(dd,J＝13.1,5.0Hz,1H),4.48(dd,J＝11.5,6.0Hz,3H),4.42(d,J＝17.3Hz,1H),3.86(d,J＝11.1Hz,2H),3.44(dd,J＝33.3,26.1Hz,8H),3.30–3.14(m,4H),3.08(ddd,J＝19.6,13.2,6.3Hz,3H),2.91(dd,J＝21.7,9.2Hz,1H),2.79(d,J＝15.7Hz,1H),2.60–2.44(m,5H),2.39(t,J＝7.0Hz,2H),2.19(dd,J＝15.9,10.9Hz,3H),1.67(dd,J＝15.0,7.2Hz,2H),1.61(dd,J＝14.8,7.3Hz,2H),1.56–1.49(m,2H).HRMS(ESI)m/z:计算值C 48H 56ClFN 9O 6S +[M+H] +,940.3741；实测值,940.3739.
实施例121
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262177)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS151025)制备得到目标化合物(SIAIS262177)(黄色固体,6.4mg,收率41％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.75(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69–7.63(m,1H),7.62–7.54(m,1H),7.38(t,J＝8.9Hz,1H), 7.34(s,1H),7.11(d,J＝7.1Hz,1H),7.03(d,J＝8.5Hz,1H),6.81(dd,J＝16.9,10.3Hz,1H),6.52(d,J＝16.9Hz,1H),5.91(d,J＝11.6Hz,1H),5.08(dd,J＝12.6,5.5Hz,1H),4.49(t,J＝5.5Hz,2H),4.29(s,2H),3.88(d,J＝10.5Hz,2H),3.62-3.58(m,8H),3.29–2.95(m,5H),2.86(dd,J＝13.5,5.7Hz,1H),2.80–2.68(m,2H),2.51(s,4H),2.25(s,2H),2.16–2.09(m,1H).HRMS(ESI)m/z:计算值C 44H 47ClFN 10O 7 +[M+H] +,881.3296；实测值,881.3296.
实施例122
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262178)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS151027)制备得到目标化合物(SIAIS262178)(黄色固体,7.8mg,收率47％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69–7.62(m,1H),7.59–7.54(m,1H),7.38(t,J＝8.9Hz,1H),7.35(s,1H),7.06(t,J＝7.7Hz,1H),6.83(dd,J＝16.8,10.4Hz,1H),6.52(d,J＝16.9Hz,1H),5.91(d,J＝11.8Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.49(s,2H),3.87(s,2H),3.71–3.35(m,12H),3.21(d,J＝10.6Hz,5H),2.85(d,J＝8.6Hz,1H),2.73(t,J＝14.4Hz,2H),2.55–2.45(m,4H),2.27(s,2H),2.12(s,1H),1.74–1.67(m,2H),1.51(d,J＝7.3Hz,2H),1.41–1.33(m,2H).HRMS(ESI)m/z:计算值C 48H 55ClFN 10O 7 +[M+H] +,937.3922；实测值,937.3926.
实施例123
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262179)的制备
参照实施例1的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS151086)制备得到目标化合物(SIAIS262179)(黄色固体,8.2mg,收率49％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.75(s,1H),7.97–7.92(m,1H),7.68-7.61(m,1H),7.59–7.53(m,1H),7.37(dd,J＝15.8,6.9Hz,2H),7.07–7.04(m,1H),6.82(s,1H),6.51(d,J＝17.0Hz,1H),5.91(dd,J＝10.3,1.5Hz,1H),5.07(dd,J＝12.1,6.0Hz,1H),4.49(s,2H),3.84(s,2H),3.72–3.32(m,12H),3.18(d,J＝15.7Hz,5H),2.85(dd,J＝13.3,4.8Hz,1H),2.78–2.67(m,2H),2.47(d,J＝23.2Hz,4H),2.31–2.17(m,2H),2.15–2.08(m,1H),1.73–1.60(m,4H),1.45(d,J＝13.6Hz,4H).HRMS(ESI)m/z:计算值C 49H 57ClFN 10O 7 +[M+H] +,951.4079；实测值,951.4075.
实施例124
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide (SIAIS262180)的制备
参照实施例102的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS1216133)制备得到目标化合物(SIAIS262180)(黄色固体,11.2mg,收率46％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.76(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.67–7.65(m,2H),7.54(t,J＝7.6Hz,1H),7.38(dd,J＝12.3,5.4Hz,2H),6.84(dd,J＝16.9,10.3Hz,1H),6.52(dd,J＝16.9,1.3Hz,1H),5.91(dd,J＝10.3,1.4Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.48(dd,J＝13.2,7.4Hz,3H),4.44–4.39(m,1H),3.83(d,J＝12.5Hz,2H),3.76–3.34(m,10H),3.19(t,J＝12.2Hz,4H),3.09-3.04(m,3H),2.96–2.88(m,1H),2.84–2.76(m,1H),2.55-2.51(m,3H),2.40(d,J＝12.8Hz,2H),2.19-2.15(m,3H),1.78–1.67(m,4H),1.53(d,J＝7.3Hz,2H),1.41(dt,J＝13.8,7.2Hz,2H).HRMS(ESI)m/z:计算值C 48H 58ClFN 9O 5S +[M+H] +,926.3949；实测值,926.3953.
实施例125
N-(4-((3-chloro-4-fluorophenyl)amino)-7-(3-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)piperazin-1-yl)piperidin-1-yl)propoxy)quinazolin-6-yl)acrylamide(SIAIS262183)的制备
参照实施例102的方法，采用卡奈替尼衍生物B和中间体LM(SIAIS264018)制备得到目标化合物(SIAIS262183)(黄色固体,12.2mg,收率50％)。 1H NMR(500MHz,MeOD)δ9.17(s,1H),8.76(s,1H),7.94(dd,J＝6.5,2.5Hz,1H),7.66-7.61(m,1H),7.56(dd,J＝8.5,7.1Hz,1H),7.40–7.34(m,2H),7.06(t,J＝7.4Hz,2H),6.84(dd,J＝16.9,10.0Hz,1H),6.52(d,J＝16.9Hz,1H),5.91(d,J＝11.7Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),4.48(t,J＝5.6Hz,2H),3.80(s,2H),3.43-3.41(m,8H),3.18(d,J＝13.1Hz,4H),2.88–2.83(m,1H),2.77–2.69(m,2H),2.50(s,2H),2.34(s,2H),2.16–2.08(m,3H),1.80(s,2H),1.76–1.70(m,2H),1.50(d,J＝10.7Hz,4H).HRMS(ESI)m/z:计算值C 48H 57ClFN 10O 6 +[M+H] +,923.4130；实测值,923.4143.
实施例126
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethyl)acetamide(SIAIS293047)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171123)制备得到目标化合物(SIAIS293047)(黄色固体,7.6mg,收率45％)。 1H NMR(500MHz,MeOD)δ8.73(s,1H),8.31(s,1H),8.00(dd,J＝6.6,2.6Hz,1H),7.78(dd,J＝7.8,0.8Hz,1H),7.72(s,1H),7.66(s,1H),7.56(t,J＝7.7Hz,1H),7.36(t,J＝8.9Hz,1H),7.28(s,1H),5.17(d,J＝8.4Hz,1H),5.01(s,1H),4.53(d,J＝17.4Hz,1H),4.47(d,J＝17.5Hz,1H),4.11(d,J＝9.7Hz,3H),3.90(q,J＝15.5Hz,2H),3.58–3.50(m,2H),3.49–3.33(m,4H),3.29–3.21(m,2H),2.90(ddd,J＝17.0,12.7,4.5Hz,1H),2.83–2.74(m,1H),2.52(dt,J＝13.1,8.4Hz,1H),2.39–2.17(m,4H),2.04(s,1H).HRMS(ESI)m/z: 计算值C 37H 38ClFN 7O 6S +[M+H] +,762.2271；实测值,762.2266.
实施例127
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)propyl)acetamide(SIAIS293048)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171124)制备得到目标化合物(SIAIS293048)(黄色固体,8.1mg,收率47％)。 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.33(s,1H),7.99(dd,J＝6.6,2.6Hz,1H),7.72(ddd,J＝8.9,4.1,2.7Hz,1H),7.68(d,J＝7.6Hz,1H),7.64(d,J＝7.3Hz,1H),7.52(t,J＝7.7Hz,1H),7.36(t,J＝8.9Hz,1H),7.28(s,1H),5.17(d,J＝9.5Hz,1H),5.04(s,1H),4.50(s,1H),4.45(d,J＝17.4Hz,1H),4.09(s,3H),3.99(s,2H),3.67–3.34(m,6H),3.20(ddd,J＝15.2,14.2,9.6Hz,2H),3.10(t,J＝7.2Hz,2H),2.95–2.85(m,1H),2.82–2.75(m,1H),2.53(ddd,J＝26.5,13.3,4.7Hz,1H),2.32(s,2H),2.22–2.16(m,1H),1.93–1.83(m,2H).HRMS(ESI)m/z:计算值C 38H 40ClFN 7O 6S +[M+H] +,776.2428；实测值,776.2424.
实施例128
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)butyl)acetamide(SIAIS293049)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171131)制备得到目标化合物(SIAIS293049)(黄色固体,8.4mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.74(s,1H),8.31(s,1H),7.99(dd,J＝6.6,2.6Hz,1H),7.74-7.71(m,1H),7.67(d,J＝7.2Hz,1H),7.60(s,1H),7.52(t,J＝7.6Hz,1H),7.36(t,J＝8.9Hz,1H),7.28(s,1H),5.15(s,1H),5.03(s,1H),4.45(s,1H),4.41(d,J＝17.6Hz,1H),4.10(s,3H),3.95(s,2H),3.82–3.33(m,6H),3.29(s,2H),3.17–3.04(m,2H),2.94–2.85(m,1H),2.78-2.74(m,1H),2.53(dt,J＝17.9,10.9Hz,1H),2.31(s,2H),2.18-2.13(m,1H),1.69(s,4H).HRMS(ESI)m/z:计算值C 39H 42ClFN 7O 6S +[M+H] +,790.2584；实测值,790.2581.
实施例129
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexyl)acetamide(SIAIS293050)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171134)制备得到目标化合物(SIAIS293050)(黄色固体,8.7mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.73(s,1H),8.35(s,1H),8.00(dd,J＝6.6,2.4Hz,1H),7.74(s,1H),7.65–7.59(m,2H),7.54–7.48(m,1H),7.36(t,J＝8.9Hz,1H),7.27(s,1H),5.16(dd,J＝13.4,5.1Hz,1H),5.08(s,1H),4.45(d,J＝17.3Hz,1H),4.38(d,J＝17.3Hz,1H),4.10(s,3H),4.00(s,2H),3.60(dd,J＝43.0,36.5Hz,4H),3.31–3.22(m,4H),3.12–3.01(m,2H),2.91(ddd,J＝17.4,14.3,7.5Hz,1H),2.84–2.75(m,1H),2.56–2.46(m, 1H),2.33(s,2H),2.21–2.14(m,1H),1.69–1.60(m,2H),1.52(dt,J＝18.4,5.4Hz,4H),1.37(dt,J＝15.7,8.0Hz,2H).HRMS(ESI)m/z:计算值C 41H 46ClFN 7O 6S +[M+H] +,818.2897；实测值,818.2892.
实施例130
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)heptyl)acetamide(SIAIS293051)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171135)制备得到目标化合物(SIAIS293051)(黄色固体,8.5mg,收率46％)。 1H NMR(500MHz,MeOD)δ8.72(s,1H),8.31–8.21(m,1H),7.99(s,1H),7.72(s,1H),7.61(d,J＝7.6Hz,2H),7.53–7.48(m,1H),7.36(t,J＝8.9Hz,1H),7.26(s,1H),5.16(dd,J＝13.3,5.2Hz,1H),5.03(s,1H),4.44(d,J＝17.3Hz,1H),4.38(d,J＝17.2Hz,1H),4.09(s,3H),4.00(s,2H),3.46(dd,J＝10.8,9.1Hz,6H),3.25(t,J＝7.1Hz,2H),3.08–3.03(m,2H),2.90(m,1H),2.82–2.76(m,1H),2.55–2.48(m,1H),2.34(s,2H),2.19(t,J＝7.5Hz,1H),1.64(dd,J＝14.8,7.2Hz,2H),1.52(d,J＝6.6Hz,2H),1.46(s,2H),1.33(s,4H).HRMS(ESI)m/z:计算值C 42H 48ClFN 7O 6S +[M+H] +,832.3054；实测值,832.3052.
实施例131
2-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)octyl)acetamide(SIAIS293052)的制备
参照实施例1的方法，采用吉非替尼衍生物C和中间体LM(SIAIS171136)制备得到目标化合物(SIAIS293052)(黄色固体,9.1mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.72(s,1H),8.35(s,1H),8.00(dd,J＝6.6,2.6Hz,1H),7.73(s,1H),7.64–7.60(m,2H),7.53–7.48(m,1H),7.36(t,J＝8.9Hz,1H),7.27(s,1H),5.16(dd,J＝13.3,5.2Hz,1H),5.08(s,1H),4.44(d,J＝17.3Hz,1H),4.38(d,J＝17.3Hz,1H),4.10(s,3H),4.01(s,2H),3.95–3.32(m,6H),3.24(dd,J＝13.0,5.9Hz,2H),3.11–3.01(m,2H),2.94–2.86(m,1H),2.78(m,1H),2.52(dt,J＝13.4,8.6Hz,1H),2.34(s,2H),2.20–2.16(m,1H),1.70–1.63(m,2H),1.56–1.44(m,4H),1.39–1.31(m,6H).HRMS(ESI)m/z:计算值C 43H 50ClFN 7O 6S +[M+H] +,846.3210；实测值,846.3217.
实施例132
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)butyl)acetamide(SIAIS293067)的制备
参照实施例1的方法，采用sapitinib衍生物A和中间体LM(SIAIS171131)制备得到目标化合物(SIAIS293067)(黄色固体,9.1mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.70(d,J＝5.0Hz,1H),8.40–8.26(m,1H),7.69–7.62(m,2H),7.53(s,3H),7.31(d,J＝13.9Hz,2H),5.14(s,1H),4.42(dd,J＝30.2,16.1Hz,2H),4.11(d,J＝14.3Hz,3H),3.97(d,J＝7.6Hz,2H),3.67–3.36(m, 5H),3.09(s,2H),2.95–2.84(m,1H),2.78(d,J＝16.3Hz,1H),2.58–2.43(m,2H),2.33(s,2H),2.18(s,1H),2.09(s,1H),1.70(s,4H).HRMS(ESI)m/z:计算值C 39H 42ClFN 7O 6S +[M+H] +,790.2584；实测值,790.2582.
实施例133
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexyl)acetamide(SIAIS293068)的制备
参照实施例1的方法，采用sapitinib衍生物A和中间体LM(SIAIS171134)制备得到目标化合物(SIAIS293068)(黄色固体,9.1mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.70(s,1H),8.30(d,J＝51.9Hz,1H),7.62(d,J＝7.5Hz,2H),7.55(d,J＝7.2Hz,3H),7.31(s,2H),5.15(s,1H),4.45(d,J＝18.1Hz,1H),4.39(d,J＝17.6Hz,1H),4.11(s,3H),4.00(s,2H),3.81–3.42(m,5H),3.05(s,2H),2.90(s,1H),2.78(d,J＝18.1Hz,1H),2.52(s,1H),2.34(s,2H),2.22–1.90(m,3H),1.75-1.71(m,2H),1.50(s,4H),1.36-1.32(m,4H).HRMS(ESI)m/z:计算值C 41H 46ClFN 7O 6S +[M+H] +,818.2897；实测值,818.2895.
实施例134
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)heptyl)acetamide(SIAIS293069)的制备
参照实施例1的方法，采用sapitinib衍生物A和中间体LM(SIAIS171135)制备得到目标化合物(SIAIS293069)(黄色固体,9.1mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.69(s,1H),8.23(s,1H),7.63(d,J＝7.6Hz,2H),7.53(dq,J＝14.8,7.4Hz,3H),7.32–7.27(m,2H),5.17(dd,J＝13.2,5.0Hz,1H),4.45(d,J＝17.4Hz,1H),4.39(d,J＝17.2Hz,1H),4.11(s,3H),4.00(s,2H),3.48(dd,J＝57.2,32.1Hz,5H),3.24(t,J＝7.0Hz,2H),3.10–3.01(m,2H),2.94–2.87(m,1H),2.79(d,J＝16.0Hz,1H),2.60–2.45(m,2H),2.36(s,2H),2.20–2.07(m,2H),1.69–1.62(m,2H),1.50(dd,J＝18.8,11.8Hz,4H),1.35(s,4H).HRMS(ESI)m/z:计算值C 42H 48ClFN 7O 6S +[M+H] +,832.3054；实测值,832.3044.
实施例135
2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)octyl)acetamide(SIAIS293070)的制备
参照实施例1的方法，采用sapitinib衍生物A和中间体LM(SIAIS171136)制备得到目标化合物(SIAIS293070)(黄色固体,9.1mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.67(s,1H),8.21(s,1H),7.62(d,J＝7.6Hz,2H),7.53-7.48(m,3H),7.33–7.27(m,2H),5.18(dd,J＝13.2,5.0Hz,1H),4.46(d,J＝17.4Hz,1H),4.36(d,J＝17.2Hz,1H),4.10(s,3H),4.00(s,2H),3.47-3.43(m,5H), 3.23(t,J＝7.0Hz,2H),3.10–3.01(m,2H),2.93–2.87(m,1H),2.77(d,J＝16.0Hz,1H),2.60–2.46(m,2H),2.34(s,2H),2.21–2.07(m,2H),1.68–1.62(m,2H),1.50-1.44(m,4H),1.35(s,4H).HRMS(ESI)m/z:计算值C 43H 50ClFN 7O 6S +[M+H] +,846.3210；实测值,846.3212.
实施例136
N-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylacetamido)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337052)的制备
Figure PCTCN2020107177-appb-000190
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171090)制备得到目标化合物(SIAIS337052)(黄色固体,9.2mg,收率45％)。 1H NMR(500MHz,DMSO-d 6)δ10.98(d,J＝7.0Hz,1H),9.28(s,1H),8.82(s,1H),8.22(s,2H),7.66(d,J＝7.7Hz,1H),7.58(t,J＝9.4Hz,2H),7.50(dt,J＝15.4,7.7Hz,1H),7.44–7.38(m,1H),7.30(s,1H),7.19(s,1H),7.05(d,J＝38.4Hz,1H),6.69(dt,J＝19.8,9.5Hz,1H),6.19(d,J＝17.1Hz,1H),5.69(d,J＝10.3Hz,1H),5.12(dd,J＝13.4,5.2Hz,1H),4.39(d,J＝17.5Hz,1H),4.25(d,J＝17.3Hz,1H),4.11(s,2H),3.93(s,3H),3.82(s,3H),3.50(d,J＝7.1Hz,4H),3.03(s,2H),2.90(t,J＝13.8Hz,1H),2.84–2.74(m,4H),2.59(s,1H),2.43(s,1H),2.02–1.96(m,1H).HRMS(ESI)m/z:计算值C 42H 44N 9O 6S +[M+H] +,802.3130；实测值,802.3132.
实施例137
N-(2-((2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylpropanamido)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acryla mide(SIAIS337053)的制备
Figure PCTCN2020107177-appb-000191
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171086)制备得到目标化合物(SIAIS337053)(黄色固体,9.7mg,收率44％)。 1H NMR(500MHz,DMSO-d 6)δ10.98 (s,1H),9.25(s,1H),8.82(s,1H),8.22(s,2H),7.57(ddt,J＝26.7,15.6,8.4Hz,4H),7.41(d,J＝6.7Hz,1H),7.29(d,J＝8.6Hz,1H),7.19(s,1H),7.02(d,J＝22.5Hz,1H),6.70(dd,J＝16.9,9.9Hz,1H),6.19(d,J＝17.0Hz,1H),5.71(d,J＝10.8Hz,1H),5.11(dd,J＝13.4,6.0Hz,1H),4.32(d,J＝17.1Hz,1H),4.19(d,J＝8.6Hz,1H),3.93(s,3H),3.84(s,3H),3.52–3.38(m,4H),3.23(d,J＝8.0Hz,2H),3.13(s,1H),2.86(s,3H),2.80(d,J＝6.5Hz,3H),2.71–2.61(m,3H),2.40(s,1H),1.98(s,1H).HRMS(ESI)m/z:计算值C 43H 46N 9O 6S +[M+H] +,816.3286；实测值,816.3277.
实施例138
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylbutanamide(SIAIS337054)的制备
Figure PCTCN2020107177-appb-000192
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171089)制备得到目标化合物(SIAIS337054)(黄色固体,9.5mg,收率51％). 1H NMR(500MHz,DMSO-d 6)δ10.98(s,1H),9.32(s,1H),8.81(s,1H),8.22(s,2H),7.65(d,J＝7.5Hz,1H),7.58-7.52(m,3H),7.40(t,J＝6.2Hz,1H),7.29(d,J＝8.2Hz,1H),7.18(s,1H),7.07(s,1H),6.75–6.63(m,1H),6.24–6.15(m,1H),5.70(d,J＝10.3Hz,1H),5.11(dd,J＝12.9,6.3Hz,1H),4.34(d,J＝17.3Hz,1H),4.20(d,J＝17.3Hz,1H),3.93(s,3H),3.83(s,3H),3.49(d,J＝6.9Hz,4H),3.16–3.09(m,2H),3.00(s,1H),2.89(s,3H),2.80(s,3H),2.43–2.33(m,3H),2.01-1.98(m,1H),1.84–1.72(m,2H).HRMS(ESI)m/z:计算值C 44H 48N 9O 6S +[M+H] +,830.3443；实测值,830.3441.
实施例139
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylpentanamide(SIAIS337055)的制备
Figure PCTCN2020107177-appb-000193
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS337055)(黄色固体,9.9mg,收率48％)。 1H NMR(500MHz,DMSO-d 6)δ10.99(s,1H),9.28(s,1H),8.82(s,1H),8.23(s,2H),7.64(d,J＝7.5Hz,1H),7.58-7.53(m,3H),7.41(t,J＝6.2Hz,1H),7.28(d,J＝8.2Hz,1H),7.18(s,1H),7.08(s,1H),6.76–6.63(m,1H),6.25–6.15(m,1H),5.71(d,J＝10.3Hz,1H),5.13(dd,J＝12.9,6.3Hz,1H),4.36(d,J＝17.3Hz,1H),4.22(d,J＝17.3Hz,1H),3.95(s,3H),3.84(s,3H),3.51-3.47(m,4H),3.17–3.09(m,2H),3.01(s,1H),2.89(s,3H),2.82(s,3H),2.44–2.33(m,3H),2.02-1.99(m,1H),1.86–1.72(m,4H).HRMS(ESI)m/z:计算值C 45H 50N 9O 6S +[M+H] +,844.3599；实测值,844.3601.
实施例140
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylhexanamide(SIAIS337056)的制备
Figure PCTCN2020107177-appb-000194
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS337056)(黄色固体,9.3mg,收率43％)。 1H NMR(500MHz,DMSO-d 6)δ10.97(s,1H),9.25(s,1H),8.84(s,1H),8.25(s,2H),7.66(d,J＝7.5Hz,1H),7.56-7.53(m,3H),7.42(t,J＝6.2Hz,1H),7.29(d,J＝8.2Hz,1H),7.16(s,1H),7.05(s,1H),6.77–6.63(m,1H),6.24–6.15(m,1H),5.72(d,J＝10.3Hz,1H),5.14(dd,J＝12.9,6.3Hz,1H),4.35(d,J＝17.3Hz,1H),4.24(d,J＝17.3Hz,1H),3.97(s,3H),3.85(s,3H),3.51-3.46(m,4H),3.18–3.11(m,2H),3.04(s,1H),2.88(s,3H),2.83(s,3H),2.45–2.33(m,3H),2.03-1.99(m,1H),1.88–1.71(m,6H).HRMS(ESI)m/z:计算值C 46H 52N 9O 6S +[M+H] +,858.3756；实测值,858.3759.
实施例141
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylheptanamide(SIAIS337057)的制备
Figure PCTCN2020107177-appb-000195
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS171092)制备得到目标化合物(SIAIS337057)(黄色固体,8.8mg,收率43％)。 1H NMR(500MHz,DMSO-d 6)δ10.99(s,1H),9.26(s,1H),8.84(s,1H),8.26(s,2H),7.68(d,J＝7.5Hz,1H),7.57-7.53(m,3H),7.43(t,J＝6.2Hz,1H),7.28(d,J＝8.2Hz,1H),7.15(s,1H),7.07(s,1H),6.79–6.63(m,1H),6.26–6.15(m,1H),5.71(d,J＝10.3Hz,1H),5.14(dd,J＝12.9,6.3Hz,1H),4.36(d,J＝17.3Hz,1H),4.25(d,J＝17.3Hz,1H),3.98(s,3H),3.86(s,3H),3.52-3.46(m,4H),3.19–3.11(m,2H),3.05(s,1H),2.89(s,3H),2.84(s,3H),2.46–2.33(m,3H),2.04-1.98(m,1H),1.89–1.71(m,8H).HRMS(ESI)m/z:计算值C 47H 54N 9O 6S +[M+H] +,872.3912；实测值,872.3904.
实施例142
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-9-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylnonanamide(SIAIS337059)的制备
Figure PCTCN2020107177-appb-000196
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS299138)制备得到目标化合物(SIAIS337059)(黄色固体,7.9mg,收率38％)。 1H NMR(500MHz,DMSO-d 6)δ10.97(s,1H),9.25(s,1H),8.83(s,1H),8.25(s,2H),7.67(d,J＝7.5Hz,1H),7.58-7.53(m,3H),7.42-7.40(m,1H),7.26(d,J＝8.2Hz,1H),7.14(s,1H),7.09(s,1H),6.77–6.63(m,1H),6.28–6.15(m,1H),5.72(d,J＝10.3Hz,1H),5.16(dd,J＝12.9,6.3Hz,1H),4.33(d,J＝17.3Hz,1H),4.23(d,J＝17.3Hz,1H),3.97(s,3H),3.84(s,3H),3.55-3.46(m,4H),3.18–3.11(m,2H),3.06(s,1H),2.87(s,3H),2.83(s,3H),2.48–2.33(m,3H),2.02-1.98(m,1H),1.86–1.70(m,10H).HRMS(ESI)m/z:计算值C 49H 58N 9O 6S +[M+H] +,900.4225；实测值,900.4217.
实施例143
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methyldecanamide(SIAIS337060)的制备
Figure PCTCN2020107177-appb-000197
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS299135)制备得到目标化合物(SIAIS337060)(黄色固体,9.5mg,收率42％)。 1H NMR(500MHz,DMSO-d 6)δ10.99(s,1H),9.26(s,1H),8.85(s,1H),8.27(s,2H),7.68(d,J＝7.5Hz,1H),7.59-7.53(m,3H),7.46-7.40(m,1H),7.25(d,J＝8.2Hz,1H),7.13(s,1H),7.08(s,1H),6.79–6.63(m,1H),6.26–6.15(m,1H),5.71(d,J＝10.3Hz,1H),5.13(dd,J＝12.9,6.3Hz,1H),4.34(d,J＝17.3Hz,1H),4.25(d,J＝17.3Hz,1H),3.98(s,3H),3.83(s,3H),3.57-3.46(m,4H),3.19–3.13(m,2H),3.08(s,1H),2.88(s,3H),2.85(s,3H),2.49–2.33(m,3H),2.03-1.99(m,1H),1.87–1.70(m,12H).HRMS(ESI)m/z:计算值C 50H 60N 9O 6S +[M+H] +,914.4382；实测值,914.4386.
实施例144
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methylundecanamide(SIAIS337061)的制备
Figure PCTCN2020107177-appb-000198
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1220099)制备得到目标化合物(SIAIS337061)(黄色固体,9.7mg,收率43％)。 1H NMR(500MHz,DMSO-d 6)δ10.98(s,1H),9.25(s,1H),8.84(s,1H),8.27(s,2H),7.69(d,J＝7.5Hz,1H),7.58-7.53(m,3H),7.48-7.40(m,1H),7.27(d,J＝8.2Hz,1H),7.14(s,1H),7.09(s,1H),6.79–6.65(m,1H),6.28–6.15(m,1H),5.72(d,J＝10.3Hz,1H),5.15(dd,J＝12.9,6.3Hz,1H),4.35(d,J＝17.3Hz,1H),4.26(d,J＝17.3Hz,1H),3.99(s,3H),3.85(s,3H),3.59-3.46(m,4H),3.19–3.12(m,2H),3.08(s,1H),2.89(s,3H),2.87(s,3H),2.49–2.36(m,3H),2.04-2.00(m,1H),1.89–1.70(m,14H).HRMS (ESI)m/z:计算值C 51H 62N 9O 6S +[M+H] +,928.4538；实测值,928.4544
实施例145
N-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)-N-methylacetamido)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337074)的制备
Figure PCTCN2020107177-appb-000199
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1213129)制备得到目标化合物(SIAIS337074)(黄色固体,9.8mg,收率44％)。 1H NMR(500MHz,Methanol-d 4)δ8.58(s,1H),8.13–8.01(m,2H),7.56–7.25(m,8H),7.15(s,1H),6.61(d,J＝11.8Hz,1H),6.49(d,J＝16.8Hz,1H),5.93(d,J＝9.7Hz,1H),5.17(dd,J＝13.2,5.0Hz,1H),4.39–4.26(m,4H),3.98(d,J＝8.6Hz,3H),3.89(s,3H),3.75–3.55(m,8H),3.07(d,J＝19.0Hz,6H),2.87–2.79(m,1H),2.74-2.70(m,1H),2.43-2.39(m,1H),2.09(s,1H).HRMS(ESI)m/z:计算值C 44H 48N 9O 7S +[M+H] +,846.3392；实测值,846.3395.
实施例146
N-(2-((2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)ethoxy)ethoxy)-N-methylacetamido)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337075)的制备
Figure PCTCN2020107177-appb-000200
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1213131)制备得到目标化合物(SIAIS337075)(黄色固体,8.8mg,收率41％)。 1H NMR(500MHz,Methanol-d 4)δ8.59(s,1H),8.14–8.01(m,2H),7.58–7.25(m,8H),7.17(s,1H),6.60(d,J＝11.8Hz,1H),6.48(d,J＝16.8Hz,1H),5.92(d,J＝9.7Hz,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.37–4.25(m,4H),3.97(d,J＝8.6Hz,3H),3.88(s,3H),3.74–3.52(m,12H),3.05(d,J＝19.0Hz,6H),2.86–2.78(m,1H), 2.73-2.70(m,1H),2.42-2.39(m,1H),2.07(s,1H).HRMS(ESI)m/z:计算值C 46H 52N 9O 8S +[M+H] +,890.3654；实测值,890.3658.
实施例147
N-(2-((14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-3-methyl-4-oxo-6,9,12-trioxa-3-azatetradecyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337076)的制备
Figure PCTCN2020107177-appb-000201
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1213133)制备得到目标化合物(SIAIS337076)(黄色固体,10.1mg,收率39％)。 1H NMR(500MHz,Methanol-d 4)δ8.60(s,1H),8.15–8.02(m,2H),7.59–7.25(m,8H),7.19(s,1H),6.61(d,J＝11.8Hz,1H),6.50(d,J＝16.8Hz,1H),5.94(d,J＝9.7Hz,1H),5.18(dd,J＝13.2,5.0Hz,1H),4.38–4.22(m,4H),3.98(d,J＝8.6Hz,3H),3.92(s,3H),3.76–3.52(m,16H),3.07(d,J＝19.0Hz,6H),2.87–2.79(m,1H),2.71(d,J＝17.7Hz,1H),2.43-2.40(m,1H),2.08(s,1H).HRMS(ESI)m/z:计算值C 48H 56N 9O 9S +[M+H] +,934.3916；实测值,934.3919.
实施例148
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methyl-3,6,9,12-tetraoxatetradecanamide(SIAIS337077)的制备
Figure PCTCN2020107177-appb-000202
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1213135)制备得到目标化合物(SIAIS337077)(黄色固体,10.9mg,收率43％)。 1H NMR(500MHz,Methanol-d 4)δ8.62(s,1H),8.17–8.02(m,2H),7.61–7.26(m,8H),7.21(s,1H),6.63(d,J＝11.8Hz,1H),6.51 (d,J＝16.8Hz,1H),5.96(d,J＝9.7Hz,1H),5.17(dd,J＝13.2,5.0Hz,1H),4.39–4.24(m,4H),3.99(d,J＝8.6Hz,3H),3.94(s,3H),3.78–3.52(m,20H),3.09-3.05(m,6H),2.88–2.79(m,1H),2.72(d,J＝17.7Hz,1H),2.45-2.41(m,1H),2.09(s,1H).HRMS(ESI)m/z:计算值C 50H 60N 9O 10S +[M+H] +,978.4178；实测值,978.4172.
实施例149
N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-17-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)-N-methyl-3,6,9,12,15-pentaoxaheptadecanamide(SIAIS337078)的制备
Figure PCTCN2020107177-appb-000203
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1213137)制备得到目标化合物(SIAIS337078)(黄色固体,9.9mg,收率34％)。 1H NMR(500MHz,Methanol-d 4)δ8.61(s,1H),8.16–8.02(m,2H),7.60–7.31(m,8H),7.22(s,1H),6.62(d,J＝11.8Hz,1H),6.50(d,J＝16.8Hz,1H),5.95(d,J＝9.7Hz,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.38–4.27(m,4H),3.98(d,J＝8.6Hz,3H),3.93(s,3H),3.77–3.52(m,24H),3.08-3.05(m,6H),2.87–2.79(m,1H),2.73(d,J＝17.7Hz,1H),2.45-2.41(m,1H),2.08(s,1H).HRMS(ESI)m/z:计算值C 52H 64N 9O 11S +[M+H] +,1022.4441；实测值,1022.4437.
实施例150
N-(2-((2-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)propyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337079)的制备
Figure PCTCN2020107177-appb-000204
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS213132)制备得到目标化合物(SIAIS337079)(黄色固体,9.8mg,收率46％)。 1H NMR(500MHz,Methanol-d 4)δ 8.52(s,1H),8.26(s,1H),8.12–7.95(m,2H),7.50(d,J＝34.1Hz,2H),7.41(d,J＝6.5Hz,1H),7.37–7.25(m,4H),7.05(d,J＝10.1Hz,1H),6.55(d,J＝10.3Hz,1H),6.48(d,J＝10.5Hz,1H),5.85(d,J＝10.0Hz,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.47(d,J＝17.4Hz,1H),4.35(d,J＝17.2Hz,1H),4.01(s,3H),3.97(s,3H),3.55-3.49(m,4H),3.23-3.21(m,2H),2.95(s,3H),2.87-2.85(m,3H),2.83(s,3H),2.75-2.69(m,1H),2.31–2.19(m,1H),2.07–1.93(m,3H).HRMS(ESI)m/z:计算值C 43H 48N 9O 5S +[M+H] +,802.3494；实测值,802.3493.
实施例151
N-(2-((2-((5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337081)的制备
Figure PCTCN2020107177-appb-000205
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS213135)制备得到目标化合物(SIAIS337081)(黄色固体,9.7mg,收率43％)。 1H NMR(500MHz,Methanol-d 4)δ8.42(d,J＝11.4Hz,1H),8.28(s,1H),7.96(d,J＝39.8Hz,2H),7.64(d,J＝7.5Hz,1H),7.52(s,2H),7.27(s,3H),7.11(d,J＝34.9Hz,2H),6.52(s,2H),5.87(s,1H),5.18(dd,J＝13.2,5.0Hz,1H),4.46(d,J＝17.4Hz,1H),4.36(d,J＝17.2Hz,1H),4.08(s,3H),3.98(s,3H),3.55-3.49(m,4H),3.28-3.23(m,2H),2.95(s,3H),2.86-2.82(m,3H),2.80(s,3H),2.75-2.69(m,1H),2.36–2.17(m,1H),2.09–1.95(m,7H).HRMS(ESI)m/z:计算值C 45H 52N 9O 5S +[M+H] +,830.3807；实测值,830.3803.
实施例152
N-(2-((2-((6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337082)的制备
Figure PCTCN2020107177-appb-000206
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1216133)制备得到目标化合物(SIAIS337082)(黄色固体,9.9mg,收率47％)。 1H NMR(500MHz,Methanol-d 4)δ8.47(d,J＝13.6Hz,1H),8.31(s,1H),8.05-8.01(m,2H),7.54(d,J＝11.4Hz,2H),7.35-7.31(m,5H),7.07(s,1H),6.58(s,1H),6.48(d,J＝17.2Hz,1H),5.85(s,1H),5.17(dd,J＝13.2,5.0Hz,1H),4.45(d,J＝17.4Hz,1H),4.35(d,J＝17.2Hz,1H),4.01(s,3H),3.96(s,3H),3.53-3.46(m,4H),3.26-3.21(m,2H),2.93(s,3H),2.85-2.82(m,3H),2.79(s,3H),2.74-2.62(m,1H),2.34–2.15(m,1H),2.06–1.93(m,9H).HRMS(ESI)m/z:计算值C 46H 54N 9O 5S +[M+H] +,844.3963；实测值,844.3967.
实施例153
N-(2-((2-((7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)heptyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337083)的制备
Figure PCTCN2020107177-appb-000207
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1216135)制备得到目标化合物(SIAIS337083)(黄色固体,8.7mg,收率35％). 1H NMR(500MHz,Methanol-d 4)δ8.62(d,J＝14.0Hz,1H),8.48(s,1H),8.24(s,1H),8.14(t,J＝7.7Hz,1H),7.73–7.64(m,2H),7.56–7.40(m,4H),7.23(s,1H),6.83–6.71(m,1H),6.65(d,J＝16.9Hz,1H),6.02(d,J＝10.4Hz,1H),5.22(dd,J＝13.2,5.0Hz,1H),4.48(d,J＝17.4Hz,1H),4.37(d,J＝17.2Hz,1H),4.09(s,3H),3.99(s,3H),3.59-3.48(m,4H),3.29-3.25(m,2H),2.98(s,3H),2.87-2.85(m,3H),2.83(s,3H),2.79-2.68(m,1H),2.37–2.15(m,1H),2.09–1.96(m,11H).HRMS(ESI)m/z:计算值C 47H 56N 9O 5S +[M+H] +,858.4120；实测值,858.4122.
实施例154
N-(2-((2-((8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)octyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337084)的制备
Figure PCTCN2020107177-appb-000208
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1216137)制备得到目标化合物(SIAIS337084)(黄色固体,9.4mg,收率43％)。 1H NMR(500MHz,Methanol-d 4)δ8.52(s,1H),8.34(s,1H),8.03(s,1H),7.98(d,J＝2.1Hz,1H),7.61(d,J＝7.0Hz,1H),7.54(d,J＝8.4Hz,1H),7.45(d,J＝9.4Hz,1H),7.42(dd,J＝8.2,1.9Hz,2H),7.37(d,J＝6.2Hz,1H),7.34–7.26(m,2H),7.08(s,1H),6.66–6.57(m,1H),6.49(d,J＝16.9Hz,1H),5.87(d,J＝10.0Hz,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.42(d,J＝17.4Hz,1H),4.33(d,J＝17.2Hz,1H),4.05(s,3H),3.95(s,3H),3.56-3.46(m,4H),3.25-3.25(m,2H),2.94(s,3H),2.87-2.85(m,3H),2.81(s,3H),2.77-2.68(m,1H),2.35–2.17(m,1H),2.07–1.96(m,13H).HRMS(ESI)m/z:计算值C 48H 58N 9O 5S +[M+H] +,872.4276；实测值,872.4278.
实施例155
N-(2-((2-((9-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)nonyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337085)的制备
Figure PCTCN2020107177-appb-000209
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1220059)制备得到目标化合物(SIAIS337085)(黄色固体,9.3mg,收率46％)。 1H NMR(500MHz,Methanol-d 4)δ8.51(d,J＝15.2Hz,1H),8.35(s,1H),8.04(s,2H),7.56(d,J＝27.2Hz,3H),7.45–7.25(m,5H),7.09(s,1H),6.61(d,J＝12.3Hz,1H),6.50(d,J＝16.8Hz,1H),5.88(d,J＝10.3Hz,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.45(d,J＝17.4Hz,1H),4.34(d,J＝17.2Hz,1H),4.03(s,3H),3.93(s,3H),3.57-3.46(m,4H),3.27-3.28(m,2H),2.93(s,3H),2.86-2.82(m,3H),2.80(s,3H),2.75-2.68(m,1H),2.34–2.16(m,1H),2.08–1.96(m,15H).HRMS(ESI)m/z:计算值C 49H 60N 9O 5S +[M+H] +,886.4433；实测值,886.4431.
实施例156
N-(2-((2-((10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)decyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337086)的制备
Figure PCTCN2020107177-appb-000210
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1220013)制备得到目标化合物(SIAIS337086)(黄色固体,9.8mg,收率47％)。 1H NMR(500MHz,MeOD)δ8.53(d,J＝15.2Hz,1H),8.37(s,1H),8.05(s,2H),7.57(d,J＝27.2Hz,3H),7.46–7.25(m,5H),7.08(s,1H),6.60(d,J＝12.3Hz,1H),6.48(d,J＝16.8Hz,1H),5.87(d,J＝10.3Hz,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.42(d,J＝17.4Hz,1H),4.33(d,J＝17.2Hz,1H),4.01(s,3H),3.92(s,3H),3.56-3.43(m,4H),3.25-3.21(m,2H),2.91(s,3H),2.85-2.82(m,3H),2.80(s,3H),2.74-2.68(m,1H),2.32–2.16(m,1H),2.08–1.96(m,17H).HRMS(ESI)m/z:计算值C 50H 62N 9O 5S +[M+H] +,900.4589；实测值,900.4586.
实施例157
N-(2-((2-((11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)undecyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337087)的制备
Figure PCTCN2020107177-appb-000211
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1220015)制备得到目标化合物(SIAIS337087)(黄色固体,8.7mg,收率42％)。 1H NMR(500MHz,Methanol-d 4)δ8.53(s,1H),8.33(s,1H),8.03(s,2H),7.60(d,J＝7.4Hz,1H),7.52(d,J＝7.3Hz,2H),7.46(t,J＝7.8Hz,1H),7.39(d,J＝6.9Hz,1H),7.28(dt,J＝27.3,7.4Hz,2H),7.06(s,1H),6.59(dd,J＝16.9,10.0Hz,1H),6.48(d,J＝17.0Hz,1H),5.85(d,J＝10.2Hz,1H),5.17–5.12(m,1H),4.37(t,J＝5.6Hz,2H),4.00(s,3H),3.94(s,3H),3.57–3.42(m,3H),3.11(q,J＝7.3Hz,3H),2.92(dd,J＝ 17.1,4.2Hz,5H),2.81(d,J＝1.5Hz,3H),2.76(d,J＝17.3Hz,1H),2.49(t,J＝6.7Hz,1H),2.20–2.11(m,1H),2.03(d,J＝6.7Hz,1H),1.55(s,4H),1.30(s,4H),1.08(d,J＝35.9Hz,10H).HRMS(ESI)m/z:计算值C 51H 64N 9O 5S +[M+H] +,914.4746；实测值,914.4743.
实施例158
N-(2-((2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337088)的制备
Figure PCTCN2020107177-appb-000212
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS1220141)制备得到目标化合物(SIAIS337088)(黄色固体,9.8mg,收率43％)。 1H NMR(500MHz,Methanol-d 4)δ8.58(s,1H),8.57–8.47(m,1H),8.05–7.94(m,1H),7.87(d,J＝7.0Hz,1H),7.59(d,J＝7.9Hz,1H),7.44–7.31(m,4H),7.25(d,J＝7.9Hz,3H),7.18(d,J＝7.8Hz,1H),7.12(d,J＝7.7Hz,1H),7.07(t,J＝7.6Hz,1H),6.69–6.54(m,2H),6.38(d,J＝10.1Hz,1H),5.96(d,J＝9.0Hz,1H),5.06–4.93(m,1H),4.64–4.55(m,1H),4.15(d,J＝12.8Hz,1H),4.12–4.05(m,1H),4.02(d,J＝5.1Hz,3H),3.98–3.77(m,3H),3.68(d,J＝5.0Hz,3H),3.58(d,J＝14.6Hz,1H),3.42(d,J＝13.3Hz,1H),3.07(s,3H),2.99(d,J＝13.4Hz,1H),2.89–2.82(m,1H),2.74(d,J＝3.3Hz,4H),2.23–2.10(m,1H).HRMS(ESI)m/z:计算值C 48H 50N 9O 5S +[M+H] +,864.3650；实测值,864.3653.
实施例159
N-(2-((2-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337089)的制备
Figure PCTCN2020107177-appb-000213
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS255121)制备得到目标化合物(SIAIS337089)(黄色固体,9.5mg,收率40％)。 1H NMR(500MHz,Methanol-d 4)δ8.46(d,J＝15.7Hz,1H),8.28(s,1H),8.08-8.00(m,2H),7.96–7.85(m,1H),7.60(dd,J＝15.1,7.3Hz,1H),7.56–7.47(m,1H),7.37–7.25(m,4H),7.07(d,J＝9.4Hz,1H),6.67–6.57(m,1H),6.48(d,J＝16.9Hz,1H),5.84(d,J＝10.1Hz,1H),5.03(d,J＝17.4Hz,1H),4.25–4.11(m,1H),4.05(s,3H),3.95(s,3H),3.76(d,J＝14.6Hz,1H),3.65(s,1H),3.51(d,J＝12.5Hz,1H),3.26(s,4H),2.98(s,3H),2.86(d,J＝13.8Hz,1H),2.80(d,J＝6.6Hz,3H),2.72(d,J＝14.2Hz,1H),2.37(s,2H),2.27–2.18(m,1H),1.91(s,3H).HRMS(ESI)m/z:计算值C 45H 48N 9O 5 +[M+H] +,794.3773；实测值,794.3775.
实施例160
N-(2-((2-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(SIAIS337090)的制备
Figure PCTCN2020107177-appb-000214
参照实施例1的方法，采用奥西替尼衍生物SIAIS337051和中间体LM(SIAIS255127)制备得到目标化合物(SIAIS337090)(黄色固体,8.7mg,收率33％)。 1H NMR(500MHz,Methanol-d 4)δ8.44(d,J＝18.1Hz,1H),8.31(s,1H),8.11–7.99(m,2H),7.70–7.63(m,1H),7.44-7.41(m,3H),7.33-7.27(m,3H),7.07(d,J＝5.6Hz,1H),6.64(t,J＝13.5Hz,1H),6.47(d,J＝16.8Hz,1H),5.84(d,J＝10.1Hz,1H),5.10(s,1H),4.26(d,J＝10.9Hz,2H),4.01(s,3H),3.98(s,1H),3.86(s,3H),3.73(d,J＝13.6Hz,1H),3.49-3.44(m,2H),3.22–3.09(m,3H),2.91(s,3H),2.81(s,3H),2.77–2.65(m,1H),2.36-2.31(m,3H),2.04(s,1H),1.61(s,2H),1.41(s,2H),1.28-1.22(m,6H).HRMS(ESI)m/z:计算值C 49H 56N 9O 5 +[M+H] +,850.4399；实测值,850.4394.
实施例161
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262064)的制备
Figure PCTCN2020107177-appb-000215
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS213135)制备得到目标化合物(SIAIS262064)(黄色固体,8.9mg,收率35％)。HRMS(ESI)m/z:计算值C 46H 54ClFN 9O 5S +[M+H] +,898.3636；实测值,898.3631.
实施例162
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS262071)的制备
Figure PCTCN2020107177-appb-000216
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS264009)制备得到目标化合物(SIAIS262071)(黄色固体,9.5mg,收率41％)。HRMS(ESI)m/z:计算值C 46H 53ClFN 10O 6 +[M+H] +,895.3817；实测值,895.3815.
实施例163
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)acetamido)piperidin-1-yl)but-2-enamide(SIAIS262110)的制备
Figure PCTCN2020107177-appb-000217
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS171090)制备得到目标化合物 (SIAIS262110)(黄色固体,9.2mg,收率48％)。HRMS(ESI)m/z:计算值C 39H 39ClFN 8O 6 +[M+H] +,801.2380；实测值,801.2389.
实施例164
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)butanamido)piperidin-1-yl)but-2-enamide(SIAIS262112)的制备
Figure PCTCN2020107177-appb-000218
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS171089)制备得到目标化合物(SIAIS262112)(黄色固体,9.5mg,收率49％)。HRMS(ESI)m/z:计算值C 41H 43ClFN 8O 6 +[M+H] +,829.2693；实测值,829.2697.
实施例165
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)pentanamide(SIAIS262113)的制备
Figure PCTCN2020107177-appb-000219
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS171079)制备得到目标化合物(SIAIS262113)(黄色固体,9.3mg,收率46％)。HRMS(ESI)m/z:计算值C 42H 45ClFN 8O 6 +[M+H] +,843.2850；实测值,843.2844.
实施例166
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)hexanamide(SIAIS262114)的制备
Figure PCTCN2020107177-appb-000220
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS171091)制备得到目标化合物(SIAIS262114)(黄色固体,9.6mg,收率45％)。HRMS(ESI)m/z:计算值C 43H 47ClFN 8O 6 +[M+H] +,857.3006；实测值,857.3009.
实施例167
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)heptanamide(SIAIS262115)的制备
Figure PCTCN2020107177-appb-000221
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS171092)制备得到目标化合物(SIAIS262115)(黄色固体,9.8mg,收率43％)。HRMS(ESI)m/z:计算值C 44H 49ClFN 8O 6 +[M+H] +,871.3163；实测值,871.3167.
实施例168
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)amino)piperidin-1-yl)but-2-enamide
(SIAIS262116)的制备
Figure PCTCN2020107177-appb-000222
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS255121)制备得到目标化合物(SIAIS262116)(黄色固体,8.4mg,收率45％)。HRMS(ESI)m/z:计算值C 42H 43ClFN 8O 5 +[M+H] +,793.3023；实测值,793.3028.
实施例169
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-((6-(2-(2,6-dioxopip eridin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)amino)piperidin-1-yl)but-2-enamide(SIAIS262117)的制备
Figure PCTCN2020107177-appb-000223
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS255119)制备得到目标化合物(SIAIS262117)(黄色固体,8.4mg,收率45％)。HRMS(ESI)m/z:计算值C 43H 45ClFN 8O 5 +[M+H] +,807.3180；实测值,807.3183.
实施例170
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)undecanamide(SIAIS262118)的制备
Figure PCTCN2020107177-appb-000224
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS1220099)制备得到目标化合物(SIAIS262118)(黄色固体,9.6mg,收率35％)。HRMS(ESI)m/z:计算值C 48H 57ClFN 8O 6 +[M+H] +,927.3789；实测值,927.3784.
实施例171
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337021)的制备
Figure PCTCN2020107177-appb-000225
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1220141)制备得到目标化合 物(SIAIS337021)(黄色固体,9.4mg,收率32％)。HRMS(ESI)m/z:计算值C 49H 52ClFN 9O 5S +[M+H] +,932.3479；实测值,932.3474.
实施例172
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337024)的制备
Figure PCTCN2020107177-appb-000226
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1221131)制备得到目标化合物(SIAIS337024)(黄色固体,9.1mg,收率33％)。HRMS(ESI)m/z:计算值C 49H 53ClFN 10O 5 +[M+H] +,915.3867；实测值,915.3864.
实施例173
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337025)的制备
Figure PCTCN2020107177-appb-000227
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1222121)制备得到目标化合物(SIAIS337025)(黄色固体,9.7mg,收率45％)。HRMS(ESI)m/z:计算值C 43H 46ClFN 9O 7 +[M+H] +,854.3187；实测值,854.3181.
实施例174
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)pentanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337026)的制备
Figure PCTCN2020107177-appb-000228
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1222125)制备得到目标化合物(SIAIS337026)(黄色固体,9.3mg,收率42％)。HRMS(ESI)m/z:计算值C 46H 52ClFN 9O 7 +[M+H] +,896.3657；实测值,896.3651.
实施例175
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337027)的制备
Figure PCTCN2020107177-appb-000229
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1222149)制备得到目标化合物(SIAIS337027)(黄色固体,8.8mg,收率39％)。HRMS(ESI)m/z:计算值C 47H 54ClFN 9O 7 +[M+H] +,910.3813；实测值,910.3811.
实施例176
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)heptanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337028)的制备
Figure PCTCN2020107177-appb-000230
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1222151)制备得到目标化合物(SIAIS337028)(黄色固体,8.6mg,收率34％)。HRMS(ESI)m/z:计算值C 48H 56ClFN 9O 7 +[M+H] +,924.3970；实测值,924.3974.
实施例177
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)hexyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337029)的制备
Figure PCTCN2020107177-appb-000231
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1222127)制备得到目标化合物(SIAIS337029)(黄色固体,8.2mg,收率31％)。HRMS(ESI)m/z:计算值C 47H 56ClFN 9O 6 +[M+H] +,896.4021；实测值,896.4029.
实施例178
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337035)的制备
Figure PCTCN2020107177-appb-000232
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1204061)制备得到目标化合物(SIAIS337035)(黄色固体,8.5mg,收率42％)。HRMS(ESI)m/z:计算值C 47H 55ClFN 10O 6 +[M+H] +,909.3973；实测值,909.3978.
实施例179
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337036)的制备
Figure PCTCN2020107177-appb-000233
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1204063)制备得到目标化合 物(SIAIS337036)(黄色固体,8.7mg,收率43％)。HRMS(ESI)m/z:计算值C 48H 57ClFN 10O 6 +[M+H] +,923.4130；实测值,923.4128.
实施例180
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)decanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337037)的制备
Figure PCTCN2020107177-appb-000234
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS299135)制备得到目标化合物(SIAIS337037)(黄色固体,8.9mg,收率41％)。HRMS(ESI)m/z:计算值C 51H 62ClFN 9O 6S +[M+H] +,982.4211；实测值,982.4218.
实施例181
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)undecanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337038)的制备
Figure PCTCN2020107177-appb-000235
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1220099)制备得到目标化合物(SIAIS337038)(黄色固体,9.3mg,收率46％)。HRMS(ESI)m/z:计算值C 52H 64ClFN 9O 6S +[M+H] +,996.4367；实测值,996.4362.
实施例182
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)decyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337039)的制备
Figure PCTCN2020107177-appb-000236
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1220013)制备得到目标化合物(SIAIS337039)(黄色固体,9.8mg,收率47％)。HRMS(ESI)m/z:计算值C 51H 64ClFN 9O 5S +[M+H] +,968.4418；实测值,968.4418.
实施例183
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)undecyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS337040)的制备
Figure PCTCN2020107177-appb-000237
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS1220015)制备得到目标化合物(SIAIS337040)(黄色固体,9.9mg,收率43％)。HRMS(ESI)m/z:计算值C 52H 66ClFN 9O 5S +[M+H] +,982.4575；实测值,982.4575.
实施例184
(2S,4R)-1-((S)-19-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-2-(tert-butyl)-4,19-dioxo-7,10,13,16-tetraoxa-3-azanonadecanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS262130)的制备
Figure PCTCN2020107177-appb-000238
参照实施例1的方法，采用采用卡奈替尼衍生物A和中间体LM(SIAIS151008)制备得到目标化合物(SIAIS262130)(白色固体,10.8mg,收率36％)。HRMS(ESI)m/z:计算值C 58H 75ClFN 10O 11S +[M+H] +,1173.5005；实测值,1173.5001.
实施例185
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(2-((2-(2,6-dioxopip eridin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)piperidin-1-yl)but-2-enamide(SIAIS249081)的制备
Figure PCTCN2020107177-appb-000239
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151025)制备得到目标化合物(SIAIS249081).(黄色固体,8.6mg,54％). 1H NMR(500MHz,Methanol-d 4)δ9.09(s,1H),8.61(s,1H),7.97(dd,J＝6.7,2.6Hz,1H),7.66(ddd,J＝8.9,4.1,2.5Hz,1H),7.57(dd,J＝8.5,7.1Hz,1H),7.33–7.27(m,2H),7.13(d,J＝7.1Hz,1H),7.00(dd,J＝14.9,7.5Hz,1H),6.89(d,J＝8.4Hz,1H),6.81(d,J＝15.1Hz,1H),5.08(dd,J＝12.6,5.5Hz,1H),4.13(s,3H),4.03(s,2H),3.99(d,J＝7.2Hz,1H),3.61-3.56(m,1H),3.23-3.16(m,1H),2.86(ddd,J＝17.8,14.3,5.2Hz,1H),2.79–2.67(m,2H),2.23–2.03(m,4H),1.88-1.78(m,2H),1.65-1.58(m,1H),1.39-1.35(m,2H).HRMS(ESI)C 39H 38ClFN 9O 7 +[M+H] +,计算值798.2561；实测值,798.2563.
实施例186
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamido)piperidin-1-yl)but-2-enamide(SIAIS249082)的制备
Figure PCTCN2020107177-appb-000240
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151026)制备得到目标化合物(SIAIS249082).(黄色固体,9.6mg,56％). 1H NMR(500MHz,Methanol-d 4)δ9.24(s,1H),8.62(s,1H),7.99(dd,J＝6.7,2.6Hz,1H),7.74–7.67(m,1H),7.59(dd,J＝8.6,7.1Hz,1H),7.36–7.26(m,2H),7.15(d,J＝8.6Hz,1H),7.06(dd,J＝14.6,7.5Hz,2H),6.80(d,J＝15.2Hz,1H),5.10(dd,J＝12.3,5.3Hz,1H),4.14(s,3H),3.98(d,J＝7.0Hz,2H),3.90(s,1H),3.75–3.66(m,1H),3.09(s,1H),2.94–2.82(m,1H),2.80–2.69(m,2H),2.58-2.51(m,2H),2.22–2.03(m,4H),1.65-1.58(m,2H),1.38-1.28(m,3H).HRMS(ESI)C 40H 40ClFN 9O 7 +[M+H] +,计算值812.2718；实测值,812.2713.
实施例187
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-((2-(2,6-dioxopip eridin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butanamido)piperidin-1-yl)but-2-enamide(SIAIS249083)的制备
Figure PCTCN2020107177-appb-000241
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151019)制备得到目标化合物(SIAIS249083).(黄色固体,8.7mg,51％). 1H NMR(500MHz,Methanol-d 4)δ9.24(s,1H),8.66(s,1H),7.97(dd,J＝6.7,2.7Hz,1H),7.68(ddd,J＝8.9,4.2,2.7Hz,1H),7.56(dd,J＝8.6,7.1Hz,1H),7.37–7.28(m,2H),7.09(d,J＝8.5Hz,1H),7.04(dd,J＝7.3,4.0Hz,1H),6.82(d,J＝15.2Hz,1H),5.07(dd,J＝12.5,5.4Hz,1H),4.15(s,3H),4.00(d,J＝7.2Hz,2H),3.81-3.75(m,1H),3.59-3.48(m,1H),3.47–3.42(m,2H),3.23–3.14(m,1H),2.91-2.85(m,1H),2.75(dt,J＝14.3,3.1Hz,2H),2.31(d,J＝8.4Hz,2H),2.13–2.08(m,1H),2.13-2.01(m,4H),1.7-1.59(m,2H),1.38-1.29(m,2H).HRMS(ESI)C 41H 42ClFN 9O 7 +[M+H] +,计算值826.2874；实测值,826.2870.
实施例188
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexanamide(SIAIS249084)的制备
Figure PCTCN2020107177-appb-000242
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151020)制备得到目标化合物(SIAIS249084).(黄色固体,11.1mg,65％). 1H NMR(500MHz,Methanol-d 4)δ9.17(s,1H),8.64(s,1H),7.98(s,1H),7.68(s,1H),7.55(s,1H),7.32(dd,J＝19.0,6.5Hz,2H),7.1-7.00(m,3H),6.82(d,J＝15.1Hz,1H),5.07(dd,J＝12.5,5.4Hz,1H),4.15(s,3H),4.00(s,1H),3.62-3.5(m,1H),3.21–3.15(m,1H),2.84(d,J＝17.2Hz,1H),2.75-2.71(m,2H),2.28-2.18(m,2H),2.09-1.99(m,4H),1.72-1.68(m,4H),1.63-1.58(m,1H)1.48-1.38(m,2H),1.35-1.28(m,4H).HRMS(ESI)C 43H 46ClFN 9O 7 +[M+H] +,计算值854.3187；实测值,854.3189.
实施例189
(E)-N-(1-(4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)-7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptana mide(SIAIS249085)的制备
Figure PCTCN2020107177-appb-000243
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151086)制备得到目标化合物(SIAIS249085).(黄色固体,10.6mg,59％). 1H NMR(500MHz,Methanol-d 4)δ9.15(s,1H),8.65(s,1H),7.96(dd,J＝6.6,2.6Hz,1H),7.66(ddd,J＝8.9,4.2,2.6Hz,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.36–7.29(m,2H),7.03(dd,J＝7.9,2.6Hz,2H),7.00(t,J＝7.4Hz,1H),6.83(d,J＝15.2Hz,1H),5.05(dd,J＝12.4,5.5Hz,1H),4.15(s,3H),4.01(d,J＝7.2Hz,2H),4.00-3.96(m,1H),3.61-3.58(m,1H),3.19-3.15(m,1H),2.91–2.80(m,1H),2.80–2.65(m,2H),2.20(q,J＝7.6Hz,2H),2.15–2.07(m,4H),1.69-1.60(m,5H),1.48–1.31(m,8H).HRMS(ESI)C 44H 48ClFN 9O 7 +[M+H] +,计算值868.3344；实测值,868.3341.
实施例190
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamido)piperidin-1-yl)but-2-enamide(SIAIS249086)的制备
Figure PCTCN2020107177-appb-000244
参照实施例1的方法，采用达克替尼衍生物B和中间体LM(SIAIS151004)制备得到目标化合物(SIAIS249086).(黄色固体,10.2mg,54％) 1H NMR(500MHz,Methanol-d 4)δ9.17(s,1H),8.68(s,1H),7.95(dd,J＝6.7,2.6Hz,1H),7.69-7.64(m,1H),7.57–7.50(m,1H),7.33(dd,J＝19.2,10.3Hz,2H),7.09(d,J＝8.5Hz,1H),7.09-6.98(m,2H),6.81(d,J＝15.2Hz,1H),5.07(dd,J＝12.4,5.5Hz,1H),4.15(s,3H),4.00(d,J＝7.2Hz,2H),3.98-3.91(m,1H),3.73(dt,J＝8.2,5.7Hz,5H),3.66–3.60(m,4H),3.49(t,J＝5.3Hz,2H),3.22–3.07(m,1H),2.91–2.77(m,1H),2.78–2.65(m,2H),2.48–2.36(m,2H),2.2-2.15(m,3H),1.83-1.80(m,2H),1.65-1.62(m,1H),1.37–1.31(m,2H).HRMS(ESI)C 44H 48ClFN 9O 9 +[M+H] +,计算值900.3242；实测值,900.3241.
实施例191
4-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-4-oxobutanamide(SIAIS249099)的制备
Figure PCTCN2020107177-appb-000245
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS164118)制备得到目标化合物(SIAIS249099).(黄色固体,10.1mg,56％).HRMS(ESI)C 45H 49ClFN 10O 9 +[M+H] +,927.3351；实测值,927.3353.
实施例192
4-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-N-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-4-oxobutanamide(SIAIS249100)的制备
Figure PCTCN2020107177-appb-000246
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS164119)制备得到目标化合物(SIAIS249100).(黄色固体,9.6mg,59％). 1H NMR(500MHz,Methanol-d 4)δ9.14(s,1H),8.74(s,1H),7.94(dd,J＝6.6,2.6Hz,1H),7.69-7.63(mz,1H),7.54(dd,J＝8.6,7.1Hz,1H),7.42–7.33(m,2H),7.12(d,J＝8.6Hz,1H),7.02(d,J＝7.1Hz,1H),6.78(dd,J＝16.9,10.3Hz,1H),6.51(dd,J＝16.9,1.6Hz,1H),5.90(dd,J＝10.2,1.6Hz,1H),5.05(dd,J＝12.7,5.5Hz,2H),4.48(t,J＝5.9Hz,2H),3.71-3.61(m,3H),3.52-3.40(m,6H),2.93-2.82(m,1H),2.77–2.66(m,4H),2.70-2.63(m,6H),2.13–2.05(m,1H),2.05-2.01(m,1H),1.39-1.36(m,2H).HRMS(ESI)C 43H 45ClFN 10O 8 +[M+H] +,883.3089；实测值,883.3081.
实施例193
(2S,4R)-1-((S)-2-(3-(4-(3-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249101)的制备
Figure PCTCN2020107177-appb-000247
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS1213011)制备得到目标化合物(SIAIS249101).(白色固体,8.2mg,37％).HRMS(ESI)C 56H 71ClFN 12O 7S +[M+H] +,1109.4956；实测值,1109.4951.
实施例194
(2S,4R)-1-((S)-2-(3-(4-(3-(4-(3-((6-acrylamido-4-((3-chloro-4-fluorophenyl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249102)的制备
Figure PCTCN2020107177-appb-000248
参照实施例1的方法，采用卡奈替尼衍生物A和中间体LM(SIAIS1213061)制备得到目标化合物(SIAIS249102).(白色固体,12mg,55％). 1H NMR(500MHz,Methanol-d 4)δ9.16(s,1H),9.12(s,1H),8.75(s,1H),7.93(dd,J＝6.6,2.7Hz,1H),7.7-7.64(m,1H),7.47(d,J＝8.3Hz,1H),7.42(d,J＝8.2Hz,2H),7.37(d,J＝3.2Hz,2H),7.15(s,4H),6.84(dd,J＝16.9,10.3Hz,1H),6.50(dd,J＝16.9,1.6Hz,1H),5.89(dd,J＝10.3,1.6Hz,1H),4.61–4.53(m,3H),4.51-4.46(m,2H),4.37(d,J＝15.5Hz,1H),4.09(s,1H),3.89(d,J＝11.0Hz,1H),3.78(dd,J＝10.9,4.0Hz,1H),3.45–3.40(m,3H),3.30-3.19(m,1H),2.94–2.82(m,5H),2.79-2.72(m,3H),2.64–2.53(m,3H),2.49(s,3H),2.28–2.17(m,1H),2.12–1.99(m,1H),1.29(s,2H),0.96(s,9H).HRMS(ESI)C 58H 67ClFN 10O 7S +[M+H] +,1101.4582；实测值,1101.4580.
实施例195
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(4-((2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-4-oxobutanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS249103)的制备
Figure PCTCN2020107177-appb-000249
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS164118)制备得到目标化合物(SIAIS249103).(黄色固体,11.6mg,64％). 1H NMR(500MHz,Methanol-d 4)δ9.27(s,1H),8.75(s,1H),7.92(dd,J＝6.7,2.6Hz,1H),7.64-7.68(m,1H),7.60-7.55(m,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.11–7.02(m,3H),6.87(d,J＝15.1Hz,1H),5.09(dd,J＝12.1,5.4Hz,1H),4.18(s,3H),4.08(s,2H),3.79(d,J＝12.6Hz,2H),3.72(dt,J＝9.0,5.1Hz,3H),3.67–3.63(m,2H),3.58(t,J＝5.2Hz,2H),3.53(dt,J＝6.0,2.6Hz,2H),3.49(t,J＝5.1Hz,2H),3.48-3.38(m,3H),3.26-3.18(m,1H),2.89–2.82(m,1H),2.79–2.70(m,3H),2.70–2.45(m,6H),2.28–2.17(m,2H),2.15-2.10(m,2H),1.38-1.32(m,2H).HRMS(ESI)C 49H 56ClFN 11O 9 +[M+H] +,996.3930；实测值,996.3931.
实施例196
(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-(4-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutanoyl)piperazin-1-yl)piperidin-1-yl)but-2-enamide(SIAIS249104)的制备
Figure PCTCN2020107177-appb-000250
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS164119)制备得到目标化合物(SIAIS249104).(黄色固体,11.8mg,70％). 1H NMR(500MHz,Methanol-d 4)δ9.26(s,1H),8.74(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.68-7.63(m,1H),7.56(dd,J＝8.6,7.1Hz,1H),7.37(t,J＝8.9Hz,1H),7.32(s,1H),7.13(d,J＝8.6Hz,1H),7.08–7.02(m,2H),6.86(d,J＝15.2Hz,1H),5.07(dd,J＝12.7,5.5Hz,1H),4.18(s,3H),4.05(s,2H),3.75(s,2H),3.50–3.41(m,8H),3.22–3.12(m,3H),2.92-2.86(m,1H),2.78–2.58(m,5H),2.55–2.41(m,4H),2.25-2.15(m,2H),2.14-2.09(m,2H),1.35-1.30(m,2H).HRMS(ESI)C 47H 52ClFN 11O 8+[M+H] +,952.3667；实测 值,952.3665.
实施例197
(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249105)的制备
Figure PCTCN2020107177-appb-000251
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS1213011)制备得到目标化合物(SIAIS249105).(白色固体,12.1mg,57％). 1H NMR(500MHz,Methanol-d 4)δ9.53(s,1H),9.26(s,1H),8.75(s,1H),7.92(dd,J＝6.6,2.6Hz,1H),7.70-7.65(m,1H),7.57–7.51(m,2H),7.50–7.44(m,2H),7.40–7.32(m,2H),7.07(dt,J＝14.8,7.2Hz,1H),6.89(d,J＝15.2Hz,1H),4.67–4.46(m,5H),4.39(dd,J＝15.8,2.0Hz,1H),4.18(s,3H),4.10(s,2H),3.97(d,J＝11.0Hz,2H),3.88–3.45(m,24H),3.28–3.20(m,2H),2.91-2.87(m,2H),2.55(s,3H),2.33–2.16(m,3H),2.12–1.98(m,1H),1.32-1.28(m,2H),1.06(s,9H).HRMS(ESI)C 60H 78ClFN 13O 7S +[M+H] +,1178.5535；实测值,1178.5531.
实施例198
(2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-((E)-4-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-4-oxobut-2-en-1-yl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)phenyl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(SIAIS249106)的制备
Figure PCTCN2020107177-appb-000252
参照实施例1的方法，采用达克替尼衍生物C和中间体LM(SIAIS1213061)制备得到目标化合物(SIAIS249106).(白色固体,13mg,56％). 1H NMR(500MHz,Methanol-d 4)δ9.26(s,1H),9.14(s,1H),8.75(s,1H),7.92(dt,J＝6.6,2.8Hz,1H),7.68-7.62(m,1H),7.49–7.45(m,2H),7.44–7.41(m,1H),7.39–7.31(m,2H),7.15(s,3H),7.07(dt,J＝14.7,7.1Hz,1H),6.88(d,J＝15.2Hz,1H),4.65–4.45(m,4H),4.38(d,J＝15.6Hz,1H),4.18(s,3H),4.09(s,2H),3.89(d,J＝11.0Hz,1H),3.79(dd,J＝10.9,4.0Hz,3H),3.62(d,J＝12.1Hz,2H),3.29–3.16(m,4H),2.92-2.81(m,5H),2.73(d,J＝7.7Hz,2H),2.63–2.53(m,2H),2.49(s,3H),2.48-2.45(m,1H),2.29–2.16(m,3H),2.13–2.00(m,1H),1.37–1.27(m,3H),0.97(s,9H),0.95–0.83(m,2H).HRMS(ESI)C 62H 74ClFN11O 7S+[M+H] +,1170.5160；实测值,1170.5161.
生物活性检测实验
材料：
Halt蛋白酶和磷酸酶抑制剂(Thermo Fisher)
Cell TITER BLUE检测试剂盒(Promega)
Cell TITER GLO检测试剂盒(Promega)
CCK8(WST)试剂(日本同仁化学研究所)
RPMI1640(GIBICO公司)
胎牛血清(GIBICO公司)
Penicillin-Streptomycin(青霉素和链霉素)(GIBICO公司)
SuperSignal West Pico Chemiluminescent Substrate(Thermo Fisher)
SuperSignal West Femto Maximum Sensitivity Substrate(Thermo Fisher)
Cycloheximide(Sigma)
抗体：
实验所使用的大部分抗体购自Cell Signaling Technology,其中包括EGFR(#4267S)；Tubulin和GAPDH的抗体来自Abcam公司。
细胞培养：
所使用的EGFR异常表达的细胞株如下：
HCC827细胞(EGFR Exon19del，非小细胞肺癌细胞)；
PC9细胞(EGFR Exon 19del，非小细胞肺癌细胞)；
PC9BracA1(EGFR Exon 19del+T790M，非小细胞肺癌细胞)
H1975(EGFR Exon T790M+L858R突变，非小细胞肺癌细胞株)
BT474细胞(HER2阳性乳腺癌细胞)
使用的肿瘤细胞系日常培养在含5％CO 2的37℃培养箱中。
HCC827和H1975细胞购自ATCC。PC9和PC9BracA1细胞来源参看文章(song，2015)和(Chmielecki,2011)。非小细胞肺癌细胞株培养基为添加有10％FCS和Penicillin-Streptomycin(青霉素和链霉素)的RPMI1640。乳腺癌细胞BT474细胞的培养基为添加有10％FCS，Insulin和Penicillin-Streptomycin(青霉素和链霉素)的RPMI1640。所使用细胞经过STR细胞鉴定为正确细胞，并通过常规检查为支原体阴性。
EGFR三突变细胞系PC9 DCT(Del19+T790M+C797S)的构建：将表达有人源EGFR的cDNA克隆至pLVX载体上，通过点突变的方式引入外显子19缺失突变(746-750)，T790M突变和C797S突变。通过慢病毒包装转入PC9细胞。通过荧光筛选获取稳定表达EGFR三突变的细胞。
蛋白质免疫印迹(Western Blot)
肿瘤细胞以1.5×10^5个细胞/每孔接种在含有1毫升RPMI1640培养基的12孔板里。第二天，以不同浓度的药物处理细胞(DMSO作为溶液体系，1微升不同浓度化合物加入1毫升细胞培养基中)。16小时后去除上清，用PBS洗涤细胞。将细胞置于冰上，加入含有Halt蛋白酶和磷酸酶抑制剂的RIPA蛋白裂解液处理细胞。裂解液经过4℃ 10000RPM离心10分钟后，收集上清。等量蛋白加入4XSDS上样液95℃ 5分钟变性处理后冻至-20C或者直接进行蛋白电泳。电泳凝胶采用金斯瑞，规格为4-20％梯度的蛋白预制胶。电泳槽及相关元件购自伯公乐司(Bio-rad)，电泳条件为等压120v 2小时。转膜使用PVDF膜，并将转膜系统置于冰上采用等流400毫安一个小时进行。转膜后，用TBST+5％奶粉封闭半小时。免疫印迹的具体步骤参考相应的抗体说明书。
化合物半抑制浓度(IC 50)测定：
本发明中化合物IC50采用氟元生物的WST试剂来进行测定。具体步骤如下：细胞以3000个细胞/每孔的数量接种在含有100微升含血清的RPMI培养基中。第二天，将原药及本发明化合物进行系列稀释后加至细胞中。本发明化合物处理72小时后，按照说明书将上述细胞活 性检测试剂加入培养液中进行细胞活性测定。阴性对照为DMSO，阳性对照为原药，采用与本发明化合物相同的处理方式处理细胞。本发明化合物对细胞的生长抑制通过Prism Graphpad软件进行绘制并从中统计本发明化合物IC50。具体结果如表所示。
实验结果
一、基于达克替尼的本发明化合物研究
1.1基于达克替尼的本发明化合物对于抑制EGFR细胞增殖研究
将各化合物在HCC827细胞和PC9细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用WST(CCK8)试剂进行检测，具体结果见表1所示。
由表1可知，各种基于达克替尼的化合物可以很好的抑制非小细胞肺癌HCC827和PC9细胞株的增殖(表3)。达克替尼对HCC827细胞的半数杀伤剂量为0.5nM，而本发明所提供的化合物具有与原药达克替尼相当的抑制效果；其中一些化合物与原药的半数杀伤剂量接近，例如，化合物(SIAIS262033)对细胞的增殖抑制为1.0nM左右。达克替尼对PC9细胞的半数杀伤剂量为0.4nM，达克替尼衍生物对细胞的杀伤剂量减弱，而本发明所提供的化合物具有与原药达克替尼相当的抑制效果；其中一些化合物与原药的半数杀伤剂量接近，例如，化合物(SIAIS249059)对细胞的增殖抑制为1.2nM左右。
此外，还对非小细胞肺癌细胞株H1975进行了浓度依赖性的研究，具体步骤同前，结果表明本发明所提供的化合物在H1975中也相应地表现出了细胞增殖抑制效果，详细结果如表2所示。
表1基于达克替尼系列的本发明化合物在肺腺癌EGFR突变靶向药物敏感细胞中的IC 50(半数抑制浓度)
待测化合物 肺腺癌细胞系 IC50(nM)
达克替尼(dacomitinib) HCC827(Exon19Del) 0.5
达克替尼衍生物A(SIAIS21983) HCC827(Exon19Del) 4.0
SIAIS219185 HCC827(Exon19Del) 15.7
SIAIS219186 HCC827(Exon19Del) 6.0
SIAIS219187 HCC827(Exon19Del) 6.7
SIAIS219188 HCC827(Exon19Del) 3.1
SIAIS219189 HCC827(Exon19Del) 3.8
SIAIS219190 HCC827(Exon19Del) 18.6
SIAIS219192 HCC827(Exon19Del) 16.4
SIAIS219193 HCC827(Exon19Del) 2.2
SIAIS219194 HCC827(Exon19Del) 5.3
SIAIS249034 HCC827(Exon19Del) 23.0
SIAIS249035 HCC827(Exon19Del) 10.0
SIAIS249036 HCC827(Exon19Del) 8.1
SIAIS249037 HCC827(Exon19Del) 6.6
SIAIS249038 HCC827(Exon19Del) 4.7
SIAIS249039 HCC827(Exon19Del) 5.2
SIAIS249046 HCC827(Exon19Del) 3.4
SIAIS249047 HCC827(Exon19Del) 23.6
SIAIS249048 HCC827(Exon19Del) 3.2
SIAIS249049 HCC827(Exon19Del) 4.6
SIAIS249056 HCC827(Exon19Del) 7.3
SIAIS249057 HCC827(Exon19Del) 11.5
SIAIS249058 HCC827(Exon19Del) 5.5
SIAIS249059 HCC827(Exon19Del) 11.1
SIAIS249060 HCC827(Exon19Del) 11.5
SIAIS249062 HCC827(Exon19Del) 3.7
SIAIS262001 HCC827(Exon19Del) 26.9
SIAIS262002 HCC827(Exon19Del) 26.1
SIAIS262003 HCC827(Exon19Del) 104.3
SIAIS262004 HCC827(Exon19Del) 7.2
SIAIS262005 HCC827(Exon19Del) 66.9
SIAIS262006 HCC827(Exon19Del) 35.5
SIAIS262007 HCC827(Exon19Del) 26.0
SIAIS262008 HCC827(Exon19Del) 46.6
SIAIS262013 HCC827(Exon19Del) 35.8
SIAIS262014 HCC827(Exon19Del) 39.5
SIAIS262015 HCC827(Exon19Del) 3.0
SIAIS262016 HCC827(Exon19Del) 4.5
SIAIS249041 HCC827(Exon19Del) 38.3
SIAIS249042 HCC827(Exon19Del) 31.3
SIAIS249043 HCC827(Exon19Del) 19.3
SIAIS249045 HCC827(Exon19Del) 41.9
达克替尼衍生物 HCC827(Exon19Del) 2.9
SIAIS262032 HCC827(Exon19Del) 3.3
SIAIS262033 HCC827(Exon19Del) 1.0
SIAIS262034 HCC827(Exon19Del) 3.6
SIAIS262035 HCC827(Exon19Del) 2.2
SIAIS262036 HCC827(Exon19Del) 2.4
SIAIS262037 HCC827(Exon19Del) 1.6
SIAIS262050 HCC827(Exon19Del) 0.8
SIAIS262051 HCC827(Exon19Del) 2.5
SIAIS262052 HCC827(Exon19Del) 1.4
SIAIS249077 HCC827(Exon19Del) 20
SIAIS249081 HCC827(Exon19Del) 12
SIAIS249082 HCC827(Exon19Del) 6
SIAIS249083 HCC827(Exon19Del) 5
SIAIS249084 HCC827(Exon19Del) 3
SIAIS249085 HCC827(Exon19Del) 3
SIAIS249086 HCC827(Exon19Del) 17
SIAIS262110 HCC827(Exon19Del) 20
SIAIS262112 HCC827(Exon19Del) 14
SIAIS262113 HCC827(Exon19Del) 49
SIAIS262114 HCC827(Exon19Del) 4
SIAIS262115 HCC827(Exon19Del) 4
SIAIS262116 HCC827(Exon19Del) 11
SIAIS262117 HCC827(Exon19Del) 16
SIAIS262118 HCC827(Exon19Del) 3
SIAIS249103 HCC827(Exon19Del) 12.8
SIAIS249104 HCC827(Exon19Del) 18.2
SIAIS249105 HCC827(Exon19Del) 54.3
SIAIS249106 HCC827(Exon19Del) 16.2
SIAIS262065 HCC827(Exon19Del) 3.1
SIAIS262071 HCC827(Exon19Del) 5.9
SIAIS262072 HCC827(Exon19Del) 16.9
SIAIS337021 HCC827(Exon19Del) 1.3
SIAIS337024 HCC827(Exon19Del) 1.1
SIAIS337025 HCC827(Exon19Del) 5.6
SIAIS337026 HCC827(Exon19Del) 0.5
SIAIS337027 HCC827(Exon19Del) 1.1
SIAIS337028 HCC827(Exon19Del) 0.9
SIAIS337029 HCC827(Exon19Del) 0.3
SIAIS337035 HCC827(Exon19Del) 4.3
SIAIS337036 HCC827(Exon19Del) 0.7
SIAIS337037 HCC827(Exon19Del) 0.3
SIAIS337038 HCC827(Exon19Del) 0.3
SIAIS337039 HCC827(Exon19Del) 5.7
SIAIS337040 HCC827(Exon19Del) 26.8
SIAIS249103 HCC827(Exon19Del) 12.8
SIAIS249104 HCC827(Exon19Del) 18.2
SIAIS249105 HCC827(Exon19Del) 54.3
SIAIS249106 HCC827(Exon19Del) 16.2
达克替尼(dacomitinib) PC9(Exon19Del) 0.4
达克替尼衍生物A(SIAIS21983) PC9(Exon19Del) 9.7
SIAIS219185 PC9(Exon19Del) 23.3
SIAIS219186 PC9(Exon19Del) 21.7
SIAIS219187 PC9(Exon19Del) 33.3
SIAIS219188 PC9(Exon19Del) 25.1
SIAIS219189 PC9(Exon19Del) 9.2
SIAIS219190 PC9(Exon19Del) 7.2
SIAIS219192 PC9(Exon19Del) 8.9
SIAIS219193 PC9(Exon19Del) 43.6
SIAIS219194 PC9(Exon19Del) 4.0
SIAIS249034 PC9(Exon19Del) 167
SIAIS249035 PC9(Exon19Del) 56.5
SIAIS249036 PC9(Exon19Del) 47.7
SIAIS249037 PC9(Exon19Del) 28.7
SIAIS249038 PC9(Exon19Del) 22.9
SIAIS249039 PC9(Exon19Del) 18.7
SIAIS249046 PC9(Exon19Del) 57
SIAIS249048 PC9(Exon19Del) 10.3
SIAIS249049 PC9(Exon19Del) 16.0
SIAIS249056 PC9(Exon19Del) 4.0
SIAIS249057 PC9(Exon19Del) 7.8
SIAIS249058 PC9(Exon19Del) 9.9
SIAIS249059 PC9(Exon19Del) 1.2
SIAIS249060 PC9(Exon19Del) 16
SIAIS249062 PC9(Exon19Del) 10
SIAIS262001 PC9(Exon19Del) 53
SIAIS262002 PC9(Exon19Del) 78
SIAIS262004 PC9(Exon19Del) 15
SIAIS262005 PC9(Exon19Del) 84
SIAIS262006 PC9(Exon19Del) 73
SIAIS262007 PC9(Exon19Del) 84
SIAIS262013 PC9(Exon19Del) 28
SIAIS262014 PC9(Exon19Del) 128
SIAIS262015 PC9(Exon19Del) 12
SIAIS262016 PC9(Exon19Del) 112
SIAIS249041 PC9(Exon19Del) 99
SIAIS249043 PC9(Exon19Del) 70.6
SIAIS249045 PC9(Exon19Del) 691
达克替尼衍生物 PC9(Exon19Del) 2.3
SIAIS262032 PC9(Exon19Del) 43.5
SIAIS262033 PC9(Exon19Del) 3.8
SIAIS262034 PC9(Exon19Del) 11.3
SIAIS262035 PC9(Exon19Del) 6.1
SIAIS262036 PC9(Exon19Del) 6.7
SIAIS262037 PC9(Exon19Del) 2.1
SIAIS262050 PC9(Exon19Del) 9.9
SIAIS262051 PC9(Exon19Del) 2.5
SIAIS262052 PC9(Exon19Del) 1.3
SIAIS249077 PC9(Exon19Del) 0.8
SIAIS249081 PC9(Exon19Del) 32.6
SIAIS249082 PC9(Exon19Del) 6.1
SIAIS249083 PC9(Exon19Del) 2.9
SIAIS249084 PC9(Exon19Del) 0.6
SIAIS249085 PC9(Exon19Del) 7.9
SIAIS249086 PC9(Exon19Del) 34.2
SIAIS262110 PC9(Exon19Del) 73.0
SIAIS262112 PC9(Exon19Del) 42.5
SIAIS262113 PC9(Exon19Del) 3.9
SIAIS262114 PC9(Exon19Del) 11.9
SIAIS262115 PC9(Exon19Del) 7.2
SIAIS262116 PC9(Exon19Del) 3.3
SIAIS262117 PC9(Exon19Del) 31.2
SIAIS262118 PC9(Exon19Del) 3.8
SIAIS249103 PC9(Exon19Del) 20.4
SIAIS249104 PC9(Exon19Del) 37.6
SIAIS249105 PC9(Exon19Del) 60.5
SIAIS249106 PC9(Exon19Del) 50.1
SIAIS262065 PC9(Exon19Del) 185
SIAIS337021 PC9(Exon19Del) 74
SIAIS337024 PC9(Exon19Del) 13
SIAIS337025 PC9(Exon19Del) 36
SIAIS337026 PC9(Exon19Del) 8.6
SIAIS337027 PC9(Exon19Del) 13.2
SIAIS337028 PC9(Exon19Del) 20.3
SIAIS337029 PC9(Exon19Del) 28.4
SIAIS337035 PC9(Exon19Del) 6.3
SIAIS337036 PC9(Exon19Del) 1.3
SIAIS337037 PC9(Exon19Del) 0.7
SIAIS337038 PC9(Exon19Del) 1.6
SIAIS337039 PC9(Exon19Del) 19.7
SIAIS249103 PC9(Exon19Del) 20.4
SIAIS249104 PC9(Exon19Del) 37.6
SIAIS249105 PC9(Exon19Del) 60.5
SIAIS249106 PC9(Exon19Del) 50.1
表2基于达克替尼系列的本发明化合物在肺腺癌EGFR靶向药物耐药细胞中的IC 50(半数抑制浓度
细胞系 测试化合物名称 IC 50(nΜ)
H1975(L858R+T790M) 达克替尼Dacomitinib 833.5
H1975(L858R+T790M) SIAIS249081 114.3
H1975(L858R+T790M) SIAIS249085 951.8
H1975(L858R+T790M) SIAIS262115 550.5
H1975(L858R+T790M) SIAIS262118 298.7
H1975(L858R+T790M) SIAIS262034 828.2
H1975(L858R+T790M) SIAIS262035 513.9
H1975(L858R+T790M) SIAIS262036 511.0
PC9Brca1(Ex19del+T790M) 达克替尼Dacomitinib 674
PC9Brca1(Ex19del+T790M) SIAIS249083 435
PC9Brca1(Ex19del+T790M) SIAIS249084 434
PC9Brca1(Ex19del+T790M) SIAIS249085 481
PC9Brca1(Ex19del+T790M) SIAIS262115 488
PC9Brca1(Ex19del+T790M) SIAIS262118 205
PC9Brca1(Ex19del+T790M) SIAIS262021 953.9
PC9Brca1(Ex19del+T790M) SIAIS262032 437.6
PC9Brca1(Ex19del+T790M) SIAIS262035 491.4
PC9Brca1(Ex19del+T790M) SIAIS262036 260.4
1.2基于达克替尼的本发明化合物对于靶蛋白EGFR表达水平的研究
将基于达克替尼设计合成的各化合物对在非小细胞肺癌细胞系HCC827、H1975中的EGFR总蛋白分别进行了研究。HCC827细胞具有EGFR19号外显子缺失突变，H1975具有 L858R和T790M基因突变。
首先在HCC827细胞中用不同浓度(1，10,50，100，500nM)的达克替尼处理细胞16小时。细胞裂解液通过蛋白质免疫印迹的方法来检测达克替尼对EGFR蛋白含量的影响，蛋白降解结果如图1所示。结果显示高浓度500nM达克替尼本身不降解EGFR蛋白。
将本发明所提供的基于达克替尼衍生物A系列和B系列的化合物对EGFR蛋白的降解效果分别如图1和图2所示。大部分化合物在随着浓度的提高都可以观察到EGFR蛋白降解。图2中，对非小细胞肺癌细胞株H1975(T790M突变细胞株，一代EGFR抑制剂最常见的突变类型)进行了浓度依赖性的降解实验研究。结果表明本发明所提供的化合物在H1975中也表现出了较好的EGFR降解效果。细胞抑制活性较好的化合物SIAIS262032,SIAIS262035，SIAIS262037都在H1975细胞系中表现出较强的EGFR蛋白降解，SIAIS262032和SIAIS262037降解的DC50均在50nM左右，为可以克服T790M突变的药物研发提供了很大潜能。
二、基于波齐替尼设计开发的本发明化合物研究
1.1基于波齐替尼的本发明化合物对于抑制EGFR突变细胞增殖的研究
将各化合物在HCC827和PC9细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用WST(CCK8)试剂进行检测，具体结果见表2所示。
各种基于波齐替尼的化合物可以很好的抑制非小细胞肺癌HCC827和PC9细胞株的增殖(表3)。波齐替尼对HCC827细胞的半数杀伤剂量为0.5nM，而本发明所提供的化合物具有与原药波齐替尼接近的抑制效果。
表3波齐替尼系列的本发明化合物在肺腺癌细胞细胞系中IC 50(半数抑制浓度)
细胞系 测试化合物名称 IC 50(nΜ)
HCC827(Exon19Del) 波齐替尼(poziotinib) 0.5
HCC827(Exon19Del) 波齐替尼衍生物A(SIAIS219149) 7.1
HCC827(Exon19Del) SIAIS249029 80
HCC827(Exon19Del) SIAIS249030 6.3
HCC827(Exon19Del) SIAIS249031 28.2
HCC827(Exon19Del) SIAIS249032 11.0
HCC827(Exon19Del) SIAIS249033 13.0
HCC827(Exon19Del) SIAIS219177 8.2
HCC827(Exon19Del) SIAIS219179 20.2
HCC827(Exon19Del) SIAIS219180 26.7
HCC827(Exon19Del) SIAIS219181 23.1
HCC827(Exon19Del) SIAIS249014 51
HCC827(Exon19Del) SIAIS249015 46
HCC827(Exon19Del) SIAIS249016 29
HCC827(Exon19Del) SIAIS249017 23
HCC827(Exon19Del) SIAIS249018 13.3
HCC827(Exon19Del) SIAIS249019 38
HCC827(Exon19Del) SIAIS219164 33
HCC827(Exon19Del) SIAIS219165 23
HCC827(Exon19Del) SIAIS219166 30
HCC827(Exon19Del) SIAIS219167 31
HCC827(Exon19Del) SIAIS219168 40
HCC827(Exon19Del) SIAIS219169 38
HCC827(Exon19Del) SIAIS249024 174
HCC827(Exon19Del) SIAIS249025 158
HCC827(Exon19Del) SIAIS249026 266
HCC827(Exon19Del) SIAIS249027 400
HCC827(Exon19Del) SIAIS249028 240
HCC827(Exon19Del) SIAIS249020 75.5
HCC827(Exon19Del) SIAIS249021 75.4
HCC827(Exon19Del) SIAIS249022 40
HCC827(Exon19Del) SIAIS249023 49
PC9(Exon19Del) 波齐替尼(poziotinib) <0.1
PC9(Exon19Del) 波齐替尼衍生物A(SIAIS219149) 17
PC9(Exon19Del) SIAIS219165 3
PC9(Exon19Del) SIAIS219177 38
PC9(Exon19Del) SIAIS249015 130
三、基于吉非替尼及sapitinib设计开发的本发明化合物研究
1.1基于吉非替尼及sapitinib(AZD8931)的本发明化合物对于抑制EGFR细胞增殖研究
将各化合物在HCC827细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用WST(CCK8)试剂进行检测。实验重复3次以上，具体结果见表3所示。
基于吉非替尼衍生物A、B合成的PROTAD化合物可以抑制非小细胞肺癌HCC827细胞的增殖，但是与阳性药有一定的差距(表3)。基于吉非替尼衍生物C合成的PROTAD化合物可以很好的抑制非小细胞肺癌HCC827细胞的增殖，吉非替尼对HCC827细胞的半数杀伤剂量为4.8nM，而本发明所提供的化合物293052具有与原药吉非替尼接近的抑制效果。基于sapitinib(AZD8931)合成的化合物都具有很好的细胞抑制水平，如化合物293067比阳性药效果更好。
表4吉非替尼及sapitinib系列的本发明化合物在肺腺癌细胞细胞系中IC 50(半数抑制浓度)
细胞系 测试化合物名称 IC 50(nΜ)
HCC827(Exon19Del) 吉非替尼(gefitinib) 6
HCC827(Exon19Del) 吉非替尼衍生物A(SIAIS184161) 10
HCC827(Exon19Del) SIAIS184164 47
HCC827(Exon19Del) SIAIS184165 58
HCC827(Exon19Del) SIAIS184166 80
HCC827(Exon19Del) SIAIS184168 43
HCC827(Exon19Del) SIAIS184169 22
HCC827(Exon19Del) SIAIS184170 186
HCC827(Exon19Del) SIAIS184184 100
HCC827(Exon19Del) SIAIS184185 113
HCC827(Exon19Del) SIAIS184186 124
HCC827(Exon19Del) 吉非替尼衍生物C(SIAIS293033) 575
HCC827(Exon19Del) SIAIS293047 12
HCC827(Exon19Del) SIAIS293048 23
HCC827(Exon19Del) SIAIS293049 2.8
HCC827(Exon19Del) SIAIS293050 1.5
HCC827(Exon19Del) SIAIS293051 6.5
HCC827(Exon19Del) SIAIS293052 0.25
HCC827(Exon19Del) SIAIS262080 41
HCC827(Exon19Del) SIAIS262085 145
HCC827(Exon19Del) SIAIS262086 59
HCC827(Exon19Del) SIAIS262087 31
HCC827(Exon19Del) SIAIS262089 102
HCC827(Exon19Del) SIAIS262090 47
PC9(Exon19Del) 吉非替尼(gefitinib) 97
PC9(Exon19Del) SIAIS184166 692
PC9(Exon19Del) SIAIS184168 317
PC9(Exon19Del) SIAIS184169 318
HCC827(Exon19Del) Sapitinib(AZD8931) 0.4
HCC827(Exon19Del) SIAIS293067 0.3
HCC827(Exon19Del) SIAIS293068 1.2
HCC827(Exon19Del) SIAIS293069 9.4
HCC827(Exon19Del) SIAIS293070 14.0
四、基于阿法替尼设计开发的本发明化合物研究
将各化合物在HCC827细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用WST(CCK8)试剂进行检测，具体结果见表5。
各种基于阿法替尼的化合物可以很好的抑制非小细胞肺癌HCC827细胞株的增殖(表5)。阿法替尼对HCC827细胞的半数杀伤剂量为1.1nM，而本发明所提供的化合物具有与原药阿 法替尼接近的抑制效果。
表5阿法替尼系列的本发明化合物在肺腺癌细胞细胞系中IC 50(半数抑制浓度)
细胞系 测试化合物名称 IC 50(nΜ)
HCC827(Exon19Del) 阿法替尼(afatinib) 1.1
HCC827(Exon19Del) 阿法替尼衍生物A(SIAIS184181) 8
HCC827(Exon19Del) SIAIS184093 86.2
HCC827(Exon19Del) SIAIS184094 104.6
HCC827(Exon19Del) SIAIS184095 174.2
HCC827(Exon19Del) SIAIS184152 131
HCC827(Exon19Del) SIAIS184153 315.8
HCC827(Exon19Del) SIAIS184154 249.6
HCC827(Exon19Del) SIAIS184155 79
HCC827(Exon19Del) SIAIS184156 977.7
HCC827(Exon19Del) SIAIS1210085 481.3
HCC827(Exon19Del) SIAIS1210087 237.8
HCC827(Exon19Del) SIAIS1210089 159.5
五、基于卡奈替尼的本发明化合物研究
5.1基于卡奈替尼的本发明化合物对于抑制EGFR细胞增殖研究
将各化合物在HCC827和PC9细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用CCK8试剂进行检测，具体结果见表5所示。
各种基于卡奈替尼的化合物可以很好的抑制非小细胞肺癌HCC827和PC9细胞株的增殖(表6)。卡奈替尼对HCC827细胞的半数杀伤剂量为0.7nM，对PC9细胞的半数杀伤剂量为0.9nM，而本发明所提供的化合物具有与原药卡奈替尼相当的抑制效果；其中一些化合物与原药的半数杀伤剂量接近，例如，化合物(SIAIS262125)对细胞的增殖抑制为0.3nM左右。
此外，还对非小细胞肺癌细胞株H1975和PC9Brca1细胞(T790M突变细胞株，一代EGFR抑制剂最常见的突变类型)进行了浓度依赖性的研究，结果表明本发明所提供的化合物在H1975和PC9Brc1中也表现出了较强的细胞增殖抑制效果(表7)。很多化合物都表现出了比卡奈替尼更好的抑制效果，如化合物(SIAIS262125)及化合物(SIAIS262182)对H1975的增殖抑制都小于25nM，这为筛选得到可以克服T790M突变的PROTAD药物奠定了强有力的基础。
表6基于卡奈替尼系列的本发明化合物在肺腺癌细胞中的IC 50(半数抑制浓度)
Figure PCTCN2020107177-appb-000253
表7基于卡奈替尼系列的本发明化合物在肺腺癌靶向药物耐药细胞中的IC 50(半数抑制浓度)
Figure PCTCN2020107177-appb-000254
Figure PCTCN2020107177-appb-000255
NA:not available
5.2基于卡奈替尼的本发明化合物对于靶蛋白EGFR表达水平的研究
将基于卡奈替尼设计合成的各化合物对在非小细胞肺癌细胞系H1975中的EGFR总蛋白分别进行了研究。H1975具有L858R和T790M基因突变。
首先在H1975细胞中用不同浓度(1，10,50，100，500nM)的PROTAD化合物处理细胞16小时。细胞裂解液通过蛋白质免疫印迹的方法来检测化合物对EGFR蛋白含量的影响，蛋白降解结果如图3所示。细胞抑制活性较好地化合物SIAIS262125,SIAIS262180，SIAIS262182都在H1975细胞系中表现出较强的EGFR蛋白降解，侧面说明降解EGFR靶蛋白的重要性。SIAIS262125和SIAIS262182降解的DC50均小于10nM，大大优于阳性对照物，为可以克服T790M突变的药物研发提供了很大潜能。
此外，还对卡奈替尼的本发明化合物进行了EGFR磷酸化水平的影响(图4)。结果表明，基于卡奈替尼的本发明化合物对EGFR蛋白水平磷酸化的抑制显著优于卡奈替尼本身。
六基于奥希替尼的本发明化合物活性研究
6.1基于奥希替尼的本发明化合物在肺腺癌中的增殖抑制活性
将各化合物在EGFR突变的HCC827、PC9、H1975、PC9Brc1细胞里进行了剂量依赖性实验。该细胞含有EGFR19号外显子缺失突变，并对EGFR的抑制剂高度敏感。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用CCK8试剂进行检测，具体结果见表8所示。
表8基于奥希替尼系列的本发明化合物在肺腺癌细胞中的IC 50(半数抑制浓度)
待测化合物 细胞 IC50(nM)
奥希替尼osimertinib HCC827 0.36
SIAIS337051 HCC827 1.0
SIAIS337052 HCC827 352.6
SIAIS337055 HCC827 460.8
SIAIS337056 HCC827 113.8
SIAIS337057 HCC827 47.7
SIAIS337059 HCC827 46.7
SIAIS337060 HCC827 121.5
SIAIS337061 HCC827 352.6
SIAIS337074 HCC827 3
SIAIS337075 HCC827 170
SIAIS337076 HCC827 10
SIAIS337077 HCC827 36
SIAIS337078 HCC827 125
SIAIS337079 HCC827 879
SIAIS337080 HCC827 770
SIAIS337081 HCC827 184
SIAIS337082 HCC827 8
SIAIS337083 HCC827 46
SIAIS337084 HCC827 353
SIAIS337085 HCC827 6
SIAIS337086 HCC827 3
SIAIS337087 HCC827 91
SIAIS337088 HCC827 5
SIAIS337089 HCC827 15
SIAIS337090 HCC827 9
奥希替尼osimertinib PC9 4
SIAIS337051 PC9 2
SIAIS337074 PC9 91
SIAIS337076 PC9 459
SIAIS337079 PC9 373
SIAIS337080 PC9 103
SIAIS337081 PC9 134
SIAIS337082 PC9 89
SIAIS337083 PC9 512
SIAIS337084 PC9 271
SIAIS337085 PC9 143
SIAIS337086 PC9 64
SIAIS337087 PC9 320
SIAIS337088 PC9 302
SIAIS337089 PC9 82
SIAIS337090 PC9 161
奥希替尼osimertinib H1975 2
SIAIS337051 H1975 1
SIAIS337057 H1975 21
SIAIS337060 H1975 171
SIAIS337074 H1975 145
SIAIS337076 H1975 187
SIAIS337079 H1975 70
SIAIS337080 H1975 34
SIAIS337081 H1975 18
SIAIS337082 H1975 55
SIAIS337083 H1975 494
SIAIS337085 H1975 462
SIAIS337086 H1975 203
SIAIS337087 H1975 242
SIAIS337088 H1975 239
SIAIS337089 H1975 16
SIAIS337090 H1975 117
奥希替尼osimertinib Pc9Brc1 354
SIAIS337051 Pc9Brc1 479
SIAIS337056 Pc9Brc1 973
SIAIS337074 Pc9Brc1 238
SIAIS337076 Pc9Brc1 303
SIAIS337079 Pc9Brc1 366
SIAIS337080 Pc9Brc1 520
SIAIS337081 Pc9Brc1 207
SIAIS337082 Pc9Brc1 218
SIAIS337083 Pc9Brc1 676
SIAIS337084 Pc9Brc1 686
SIAIS337085 Pc9Brc1 239
SIAIS337086 Pc9Brc1 194
SIAIS337087 Pc9Brc1 598
SIAIS337088 Pc9Brc1 662
SIAIS337089 Pc9Brc1 107
SIAIS337090 Pc9Brc1 413
七、本发明化合物对EGFR三突变阳性的细胞具有良好的抗肿瘤作用
进一步使用了过表达EGFR三突变(Del+T790M+C797S)的PC9细胞进行了细胞杀伤实验。结果显示(表9)波齐替尼化合物与波齐替尼衍生物前药相比可以更好地抑制具有EGFR靶向药物耐药的三突变细胞的生长。
我们使用本发明化合物处理EGFR三突变(Del+T790M+C797S)细胞，结果表明本发明化合物可以有效地降解具有突变的EGFR蛋白(图5)。说明本发明化合物对含耐药突变的EGFR三突变肺腺癌细胞具有良好的抗肿瘤作用。
表9基于卡奈替尼系列的本发明化合物在EGFR三突变肺腺癌细胞中的IC 50(半数抑制浓度)
待测化合物 细胞 IC50(nM)
PC9(Del+T790M+C797S) 波齐替尼衍生物A(SIAIS219149) 5.2
PC9(Del+T790M+C797S) SIAIS219164 4.8
PC9(Del+T790M+C797S) SIAIS219165 4.6
PC9(Del+T790M+C797S) SIAIS219166 4.6
PC9(Del+T790M+C797S) SIAIS219167 4.1
PC9(Del+T790M+C797S) SIAIS219168 2.9
PC9(Del+T790M+C797S) SIAIS219169 3.6
PC9(Del+T790M+C797S) SIAIS219177 2.4
PC9(Del+T790M+C797S) SIAIS219179 3.9
PC9(Del+T790M+C797S) SIAIS219180 3.3
PC9(Del+T790M+C797S) SIAIS219181 3.8
PC9(Del+T790M+C797S) SIAIS249014 1.8
PC9(Del+T790M+C797S) SIAIS249015 4.7
PC9(Del+T790M+C797S) SIAIS249016 1.5
PC9(Del+T790M+C797S) SIAIS249017 2.2
八、本发明化合物在HER2阳性乳腺癌细胞系中的抗肿瘤作用
将各化合物在BT474HER2阳性乳腺癌细胞里进行了剂量依赖性实验。该细胞高度表达HER2蛋白。化合物以不同浓度(10μM起始，3倍稀释因子，10个浓度)对细胞进行处理72小时后，细胞利用CCK8试剂进行检测，具体结果见表10所示。部分本发明化合物如SIAIS262125等显示出了优于原药的优越活性。
同时，我们还对BT474中的HER2蛋白进行了研究，结果表明本发明化合物在高浓度对HER2有一定的降解功能(图6)。
表10基于卡奈替尼系列的本发明化合物在肺腺癌细胞中的IC 50(半数抑制浓度)
细胞 待测化合物 IC50(nM)
BT474 波齐替尼poziotinib <0.1
BT474 SIAIS219149 81.2
BT474 SIAIS219165 2.7
BT474 SIAIS219177 35.9
BT474 SIAIS249015 87.0
BT474 卡奈替尼Caneritinib 17.5
BT474 SIAIS249092 1.2
BT474 SIAIS249099 35.6
BT474 SIAIS249102 3.8
BT474 SIAIS262121 5.3
BT474 SIAIS262122 48.0
BT474 SIAIS262123 48.9
BT474 SIAIS262124 16.4
BT474 SIAIS262125 9.6
BT474 SIAIS262126 17.6
BT474 SIAIS262128 42.1
BT474 SIAIS262131 5.1
BT474 SIAIS262182 5.0
BT474 Canertinib B NA
BT474 SIAIS249153 15.3
BT474 SIAIS262174 28.2
BT474 SIAIS262175 22.5
BT474 SIAIS262176 1.4
BT474 SIAIS262177 8.2
BT474 SIAIS262178 2.1
BT474 SIAIS262179 14.6
BT474 SIAIS262180 4.4
BT474 SIAIS262183 11.9
BT474 达克替尼衍生物SIAIS262021 32.6
BT474 SIAIS262033 0.7
BT474 SIAIS262035 2.1
BT474 SIAIS262036 0.3
BT474 SIAIS262037 0.9
BT474 SIAIS249077 12.35
BT474 SIAIS249082 52.48
BT474 SIAIS249083 64.93
BT474 SIAIS249084 6.077
BT474 SIAIS249085 39.29
BT474 SIAIS262113 67.72
BT474 SIAIS262114 89.98
BT474 SIAIS262115 33.66
BT474 SIAIS262116 82.99
BT474 SIAIS262117 483.7
BT474 SIAIS262118 63.16
BT474 SIAIS262064 1.846
BT474 SIAIS337024 51.46
NA:Not available
综上所述，本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术 的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。

Claims (43)

  1. 一种双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，所述双功能化合物的化学结构式如式I所示：
    Figure PCTCN2020107177-appb-100001
    其中，EGFR Binders可以结合EGFR蛋白；
    ULM表示：
    Figure PCTCN2020107177-appb-100002
    其中，A选自-CH 2-、-(C＝O)-；
    B、X、Y、Z各自独立地选自CH、N；
    R选自-S-、-SO-、-SO 2-、
    Figure PCTCN2020107177-appb-100003
    -CH 2-、-(C＝O)-、-NH-、-O-、亚乙炔基、或者不存在；
    D选自-(C＝O)-、或D不存在；
    或者，ULM表示：
    Figure PCTCN2020107177-appb-100004
    其中，Z选自-(C＝O)-、或Z不存在；
    或者，ULM表示：
    Figure PCTCN2020107177-appb-100005
    其中，A选自-CH 2-、-NR’-、-O-、-S-、-(C＝O)-，其中，R’选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
    B选自-(C＝O)-、或B不存在；
    D 1、D 2、D 3、D 4、D 5、D 6、D 7、D 8各自独立地选自F、Cl、Br、OH、Me、Et、iPr、H和D；
    LIN表示分别与EGFR Binders和ULM通过共价键连接的连接基团。
  2. 如权利要求1所述的双功能化合物，其特征在于，EGFR Binders选自EGFR TKIs，所述EGFR TKIs可以作用于EGFR胞内蛋白酪氨酸激酶区。
  3. 如权利要求2所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下所示的基团：
    Figure PCTCN2020107177-appb-100006
    其中，R 1、R 2、R 3、R 4各自独立地选自H、卤素、Cl、F、C 1-10烷基、C 1-10卤代烷基、C 1-10炔基、C 1-10烷氧基、芳基甲氧基、杂芳基甲氧基，所述芳基甲氧基和杂芳基甲氧基中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素和C 1-10卤代烷基的取代基取代；
    R 5和R 6其中之一与LIN通过共价键连接、且形成选自-NR”-、化学结构式如下所示的基团，R”选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
    Figure PCTCN2020107177-appb-100007
    其中，P 1选自
    Figure PCTCN2020107177-appb-100008
    CHR b，其中，R b选自-NH-、亚哌嗪基，n＝0～3，R c表示亚乙烯 基或不存在；
    R 5、R 6其中之一选自H、N、卤素、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基、氨基、酰氨基、烷基氨基、C 1-10二烷基氨基、氰基、芳基、杂芳基、呋喃基、吡咯基、咪唑基、恶唑基、异恶唑基、三唑基、C 3-9环烷基、C 3-9环烷基氧基、杂环烷基、杂环烷基氧基、-NHC(O)R 14，其中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素、C 1-10卤代烷基、氰基、R 7SO 2(CH 2)sNHCH 2-、-OR 8、-NHC(O)R 9的取代基取代，其中，R 7选自C 1-10烷基且s为0、1、2、3，R 8选自任选地被独立地选自羟基、C 1-10烷氧基、氨基、C 1-10烷基氨基、C 1-10二烷基氨基单取代或多取代的C 1-10烷基，R 9选自如下所示的基团：
    Figure PCTCN2020107177-appb-100009
    R 10、R 11各自独立地选自H、C 1-10烷基；
    R 12、R 13各自独立地选自H、C 1-10烷基，或者与相邻的氮原子一起形成杂环烷基；
    R 14选自C 1-10烷基、烯基。
  4. 如权利要求3所述的双功能化合物，其特征在于，式V中，R 1、R 2、R 3、R 4各自独立地选自H、卤素、Cl、F；
    R 5和R 6其中之一与LIN通过共价键连接、且形成选自-NR”-、或化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100010
    其中，P 1选自
    Figure PCTCN2020107177-appb-100011
    CHR b，其中，R b选自-NH-、亚哌嗪基，n＝0～3，R c表示亚乙烯基或不存在；
    R”选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基；
    R 5、R 6其中之一选自C 1-C 10烷氧基、杂环烷基氧基、-NHC(O)R 14，R 14选自C 1-C 10烷基、烯基。
  5. 如权利要求4所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100012
  6. 如权利要求2所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下所示的基团：
    Figure PCTCN2020107177-appb-100013
    其中，R 16、R 17、R 18、R 19、R 20各自独立地选自H、OH、F、Br、Cl、OMe；
    R 15与LIN通过共价键连接、且形成选自化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100014
    其中，P 2选自
    Figure PCTCN2020107177-appb-100015
    CHR d，其中，R d选自-NH-、亚哌嗪基。
  7. 如权利要求6所述的双功能化合物，其特征在于，式VI中，R 16、R 17、R 18、R 19、R 20各自独立地选自H、OH、F；
    R 15与LIN通过共价键连接、且形成选自化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100016
    其中，P 2选自
    Figure PCTCN2020107177-appb-100017
    CHR d，其中，R d选自-NH-、亚哌嗪基。
  8. 如权利要求7所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100018
  9. 如权利要求2所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下所示的基团：
    Figure PCTCN2020107177-appb-100019
    R 21和R 22其中之一与LIN通过共价键连接、且形成选自-NR”’-、化学结构式如下所示的基团，R”’选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
    Figure PCTCN2020107177-appb-100020
    Figure PCTCN2020107177-appb-100021
    其中，P 3选自
    Figure PCTCN2020107177-appb-100022
    CHR e，其中，R e选自-NH-、亚哌嗪基，n＝0、1、2、或3，R c’表示亚乙烯基或不存在；
    R 21、R 22其中之一选自H、N、卤素、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基、氨基、酰氨基、烷基氨基、C 1-10二烷基氨基、氰基、芳基、杂芳基、呋喃基、吡咯基、咪唑基、恶唑基、异恶唑基、三唑基、C 3-9环烷基、C 3-9环烷基氧基、杂环烷基、杂环烷基氧基、-NHC(O)R 31，其中，芳基和杂芳基为未取代的、或被1-2个选自C 1-10烷基、卤素、C 1-10卤代烷基、氰基、R 24SO 2(CH 2)sNHCH 2-、-OR 25、-NHC(O)R 26的取代基取代，其中，R 24选自C 1-10烷基且s为0、1、2、3，R 25选自任选地被独立地选自羟基、C 1-10烷氧基、氨基、C 1-10烷基氨基、C 1-10二烷基氨基单取代或多取代的C 1-10烷基，R 26选自如下所示的基团：
    Figure PCTCN2020107177-appb-100023
    R 27、R 28各自独立地选自H、C 1-10烷基；
    R 29、R 30各自独立地选自H、C 1-10烷基，或者与相邻的氮原子一起形成杂环烷基；
    R 31选自C 1-10烷基、烯基。
  10. 如权利要求9所述的双功能化合物，其特征在于，R 21和R 22其中之一与LIN通过共价键连接、且形成选自-NR”’-、化学结构式如下所示的基团，R”’选自H、直链或支链的C 1-C 10烷基或C 3-C 9环烷基：
    Figure PCTCN2020107177-appb-100024
    其中，P 3选自
    Figure PCTCN2020107177-appb-100025
    CHR e，其中，R e选自-NH-、亚哌嗪基，n＝0、1、2、或3，R c’表示亚乙烯基或不存在；
    R 21、R 22其中之一选自C 1-C 10烷氧基、杂环烷基氧基、-NHC(O)R 23、
    Figure PCTCN2020107177-appb-100026
    Figure PCTCN2020107177-appb-100027
    R 23选自C 1-C 10烷基、烯基，其中，n＝0、1、2、或3。
  11. 如权利要求9所述的双功能化合物，其特征在于，所述EGFR TKIs表示化学结构式如下之一所示的基团：
    Figure PCTCN2020107177-appb-100028
  12. 如权利要求1所述的双功能化合物，其特征在于，所述LIN表示：
    -W-亚烷基-；
    其中，所述亚烷基是可选地被一或多个选自以下的基团中断一次或多次的直链或支链的亚烷基：-O-、-CONH-、-NHCO-、-NH-、-NHCONH-、-S-、亚磺酰基、磺酰基、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一个或多个取代基取代；
    W选自-(C＝O)-、-(C＝O)O-、-NR””-、或不存在，其中R””选自H、直链或支链的C 1-C 10亚烷基或C 3-C 10亚环烷基。
  13. 如权利要求12所述的双功能化合物，其特征在于，所述直链或支链的亚烷基的取代基各自独立地选自羟基、氨基、巯基和卤素。
  14. 如权利要求12所述的双功能化合物，其特征在于，所述亚烷基为C 1-30亚烷基。
  15. 如权利要求12所述的双功能化合物，其特征在于，所述LIN表示：
    -W-C 1-30亚烷基-、-W-(CH 2) n1-(O(CH 2) n2) m1-、-W-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-、-W-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-(CH 2) n3-、-W-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-W-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-、-W-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-、-W-(CH 2) n1-(NHCO-(CH 2) n2) m1-、-W-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-、-W-(CH 2) n1-CONH-(O(CR a27R a28) n2) m1-、-(CH 2) n1-NHCONH-(CH 2) n2-、-(CH 2) n1-S-(CH 2) n2-、-(CH 2) n1-SO-(CH 2) n2-、-(CH 2) n1-SO 2-(CH 2) n2-、-(CH 2) n1-CH＝CH-(CH 2) n2-、-(CH 2) n1-C≡C-(CH 2) n2-、-(CH 2) n1-C≡C-C≡C-(CH 2) n2-、-(CH 2) n1-哌嗪亚基-(CH 2) n2-、-(CH 2) n1-亚苯基-(CH 2) n2-、和其碳链被一个或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一次或多次的-W-(CH 2) n1-(O(CH 2) n2) m1-；
    R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26、R a27、R a28分别独立地选自H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26、R a27、R a28不同时为H；
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
  16. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2-、-W-(CH 2) 2-、-W-(CH 2) 3-、-W-(CH 2) 4-、-W-(CH 2) 5-、-W-(CH 2) 6-、-W-(CH 2) 7-、-W-(CH 2) 8-、-W-(CH 2) 9-、-W-(CH 2) 10-、-W-(CH 2) 11-、-W-(CH 2) 12-、-W-(CH 2) 13-、-W-(CH 2) 14-、-W-(CH 2) 15-、-W-(CH 2) 16-、-W-(CH 2) 17-、-W-(CH 2) 18-、-W-(CH 2) 19-；-W-(CH 2) 20-；-W-(CH 2) 21-；-W-(CH 2) 22-；-W-(CH 2) 23-、-W-(CH 2) 24-、-W-(CH 2) 25-、-W-(CH 2) 26-、-W-(CH 2) 27-、-W-(CH 2) 28-、-W-(CH 2) 29-、或-W-(CH 2) 30-。
  17. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2-O-(CH 2) 2-、-W-CH 2-(O(CH 2) 2) 2-、-W-CH 2-(O(CH 2) 2) 3-、-W-CH 2-(O(CH 2) 2) 4-、-W-CH 2-(O(CH 2) 2) 5-、-W-CH 2-(O(CH 2) 2) 6-、-W-CH 2-(O(CH 2) 2) 7-、-W-CH 2-(O(CH 2) 2) 8-、-W-CH 2-(O(CH 2) 2) 9-、-W-CH 2-(O(CH 2) 2) 10-、-W-(CH 2) 2-O-(CH 2) 2-、-W-(CH 2) 2-(O(CH 2) 2) 2-、 -W-(CH 2) 2-(O(CH 2) 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-、-W-(CH 2) 2-(O(CH 2) 2) 5-、-W-(CH 2) 2-(O(CH 2) 2) 6-、-W-(CH 2) 2-(O(CH 2) 2) 7-、-W-(CH 2) 2-(O(CH 2) 2) 8-、-W-(CH 2) 2-(O(CH 2) 2) 9-、-W-(CH 2) 2-(O(CH 2) 2) 10-、-W-(CH 2) 3-O-(CH 2) 2-、-W-(CH 2) 3-(O(CH 2) 2) 2-、-W-(CH 2) 3-(O(CH 2) 2) 3-、-W-(CH 2) 3-(O(CH 2) 2) 4-、-W-(CH 2) 3-(O(CH 2) 2) 5-、-W-(CH 2) 3-(O(CH 2) 2) 6-、-W-(CH 2) 3-(O(CH 2) 2) 7-、-W-(CH 2) 3-(O(CH 2) 2) 8-、-W-(CH 2) 3-(O(CH 2) 2) 9-、-W-(CH 2) 3-(O(CH 2) 2) 10-、-W-(CH 2) 4-O-(CH 2) 2-、-W-(CH 2) 4-(O(CH 2) 2) 2-、-W-(CH 2) 4-(O(CH 2) 2) 3-、-W-(CH 2) 4-(O(CH 2) 2) 4-、-W-(CH 2) 4-(O(CH 2) 2) 5-、-W-(CH 2) 4-(O(CH 2) 2) 6-、-W-(CH 2) 4-(O(CH 2) 2) 7-、-W-(CH 2) 4-(O(CH 2) 2) 8-、-W-(CH 2) 4-(O(CH 2) 2) 9-、-W-(CH 2) 4-(O(CH 2) 2) 10-、-W-CH 2-O-(CH 2) 3-、-W-CH 2-(O(CH 2) 3) 2-、-W-CH 2-(O(CH 2) 3) 3-、-W-CH 2-(O(CH 2) 3) 4-、-W-CH 2-(O(CH 2) 3) 5-、-W-CH 2-(O(CH 2) 3) 6-、-W-CH 2-(O(CH 2) 3) 7-、-W-CH 2-(O(CH 2) 3) 8-、-W-CH 2-(O(CH 2) 3) 9-、-W-CH 2-(O(CH 2) 3) 10-、-W-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 2-(O(CH 2) 3) 3-、-W-(CH 2) 2-(O(CH 2) 3) 4-、-W-(CH 2) 2-(O(CH 2) 3) 5-、-W-(CH 2) 2-(O(CH 2) 3) 6-、-W-(CH 2) 2-(O(CH 2) 3) 7-、-W-(CH 2) 2-(O(CH 2) 3) 8-、-W-(CH 2) 2-(O(CH 2) 3) 9-、-W-(CH 2) 2-(O(CH 2) 3) 10-、-W-(CH 2) 3-O-(CH 2) 3-、-W-(CH 2) 3-(O(CH 2) 3) 2-、-W-(CH 2) 3-(O(CH 2) 3) 3-、-W-(CH 2) 3-(O(CH 2) 3) 4-、-W-(CH 2) 3-(O(CH 2) 3) 5-、-W-(CH 2) 3-(O(CH 2) 3) 6-、-W-(CH 2) 3-(O(CH 2) 3) 7-、-W-(CH 2) 3-(O(CH 2) 3) 8-、-W-(CH 2) 3-(O(CH 2) 3) 9-、-W-(CH 2) 3-(O(CH 2) 3) 10-、-W-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-W-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-W-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-W-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-W-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-W-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-W-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-W-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-W-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-W-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-W-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、 -W-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-W-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-W-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-W-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-W-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-W-CH 2-O-(CH 2) 2-O-CH 2-、-W-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-W-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-W-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-。
  18. 如权利要求13所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 3CH(OH)CH(OH)(CH 2) 4-。
  19. 如权利要求12所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) n1-三唑亚基-(CH 2) n2-、-W-(CH 2) n1-亚三唑基-(CH 2) n2-(O(CH 2) n3) m1-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-三唑亚基-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、-W-(CH 2) n1-三唑亚基-(CH 2) n2-(O(CH 2) n3) m1-O-(CH 2) n4-、-W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-三唑亚基-(CH 2) n4-；
    其中，n1、n2、n3、n4、n5、n6、m1、m2分别独立地选自1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  20. 如权利要求19所述的双功能化合物，其特征在于，所述LIN表示：-W-(CH 2) 3-亚三唑基-(CH 2) 5-、-W-(CH 2) 2-亚三唑基-(CH 2) 5-、-W-CH 2-亚三唑基-(CH 2) 5-、-W-(CH 2) 2-亚三唑基-(CH 2) 4-、-W-(CH 2) 3-亚三唑基-(CH 2) 3-、-W-(CH 2) 5-亚三唑基-(CH 2) 5-、-W-(CH 2) 5-亚三唑基-(CH 2) 8-、-W-(CH 2) 3-亚三唑基-(CH 2) 2-O(CH 2) 2-、-W-(CH 2) 2-亚三唑基-(CH 2) 2-O(CH 2) 2-、W-CH 2-亚三唑基-(CH 2) 2-O(CH 2) 2。
  21. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2CONHCH 2-、-W-(CH 2) 2CONH(CH 2) 2-、-W-(CH 2) 3CONH(CH 2) 3-、-W-(CH 2) 3CONH(CH 2) 4-、-W-(CH 2) 4CONH(CH 2) 4-、-W-(CH 2) 5CONH(CH 2) 5-、-W-(CH 2) 6CONH(CH 2) 7-、-W-(CH 2) 6CONH(CH 2) 6-、-W-(CH 2) 7CONH(CH 2) 7-、-W-(CH 2) 8CONH(CH 2) 8、W-(CH 2) 9CONH(CH 2) 9-、-W-(CH 2) 10CONH(CH 2) 10-、-W-(CH 2) 2CONH(CH 2) 5-、-W-(CH 2) 2CONH(CH 2) 3-、-W-(CH 2) 2CONH(CH 2) 4-、-W-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
  22. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2NHCOCH 2-、-W-(CH 2) 2NHCO(CH 2) 2-、-W-(CH 2) 3NHCO(CH 2) 3-、-W-(CH 2) 3NHCO(CH 2) 4-、-W-(CH 2) 4NHCO(CH 2) 4-、-W-(CH 2) 5NHCO(CH 2) 5-、-W-(CH 2) 6NHCO(CH 2) 7-、-W-(CH 2) 6NHCO(CH 2) 6-、-W-(CH 2) 7NHCO(CH 2) 7-、 -W-(CH 2) 8NHCO(CH 2) 8、-W-(CH 2) 9NHCO(CH 2) 9-、-W-(CH 2) 10NHCO(CH 2) 10-、-W-(CH 2) 2NHCO(CH 2) 5-、-W-(CH 2) 2NHCO(CH 2) 3-、-W-(CH 2) 2NHCO(CH 2) 4-、-W-(CH 2) 4NHCO(CH 2) 8-、-W-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-、-W-(CH 2) 4NHCOCH 2-。
  23. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 4NHCONH(CH 2) 4-。
  24. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 5S(CH 2) 5-、-W-(CH 2) 6S(CH 2) 5-。
  25. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 5SO(CH 2) 5-、-W-(CH 2) 6SO(CH 2) 5-。
  26. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 5SO 2(CH 2) 5-、-W-(CH 2) 6SO 2(CH 2) 5-。
  27. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 4CH＝CH(CH 2) 3-。
  28. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-(CH 2) 2C≡C(CH 2) 2-、-W-(CH 2) 5C≡C(CH 2) 4-。
  29. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2-哌嗪亚基-CH 2-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 2-、-W-(CH 2) 3-哌嗪亚基-(CH 2) 3-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 3-、-W-CH 2-哌嗪亚基-(CH 2) 2-、-W-CH 2-哌嗪亚基-(CH 2) 3-、-W-(CH 2) 2-哌嗪亚基-(CH 2) 3-。
  30. 如权利要求15所述的双功能化合物，其特征在于，所述LIN表示：
    -W-CH 2-亚苯基-CH 2-、-W-(CH 2) 2-亚苯基-(CH 2) 2-、-W-CH 2-亚苯基-(CH 2) 2-、-W-(CH 2) 2-亚苯基-CH 2-、-W-(CH 2) 3-亚苯基-(CH 2) 3-、-W-CH 2-亚苯基-(CH 2) 3-、-W-(CH 2) 2-亚苯基-(CH 2) 3-、-W-(CH 2) 3-亚苯基-(CH 2) 2-、-W-(CH 2) 3-亚苯基-CH 2-、-W-(CH 2) 2-O-CH 2-亚苯基-CH 2-O-(CH 2) 2-。
  31. 如权利要求1所述的双功能化合物，其特征在于，所述LIN表示-W-哌嗪亚基-、-W-亚螺环基、-W-亚苯基-、-W-C≡C-C≡C-。
  32. 如权利要求31所述的双功能化合物，其特征在于，所述LIN表示：
    Figure PCTCN2020107177-appb-100029
  33. 如权利要求1所述的双功能化合物，其特征在于，所述ULM表示：
    Figure PCTCN2020107177-appb-100030
    其中，A选自-CH 2-、-(C＝O)-；
    B选自C、N；
    X、Y、Z各自独立地选自CH、N；
    R选自-S-、-NH-、-O-、亚乙炔基、或者不存在；
    D选自-(C＝O)-、或者不存在。
  34. 如权利要求30所述的双功能化合物，其特征在于，所述ULM表示选自如下之一的化学结构式所示的基团：
    Figure PCTCN2020107177-appb-100031
  35. 如权利要求1所述的双功能化合物，其特征在于，所述ULM表示选自如下之一的化学结构式所示的基团：
    Figure PCTCN2020107177-appb-100032
  36. 如权利要求1所述的双功能化合物，其特征在于，所述异构体选自对映异构体、非对 映异构体、顺反异构体或立体异构体。
  37. 如权利要求1所述的双功能化合物，其特征在于，所述双功能化合物选自：
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)-3,6,9,12-四氧杂十五烷-15酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)丁酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)戊酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)庚基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)氨基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)氨基)丁酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)氨基)戊酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)氨基)己酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)氨基)庚基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)丁酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)戊酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)庚基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)-3,6,9,12-四氧杂十四烷酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丁酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)戊酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)庚基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异 二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)-3,6,9,12四氧杂-1-酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)丁-2-烯酰胺；
    (2S,4R)-1-((S)-2-(3-(2-(3-(4-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(4-(4-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基-6-基)氨基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)-4-氧代丁酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(6-(4-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基-6-基)氨基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)-6-氧代己酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(8-(4-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基-6-基)氨基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)-8-氧代辛酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6—二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(7-((2-(2,6--二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)庚基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-((2-(2,6--二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6--二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-((2-(2,6--二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(7-((2-(2,6--dioxopiperidin-3-基)-1,3-dioxoisoindolin-4-基)氨基)庚基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    4-((2-(3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-3-氧代丙氧基)乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(2-(3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-3-氧代丙氧基)乙氧基)乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(2-(2-(3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-3-氧代丙氧基)乙 氧基)乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((15-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-15-氧代-3,6,9,12-四氧杂十五烷基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((18-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-18-氧代-3,6,9,12,15-五氧杂十八烷基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-2-氧代乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((4-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-4-氧代丁基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((5-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-5-氧代戊基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((6-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-6-氧代己基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-3-氧代丙基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((4-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-4-氧代丁基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((5-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-5-氧代戊基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((6-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-6-氧代己基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((7-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-7-氧代庚基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    3-(4-((2-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-2-氧代乙基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-3-氧代丙基)硫代)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((4-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-4-氧代丁基)硫代)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((5-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-5-氧代戊基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-6-氧代己基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((7-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-7-氧代庚基)硫代)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    (2S,4R)-1-((S)-2-(2-(2-(2-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉--6-基)氧基)哌啶-1-基)-2-氧代乙氧基)乙氧基)乙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(3-(2-(3-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉--6-基)氧基)哌啶-1-基)-3-氧代丙氧基)乙氧基)丙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-16-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基-6-基)氧基)哌啶-1-基)-4,16-二氧代-7,10,13-三氧杂-3-氮杂十六烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-19-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基-6-基)氧基)哌啶-1-基)-4,19二氧代-7,10,13,16-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-22-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基-6-基)氧基)哌啶-1-基)-4,22二氧代-7,10,13,16,19-五氧-3-氮杂二十二烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(4-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-4-氧代丁酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(6-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-6-氧代己酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(8-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-8-氧代辛酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    (2S,4R)-1-((S)-2-(10-(4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-10-氧代葵酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    4-((2-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((4-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-4-氧代丁基)硫代)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((6-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(2-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((2-(2-(2-(2-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    4-((17-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-17-氧代-3,6,9,12,15-五氧杂十七烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮；
    3-(4-((2-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((4-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-4-氧代丁基)硫 代)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((2-(4-(1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((5-(4-(1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-(1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)乙酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)丁酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)己酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)-3,6,9,12四氧杂-1-酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)硫基)-3,6,9,12,15-五氧杂十七烷-1-酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丙酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丁酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    3-(4-(5-(4-(1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)戊-1-炔-1-基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    3-(4-(6-(4-(1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)己-1-炔-1-基)-1-氧代异二氢吲哚-2-基)哌啶-2,6-二酮；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)乙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)戊酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)庚基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    (2S,4R)-1-((S)-2-(5-(4-(3-((6-丙烯酰氨基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-5-氧代戊酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-(2-(2,6-二氧代哌啶-3-基)-3-氧代异二氢吲哚-1-基)己-5-炔-1-基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)戊酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基) 乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)庚基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异二氢吲哚-4-基)氨基)己基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)乙基)乙酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丙基)乙酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丁基)乙酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己基)乙酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)庚基)乙酰胺；
    2-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)辛基)乙酰胺；
    2-(4-((4-((3-氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)丁基)乙酰胺；
    2-(4-((4-((3-氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)己基)乙酰胺；
    2-(4-((4-((3-氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)庚基)乙酰胺；
    2-(4-((4-((3-氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异二氢吲哚-4-基)硫基)辛基)乙酰胺；
    (2S,4R)-1-((S)-2-(10-(4-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)-10-氧代癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十七烷酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丁酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)戊酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)己酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)庚酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁酰胺基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)己酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚酰胺；
    (2S,4R)-1-((S)-2-(2-(2-(2-((1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)氨基)-2-氧代乙氧基)乙氧基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    N1-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-N5-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苯甲基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)戊二酰胺；
    N1-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-N8-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苯甲基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)辛二酰胺；
    N1-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)-N11-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苯甲基)氨甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)十一烷二酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)戊-4-炔-1-基)氨基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (2S,4R)-1-((S)-2-(2-(2-(2-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(叔丁基)-19-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(4-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-4-氧代丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(6-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-6-氧代己酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(8-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-8-氧代辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(10-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-10-氧代癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)己酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)丁-2-烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)己基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)辛基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)庚-6-炔-1-基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(8-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-1-基)辛-7-炔-1-基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    (2S,4R)-1-((S)-2-(8-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-8-氧代辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(11-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-11-氧代十一烷酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)己酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺；
    (2S,4R)-1-((S)-2-(3-(2-(3-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-19-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-2-(叔丁基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(4-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-4-氧代丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(6-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-6-氧代己酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(8-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-8-氧代辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(10-(4-(1-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌啶-4-基)哌嗪-1-基)-10-氧代癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)己基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)辛基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)十一烷基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-苯基-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12-四氧杂十五烷-15-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-3,6,9,12,15-五氧杂十八烷-18-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丙基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)己酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)己酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丙基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)丁基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)戊基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)己基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)庚基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)辛基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12-四氧杂十四烷-1-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)-3,6,9,12,15-五氧杂十七烷-1-酰基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊-4-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)己-5-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    2-(6-(4-(4-(9-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)壬-8-炔-1-基)哌嗪-1-基)哌啶-1-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺；
    (2S,4R)-1-((2S)-2-(3-(2-(3-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((2S)-2-(叔丁基)-19-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十九烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((2S)-2-(4-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-4-氧代丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((2S)-2-(6-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-6-氧代己酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((2S)-2-(8-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-8-氧代辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((2S)-2-(10-(4-(1-(2-(1-(5-氟-2-羟基苯基)-2-氧代-2-(噻唑-2-基氨基)乙基)-3-氧代异吲哚啉-5-基)哌啶-4-基)哌嗪-1-基)-10-氧代癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苯甲基)吡咯烷-2-羧酰胺；
    N-(2-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基-硫基)-N-甲基乙酰氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-(3-((2-(2,6-二氧代哌啶-3-基)-氧代异吲哚啉-4-基)硫基)-N-甲基丙酰胺基)乙基)(甲基(氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基丁酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基((甲基)氨基)乙基)-5-((2-(2,6-二氧代哌啶-3-基(-1-氧代异吲哚-4-基)硫基)-N-甲基戊酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基己酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基(嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基庚酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基壬酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基癸酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基十一碳酰胺；
    N-(2-((2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫代)乙氧基)-N-甲基乙酰氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚-4-基-硫基)乙氧基)乙氧基)乙氧基)-N-甲基乙酰胺基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基-硫基)-3-甲基-4-氧-6,9,12-三氧杂-3-氮杂十四烷基(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-14-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基-3,6,9,12-四氧杂环丁酸酯；
    N-(2-((2-丙烯酰胺基-5-甲氧基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)(甲基)氨基)乙基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)-N-甲基-3,6,9,12,15-五氧杂庚酰胺；
    N-(2-((2-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫代)丙基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((5-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚基-4-基)硫代)戊基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((5-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚基-4-基)硫代)戊基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)己基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫基)庚基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫基)辛基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)壬基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫基)癸基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫代)十一烷基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((4-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)硫代)甲基)苄基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((5-(2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚-4-基)戊-4-炔基-1-基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-((2-((5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊-4-炔基-1-基)(甲基)氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    (E)-N-(4-(((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)戊-4-炔基-1-基)氨基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)己基-5-炔基-1-基)氨基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(1-(4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧丁-2-烯-1-基)哌啶-4-基)-11-((2-(2,6-二氧哌啶-3-基)-1-氧异吲哚-4-基)硫)十一烷酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫)甲基)苄基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-(((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)甲基)苄基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-(((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙酰基哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-(((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)戊酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲 哚-4-基)氧)己酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧)庚酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧)己基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)癸酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)十一烷酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(10-((2-(2,6,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)癸基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫基)十一烷基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (2S,4R)-1-((S)-19-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-2-(叔丁基)-4,19-二氧代-7,10,13,16-四氧杂-3-氮杂十二烷酰基)-4-羟基-N-(4-(4-甲基噻唑)-5-基)苄基)吡咯烷-2-羧酰胺；
    4-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟代苯基氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙基)-4-氧代丁酰胺；
    4-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟代苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-N-(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)-4-氧代丁酰胺；
    4-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟代苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-N-(2-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙基)-4-氧丁酰胺；
    (2S,4R)-1-((S)-2-(3-(4-(3-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基))氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)哌嗪-1-基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑)-5-基)苄基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(3-(4-(3-(4-(3-((6-丙烯酰胺基-4-((3-氯-4-氟苯基)氨基)喹唑啉-7-基)氧基)丙基)哌嗪-1-基)-3-氧丙基)苯基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙氧基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(4-(4-((2-((2-((2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)乙基)氨基)-4-氧代丁酰基)哌嗪-1-基)哌啶-1-基)丁-2-烯酰胺；
    (2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2-烯-1-基)哌啶-4-基)哌嗪-1-基)-3-氧丙基)哌嗪-1-基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺；
    (2S,4R)-1-((S)-2-(3-(4-(3-(4-(1-((E)-4-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氨基)-4-氧代丁-2- 烯-1-基)哌啶-4-基)哌嗪-1-基)-3-氧丙基)苯基)丙酰胺基)-3，3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-羧酰胺；
    N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-甲基乙酰氨基)乙氧基)-4-甲氧基-5–((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚啉-4-基)硫代)乙酰基)哌嗪-1-基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)乙酰胺基)哌啶-1-基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    N-(2-(2-(4-(4-(2-(((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚-4-基]硫基)硫代)乙酰基]哌嗪-1-基)哌啶-1-基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺；
    (E)-N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚-4-基)硫代)乙酰基)哌嗪-1-基)丁-2-烯酰胺；
    (E)-N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)-4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)乙酰氨基)哌啶-1-基)丁-2-烯酰胺；
    (E)-N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)-4-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)硫代)乙酰基)哌嗪-1-基)哌啶-1基)丁-2-烯酰胺。
  38. 如权利要求1～37任一权利要求所述的双功能化合物在制备药物中的用途。
  39. 如权利要求38所述的用途，其特征在于，所述药物选自用于调节表皮生长因子受体(EGFR)和/或其突变体的药物，优选为表皮生长因子受体(EGFR)抑制剂。
  40. 如权利要求38所述的用途，其特征在于，所述药物选自用于治疗受体酪氨酸激酶(RTK)相关疾病的药物。
  41. 如权利要求38所述的用途，其特征在于，所述药物选自用于治疗EGFR依赖的相关疾病，优选为，与EGFR过表达或高活性相关的疾病的药物。
  42. 如权利要求41所述的用途，其特征在于，所述药物选自用于治疗选自肿瘤、髓瘤或实体瘤，癌症，白血病，淋巴瘤，结肠直肠癌，脑癌，骨癌，上皮细胞-来源的肿瘤(上皮癌)，基底细胞癌，腺癌，胃肠癌，唇癌，口腔癌，食道癌，小肠癌，胃癌，结肠癌，肝癌，膀胱癌，胰腺癌，卵巢癌，宫颈癌，肺癌，乳腺癌，皮肤癌，鳞状细胞和/或基底细胞癌，前列腺癌，神经胶质瘤，胶质母细胞瘤，肾细胞癌和其他已知影响全身上皮细胞的癌症，慢性粒细胞白血病(CML)，急性髓性白血病(AML)和急性早幼粒细胞白血病(APL)中的一种或多种的组合的药物。
  43. 一种药物组合物，包括如权利要求1～37任一权利要求所述的双功能化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物，以及至少一种药学上可接受的载体、 添加剂、助剂或赋形剂。
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