WO2023078207A1 - 6-position-substituted indolinone derivative, preparation method therefor, and medical use thereof - Google Patents

6-position-substituted indolinone derivative, preparation method therefor, and medical use thereof Download PDF

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WO2023078207A1
WO2023078207A1 PCT/CN2022/128606 CN2022128606W WO2023078207A1 WO 2023078207 A1 WO2023078207 A1 WO 2023078207A1 CN 2022128606 W CN2022128606 W CN 2022128606W WO 2023078207 A1 WO2023078207 A1 WO 2023078207A1
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tert
butyl
methyl
dimethyl
ylidene
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PCT/CN2022/128606
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French (fr)
Chinese (zh)
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胡立宏
王均伟
吕祁
王丹
潘祥
戎全金
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南京中医药大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • the present invention relates to the field of medicinal chemistry, in particular to a 6-substituted indolinone derivative or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions containing these compounds, their preparation methods and their use in antitumor .
  • the body's immune system has the characteristics of immune memory, which can help patients form memory immunity, which has significant advantages in preventing tumor recurrence and metastasis.
  • immune memory which can help patients form memory immunity, which has significant advantages in preventing tumor recurrence and metastasis.
  • LAG3, OX40 and other targets that are still on the way, without exception, they all focus on how to restore T lymphocyte function or how to improve the acquired immune system function is performed.
  • the role of the innate immune system in tumor immunotherapy has not been brought into play for a long time.
  • tumor-associated macrophages tumor-associated macrophages
  • TAMs tumor-associated macrophages
  • colony-stimulating factor 1 (CSF-1) will lead to the abnormal activation of its receptor CSF-1R, promote a large number of macrophages to chemotaxis to tumor cells, infiltrate tumor tissue, and induce macrophages.
  • CSF-1R colony-stimulating factor 1
  • the differentiation of cells into M2 TAMs is closely related to the occurrence, development and poor prognosis of various malignant tumors. Blocking CSF-1/CSF-1R signaling significantly reduced macrophage infiltration at tumor sites, inhibited the differentiation of M2-type TAMs, slowed primary tumor growth, and reduced tumor metastasis.
  • CSF-1R small-molecule inhibitors can inhibit the activation of CSF-1R by competitively occupying the ATP-binding site of CSF-1R, which can block CSF-1/CSF-1R signal transduction, inhibit the survival and differentiation of TAMs, and improve tumor microenvironment to achieve tumor immunotherapy. Therefore, small-molecule inhibitors targeting CSF-1R open up new avenues for immunotherapy of tumors and other diseases. In recent years, with the continuous development of tumor immunotherapy and the deepening of research on CSF-1R inhibitors, several active CSF-1R inhibitors have entered clinical research one after another.
  • CSF-1R inhibitors Although the research on CSF-1R inhibitors has made great progress, most of the CSF-1R inhibitors under development have limited curative effect on colorectal cancer and other solid tumors as a single drug due to the single way of regulating TAMs, and the remission rate is low. lower. Therefore, how to obtain highly active new CSF-1R small molecule inhibitors to achieve efficient and precise treatment of solid tumors such as colorectal cancer is the main problem and challenge facing the research and development of CSF-1R inhibitors.
  • the present invention provides a 6-position substituted indolinone derivatives shown in general formula I, and their tautomers, enantiomers, diastereomers, elimination Spin body or its pharmaceutically acceptable salt.
  • the technical solution of the present invention is: a 6-substituted indolinone derivative or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate, characterized in that the The chemical structural formula of derivative is as shown in formula I:
  • Ring A is selected from 5-6 membered aromatic heterocycles, benzene rings, multi-substituted 5-6-membered aromatic heterocycles, multi-substituted benzene rings, mono-substituted 5-6-membered aromatic heterocycles or mono-substituted benzene rings;
  • R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
  • R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
  • R2 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
  • R3 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
  • R 4 is selected from one or more of hydrogen atom, hydroxyl, alkyl, alkoxy, (CH 2 ) m NR 7 R 8 ;
  • R 5 and R 6 are respectively selected from hydrogen, methyl, or R 5 and R 6 form cyclopropane
  • R 7 and R 8 are respectively selected from one or more of hydrogen, alkyl, cycloalkyl and heterocycloalkyl;
  • R 7 and R 8 can form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocyclic ring contains one or more N, O, S atoms, and the 4-7 membered heterocyclic ring is surrounded by one or more Alkyl substitution;
  • X is selected from C atom or N atom
  • Y is selected from C atom or N atom
  • Z is selected from CONH, NHCO, SO2NH or NHSO2 ;
  • n 0 or 1
  • m 1-6.
  • Preferred typical compounds of the present invention are as follows, but not limited to:
  • Another object of the present invention is to provide a method for preparing 6-substituted indolinone derivatives, which mainly includes two synthetic routes.
  • the first step compound II and phenyl chloroformate react to generate compound III under the action of a base;
  • compound II was dissolved in anhydrous tetrahydrofuran, and then K 2 CO 3 and phenyl chloroformate were added in sequence, and reacted at room temperature for 4 hours. After the reaction was monitored by LC-MS, the reaction solution was filtered with suction, the filter cake was washed with a small amount of tetrahydrofuran, and dried in vacuum to obtain compound III;
  • compound III, IV and DMAP were dissolved in DCM, TEA was added under stirring, and heated to 50° C. for 20 h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, washed the filter cake with a small amount of ethyl acetate, and dried in vacuo to obtain compound V;
  • Step 3 compound V and VI undergo an aldol condensation reaction under the action of a base to generate compound I;
  • compound II was dissolved in acetonitrile, and then compound VII, TCFH and NMI were added in sequence, and reacted at room temperature for 4 h. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water, extracted with ethyl acetate, the organic layers were combined, washed with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentrated to obtain compound VIII;
  • Step 3 compounds IX and IV undergo an aldol condensation reaction to generate compound X under the action of a base;
  • Step 4 compound X and VI undergo aldol condensation reaction under the action of a base to generate compound I, and the method is the same as the synthesis route one.
  • the isomer is selected from one or more of enantiomers, diastereomers, geometric isomers or stereoisomers.
  • 6-substituted indolinone derivatives are selected from:
  • the object of the present invention is to provide a pharmaceutical composition, including the 6-substituted indolinone derivatives, their pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates , and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.
  • Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of tyrosine kinase inhibitors such as CSF-1R.
  • the compound of the present invention or its pharmaceutically acceptable salt, and the pharmaceutical composition thereof have the effect on receptor tyrosine kinases such as CSF-1R, VEGFR-1, VEGFR-2, PDGFR ⁇ , PDGFR- ⁇ , FLT3, c-KIT, etc. It has remarkable inhibitory activity, especially has strong inhibitory activity on CSF-1R, so it can be used to prepare medicines for treating related tumor diseases caused by abnormal expression of tyrosine kinase.
  • Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in regulating the function of tumor-associated macrophages.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can specifically inhibit the chemotaxis of macrophages to tumors and induce the repolarization of M2-type TAMs to the M1 phenotype, so they can be used as tumor-associated macrophages.
  • Modulators of cells are used in the immunotherapy of malignancies, inflammatory diseases, bone diseases and neurological diseases.
  • Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of antitumor drugs.
  • Anti-tumor tests in vivo and in vitro show that the conditioned medium of M2 macrophages stimulated by the compound of the present invention can significantly inhibit the growth of malignant tumors such as liver cancer, lung cancer, pancreatic cancer, and colorectal cancer. Therefore, the compound of the present invention or its pharmaceutically acceptable salt, and its pharmaceutical composition can be used as a single therapeutic agent, or used in combination with other antineoplastic drugs (including targeted drugs and immunotherapy drugs) for a variety of malignant Tumor treatment.
  • Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of drugs for treating colorectal cancer.
  • the in vitro anti-tumor activity test shows that the conditioned medium of M2 macrophages stimulated by the compound of the present invention can significantly inhibit the proliferation of colorectal cancer cells.
  • Whole animal experiments show that the compound of the present invention has a good curative effect on colorectal cancer, and its antitumor effect is significantly better than that of PLX3397, and it has a synergistic effect in combination with the immune checkpoint inhibitor PD-L1 monoclonal antibody. Therefore, the compound of the present invention or its pharmaceutically acceptable salt, and its pharmaceutical composition can be used as a single therapeutic agent, or used in combination with immune checkpoint inhibitors, for the treatment of colorectal cancer.
  • the 6-position substituted indolinone derivatives described in the present invention are a new structural type of CSF-1R inhibitors, and have stronger CSF-1R inhibitory activity, stronger in vitro anti-tumor activity and stronger in vivo anti-tumor activity, especially for the treatment of colorectal cancer, the onset dose is lower, and the tumor inhibition rate at the same dose is significantly better than PLX3397, and Combination with PD-L1 monoclonal antibody has a good synergistic effect, therefore, the CSF-1R inhibitor of the present invention has good industrialization prospects.
  • the Mobility Shift Assay method was used to determine the in vitro inhibitory activity of the compound on CSF-1R kinase: the compound was diluted 3 times to 10 concentrations from the initial concentration of 1 ⁇ M, and then transferred 250 nL to a 384-well plate with Echo550, negative control 250 nL of 100% DMSO was added to the wells and the positive control wells respectively. Add 10 ⁇ L of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 ⁇ L of kinase buffer to negative control wells.
  • MC-38 is a mouse colon cancer cell line.
  • the in vitro pro-apoptotic activity of the compound on solid tumor cells was determined by flow cytometry: M2 macrophages were induced in vitro, with or without I-17 (10, 30, 100 nM) and I-19 (10, 30, 100 nM) M2 macrophages were treated and the medium was subsequently replaced with fresh medium. After 48 h, the supernatant was collected as conditioned medium.
  • trypsin was used to digest MC-38 cells in the logarithmic growth phase, and after counting, an appropriate amount of cell suspension was inoculated in a 6-well plate.
  • MC-38 is a mouse colon cancer cell line.
  • the in vitro antiproliferative activity of the compound on solid tumor cells was determined by CCK-8 method: M2 macrophages were induced in vitro, with or without I-17 (10, 30, 100 nM) and I-19 (10, 30, 100 nM) treatment
  • M2 macrophages the medium was subsequently replaced with fresh medium. After 48 h, the supernatant was collected as conditioned medium.
  • trypsin was used to digest MC-38 cells in the logarithmic growth phase, and after counting, an appropriate amount of cell suspension was inoculated in a 96-well plate.
  • Mobility Shift Assay method was used to determine the in vitro inhibitory activity of compound I-19 on some tyrosine kinases: the compound was diluted 3 times from the initial concentration of 1 ⁇ M to 10 concentrations, and then transferred 250 nL to a 384-well plate with Echo550 250 nL of 100% DMSO was added to negative control wells and positive control wells respectively. Add 10 ⁇ L of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 ⁇ L of kinase buffer to negative control wells.
  • MC-38 cells were cultured and expanded in vitro, and an appropriate amount of cells in the logarithmic growth phase were resuspended in serum-free DMEM medium, and a cell suspension of 1 ⁇ 10 6 /100 ⁇ L was prepared under sterile conditions. 100 ⁇ L of the cell suspension was inoculated subcutaneously in the axilla of the anterior left limb of female C57BL/6 mice. When the tumor volume grew to about 100 mm 3 , animals with moderate tumor size were selected and divided into random groups, with 6 animals in each group.
  • MC-38 cell bodies were cultured and expanded in vitro, and an appropriate amount of cells in the logarithmic growth phase were resuspended in serum-free DMEM medium, and a cell suspension of 1 ⁇ 10 6 /100 ⁇ L was prepared under sterile conditions. Using a syringe, 100 ⁇ L of the cell suspension was inoculated subcutaneously in the axilla of the anterior left limb of female C57BL/6 mice. When the tumor volume grew to about 100 mm 3 , animals with moderate tumor size were selected and divided into random groups, with 6 animals in each group.
  • CMC-Na blank medium
  • I-19 (20mg/kg/d) anti-PD-L1 (100 ⁇ g/mouse)
  • I-19 was intragastrically administered once a day
  • anti-PD-L1 was injected intraperitoneally once every 3 days for 2 weeks.
  • the body weight and tumor diameter of the mice were measured every day. After the experiment, the animals were killed by cervical dislocation, and the tumors were weighed.

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Abstract

Disclosed are a 6-position-substituted indolinone derivative, a preparation method therefor, and a medical use thereof. The present invention belongs to the field of medicinal chemistry; the 6-position-substituted indolinone derivative of the present invention is a CSF-1R inhibitor having a novel structure. The described derivative has strong CSF-1R inhibitory activity, can achieve immunotherapy for a variety of solid tumors by means of specifically inhibiting the chemotaxis of macrophages to tumors and inducing the repolarization of M2-type TAMs to the M1 phenotype. In particular, the effective dose for the treatment of colorectal cancer is relatively low, and the tumor inhibition rate at the same dose is significantly better than that of PLX3397. In addition, said derivative has a good synergistic effect in combination with a PD-L1 monoclonal antibody.

Description

6-位取代的吲哚酮衍生物、其制备方法及其医药用途6-position substituted indolinone derivatives, preparation method and medical use thereof 技术领域technical field
本发明涉及药物化学领域，具体涉及一种6-位取代的吲哚酮衍生物或其药学上可接受的盐，以及含有这些化合物的药物组合物，它们的制备方法以及在抗肿瘤方面的用途。The present invention relates to the field of medicinal chemistry, in particular to a 6-substituted indolinone derivative or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions containing these compounds, their preparation methods and their use in antitumor .
背景技术Background technique
恶性肿瘤治疗一直是世界性医学难题，手术、放疗、化疗、靶向治疗等方法都把目标集中在肿瘤细胞上，然而肿瘤细胞是体内细胞变异产生的，不是外部入侵的病菌，所以在治疗过程中，肿瘤细胞无法清除干净，转移和复发的情况比比皆是。近年来，随着分子生物学、肿瘤免疫学的迅速发展，以选择性增强患者免疫应答为重点的免疫治疗如免疫检查点抑制剂、CAR-T细胞治疗等已成为一种新的肿瘤治疗手段。免疫治疗将治疗目标从肿瘤细胞转移到免疫细胞上面，通过增强患者自身的免疫力来***，与传统治疗相比具有杀伤精准、副作用小、疗效持久、个性化程度高等优势。此外，机体免疫***具有免疫记忆的特性，可以帮助患者形成记忆型免疫，在防止肿瘤复发和转移上具有显著优势。目前，无论是久热不止的PD-1和PD-L1单抗，还是LAG3、OX40等仍在路上的靶点，无一例外都是围绕如何恢复T淋巴细胞功能或如何提高获得性免疫***的功能进行的。然而，固有免疫***在肿瘤免疫治疗中的作用，却长期没有得到发挥。事实上在整个肿瘤浸润区域，肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)约占肿瘤间质免疫细胞总数的50％以上，是肿瘤微环境中最为丰富的免疫细胞，与肿瘤的发生发展及不良预后密切相关。因此，除了围绕T细胞的过继转移细胞疗法和检查点抑制剂疗法，基于TAMs的免疫疗法也越来越受到关注。The treatment of malignant tumors has always been a worldwide medical problem. Methods such as surgery, radiotherapy, chemotherapy, and targeted therapy all focus on tumor cells. In cancer, tumor cells cannot be cleared, and metastasis and recurrence abound. In recent years, with the rapid development of molecular biology and tumor immunology, immunotherapy that focuses on selectively enhancing the immune response of patients, such as immune checkpoint inhibitors and CAR-T cell therapy, has become a new tumor treatment method. . Immunotherapy transfers the treatment target from tumor cells to immune cells, and treats tumors by enhancing the patient's own immunity. Compared with traditional treatments, it has the advantages of precise killing, small side effects, long-lasting curative effect, and high degree of individualization. In addition, the body's immune system has the characteristics of immune memory, which can help patients form memory immunity, which has significant advantages in preventing tumor recurrence and metastasis. At present, whether it is the long-lasting PD-1 and PD-L1 monoclonal antibodies, or LAG3, OX40 and other targets that are still on the way, without exception, they all focus on how to restore T lymphocyte function or how to improve the acquired immune system function is performed. However, the role of the innate immune system in tumor immunotherapy has not been brought into play for a long time. In fact, in the entire tumor infiltration area, tumor-associated macrophages (tumor-associated macrophages, TAMs) account for more than 50% of the total number of tumor stromal immune cells, and are the most abundant immune cells in the tumor microenvironment. are closely related to poor prognosis. Therefore, in addition to adoptive transfer cell therapy and checkpoint inhibitor therapy around T cells, TAMs-based immunotherapy has also attracted more and more attention.
集落刺激因子1(colony-stimulating factor 1,CSF-1)的过表达会导致其受体CSF-1R的异常激活，促进大量的巨噬细胞向肿瘤细胞趋化，浸润肿瘤组织，并诱导巨噬细胞向M2型TAMs分化，与多种恶性肿瘤的发生发展及不良预后密切相关。阻断CSF-1/CSF-1R信号传导可显著降低巨噬细胞在肿瘤部位的浸润，抑制M2型TAMs的分化，并减缓原发性肿瘤生长、减少肿瘤转移。CSF-1R小分子抑制剂通过竞争性地占据CSF-1R的ATP结合位点，抑制CSF-1R的激活，可以阻断CSF-1/CSF-1R信号传导，抑制TAMs的存活和分化，改善肿瘤微环境，实现对肿瘤的免疫治疗。因此，以CSF-1R为靶标的小分子抑制剂为肿瘤等疾病的免疫治疗开辟了新途径。近年来，随着肿瘤免疫治疗的不断发展以及对CSF-1R抑制剂研究的不断深入，多个活性良好的CSF-1R抑制剂陆续进入临床研究。The overexpression of colony-stimulating factor 1 (CSF-1) will lead to the abnormal activation of its receptor CSF-1R, promote a large number of macrophages to chemotaxis to tumor cells, infiltrate tumor tissue, and induce macrophages. The differentiation of cells into M2 TAMs is closely related to the occurrence, development and poor prognosis of various malignant tumors. Blocking CSF-1/CSF-1R signaling significantly reduced macrophage infiltration at tumor sites, inhibited the differentiation of M2-type TAMs, slowed primary tumor growth, and reduced tumor metastasis. CSF-1R small-molecule inhibitors can inhibit the activation of CSF-1R by competitively occupying the ATP-binding site of CSF-1R, which can block CSF-1/CSF-1R signal transduction, inhibit the survival and differentiation of TAMs, and improve tumor microenvironment to achieve tumor immunotherapy. Therefore, small-molecule inhibitors targeting CSF-1R open up new avenues for immunotherapy of tumors and other diseases. In recent years, with the continuous development of tumor immunotherapy and the deepening of research on CSF-1R inhibitors, several active CSF-1R inhibitors have entered clinical research one after another.
虽然CSF-1R抑制剂的研究取得了较大的进展，然而大多数正在开发中的CSF-1R抑制剂由于调节TAMs的方式单一，作为单一药物对结直肠癌等实体瘤的疗效有限，缓解率较低。因此，如何获得高活性的新型CSF-1R小分子抑制剂实现对结直肠癌等实体瘤高效、精准的治疗是目前CSF-1R抑制剂研究开发面临的主要问题和挑战。本发明通过对CSF-1R蛋白结合口袋的分析研究，基于老药Sunitinib的吲哚酮骨架进行合理的药物设计和***的活性筛选，发现了对结直肠癌等实体瘤治疗效果显著的6-位取代的吲哚酮类新型CSF-1R抑制剂候选化合物。Although the research on CSF-1R inhibitors has made great progress, most of the CSF-1R inhibitors under development have limited curative effect on colorectal cancer and other solid tumors as a single drug due to the single way of regulating TAMs, and the remission rate is low. lower. Therefore, how to obtain highly active new CSF-1R small molecule inhibitors to achieve efficient and precise treatment of solid tumors such as colorectal cancer is the main problem and challenge facing the research and development of CSF-1R inhibitors. In the present invention, through the analysis and research of the CSF-1R protein binding pocket, rational drug design and systematic activity screening are carried out based on the indolinone skeleton of the old drug Sunitinib, and the 6-position with significant therapeutic effect on solid tumors such as colorectal cancer is discovered. Novel CSF-1R inhibitor candidate compounds from the class of substituted indolinones.
发明内容Contents of the invention
发明目的：针对上述问题，本发明提供了一种通式I所示的6-位取代的吲哚酮类衍生物，以及它们的互变异构体、对映体、非对映体、消旋体或其药学上可接受的盐。Purpose of the invention: for the above problems, the present invention provides a 6-position substituted indolinone derivatives shown in general formula I, and their tautomers, enantiomers, diastereomers, elimination Spin body or its pharmaceutically acceptable salt.
本发明的技术方案是：一种6-位取代的吲哚酮类衍生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，其特征在于，所述衍生物的化学结构式如式I所示：The technical solution of the present invention is: a 6-substituted indolinone derivative or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate, characterized in that the The chemical structural formula of derivative is as shown in formula I:
Figure PCTCN2022128606-appb-000001
Figure PCTCN2022128606-appb-000001
其中：in:
A环选自5～6元芳杂环、苯环、多取代的5～6元芳杂环、多取代的苯环、单取代的5～6元芳杂环或单取代的苯环；Ring A is selected from 5-6 membered aromatic heterocycles, benzene rings, multi-substituted 5-6-membered aromatic heterocycles, multi-substituted benzene rings, mono-substituted 5-6-membered aromatic heterocycles or mono-substituted benzene rings;
R选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种；R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
R 1选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R2 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R3 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
R 4选自氢原子、羟基、烷基、烷氧基、(CH 2) mNR 7R 8中的一种或几种； R 4 is selected from one or more of hydrogen atom, hydroxyl, alkyl, alkoxy, (CH 2 ) m NR 7 R 8 ;
R 5和R 6分别选自氢、甲基、或者R 5和R 6形成环丙烷； R 5 and R 6 are respectively selected from hydrogen, methyl, or R 5 and R 6 form cyclopropane;
R 7和R 8分别选自氢、烷基、环烷基及杂环烷基一种或几种； R 7 and R 8 are respectively selected from one or more of hydrogen, alkyl, cycloalkyl and heterocycloalkyl;
R 7和R 8可以形成一个4-7元杂环烷基，其中4-7元杂环内含有一个或多个N、O、S原子，且4-7元杂环上被一个或多个烷基取代； R 7 and R 8 can form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocyclic ring contains one or more N, O, S atoms, and the 4-7 membered heterocyclic ring is surrounded by one or more Alkyl substitution;
X选自C原子或N原子；X is selected from C atom or N atom;
Y选自C原子或N原子；Y is selected from C atom or N atom;
Z选自CONH、NHCO、SO 2NH或NHSO 2； Z is selected from CONH, NHCO, SO2NH or NHSO2 ;
n是0或1；n is 0 or 1;
m是1-6。m is 1-6.
本发明优选的典型化合物如下，但不限于：Preferred typical compounds of the present invention are as follows, but not limited to:
表1.化合物的编号、名称及结构Table 1. Compound number, name and structure
Figure PCTCN2022128606-appb-000002
Figure PCTCN2022128606-appb-000002
Figure PCTCN2022128606-appb-000003
Figure PCTCN2022128606-appb-000003
Figure PCTCN2022128606-appb-000004
Figure PCTCN2022128606-appb-000004
Figure PCTCN2022128606-appb-000005
Figure PCTCN2022128606-appb-000005
Figure PCTCN2022128606-appb-000006
Figure PCTCN2022128606-appb-000006
Figure PCTCN2022128606-appb-000007
Figure PCTCN2022128606-appb-000007
Figure PCTCN2022128606-appb-000008
Figure PCTCN2022128606-appb-000008
Figure PCTCN2022128606-appb-000009
Figure PCTCN2022128606-appb-000009
本发明的另一目的在于提供一种制备6-位取代的吲哚酮衍生物的方法，主要包括两种合成路线。Another object of the present invention is to provide a method for preparing 6-substituted indolinone derivatives, which mainly includes two synthetic routes.
第一种合成路线：The first synthetic route:
Figure PCTCN2022128606-appb-000010
Figure PCTCN2022128606-appb-000010
第一步：化合物II和氯甲酸苯酯在碱的作用下，反应生成化合物III；The first step: compound II and phenyl chloroformate react to generate compound III under the action of a base;
具体步骤，将化合物II溶解于无水四氢呋喃，后依次加入K 2CO 3，氯甲酸苯酯，室温反应4h。LC-MS监测反应完毕后，将反应液抽滤，滤饼用少量四氢呋喃洗涤，真空干燥得到化合物III； In specific steps, compound II was dissolved in anhydrous tetrahydrofuran, and then K 2 CO 3 and phenyl chloroformate were added in sequence, and reacted at room temperature for 4 hours. After the reaction was monitored by LC-MS, the reaction solution was filtered with suction, the filter cake was washed with a small amount of tetrahydrofuran, and dried in vacuum to obtain compound III;
第二步：化合物III和IV在TEA，DMAP的作用下，反应生成化合物V；The second step: compound III and IV react to generate compound V under the action of TEA and DMAP;
具体步骤，将化合物III、IV和DMAP溶解于DCM，于搅拌下加入TEA，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥得化合物V；In specific steps, compound III, IV and DMAP were dissolved in DCM, TEA was added under stirring, and heated to 50° C. for 20 h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, washed the filter cake with a small amount of ethyl acetate, and dried in vacuo to obtain compound V;
第三步：化合物V和VI在碱的作用下，经过羟醛缩合反应生成化合物I；Step 3: compound V and VI undergo an aldol condensation reaction under the action of a base to generate compound I;
具体步骤，将化合物V和VI溶解于乙醇中，加入吡咯烷，加热至50℃反应2h；反应完毕后，抽滤，滤饼经乙醇洗涤，真空干燥得化合物I。Concrete steps, dissolving compounds V and VI in ethanol, adding pyrrolidine, heating to 50°C for 2 hours; after the reaction, suction filtration, washing the filter cake with ethanol, and drying in vacuo to obtain compound I.
第二种合成路线：The second synthetic route:
Figure PCTCN2022128606-appb-000011
Figure PCTCN2022128606-appb-000011
第一步：化合物II和VII在TCFH、NMI的作用下，反应生成化合物VIII；The first step: compound II and VII are reacted to form compound VIII under the action of TCFH and NMI;
具体步骤，将化合物II溶于乙腈，后依次加入化合物VII，TCFH和NMI，室温反应4h。LC-MS监测反应完毕后，将反应液加入水中，乙酸乙酯萃取，合并有机层，水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩得化合物VIII；In specific steps, compound II was dissolved in acetonitrile, and then compound VII, TCFH and NMI were added in sequence, and reacted at room temperature for 4 h. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water, extracted with ethyl acetate, the organic layers were combined, washed with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentrated to obtain compound VIII;
第二步：化合物VIII在碱的作用下，反应生成化合物IX；The second step: compound VIII is reacted to generate compound IX under the action of a base;
具体步骤，将化合物VIII溶解于CH 3OH/H 2O，然后加入LiOH .H 2O，室温反应2h。LC-MS监测反应完毕后，用1N的HCl将反应液调至PH＝1，待固体析出，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥得化合物IX； In specific steps, compound VIII was dissolved in CH 3 OH/H 2 O, then LiOH . H 2 O was added, and reacted at room temperature for 2 h. After the reaction was monitored by LC-MS, the reaction solution was adjusted to pH = 1 with 1N HCl, and the solid was precipitated, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain Compound IX;
第三步：化合物IX和IV在碱的作用下，经过羟醛缩合反应生成化合物X；Step 3: compounds IX and IV undergo an aldol condensation reaction to generate compound X under the action of a base;
具体步骤，将化合物IX和IV溶于乙醇中，加入吡咯烷，加热至50℃反应2h。反应完毕后，抽滤，滤饼经乙醇洗涤，真空干燥得化合物X；Concrete steps, dissolving compounds IX and IV in ethanol, adding pyrrolidine, heating to 50° C. for 2 h. After the reaction was completed, filter with suction, wash the filter cake with ethanol, and dry in vacuo to obtain compound X;
第四步：化合物X和VI在碱的作用下，经过羟醛缩合反应生成化合物I，方法同合成路线一。Step 4: compound X and VI undergo aldol condensation reaction under the action of a base to generate compound I, and the method is the same as the synthesis route one.
具体化合物的合成路线详见下述实例。The synthetic routes of specific compounds are detailed in the following examples.
进一步的，所述异构体选自对映异构体、非对映异构体、几何异构体或立体异构体中的一种或者几种。Further, the isomer is selected from one or more of enantiomers, diastereomers, geometric isomers or stereoisomers.
进一步的，所述的6-位取代的吲哚酮衍生物选自：Further, the 6-substituted indolinone derivatives are selected from:
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐；(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride;
(R,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐；(R,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-4-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-4-carboxamide hydrochloride;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-2-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-2-carboxamide hydrochloride;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-3-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-3-carboxamide hydrochloride;
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-3-甲酰胺盐酸盐；(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-3-carboxamide hydrochloride;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(哌啶-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(piperidin-1-yl)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(4-甲基哌嗪-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二乙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(diethylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二甲氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(dimethylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(乙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(ethylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(丙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(propylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(叔丁氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(tert-butylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(环戊氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(cyclopentylamino)propionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-吗啉基丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-morpholinopropionamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(吡咯烷-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(pyrrolidin-1-yl)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(哌啶-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(piperidin-1-yl)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(二乙氨基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(diethylamino)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-吗啉基乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-morpholinoacetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(环戊氨基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(cyclopentylamino)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene )methyl)-2,4-dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -N-(2-(diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene )methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((6-(3-(5-甲基异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((6-(3-(5-methylisoxazol-3-yl)ureido )-2-oxindole-3-ylidene)methyl)-1H-pyrrole-3-carboxamide;
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3-(三氟甲基)异恶唑-5-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxido-6-(3-(3-(trifluoromethyl)isoxane Azol-5-yl)ureido)indol-3-ylidene)methyl)-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)ureido)-2-oxindole-3-ylidene )methyl)-N-(2-(diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(4-氯-3-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(三氟甲基)吡啶-3-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxygen-6-(3-(trifluoromethyl)pyridin-3-yl ) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(4-(叔丁基)-3-氯苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(4-(tert-butyl)-3-chlorophenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-( 2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(4-(叔丁基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰 胺；(Z)-5-((6-(3-(4-(tert-butyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-(2-(di Ethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(3-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(2-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(2-Chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-N-(2-(二乙氨基)乙基)-5-((6-(3-(3-甲氧基-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-5-((6-(3-(3-methoxy-4-(trifluoromethyl)phenyl)ureido)-2 -oxindole-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3,4,5-三甲氧基苯基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(3-(3,4,5-trimethoxybenzene base) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide;
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-dimethyl-1H-pyrrol-3-yl)acetamide;
(Z)-N 1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N,2,4-三甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-N, 2,4-Trimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxamide;
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸甲酯；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid methyl ester;
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid;
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene) -2-oxindol-6-yl)urea;
(Z)-1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
(Z)-N 1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-甲氧基-4-(三氟甲基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-methoxy-4-(trifluoromethane base) phenyl) urea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(叔丁基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(tert-butyl)phenyl)urea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)-1-methyl -1H-pyrazol-5-yl)urea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)isoxazole-5 - base) urea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-氯-4-(三氟甲基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-chloro-4-(trifluoromethyl) Phenyl) urea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(哌啶-4-基)苯基)脲盐酸盐；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(piperidin-4-yl)phenyl ) urea hydrochloride;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-((4,4-二甲基哌啶-1-基)甲基)苯基脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-((4,4-dimethylpiper (pyridin-1-yl)methyl)phenylurea;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-5-氟-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-5-fluoro-2-oxindol-6-yl)-3-(3-(tert-butyl)iso oxazol-5-yl) urea;
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(5-氟-3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(5-fluoro-3-((4-methyl-1H-imidazol-5-yl)methylene )-2-oxindol-6-yl)urea;
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Oxydolin-6-yl) urea;
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Piperazin-1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide;
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) -3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide;
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺；(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((4-((2-(diethylamino)ethyl)carbamoyl)-3 ,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide;
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((3,5-二甲基-4-(2-(4-甲基哌啶-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺；(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((3,5-dimethyl-4-(2-(4-methylpiperidine -1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide;
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Piperazin-1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide;
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) -3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide;
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸乙酯；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester;
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Oxydolin-6-yl) urea;
(Z)-1-(3-((1H-咪唑-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-imidazol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
(Z)-N 1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
(Z)-5-((6-(3-(3-(叔丁基)异恶唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺。(Z)-5-((6-(3-(3-(tert-butyl)isoxazol-5-yl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(Diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide.
本发明的目的在于提供一种药物组合物，包括所述的6-位取代的吲哚酮类衍生物、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。The object of the present invention is to provide a pharmaceutical composition, including the 6-substituted indolinone derivatives, their pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates , and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备CSF-1R等酪氨酸激酶抑制剂中的用途。本发明的化合物或其药学上可接受的盐，及其药物组合物对CSF-1R、VEGFR-1、VEGFR-2、PDGFRα、PDGFR-β、FLT3、c-KIT等受体酪氨酸激酶具有显著的抑制活性，尤其对CSF-1R具有很强的抑制活性，因此可以用于制备治疗酪氨酸激酶表达异常引起的相关肿瘤疾病的药物。Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of tyrosine kinase inhibitors such as CSF-1R. The compound of the present invention or its pharmaceutically acceptable salt, and the pharmaceutical composition thereof have the effect on receptor tyrosine kinases such as CSF-1R, VEGFR-1, VEGFR-2, PDGFRα, PDGFR-β, FLT3, c-KIT, etc. It has remarkable inhibitory activity, especially has strong inhibitory activity on CSF-1R, so it can be used to prepare medicines for treating related tumor diseases caused by abnormal expression of tyrosine kinase.
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在调节肿瘤相关巨噬细胞功能中的用途。本发明的化合物或其药学上可接受的盐，及其药物组合物可以特异性抑制巨噬细胞向肿瘤的趋化、诱导M2型TAMs向M1表型再极化，因此可以作为肿瘤相关巨噬细胞的调节剂用于恶性肿瘤、炎症性疾病、骨疾病和神经性疾病的免疫治疗。Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in regulating the function of tumor-associated macrophages. The compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof can specifically inhibit the chemotaxis of macrophages to tumors and induce the repolarization of M2-type TAMs to the M1 phenotype, so they can be used as tumor-associated macrophages. Modulators of cells are used in the immunotherapy of malignancies, inflammatory diseases, bone diseases and neurological diseases.
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备抗肿瘤药物中的用途。体内外抗肿瘤试验表明，本发明化合物刺激的M2型巨噬细胞条件培养基能够显著抑制肝癌、肺癌、胰腺癌、结直肠癌等恶性肿瘤的生长。因此，本发明的化合物或其药学上可接受的盐，及其药物组合物可作为单一治疗剂，或者与其它抗肿瘤药物(包括靶向药物和免疫治疗药物)联合使用，用于多种恶性肿瘤的治疗。Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of antitumor drugs. Anti-tumor tests in vivo and in vitro show that the conditioned medium of M2 macrophages stimulated by the compound of the present invention can significantly inhibit the growth of malignant tumors such as liver cancer, lung cancer, pancreatic cancer, and colorectal cancer. Therefore, the compound of the present invention or its pharmaceutically acceptable salt, and its pharmaceutical composition can be used as a single therapeutic agent, or used in combination with other antineoplastic drugs (including targeted drugs and immunotherapy drugs) for a variety of malignant Tumor treatment.
本发明的另一目的在于提供所述6-位取代的吲哚酮衍生物或药学上可接受的盐、及其药物组合物在制备治疗结直肠癌药物中的用途。体外抗肿瘤活性实验表明，本发明的化合物刺激的M2型巨噬细胞条件培养基能够显著抑制结直肠癌细胞的增殖。整体动物试验表明，本发明化合物对结直肠癌具有很好的疗效，抑瘤效果显著优于PLX3397，并且与免疫检查点抑制剂PD-L1单抗联用具有协同增效作用。因此，本发明的化合物或其药学上可接受的盐，及其药物组合物可作为单一治疗剂，或者与免疫检查点抑制剂联合使用，用于结直肠癌的治疗。Another object of the present invention is to provide the use of the 6-substituted indolinone derivatives or pharmaceutically acceptable salts and pharmaceutical compositions thereof in the preparation of drugs for treating colorectal cancer. The in vitro anti-tumor activity test shows that the conditioned medium of M2 macrophages stimulated by the compound of the present invention can significantly inhibit the proliferation of colorectal cancer cells. Whole animal experiments show that the compound of the present invention has a good curative effect on colorectal cancer, and its antitumor effect is significantly better than that of PLX3397, and it has a synergistic effect in combination with the immune checkpoint inhibitor PD-L1 monoclonal antibody. Therefore, the compound of the present invention or its pharmaceutically acceptable salt, and its pharmaceutical composition can be used as a single therapeutic agent, or used in combination with immune checkpoint inhibitors, for the treatment of colorectal cancer.
本发明的有益效果是：本发明所述的6-位取代的吲哚酮衍生物是一种全新结构类型的CSF-1R抑制剂，相比目前上市CSF-1R抑制剂PLX3397，具有更强的CSF-1R抑制活性，更强的体外抗肿瘤活性和更强的体内抗肿瘤活性，尤其是用于结直肠癌治疗的起效剂量更低，同等剂量下的抑瘤率明显优于PLX3397，并且与PD-L1单抗联用有很好的协同增效作用，因此，本发明的CSF-1R抑制剂具有良好的产业化前景。The beneficial effects of the present invention are: the 6-position substituted indolinone derivatives described in the present invention are a new structural type of CSF-1R inhibitors, and have stronger CSF-1R inhibitory activity, stronger in vitro anti-tumor activity and stronger in vivo anti-tumor activity, especially for the treatment of colorectal cancer, the onset dose is lower, and the tumor inhibition rate at the same dose is significantly better than PLX3397, and Combination with PD-L1 monoclonal antibody has a good synergistic effect, therefore, the CSF-1R inhibitor of the present invention has good industrialization prospects.
具体实施方式Detailed ways
为了更清楚地说明本发明的技术方案，下面对本发明的技术方案做进一步的详细说明：In order to illustrate the technical solution of the present invention more clearly, the technical solution of the present invention is described in further detail below:
实施例1Example 1
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐(I-1)的合成：(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride (I-1) synthesis:
Figure PCTCN2022128606-appb-000012
Figure PCTCN2022128606-appb-000012
中间体III-1的合成：将化合物II-1(0.70g,7.13mmol)溶解于无水四氢呋喃(20mL)，然后加入K 2CO 3(1.22g,8.83mmol)，氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体1.17g，收率75％。 Synthesis of Intermediate III-1: Compound II-1 (0.70g, 7.13mmol) was dissolved in anhydrous tetrahydrofuran (20mL), then K 2 CO 3 (1.22g, 8.83mmol), phenyl chloroformate (0.94mL , 7.49mmol), reacted at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 1.17 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000013
Figure PCTCN2022128606-appb-000013
中间体V-1的合成：将化合物III-1(0.31g,1.44mmol)，IV-1(0.20g,1.20mmol)，DMAP(0.0090g,0.07mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.025mL,0.18mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到灰色固体0.27g，收率75％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d,J＝7.9Hz),6.80(1H,d,J＝8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,177.3,158.8,151.7,144.6,138.8,125.0,119.9,111.4,100.6,92.9,35.8,32.9,28.8(3C)。 Synthesis of intermediate V-1: Compound III-1 (0.31g, 1.44mmol), IV-1 (0.20g, 1.20mmol), DMAP (0.0090g, 0.07mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.025mL, 0.18mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.27 g of a gray solid with a yield of 75%. . 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d, J=7.9Hz),6.80(1H,d,J=8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 ) δ (ppm): 180.6, 177.3, 158.8, 151.7, 144.6, 138.8, 125.0, 119.9, 111.4, 100.6, 92.9, 35.8, 32.9, 28.8 (3C).
Figure PCTCN2022128606-appb-000014
Figure PCTCN2022128606-appb-000014
中间体XI-1的合成：将化合物V-1(0.80g,2.55mmol)和VI-1(0.43g,2.55mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.27mL,3.31mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体1.00g，收率85％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d,J＝8.3Hz),7.59(1H,s),7.32(1H,s),6.94(1H,d,J＝8.3Hz),6.51(1H,s),2.63(3H,s),2.55(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO)δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4,120.8,119.5,112.0,100.8,92.9,33.0,28.8(3C),15.3,11.5。 Synthesis of Intermediate XI-1: Compounds V-1 (0.80g, 2.55mmol) and VI-1 (0.43g, 2.55mmol) were dissolved in ethanol (10mL), then pyrrolidine (0.27mL, 3.31mmol) was added, Heated to 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 1.00 g of an orange-yellow solid with a yield of 85%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d, J＝8.3Hz), 7.59(1H,s), 7.32(1H,s), 6.94(1H,d, J＝8.3Hz), 6.51(1H,s), 2.63(3H,s), 2.55(3H, s),1.31(9H,s). 13 C NMR(125MHz,DMSO)δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4,120.8,119.5 , 112.0, 100.8, 92.9, 33.0, 28.8 (3C), 15.3, 11.5.
Figure PCTCN2022128606-appb-000015
Figure PCTCN2022128606-appb-000015
中间体XII-1的合成：将化合物XI-1(0.20g,0.43mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂，加入氯化铵(0.23g,4.31mmol)的饱和溶液(1mL)，加热至50℃，分批加入锌粉(0.14g,2.15mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，甲醇打浆纯化，抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.10g，收率54％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d,J＝8.3Hz),7.31(1H,s),7.25(1H,d,J＝1.6Hz),6.85(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.51(1H,s),3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO)δ(ppm):180.6,169.9,158.9,151.6,138.4,136.6,132.9,125.0,123.8,122.0,121.6,118.1,116.6,111.5,110.8,100.6,92.9,32.9,28.8(3C),11.6,8.9。 Synthesis of intermediate XII-1: Dissolve compound XI-1 (0.20g, 0.43mmol) in a mixed solvent of tetrahydrofuran and methanol (10mL/5mL, v/v), add ammonium chloride (0.23g, 4.31mmol) The saturated solution (1 mL) was heated to 50°C, and zinc powder (0.14 g, 2.15 mmol) was added in batches, and the reaction was continued for 0.5 h. After the reaction was completed by LC-MS monitoring, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and wash with water and saturated sodium chloride successively The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, purification by beating with methanol, suction filtration, washing the filter cake with a small amount of methanol, and drying in vacuo to obtain 0.10 g of a yellow solid with a yield of 54%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d, J＝8.3Hz), 7.31(1H,s), 7.25(1H,d, J＝1.6Hz), 6.85(1H,dd, J1 ＝8.3Hz, J2 ＝1.8Hz), 6.51(1H,s) ,3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO)δ(ppm):180.6,169.9,158.9,151.6, 138.4, 136.6, 132.9, 125.0, 123.8, 122.0, 121.6, 118.1, 116.6, 111.5, 110.8, 100.6, 92.9, 32.9, 28.8 (3C), 11.6, 8.9.
Figure PCTCN2022128606-appb-000016
Figure PCTCN2022128606-appb-000016
中间体XIII-1的合成：将化合物XII-1(0.40g,0.92mmol)和Boc-L-脯氨酸(0.22g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol)，于室温反应12h。TLC监测反应完毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩滤液，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.45g，收率77％。Synthesis of Intermediate XIII-1: Compound XII-1 (0.40g, 0.92mmol) and Boc-L-proline (0.22g, 1.01mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol), react at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated, and purified by column chromatography (dichloromethane:methanol=50:1～20:1) to obtain 0.45 g of a yellow solid with a yield of 77%.
Figure PCTCN2022128606-appb-000017
Figure PCTCN2022128606-appb-000017
化合物I-1的合成：将化合物XIII-1(0.10g,0.16mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.072g,收率75％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.40(1H,s),10.87(1H,s),10.06(1H,brs),9.98(1H,s),9.81(1H,s),9.72(1H,s),8.65(1H,brs),7.63(1H,d,J＝8.3Hz),7.47(1H,s),7.30(1H,d,J＝1.7Hz),6.95(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.53(1H,s),4.39-4.43(1H,m),3.24-3.29(2H,m),2.21(3H,s),2.21(3H,s),1.94-2.02(4H,m),1.30(9H,s). 13C NMR(125MHz,DMSO)δ(ppm):180.4,170.3,168.0,158.7,151.9,139.4,138.4,130.1,125.4,124.9,122.3,120.4,120.3,119.3,115.0,111.4,100.4,93.0,59.5,46.0,32.9,30.7,28.8(3C),24.1,12.1,9.6.HRMS(ESI):m/z[M+H] +calcd for C 28H 34N 7O 4 +,532.2672；found,532.2665. Synthesis of Compound I-1: Compound XIII-1 (0.10 g, 0.16 mmol) was dissolved in ethanol (5 mL), and saturated HCl in ethanol (5 mL) was added, and the reaction was stirred at room temperature. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.072 g of a yellow solid with a yield of 75%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.40(1H,s),10.87(1H,s),10.06(1H,brs),9.98(1H,s), 9.81(1H,s),9.72(1H,s),8.65(1H,brs),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.30(1H,d,J=1.7Hz ),6.95(1H,dd,J 1 =8.3Hz,J 2 =1.7Hz),6.53(1H,s),4.39-4.43(1H,m),3.24-3.29(2H,m),2.21(3H, s),2.21(3H,s),1.94-2.02(4H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO)δ(ppm):180.4,170.3,168.0,158.7,151.9,139.4 ,138.4,130.1,125.4,124.9,122.3,120.4,120.3,119.3,115.0,111.4,100.4,93.0,59.5,46.0,32.9,30.7,28.8(3C),24.1,12.1,9.6.HRMS(ESI) :m /z[M+H] + calcd for C 28 H 34 N 7 O 4 + ,532.2672; found, 532.2665.
实施例2Example 2
(R,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐(I-2)的合成：(R,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride (I-2) synthesis:
Figure PCTCN2022128606-appb-000018
Figure PCTCN2022128606-appb-000018
中间体XII-2的合成：将化合物XIII-1(0.40g,0.92mmol)和Boc-L-脯氨酸(0.22g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol)，于室温反应12h。TLC监测反应完毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.44g,收率75％。Synthesis of Intermediate XII-2: Compound XIII-1 (0.40g, 0.92mmol) and Boc-L-proline (0.22g, 1.01mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol), react at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol=50:1-20:1) gave 0.44 g of a yellow solid with a yield of 75%.
Figure PCTCN2022128606-appb-000019
Figure PCTCN2022128606-appb-000019
化合物I-2的合成：将化合物XIII-2(0.10g,0.16mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩滤液，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.064g,收率70％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.40(1H,s),10.88(1H,s),9.90(1H,s),9.77(1H,brs),9.71(1H,s),9.44(1H,s),8.66(1H,brs),7.64(1H,d,J＝8.3Hz),7.48(1H,s),7.30(1H,d,J＝1.7Hz),6.94(1H,dd,J 1＝8.1Hz,J 2＝1.7Hz),6.53(1H,s),4.39-4.42(1H,m),3.24-3.29(2H,m),2.44-2.48(1H,m),2.21(3H,s),2.21(3H,s),1.95-2.02(3H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,170.3,168.0,158.8,151.8,139.4,138.2,130.2,125.4,124.9,122.4,120.5,120.2,119.3,115.0,111.6,100.5,92.9,59.6,46.1,32.9,30.6,28.8(3C),24.1,12.0,9.5.HRMS(ESI):m/z[M+H] +calcd for C 28H 34N 7O 4 +,532.2672；found,532.2668。 Synthesis of Compound I-2: Compound XIII-2 (0.10 g, 0.16 mmol) was dissolved in ethanol (5 mL), and saturated HCl in ethanol (5 mL) was added, and the reaction was stirred at room temperature. After the completion of the reaction as monitored by TLC, the filtrate was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.064 g of a yellow solid with a yield of 70%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.40(1H,s),10.88(1H,s),9.90(1H,s),9.77(1H,brs), 9.71(1H,s),9.44(1H,s),8.66(1H,brs),7.64(1H,d,J=8.3Hz),7.48(1H,s),7.30(1H,d,J=1.7Hz ),6.94(1H,dd,J 1 =8.1Hz,J 2 =1.7Hz),6.53(1H,s),4.39-4.42(1H,m),3.24-3.29(2H,m),2.44-2.48( 1H,m),2.21(3H,s),2.21(3H,s),1.95-2.02(3H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm) :180.5,170.3,168.0,158.8,151.8,139.4,138.2,130.2,125.4,124.9,122.4,120.5,120.2,119.3,115.0,111.6,100.5,92.9,59.6,46.1,32. 9,30.6,28.8(3C), 24.1, 12.0, 9.5. HRMS (ESI): m/z[M+H] + calcd for C 28 H 34 N 7 O 4 + , 532.2672; found, 532.2668.
实施例3Example 3
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-4-甲酰胺盐酸盐(I-3)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)piperidine-4-carboxamide hydrochloride (I-3):
Figure PCTCN2022128606-appb-000020
Figure PCTCN2022128606-appb-000020
中间体XIII-3的合成：将化合物XII-1(0.40g,0.92mmol)和Boc-4-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol)，于室温反应12h。TLC监测反应完毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.44g,收率80％。Synthesis of Intermediate XIII-3: Compound XII-1 (0.40g, 0.92mmol) and Boc-4-piperidinecarboxylic acid (0.23g, 1.01mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol), react at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol=50:1-20:1) gave 0.44 g of a yellow solid with a yield of 80%.
Figure PCTCN2022128606-appb-000021
Figure PCTCN2022128606-appb-000021
化合物I-3的合成：将化合物XIII-3(0.10g,0.15mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.055g,收率65％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.35(1H,s),10.84(1H,s),9.68(1H,s),9.38(1H,s),9.23(1H,s),8.98(1H,brs),8.61(1H,brs),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.29(1H,d,J＝1.7Hz),6.92(1H,dd,J 1＝8.2Hz,J 2＝1.0Hz),6.52(1H,s),3.27-3.31(1H,m),2.91-2.98(2H,m),2.62-2.70(2H,m),2.21(3H,s),2.12(3H,s),1.97-2.02(2H,m),1.80-1.88(2H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,173.0,170.3,158.8,151.8,139.3,138.1,130.6,125.9,124.8,122.5,121.5,120.6,119.1,114.3,111.5,100.4,93.0,42.8(2C),32.9(2C),28.8(3C),25.8(2C),12.1,9.5.HRMS(ESI):m/z[M+H] +calcd for C 29H 36N 7O 4 +,546.2829；found,546.2819。 Synthesis of Compound I-3: Compound XIII-3 (0.10 g, 0.15 mmol) was dissolved in ethanol (5 mL), and saturated HCl in ethanol (5 mL) was added, and the reaction was stirred at room temperature. After the completion of the reaction as monitored by TLC, it was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.055 g of a yellow solid with a yield of 65%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.35(1H,s),10.84(1H,s),9.68(1H,s),9.38(1H,s), 9.23(1H,s),8.98(1H,brs),8.61(1H,brs),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,d,J=1.7Hz ),6.92(1H,dd,J 1 =8.2Hz,J 2 =1.0Hz),6.52(1H,s),3.27-3.31(1H,m),2.91-2.98(2H,m),2.62-2.70( 2H,m),2.21(3H,s),2.12(3H,s),1.97-2.02(2H,m),1.80-1.88(2H,m),1.30(9H,s). 13 C NMR(125MHz, DMSO-d 6 )δ (ppm): 180.5, 173.0, 170.3, 158.8, 151.8, 139.3, 138.1, 130.6, 125.9, 124.8, 122.5, 121.5, 120.6, 119.1, 114.3, 111.5, 100.4, 93.0, 42.8(2C) ,32.9(2C),28.8(3C),25.8(2C),12.1,9.5.HRMS(ESI):m/z[M+H] + calcd for C 29 H 36 N 7 O 4 + ,546.2829;found, 546.2819.
实施例4Example 4
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-2-甲酰胺盐酸盐(I-4)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)piperidine-2-carboxamide hydrochloride (I-4):
Figure PCTCN2022128606-appb-000022
Figure PCTCN2022128606-appb-000022
中间体XIII-4的合成：将化合物XII-1(0.40g,0.92mmol)和Boc-2-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol),于室温反应12h。TLC监测反应完毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.49g,收率83％。Synthesis of Intermediate XIII-4: Compound XII-1 (0.40g, 0.92mmol) and Boc-2-piperidinecarboxylic acid (0.23g, 1.01mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol), reacted at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol=50:1～20:1) gave 0.49 g of a yellow solid with a yield of 83%.
Figure PCTCN2022128606-appb-000023
Figure PCTCN2022128606-appb-000023
化合物I-4的合成：将化合物XIII-4(0.10g,0.15mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.060g,收率71％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.39(1H,s),10.86(1H,s),9.82(1H,s), 9.72(1H,s),9.49(1H,s),9.28(1H,brs),8.77(1H,brs),7.63(1H,d,J＝8.3Hz),7.47(1H,s),7.29(1H,d,J＝1.5Hz),6.94(1H,dd,J 1＝8.2Hz,J 2＝1.5Hz),6.52(1H,s),3.25-3.29(1H,m),2.96-2.99(1H,m),2.26-2.33(2H,m),2.20(3H,s),2.16(3H,s),1.84-1.86(1H,m),1.73-1.76(1H,m),1.54-1.60(1H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,170.3,168.5,158.8,151.8,139.4,138.2,130.2,125.5,124.9,122.4,120.4,120.2,119.3,115.0,111.5,100.5,92.9,57.5,43.7,32.9,28.8(3C),27.9,22.1,21.7,12.0,9.5.HRMS(ESI):m/z[M+H] +calcd for C 29H 36N 7O 4 +,546.2829；found,546.2814。 Synthesis of Compound I-4: Compound XIII-4 (0.10 g, 0.15 mmol) was dissolved in ethanol (5 mL), and saturated HCl in ethanol (5 mL) was added, and the reaction was stirred at room temperature. After the completion of the reaction as monitored by TLC, it was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.060 g of a yellow solid with a yield of 71%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.39(1H,s),10.86(1H,s),9.82(1H,s), 9.72(1H,s), 9.49(1H,s),9.28(1H,brs),8.77(1H,brs),7.63(1H,d,J=8.3Hz),7.47(1H,s),7.29(1H,d,J=1.5Hz ),6.94(1H,dd,J 1 =8.2Hz,J 2 =1.5Hz),6.52(1H,s),3.25-3.29(1H,m),2.96-2.99(1H,m),2.26-2.33( 2H,m),2.20(3H,s),2.16(3H,s),1.84-1.86(1H,m),1.73-1.76(1H,m),1.54-1.60(1H,m),1.30(9H, s). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.5, 170.3, 168.5, 158.8, 151.8, 139.4, 138.2, 130.2, 125.5, 124.9, 122.4, 120.4, 120.2, 119.3, 115.0, 11 1.5 ,100.5,92.9,57.5,43.7,32.9,28.8(3C),27.9,22.1,21.7,12.0,9.5.HRMS(ESI):m/z[M+H] + calcd for C 29 H 36 N 7 O 4 + ,546.2829; found, 546.2814.
实施例5Example 5
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-3-甲酰胺盐酸盐(I-5)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)piperidine-3-carboxamide hydrochloride (I-5):
Figure PCTCN2022128606-appb-000024
Figure PCTCN2022128606-appb-000024
中间体XIII-5的合成：将化合物XII-1(0.40g,0.92mmol)和Boc-2-哌啶甲酸(0.23g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol)，于室温反应12h。TLC监测反应完毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.46g,收率78％。Synthesis of Intermediate XIII-5: Compound XII-1 (0.40g, 0.92mmol) and Boc-2-piperidinecarboxylic acid (0.23g, 1.01mmol) were dissolved in DMF (50mL), and the condensing agent PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol), react at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol=50:1-20:1) gave 0.46 g of a yellow solid with a yield of 78%.
Figure PCTCN2022128606-appb-000025
Figure PCTCN2022128606-appb-000025
化合物I-5的合成：将将化合物XIII-5(0.10g,0.15mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.064g,收率73％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.84(1H,s),9.62(1H,s),9.39(1H,s),9.23(1H,s),8.85(1H,brs),8.70(1H,brs),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.4Hz),6.92(1H,dd,J 1＝8.2Hz,J 2＝1.6Hz),6.52(1H,s),3.29-3.32(1H,m),3.14-3.22(1H,m),3.02-3.09(1H,m),2.87-2.95(2H,m),2.18(3H,s),2.14(3H,s),2.04-2.09(1H,m),1.81-1.88(1H,m),1.70-1.76(2H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,171.7,170.3,158.8,151.7,139.3,138.0,130.5,125.8,124.8,122.5,121.1,120.6,119.2,114.5,111.6,100.6,92.9,44.8,43.5,39.0,32.9,28.8(3C),27.0,21.6,12.1,9.5.HRMS(ESI):m/z[M+H] +calcd for C 29H 36N 7O 4 +,546.2829；found,546.2812。 Synthesis of compound I-5: Dissolve compound XIII-5 (0.10 g, 0.15 mmol) in ethanol (5 mL), add saturated ethanol solution of HCl (5 mL), and stir the reaction at room temperature. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.064 g of a yellow solid with a yield of 73%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.84(1H,s),9.62(1H,s),9.39(1H,s), 9.23(1H,s),8.85(1H,brs),8.70(1H,brs),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.28(1H,d,J=1.4Hz ),6.92(1H,dd,J 1 =8.2Hz,J 2 =1.6Hz),6.52(1H,s),3.29-3.32(1H,m),3.14-3.22(1H,m),3.02-3.09( 1H,m),2.87-2.95(2H,m),2.18(3H,s),2.14(3H,s),2.04-2.09(1H,m),1.81-1.88(1H,m),1.70-1.76( 2H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,171.7,170.3,158.8,151.7,139.3,138.0,130.5,125.8,124.8,122.5, 121.1, 120.6, 119.2, 114.5, 111.6, 100.6, 92.9, 44.8, 43.5, 39.0, 32.9, 28.8 (3C), 27.0, 21.6, 12.1, 9.5. HRMS (ESI): m/z[M+H] + calcd for C 29 H 36 N 7 O 4 + , 546.2829; found, 546.2812.
实施例6Example 6
(S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-3-甲酰胺盐酸盐(I-6)的合成：(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-3-carboxamide hydrochloride (I-6) synthesis:
Figure PCTCN2022128606-appb-000026
Figure PCTCN2022128606-appb-000026
中间体XIII-6的合成：将化合物XII-1(0.40g,0.92mmol)和(R)-1-Boc-3-吡咯烷甲酸(0.22g,1.01mmol)溶于DMF(50mL)，加入缩合剂PyBOP(0.57g,1.10mmol)和DIPEA(1.07mL,6.44mmol)，于室温反应12h。TLC监测反应完 毕后，将反应液加入水(50mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇＝50:1～20:1)得到黄色固体0.44g,收率75％。Synthesis of Intermediate XIII-6: Dissolve compound XII-1 (0.40g, 0.92mmol) and (R)-1-Boc-3-pyrrolidinecarboxylic acid (0.22g, 1.01mmol) in DMF (50mL), add The mixture of PyBOP (0.57g, 1.10mmol) and DIPEA (1.07mL, 6.44mmol) was reacted at room temperature for 12h. After the completion of the reaction as monitored by TLC, the reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol=50:1-20:1) gave 0.44 g of a yellow solid with a yield of 75%.
Figure PCTCN2022128606-appb-000027
Figure PCTCN2022128606-appb-000027
化合物I-6的合成：将化合物XIII-6(0.10g,0.16mmol)溶于乙醇(5mL)，加入饱和HCl的乙醇溶液(5mL)，于室温搅拌反应。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.068g,收率75％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.84(1H,s),9.74(1H,s),9.55(1H,s),9.51(1H,s),9.41(1H,brs),9.15(1H,brs),7.62(1H,d,J＝8.2Hz),7.45(1H,s),7.29(1H,s),6.94(1H,d,J＝8.1Hz),6.53(1H,s),3.39-3.45(1H,m),3.27-3.33(2H,m),3.20-3.24(2H,m),2.25-2.31(1H,m),2.18(3H,s),2.16(3H,s),2.03-2.10(1H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,171.2,170.3,158.8,151.8,139.3,138.1,130.4,125.7,124.8,122.5,121.3,120.5,119.2,114.5,111.5,100.5,92.9,47.3,45.2,42.5,32.9,29.7,28.8(3C),12.1,9.6.HRMS(ESI):m/z[M+H] +calcd for C 28H 34N 7O 4 +,532.2672；found,532.2653。 Synthesis of Compound I-6: Compound XIII-6 (0.10 g, 0.16 mmol) was dissolved in ethanol (5 mL), and saturated HCl in ethanol (5 mL) was added, and the reaction was stirred at room temperature. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was purified by adding ethyl acetate (5 mL) to make a slurry, filtered by suction, and dried in vacuo to obtain 0.068 g of a yellow solid with a yield of 75%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.84(1H,s),9.74(1H,s),9.55(1H,s), 9.51(1H,s),9.41(1H,brs),9.15(1H,brs),7.62(1H,d,J＝8.2Hz),7.45(1H,s),7.29(1H,s),6.94(1H ,d,J=8.1Hz),6.53(1H,s),3.39-3.45(1H,m),3.27-3.33(2H,m),3.20-3.24(2H,m),2.25-2.31(1H,m ),2.18(3H,s),2.16(3H,s),2.03-2.10(1H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.5, 171.2, 170.3, 158.8, 151.8, 139.3, 138.1, 130.4, 125.7, 124.8, 122.5, 121.3, 120.5, 119.2, 114.5, 111.5, 100.5, 92.9, 47.3, 45.2, 42.5, 32.9, 29.7, 28.8(3C), 12.1 , 9.6. HRMS (ESI): m/z[M+H] + calcd for C 28 H 34 N 7 O 4 + , 532.2672; found, 532.2653.
实施例7Example 7
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺(I-7)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propionamide (I-7):
Figure PCTCN2022128606-appb-000028
Figure PCTCN2022128606-appb-000028
中间体XIII-7的合成：化合物XII-1(0.50g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.50mL,3.45mmol)，降温至0℃，滴加3-氯丙酰氯(0.10mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.48g,收率80％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.82(1H,s),9.50(1H,s),9.26(1H,s),8.94(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.29(1H,d,J＝1.7Hz),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.52(1H,s),3.88(2H,t,J＝6.2Hz),2.78(2H,t,J＝6.1Hz),2.19(3H,s),2.15(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO)δ(ppm):180.6,170.3,168.7,158.8,151.7,139.3,137.8,130.8,126.0,124.8,122.6,121.7,120.7,119.2,114.3,111.6,100.6,92.9,41.8,38.7,32.9,28.8(3C),12.1,9.6。 Synthesis of Intermediate XIII-7: Dissolve compound XII-1 (0.50g, 1.15mmol) in THF (20mL), add DIPEA (0.50mL, 3.45mmol), cool to 0°C, add dropwise 3-chloropropionyl chloride (0.10 mL, 5.75mmol), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.48 g of a yellow solid with a yield of 80%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.82(1H,s),9.50(1H,s),9.26(1H,s),8.94(1H,s) ,7.63(1H,d,J=8.3Hz),7.46(1H,s),7.29(1H,d,J=1.7Hz),6.90(1H,dd,J 1 ＝8.3Hz,J 2 ＝1.8Hz) ,6.52(1H,s),3.88(2H,t,J=6.2Hz),2.78(2H,t,J=6.1Hz),2.19(3H,s),2.15(3H,s),1.31(9H, s). 13 C NMR (125MHz, DMSO) δ (ppm): 180.6, 170.3, 168.7, 158.8, 151.7, 139.3, 137.8, 130.8, 126.0, 124.8, 122.6, 121.7, 120.7, 119.2, 114.3, 111.6, 1 00.6, 92.9, 41.8, 38.7, 32.9, 28.8 (3C), 12.1, 9.6.
Figure PCTCN2022128606-appb-000029
Figure PCTCN2022128606-appb-000029
化合物I-7的合成：将化合物XIII-7(0.17mg,0.30mmol)溶于DMF(5mL)，加入吡咯烷(0.12mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率79％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.82(1H,s),9.60(1H,s),9.23(1H,s),9.19(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.28(1H,d,J＝1.4Hz),6.91(1H,dd,J 1＝8.2Hz,J 2＝1.5Hz),6.52(1H,s),2.74(2H,t,J＝6.0Hz),2.51-2.60(4H,m),2.46(2H,t,J＝7.0Hz),2.18(3H,s),2.13(3H,s), 1.66-1.76(4H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.9,170.3,158.8,151.7,139.2,137.9,130.7,125.9,124.8,122.6,122.0,120.7,119.1,114.1,111.6,100.6,92.9,53.8(2C),52.3,35.5,32.9,28.8(3C),23.6(2C),12.1,9.5.HRMS(ESI):m/z[M+H] +calcd for C 30H 38N 7O 4 +,560.2985；found,560.2964。 Synthesis of compound I-7: Compound XIII-7 (0.17 mg, 0.30 mmol) was dissolved in DMF (5 mL), added pyrrolidine (0.12 mL, 1.50 mmol), and reacted at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, and vacuum drying gave 0.13 g of yellow solid with a yield of 79%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.82(1H,s),9.60(1H,s),9.23(1H,s), 9.19(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.4Hz),6.91(1H,dd,J = 8.2Hz, J 2 =1.5Hz),6.52(1H,s),2.74(2H,t,J=6.0Hz),2.51-2.60(4H,m),2.46(2H,t,J=7.0Hz),2.18(3H ,s),2.13(3H,s), 1.66-1.76(4H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.9,170.3,158.8 ,151.7,139.2,137.9,130.7,125.9,124.8,122.6,122.0,120.7,119.1,114.1,111.6,100.6,92.9,53.8(2C),52.3,35.5,32.9,28.8(3C),23.6 (2C), 12.1, 9.5. HRMS (ESI): m/z [M+H] + calcd for C 30 H 38 N 7 O 4 + , 560.2985; found, 560.2964.
实施例8Example 8
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(哌啶-1-基)丙酰胺(I-8)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(piperidin-1-yl)propionamide (I-8):
Figure PCTCN2022128606-appb-000030
Figure PCTCN2022128606-appb-000030
化合物I-8的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入哌啶(0.15mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率76％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.81(1H,s),9.48(1H,s),9.20(1H,s),8.90(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J＝7.5Hz),6.51(1H,s),2.59(2H,t,J＝6.6Hz),2.33-2.43(6H,m),2.19(3H,s),2.15(3H,s),1.46-1.52(4H,m),1.36-1.43(2H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,171.0,170.3,1588,151.7,139.2,137.7,130.8,126.0,124.8,122.6,122.0,120.8,119.1,114.0,111.7,100.6,92.9,55.4,54.2(2C),33.8,32.9,28.8(3C),26.1(2C),24.5,12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 31H 40N 7O 4 +,574.3142；found,574.3123。 Synthesis of compound I-8: Compound XIII-7 (0.17g, 0.30mmol) was dissolved in DMF (5mL), piperidine (0.15mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.13 g of yellow solid, yield 76%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.81(1H,s),9.48(1H,s),9.20(1H,s), 8.90(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J=7.5Hz),6.51(1H,s ),2.59(2H,t,J＝6.6Hz),2.33-2.43(6H,m),2.19(3H,s),2.15(3H,s),1.46-1.52(4H,m),1.36-1.43( 2H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,171.0,170.3,1588,151.7,139.2,137.7,130.8,126.0,124.8,122.6, 122.0, 120.8, 119.1, 114.0, 111.7, 100.6, 92.9, 55.4, 54.2(2C), 33.8, 32.9, 28.8(3C), 26.1(2C), 24.5, 12.2, 9.6.HRMS(ESI):m/z[ M+H] + calcd for C 31 H 40 N 7 O 4 + , 574.3142; found, 574.3123.
实施例9Example 9
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(4-甲基哌嗪-1-基)丙酰胺(I-9)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propionamide (I-9):
Figure PCTCN2022128606-appb-000031
Figure PCTCN2022128606-appb-000031
化合物I-9的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.17mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率75％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.81(1H,s),9.54(1H,s),9.16(1H,s),9.04(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J＝8.1Hz),6.52(1H,s),2.62(2H,t,J＝6.7Hz),2.42(4H,t,J＝6.7Hz),2.25-2.39(6H,m),2.19(3H,s),2.18(3H,s),2.15(3H,s)1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.9,170.3,158.8,151.7,139.2,137.8,130.8,126.0,124.8,122.6,122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.2(2C),54.6,52.8(2C),46.1,33.8,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 31H 41N 8O 4 +,589.3251；found,589.3227。 Synthesis of Compound I-9: Compound XIII-7 (0.17g, 0.30mmol) was dissolved in DMF (5mL), N-methylpiperazine (0.17mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.13 g of yellow solid, yield 75%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.81(1H,s),9.54(1H,s),9.16(1H,s), 9.04(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.90(1H,d,J=8.1Hz),6.52(1H,s ),2.62(2H,t,J=6.7Hz),2.42(4H,t,J=6.7Hz),2.25-2.39(6H,m),2.19(3H,s),2.18(3H,s),2.15 (3H,s)1.31(9H,s). 13 C NMR (125MHz,DMSO-d 6 )δ(ppm):180.6,170.9,170.3,158.8,151.7,139.2,137.8,130.8,126.0,124.8,122.6, 122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.2(2C),54.6,52.8(2C),46.1,33.8,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[ M+H] + calcd for C 31 H 41 N 8 O 4 + , 589.3251; found, 589.3227.
实施例10Example 10
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二乙氨基)丙酰胺(I-10)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(diethylamino)propionamide (I-10):
Figure PCTCN2022128606-appb-000032
Figure PCTCN2022128606-appb-000032
化合物I-10的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入二乙胺(0.16mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率68％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.34(1H,s),10.82(1H,s),9.60(1H,s),9.33(1H,s),9.19(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.29(1H,s),6.92(1H,d,J＝8.3Hz),6.52(1H,s),2.64-2.94(7H,m),2.18(3H,s),2.15(3H,s),1.96-2.04(1H,m),1.30(9H,s),1.06-1.12(6H,m). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.4,170.3,158.8,151.8,139.2,137.9,130.6,125.9,124.8,122.5,121.7,120.7,119.1,114.3,111.6,100.6,92.9,48.5,46.7(2C),32.9(2C),28.8(3C),12.2(2C),9.6(2C).HRMS(ESI):m/z[M+H] +calcd for C 30H 40N 7O 4 +,562.3142；found,562.3123。 Synthesis of Compound I-10: Compound XIII-7 (0.17g, 0.30mmol) was dissolved in DMF (5mL), added diethylamine (0.16mL, 1.50mmol), and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 68%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.34(1H,s),10.82(1H,s),9.60(1H,s),9.33(1H,s), 9.19(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.92(1H,d,J=8.3Hz),6.52(1H,s ),2.64-2.94(7H,m),2.18(3H,s),2.15(3H,s),1.96-2.04(1H,m),1.30(9H,s),1.06-1.12(6H,m). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.6, 170.4, 170.3, 158.8, 151.8, 139.2, 137.9, 130.6, 125.9, 124.8, 122.5, 121.7, 120.7, 119.1, 114.3, 111.6, 100.6, 92.9,48.5,46.7(2C),32.9(2C),28.8(3C),12.2(2C),9.6(2C).HRMS(ESI):m/z[M+H] + calcd for C 30 H 40 N 7 O 4 + , 562.3142; found, 562.3123.
实施例11Example 11
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二甲氨基)丙酰胺(I-11)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(dimethylamino)propionamide (I-11):
Figure PCTCN2022128606-appb-000033
Figure PCTCN2022128606-appb-000033
化合物I-11的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入二甲胺(0.076mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率72％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.34(1H,s),10.81(1H,s),9.54(1H,s),9.20(1H,s),9.04(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.28(1H,d,J＝1.2Hz),6.90(1H,dd,J 1＝8.2Hz,J 2＝1.3Hz),6.52(1H,s),2.60(2H,t,J＝7.1Hz),2.43(2H,t,J＝7.1Hz),2.22(6H,s),2.18(3H,s),2.14(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.8,170.3,158.8,151.7,139.2,137.8,130.7,125.9,124.8,122.6,122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.9,45.3(2C),34.1,32.9,28.8(3C),12.1,9.5.HRMS(ESI):m/z[M+H] +calcd for C 28H 36N 7O 4 +,534.2829；found,534.2806。 Synthesis of compound I-11: Dissolve compound XIII-7 (0.17g, 0.30mmol) in DMF (5mL), add dimethylamine (0.076mL, 1.50mmol), and react at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 72%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.34(1H,s),10.81(1H,s),9.54(1H,s),9.20(1H,s), 9.04(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.2Hz),6.90(1H,dd,J = 8.2Hz, J 2 =1.3Hz),6.52(1H,s),2.60(2H,t,J=7.1Hz),2.43(2H,t,J=7.1Hz),2.22(6H,s),2.18(3H,s ),2.14(3H,s),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.8,170.3,158.8,151.7,139.2,137.8,130.7,125.9, 124.8,122.6,122.0,120.8,119.1,114.1,111.6,100.6,92.9,55.9,45.3(2C),34.1,32.9,28.8(3C),12.1,9.5.HRMS(ESI):m/z[M+H ] + calcd for C 28 H 36 N 7 O 4 + , 534.2829; found, 534.2806.
实施例12Example 12
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(乙氨基)丙酰胺(I-12)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(ethylamino)propionamide (I-12):
Figure PCTCN2022128606-appb-000034
Figure PCTCN2022128606-appb-000034
化合物I-12的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入乙胺(0.083mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩滤液，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干 燥得到黄色固体0.11g,收率70％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.34(1H,s),10.81(1H,s),9.60(1H,s),9.30(1H,s),9.16-9.20(1H,m),7.62(1H,d,J＝8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J＝8.2Hz),6.52(1H,s),2.90(2H,t,J＝6.7Hz),2.69(2H,q,J＝7.0Hz),2.56(1H,t,J＝6.9Hz),2.42(1H,t,J＝7.0Hz),2.20(1H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s),1.08(3H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.6,170.3,158.8,151.7,139.2,137.9,130.6,125.9,124.7,122.5,121.8,120.7,119.1,114.2,111.6,100.5,92.9,55.9,45.4,43.4,32.9,28.8(3C),14.5,12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 28H 36N 7O 4 +,534.2829；found,534.2811。 Synthesis of compound I-12: Compound XIII-7 (0.17g, 0.30mmol) was dissolved in DMF (5mL), ethylamine (0.083mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, and vacuum drying gave 0.11 g of a yellow solid with a yield of 70%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.34(1H,s),10.81(1H,s),9.60(1H,s),9.30(1H,s), 9.16-9.20(1H,m),7.62(1H,d,J=8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J=8.2Hz),6.52(1H ,s),2.90(2H,t,J=6.7Hz),2.69(2H,q,J=7.0Hz),2.56(1H,t,J=6.9Hz),2.42(1H,t,J=7.0Hz ),2.20(1H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s),1.08(3H,t,J＝7.1Hz). 13 C NMR(125MHz,DMSO- d 6 )δ(ppm): 180.6, 170.6, 170.3, 158.8, 151.7, 139.2, 137.9, 130.6, 125.9, 124.7, 122.5, 121.8, 120.7, 119.1, 114.2, 111.6, 100.5, 92.9, 55.9 ,45.4,43.4, 32.9, 28.8 (3C), 14.5, 12.2, 9.6. HRMS (ESI): m/z [M+H] + calcd for C 28 H 36 N 7 O 4 + , 534.2829; found, 534.2811.
实施例13Example 13
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(丙氨基)丙酰胺(I-13)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(propylamino)propionamide (I-13):
Figure PCTCN2022128606-appb-000035
Figure PCTCN2022128606-appb-000035
化合物I-13的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入正丙胺(0.12mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩滤液，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率75％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.81(1H,s),9.58(1H,s),9.29(1H,s),9.13(1H,s),7.62(1H,d,J＝8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J＝8.2Hz),6.52(1H,s),2.85(2H,t,J＝6.7Hz),2.56(2H,t,J＝7.0Hz),2.46(2H,t,J＝6.6Hz),2.20(1H,s),2.18(3H,s),2.14(3H,s),1.46(2H,q,J＝7.0Hz),1.30(9H,s),0.88(3H,t,J＝7.4Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,171.0,170.3,158.8,151.7,139.2,137.9,130.7,125.9,124.8,122.6,121.9,120.7,119.1,114.1,111.6,100.6,92.9,56.0,51.1,46.0,45.4,32.9,28.8(3C),22.7,12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 29H 38N 7O 4 +,548.2985；found,548.2966。 Synthesis of compound I-13: Dissolve compound XIII-7 (0.17g, 0.30mmol) in DMF (5mL), add n-propylamine (0.12mL, 1.50mmol), and react at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, addition of ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, and vacuum drying gave 0.12 g of a yellow solid with a yield of 75%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.81(1H,s),9.58(1H,s),9.29(1H,s), 9.13(1H,s),7.62(1H,d,J=8.2Hz),7.45(1H,s),7.28(1H,s),6.91(1H,d,J=8.2Hz),6.52(1H,s ),2.85(2H,t,J=6.7Hz),2.56(2H,t,J=7.0Hz),2.46(2H,t,J=6.6Hz),2.20(1H,s),2.18(3H,s ), 2.14(3H, s), 1.46(2H, q, J=7.0Hz), 1.30(9H, s), 0.88(3H, t, J=7.4Hz). 13 C NMR (125MHz, DMSO-d 6 )δ (ppm): 180.6, 171.0, 170.3, 158.8, 151.7, 139.2, 137.9, 130.7, 125.9, 124.8, 122.6, 121.9, 120.7, 119.1, 114.1, 111.6, 100.6, 92.9, 56.0, 51 .1,46.0,45.4, 32.9, 28.8 (3C), 22.7, 12.2, 9.6. HRMS (ESI): m/z [M+H] + calcd for C 29 H 38 N 7 O 4 + , 548.2985; found, 548.2966.
实施例14Example 14
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(叔丁氨基)丙酰胺(I-14)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(tert-butylamino)propionamide (I-14):
Figure PCTCN2022128606-appb-000036
Figure PCTCN2022128606-appb-000036
化合物I-14的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入叔丁胺(0.16mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率72％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.35(1H,s),10.83(1H,s),9.70(1H,s),9.43(2H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.29(1H,s),6.93(1H,d,J＝8.1Hz),6.52(1H,s),3.11(2H,t,J＝6.8Hz),2.78(2H,t,J＝7.0Hz),2.20(3H,s),2.16(3H,s),1.30(18H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,170.3,158.8,151.8,139.6,139.3,138.0,130.5,125.8,124.8,122.5,121.5,120.6,119.1,114.4,111.5,100.5,92.9,37.7,32.9,29.5,28.8(6C),26.0,12.3,9.7.HRMS(ESI):m/z[M+H] +calcd for C 30H 40N 7O 4 +,562.3142；found,562.3124。 Synthesis of compound I-14: Dissolve compound XIII-7 (0.17g, 0.30mmol) in DMF (5mL), add tert-butylamine (0.16mL, 1.50mmol), and react at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 72%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.35(1H,s),10.83(1H,s),9.70(1H,s),9.43(2H,s), 7.62(1H,d,J=8.3Hz),7.45(1H,s),7.29(1H,s),6.93(1H,d,J=8.1Hz),6.52(1H,s),3.11(2H,t , J=6.8Hz), 2.78(2H, t, J=7.0Hz), 2.20(3H,s), 2.16(3H,s), 1.30(18H,s). 13 C NMR (125MHz, DMSO-d 6 )δ (ppm): 180.5, 170.3, 158.8, 151.8, 139.6, 139.3, 138.0, 130.5, 125.8, 124.8, 122.5, 121.5, 120.6, 119.1, 114.4, 111.5, 100.5, 92.9, 37.7, 32 .9,29.5,28.8( 6C), 26.0, 12.3, 9.7. HRMS (ESI): m/z[M+H] + calcd for C 30 H 40 N 7 O 4 + , 562.3142; found, 562.3124.
实施例15Example 15
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(环戊氨基)丙酰胺(I-15)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(cyclopentylamino)propionamide (I-15):
Figure PCTCN2022128606-appb-000037
Figure PCTCN2022128606-appb-000037
化合物I-15的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入环戊胺(0.15mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率78％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.81(1H,s),9.49(1H,s),9.28(1H,s),8.89(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.28(1H,s),6.90(1H,d,J＝8.2Hz),6.51(1H,s),3.03-3.07(1H,m),2.79(2H,t,J＝6.6Hz),2.41(2H,t,J＝6.5Hz),2.19(1H,s),2.18(3H,s),2.14(3H,s),1.70-1.75(2H,m),1.57-1.64(2H,m),1.44-1.51(2H,m),1.31-1.36(2H,m),1.30(18H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,171.3,170.3,158.9,151.7,139.2,137.7,130.7,126.0,124.8,122.6,122.0,120.8,119.1,114.1,111.7,100.7,92.9,59.4(2C),44.9,36.5,32.9(2C),28.8(3C),24.0(2C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 31H 41N 7O 4 +,574.3142；found,574.3119。 Synthesis of compound I-15: Compound XIII-7 (0.17g, 0.30mmol) was dissolved in DMF (5mL), cyclopentylamine (0.15mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.13 g of yellow solid, yield 78%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.81(1H,s),9.49(1H,s),9.28(1H,s), 8.89(1H,s),7.62(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,s),6.90(1H,d,J=8.2Hz),6.51(1H,s ),3.03-3.07(1H,m),2.79(2H,t,J=6.6Hz),2.41(2H,t,J=6.5Hz),2.19(1H,s),2.18(3H,s),2.14 (3H,s),1.70-1.75(2H,m),1.57-1.64(2H,m),1.44-1.51(2H,m),1.31-1.36(2H,m),1.30(18H,s) . C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,171.3,170.3,158.9,151.7,139.2,137.7,130.7,126.0,124.8,122.6,122.0,120.8,119.1,114.1,111.7,100 .7,92.9 ,59.4(2C),44.9,36.5,32.9(2C),28.8(3C),24.0(2C),12.2,9.6. HRMS(ESI):m/z[M+H] + calcd for C 31 H 41 N 7 O 4 + , 574.3142; found, 574.3119.
实施例16Example 16
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-吗啉基丙酰胺(I-16)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-morpholino propionamide (I-16):
Figure PCTCN2022128606-appb-000038
Figure PCTCN2022128606-appb-000038
化合物I-16的合成：将化合物XIII-7(0.17g,0.30mmol)溶于DMF(5mL)，加入吗啉(0.13mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率74％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.81(1H,s),9.46(1H,s),9.13(1H,s),8.86(1H,s),7.62(1H,d,J＝8.2Hz),7.46(1H,s),7.28(1H,s),6.89(1H,d,J＝8.2Hz),6.51(1H,s),3.55-3.63(4H,m),2.62(2H,t,J＝7.0Hz),2.42-2.45(6H,m),2.19(3H,s),2.15(3H,s),2.14(3H,s),1.31(9H,m). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.8,170.3,158.8,151.6,139.2,137.5,130.8,126.1,124.9,122.5,122.0,120.8,119.1,114.1,111.7,100.7,92.9,66.7(2C),55.1,53.5(2C),33.5,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 30H 38N 7O 5 +,576.2934；found,576.2914。 Synthesis of compound I-16: Dissolve compound XIII-7 (0.17g, 0.30mmol) in DMF (5mL), add morpholine (0.13mL, 1.50mmol), and react at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.13 g of yellow solid, yield 74%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.81(1H,s),9.46(1H,s),9.13(1H,s), 8.86(1H,s),7.62(1H,d,J=8.2Hz),7.46(1H,s),7.28(1H,s),6.89(1H,d,J=8.2Hz),6.51(1H,s ),3.55-3.63(4H,m),2.62(2H,t,J＝7.0Hz),2.42-2.45(6H,m),2.19(3H,s),2.15(3H,s),2.14(3H, s),1.31(9H,m). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.8,170.3,158.8,151.6,139.2,137.5,130.8,126.1,124.9,122.5,122.0, 120.8,119.1,114.1,111.7,100.7,92.9,66.7(2C),55.1,53.5(2C),33.5,32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H] + calcd for C 30 H 38 N 7 O 5 + , 576.2934; found, 576.2914.
实施例17Example 17
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺(I-17)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propionamide (I-17):
Figure PCTCN2022128606-appb-000039
Figure PCTCN2022128606-appb-000039
中间体XIII-8的合成：化合物XII-1(0.50g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.57mL,3.45mmol)，降温至0℃，滴加氯乙酰氯(0.46mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.46g,收率78％。 1H NMR (500MHz,DMSO-d 6)δ(ppm):13.37(1H,s),10.84(1H,s),9.59(1H,s),9.52(1H,s),9.18(1H,s),7.63(1H,d,J＝8.3Hz),7.47(1H,s),7.29(1H,d,J＝1.7Hz),6.92(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.52(1H,s),4.26(2H,s),2.19(3H,s),2.15(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO)δ(ppm):180.6,170.3,165.8,158.8,151.7,139.3,137.9,130.5,125.8,124.8,122.6,120.9,120.7,119.3,114.6,111.7,100.6,92.9,43.2,32.9,28.8(3C),12.1,9.5。 Synthesis of Intermediate XIII-8: Dissolve compound XII-1 (0.50g, 1.15mmol) in THF (20mL), add DIPEA (0.57mL, 3.45mmol), cool to 0°C, add dropwise chloroacetyl chloride (0.46mL, 5.75mmol), the addition was completed, and reacted at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.46 g of a yellow solid with a yield of 78%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):13.37(1H,s),10.84(1H,s),9.59(1H,s),9.52(1H,s),9.18(1H,s) ,7.63(1H,d,J=8.3Hz),7.47(1H,s),7.29(1H,d,J=1.7Hz),6.92(1H,dd,J 1 ＝8.3Hz,J 2 ＝1.8Hz) ,6.52(1H,s),4.26(2H,s),2.19(3H,s),2.15(3H,s),1.31(9H,s). 13 C NMR(125MHz,DMSO)δ(ppm):180.6 ,170.3,165.8,158.8,151.7,139.3,137.9,130.5,125.8,124.8,122.6,120.9,120.7,119.3,114.6,111.7,100.6,92.9,43.2,32.9,28.8(3C), 12.1, 9.5.
Figure PCTCN2022128606-appb-000040
Figure PCTCN2022128606-appb-000040
化合物I-17的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入吡咯烷(0.12mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率79％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.82(1H,s),9.55(1H,s),9.05(1H,s),8.99(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.29(1H,d,J＝1.4Hz),6.90(1H,dd,J 1＝8.2Hz,J 2＝1.5Hz),6.52(1H,s),3.25(2H,s),2.59-2.68(4H,m),2.18(3H,s),2.14(3H,s),1.72-1.81(4H,m),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,169.5,159.1,151.7,139.2,137.8,130.9,126.3,124.8,122.6,121.6,120.8,119.2,114.2,111.6,100.6,92.9,59.4,54.2(2C),32.9,28.8(3C),23.9(2C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 30H 38N 7O 4 +,546.2829；found,546.2820。 Synthesis of compound I-17: Dissolve compound XIII-8 (0.15 g, 0.30 mmol) in DMF (5 mL), add pyrrolidine (0.12 mL, 1.50 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, and vacuum drying gave 0.13 g of yellow solid with a yield of 79%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.82(1H,s),9.55(1H,s),9.05(1H,s), 8.99(1H,s),7.63(1H,d,J=8.3Hz),7.46(1H,s),7.29(1H,d,J=1.4Hz),6.90(1H,dd,J = 8.2Hz, J 2 =1.5Hz),6.52(1H,s),3.25(2H,s),2.59-2.68(4H,m),2.18(3H,s),2.14(3H,s),1.72-1.81(4H, m),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.3,169.5,159.1,151.7,139.2,137.8,130.9,126.3,124.8,122.6,121.6, 120.8,119.2,114.2,111.6,100.6,92.9,59.4,54.2(2C),32.9,28.8(3C),23.9(2C),12.2,9.6.HRMS(ESI):m/z[M+H] + calcd for C 30 H 38 N 7 O 4 + , 546.2829; found, 546.2820.
实施例18Example 18
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(哌啶-1-基)乙酰胺(I-18)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-2-(piperidin-1-yl)acetamide (I-18):
Figure PCTCN2022128606-appb-000041
Figure PCTCN2022128606-appb-000041
化合物I-18的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入哌啶(0.15mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率73％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.82(1H,s),9.48(1H,s),8.95(1H,s),8.89(1H,s),7.63(1H,d,J＝8.3Hz),7.47(1H,s),7.28(1H,d,J＝1.5Hz),6.90(1H,dd,J 1＝8.1Hz,J 2＝1.6Hz),6.52(1H,s),3.06(2H,s),2.37-2.50(4H,m),2.19(3H,s),2.14(3H,s),1.54-1.64(4H,m),1.36-1.46(2H,m),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,169.3,158.8,151.6,139.2,137.8,130.8,126.1,124.8,122.6,121.5,120.8,119.2,114.2,111.7,100.6,92.9,62.7,54.7(2C),32.9(2C),28.8(3C),25.9,24.0,12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 30H 38N 7O 4 +,560.2985；found,560.2978。 Synthesis of Compound I-18: Compound XIII-8 (0.15g, 0.30mmol) was dissolved in DMF (5mL), piperidine (0.15mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 73%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.82(1H,s),9.48(1H,s),8.95(1H,s), 8.89 (1H, s), 7.63 (1H, d, J = 8.3Hz), 7.47 (1H, s), 7.28 (1H, d, J = 1.5Hz), 6.90 (1H, dd, J = 8.1Hz, J 2 =1.6Hz),6.52(1H,s),3.06(2H,s),2.37-2.50(4H,m),2.19(3H,s),2.14(3H,s),1.54-1.64(4H, m),1.36-1.46(2H,m),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.3,169.3,158.8,151.6,139.2,137.8,130.8 ,126.1,124.8,122.6,121.5,120.8,119.2,114.2,111.7,100.6,92.9,62.7,54.7(2C),32.9(2C),28.8(3C),25.9,24.0,12.2,9.6.HRMS(ESI) : m/z[M+H] + calcd for C 30 H 38 N 7 O 4 + , 560.2985; found, 560.2978.
实施例19Example 19
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺(I-19)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide (I-19):
Figure PCTCN2022128606-appb-000042
Figure PCTCN2022128606-appb-000042
化合物I-19的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.17mL,1.50mmol)， 于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.13g,收率77％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s),8.98(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.29(1H,d,J＝1.0Hz),6.93(1H,dd,J 1＝8.3Hz,J 2＝0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64(4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.5,170.3,169.0,158.8,151.9,139.3,138.1,130.7,126.0,124.8,122.5,121.4,120.5,119.1,114.3,111.4,100.4,93.0,61.6,54.8(2C),52.9,45.9,32.9(2C),28.9(3C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 30H 39N 8O 4 +,575.3094；found,575.3088。 Synthesis of Compound I-19: Compound XIII-8 (0.15g, 0.30mmol) was dissolved in DMF (5mL), N-methylpiperazine (0.17mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.13 g of yellow solid, yield 77%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s), 8.98(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.29(1H,d,J＝1.0Hz),6.93(1H,dd,J ＝ 8.3Hz, J 2 =0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64(4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H, s),2.14(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.5,170.3,169.0,158.8,151.9,139.3,138.1,130.7,126.0 ,124.8,122.5,121.4,120.5,119.1,114.3,111.4,100.4,93.0,61.6,54.8(2C),52.9,45.9,32.9(2C),28.9(3C),12.2,9.6.HRMS(ESI):m /z[M+H] + calcd for C 30 H 39 N 8 O 4 + ,575.3094; found, 575.3088.
实施例20Example 20
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(二乙氨基)乙酰胺(I-20)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-2-(diethylamino)acetamide (I-20):
Figure PCTCN2022128606-appb-000043
Figure PCTCN2022128606-appb-000043
化合物I-20的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入二乙胺(0.16mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率73％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.37(1H,s),10.82(1H,s),9.49(1H,s),8.97(1H,s),8.93(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.51(1H,s),3.14(2H,s),2.62(4H,q,J＝6.8Hz),2.18(3H,s),2.14(3H,s),1.30(9H,s),1.07(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.6,170.3,158.8,151.7,139.2,137.8,130.8,126.2,124.8,122.6,121.6,120.8,119.2,114.2,111.6,100.6,92.9,57.3,48.5(2C),32.9(2C),28.8(3C),12.5,12.2,9.5.HRMS(ESI):m/z[M+H] +calcd for C 29H 38N 7O 4 +,548.2985；found,548.2982。 Synthesis of compound I-20: Dissolve compound XIII-8 (0.15 g, 0.30 mmol) in DMF (5 mL), add diethylamine (0.16 mL, 1.50 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 73%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.37(1H,s),10.82(1H,s),9.49(1H,s),8.97(1H,s), 8.93(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd,J ＝ 8.3Hz, J 2 =1.7Hz),6.51(1H,s),3.14(2H,s),2.62(4H,q,J=6.8Hz),2.18(3H,s),2.14(3H,s),1.30(9H ,s),1.07(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.6,170.3,158.8,151.7,139.2,137.8,130.8,126.2, 124.8,122.6,121.6,120.8,119.2,114.2,111.6,100.6,92.9,57.3,48.5(2C),32.9(2C),28.8(3C),12.5,12.2,9.5.HRMS(ESI):m/z[ M+H] + calcd for C 29 H 38 N 7 O 4 + , 548.2985; found, 548.2982.
实施例21Example 21
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-吗啉基乙酰胺(I-21)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-2-morpholinoacetamide (I-21):
Figure PCTCN2022128606-appb-000044
Figure PCTCN2022128606-appb-000044
化合物I-21的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入吗啉(0.13mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率72％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.37(1H,s),10.82(1H,s),9.47(1H,s),9.04(1H,s),8.87(1H,s),7.64(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),6.51(1H,s),3.62-3.72(4H,m),3.13(2H,s),2.50-2.62(4H,m),2.18(3H,s),2.14(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.3,168.8,158.8,151.6,139.2,137.8,130.9,126.2,124.8,122.6,121.5,120.8,119.2,114.2,111.7,100.7,92.9,66.5(2C),62.0,53.8(2C),32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 29H 36N 7O 5 +,562.2778；found,562.2771。 Synthesis of compound I-21: Compound XIII-8 (0.15g, 0.30mmol) was dissolved in DMF (5mL), added morpholine (0.13mL, 1.50mmol), and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 72%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.37(1H,s),10.82(1H,s),9.47(1H,s),9.04(1H,s), 8.87(1H,s),7.64(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd,J ＝ 8.3Hz, J 2 =1.6Hz),6.51(1H,s),3.62-3.72(4H,m),3.13(2H,s),2.50-2.62(4H,m),2.18(3H,s),2.14(3H, s),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.3,168.8,158.8,151.6,139.2,137.8,130.9,126.2,124.8,122.6,121.5, 120.8,119.2,114.2,111.7,100.7,92.9,66.5(2C),62.0,53.8(2C),32.9,28.8(3C),12.2,9.6.HRMS(ESI):m/z[M+H] + calcd for C 29 H 36 N 7 O 5 + , 562.2778; found, 562.2771.
实施例22Example 22
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(环戊氨基) 乙酰胺(I-22)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)-2-(cyclopentylamino)acetamide (I-22):
Figure PCTCN2022128606-appb-000045
Figure PCTCN2022128606-appb-000045
化合物I-22的合成：将化合物XIII-8(0.15g,0.30mmol)溶于DMF(5mL)，加入环戊胺(0.15mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.12g,收率74％。mp:>300℃. 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.36(1H,s),10.82(1H,s),9.51(1H,s),9.13(1H,s),8.94(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd,J 1＝8.0Hz,J 2＝0.9Hz),6.51(1H,s),3.10-3.13(1H,m),2.19(3H,s),2.14(3H,s),1.74-1.77(2H,m),1.63-1.69(2H,m),1.47-1.52(2H,m),1.38-1.42(2H,m),1.31(9H,s),1.24-1.26(2H,m). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,158.8,151.7,139.3,137.8,130.7,126.0,124.8,122.6,122.6,121.4,120.8,119.2,114.3,111.7,100.6,92.9,59.6,51.1,32.9,32.5(2C),28.8(3C),24.0(2C),12.2,9.6.HRMS(ESI):m/z[M+H] +calcd for C 30H 38N 7O 4 +,560.2985；found,560.2983。 Synthesis of compound I-22: Compound XIII-8 (0.15g, 0.30mmol) was dissolved in DMF (5mL), cyclopentylamine (0.15mL, 1.50mmol) was added, and reacted at 50°C for 12h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.12 g of yellow solid, yield 74%. mp:>300℃. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.36(1H,s),10.82(1H,s),9.51(1H,s),9.13(1H,s), 8.94(1H,s),7.63(1H,d,J＝8.3Hz),7.46(1H,s),7.28(1H,d,J＝1.6Hz),6.90(1H,dd, J ＝8.0Hz, J 2 =0.9Hz),6.51(1H,s),3.10-3.13(1H,m),2.19(3H,s),2.14(3H,s),1.74-1.77(2H,m),1.63-1.69( 2H,m),1.47-1.52(2H,m),1.38-1.42(2H,m),1.31(9H,s),1.24-1.26(2H,m). 13 C NMR(125MHz,DMSO-d 6 ) δ (ppm): 180.6, 170.3, 158.8, 151.7, 139.3, 137.8, 130.7, 126.0, 124.8, 122.6, 122.6, 121.4, 120.8, 119.2, 114.3, 111.7, 100.6, 92.9, 59.6, 51. 1,32.9,32.5 (2C ), 28.8(3C), 24.0(2C), 12.2, 9.6. HRMS(ESI): m/z[M+H] + calcd for C 30 H 38 N 7 O 4 + , 560.2985; found, 560.2983.
实施例23Example 23
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺(I-23)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene ) methyl)-2,4-dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide (I-23):
Figure PCTCN2022128606-appb-000046
Figure PCTCN2022128606-appb-000046
中间体V-2的合成：将化合物III-1(0.31g,1.44mmol)，IV-2(0.20g,1.20mmol)，DMAP(0.0090g,0.07mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.025mL,0.18mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到灰色固体0.27g，收率75％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d,J＝7.9Hz),6.80(1H,d,J＝8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,177.3,158.8,151.7,144.6,138.8,125.0,119.9,111.4,100.6,92.9,35.8,32.9,28.8(3C)。 Synthesis of Intermediate V-2: Compound III-1 (0.31g, 1.44mmol), IV-2 (0.20g, 1.20mmol), DMAP (0.0090g, 0.07mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.025mL, 0.18mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.27 g of a gray solid with a yield of 75%. . 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):10.37(1H,s),9.45(1H,s),8.84(1H,s),7.23(1H,s),7.09(1H,d, J=7.9Hz),6.80(1H,d,J=8.0Hz),6.49(1H,s),3.40(2H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 ) δ (ppm): 180.6, 177.3, 158.8, 151.7, 144.6, 138.8, 125.0, 119.9, 111.4, 100.6, 92.9, 35.8, 32.9, 28.8 (3C).
Figure PCTCN2022128606-appb-000047
Figure PCTCN2022128606-appb-000047
中间体XI-2的合成：将化合物V-2(0.80g,2.55mmol)和VI-1(0.43g,2.55mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.27mL,3.31mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体1.00g，收率85％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d,J＝8.3Hz),7.59(1H,s),7.32(1H,s),6.94(1H,d,J＝8.3Hz),6.51(1H,s),2.63(3H,s),2.55(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4,120.8,119.5,112.0,100.8,92.9,33.0,28.8(3C),15.3,11.5。 Synthesis of intermediate XI-2: Compound V-2 (0.80g, 2.55mmol) and VI-1 (0.43g, 2.55mmol) were dissolved in ethanol (10mL), then pyrrolidine (0.27mL, 3.31mmol) was added, Heated to 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 1.00 g of an orange-yellow solid with a yield of 85%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):14.22(1H,s),11.12(1H,s),9.57(1H,s),9.10(1H,s),7.78(1H,d, J＝8.3Hz), 7.59(1H,s), 7.32(1H,s), 6.94(1H,d, J＝8.3Hz), 6.51(1H,s), 2.63(3H,s), 2.55(3H, s),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.5,158.8,151.6,144.6,140.4,139.5,136.5,133.9,125.4,123.9,121.4, 120.8, 119.5, 112.0, 100.8, 92.9, 33.0, 28.8 (3C), 15.3, 11.5.
Figure PCTCN2022128606-appb-000048
Figure PCTCN2022128606-appb-000048
中间体XII-2的合成：将化合物XI-2(0.20g,0.43mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂，加入氯化铵(0.23g,4.31mmol)的饱和溶液(1mL)，加热至50℃，分批加入锌粉(0.14g,2.15mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，甲醇打浆纯化,抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.10g，收率54％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d,J＝8.3Hz),7.31(1H,s),7.25(1H,d,J＝1.6Hz),6.85(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.51(1H,s),3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,169.9,158.9,151.6,138.4,136.6,132.9,125.0,123.8,122.0,121.6,118.1,116.6,111.5,110.8,100.6,92.9,32.9,28.8(3C),11.6,8.9。 Synthesis of intermediate XII-2: Dissolve compound XI-2 (0.20g, 0.43mmol) in a mixed solvent of tetrahydrofuran and methanol (10mL/5mL, v/v), add ammonium chloride (0.23g, 4.31mmol) The saturated solution (1 mL) was heated to 50°C, and zinc powder (0.14 g, 2.15 mmol) was added in batches, and the reaction was continued for 0.5 h. After the LC-MS monitoring reaction was complete, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and successively wash with water and saturated sodium chloride The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, purification by beating with methanol, suction filtration, washing the filter cake with a small amount of methanol, and vacuum drying to obtain 0.10 g of a yellow solid with a yield of 54%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.22(1H,s),10.66(1H,s),9.45(1H,s),8.81(1H,s),7.55(1H,d, J＝8.3Hz), 7.31(1H,s), 7.25(1H,d, J＝1.6Hz), 6.85(1H,dd, J1 ＝8.3Hz, J2 ＝1.8Hz), 6.51(1H,s) ,3.92(2H,s),2.24(3H,s),2.13(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,169.9,158.9 ,151.6,138.4,136.6,132.9,125.0,123.8,122.0,121.6,118.1,116.6,111.5,110.8,100.6,92.9,32.9,28.8(3C),11.6,8.9.
Figure PCTCN2022128606-appb-000049
Figure PCTCN2022128606-appb-000049
中间体XIII-9的合成：化合物XII-2(0.50g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.50mL,3.45mmol)，降温至0℃，滴加3-氯丙酰氯(0.10mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.48g,收率80％。Synthesis of Intermediate XIII-9: Compound XII-2 (0.50g, 1.15mmol) was dissolved in THF (20mL), added DIPEA (0.50mL, 3.45mmol), cooled to 0°C, and 3-chloropropionyl chloride (0.10 mL, 5.75mmol), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.48 g of a yellow solid with a yield of 80%.
Figure PCTCN2022128606-appb-000050
Figure PCTCN2022128606-appb-000050
化合物I-23的合成：将化合物XIII-9(0.070g,0.14mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.15mL,1.37mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5ml)打浆纯化，抽滤，真空干燥得到黄色固体0.050g,收率59％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s),8.98(1H,s),7.63(1H,d,J＝8.3Hz),6.93(1H,dd,J 1＝8.3Hz,J 2＝0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64(4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.8,170.2,169.0,158.7,151.5,149.6,147.7,134.8,131.8,127.2,124.9,124.1,121.8,120.7,113.6,105.9,102.0,92.8,61.8,55.0(2C),53.2(2C),46.2,33.0,28.8(3C),12.3,9.6。 Synthesis of compound I-23: Dissolve compound XIII-9 (0.070 g, 0.14 mmol) in DMF (5 mL), add N-methylpiperazine (0.15 mL, 1.37 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5ml) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.050 g of yellow solid, yield 59%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.37(1H,s),10.83(1H,s),9.73(1H,s),9.52(1H,s),8.98(1H,s) ,7.63(1H,d,J=8.3Hz),6.93(1H,dd,J 1 =8.3Hz,J 2 =0.7Hz),6.52(1H,s),3.11(2H,s),2.57-2.64( 4H,m),2.36-2.50(4H,m),2.24(3H,s),2.18(3H,s),2.14(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO- d 6 )δ(ppm): 180.8, 170.2, 169.0, 158.7, 151.5, 149.6, 147.7, 134.8, 131.8, 127.2, 124.9, 124.1, 121.8, 120.7, 113.6, 105.9, 102.0, 92.8, 61.8 ,55.0(2C) , 53.2 (2C), 46.2, 33.0, 28.8 (3C), 12.3, 9.6.
实施例24Example 24
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-24)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene ) methyl)-N-(2-(diethylamino) ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-24):
Figure PCTCN2022128606-appb-000051
Figure PCTCN2022128606-appb-000051
化合物I-24的合成：将化合物V-1(0.35g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.13mL,1.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.30g，收率49％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):δ13.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H,d,J＝11.5Hz),7.78(1H,d,J＝6.7Hz),7.61(1H,s),7.43(1H,t,J＝4.3Hz),6.48(1H,s),3.28(2H,dd,J 1＝13.0Hz,J 2＝6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.41(3H,s),1.31(9H,s),1.00(6H,t,J＝7.0Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.8,170.3,165.0,158.7,151.4,136.3,135.1,129.7,126.3,125.5,125.4,123.8,120.9,120.3(2C),115.4,102.0,92.8,52.1,47.0(2C),37.4,33.0,28.8(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-24: Dissolve compound V-1 (0.35g, 1.05mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (10mL), then add pyrrolidine (0.13mL, 1.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.30 g of an orange-yellow solid with a yield of 49%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):δ13.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H, d,J=11.5Hz),7.78(1H,d,J=6.7Hz),7.61(1H,s),7.43(1H,t,J=4.3Hz),6.48(1H,s),3.28(2H, dd, J 1 =13.0Hz, J 2 =6.3Hz), 2.52-2.56(6H,m), 2.44(3H,s), 2.41(3H,s), 1.31(9H,s), 1.00(6H,t , J=7.0Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.8, 170.3, 165.0, 158.7, 151.4, 136.3, 135.1, 129.7, 126.3, 125.5, 125.4, 123.8, 120.9, 120.3 (2C), 115.4, 102.0, 92.8, 52.1, 47.0 (2C), 37.4, 33.0, 28.8 (3C), 13.8, 12.4 (2C), 11.1.
实施例25Example 25
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-25)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene ) methyl)-N-(2-(diethylamino) ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-25):
Figure PCTCN2022128606-appb-000052
Figure PCTCN2022128606-appb-000052
化合物I-25的合成：将化合物V-2(0.35g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.13mL,1.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.30g，收率49％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):3.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H,d,J＝11.5Hz),7.78(1H,d,J＝6.7Hz),7.61(1H,s),7.43(1H,t,J＝4.3Hz),6.48(1H,s),3.28(2H,dd,J 1＝13.0Hz,J 2＝6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.41(3H,s),1.31(9H,s),1.00(6H,t,J＝7.0Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.8,170.3,165.0,158.7,151.4,136.3,135.1,129.7,126.3,125.5,125.4,123.8,120.9,120.3(2C),115.4,102.0,92.8,52.1,47.0(2C),37.4,33.0,28.8(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-25: Dissolve compound V-2 (0.35g, 1.05mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (10mL), then add pyrrolidine (0.13mL, 1.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.30 g of an orange-yellow solid with a yield of 49%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):3.55(1H,s),10.91(1H,s),9.90(1H,s),8.87(1H,s),7.84(1H,d, J=11.5Hz), 7.78(1H,d,J=6.7Hz),7.61(1H,s),7.43(1H,t,J=4.3Hz),6.48(1H,s),3.28(2H,dd, J 1 =13.0Hz, J 2 =6.3Hz), 2.52-2.56(6H,m), 2.44(3H,s), 2.41(3H,s), 1.31(9H,s), 1.00(6H,t,J =7.0Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.8, 170.3, 165.0, 158.7, 151.4, 136.3, 135.1, 129.7, 126.3, 125.5, 125.4, 123.8, 120.9, 120.3 (2C ), 115.4, 102.0, 92.8, 52.1, 47.0 (2C), 37.4, 33.0, 28.8 (3C), 13.8, 12.4 (2C), 11.1.
实施例26Example 26
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((6-(3-(5-甲基异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-26)的合成：(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((6-(3-(5-methylisoxazol-3-yl)ureido Synthesis of )-2-oxindole-3-ylidene)methyl)-1H-pyrrole-3-carboxamide (I-26):
Figure PCTCN2022128606-appb-000053
Figure PCTCN2022128606-appb-000053
中间体III-2的合成：将化合物II-2(0.70g,7.13mmol)溶解于无水四氢呋喃(20mL)，然后加入K 2CO 3(1.22g,8.83mmol)，氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体1.17g，收率75％。 Synthesis of Intermediate III-2: Compound II-2 (0.70g, 7.13mmol) was dissolved in anhydrous tetrahydrofuran (20mL), then K 2 CO 3 (1.22g, 8.83mmol), phenyl chloroformate (0.94mL , 7.49mmol), reacted at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 1.17 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000054
Figure PCTCN2022128606-appb-000054
中间体V-3的合成：将化合物III-2(0.31g,1.44mmol)，IV-1(0.20g,1.20mmol)，DMAP(0.0090g,0.07mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.025mL,0.18mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到灰色固体0.27g，收率69％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.35(1H,s),9.39(1H,s),8.83(1H,s),7.23(1H,d,J＝1.9Hz),7.10(1H,d,J＝8.0Hz),6.80(1H,dd,J 1＝8.0Hz,J 2＝2.0Hz),6.53(1H,s),3.40(2H,s),2.37(3H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):177.2,169.6,159.1,151.7,144.6,138.9,125.0,119.9,111.4,100.7,96.0,35.8,12.6。 Synthesis of Intermediate V-3: Compound III-2 (0.31g, 1.44mmol), IV-1 (0.20g, 1.20mmol), DMAP (0.0090g, 0.07mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.025mL, 0.18mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, purify by beating with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.27 g of a gray solid with a yield of 69%. . 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 10.35 (1H, s), 9.39 (1H, s), 8.83 (1H, s), 7.23 (1H, d, J = 1.9Hz), 7.10 (1H,d,J=8.0Hz),6.80(1H,dd,J 1 ＝8.0Hz,J 2 ＝2.0Hz),6.53(1H,s),3.40(2H,s),2.37(3H,s) . 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 177.2, 169.6, 159.1, 151.7, 144.6, 138.9, 125.0, 119.9, 111.4, 100.7, 96.0, 35.8, 12.6.
Figure PCTCN2022128606-appb-000055
Figure PCTCN2022128606-appb-000055
化合物I-26的合成：将化合物V-3(0.29g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.13mL,1.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.38g，收率70％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.87(1H,s),9.43(1H,s),8.90(1H,s),7.68(1H,d,J＝8.3Hz),7.51(1H,s),7.37(1H,t,J＝5.5Hz),7.31(1H,d,J＝1.7Hz),6.89(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.55(1H,s),3.28(2H,dd,J 1＝13.0Hz,J 2＝6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),2.37(3H,s),0.99(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,169.7,165.1,159.1,151.6,139.6,138.2,135.5,128.6,126.2,122.3,120.6,120.5,119.6,115.9,111.8,100.7,96.0,52.15,47.0(2C),37.5,13.76,12.59,12.4(2C),11.0。 Synthesis of compound I-26: Dissolve compound V-3 (0.29g, 1.05mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (10mL), then add pyrrolidine (0.13mL, 1.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.38 g of an orange-yellow solid with a yield of 70%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.87(1H,s),9.43(1H,s),8.90(1H,s),7.68(1H,d, J=8.3Hz),7.51(1H,s),7.37(1H,t,J=5.5Hz),7.31(1H,d,J=1.7Hz),6.89(1H,dd,J 1 =8.3Hz,J 2 =1.8Hz), 6.55(1H,s), 3.28(2H,dd, J 1 =13.0Hz, J 2 =6.3Hz), 2.52-2.56(6H,m), 2.44(3H,s), 2.40( 3H, s), 2.37 (3H, s), 0.99 (6H, t, J=7.1Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 169.7, 165.1, 159.1, 151.6, 139.6,138.2,135.5,128.6,126.2,122.3,120.6,120.5,119.6,115.9,111.8,100.7,96.0,52.15,47.0(2C),37.5,13.76,12.59,12.4(2C),11. 0.
实施例27Example 27
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3-(三氟甲基)异恶唑-5-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-27)的合成：(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxido-6-(3-(3-(trifluoromethyl)isoxane Synthesis of azole-5-yl)ureido)indol-3-ylidene)methyl)-1H-pyrrole-3-carboxamide (I-27):
Figure PCTCN2022128606-appb-000056
Figure PCTCN2022128606-appb-000056
中间体III-3的合成：将化合物II-3(1.00g,7.13mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(1.22g,8.83mmol)，氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体1.40g，收率75％。 Synthesis of Intermediate III-3: Compound II-3 (1.00g, 7.13mmol) was dissolved in anhydrous THF (15mL), then K 2 CO 3 (1.22g, 8.83mmol), phenyl chloroformate (0.94mL , 7.49mmol), reacted at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 1.40 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000057
Figure PCTCN2022128606-appb-000057
中间体V-4的合成：将化合物III-3(0.17g,0.61mmol)，IV-1(0.080g,0.51mmol)，DMAP(0.0040g,0.030mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.21mL,1.53mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，柱层析纯化(二氯甲烷：甲醇)得灰色固体0.12g，收率70％。 1H NMR(500MHz,MeOD)δ(ppm):7.31(1H,d,J＝1.9Hz),7.19(1H,d,J＝8.1Hz),6.96(1H,dd,J 1＝8.0Hz,J 2＝2.0Hz),6.45(1H,s),3.50(2H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):177.2,174.9,165.6,149.7,147.6,144.7,138.2,125.0,120.6,111.9,101.0,83.5,35.8。 Synthesis of Intermediate V-4: Compound III-3 (0.17g, 0.61mmol), IV-1 (0.080g, 0.51mmol), DMAP (0.0040g, 0.030mmol) were dissolved in DCM (10mL), under stirring TEA (0.21 mL, 1.53 mmol) was added and heated to 50° C. for 20 h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol) to obtain 0.12 g of a gray solid, with a yield of 70%. 1 H NMR (500MHz, MeOD) δ (ppm): 7.31 (1H, d, J = 1.9Hz), 7.19 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J 1 = 8.0Hz, J 2 = 2.0Hz), 6.45(1H, s), 3.50(2H, s). 13 C NMR (125MHz, DMSO-d 6 ) δ(ppm): 177.2, 174.9, 165.6, 149.7, 147.6, 144.7, 138.2, 125.0, 120.6, 111.9, 101.0, 83.5, 35.8.
Figure PCTCN2022128606-appb-000058
Figure PCTCN2022128606-appb-000058
化合物I-27的合成：将化合物V-4(0.10g,0.30mmol)和VI-2(0.12g,0.45mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.030mL,0.30mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.37g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.51(1H,s),10.90(1H,s),10.44(1H,s),9.04(1H,s),7.67(1H,d,J＝8.3Hz),7.51(1H,s),7.44(1H,t,J＝5.3Hz),7.34(1H,d,J＝1.4Hz),6.99(1H,dd,J 1＝8.3Hz,J 2＝1.5Hz),6.43(1H,s),3.33(2H,d,J＝6.05Hz),2.63(6H,t,J＝7.5Hz),2.44(3H,s),2.40(3H,s),1.02(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,167.8,165.3,155.7,155.4,151.3,139.5,138.4,135.6,128.5,126.2,122.1,121.5,120.4,119.5,116.0,112.0,100.8,82.8,51.9,47.0(2C),37.2,13.8,11.9(2C),11.0。 Synthesis of compound I-27: Dissolve compound V-4 (0.10g, 0.30mmol) and VI-2 (0.12g, 0.45mmol) in ethanol (10mL), then add pyrrolidine (0.030mL, 0.30mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.37 g of an orange-yellow solid with a yield of 65%. 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 13.51 (1H, s), 10.90 (1H, s), 10.44 (1H, s), 9.04 (1H, s), 7.67 (1H, d, J=8.3Hz),7.51(1H,s),7.44(1H,t,J=5.3Hz),7.34(1H,d,J=1.4Hz),6.99(1H,dd,J 1 =8.3Hz,J 2 =1.5Hz),6.43(1H,s),3.33(2H,d,J=6.05Hz),2.63(6H,t,J=7.5Hz),2.44(3H,s),2.40(3H,s) ,1.02(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):170.4,167.8,165.3,155.7,155.4,151.3,139.5,138.4,135.6,128.5,126.2 , 122.1, 121.5, 120.4, 119.5, 116.0, 112.0, 100.8, 82.8, 51.9, 47.0 (2C), 37.2, 13.8, 11.9 (2C), 11.0.
实施例28Example 28
(Z)-5-((6-(3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺(I-28)的合成：(Z)-5-((6-(3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)ureido)-2-oxindole-3-ylidene ) methyl)-N-(2-(diethylamino) ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-28):
Figure PCTCN2022128606-appb-000059
Figure PCTCN2022128606-appb-000059
中间体III-4的合成：将化合物II-4(0.20g,1.31mmol)溶解于无水四氢呋喃(10mL)，然后加入K 2CO 3(0.22g,1.62mmol)，氯甲酸苯酯(0.17mL,1.37mmol)，室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到黄色油状液体0.23g，收率64％。 Synthesis of Intermediate III-4: Compound II-4 (0.20g, 1.31mmol) was dissolved in anhydrous tetrahydrofuran (10mL), then K 2 CO 3 (0.22g, 1.62mmol), phenyl chloroformate (0.17mL , 1.37mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.23 g of a yellow oily liquid with a yield of 64%.
Figure PCTCN2022128606-appb-000060
Figure PCTCN2022128606-appb-000060
中间体V-5的合成：将化合物III-4(0.23g,0.84mmol)，IV-1(0.11g,0.70mmol)，DMAP(0.0050g,0.040mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.030mL,0.20mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，柱层析纯化(二氯甲烷：甲醇)得灰色固体0.19g，收率58％。 1H NMR(500MHz,CDCl 3)δ(ppm):6.88(1H,s),6.71(1H,d,J＝8.1Hz),6.52(1H,s),6.12(1H,s),3.77(3H,s),3.49(2H,s),1.33(9H,s)。 Synthesis of Intermediate V-5: Compound III-4 (0.23g, 0.84mmol), IV-1 (0.11g, 0.70mmol), DMAP (0.0050g, 0.040mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.030mL, 0.20mmol), heat to 50°C for 20h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol) to obtain 0.19 g of a gray solid, with a yield of 58%. 1 H NMR (500MHz, CDCl 3 ) δ (ppm): 6.88 (1H, s), 6.71 (1H, d, J=8.1Hz), 6.52 (1H, s), 6.12 (1H, s), 3.77 (3H ,s), 3.49(2H,s), 1.33(9H,s).
Figure PCTCN2022128606-appb-000061
Figure PCTCN2022128606-appb-000061
化合物I-28的合成：将化合物V-5(0.19g,0.58mmol)和VI-2(0.23g,0.87mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.050mL,0.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.37g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d,J＝8.3Hz),7.48(1H,s),7.39(1H,t,J＝5.5Hz),7.31(1H,d,J＝1.7 Hz),6.95(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39(3H,s),1.22(9H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,159.1,152.1,139.6,139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-28: Dissolve compound V-5 (0.19g, 0.58mmol) and VI-2 (0.23g, 0.87mmol) in ethanol (10mL), then add pyrrolidine (0.050mL, 0.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.37 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d, J＝8.3Hz), 7.48(1H, s), 7.39(1H, t, J＝5.5Hz), 7.31(1H, d, J＝1.7 Hz), 6.95(1H, dd, J ＝ 8.3Hz, J 2 =1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39( 3H, s), 1.22 (9H, s), 0.98 (6H, t, J=7.1Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 159.1, 152.1, 139.6, 139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,1 2.4(2C) , 11.1.
实施例29Example 29
(Z)-5-((6-(3-(4-氯-3-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-29)的合成：(Z)-5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- Synthesis of (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-29):
Figure PCTCN2022128606-appb-000062
Figure PCTCN2022128606-appb-000062
中间体III-5的合成：将化合物II-5(0.40g,2.05mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.35g,2.54mmol)，氯甲酸苯酯(0.27mL,2.15mmol)，室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.50g，收率77％。 Synthesis of Intermediate III-5: Compound II-5 (0.40g, 2.05mmol) was dissolved in anhydrous tetrahydrofuran (15mL), then K 2 CO 3 (0.35g, 2.54mmol), phenyl chloroformate (0.27mL , 2.15mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.50 g of a white solid with a yield of 77%.
Figure PCTCN2022128606-appb-000063
Figure PCTCN2022128606-appb-000063
中间体V-6的合成：将化合物III-5(0.50g,1.58mmol)，IV-1(0.21g,1.32mmol)，DMAP(0.010g,0.08mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.055mL,0.33mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.30g，收率60％。Synthesis of Intermediate V-6: Compound III-5 (0.50g, 1.58mmol), IV-1 (0.21g, 1.32mmol), DMAP (0.010g, 0.08mmol) were dissolved in DCM (15mL), under stirring TEA (0.055 mL, 0.33 mmol) was added and heated to 50° C. for 20 h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.30 g of a white solid, with a yield of 60%. .
Figure PCTCN2022128606-appb-000064
Figure PCTCN2022128606-appb-000064
化合物I-29的合成：将化合物V-6(0.21g,0.58mmol)和VI-2(0.23g,0.87mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.050mL,0.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.21g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.87(1H,s),9.16(1H,s),8.97(1H,s),8.14(1H,s),7.67(1H,d,J＝8.3Hz),7.63(1H,s),7.62(1H,s),7.50(1H,s),7.39(1H,t,J＝4.8Hz),7.32(1H,s),6.94(1H,d,J＝8.2Hz),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.0Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,152.7,139.9,139.5,138.6,135.5,132.4,128.4,127.3,127.0,126.2,123.5,122.7,122.01,120.5,120.2,119.5,117.2,116.0,111.9,100.8,52.1,47.0(2C),31.4,14.4,13.8(2C),11.1。 Synthesis of compound I-29: Dissolve compound V-6 (0.21g, 0.58mmol) and VI-2 (0.23g, 0.87mmol) in ethanol (10mL), then add pyrrolidine (0.050mL, 0.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.21 g of an orange-yellow solid with a yield of 60%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.87(1H,s),9.16(1H,s),8.97(1H,s),8.14(1H,s) ,7.67(1H,d,J=8.3Hz),7.63(1H,s),7.62(1H,s),7.50(1H,s),7.39(1H,t,J=4.8Hz),7.32(1H, s),6.94(1H,d,J=8.2Hz),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s), 0.98 (6H, t, J=7.0Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 152.7, 139.9, 139.5, 138.6, 135.5, 132.4, 128.4, 127.3, 127.0, 126.2, 123.5, 122.7, 122.01, 120.5, 120.2, 119.5, 117.2, 116.0, 111.9, 100.8, 52.1, 47.0 (2C), 31.4, 14.4, 13.8 (2C), 11.1.
实施例30Example 30
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(三氟甲基)吡啶-3-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-30)的合成：(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxygen-6-(3-(trifluoromethyl)pyridin-3-yl ) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide (I-30) synthesis:
Figure PCTCN2022128606-appb-000065
Figure PCTCN2022128606-appb-000065
中间体III-6的合成：将化合物II-6(0.30g,1.85mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.32g,2.30mmol)，氯甲酸苯酯(0.30mL,1.94mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.40g，收率76％。 Synthesis of Intermediate III-6: Compound II-6 (0.30g, 1.85mmol) was dissolved in anhydrous tetrahydrofuran (15mL), then K 2 CO 3 (0.32g, 2.30mmol), phenyl chloroformate (0.30mL , 1.94mmol), reacted at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.40 g of a white solid with a yield of 76%.
Figure PCTCN2022128606-appb-000066
Figure PCTCN2022128606-appb-000066
中间体V-7的合成：将化合物III-6(0.40g,1.42mmol)，IV-1(0.19g,1.18mmol)，DMAP(0.0090g,0.070mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.049mL,0.33mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.24g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.36(1H,s),9.32(1H,s),9.04(1H,s),8.19(1H,dd,J 1＝8.6Hz,J 2＝2.1Hz),7.82(1H,d,J＝8.7Hz),7.26(1H,d,J＝1.5Hz),7.11(1H,d,J＝8.0Hz),6.86(1H,dd,J 1＝8.0Hz,J 2＝1.8Hz),6.80(1H,d,J＝8.4Hz),3.41(2H,s)。 Synthesis of Intermediate V-7: Compound III-6 (0.40g, 1.42mmol), IV-1 (0.19g, 1.18mmol), DMAP (0.0090g, 0.070mmol) were dissolved in DCM (15mL), under stirring Add TEA (0.049mL, 0.33mmol), heat to 50°C for 20h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.24 g of white solid, yield 60% . 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 10.36 (1H, s), 9.32 (1H, s), 9.04 (1H, s), 8.19 (1H, dd, J 1 =8.6Hz, J 2 = 2.1Hz), 7.82 (1H, d, J = 8.7Hz), 7.26 (1H, d, J = 1.5Hz), 7.11 (1H, d, J = 8.0Hz), 6.86 (1H, dd, J 1 = 8.0 Hz, J2 = 1.8 Hz), 6.80 (1H, d, J = 8.4 Hz), 3.41 (2H, s).
Figure PCTCN2022128606-appb-000067
Figure PCTCN2022128606-appb-000067
化合物I-30的合成：将化合物V-7(0.050g,0.15mmol)和VI-2(0.060g,0.22mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.012mL,0.15mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.53g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.88(1H,s),9.29(1H,s),9.08(1H,s),8.77(1H,d,J＝2.1Hz),8.21(1H,dd,J 1＝8.5Hz,J 2＝1.9Hz),7.83(1H,d,J＝8.7Hz),7.69(1H,d,J＝8.3Hz),7.51(1H,s),7.38(1H,t,J＝5.1Hz),7.33(1H,d,J＝1.4Hz),6.96(1H,dd,J 1＝8.3Hz,J 2＝1.5Hz),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,152.6,140.3,140.0,139.5,139.3,138.4,135.5,128.5,126.2,125.7,123.5,122.2,121.7,120.6,120.4,119.6,115.9,111.9,100.8,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。 Synthesis of compound I-30: Dissolve compound V-7 (0.050g, 0.15mmol) and VI-2 (0.060g, 0.22mmol) in ethanol (5mL), then add pyrrolidine (0.012mL, 0.15mmol), heat Reaction at 50°C for 2h. After the reaction was completed as monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.53 g of an orange-yellow solid with a yield of 60%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.88(1H,s),9.29(1H,s),9.08(1H,s),8.77(1H,d, J=2.1Hz), 8.21(1H,dd, J1 =8.5Hz, J2 =1.9Hz),7.83(1H,d,J=8.7Hz),7.69(1H,d,J=8.3Hz),7.51 (1H, s), 7.38 (1H, t, J = 5.1Hz), 7.33 (1H, d, J = 1.4Hz), 6.96 (1H, dd, J 1 = 8.3Hz, J 2 = 1.5Hz), 3.28 (2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98 ( 6H,t,J=7.1Hz). 125MHz,DMSO-d 6 )δ(ppm):170.4,165.2,152.6,140.3,140.0,139.5,139.3,138.4,135.5,128.5,126.2,125.7,123.5,122.2,121.7,120.6,120.4, 119.6, 115.9, 111.9, 100.8, 52.1, 47.0 (2C), 37.4, 13.8, 12.4 (2C), 11.1.
实施例31Example 31
(Z)-5-((6-(3-(4-(叔丁基)-3-氯苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-31)的合成：(Z)-5-((6-(3-(4-(tert-butyl)-3-chlorophenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-( Synthesis of 2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-31):
Figure PCTCN2022128606-appb-000068
Figure PCTCN2022128606-appb-000068
中间体III-7的合成：将化合物II-7(0.20g,1.09mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.19g,2.03mmol)，氯甲酸苯酯(0.14mL,1.14mmol)，室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.24g，收率72％。 Synthesis of Intermediate III-7: Compound II-7 (0.20g, 1.09mmol) was dissolved in anhydrous tetrahydrofuran (15mL), then K 2 CO 3 (0.19g, 2.03mmol), phenyl chloroformate (0.14mL , 1.14mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.24 g of a white solid with a yield of 72%.
Figure PCTCN2022128606-appb-000069
Figure PCTCN2022128606-appb-000069
中间体V-8的合成：将化合物III-7(0.24g,0.782mmol)，IV-1(0.11g,0.65mmol)，DMAP(0.0050g,0.040mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.042mL,0.20mmol)，加热至50℃反应20h。LC-MS监测反应完毕后， 停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得灰色固体0.13g，收率54％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.34(1H,s),8.72(2H,d,J＝10.5Hz),7.64(1H,d,J＝2.1Hz),7.35(1H,d,J＝8.7Hz),7.24(1H,s),7.22(1H,dd,J 1＝8.8Hz,J 2＝2.2Hz),7.08(1H,d,J＝8.0Hz),6.82-6.81(1H,m),3.39(2H,s),1.42(9H,s)。 Synthesis of Intermediate V-8: Compound III-7 (0.24g, 0.782mmol), IV-1 (0.11g, 0.65mmol), DMAP (0.0050g, 0.040mmol) were dissolved in DCM (10mL), under stirring TEA (0.042mL, 0.20mmol) was added and heated to 50°C for 20h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, washed the filter cake with a small amount of ethyl acetate, and dried in vacuo to obtain 0.13 g of a gray solid with a yield of 54%. . 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 10.34 (1H, s), 8.72 (2H, d, J = 10.5Hz), 7.64 (1H, d, J = 2.1Hz), 7.35 (1H ,d,J=8.7Hz),7.24(1H,s),7.22(1H,dd,J 1 =8.8Hz,J 2 =2.2Hz),7.08(1H,d,J=8.0Hz),6.82-6.81 (1H,m), 3.39(2H,s), 1.42(9H,s).
Figure PCTCN2022128606-appb-000070
Figure PCTCN2022128606-appb-000070
化合物I-31的合成：将化合物V-8(0.13g,0.35mmol)和VI-2(0.14g,0.52mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.029mL,0.35mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.13g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.86(1H,s),8.80(1H,s),8.76(1H,s),7.67(1H,s),7.65(1H,s),7.49(1H,s),7.37(1H,s),7.35(1H,s),7.31(1H,d,J＝1.5Hz),7.24(1H,dd,J 1＝8.7Hz,J 2＝2.2Hz),6.91(1H,dd,J 1＝8.3Hz,J 2＝1.5Hz),3.29(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.43(9H,s),0.97(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.5,152.8,139.5,139.4,139.1,138.8,135.5,132.9,128.5(2C),126.2,122.0,121.3,120.4,120.0,119.5,117.2,116.0,111.9,100.7,52.0,46.9(2C),37.3,35.6,30.0(3C),13.7,12.2(2C),11.0。 Synthesis of compound I-31: Dissolve compound V-8 (0.13g, 0.35mmol) and VI-2 (0.14g, 0.52mmol) in ethanol (10mL), then add pyrrolidine (0.029mL, 0.35mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.13 g of an orange-yellow solid with a yield of 60%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.86(1H,s),8.80(1H,s),8.76(1H,s),7.67(1H,s) ,7.65(1H,s),7.49(1H,s),7.37(1H,s),7.35(1H,s),7.31(1H,d,J=1.5Hz),7.24(1H,dd,J 1 = 8.7Hz, J 2 =2.2Hz), 6.91(1H,dd,J 1 =8.3Hz, J 2 =1.5Hz), 3.29(2H,q,J=6.4Hz), 2.52-2.56(6H,m), 2.44(3H,s),2.40(3H,s),1.43(9H,s),0.97(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):170.4 ,165.5,152.8,139.5,139.4,139.1,138.8,135.5,132.9,128.5(2C),126.2,122.0,121.3,120.4,120.0,119.5,117.2,116.0,111.9,100.7,52 .0,46.9(2C),37.3 , 35.6, 30.0 (3C), 13.7, 12.2 (2C), 11.0.
实施例32Example 32
(Z)-5-((6-(3-(4-(叔丁基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-32)的合成：(Z)-5-((6-(3-(4-(tert-butyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-(2-(di Synthesis of ethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-32):
Figure PCTCN2022128606-appb-000071
Figure PCTCN2022128606-appb-000071
中间体III-8的合成：将化合物II-8(0.20g,1.34mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.23g,1.66mmol)，氯甲酸苯酯(0.18mL,1.41mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.38g，收率75％。 Synthesis of Intermediate III-8: Compound II-8 (0.20g, 1.34mmol) was dissolved in anhydrous tetrahydrofuran (15mL), then K 2 CO 3 (0.23g, 1.66mmol), phenyl chloroformate (0.18mL , 1.41mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.38 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000072
Figure PCTCN2022128606-appb-000072
中间体V-9的合成：将化合物III-8(0.20g,0.74mmol)，IV-1(0.10g,0.62mmol)，DMAP(0.0050g,0.040mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.026mL,0.62mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得灰色固体0.11g，收率54％。Synthesis of Intermediate V-9: Compound III-8 (0.20g, 0.74mmol), IV-1 (0.10g, 0.62mmol), DMAP (0.0050g, 0.040mmol) were dissolved in DCM (10mL), under stirring TEA (0.026mL, 0.62mmol) was added and heated to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.11 g of a gray solid, with a yield of 54%. .
Figure PCTCN2022128606-appb-000073
Figure PCTCN2022128606-appb-000073
化合物I-32的合成：将化合物V-9(0.11g,0.33mmol)和VI-2(0.132g,0.50mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.027mL,0.33mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率61％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d,J＝8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89(1H,d,J＝8.2Hz),3.29(2H,q,J＝6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.98(6H,t,J＝7.0Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,152.9,144.6,139.6,139.3,137.5,135.3,128.2,126.2,125.8(2C),121.8,120.5,119.7,119.6,118.5(2C),116.2,111.4,100.4,52.2,47.0(2C),37.4,34.4,31.7(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-32: Dissolve compound V-9 (0.11g, 0.33mmol) and VI-2 (0.132g, 0.50mmol) in ethanol (10mL), then add pyrrolidine (0.027mL, 0.33mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 61%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d, J＝8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89( 1H,d,J=8.2Hz),3.29(2H,q,J=6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s ), 0.98 (6H, t, J=7.0Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 152.9, 144.6, 139.6, 139.3, 137.5, 135.3, 128.2, 126.2, 125.8(2C), 121.8, 120.5, 119.7, 119.6, 118.5(2C), 116.2, 111.4, 100.4, 52.2, 47.0(2C), 37.4, 34.4, 31.7(3C), 13.8, 12.4(2C), 11.1.
实施例33Example 33
(Z)-5-((6-(3-(3-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-33)的合成：(Z)-5-((6-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- Synthesis of (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-33):
Figure PCTCN2022128606-appb-000074
Figure PCTCN2022128606-appb-000074
中间体III-9的合成：将化合物II-9(0.40g,2.05mm°l)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.35g,2.54mmol)，氯甲酸苯酯(0.270mL,2.15mmol)，室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.49g，收率75％。 Synthesis of Intermediate III-9: Dissolve compound II-9 (0.40g, 2.05mm°l) in anhydrous tetrahydrofuran (15mL), then add K 2 CO 3 (0.35g, 2.54mmol), phenyl chloroformate ( 0.270mL, 2.15mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.49 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000075
Figure PCTCN2022128606-appb-000075
中间体V-10的合成：将化合物III-9(0.22g,0.69mmol)，IV-1(0.090g,0.58mmol)，DMAP(0.0040g,0.030mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.024mL,0.17mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.11g，收率59％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.36(1H,s),9.25(1H,s),8.94(1H,s),7.92(1H,d,J＝1.8Hz),7.74(1H,d,J＝8.7Hz),7.47(1H,dd,J 1＝8.6Hz,J 2＝1.4Hz),7.23(1H,d,J＝1.8Hz),7.10(1H,d,J＝8.0Hz),6.85(1H,dd,J 1＝8.0Hz,J 2＝1.9Hz),3.41(2H,s)。 Synthesis of Intermediate V-10: Compound III-9 (0.22g, 0.69mmol), IV-1 (0.090g, 0.58mmol), DMAP (0.0040g, 0.030mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.024mL, 0.17mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.11 g of white solid, yield 59% . 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 10.36 (1H, s), 9.25 (1H, s), 8.94 (1H, s), 7.92 (1H, d, J = 1.8Hz), 7.74 (1H,d,J=8.7Hz),7.47(1H,dd,J 1 =8.6Hz,J 2 =1.4Hz),7.23(1H,d,J=1.8Hz),7.10(1H,d,J= 8.0 Hz), 6.85 (1H, dd, J 1 =8.0 Hz, J 2 =1.9 Hz), 3.41 (2H, s).
Figure PCTCN2022128606-appb-000076
Figure PCTCN2022128606-appb-000076
化合物I-33的合成：将化合物V-10(0.11g,0.30mmol)和VI-2(0.12g,0.44mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.020mL,0.23mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.21g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.88(1H,s),9.26(1H,s),9.01(1H,s),7.93(1H,d,J＝1.6Hz),7.75(1H,d,J＝8.8Hz),7.68(1H,d,J＝8.3Hz),7.51(1H,s),7.49(1H,dd,J 1＝8.6Hz,J 2＝1.4Hz),7.38(1H,t,J＝5.4Hz),7.30(1H,d,J＝1.7Hz),6.96(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),3.29(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.4,152.4,145.0,139.4,138.3,135.7,131.7,128.9,128.6,126.2,124.7,122.5,122.2,120.4,120.4,119.9,119.5,116.6,115.9,112.1,101.0,52.0,46.9(2C),37.3,13.7,12.1(2C),11.0。 Synthesis of compound I-33: Dissolve compound V-10 (0.11g, 0.30mmol) and VI-2 (0.12g, 0.44mmol) in ethanol (6mL), then add pyrrolidine (0.020mL, 0.23mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.21 g of an orange-yellow solid with a yield of 60%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.88(1H,s),9.26(1H,s),9.01(1H,s),7.93(1H,d, J=1.6Hz),7.75(1H,d,J=8.8Hz),7.68(1H,d,J=8.3Hz),7.51(1H,s),7.49(1H,dd,J 1 =8.6Hz,J 2 = 1.4Hz), 7.38 (1H, t, J = 5.4Hz), 7.30 (1H, d, J = 1.7Hz), 6.96 (1H, dd, J 1 = 8.3Hz, J 2 = 1.7Hz), 3.29 (2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98( 6H ,t,J=7.1Hz). 125MHz,DMSO-d 6 )δ(ppm):170.4,165.4,152.4,145.0,139.4,138.3,135.7,131.7,128.9,128.6,126.2,124.7,122.5,122.2,120.4,120.4,119.9, 119.5, 116.6, 115.9, 112.1, 101.0, 52.0, 46.9 (2C), 37.3, 13.7, 12.1 (2C), 11.0.
实施例34Example 34
(Z)-5-((6-(3-(2-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-34)的合成：(Z)-5-((6-(3-(2-Chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- Synthesis of (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-34):
Figure PCTCN2022128606-appb-000077
Figure PCTCN2022128606-appb-000077
中间体III-10的合成：将化合物II-10(0.40g,2.05mmol)溶解于无水四氢呋喃(15mL)，然后加入K 2CO 3(0.35g,2.54mmol)，氯甲酸苯酯(0.27mL,2.15mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.50g，收率77％。 Synthesis of Intermediate III-10: Compound II-10 (0.40g, 2.05mmol) was dissolved in anhydrous tetrahydrofuran (15mL), then K 2 CO 3 (0.35g, 2.54mmol), phenyl chloroformate (0.27mL , 2.15mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.50 g of a white solid with a yield of 77%.
Figure PCTCN2022128606-appb-000078
Figure PCTCN2022128606-appb-000078
中间体V-11的合成：将化合物III-10(0.50g,1.58mmol)，IV-1(0.21g,1.32mmol)，DMAP(0.010g,0.080mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.055mL,0.33mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.30g，收率60％。 1H NMR(500MHz,DMSO)δ(ppm):10.39(1H,s),9.63(1H,s),9.55(1H,s),7.92(1H,d,J＝1.8Hz),7.88(1H,d,J＝1.7Hz),7.68(1H,dd,J 1＝8.9Hz,J 2＝1.7Hz),7.27(1H,d,J＝1.7Hz),7.12(1H,d,J＝8.0Hz),6.84(1H,dd,J 1＝8.0Hz,J 2＝1.9Hz),3.42(2H,s)。 Synthesis of Intermediate V-11: Compound III-10 (0.50g, 1.58mmol), IV-1 (0.21g, 1.32mmol), DMAP (0.010g, 0.080mmol) were dissolved in DCM (15mL), under stirring TEA (0.055 mL, 0.33 mmol) was added and heated to 50° C. for 20 h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.30 g of a white solid, with a yield of 60%. . 1 H NMR (500MHz, DMSO) δ (ppm): 10.39 (1H, s), 9.63 (1H, s), 9.55 (1H, s), 7.92 (1H, d, J = 1.8Hz), 7.88 (1H, d, J = 1.7Hz), 7.68 (1H, dd, J 1 = 8.9Hz, J 2 = 1.7Hz), 7.27 (1H, d, J = 1.7Hz), 7.12 (1H, d, J = 8.0Hz) , 6.84 (1H, dd, J 1 =8.0 Hz, J 2 =1.9 Hz), 3.42 (2H, s).
Figure PCTCN2022128606-appb-000079
Figure PCTCN2022128606-appb-000079
化合物I-34的合成：将化合物V-11(0.070g,0.19mmol)和VI-2(0.080g,0.288mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.020mL,0.23mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.08g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.91(1H,s),9.71(1H,s),8.60(1H,s),8.49(1H,d,J＝8.6Hz),7.89(1H,d,J＝1.5Hz),7.71(1H,d,J＝8.2Hz),7.68(1H,s),7.52(1H,s),7.39(1H,t,J＝5.4Hz),7.33(1H,d,J＝1.7Hz),6.94(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.1,152.0,140.3,139.6,138.3,135.6,128.6,126.8,126.2,125.3,123.4,123.2,122.3,121.9,120.7,120.6,120.5,119.7,115.9,111.6,100.6,52.1,47.0(2C),37.4,13.8,12.4(2C),11.0。 Synthesis of compound I-34: Dissolve compound V-11 (0.070g, 0.19mmol) and VI-2 (0.080g, 0.288mmol) in ethanol (6mL), then add pyrrolidine (0.020mL, 0.23mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.08 g of an orange-yellow solid with a yield of 65%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.91(1H,s),9.71(1H,s),8.60(1H,s),8.49(1H,d, J=8.6Hz),7.89(1H,d,J=1.5Hz),7.71(1H,d,J=8.2Hz),7.68(1H,s),7.52(1H,s),7.39(1H,t, J=5.4Hz), 7.33(1H,d,J=1.7Hz),6.94(1H,dd,J 1 =8.3Hz,J 2 =1.7Hz),3.28(2H,q,J=6.4Hz),2.52 -2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm): 170.4, 165.1, 152.0, 140.3, 139.6, 138.3, 135.6, 128.6, 126.8, 126.2, 125.3, 123.4, 123.2, 122.3, 121.9, 120.7, 120.6, 120.5, 119.7, 115.9, 1 11.6, 100.6, 52.1, 47.0 (2C) , 37.4, 13.8, 12.4 (2C), 11.0.
实施例35Example 35
(Z)-N-(2-(二乙氨基)乙基)-5-((6-(3-(3-甲氧基-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-35)的合成：(Z)-N-(2-(diethylamino)ethyl)-5-((6-(3-(3-methoxy-4-(trifluoromethyl)phenyl)ureido)-2 Synthesis of -oxindole-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-35):
Figure PCTCN2022128606-appb-000080
Figure PCTCN2022128606-appb-000080
中间体III-11的合成：将化合物II-11(0.30g,1.57mmol)溶解于无水四氢呋喃(10mL)，然后加入K 2CO 3(0.27g,1.95mmol)，氯甲酸苯酯(0.21mL,1.65mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗 涤，真空干燥，得到白色固体0.48g，收率98％。 Synthesis of Intermediate III-11: Compound II-11 (0.30g, 1.57mmol) was dissolved in anhydrous tetrahydrofuran (10mL), then K 2 CO 3 (0.27g, 1.95mmol), phenyl chloroformate (0.21mL , 1.65mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.48 g of a white solid with a yield of 98%.
Figure PCTCN2022128606-appb-000081
Figure PCTCN2022128606-appb-000081
中间体V-12的合成：将化合物III-11(0.48g,1.56mmol)，IV-1(0.17g,1.05mmol)，DMAP(0.0080g,0.060mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.055mL,0.32mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.22g，收率57％。 1H NMR(500MHz,DMSO)δ(ppm):10.33(1H,s),8.71(2H,d,J＝3.0Hz),7.85(1H,d,J＝2.1Hz),7.56(1H,dd,J 1＝8.8Hz,J 2＝1.7Hz),7.26(1H,s),7.21(1H,d,J＝9.0Hz),7.08(1H,d,J＝8.0Hz),6.81(1H,dd,J 1＝7.8Hz,J 2＝1.1Hz),3.85(3H,s),3.39(2H,s)。 Synthesis of Intermediate V-12: Compound III-11 (0.48g, 1.56mmol), IV-1 (0.17g, 1.05mmol), DMAP (0.0080g, 0.060mmol) were dissolved in DCM (15mL), under stirring TEA (0.055 mL, 0.32 mmol) was added, heated to 50° C. for 20 h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.22 g of white solid with a yield of 57%. . 1 H NMR (500MHz, DMSO) δ (ppm): 10.33 (1H, s), 8.71 (2H, d, J = 3.0Hz), 7.85 (1H, d, J = 2.1Hz), 7.56 (1H, dd, J 1 =8.8Hz, J 2 =1.7Hz),7.26(1H,s),7.21(1H,d,J=9.0Hz),7.08(1H,d,J=8.0Hz),6.81(1H,dd, J 1 =7.8Hz, J 2 =1.1Hz), 3.85(3H,s), 3.39(2H,s).
Figure PCTCN2022128606-appb-000082
Figure PCTCN2022128606-appb-000082
化合物I-35的合成：将化合物V-12(0.22g,0.60mmol)和VI-2(0.24g,0.90mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.050mL,0.60mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.25g，收率67％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d,J＝2.5Hz),7.65(1H,d,J＝8.3Hz),7.58(1H,dd,J 1＝8.9Hz,J 2＝2.3Hz),7.48(1H,s),7.37(1H,t,J＝5.5Hz),7.32(1H,d,J＝1.6Hz),7.21(1H,d,J＝9.1Hz),6.92(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),3.86(3H,s),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,153.1,152.4,139.6,139.1,135.4,133.1,128.3,126.2,125.2,124.4,123.0,121.9,120.5,119.9,119.5,117.1,116.1,114.0,111.6,100.6,56.7,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。 Synthesis of compound I-35: Dissolve compound V-12 (0.22g, 0.60mmol) and VI-2 (0.24g, 0.90mmol) in ethanol (7mL), then add pyrrolidine (0.050mL, 0.60mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.25 g of an orange-yellow solid with a yield of 67%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d, J=2.5Hz),7.65(1H,d,J=8.3Hz),7.58(1H,dd,J 1 ＝8.9Hz,J 2 ＝2.3Hz),7.48(1H,s),7.37(1H,t, J = 5.5Hz), 7.32 (1H, d, J = 1.6Hz), 7.21 (1H, d, J = 9.1Hz), 6.92 (1H, dd, J 1 = 8.3Hz, J 2 = 1.6Hz), 3.86 (3H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1 Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 153.1, 152.4, 139.6, 139.1, 135.4, 133.1, 128.3, 126.2, 125.2, 124.4, 123.0, 121.9, 120.5, 11 9.9 , 119.5, 117.1, 116.1, 114.0, 111.6, 100.6, 56.7, 52.1, 47.0 (2C), 37.4, 13.8, 12.4 (2C), 11.1.
实施例36Example 36
(Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3,4,5-三甲氧基苯基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺(I-36)的合成：(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(3-(3,4,5-trimethoxybenzene base) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide (I-36) synthesis:
Figure PCTCN2022128606-appb-000083
Figure PCTCN2022128606-appb-000083
中间体III-12的合成：将化合物II-12(0.30g,1.64mmol)溶解于无水四氢呋喃(10mL)，然后加入K 2CO 3(0.28g,2.00mmol)，氯甲酸苯酯(0.22mL,1.72mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.38g，收率75％。 Synthesis of Intermediate III-12: Compound II-12 (0.30g, 1.64mmol) was dissolved in anhydrous tetrahydrofuran (10mL), then K 2 CO 3 (0.28g, 2.00mmol), phenyl chloroformate (0.22mL , 1.72mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.38 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000084
Figure PCTCN2022128606-appb-000084
中间体V-13的合成：将化合物III-12(0.38g,1.24mmol)，IV-1(0.17g,1.05mmol)，DMAP(0.0080g,0.060mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.055mL,0.32mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体 0.21g，收率55％。 1H NMR(500MHz,MeOD)δ(ppm):7.28(1H,d,J＝1.9Hz),7.16(1H,d,J＝8.0Hz),6.90(1H,dd,J 1＝8.0Hz,J 2＝2.0Hz),6.81(2H,s),3.85(6H,s),3.75(3H,s),3.49(2H,s)。 Synthesis of Intermediate V-13: Compound III-12 (0.38g, 1.24mmol), IV-1 (0.17g, 1.05mmol), DMAP (0.0080g, 0.060mmol) were dissolved in DCM (15mL), under stirring TEA (0.055 mL, 0.32 mmol) was added, heated to 50° C. for 20 h. After the completion of the reaction as monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.21 g of a white solid with a yield of 55%. . 1 H NMR (500MHz, MeOD) δ (ppm): 7.28 (1H, d, J = 1.9Hz), 7.16 (1H, d, J = 8.0Hz), 6.90 (1H, dd, J 1 = 8.0Hz, J 2 = 2.0Hz), 6.81(2H,s), 3.85(6H,s), 3.75(3H,s), 3.49(2H,s).
Figure PCTCN2022128606-appb-000085
Figure PCTCN2022128606-appb-000085
化合物I-36的合成：将化合物V-13(0.21g,0.59mmol)和VI-2(0.23g,0.88mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.050mL,0.59mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.24g，收率66％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.83(1H,s),8.73(1H,s),8.62(1H,d,J＝9.7Hz),7.65(1H,d,J＝8.3Hz),7.48(1H,s),7.36(1H,s),6.88(1H,d,J＝8.2Hz),6.81(2H,s),6.80(1H,s),3.76(6H,s),3.75(3H,s),3.28(2H,q,J＝6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,153.3(2C),144.6,139.6,139.1,136.3,135.3,132.9,128.3,126.2,124.9,121.9,120.5,119.7,119.1,116.1,100.5,96.4(2C),60.6,56.1,56.2,52.2,47.0(2C),37.4,13.8,12.4(2C),11.1。 Synthesis of compound I-36: Dissolve compound V-13 (0.21g, 0.59mmol) and VI-2 (0.23g, 0.88mmol) in ethanol (7mL), then add pyrrolidine (0.050mL, 0.59mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.24 g of an orange-yellow solid with a yield of 66%. 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 13.48 (1H, s), 10.83 (1H, s), 8.73 (1H, s), 8.62 (1H, d, J = 9.7Hz), 7.65 (1H,d,J=8.3Hz),7.48(1H,s),7.36(1H,s),6.88(1H,d,J=8.2Hz),6.81(2H,s),6.80(1H,s) ,3.76(6H,s),3.75(3H,s),3.28(2H,q,J=6.3Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s), 0.98(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):170.4,165.2,153.3(2C),144.6,139.6,139.1,136.3,135.3,132.9,128.3 ,126.2,124.9,121.9,120.5,119.7,119.1,116.1,100.5,96.4(2C),60.6,56.1,56.2,52.2,47.0(2C),37.4,13.8,12.4(2C),11.1.
实施例37Example 37
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺(I-37)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) Synthesis of -2,4-dimethyl-1H-pyrrol-3-yl)acetamide (I-37):
Figure PCTCN2022128606-appb-000086
Figure PCTCN2022128606-appb-000086
化合物I-37的合成：化合物XII-1(0.17g,0.39mmol)溶于THF(10mL)，加入DIPEA(0.19mL,1.17mmol)，降温至0℃，滴加乙酰氯(0.040mL,0.58mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.14g,收率78％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.33(1H,s),10.80(1H,s),9.46(1H,s),9.08(1H,s),8.86(1H,s),7.63(1H,d,J＝8.3Hz),7.45(1H,s),7.28(1H,d,J＝1.7Hz),6.89(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.51(1H,s),2.18(3H,s),2.14(3H,s),2.10(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,168.9,158.9,151.7,139.2,137.7,130.8,126.0,124.7,122.6,122.1,120.8,119.1,114.1,111.7,100.6,92.9,32.9,28.8(3C),23.1,12.2,9.6。 Synthesis of Compound I-37: Compound XII-1 (0.17g, 0.39mmol) was dissolved in THF (10mL), DIPEA (0.19mL, 1.17mmol) was added, cooled to 0°C, acetyl chloride (0.040mL, 0.58mmol) was added dropwise ), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.14 g of a yellow solid with a yield of 78%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.33(1H,s),10.80(1H,s),9.46(1H,s),9.08(1H,s),8.86(1H,s) ,7.63(1H,d,J=8.3Hz),7.45(1H,s),7.28(1H,d,J=1.7Hz),6.89(1H,dd,J 1 ＝8.3Hz,J 2 ＝1.8Hz) ,6.51(1H,s),2.18(3H,s),2.14(3H,s),2.10(3H,s),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm ):180.6, 170.3, 168.9, 158.9, 151.7, 139.2, 137.7, 130.8, 126.0, 124.7, 122.6, 122.1, 120.8, 119.1, 114.1, 111.7, 100.6, 92.9, 32.9, 28.8 (3C ), 23.1, 12.2, 9.6 .
实施例38Example 38
(Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-4-甲基-1H-吡咯-3-基)乙酰胺(I-38)的合成：(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) - Synthesis of 4-methyl-1H-pyrrol-3-yl)acetamide (I-38):
Figure PCTCN2022128606-appb-000087
Figure PCTCN2022128606-appb-000087
中间体XI-3的合成：将化合物V-1(0.63g,2.02mmol)和VI-3(0.40g,2.60mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.17mL,2.02mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.86g，收率95％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):14.13(1H,s), 11.15(1H,s),9.53(1H,s),8.97(1H,s),8.25(1H,d,J＝3.4Hz),7.81(1H,d,J＝8.3Hz),7.62(1H,s),7.34(1H,d,J＝1.8Hz),6.93(1H,dd,J 1＝8.3Hz,J 2＝1.9Hz),6.52(1H,s),2.58(3H,s),1.31(9H,s)。 Synthesis of Intermediate XI-3: Compounds V-1 (0.63g, 2.02mmol) and VI-3 (0.40g, 2.60mmol) were dissolved in ethanol (10mL), then pyrrolidine (0.17mL, 2.02mmol) was added, Heated to 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.86 g of an orange-yellow solid with a yield of 95%. 1 H NMR (500MHz, DMSO-d 6 )δ(ppm): 14.13(1H,s), 11.15(1H,s), 9.53(1H,s), 8.97(1H,s), 8.25(1H,d, J＝3.4Hz), 7.81(1H,d,J＝8.3Hz),7.62(1H,s),7.34(1H,d,J＝1.8Hz),6.93(1H,dd, J ＝8.3Hz,J 2 = 1.9Hz), 6.52(1H,s), 2.58(3H,s), 1.31(9H,s).
Figure PCTCN2022128606-appb-000088
Figure PCTCN2022128606-appb-000088
中间体XII-3的合成：将化合物XI-3(0.86g,1.90mmol)溶于四氢呋喃和甲醇(10mL/5mL,v/v)的混合溶剂，加入氯化铵(0.31g,5.72mmol)的饱和溶液(1mL)，加热至50℃，分批加入锌粉(0.63g,9.60mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，甲醇打浆纯化,抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.32g，收率54％。Synthesis of intermediate XII-3: Dissolve compound XI-3 (0.86g, 1.90mmol) in a mixed solvent of tetrahydrofuran and methanol (10mL/5mL, v/v), add ammonium chloride (0.31g, 5.72mmol) The saturated solution (1 mL) was heated to 50°C, and zinc powder (0.63 g, 9.60 mmol) was added in batches, and the reaction was continued for 0.5 h. After the reaction was completed by LC-MS monitoring, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and wash with water and saturated sodium chloride successively The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, purification by beating with methanol, suction filtration, washing the filter cake with a small amount of methanol, and drying in vacuo to obtain 0.32 g of a yellow solid with a yield of 54%.
Figure PCTCN2022128606-appb-000089
Figure PCTCN2022128606-appb-000089
化合物I-38的合成：化合物XII-3(0.22g,0.53mmol)溶于THF(10mL)，加入DIPEA(0.19mL,1.17mmol)，降温至0℃，滴加乙酰氯(0.060mL,0.80mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.14g,收率41％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.21(1H,d,J＝2.4Hz),10.86(1H,s),9.48(1H,s),9.30(1H,s),8.87(1H,s),7.66(1H,d,J＝8.3Hz),7.56(1H,d,J＝8.3Hz),7.50(1H,s),7.29(1H,d,J＝1.7Hz),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.52(1H,s),2.26(3H,s),2.04(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.2,167.9,158.8,151.6,139.7,138.2,125.5,124.8,122.7,120.5,119.5,119.2,118.0,116.2,111.7,100.6,92.9,33.0,28.8(3C),23.4,9.3。 Synthesis of Compound I-38: Compound XII-3 (0.22g, 0.53mmol) was dissolved in THF (10mL), added DIPEA (0.19mL, 1.17mmol), cooled to 0°C, and acetyl chloride (0.060mL, 0.80mmol) was added dropwise ), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.14 g of a yellow solid with a yield of 41%. 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 13.21 (1H, d, J = 2.4Hz), 10.86 (1H, s), 9.48 (1H, s), 9.30 (1H, s), 8.87 (1H,s),7.66(1H,d,J=8.3Hz),7.56(1H,d,J=8.3Hz),7.50(1H,s),7.29(1H,d,J=1.7Hz),6.90 (1H, dd, J 1 =8.3Hz, J 2 =1.7Hz), 6.52(1H,s), 2.26(3H,s), 2.04(3H,s), 1.31(9H,s). 13 C NMR( 125MHz,DMSO-d 6 )δ(ppm):180.7,170.2,167.9,158.8,151.6,139.7,138.2,125.5,124.8,122.7,120.5,119.5,119.2,118.0,116.2,111.7,100.6, 92.9, 33.0, 28.8(3C), 23.4, 9.3.
实施例39Example 39
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N,2,4-三甲基-1H-吡咯-3-甲酰胺(I-39)的合成：(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-N, Synthesis of 2,4-trimethyl-1H-pyrrole-3-carboxamide (I-39):
Figure PCTCN2022128606-appb-000090
Figure PCTCN2022128606-appb-000090
中间体VI-5的合成：将化合物VI-4(0.15g,0.90mmol)溶解于乙腈(10mL)，然后加入HOBT(0.015g,0.14mmol)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.22g,1.17mmol)，甲酰胺(0.079ml,1.62mmol)，TEA(0.25ml,1.80mmol)，室温反应12h，LC-MS监测反应完毕后，抽滤，减压浓缩，柱层析纯化(二氯甲烷：甲醇)得白色固体0.060g，收率37％。 1H NMR(500MHz,MeOD)δ(ppm):9.54(1H,s),2.90(3H,s),2.44(3H,s),2.39(3H,s)。 Synthesis of Intermediate VI-5: Compound VI-4 (0.15g, 0.90mmol) was dissolved in acetonitrile (10mL), then HOBT (0.015g, 0.14mmol), 1-ethyl-(3-dimethylamino Propyl) carbodiimide hydrochloride (0.22g, 1.17mmol), formamide (0.079ml, 1.62mmol), TEA (0.25ml, 1.80mmol), reacted at room temperature for 12h, after the reaction was monitored by LC-MS, Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane: methanol) gave 0.060 g of white solid, yield 37%. 1 H NMR (500 MHz, MeOD) δ (ppm): 9.54 (1H, s), 2.90 (3H, s), 2.44 (3H, s), 2.39 (3H, s).
Figure PCTCN2022128606-appb-000091
Figure PCTCN2022128606-appb-000091
化合物I-39的合成：将化合物V-1(0.087g,0.28mmol)和VI-5(0.060g,0.33mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.023mL,0.28mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率80％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.89(1H,s),9.48(1H,s),8.88(1H,s),7.69(1H,d,J＝8.3Hz),7.51(1H,s),7.49(1H,d,J＝4.7Hz),7.30(1H,d,J＝1.8Hz),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.8Hz),6.51(1H,s),2.75(3H,d,J＝4.6Hz),2.42(3H,s),2.39(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.4,165.9,158.8,151.6,139.5,138.2,135.4,128.7,126.2,122.3,120.7,120.5,119.6,115.8,111.8,100.7,92.9,33.0,28.8(3C),26.4,13.7,11.0。 Synthesis of compound I-39: Dissolve compound V-1 (0.087g, 0.28mmol) and VI-5 (0.060g, 0.33mmol) in ethanol (5mL), then add pyrrolidine (0.023mL, 0.28mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 80%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.89(1H,s),9.48(1H,s),8.88(1H,s),7.69(1H,d, J=8.3Hz),7.51(1H,s),7.49(1H,d,J=4.7Hz),7.30(1H,d,J=1.8Hz),6.90(1H,dd,J 1 =8.3Hz,J 2 = 1.8Hz), 6.51(1H, s), 2.75(3H, d, J = 4.6Hz), 2.42(3H, s), 2.39(3H, s), 1.31(9H, s). 13 C NMR ( 125MHz,DMSO-d 6 )δ(ppm):180.7,170.4,165.9,158.8,151.6,139.5,138.2,135.4,128.7,126.2,122.3,120.7,120.5,119.6,115.8,111.8,100.7, 92.9, 33.0, 28.8 (3C), 26.4, 13.7, 11.0.
实施例40Example 40
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺(I-40)的合成：(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, Synthesis of 4-dimethyl-1H-pyrrole-3-carboxamide (I-40):
Figure PCTCN2022128606-appb-000092
Figure PCTCN2022128606-appb-000092
中间体VI-6的合成：将化合物VI-4(0.10g,0.60mmol)溶解于无水四氢呋喃(7mL)，0℃下滴加SOCl 2，室温反应1h后滴加25％的NH 4OH，室温下继续反应1h。LC-MS监测反应完毕后，将反应液加入水(15mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，柱层析纯化(二氯甲烷:甲醇)得到白色固体0.030g，收率30％。 Synthesis of intermediate VI-6: Dissolve compound VI-4 (0.10 g, 0.60 mmol) in anhydrous THF (7 mL), add SOCl 2 dropwise at 0°C, react at room temperature for 1 h, then add 25% NH 4 OH dropwise, The reaction was continued for 1 h at room temperature. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, and purification by column chromatography (dichloromethane:methanol) gave 0.030 g of a white solid with a yield of 30%.
Figure PCTCN2022128606-appb-000093
Figure PCTCN2022128606-appb-000093
化合物I-40的合成：将化合物V-1(0.050g,0.15mmol)和VI-6(0.030g,0.18mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.013mL,0.15mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.060g，收率81％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.88(1H,s),9.47(1H,s),8.88(1H,s),7.69(1H,d,J＝8.3Hz),7.51(1H,s),7.30(1H,d,J＝1.5Hz),7.07(1H,s),7.01(1H,s),6.90(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),6.51(1H,s),2.46(3H,s),2.41(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.4,167.3,158.8,151.6,139.5,138.2,136.0,129.1,126.2,122.4,120.5,120.3,119.6,115.8,111.8,100.7,92.9,33.0,28.8(3C),14.0,11.2。 Synthesis of compound I-40: Dissolve compound V-1 (0.050g, 0.15mmol) and VI-6 (0.030g, 0.18mmol) in ethanol (5mL), then add pyrrolidine (0.013mL, 0.15mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.060 g of an orange-yellow solid with a yield of 81%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.88(1H,s),9.47(1H,s),8.88(1H,s),7.69(1H,d, J＝8.3Hz), 7.51(1H, s), 7.30(1H, d, J＝1.5Hz), 7.07(1H, s), 7.01(1H, s), 6.90(1H, dd, J ＝ 8.3Hz , J 2 =1.6Hz), 6.51(1H,s), 2.46(3H,s), 2.41(3H,s), 1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm ):180.7, 170.4, 167.3, 158.8, 151.6, 139.5, 138.2, 136.0, 129.1, 126.2, 122.4, 120.5, 120.3, 119.6, 115.8, 111.8, 100.7, 92.9, 33.0, 28.8 (3C ), 14.0, 11.2.
实施例41Example 41
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸甲酯(I-41)的合成：(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, Synthesis of 4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester (I-41):
Figure PCTCN2022128606-appb-000094
Figure PCTCN2022128606-appb-000094
中间体VI-7的合成：将化合物VI-7(0.20g,1.20mmol)溶于丙酮(10mL)，加入K 2CO 3(0.18g,1.32mmol)，硫酸二甲酯(0.12ml,1.26mmol)，室温下反应12h。LC-MS监测反应完毕后，抽滤，滤饼用乙酸乙酯洗涤，减压浓缩，柱层析纯化(二氯甲烷:甲醇)得到白色固体0.14g，收率65％。 1H NMR(500MHz,CDCl 3)δ(ppm):9.85(1H,s),9.64(1H,s),3.86(3H,s),2.59(3H,s),2.57(3H,s)。 Synthesis of intermediate VI-7: Dissolve compound VI-7 (0.20g, 1.20mmol) in acetone (10mL), add K 2 CO 3 (0.18g, 1.32mmol), dimethyl sulfate (0.12ml, 1.26mmol ), reacted at room temperature for 12h. After the reaction was monitored by LC-MS, it was suction filtered, the filter cake was washed with ethyl acetate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol) to obtain 0.14 g of a white solid with a yield of 65%. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm): 9.85 (1H, s), 9.64 (1H, s), 3.86 (3H, s), 2.59 (3H, s), 2.57 (3H, s).
Figure PCTCN2022128606-appb-000095
Figure PCTCN2022128606-appb-000095
化合物I-41的合成：将化合物V-1(0.050g,0.15mmol)和VI-7(0.044g,0.24mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.013mL,0.15mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.060g，收率83％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.75(1H,s),10.96(1H,s),9.48(1H,s),8.90(1H,s),7.71(1H,d,J＝8.3Hz),7.55(1H,s),7.30(1H,d,J＝1.6Hz),6.91(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.51(1H,s),3.76(3H,s),2.54(3H,s),2.48(3H,s),1.31(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.4,165.4,158.8,151.6,140.1,139.9,138.67,131.2,126.6,122.0,120.2,120.0,117.4,113.4,111.9,100.7,92.9,51.1,33.0,28.8(3C),14.9,11.9。 Synthesis of compound I-41: Dissolve compound V-1 (0.050g, 0.15mmol) and VI-7 (0.044g, 0.24mmol) in ethanol (5mL), then add pyrrolidine (0.013mL, 0.15mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.060 g of an orange-yellow solid with a yield of 83%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.75(1H,s),10.96(1H,s),9.48(1H,s),8.90(1H,s),7.71(1H,d, J＝8.3Hz), 7.55(1H,s), 7.30(1H,d, J＝1.6Hz), 6.91(1H,dd, J1 ＝8.3Hz, J2 ＝1.7Hz), 6.51(1H,s) ,3.76(3H,s),2.54(3H,s),2.48(3H,s),1.31(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.4,165.4 ,158.8,151.6,140.1,139.9,138.67,131.2,126.6,122.0,120.2,120.0,117.4,113.4,111.9,100.7,92.9,51.1,33.0,28.8(3C),14.9,11.9.
实施例42Example 42
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸(I-42)的合成：(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, Synthesis of 4-dimethyl-1H-pyrrole-3-carboxylic acid (I-42):
Figure PCTCN2022128606-appb-000096
Figure PCTCN2022128606-appb-000096
化合物I-42的合成：将化合物V-1(0.41g,1.30mmol)和化合物VI-4(0.26g,1.57mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.14mL,1.70mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.51g，收率85％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.69(1H,s),12.09(1H,s),10.95(1H,s),9.56(1H,s),8.97(1H,s),7.71(1H,d,J＝8.3Hz),7.55(1H,s),7.31(1H,d,J＝1.2Hz),6.91(1H,dd,J 1＝8.2Hz,J 2＝1.2Hz),6.52(1H,s),2.53(3H,s),2.48(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.4,170.1,158.8,151.6,140.2,139.8,138.4,131.7,126.5,124.1,124.0,122.2,120.3,119.9,111.9,100.7,92.9,33.0,28.8(3C),14.9,11.9。 Synthesis of compound I-42: Dissolve compound V-1 (0.41g, 1.30mmol) and compound VI-4 (0.26g, 1.57mmol) in ethanol (10mL), then add pyrrolidine (0.14mL, 1.70mmol), Heated to 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuum to obtain 0.51 g of an orange-yellow solid with a yield of 85%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.69(1H,s),12.09(1H,s),10.95(1H,s),9.56(1H,s),8.97(1H,s) ,7.71(1H,d,J=8.3Hz),7.55(1H,s),7.31(1H,d,J=1.2Hz),6.91(1H,dd,J 1 ＝8.2Hz,J 2 ＝1.2Hz) ,6.52(1H,s),2.53(3H,s),2.48(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.4,170.1 ,158.8,151.6,140.2,139.8,138.4,131.7,126.5,124.1,124.0,122.2,120.3,119.9,111.9,100.7,92.9,33.0,28.8(3C),14.9,11.9.
实施例43Example 43
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)脲(I-43)的合成：(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene) -Synthesis of 2-oxindol-6-yl)urea (I-43):
Figure PCTCN2022128606-appb-000097
Figure PCTCN2022128606-appb-000097
化合物I-43的合成：将化合物V-1(0.10g,0.32mmol)和VI-8(0.059g,0.48mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.031mL,0.38mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率85％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.21(1H,s),10.79(1H,s),9.47(1H,s),8.85(1H,s),7.62(1H,d,J＝8.3Hz),7.45(1H,s),7.28(1H,d,J＝1.4Hz),6.89(1H,dd,J 1＝8.3Hz,J 2＝1.5Hz),6.51(1H,s),5.98(1H,s),2.31(3H,s),2.29(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,158.9,151.6,139.2,137.6,135.3,131.1,127.0,122.4,120.9,119.0,113.5,112.7,111.6,100.6,92.9,33.0,28.8(3C),14.0,11.8。 Synthesis of compound I-43: Dissolve compound V-1 (0.10g, 0.32mmol) and VI-8 (0.059g, 0.48mmol) in ethanol (6mL), then add pyrrolidine (0.031mL, 0.38mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 85%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.21(1H,s),10.79(1H,s),9.47(1H,s),8.85(1H,s),7.62(1H,d, J＝8.3Hz), 7.45(1H,s), 7.28(1H,d, J＝1.4Hz), 6.89(1H,dd, J1 ＝8.3Hz, J2 ＝1.5Hz), 6.51(1H,s) ,5.98(1H,s),2.31(3H,s),2.29(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.3,158.9 ,151.6,139.2,137.6,135.3,131.1,127.0,122.4,120.9,119.0,113.5,112.7,111.6,100.6,92.9,33.0,28.8(3C),14.0,11.8.
实施例44Example 44
(Z)-1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-44)的合成：(Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 -Synthesis of urea (I-44):
Figure PCTCN2022128606-appb-000098
Figure PCTCN2022128606-appb-000098
化合物I-44的合成：将化合物V-1(0.10g,0.32mmol)和VI-9(0.045g,0.38mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.031mL,0.38mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率86％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.22(1H,s),10.91(1H,s),9.51(1H,s),8.90(1H,s),7.61(1H,s),7.54(1H,d,J＝8.2Hz),7.33(1H,s),7.32(1H,s),6.88(1H,d,J＝8.1Hz),6.78(1H,s),6.52(1H,s),6.34(1H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.1,158.8,151.6,140.1,138.6,130.1,125.5,125.2,120.0(2C),119.5,117.5,111.9,111.7,100.7,92.9,33.0,28.8(3C)。 Synthesis of compound I-44: Dissolve compound V-1 (0.10g, 0.32mmol) and VI-9 (0.045g, 0.38mmol) in ethanol (6mL), then add pyrrolidine (0.031mL, 0.38mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 86%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.22(1H,s),10.91(1H,s),9.51(1H,s),8.90(1H,s),7.61(1H,s) ,7.54(1H,d,J=8.2Hz),7.33(1H,s),7.32(1H,s),6.88(1H,d,J=8.1Hz),6.78(1H,s),6.52(1H, s),6.34(1H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.1,158.8,151.6,140.1,138.6,130.1,125.5,125.2 , 120.0 (2C), 119.5, 117.5, 111.9, 111.7, 100.7, 92.9, 33.0, 28.8 (3C).
实施例45Example 45
(Z)-N 1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺(I-45)的合成： (Z)-N 1 -(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole Synthesis of -3-yl) malonamide (I-45):
Figure PCTCN2022128606-appb-000099
Figure PCTCN2022128606-appb-000099
中间体VIII-1的合成：将化合物II-1(1.00g,7.13mmol)溶于乙腈(20mL)，然后化合物VII-1(0.84g,7.13mmol)，TCFH(2.40g,8.65mmol)，NMI(2.00ml,25.00mmol)，室温反应4h。LC-MS监测反应完毕后，将反应液加入水(15mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，得到白色固体0.85g，收率50％。Synthesis of intermediate VIII-1: Compound II-1 (1.00g, 7.13mmol) was dissolved in acetonitrile (20mL), then compound VII-1 (0.84g, 7.13mmol), TCFH (2.40g, 8.65mmol), NMI (2.00ml, 25.00mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration and concentration under reduced pressure afforded 0.85 g of a white solid with a yield of 50%.
Figure PCTCN2022128606-appb-000100
Figure PCTCN2022128606-appb-000100
中间体IX-1的合成：将化合物VIII-1(0.85g,3.54mmol)溶解于CH 3OH/H 2O(20mL)，然后加入LiOH .H 2O(0.30g,7.08mmol)，室温反应2h。LC-MS监测反应完毕后，用1N的HCl将反应液调至PH＝1，待固体析出，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到橙黄色固体0.57g，收率71％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):12.72(1H,s),11.11(1H,s),6.57(1H,s),3.39(2H,s),1.30(9H,s)。 Synthesis of Intermediate IX-1: Compound VIII-1 (0.85g, 3.54mmol) was dissolved in CH 3 OH/H 2 O (20mL), then LiOH . H 2 O (0.30g, 7.08mmol) was added and reacted at room temperature 2h. After the completion of the reaction monitored by LC-MS, the reaction solution was adjusted to PH = 1 with 1N HCl, and the solid was precipitated, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.57 g of an orange-yellow solid with a yield of 71 %. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):12.72(1H,s),11.11(1H,s),6.57(1H,s),3.39(2H,s),1.30(9H,s) .
Figure PCTCN2022128606-appb-000101
Figure PCTCN2022128606-appb-000101
中间体X-1的合成：将化合物IV-1(0.45g,3.03mmol)溶解于DMF(15mL)，于搅拌下加入IX-1(0.57g,2.52mmol)，TCFH(0.85g,3.03mmol)，DIPEA(1.25mL,7.56mmol)，室温反应2h。LC-MS监测反应完毕后，向反应液中加入水(10ml)，待固体析出后，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得黄色固体0.58g，收率65％。Synthesis of Intermediate X-1: Dissolve compound IV-1 (0.45g, 3.03mmol) in DMF (15mL), add IX-1 (0.57g, 2.52mmol), TCFH (0.85g, 3.03mmol) under stirring , DIPEA (1.25mL, 7.56mmol), react at room temperature for 2h. After the reaction was monitored by LC-MS, water (10ml) was added to the reaction solution. After the solid precipitated, it was filtered with suction, and the filter cake was washed with a small amount of ethyl acetate and dried in vacuo to obtain 0.58 g of a yellow solid, with a yield of 65%.
Figure PCTCN2022128606-appb-000102
Figure PCTCN2022128606-appb-000102
化合物I-45的合成：将化合物X-1(0.080g,0.23mmol)和VI-10(0.026g,0.27mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.020mL,0.22mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到黄色固体0.090g，收率86％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.61(1H,s),11.15(1H,s),10.95(1H,s),10.25(1H,s),7.98(1H,s),7.69(1H,s),7.59(1H,d,J＝8.3Hz),7.54(1H,s),7.45(1H,d,J＝1.6Hz),7.09(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),6.61(1H,s),3.52(2H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):181.0(2C),169.7,166.2,165.4,158.2,140.8,139.4,120.8,120.2(2C),112.5,101.4,93.6(2C),56.5,45.8,33.0,28.8(3C),19.0。 Synthesis of compound I-45: Dissolve compound X-1 (0.080g, 0.23mmol) and VI-10 (0.026g, 0.27mmol) in ethanol (6mL), then add pyrrolidine (0.020mL, 0.22mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuum to obtain 0.090 g of a yellow solid with a yield of 86%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.61(1H,s),11.15(1H,s),10.95(1H,s),10.25(1H,s),7.98(1H,s) ,7.69(1H,s),7.59(1H,d,J＝8.3Hz),7.54(1H,s),7.45(1H,d,J＝1.6Hz),7.09(1H,dd, J ＝8.3Hz , J 2 =1.6Hz), 6.61(1H,s), 3.52(2H,s), 1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm): 181.0(2C), 169.7, 166.2, 165.4, 158.2, 140.8, 139.4, 120.8, 120.2 (2C), 112.5, 101.4, 93.6 (2C), 56.5, 45.8, 33.0, 28.8 (3C), 19.0.
实施例46Example 46
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-甲氧基-4-(三氟甲基)苯基)脲(I-46)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-methoxy-4-(trifluoromethane Base) phenyl) urea (I-46) synthesis:
Figure PCTCN2022128606-appb-000103
Figure PCTCN2022128606-appb-000103
化合物I-46的合成：将化合物V-12(0.22g,0.60mmol)和VI-10(0.026g,0.27mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.050mL,0.60mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.25g，收率67％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d,J＝2.5Hz),7.65(1H,d,J＝8.3Hz),7.58(1H,dd,J 1＝8.9Hz,J 2＝2.3Hz),7.48(1H,s),7.37(1H,t,J＝5.5Hz),7.32(1H,d,J＝1.6Hz),7.21(1H,d,J＝9.1Hz),6.92(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),3.86(3H,s),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,153.1,152.4,139.6,139.1,135.4,133.1,128.3,126.2,125.2,124.4,123.0,121.9,120.5,119.9,119.5,117.1,116.1,114.0,111.6,100.6,56.7,52.1,47.0(2C),37.4,13.8,12.4(2C),11.1。 Synthesis of compound I-46: Dissolve compound V-12 (0.22g, 0.60mmol) and VI-10 (0.026g, 0.27mmol) in ethanol (7mL), then add pyrrolidine (0.050mL, 0.60mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.25 g of an orange-yellow solid with a yield of 67%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.85(1H,s),8.80(1H,s),8.74(1H,s),7.87(1H,d, J=2.5Hz),7.65(1H,d,J=8.3Hz),7.58(1H,dd,J 1 ＝8.9Hz,J 2 ＝2.3Hz),7.48(1H,s),7.37(1H,t, J = 5.5Hz), 7.32 (1H, d, J = 1.6Hz), 7.21 (1H, d, J = 9.1Hz), 6.92 (1H, dd, J 1 = 8.3Hz, J 2 = 1.6Hz), 3.86 (3H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),0.98(6H,t,J=7.1 Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 153.1, 152.4, 139.6, 139.1, 135.4, 133.1, 128.3, 126.2, 125.2, 124.4, 123.0, 121.9, 120.5, 11 9.9 , 119.5, 117.1, 116.1, 114.0, 111.6, 100.6, 56.7, 52.1, 47.0 (2C), 37.4, 13.8, 12.4 (2C), 11.1.
实施例47Example 47
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(叔丁基)苯基)脲(I-47)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(tert-butyl)phenyl)urea ( I-47) Synthesis:
Figure PCTCN2022128606-appb-000104
Figure PCTCN2022128606-appb-000104
化合物I-47的合成：将化合物V-9(0.11g,0.33mmol)和VI-10(0.132g,0.50mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.027mL,0.33mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率61％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d,J＝8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89(1H,d,J＝8.2Hz),3.29(2H,q,J＝6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.98(6H,t,J＝7.0Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,152.9,144.6,139.6,139.3,137.5,135.3,128.2,126.2,125.8(2C),121.8,120.5,119.7,119.6,118.5(2C),116.2,111.4,100.4,52.2,47.0(2C),37.4,34.4,31.7(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-47: Dissolve compound V-9 (0.11g, 0.33mmol) and VI-10 (0.132g, 0.50mmol) in ethanol (10mL), then add pyrrolidine (0.027mL, 0.33mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 61%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.85(1H,s),8.72(1H,s),8.55(1H,s),7.65(1H,d, J＝8.2Hz),7.48(1H,s),7.38(1H,s),7.37(2H,s),7.34(1H,s),7.31(1H,s),7.29(1H,s),6.89( 1H,d,J=8.2Hz),3.29(2H,q,J=6.2Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s ), 0.98 (6H, t, J=7.0Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 152.9, 144.6, 139.6, 139.3, 137.5, 135.3, 128.2, 126.2, 125.8(2C), 121.8, 120.5, 119.7, 119.6, 118.5(2C), 116.2, 111.4, 100.4, 52.2, 47.0(2C), 37.4, 34.4, 31.7(3C), 13.8, 12.4(2C), 11.1.
实施例48Example 48
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲(I-48)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)-1-methyl Synthesis of -1H-pyrazol-5-yl)urea (I-48):
Figure PCTCN2022128606-appb-000105
Figure PCTCN2022128606-appb-000105
化合物I-48的合成：将化合物V-5(0.19g,0.58mmol)和VI-10(0.23g,0.87mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.050mL,0.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.37g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d,J＝8.3Hz),7.48(1H,s),7.39(1H,t,J＝5.5Hz),7.31(1H,d,J＝1.7Hz),6.95(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39(3H,s),1.22(9H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.4,165.2,159.1,152.1,139.6,139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,12.4(2C),11.1。 Synthesis of compound I-48: Dissolve compound V-5 (0.19g, 0.58mmol) and VI-10 (0.23g, 0.87mmol) in ethanol (10mL), then add pyrrolidine (0.050mL, 0.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.37 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.48(1H,s),10.88(1H,s),9.88(1H,s),9.42(1H,s),7.65(1H,d, J＝8.3Hz), 7.48(1H, s), 7.39(1H, t, J＝5.5Hz), 7.31(1H, d, J＝1.7Hz), 6.95(1H, dd, J ＝ 8.3Hz, J 2 =1.7Hz),6.07(1H,s),3.65(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.39( 3H, s), 1.22 (9H, s), 0.98 (6H, t, J=7.1Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 170.4, 165.2, 159.1, 152.1, 139.6, 139.3,138.0,135.3,128.2,126.2,121.8,120.5,119.7,119.6,116.2,111.1,100.0,92.7,52.1,47.0(2C),37.4,35.7,32.3,30.9(3C),13.8,1 2.4(2C) , 11.1.
实施例49Example 49
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲(I-49)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)isoxazole-5 -Synthesis of urea (I-49):
Figure PCTCN2022128606-appb-000106
Figure PCTCN2022128606-appb-000106
中间体III-13的合成：将化合物II-13(1.00g,7.13mmol)溶解于无水四氢呋喃(20mL)，然后加入K 2CO 3(1.22g,8.83mmol)，氯甲酸苯酯(0.94mL,7.49mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体1.17g，收率75％。 Synthesis of Intermediate III-13: Compound II-13 (1.00g, 7.13mmol) was dissolved in anhydrous tetrahydrofuran (20mL), then K 2 CO 3 (1.22g, 8.83mmol), phenyl chloroformate (0.94mL , 7.49mmol), reacted at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 1.17 g of a white solid with a yield of 75%.
Figure PCTCN2022128606-appb-000107
Figure PCTCN2022128606-appb-000107
中间体V-14的合成：将化合物III-13(0.31g,1.44mmol)，IV-1(0.20g,1.20mmol)，DMAP(0.0090g,0.070mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.025mL,0.18mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到灰色固体0.27g，收率75％。 1H NMR(500MHz,MeOD)δ(ppm):7.30(1H,d,J＝1.8Hz),7.19(1H,d,J＝8.0Hz),6.93(1H,dd,J 1＝8.0Hz,J 2＝2.0Hz),6.13(1H,s),5.51(1H,s),1.34(9H,s)。 Synthesis of Intermediate V-14: Compound III-13 (0.31g, 1.44mmol), IV-1 (0.20g, 1.20mmol), DMAP (0.0090g, 0.070mmol) were dissolved in DCM (10mL), under stirring Add TEA (0.025mL, 0.18mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.27 g of a gray solid with a yield of 75%. . 1 H NMR (500MHz, MeOD) δ (ppm): 7.30 (1H, d, J = 1.8Hz), 7.19 (1H, d, J = 8.0Hz), 6.93 (1H, dd, J 1 = 8.0Hz, J 2 =2.0Hz), 6.13(1H,s), 5.51(1H,s), 1.34(9H,s).
Figure PCTCN2022128606-appb-000108
Figure PCTCN2022128606-appb-000108
化合物I-49的合成：将化合物V-14(0.20g,0.64mmol)和VI-10(0.09g,0.96mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.053mL,0.64mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.16g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.62(1H,s),11.03(1H,s),10.10(1H,s),8.97(1H,s),8.00(1H,s),7.71(1H,s),7.59(1H,s),7.57(1H,s),7.35(1H,d,J＝1.4Hz),6.93(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),6.08(1H,s),1.27(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):173.0,169.9,162.1,150.0,141.0,139.7,139.4,138.1,128.7,121.5,120.6,120.4,119.4,112.1,100.8,84.2,32.4,29.5(3C)。 Synthesis of compound I-49: Dissolve compound V-14 (0.20g, 0.64mmol) and VI-10 (0.09g, 0.96mmol) in ethanol (7mL), then add pyrrolidine (0.053mL, 0.64mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.16 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.62(1H,s),11.03(1H,s),10.10(1H,s),8.97(1H,s),8.00(1H,s) ,7.71(1H,s),7.59(1H,s),7.57(1H,s),7.35(1H,d,J=1.4Hz),6.93(1H,dd,J 1 ＝8.3Hz,J 2 ＝1.6 Hz),6.08(1H,s),1.27(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):173.0,169.9,162.1,150.0,141.0,139.7,139.4,138.1,128.7 , 121.5, 120.6, 120.4, 119.4, 112.1, 100.8, 84.2, 32.4, 29.5 (3C).
实施例50Example 50
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-氯-4-(三氟甲基)苯基)脲(I-50)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-chloro-4-(trifluoromethyl) Synthesis of phenyl)urea (I-50):
Figure PCTCN2022128606-appb-000109
Figure PCTCN2022128606-appb-000109
化合物I-50的合成：将化合物V-10(0.15g,0.41mmol)和VI-10(0.047g,0.49mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.030mL,0.41mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.11g，收率60％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.63(1H,s),11.00(1H,s),9.30(1H,s),9.09(1H,s),7.99(1H,s),7.93(1H,d,J＝1.8Hz),7.75(1H,d,J＝1.8Hz),7.70(1H,s),7.59(1H,s),7.57(1H,s),7.49(1H,dd,J 1＝8.5Hz,J 2＝1.2Hz),7.35(1H,d,J＝1.6Hz),6.95(1H,dd,J 1＝8.3Hz,J 2＝1.7Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):169.7,152.4,145.0,141.0,139.7,139.1,131.7,129.0,128.9,124.7,122.6,120.9,120.3,120.0,119.7,119.5,119.2,116.7,112.1,100.8。 Synthesis of compound I-50: Dissolve compound V-10 (0.15g, 0.41mmol) and VI-10 (0.047g, 0.49mmol) in ethanol (5mL), then add pyrrolidine (0.030mL, 0.41mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.11 g of an orange-yellow solid with a yield of 60%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.63(1H,s),11.00(1H,s),9.30(1H,s),9.09(1H,s),7.99(1H,s) ,7.93(1H,d,J=1.8Hz),7.75(1H,d,J=1.8Hz),7.70(1H,s),7.59(1H,s),7.57(1H,s),7.49(1H, dd, J 1 =8.5Hz, J 2 =1.2Hz), 7.35 (1H, d, J = 1.6Hz), 6.95 (1H, dd, J 1 =8.3Hz, J 2 =1.7Hz). 13 C NMR ( 125MHz,DMSO-d 6 )δ(ppm):169.7,152.4,145.0,141.0,139.7,139.1,131.7,129.0,128.9,124.7,122.6,120.9,120.3,120.0,119.7,119.5,119.2, 116.7, 112.1, 100.8.
实施例51Example 51
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(哌啶-4-基)苯基)脲盐酸盐(I-51)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(piperidin-4-yl)phenyl ) Synthesis of urea hydrochloride (I-51):
Figure PCTCN2022128606-appb-000110
Figure PCTCN2022128606-appb-000110
中间体III-14的合成：将化合物II-14(0.20g,0.72mmol)溶解于无水四氢呋喃(10mL)，然后加入K 2CO 3(0.12g,0.90mmol)，氯甲酸苯酯(0.10mL,0.80mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.24g，收率85％。 Synthesis of Intermediate III-14: Compound II-14 (0.20g, 0.72mmol) was dissolved in anhydrous tetrahydrofuran (10mL), then K 2 CO 3 (0.12g, 0.90mmol), phenyl chloroformate (0.10mL , 0.80mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.24 g of a white solid with a yield of 85%.
Figure PCTCN2022128606-appb-000111
Figure PCTCN2022128606-appb-000111
中间体V-15的合成：将化合物III-14(0.20g,0.51mmol)，IV-1(0.055g,0.34mmol)，DMAP(0.0030g,0.020mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.014mL,0.10mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.11g，收率72％。Synthesis of Intermediate V-15: Compound III-14 (0.20g, 0.51mmol), IV-1 (0.055g, 0.34mmol), DMAP (0.0030g, 0.020mmol) were dissolved in DCM (15mL), under stirring Add TEA (0.014mL, 0.10mmol), heat to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.11 g of a white solid with a yield of 72%. .
Figure PCTCN2022128606-appb-000112
Figure PCTCN2022128606-appb-000112
化合物XI-4的合成：将化合物V-15(0.11g,0.30mmol)和VI-10(0.12g,0.45mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.025mL,0.30mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.10g，收率67％。Synthesis of compound XI-4: Dissolve compound V-15 (0.11g, 0.30mmol) and VI-10 (0.12g, 0.45mmol) in ethanol (5mL), then add pyrrolidine (0.025mL, 0.30mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.10 g of an orange-yellow solid with a yield of 67%.
Figure PCTCN2022128606-appb-000113
Figure PCTCN2022128606-appb-000113
化合物I-51的合成：将化合物XI-4(0.10g,0.19mmol)用少量乙酸乙酯溶解，后加入盐酸乙酸乙酯溶液，于室温下搅拌反应。TLC检测反应完全后，抽滤，滤饼用乙酸乙酯洗涤，真空干燥，得到橙黄色固体0.070g，收率80％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):14.97(1H,s),11.23(1H,s),9.75(1H,s),9.42(1H,s),9.07(1H,s),8.94(1H,d,J＝10.2Hz),8.76(1H,d,J＝11.1Hz),8.22(1H,s),7.65(1H,s),7.57(1H,d,J＝8.6Hz),7.43(2H,d,J＝11.1Hz),7.41(1H,d,J＝1.8Hz),7.15(2H,d,J＝8.5Hz),6.99(1H,dd,J 1＝8.4Hz,J 2＝1.7Hz),3.35(2H,d,J＝12.4Hz),2.97(2H,q,J＝12.0Hz),2.81-2.76(1H,m),1.91(2H,d,J＝12.8Hz),1.85-1.78(2H,m). 13C NMR(125MHz,DMSO-d 6)δ(ppm):169.6,153.0,142.6,142.3,138.6,138.5,136.0,129.0,127.6,127.3(2C),124.1,121.7,118.7(2C),117.1,116.8,111.7,100.3,44.0(2C),38.8,30.0(2C)。 Synthesis of compound I-51: Dissolve compound XI-4 (0.10 g, 0.19 mmol) in a small amount of ethyl acetate, then add hydrochloric acid ethyl acetate solution, and stir the reaction at room temperature. After the reaction was complete as detected by TLC, it was suction filtered, the filter cake was washed with ethyl acetate, and dried in vacuo to obtain 0.070 g of an orange-yellow solid with a yield of 80%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):14.97(1H,s),11.23(1H,s),9.75(1H,s),9.42(1H,s),9.07(1H,s) ,8.94(1H,d,J=10.2Hz),8.76(1H,d,J=11.1Hz),8.22(1H,s),7.65(1H,s),7.57(1H,d,J=8.6Hz) ,7.43(2H,d,J=11.1Hz),7.41(1H,d,J=1.8Hz),7.15(2H,d,J=8.5Hz),6.99(1H,dd,J 1 =8.4Hz,J 2 = 1.7Hz), 3.35 (2H, d, J = 12.4Hz), 2.97 (2H, q, J = 12.0Hz), 2.81-2.76 (1H, m), 1.91 (2H, d, J = 12.8Hz) ,1.85-1.78(2H,m). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):169.6,153.0,142.6,142.3,138.6,138.5,136.0,129.0,127.6,127.3(2C),124.1 , 121.7, 118.7 (2C), 117.1, 116.8, 111.7, 100.3, 44.0 (2C), 38.8, 30.0 (2C).
实施例52Example 52
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-((4,4-二甲基哌啶-1-基)甲基)苯基脲(I-52)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-((4,4-dimethylpiper Synthesis of pyridin-1-yl)methyl)phenylurea (I-52):
Figure PCTCN2022128606-appb-000114
Figure PCTCN2022128606-appb-000114
中间体II-15的合成：将4,4-二甲基哌啶(0.10g,0.88mmol)，4-氨基苯甲醛(0.13g,1.06mmol)溶于无水二氯甲烷(10mL)，搅拌10min后加入NaBH(OAc) 3(0.080g,3.54mmol)，TEA(0.24mL,1.77mmol),室温反应12h。LC-MS监测反应完毕后，将反应液加入NaHCO 3中，二氯甲烷:甲醇(10:1)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。柱层析纯化(二氯甲烷：甲醇)得到白色固体0.092g，收率48％。 Synthesis of Intermediate II-15: Dissolve 4,4-dimethylpiperidine (0.10g, 0.88mmol), 4-aminobenzaldehyde (0.13g, 1.06mmol) in anhydrous dichloromethane (10mL), stir After 10 min, NaBH(OAc) 3 (0.080 g, 3.54 mmol), TEA (0.24 mL, 1.77 mmol) were added and reacted at room temperature for 12 h. After the completion of the reaction monitored by LC-MS, the reaction solution was added to NaHCO 3 , extracted with dichloromethane:methanol (10:1), the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Purified by column chromatography (dichloromethane:methanol) to obtain 0.092 g of a white solid with a yield of 48%.
Figure PCTCN2022128606-appb-000115
Figure PCTCN2022128606-appb-000115
中间体III-15的合成：将化合物II-15(0.092g,0.42mmol)溶解于无水四氢呋喃(10mL)，然后加入K 2CO 3(0.72g,0.52mmol)，氯甲酸苯酯(0.053mL,0.42mmol),室温反应4h。LC-MS监测反应完毕后，抽滤，滤饼用少量四氢呋喃洗涤，真空干燥，得到白色固体0.14g，收率85％。 Synthesis of Intermediate III-15: Compound II-15 (0.092g, 0.42mmol) was dissolved in anhydrous tetrahydrofuran (10mL), then K 2 CO 3 (0.72g, 0.52mmol), phenyl chloroformate (0.053mL , 0.42mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, suction filtration was performed, the filter cake was washed with a small amount of tetrahydrofuran, and vacuum-dried to obtain 0.14 g of a white solid with a yield of 85%.
Figure PCTCN2022128606-appb-000116
Figure PCTCN2022128606-appb-000116
中间体V-16的合成：将化合物III-15(0.14g,0.43mmol)，IV-1(0.055g,0.34mmol)，DMAP(0.0030g,0.020mmol)溶解于DCM(15mL)，于搅拌下加入TEA(0.014mL,0.10mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得白色固体0.10g，收率72％。Synthesis of Intermediate V-16: Compound III-15 (0.14g, 0.43mmol), IV-1 (0.055g, 0.34mmol), DMAP (0.0030g, 0.020mmol) were dissolved in DCM (15mL), under stirring Add TEA (0.014mL, 0.10mmol), heat to 50°C for 20h. After the completion of the reaction monitored by LC-MS, the heating was stopped, cooled to room temperature, concentrated under reduced pressure, purified by beating with ethyl acetate, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.10 g of a white solid with a yield of 72%. .
Figure PCTCN2022128606-appb-000117
Figure PCTCN2022128606-appb-000117
化合物I-52的合成：将化合物V-16(0.10g,0.25mmol)和VI-10(0.020g,0.25mmol)溶解于乙醇(5mL)，然后加入吡咯烷(0.0021mL,0.25mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.080g，收率67％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.63(1H,s),10.96(1H,s),8.85(1H,s),8.67(1H,s),7.98(1H,s),7.66(1H,s),7.57(1H,s),7.54(1H,d,J＝8.2Hz),7.41(1H,s),7.39(2H,s),7.19(2H,d,J＝8.2Hz),6.89(1H,dd,J 1＝8.2Hz,J 2＝1.2Hz),3.40(4H,s),2.32(4H,s),1.32(4H,t,J＝4.9Hz),0.89(6H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):170.0,152.8,141.0,140.6,139.5,138.8,138.6,137.7,131.5,129.7,128.7,128.2,120.9,120.4,118.7,118.5,118.4,112.4,111.7,100.5,62.4,55.7,49.7,38.8,28.7。 Synthesis of compound I-52: Dissolve compound V-16 (0.10g, 0.25mmol) and VI-10 (0.020g, 0.25mmol) in ethanol (5mL), then add pyrrolidine (0.0021mL, 0.25mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, and suction filtered. The filter cake was washed with a small amount of ethanol and dried in vacuo to obtain 0.080 g of an orange-yellow solid with a yield of 67%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.63(1H,s),10.96(1H,s),8.85(1H,s),8.67(1H,s),7.98(1H,s) ,7.66(1H,s),7.57(1H,s),7.54(1H,d,J=8.2Hz),7.41(1H,s),7.39(2H,s),7.19(2H,d,J=8.2 Hz),6.89(1H,dd,J 1 =8.2Hz,J 2 =1.2Hz),3.40(4H,s),2.32(4H,s),1.32(4H,t,J=4.9Hz),0.89( 6h, s). 13 C NMR (125MHz, DMSO-D 6 ) Δ (PPM): 170.0,152.8,141.0,140.6,139.5,138.6,137.7,131.5,129.7,128.2,120.4,118. 7 , 118.5, 118.4, 112.4, 111.7, 100.5, 62.4, 55.7, 49.7, 38.8, 28.7.
实施例53Example 53
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-5-氟-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲(I-53)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-5-fluoro-2-oxindol-6-yl)-3-(3-(tert-butyl)iso Synthesis of oxazol-5-yl)urea (I-53):
Figure PCTCN2022128606-appb-000118
Figure PCTCN2022128606-appb-000118
中间体V-17的合成：将化合物III-13(0.27g,1.05mmol)，IV-2(0.12g,0.70mmol)，DMAP(0.0050g,0.06mmol)溶解于DCM(10mL)，于搅拌下加入TEA(0.029mL,0.21mmol)，加热至50℃反应20h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，乙酸乙酯打浆纯化，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到灰色固体0.27g，收率75％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):10.42(1H,s),10.34(1H,s),8.70(1H,d,J＝2.5Hz),7.67(1H,d,J＝6.8Hz),7.18(1H,d,J＝10.6Hz),6.07(1H,s),3.45(2H,s),1.26(9H,s)。 Synthesis of intermediate V-17: Compound III-13 (0.27g, 1.05mmol), IV-2 (0.12g, 0.70mmol), DMAP (0.0050g, 0.06mmol) were dissolved in DCM (10mL), under stirring TEA (0.029mL, 0.21mmol) was added and heated to 50°C for 20h. After the completion of the reaction as monitored by LC-MS, stop heating, cool to room temperature, concentrate under reduced pressure, beating and purifying with ethyl acetate, filter with suction, wash the filter cake with a small amount of ethyl acetate, and dry in vacuo to obtain 0.27 g of a gray solid with a yield of 75%. . 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 10.42 (1H, s), 10.34 (1H, s), 8.70 (1H, d, J = 2.5Hz), 7.67 (1H, d, J = 6.8Hz), 7.18(1H,d,J=10.6Hz), 6.07(1H,s), 3.45(2H,s), 1.26(9H,s).
Figure PCTCN2022128606-appb-000119
Figure PCTCN2022128606-appb-000119
化合物I-53的合成：将化合物V-17(0.20g,0.64mmol)和VI-10(0.090g,0.96mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.053mL,0.64mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.16g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.65(1H,s),11.05(1H,s),10.41(1H,s),8.82(1H,s),8.01(1H,s),7.78(2H,s),7.69(1H,d,J＝10.8Hz),7.60(1H,s),6.10(1H,s),1.27(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):173.1,169.6,161.7,149.7,149.4,147.5,136.7,126.8,126.7,120.5,119.2,119.1,107.3,107.1,101.9,84.2,32.4,29.5(3C)。 Synthesis of compound I-53: Dissolve compound V-17 (0.20g, 0.64mmol) and VI-10 (0.090g, 0.96mmol) in ethanol (7mL), then add pyrrolidine (0.053mL, 0.64mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.16 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.65(1H,s),11.05(1H,s),10.41(1H,s),8.82(1H,s),8.01(1H,s) ,7.78(2H,s),7.69(1H,d,J=10.8Hz),7.60(1H,s),6.10(1H,s),1.27(9H,s). 13 C NMR(125MHz,DMSO-d 6 ) δ (ppm): 173.1, 169.6, 161.7, 149.7, 149.4, 147.5, 136.7, 126.8, 126.7, 120.5, 119.2, 119.1, 107.3, 107.1, 101.9, 84.2, 32.4, 29.5 (3C).
实例54Example 54
实施例54Example 54
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(5-氟-3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-54)的合成：(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(5-fluoro-3-((4-methyl-1H-imidazol-5-yl)methylene )-2-oxindol-6-yl)urea (I-54) synthesis:
Figure PCTCN2022128606-appb-000120
Figure PCTCN2022128606-appb-000120
化合物I-54的合成：将化合物V-17(0.060g,0.17mmol)和VI-11(0.020g,0.21mmol)溶解于乙醇(4mL)，然后加入吡咯烷(0.0010mL,0.17mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，柱层析纯化(二氯甲烷：甲醇)得到橙黄色固体0.030g，收率48％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.81(1H,s),11.04(1H,s),10.43(1H,s),8.82(1H,d,J＝2.7Hz),8.00(1H,s),7.89(1H,d,J＝11.3Hz),7.78(1H,d,J＝6.7Hz),7.74(1H,s),6.93(1H,dd,J 1＝8.3Hz,J 2＝1.6Hz),6.10(1H,s),2.46(3H,s),1.27(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):173.0,170.3,162.1,150.0,147.0,140.5,139.0,138.2,127.9,125.0,121.2,120.5,119.9,112.0,100.8,84.1,32.4,29.5(3C),13.5。 Synthesis of compound I-54: Dissolve compound V-17 (0.060g, 0.17mmol) and VI-11 (0.020g, 0.21mmol) in ethanol (4mL), then add pyrrolidine (0.0010mL, 0.17mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, and purified by column chromatography (dichloromethane: methanol) to obtain 0.030 g of an orange-yellow solid with a yield of 48%. 1 H NMR (500MHz, DMSO-d 6 ) δ (ppm): 13.81 (1H, s), 11.04 (1H, s), 10.43 (1H, s), 8.82 (1H, d, J = 2.7Hz), 8.00 (1H,s),7.89(1H,d,J＝11.3Hz),7.78(1H,d,J＝6.7Hz),7.74(1H,s),6.93(1H,dd, J ＝8.3Hz,J 2 =1.6Hz), 6.10(1H,s), 2.46(3H,s), 1.27(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):173.0,170.3,162.1,150.0 , 147.0, 140.5, 139.0, 138.2, 127.9, 125.0, 121.2, 120.5, 119.9, 112.0, 100.8, 84.1, 32.4, 29.5 (3C), 13.5.
实施例55Example 55
(Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-55)的合成：(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Synthesis of Oxindol-6-yl)urea (I-55):
Figure PCTCN2022128606-appb-000121
Figure PCTCN2022128606-appb-000121
化合物I-55的合成：将化合物V-14(0.090g,0.28mmol)和VI-11(0.030g,0.25mmol)溶解于乙醇(4mL)，然后加入吡咯烷(0.0020mL,0.28mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，柱层析纯化(二氯甲烷：甲醇)得到橙黄色固体0.060g，收率57％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.71(1H,s),11.00(1H,s),10.11(1H,s),8.97(1H,s),7.90(1H,s),7.74(1H,d,J＝8.3Hz),7.64(1H,s),7.31(1H,d,J＝1.8Hz),6.95(1H,dd,J 1＝8.3Hz,J 2＝1.9Hz),6.08(1H,s),2.43(3H,s),1.27(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):173.0,170.3,162.1,150.0,147.0,140.5,139.0,138.2,127.9,125.0,121.2,120.5,119.9,118.6,112.0,100.8,84.1,32.4,29.5(3C),13.5。 Synthesis of compound I-55: Dissolve compound V-14 (0.090g, 0.28mmol) and VI-11 (0.030g, 0.25mmol) in ethanol (4mL), then add pyrrolidine (0.0020mL, 0.28mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, and purified by column chromatography (dichloromethane: methanol) to obtain 0.060 g of an orange-yellow solid with a yield of 57%. 1 H NMR (500MHz, DMSO-d 6) δ (ppm): 13.71 (1H, s), 11.00 (1H, s), 10.11 (1H, s), 8.97 (1H, s), 7.90 (1H, s) ,7.74(1H,d,J=8.3Hz),7.64(1H,s),7.31(1H,d,J=1.8Hz),6.95(1H,dd,J 1 ＝8.3Hz,J 2 ＝1.9Hz) ,6.08(1H,s),2.43(3H,s),1.27(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):173.0,170.3,162.1,150.0,147.0,140.5, 139.0, 138.2, 127.9, 125.0, 121.2, 120.5, 119.9, 118.6, 112.0, 100.8, 84.1, 32.4, 29.5 (3C), 13.5.
实施例56Example 56
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺(I-56)的合成： (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Synthesis of piperazin-1-yl)acetamido)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide (I-56):
Figure PCTCN2022128606-appb-000122
Figure PCTCN2022128606-appb-000122
化合物XI-1的合成：将化合物X-1(1.10g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.20mL,2.20mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到黄色固体1.31g，收率86％。Synthesis of compound XI-1: Dissolve compound X-1 (1.10g, 3.00mmol) and VI-1 (0.26g, 3.24mmol) in ethanol (10mL), then add pyrrolidine (0.20mL, 2.20mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuum to obtain 1.31 g of a yellow solid with a yield of 86%.
Figure PCTCN2022128606-appb-000123
Figure PCTCN2022128606-appb-000123
中间体XII-1的合成：将化合物XI-1(1.31g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂，加入氯化铵(1.38g,25.86mmol)的饱和溶液，加热至50℃，分批加入锌粉(0.84g,12.90mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，甲醇打浆纯化，抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.66g，收率54％。Synthesis of intermediate XII-1: Dissolve compound XI-1 (1.31g, 2.58mmol) in a mixed solvent of tetrahydrofuran and methanol (20mL/10mL, v/v), add ammonium chloride (1.38g, 25.86mmol) The saturated solution was heated to 50°C, and zinc powder (0.84g, 12.90mmol) was added in batches, and the reaction was continued for 0.5h. After the reaction was completed by LC-MS monitoring, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and wash with water and saturated sodium chloride successively The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, purification by beating with methanol, suction filtration, washing the filter cake with a small amount of methanol, and drying in vacuo to obtain 0.66 g of a yellow solid with a yield of 54%.
Figure PCTCN2022128606-appb-000124
Figure PCTCN2022128606-appb-000124
中间体XIII-1的合成：将化合物XII-1(0.58g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.50mL,3.45mmol)，降温至0℃，滴加氯乙酰氯(0.46mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.50g,收率80％。Synthesis of intermediate XIII-1: Dissolve compound XII-1 (0.58g, 1.15mmol) in THF (20mL), add DIPEA (0.50mL, 3.45mmol), cool to 0°C, add dropwise chloroacetyl chloride (0.46mL , 5.75mmol), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.50 g of a yellow solid with a yield of 80%.
Figure PCTCN2022128606-appb-000125
Figure PCTCN2022128606-appb-000125
化合物I-56的合成：将化合物XIII-1(0.10g,0.18mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.17mL,1.50mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.070g,收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.39(1H,s),11.14(1H,s),10.84(1H,s),10.16(1H,s),8.95(1H,s),7.65(1H,d,J＝8.3Hz),7.48(1H,s),7.42(1H,d,J＝1.9Hz),7.08(1H,dd,J＝8.3,1.9Hz),6.61(1H,s),3.51(2H,s),3.10(2H,s),2.63-2.57(4H,m),2.4-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):181.0,170.2,169.0,166.3,165.1,158.2,139.0,137.7,131.0,126.3,124.8,122.9,121.6,121.6,119.0,114.0,112.3,101.3,93.6,61.8,55.0(2C),53.3(2C),46.2,45.7,33.0,28.8(3C),12.2,9.6。 Synthesis of compound I-56: Dissolve compound XIII-1 (0.10 g, 0.18 mmol) in DMF (5 mL), add N-methylpiperazine (0.17 mL, 1.50 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.070 g of yellow solid, yield 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.39(1H,s),11.14(1H,s),10.84(1H,s),10.16(1H,s),8.95(1H,s) ,7.65(1H,d,J=8.3Hz),7.48(1H,s),7.42(1H,d,J=1.9Hz),7.08(1H,dd,J=8.3,1.9Hz),6.61(1H, s),3.51(2H,s),3.10(2H,s),2.63-2.57(4H,m),2.4-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.30 (9H,s) .13C NMR(125MHz,DMSO-d 6 )δ(ppm):181.0,170.2,169.0,166.3,165.1,158.2,139.0,137.7,131.0,126.3,124.8,122.9,121.6,121.6, 119.0, 114.0, 112.3, 101.3, 93.6, 61.8, 55.0 (2C), 53.3 (2C), 46.2, 45.7, 33.0, 28.8 (3C), 12.2, 9.6.
实施例57Example 57
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺(I-57)的合成： (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) Synthesis of -3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide (I-57):
Figure PCTCN2022128606-appb-000126
Figure PCTCN2022128606-appb-000126
化合物I-57的合成：将化合物X-1(1.10g,3.00mmol)和VI-2(0.23g,0.88mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.050mL,0.59mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.24g，收率66％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.51(1H,s),11.15(1H,s),10.91(1H,s),10.19(1H,s),7.70(1H,d,J＝8.3Hz),7.53(1H,s),7.43(1H,d,J＝1.8Hz),7.39(1H,t,J＝5.6Hz),7.09(1H,dd,J＝8.3,1.9Hz),6.61(1H,s),3.52(2H,s),3.31-3.24(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.30(9H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):181.02,170.29,166.22,165.16,165.11,158.17,139.31,138.13,135.72,128.81,126.21,122.61,121.32,120.70,119.43,115.74,112.35,101.34,93.56,52.14,46.97(2C),37.44,32.99,28.81(3C),22.54,13.77,12.37(2C),11.03。 Synthesis of compound I-57: Dissolve compound X-1 (1.10g, 3.00mmol) and VI-2 (0.23g, 0.88mmol) in ethanol (7mL), then add pyrrolidine (0.050mL, 0.59mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.24 g of an orange-yellow solid with a yield of 66%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.51(1H,s),11.15(1H,s),10.91(1H,s),10.19(1H,s),7.70(1H,d, J=8.3Hz),7.53(1H,s),7.43(1H,d,J=1.8Hz),7.39(1H,t,J=5.6Hz),7.09(1H,dd,J=8.3,1.9Hz) ,6.61(1H,s),3.52(2H,s),3.31-3.24(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.30(9H ,s),0.98(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):181.02,170.29,166.22,165.16,165.11,158.17,139.31,138.13,135.72, 128.81, 126.21, 122.61, 121.32, 120.70, 119.43, 115.74, 112.35, 101.34, 93.56, 52.14, 46.97(2C), 37.44, 32.99, 28.81(3C), 22.54, 13.77, 12 .37(2C), 11.03.
实施例58Example 58
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺(I-58)的合成：(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((4-((2-(diethylamino)ethyl)carbamoyl)-3 , Synthesis of 5-dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide (I-58):
Figure PCTCN2022128606-appb-000127
Figure PCTCN2022128606-appb-000127
中间体VIII-2的合成：将化合物II-1(1.00g,7.13mmol)溶解于乙腈(20mL)，然后加入化合物VII-2(1.03g,7.13mmol)，TCFH(2.40g,8.65mmol)，NMI(2.00ml,25.00mmol)，室温反应4h。LC-MS监测反应完毕后，将反应液加入水(15mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，得到白色固体1.04g，收率55％。Synthesis of intermediate VIII-2: Compound II-1 (1.00g, 7.13mmol) was dissolved in acetonitrile (20mL), then compound VII-2 (1.03g, 7.13mmol), TCFH (2.40g, 8.65mmol) were added, NMI (2.00ml, 25.00mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration and concentration under reduced pressure afforded 1.04 g of white solid with a yield of 55%.
Figure PCTCN2022128606-appb-000128
Figure PCTCN2022128606-appb-000128
中间体IX-2的合成：将化合物VIII-2(0.94g,3.54mmol)溶解于CH 3OH/H 2O(20mL)，然后加入LiOH·H 2O(0.30g,7.08mmol)，室温反应2h。LC-MS监测反应完毕后，用1N的HCl将反应液调至PH＝1，待固体析出，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到橙黄色固体0.62g，收率69％。 Synthesis of Intermediate IX-2: Compound VIII-2 (0.94g, 3.54mmol) was dissolved in CH 3 OH/H 2 O (20mL), then LiOH·H 2 O (0.30g, 7.08mmol) was added and reacted at room temperature 2h. After the completion of the reaction monitored by LC-MS, the reaction solution was adjusted to PH = 1 with 1N HCl, and the solid was precipitated, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.62 g of an orange-yellow solid with a yield of 69 %.
Figure PCTCN2022128606-appb-000129
Figure PCTCN2022128606-appb-000129
中间体X-2的合成：将化合物IX-2(0.76g,3.03mmol)溶解于DMF(15mL)，于搅拌下加入IV-1(0.38g,2.52mmol)，TCFH(0.85g,3.03mmol)，DIPEA(1.25mL,7.56mmol)，室温反应2h。LC-MS监测反应完毕后，向反应液中加入水(10mL)，待固体析出后，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得黄色固体0.78g，收率67％。Synthesis of Intermediate X-2: Compound IX-2 (0.76g, 3.03mmol) was dissolved in DMF (15mL), and IV-1 (0.38g, 2.52mmol), TCFH (0.85g, 3.03mmol) were added under stirring , DIPEA (1.25mL, 7.56mmol), react at room temperature for 2h. After the reaction was monitored by LC-MS, water (10 mL) was added to the reaction solution. After the solid precipitated, it was filtered with suction, and the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.78 g of a yellow solid, with a yield of 67%.
Figure PCTCN2022128606-appb-000130
Figure PCTCN2022128606-appb-000130
化合物I-58的合成：将化合物X-2(0.40g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.13mL,1.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.48g，收率72％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.51(1H,s),11.12(1H,s),10.93(1H,s),9.95(1H,s),7.70(1H,d,J＝8.3Hz),7.54(1H,s),7.43(1H,d,J＝1.9Hz),7.40(1H,t,J＝5.6Hz),7.16(1H,dd,J＝8.3,1.9Hz),6.62(1H,s),3.28(2H,q,J＝6.5Hz),2.53(6H,d,J＝8.2Hz),2.44(3H,s),2.40(3H,s),1.52-1.46(4H,m),1.30(9H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.3,169.1,168.1,165.1,139.1,138.1,135.7,128.8,126.2,122.7,121.4,120.7,119.1,115.8,113.7,102.7,94.3,52.1,47.0(2C),37.4,33.0,31.9,28.8(4C),16.4(2C),13.8,12.4(2C),11.0。 Synthesis of compound I-58: Dissolve compound X-2 (0.40g, 1.05mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (10mL), then add pyrrolidine (0.13mL, 1.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.48 g of an orange-yellow solid with a yield of 72%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.51(1H,s),11.12(1H,s),10.93(1H,s),9.95(1H,s),7.70(1H,d, J=8.3Hz),7.54(1H,s),7.43(1H,d,J=1.9Hz),7.40(1H,t,J=5.6Hz),7.16(1H,dd,J=8.3,1.9Hz) ,6.62(1H,s),3.28(2H,q,J=6.5Hz),2.53(6H,d,J=8.2Hz),2.44(3H,s),2.40(3H,s),1.52-1.46( 4H, m), 1.30 (9H, s), 0.98 (6H, t, J=7.1Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.6, 170.3, 169.1, 168.1, 165.1, 139.1, 138.1, 135.7, 128.8, 126.2, 122.7, 121.4, 120.7, 119.1, 115.8, 113.7, 102.7, 94.3, 52.1, 47.0(2C), 37.4, 33.0, 31.9, 28.8(4C), 16.4(2 C), 13.8 , 12.4(2C), 11.0.
实施例59Example 59
(Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((3,5-二甲基-4-(2-(4-甲基哌啶-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺(I-59)的合成：(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((3,5-dimethyl-4-(2-(4-methylpiperidine Synthesis of -1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide (I-59):
Figure PCTCN2022128606-appb-000131
Figure PCTCN2022128606-appb-000131
化合物XI-2的合成：将化合物X-2(1.15g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.20mL,2.20mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到黄色固体1.30g，收率86％。Synthesis of compound XI-2: Dissolve compound X-2 (1.15g, 3.00mmol) and VI-1 (0.26g, 3.24mmol) in ethanol (10mL), then add pyrrolidine (0.20mL, 2.20mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 1.30 g of a yellow solid with a yield of 86%.
Figure PCTCN2022128606-appb-000132
Figure PCTCN2022128606-appb-000132
中间体XII-2的合成：将化合物XI-2(1.37g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂，加入氯化铵(1.38g,25.86mmol)的饱和溶液，加热至50℃，分批加入锌粉(0.84g,12.90mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，浓缩滤液，甲醇打浆纯化，抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.71g，收率55％。Synthesis of intermediate XII-2: Dissolve compound XI-2 (1.37g, 2.58mmol) in a mixed solvent of tetrahydrofuran and methanol (20mL/10mL, v/v), add ammonium chloride (1.38g, 25.86mmol) The saturated solution was heated to 50°C, and zinc powder (0.84g, 12.90mmol) was added in batches, and the reaction was continued for 0.5h. After the reaction was completed by LC-MS monitoring, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and wash with water and saturated sodium chloride successively The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate, purification by beating with methanol, suction filtration, washing of the filter cake with a small amount of methanol, and vacuum drying gave 0.71 g of a yellow solid with a yield of 55%.
Figure PCTCN2022128606-appb-000133
Figure PCTCN2022128606-appb-000133
中间体XIII-2的合成：化合物XII-2(0.58g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.50mL,3.45mmol)，降温至0℃，滴加氯乙酰氯(0.46mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.47g,收率79％。Synthesis of Intermediate XIII-2: Dissolve compound XII-2 (0.58g, 1.15mmol) in THF (20mL), add DIPEA (0.50mL, 3.45mmol), cool to 0°C, add dropwise chloroacetyl chloride (0.46mL, 5.75mmol), the addition was completed, and reacted at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.47 g of a yellow solid with a yield of 79%.
Figure PCTCN2022128606-appb-000134
Figure PCTCN2022128606-appb-000134
化合物I-59的合成：将化合物XIII-2(0.10g,0.18mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.17mL,1.5mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.07g,收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.40(1H,s),11.13(1H,s),10.85(1H,s),9.90(1H,s),8.95(1H,s),7.65(1H,d,J＝8.3Hz),7.49(1H,s),7.42(1H,d,J＝1.9Hz),7.15(1H,dd,J＝8.3,1.9Hz),6.62(1H,s),3.10(2H,s),2.62-2.52(4H,m),2.4-2.35(4H,m),2.19(6H,d,J＝2.4Hz),2.14(3H,s),1.53-1.43(4H,m),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,170.2,169.1,169.0,168.1,158.5,138.8,137.6,131.0,126.4,124.8,123.0,121.8,121.6,118.6,114.1,113.6,102.7,94.3,61.8,55.0(2C),53.2(2C),46.2,33.0,31.8,28.8(4C),16.4,12.2,9.6。 Synthesis of compound I-59: Dissolve compound XIII-2 (0.10 g, 0.18 mmol) in DMF (5 mL), add N-methylpiperazine (0.17 mL, 1.5 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.07 g of yellow solid, yield 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.40(1H,s),11.13(1H,s),10.85(1H,s),9.90(1H,s),8.95(1H,s) ,7.65(1H,d,J=8.3Hz),7.49(1H,s),7.42(1H,d,J=1.9Hz),7.15(1H,dd,J=8.3,1.9Hz),6.62(1H, s), 3.10(2H, s), 2.62-2.52(4H, m), 2.4-2.35(4H, m), 2.19(6H, d, J=2.4Hz), 2.14(3H, s), 1.53-1.43 (4H,m),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,170.2,169.1,169.0,168.1,158.5,138.8,137.6,131.0,126.4,124.8 ,123.0,121.8,121.6,118.6,114.1,113.6,102.7,94.3,61.8,55.0(2C),53.2(2C),46.2,33.0,31.8,28.8(4C),16.4,12.2,9.6.
实施例60Example 60
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺(I-60)的合成： (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Piperazin-1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide (I-60) Synthesis:
Figure PCTCN2022128606-appb-000135
Figure PCTCN2022128606-appb-000135
中间体VIII-3的合成：将化合物II-1(1.00g,7.13mmol)溶解于乙腈(20mL)，然后加入化合物VII-3(1.04g,7.13mmol)，TCFH(2.40g,8.65mmol)，NMI(2.00mL,25.00mmol)，室温反应4h。LC-MS监测反应完毕后，将反应液加入水(15mL)中，乙酸乙酯(30mL×2)萃取，合并有机层，一次用水和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，得到白色固体1.05g，收率55％。Synthesis of intermediate VIII-3: Compound II-1 (1.00g, 7.13mmol) was dissolved in acetonitrile (20mL), then compound VII-3 (1.04g, 7.13mmol), TCFH (2.40g, 8.65mmol) were added, NMI (2.00mL, 25.00mmol), react at room temperature for 4h. After the completion of the reaction was monitored by LC-MS, the reaction solution was added to water (15 mL), extracted with ethyl acetate (30 mL×2), and the organic layers were combined, washed once with water and sodium chloride solution, and dried over anhydrous sodium sulfate. Suction filtration and concentration under reduced pressure gave 1.05 g of white solid with a yield of 55%.
Figure PCTCN2022128606-appb-000136
Figure PCTCN2022128606-appb-000136
中间体IX-3的合成：将化合物VIII-3(0.95g,3.54mmol)溶解于CH 3OH/H 2O(20mL)，然后加入LiOH·H 2O(0.30g,7.08mmol)，室温反应2h。LC-MS监测反应完毕后，用1N的HCl将反应液调至PH＝1，待固体析出，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得到橙黄色固体0.63g，收率70％。 Synthesis of Intermediate IX-3: Compound VIII-3 (0.95g, 3.54mmol) was dissolved in CH 3 OH/H 2 O (20mL), then LiOH·H 2 O (0.30g, 7.08mmol) was added and reacted at room temperature 2h. After the completion of the reaction monitored by LC-MS, the reaction solution was adjusted to PH = 1 with 1N HCl, and the solid was precipitated, filtered with suction, the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.63 g of an orange-yellow solid with a yield of 70 %.
Figure PCTCN2022128606-appb-000137
Figure PCTCN2022128606-appb-000137
中间体X-3的合成：将化合物IX-3(0.77g,3.03mmol)溶解于DMF(15mL)，于搅拌下加入IV-1(0.38g,2.52mmol)，TCFH(0.85g,3.03mmol)，DIPEA(1.25mL,7.56mmol)，室温反应2h。LC-MS监测反应完毕后，向反应液中加入水(10mL)，待固体析出后，抽滤，滤饼用少量乙酸乙酯洗涤，真空干燥，得黄色固体0.79g，收率67％。Synthesis of Intermediate X-3: Compound IX-3 (0.77g, 3.03mmol) was dissolved in DMF (15mL), and IV-1 (0.38g, 2.52mmol), TCFH (0.85g, 3.03mmol) were added under stirring , DIPEA (1.25mL, 7.56mmol), react at room temperature for 2h. After the reaction was monitored by LC-MS, water (10 mL) was added to the reaction liquid. After the solid precipitated, it was filtered with suction, and the filter cake was washed with a small amount of ethyl acetate, and dried in vacuo to obtain 0.79 g of a yellow solid, with a yield of 67%.
Figure PCTCN2022128606-appb-000138
Figure PCTCN2022128606-appb-000138
化合物XI-3的合成：将化合物X-3(1.16g,3.00mmol)和VI-1(0.26g,3.24mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.20mL,2.20mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到黄色固体1.38g，收率86％。Synthesis of compound XI-3: Dissolve compound X-3 (1.16g, 3.00mmol) and VI-1 (0.26g, 3.24mmol) in ethanol (10mL), then add pyrrolidine (0.20mL, 2.20mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 1.38 g of a yellow solid with a yield of 86%.
Figure PCTCN2022128606-appb-000139
Figure PCTCN2022128606-appb-000139
中间体XII-3的合成：将化合物XI-3(1.38g,2.58mmol)溶于四氢呋喃和甲醇(20mL/10mL,v/v)的混合溶剂，加入氯化铵(1.38g,25.86mmol)的饱和溶液，加热至50℃，分批加入锌粉(0.84g,12.90mmol)，继续反应0.5h。LC-MS监测反应完毕后，停止加热，冷却至室温，减压浓缩，残留物用乙酸乙酯(100mL)和饱和碳酸钠溶液(100mL)溶解，分出有机层，依次用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，甲醇打浆纯化,抽滤，滤饼用少量甲醇洗涤，真空干燥，得到黄色固体0.72g，收率55％。Synthesis of intermediate XII-3: Dissolve compound XI-3 (1.38g, 2.58mmol) in a mixed solvent of tetrahydrofuran and methanol (20mL/10mL, v/v), add ammonium chloride (1.38g, 25.86mmol) The saturated solution was heated to 50°C, and zinc powder (0.84g, 12.90mmol) was added in batches, and the reaction was continued for 0.5h. After the reaction was completed by LC-MS monitoring, stop heating, cool to room temperature, concentrate under reduced pressure, dissolve the residue with ethyl acetate (100mL) and saturated sodium carbonate solution (100mL), separate the organic layer, and wash with water and saturated sodium chloride successively The solution was washed and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, purification by beating with methanol, suction filtration, washing the filter cake with a small amount of methanol, and drying in vacuo to obtain 0.72 g of a yellow solid with a yield of 55%.
Figure PCTCN2022128606-appb-000140
Figure PCTCN2022128606-appb-000140
中间体XIII-3的合成：化合物XII-3(0.58g,1.15mmol)溶于THF(20mL)，加入DIPEA(0.5mL,3.45mmol)，降温至0℃，滴加3-氯丙酰氯(0.1mL,5.75mmol)，加毕，室温反应0.5h。TLC监测反应完毕后，减压浓缩，残留物加入乙酸乙酯(10mL)打浆。抽滤，滤饼用乙酸乙酯(1mL)洗涤，真空干燥得到黄色固体0.47g,收率79％。Synthesis of Intermediate XIII-3: Compound XII-3 (0.58g, 1.15mmol) was dissolved in THF (20mL), DIPEA (0.5mL, 3.45mmol) was added, cooled to 0°C, and 3-chloropropionyl chloride (0.1 mL, 5.75mmol), after addition, react at room temperature for 0.5h. After the reaction was monitored by TLC, it was concentrated under reduced pressure, and the residue was slurried by adding ethyl acetate (10 mL). After suction filtration, the filter cake was washed with ethyl acetate (1 mL), and dried in vacuo to obtain 0.47 g of a yellow solid with a yield of 79%.
Figure PCTCN2022128606-appb-000141
Figure PCTCN2022128606-appb-000141
化合物I-60的合成：将化合物XIII-3(0.10g,0.18mmol)溶于DMF(5mL)，加入N-甲基哌嗪(0.17mL,1.5mmol)，于50℃反应12h。TLC监测反应完毕后，将反应液倒入水中，乙酸乙酯溶液(30mL×2)萃取，合并有机层，依次用水和饱和的氯化钠溶液洗涤，无水硫酸钠干燥。抽滤，减压浓缩，残留物加入乙酸乙酯(5mL)打浆纯化，抽滤，真空干燥得到黄色固体0.070g,收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.39(1H,s),10.87(1H,s),10.69(1H,s),9.39(1H,s),8.95(1H,s),7.65(1H,d,J＝8.3Hz),7.49(1H,s),7.44(1H,d,J＝1.9Hz),7.21(1H,dd,J＝8.4,1.9Hz),6.63(1H,s),3.10(2H,s),2.63-2.57(4H,m),2.47-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.53(6H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,172.7,171.8,170.3,169.0,158.8,138.8,137.9,131.0,126.3,124.8,122.9,121.6,121.56,118.6,114.2,113.5,102.5,94.2,61.8,55.0(2C),53.3(2C),46.2,32.9,28.8(4C),23.5,21.2,12.2,9.6。 Synthesis of compound I-60: Dissolve compound XIII-3 (0.10 g, 0.18 mmol) in DMF (5 mL), add N-methylpiperazine (0.17 mL, 1.5 mmol), and react at 50° C. for 12 h. After the reaction was monitored by TLC, the reaction solution was poured into water, extracted with ethyl acetate solution (30 mL×2), the organic layers were combined, washed with water and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. Suction filtration, concentration under reduced pressure, adding ethyl acetate (5 mL) to the residue for slurry purification, suction filtration, vacuum drying to obtain 0.070 g of yellow solid, yield 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.39(1H,s),10.87(1H,s),10.69(1H,s),9.39(1H,s),8.95(1H,s) ,7.65(1H,d,J=8.3Hz),7.49(1H,s),7.44(1H,d,J=1.9Hz),7.21(1H,dd,J=8.4,1.9Hz),6.63(1H, s),3.10(2H,s),2.63-2.57(4H,m),2.47-2.34(4H,m),2.18(6H,s),2.14(3H,s),1.53(6H,s),1.30 (9H,s) .13C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,172.7,171.8,170.3,169.0,158.8,138.8,137.9,131.0,126.3,124.8,122.9,121.6,121.56, 118.6, 114.2, 113.5, 102.5, 94.2, 61.8, 55.0 (2C), 53.3 (2C), 46.2, 32.9, 28.8 (4C), 23.5, 21.2, 12.2, 9.6.
实施例61Example 61
(Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺(I-61)的合成： (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) Synthesis of -3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide (I-61) :
Figure PCTCN2022128606-appb-000142
Figure PCTCN2022128606-appb-000142
化合物I-61的合成：将化合物X-3(0.40g,1.05mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.13mL,1.58mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.48g，收率72％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.50(1H,s),10.93(1H,s),10.68(1H,s),9.41(1H,s),7.70(1H,d,J＝8.4Hz),7.53(1H,s),7.45(1H,d,J＝1.8Hz),7.38(1H,t,J＝5.6Hz),7.22(1H,dd,J＝8.4,1.9Hz),6.63(1H,s),3.31-3.25(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.54(6H,s),1.30(9H,s),0.98(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.6,172.7,171.8,170.4,165.1,158.8,139.1,138.4,135.7,128.8,126.2,122.6,121.3,120.7,119.1,115.9,113.6,102.5,94.2,52.7,52.2,47.0(2C),37.4,32.9,28.8(4C),23.5(2C),13.8,12.4(2C),11.0。 Synthesis of compound I-61: Dissolve compound X-3 (0.40g, 1.05mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (10mL), then add pyrrolidine (0.13mL, 1.58mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.48 g of an orange-yellow solid with a yield of 72%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):13.50(1H,s),10.93(1H,s),10.68(1H,s),9.41(1H,s),7.70(1H,d, J=8.4Hz),7.53(1H,s),7.45(1H,d,J=1.8Hz),7.38(1H,t,J=5.6Hz),7.22(1H,dd,J=8.4,1.9Hz) ,6.63(1H,s),3.31-3.25(2H,m),2.57-2.51(6H,m),2.44(3H,s),2.40(3H,s),1.54(6H,s),1.30(9H ,s),0.98(6H,t,J=7.1Hz). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.6,172.7,171.8,170.4,165.1,158.8,139.1,138.4,135.7, 128.8, 126.2, 122.6, 121.3, 120.7, 119.1, 115.9, 113.6, 102.5, 94.2, 52.7, 52.2, 47.0(2C), 37.4, 32.9, 28.8(4C), 23.5(2C), 13.8, 12.4(2C), 11.0.
实施例62Example 62
(Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸乙酯(I-62)的合成：(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, Synthesis of ethyl 4-dimethyl-1H-pyrrole-3-carboxylate (I-62):
Figure PCTCN2022128606-appb-000143
Figure PCTCN2022128606-appb-000143
化合物I-62的合成：将化合物V-1(0.80g,2.55mmol)和VI-12(0.50g,2.55mmol)溶解于乙醇(10mL)，然后加入吡咯烷(0.27mL,3.31mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体1.10g，收率85％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.75(1H,s),10.97(1H,s),9.50(1H,s),8.91(1H,s),7.71(1H,d,J＝8.2Hz),7.55(1H,s),7.30(1H,d,J＝1.8Hz),6.91(1H,dd,J＝8.2,2.0Hz),6.51(1H,s),4.22(2H,q,J＝7.1Hz),2.54(3H,s),2.48(3H,s),1.33-1.28(12H,m). 13C NMR(125MHz,DMSO-d 6) δ(ppm):180.7,170.4,164.9,158.8,151.6,140.0,139.8,138.6,131.3,126.6,122.0,120.2,120.0,117.3,113.6,111.9,100.7,92.9,59.5,33.0,28.8(3C),15.0,14.8,11.8。 Synthesis of compound I-62: Dissolve compound V-1 (0.80g, 2.55mmol) and VI-12 (0.50g, 2.55mmol) in ethanol (10mL), then add pyrrolidine (0.27mL, 3.31mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 1.10 g of an orange-yellow solid with a yield of 85%. 1 H NMR (500MHz,DMSO-d 6 )δ(ppm):13.75(1H,s),10.97(1H,s),9.50(1H,s),8.91(1H,s),7.71(1H,d, J=8.2Hz),7.55(1H,s),7.30(1H,d,J=1.8Hz),6.91(1H,dd,J=8.2,2.0Hz),6.51(1H,s),4.22(2H, q,J=7.1Hz),2.54(3H,s),2.48(3H,s),1.33-1.28(12H,m). 13 C NMR(125MHz,DMSO-d 6 ) δ(ppm):180.7,170.4 ,164.9,158.8,151.6,140.0,139.8,138.6,131.3,126.6,122.0,120.2,120.0,117.3,113.6,111.9,100.7,92.9,59.5,33.0,28.8(3C),15.0,1 4.8, 11.8.
实施例63Example 63
(Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-63)的合成：(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 -Synthesis of urea (I-63):
Figure PCTCN2022128606-appb-000144
Figure PCTCN2022128606-appb-000144
化合物I-63的合成：将化合物V-1(0.20g,0.64mmol)和VI-10(0.090g,0.96mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.053mL,0.64mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.16g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.62(1H,s),11.00(1H,s),9.51(1H,s),8.95(1H,s),7.99(1H,s),7.69(1H,s),7.58(1H,s),7.57-7.55(1H,m),7.35(1H,d,J＝1.9Hz),6.90(1H,dd,J＝8.2,1.9Hz),6.52(1H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,169.9,158.8,151.6,141.0,139.7,139.6,138.0,128.7,121.4,120.6,120.4,119.2,112.0,100.8,92.9,33.0,28.8(3C)。 Synthesis of compound I-63: Dissolve compound V-1 (0.20g, 0.64mmol) and VI-10 (0.090g, 0.96mmol) in ethanol (7mL), then add pyrrolidine (0.053mL, 0.64mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.16 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.62(1H,s),11.00(1H,s),9.51(1H,s),8.95(1H,s),7.99(1H,s) ,7.69(1H,s),7.58(1H,s),7.57-7.55(1H,m),7.35(1H,d,J=1.9Hz),6.90(1H,dd,J=8.2,1.9Hz), 6.52(1H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,169.9,158.8,151.6,141.0,139.7,139.6,138.0,128.7,121.4, 120.6, 120.4, 119.2, 112.0, 100.8, 92.9, 33.0, 28.8 (3C).
实施例64Example 64
(Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲(I-64)的合成：(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Synthesis of Oxindol-6-yl)urea (I-64):
Figure PCTCN2022128606-appb-000145
Figure PCTCN2022128606-appb-000145
化合物I-64的合成：将化合物V-1(0.090g,0.28mmol)和VI-11(0.030g,0.25mmol)溶解于乙醇(4mL)，然后加入吡咯烷(0.0020mL,0.28mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，柱层析纯化(二氯甲烷：甲醇)得到橙黄色固体0.050g，收率45％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.71(1H,s),10.97(1H,s),9.51(1H,s),8.92(1H,s),7.90(1H,s),7.73(1H,d,J＝8.2Hz),7.62(1H,s),7.32(1H,d,J＝2.0Hz),6.92(1H,dd,J＝8.2,2.0Hz),6.52(1H,s),2.43(3H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.3,158.8,151.6,147.0,140.5,139.2,138.2,125.0,121.1,120.5,119.7,118.6,111.9,100.7,92.9,33.0,28.8(3C),13.5。 Synthesis of compound I-64: Dissolve compound V-1 (0.090g, 0.28mmol) and VI-11 (0.030g, 0.25mmol) in ethanol (4mL), then add pyrrolidine (0.0020mL, 0.28mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, and purified by column chromatography (dichloromethane: methanol) to obtain 0.050 g of an orange-yellow solid with a yield of 45%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.71(1H,s),10.97(1H,s),9.51(1H,s),8.92(1H,s),7.90(1H,s) ,7.73(1H,d,J=8.2Hz),7.62(1H,s),7.32(1H,d,J=2.0Hz),6.92(1H,dd,J=8.2,2.0Hz),6.52(1H, s),2.43(3H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,170.3,158.8,151.6,147.0,140.5,139.2,138.2,125.0 , 121.1, 120.5, 119.7, 118.6, 111.9, 100.7, 92.9, 33.0, 28.8 (3C), 13.5.
实施例65Example 65
(Z)-1-(3-((1H-咪唑-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲(I-65)的合成：(Z)-1-(3-((1H-imidazol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 -Synthesis of urea (I-65):
Figure PCTCN2022128606-appb-000146
Figure PCTCN2022128606-appb-000146
化合物I-65的合成：将化合物V-1(0.090g,0.28mmol)和VI-13(0.023g,0.25mmol)溶解于乙醇(4mL)，然后加入吡咯烷(0.0020mL,0.28mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，柱层析纯化(二氯甲烷：甲醇)得到橙黄色固体0.050g，收率45％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.95(1H,s),11.14(1H,s),9.52(1H,s),9.00(1H,s),7.73(1H,d,J＝8.3Hz),7.65(1H,s),7.52(1H,d,J＝2.1Hz),7.39(1H,d,J＝1.9Hz),7.31(1H,t,J＝1.2Hz),6.89(1H,dd,J＝8.3,1.9Hz),6.52(1H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,169.9,158.7,151.6,144.3,141.3,140.4,132.7,124.1,122.9,121.3,120.7,118.7,112.1,100.8,92.9,33.0,28.8(3C)。 Synthesis of compound I-65: Dissolve compound V-1 (0.090g, 0.28mmol) and VI-13 (0.023g, 0.25mmol) in ethanol (4mL), then add pyrrolidine (0.0020mL, 0.28mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, and purified by column chromatography (dichloromethane: methanol) to obtain 0.050 g of an orange-yellow solid with a yield of 45%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.95(1H,s),11.14(1H,s),9.52(1H,s),9.00(1H,s),7.73(1H,d, J=8.3Hz),7.65(1H,s),7.52(1H,d,J=2.1Hz),7.39(1H,d,J=1.9Hz),7.31(1H,t,J=1.2Hz),6.89 (1H,dd,J=8.3,1.9Hz),6.52(1H,s),1.30(9H,s). 13 C NMR(125MHz,DMSO-d 6 )δ(ppm):180.7,169.9,158.7,151.6 , 144.3, 141.3, 140.4, 132.7, 124.1, 122.9, 121.3, 120.7, 118.7, 112.1, 100.8, 92.9, 33.0, 28.8 (3C).
实施例66Example 66
(Z)-N 1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺(I-66)的合成： (Z)-N 1 -(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole Synthesis of -3-yl) malonamide (I-66):
Figure PCTCN2022128606-appb-000147
Figure PCTCN2022128606-appb-000147
化合物I-66的合成：将化合物X-1(0.080g,0.23mmol)和VI-9(0.026g,0.27mmol)溶解于乙醇(6mL)，然后加入吡咯烷(0.020mL,0.22mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到黄色固体0.090g，收率86％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.24(1H,s),11.15(1H，s),10.91(1H,s),10.21(1H,s),7.62(1H,s),7.56(1H,d,J＝8.3Hz),7.44(1H,d,J＝1.8Hz),7.33(1H,td,J＝2.7,1.4Hz),7.08(dd,J＝8.3,1.9Hz,1H),6.79(1H,dt,J＝3.7,1.8Hz),6.61(1H,s),6.34(1H,dt,J＝3.7,2.3Hz),3.52(2H,s),1.30(9H,s). 13C NMR(125MHz,DMSO-d 6)δ(ppm):181.0,170.0,166.2,165.2,158.2,139.9,138.5,130.1,125.7,125.5,120.9,120.2,119.4,117.4,112.5,111.7,101.4,93.6,45.8,33.0,28.8(3C)。 Synthesis of compound I-66: Dissolve compound X-1 (0.080g, 0.23mmol) and VI-9 (0.026g, 0.27mmol) in ethanol (6mL), then add pyrrolidine (0.020mL, 0.22mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuum to obtain 0.090 g of a yellow solid with a yield of 86%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.24(1H,s),11.15(1H,s),10.91(1H,s),10.21(1H,s),7.62(1H,s) ,7.56(1H,d,J=8.3Hz),7.44(1H,d,J=1.8Hz),7.33(1H,td,J=2.7,1.4Hz),7.08(dd,J=8.3,1.9Hz, 1H), 6.79(1H, dt, J=3.7, 1.8Hz), 6.61(1H, s), 6.34(1H, dt, J=3.7, 2.3Hz), 3.52(2H, s), 1.30(9H, s ). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 181.0, 170.0, 166.2, 165.2, 158.2, 139.9, 138.5, 130.1, 125.7, 125.5, 120.9, 120.2, 119.4, 117.4, 112.5, 111 .7, 101.4, 93.6, 45.8, 33.0, 28.8 (3C).
实施例67Example 67
(Z)-5-((6-(3-(3-(叔丁基)异恶唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺(I-67)的合成：(Z)-5-((6-(3-(3-(tert-butyl)isoxazol-5-yl)ureido)-2-oxindole-3-ylidene)methyl)-N- Synthesis of (2-(diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (I-67):
Figure PCTCN2022128606-appb-000148
Figure PCTCN2022128606-appb-000148
化合物I-67的合成：将化合物V-14(0.20g,0.64mmol)和VI-2(0.42g,1.58mmol)溶解于乙醇(7mL)，然后加入吡咯烷(0.053mL,0.64mmol)，加热至50℃反应2h。LC-MS监测反应完毕后，停止加热，冷却至室温，抽滤，滤饼用少量乙醇洗涤，真空干燥，得到橙黄色固体0.16g，收率65％。 1H NMR(500MHz,DMSO-d 6)δ(ppm):13.49(1H,s),10.91(1H,s),10.06(1H,s),8.91(1H,s),7.69(1H,d,J＝8.3Hz),7.52(1H,s),7.39(1H,t,J＝5.3Hz),7.28(1H,d,J＝1.6Hz),6.94(1H,dd,J 1＝8.2Hz,J 2＝1.7Hz),6.07(1H,s),3.28(2H,q,J＝6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27(9H,s),0.99(6H,t,J＝7.1Hz). 13C NMR(125MHz,DMSO-d 6)δ(ppm):180.7,170.4,165.2,158.8,151.6,139.6,138.3,135.6,128.6,126.2,122.3,120.5(2C),119.6,115.9,111.8,100.7,92.9,52.0,47.0(2C),37.4,33.0,28.8(3C),13.8,12.1(2C),11.1。 Synthesis of compound I-67: Dissolve compound V-14 (0.20g, 0.64mmol) and VI-2 (0.42g, 1.58mmol) in ethanol (7mL), then add pyrrolidine (0.053mL, 0.64mmol), heat Reaction at 50°C for 2h. After the completion of the reaction was monitored by LC-MS, the heating was stopped, cooled to room temperature, filtered with suction, the filter cake was washed with a small amount of ethanol, and dried in vacuo to obtain 0.16 g of an orange-yellow solid with a yield of 65%. 1 H NMR(500MHz,DMSO-d 6 )δ(ppm):13.49(1H,s),10.91(1H,s),10.06(1H,s),8.91(1H,s),7.69(1H,d, J=8.3Hz),7.52(1H,s),7.39(1H,t,J=5.3Hz),7.28(1H,d,J=1.6Hz),6.94(1H,dd,J 1 =8.2Hz,J 2 =1.7Hz),6.07(1H,s),3.28(2H,q,J=6.4Hz),2.52-2.56(6H,m),2.44(3H,s),2.40(3H,s),1.27( 9H, s), 0.99 (6H, t, J=7.1Hz). 13 C NMR (125MHz, DMSO-d 6 ) δ (ppm): 180.7, 170.4, 165.2, 158.8, 151.6, 139.6, 138.3, 135.6, 128.6 ,126.2,122.3,120.5(2C),119.6,115.9,111.8,100.7,92.9,52.0,47.0(2C),37.4,33.0,28.8(3C),13.8,12.1(2C),11.1.
实施例68Example 68
化合物对CSF-1R的抑制活性：Inhibitory activity of compounds against CSF-1R:
实验方法：采用Mobility Shift Assay的方法测定化合物对CSF-1R激酶的体外抑制活性：将化合物从1μM起始浓度，3倍稀释成10个浓度，然后用Echo550转移250nL至384孔板中，阴性对照孔和阳性对照孔中分别加入250nL的100％DMSO。在化合物孔和阳性对照孔中分别加入10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加入10μL的激酶buffer。1000rpm离心30秒，振荡混匀后室温孵育10分钟，加入15μL的25/15倍终浓度的ATP和激酶底物的混合溶液。将384孔板于1000rpm离心30秒，振荡混匀后室温孵育30分钟，加入30μL终止检测液，停止激酶反应，1000rpm离心30秒，振荡混匀，用Caliper EZ ReaderⅡ读取转化率。采用Graphpad Prism 5软件分析处理数据，求得IC 50值。结果显示：大部分化合物对CSF-1R具有较好的抑制活性，优于PLX3397(表2)。 Experimental method: The Mobility Shift Assay method was used to determine the in vitro inhibitory activity of the compound on CSF-1R kinase: the compound was diluted 3 times to 10 concentrations from the initial concentration of 1 μM, and then transferred 250 nL to a 384-well plate with Echo550, negative control 250 nL of 100% DMSO was added to the wells and the positive control wells respectively. Add 10 μL of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 μL of kinase buffer to negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 10 minutes, add 15 μL of a mixed solution of ATP and kinase substrate at 25/15 times the final concentration. Centrifuge the 384-well plate at 1000rpm for 30 seconds, shake and mix well, incubate at room temperature for 30 minutes, add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix well, and read the conversion rate with Caliper EZ Reader II. Graphpad Prism 5 software was used to analyze and process the data, and the IC50 value was obtained. The results showed that most of the compounds had better inhibitory activity on CSF-1R, better than PLX3397 (Table 2).
表2.实施例化合物对CSF-1R的抑制活性Table 2. Inhibitory activity of example compounds on CSF-1R
Figure PCTCN2022128606-appb-000149
Figure PCTCN2022128606-appb-000149
Figure PCTCN2022128606-appb-000150
Figure PCTCN2022128606-appb-000150
实施例69Example 69
化合物I-17和I-19对结直肠癌细胞的体外促凋亡活性：In vitro pro-apoptotic activity of compounds I-17 and I-19 on colorectal cancer cells:
实验方法：MC-38为小鼠结肠癌细胞系。采用流式细胞术测定化合物对实体瘤细胞的体外促凋亡活性：体外诱导形成M2型巨噬细胞，加或不加I-17(10,30,100nM)和I-19(10,30,100nM)处理M2型巨噬细胞，随后用新鲜培养基替换培养基。48h后，收集上清液作为条件培养基。为了定量评估不同条件培养基的促凋亡效应，使用胰酶消化处于对数生长期的MC-38细胞，计数后取适量细胞悬液接种于6孔板中，过夜培养后，每孔加入上述不同的条件培养基，于37℃、5％CO 2孵箱培养24h后。采用AnnexinV-PI试剂盒检测细胞凋亡情况。采用Graphpad Prism5软件分析处理数据。 Experimental method: MC-38 is a mouse colon cancer cell line. The in vitro pro-apoptotic activity of the compound on solid tumor cells was determined by flow cytometry: M2 macrophages were induced in vitro, with or without I-17 (10, 30, 100 nM) and I-19 (10, 30, 100 nM) M2 macrophages were treated and the medium was subsequently replaced with fresh medium. After 48 h, the supernatant was collected as conditioned medium. In order to quantitatively evaluate the pro-apoptotic effects of different conditional media, trypsin was used to digest MC-38 cells in the logarithmic growth phase, and after counting, an appropriate amount of cell suspension was inoculated in a 6-well plate. After overnight culture, each well was added with the above Different conditioned media were cultured in a 37°C, 5% CO 2 incubator for 24 hours. Cell apoptosis was detected by AnnexinV-PI kit. The data were analyzed and processed by Graphpad Prism5 software.
表3.化合物I-17和I-19对结直肠癌细胞的体外促凋亡活性Table 3. In vitro pro-apoptotic activity of compounds I-17 and I-19 on colorectal cancer cells
Figure PCTCN2022128606-appb-000151
Figure PCTCN2022128606-appb-000151
结果显示：用化合物I-17和I-19刺激M2巨噬细胞的条件培养基处理显著增加了MC-38细胞的凋亡(表3)，并且在同等浓度下其促凋亡的活性都优于PLX3397。The results showed that the conditioned medium treatment of M2 macrophages stimulated by compounds I-17 and I-19 significantly increased the apoptosis of MC-38 cells (Table 3), and their pro-apoptotic activities were superior at the same concentration. on PLX3397.
实施例70Example 70
化合物I-17和I-19对结直肠癌细胞的体外抗增殖活性：In vitro antiproliferative activity of compounds I-17 and I-19 against colorectal cancer cells:
实验方法：MC-38为小鼠结肠癌细胞系。采用CCK-8法测定化合物对实体瘤细胞的体外抗增殖活性：体外诱导形成M2型巨噬细胞，加或不加I-17(10,30,100nM)和I-19(10,30,100nM)处理M2型巨噬细胞，随后用新鲜培养基替换培养基。48h后，收集上清液作为条件培养基。为了定量评估不同条件培养基的抗增殖效应，使用胰酶消化处于对数生长期的MC-38细胞，计数后取适量细胞悬液接种于96孔板中，过夜培养后，每孔加入上述不同的条件培养基，于37℃、5％CO 2孵箱培养20h后，加入CCK-8(10μL)继续培养4h。采用全波长酶标仪检测波长为490nm处的吸光度值。采用Graphpad Prism 5软件分析处理数据，并计算抑制率。 Experimental method: MC-38 is a mouse colon cancer cell line. The in vitro antiproliferative activity of the compound on solid tumor cells was determined by CCK-8 method: M2 macrophages were induced in vitro, with or without I-17 (10, 30, 100 nM) and I-19 (10, 30, 100 nM) treatment For M2 macrophages, the medium was subsequently replaced with fresh medium. After 48 h, the supernatant was collected as conditioned medium. In order to quantitatively evaluate the anti-proliferation effects of different conditioned media, trypsin was used to digest MC-38 cells in the logarithmic growth phase, and after counting, an appropriate amount of cell suspension was inoculated in a 96-well plate. After overnight culture, each well was added with the above-mentioned different After culturing for 20 h in a 37° C., 5% CO 2 incubator, CCK-8 (10 μL) was added to continue culturing for 4 h. A full-wavelength microplate reader was used to detect the absorbance at a wavelength of 490 nm. The data were analyzed and processed by Graphpad Prism 5 software, and the inhibition rate was calculated.
表4.化合物I-17和I-19对结直肠癌细胞的体外抗增殖活性Table 4. In vitro antiproliferative activity of compounds I-17 and I-19 on colorectal cancer cells
Figure PCTCN2022128606-appb-000152
Figure PCTCN2022128606-appb-000152
结果显示：用化合物I-17和I-19刺激巨噬细胞的条件培养基处理显著抑制了MC-38细胞的增殖(表4)，并且在同等浓度下其抗增殖增殖的活性都优于PLX3397。The results showed that the conditioned medium treatment of macrophages stimulated by compounds I-17 and I-19 significantly inhibited the proliferation of MC-38 cells (Table 4), and their anti-proliferation activity was better than that of PLX3397 at the same concentration .
实施例71Example 71
化合物I-19对部分酪氨酸激酶的体外抑制活性：In vitro inhibitory activity of compound I-19 on some tyrosine kinases:
实验方法：采用Mobility Shift Assay的方法测定化合物I-19对部分酪氨酸激酶的体外抑制活性：将化合物从1μM起始浓度，3倍稀释成10个浓度，然后用Echo550转移250nL至384孔板中，阴性对照孔和阳性对照孔中分别加入250nL的100％DMSO。在化合物孔和阳性对照孔中分别加入10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加入10μL的激酶buffer。1000rpm离心30秒，振荡混匀后室温孵育10分钟，加入15μL的25/15倍终浓度的ATP和激酶底物的混合溶液。将384孔板于1000rpm离心30秒，振荡混匀后室温孵育30分钟，加入30μL终止检测液，停止激酶反应，1000rpm离心30秒，振荡混匀，用Caliper EZ ReaderⅡ读取转化率。采用Graphpad Prism 5软件分析处理数据，求得IC 50值。结果显示：化合物I-19对PDGFRα、PDGFRβ、c-KIT、FLT3等多种酪氨酸激酶都显示出一定的抑制活性，尤其是对PDGFRα、PDGFRβ和c-KIT显示出较强的抑制活性(表5)。 Experimental method: Mobility Shift Assay method was used to determine the in vitro inhibitory activity of compound I-19 on some tyrosine kinases: the compound was diluted 3 times from the initial concentration of 1 μM to 10 concentrations, and then transferred 250 nL to a 384-well plate with Echo550 250 nL of 100% DMSO was added to negative control wells and positive control wells respectively. Add 10 μL of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 μL of kinase buffer to negative control wells. Centrifuge at 1000 rpm for 30 seconds, shake to mix and incubate at room temperature for 10 minutes, add 15 μL of a mixed solution of ATP and kinase substrate at 25/15 times the final concentration. Centrifuge the 384-well plate at 1000rpm for 30 seconds, shake and mix well, incubate at room temperature for 30 minutes, add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix well, and read the conversion rate with Caliper EZ Reader II. Graphpad Prism 5 software was used to analyze and process the data, and the IC50 value was obtained. The results showed that compound I-19 showed certain inhibitory activity on PDGFRα, PDGFRβ, c-KIT, FLT3 and other tyrosine kinases, especially PDGFRα, PDGFRβ and c-KIT showed strong inhibitory activity ( table 5).
表5.化合物I-19对部分酪氨酸激酶的体外抑制活性Table 5. In vitro inhibitory activity of compound I-19 on some tyrosine kinases
Figure PCTCN2022128606-appb-000153
Figure PCTCN2022128606-appb-000153
实施例72Example 72
化合物I-17和I-19抑制MC-38结直肠癌小鼠移植瘤生长的作用：Compounds I-17 and I-19 inhibit the growth of xenograft tumors in MC-38 colorectal cancer mice:
实验方法：将MC-38细胞进行体外培养扩增，取适量处于对数生长期的细胞重悬于无血清DMEM培养基中，无菌条件下制备成1×10 6/100μL细胞悬液，用注射器将100μL细胞悬液接种于雌性C57BL/6小鼠前左肢腋窝皮下。待肿瘤体积生长至100mm 3左右时，选取肿瘤大小适中的动物随机分组，每组6只。分别给予空白媒介(CMC-Na)、PLX3397(20mg/kg/d)、I-17低剂量(5mg/kg/d)、I-17中剂量(10mg/kg/d)、I-17高剂量(20mg/kg/d)、I-19低剂量(5mg/kg/d)、I-19中剂量(10mg/kg/d)、I-19高剂量(20mg/kg/d)，每天灌胃一次，给药2周。给药期间，每天测量小鼠体重和瘤径。实验结束后颈椎脱臼处死，取瘤称重。 Experimental method: MC-38 cells were cultured and expanded in vitro, and an appropriate amount of cells in the logarithmic growth phase were resuspended in serum-free DMEM medium, and a cell suspension of 1×10 6 /100 μL was prepared under sterile conditions. 100 μL of the cell suspension was inoculated subcutaneously in the axilla of the anterior left limb of female C57BL/6 mice. When the tumor volume grew to about 100 mm 3 , animals with moderate tumor size were selected and divided into random groups, with 6 animals in each group. Give blank vehicle (CMC-Na), PLX3397 (20mg/kg/d), I-17 low dose (5mg/kg/d), I-17 medium dose (10mg/kg/d), I-17 high dose (20mg/kg/d), I-19 low dose (5mg/kg/d), I-19 medium dose (10mg/kg/d), I-19 high dose (20mg/kg/d), intragastric administration every day Once, administer for 2 weeks. During the administration period, the body weight and tumor diameter of the mice were measured every day. After the experiment, the animals were killed by cervical dislocation, and the tumors were weighed.
肿瘤体积(tumor volume，TV)的计算公式为：TV＝1/2×a×b 2，a表示肿瘤长径；b表示肿瘤短径。 The calculation formula of tumor volume (TV) is: TV=1/2×a×b 2 , where a represents the long diameter of the tumor; b represents the short diameter of the tumor.
表6.化合物I-17及I-19在MC-38结直肠癌小鼠模型上的抑瘤效果Table 6. Antitumor effect of compounds I-17 and I-19 on MC-38 colorectal cancer mouse model
Figure PCTCN2022128606-appb-000154
Figure PCTCN2022128606-appb-000154
*,p<0.05； **,p<0.01(与溶剂对照比较)。 * , p<0.05; ** , p<0.01 (compared to solvent control).
结果显示：在MC-38小鼠移植瘤模型上，连续灌胃给药2周，化合物I-17(10,20mg/kg)和I-19(5,10,20mg/kg)能够剂量依赖性地抑制肿瘤的生长，并且对小鼠体重没有影响。其中I-17和I-19在20mg/kg/d剂量下的抑瘤率分别达到53.30％和66.81％，明显优于PLX3397在20mg/kg/d剂量下的抑瘤率(39.23％)(表6)。The results show that: on the MC-38 mouse xenograft tumor model, compound I-17 (10, 20 mg/kg) and I-19 (5, 10, 20 mg/kg) can dose-dependently significantly inhibited tumor growth and had no effect on the body weight of mice. Wherein I-17 and I-19 reach 53.30% and 66.81% respectively under the dose of 20mg/kg/d tumor inhibition rate, obviously better than PLX3397 tumor inhibition rate (39.23%) under the dose of 20mg/kg/d (table 6).
实施例73Example 73
化合物I-19与免疫检查点抑制剂PD-L1单抗的协同抗肿瘤作用：Synergistic antitumor effect of compound I-19 and immune checkpoint inhibitor PD-L1 monoclonal antibody:
实验方法：将MC-38细胞体进行外培养扩增，取适量处于对数生长期的细胞重悬于无血清DMEM培养基中，无菌条件下制备成1×10 6/100μL细胞悬液，用注射器将100μL细胞悬液接种于雌性C57BL/6小鼠前左肢腋窝皮下。待肿瘤体积生长至100mm 3左右时，选取肿瘤大小适中的动物随机分组，每组6只。分别给予空白媒介(CMC-Na)、I-19(20mg/kg/d)、anti-PD-L1(100μg/mouse)、I-19(20mg/kg/d)+anti-PD-L1(100μg/mouse)，I-19每天灌胃一次，anti-PD-L1每3天腹腔注射一次，给药2周。给药期间，每天测量小鼠体重和瘤径。实验结束后颈椎脱臼处死，取瘤称重。 Experimental method: MC-38 cell bodies were cultured and expanded in vitro, and an appropriate amount of cells in the logarithmic growth phase were resuspended in serum-free DMEM medium, and a cell suspension of 1×10 6 /100 μL was prepared under sterile conditions. Using a syringe, 100 μL of the cell suspension was inoculated subcutaneously in the axilla of the anterior left limb of female C57BL/6 mice. When the tumor volume grew to about 100 mm 3 , animals with moderate tumor size were selected and divided into random groups, with 6 animals in each group. Give blank medium (CMC-Na), I-19 (20mg/kg/d), anti-PD-L1 (100μg/mouse), I-19 (20mg/kg/d)+anti-PD-L1 (100μg /mouse), I-19 was intragastrically administered once a day, and anti-PD-L1 was injected intraperitoneally once every 3 days for 2 weeks. During the administration period, the body weight and tumor diameter of the mice were measured every day. After the experiment, the animals were killed by cervical dislocation, and the tumors were weighed.
肿瘤体积(tumor volume，TV)的计算公式为：TV＝1/2×a×b 2，a表示肿瘤长径；b表示肿瘤短径。 The calculation formula of tumor volume (TV) is: TV=1/2×a×b 2 , where a represents the long diameter of the tumor; b represents the short diameter of the tumor.
表7.化合物I-19增强免疫检查点抑制剂的抗肿瘤作用Table 7. Compound I-19 enhances the antitumor effect of immune checkpoint inhibitors
Figure PCTCN2022128606-appb-000155
Figure PCTCN2022128606-appb-000155
Figure PCTCN2022128606-appb-000156
Figure PCTCN2022128606-appb-000156
*,p<0.05； **,p<0.01(与溶剂对照比较)。 * , p<0.05; ** , p<0.01 (compared to solvent control).
结果显示：在MC-38小鼠移植瘤模型上，连续给药2周，化合物I-19(20mg/kg)和anti-PD-L1均明显抑制肿瘤的生长，且I-19可以增强anti-PD-L1的抗肿瘤作用，抑瘤率可达83.69％(表7)。The results showed that: on the MC-38 mouse xenograft tumor model, compound I-19 (20 mg/kg) and anti-PD-L1 both significantly inhibited the growth of tumor after continuous administration for 2 weeks, and I-19 could enhance anti-PD-L1. The anti-tumor effect of PD-L1, the tumor inhibition rate can reach 83.69% (Table 7).
以上仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，应视为本发明的保护范围。The above are only preferred implementations of the present invention, and the protection scope of the present invention is not limited to the above-mentioned embodiments, and all technical solutions under the idea of the present invention belong to the protection scope of the present invention. It should be pointed out that for those skilled in the art, some improvements and modifications without departing from the principle of the present invention should be regarded as the protection scope of the present invention.

Claims (10)

  1. 6-位取代的吲哚酮衍生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，其特征在于，所述化合物的化学结构式如式I所示：6-position substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof, characterized in that the chemical structural formula of the compound is as shown in formula I:
    Figure PCTCN2022128606-appb-100001
    Figure PCTCN2022128606-appb-100001
    其中：in:
    A环选自5～6元芳杂环、苯环、多取代的5～6元芳杂环、多取代的苯环、单取代的5～6元芳杂环或单取代的苯环；Ring A is selected from 5-6 membered aromatic heterocycles, benzene rings, multi-substituted 5-6-membered aromatic heterocycles, multi-substituted benzene rings, mono-substituted 5-6-membered aromatic heterocycles or mono-substituted benzene rings;
    R选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种；R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
    R 1选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
    R 2选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R2 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
    R 3选自氢原子、卤素、烷基、烷氧基、卤代烷基中的一种或几种； R3 is selected from one or more of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl;
    R 4选自氢原子、羟基、烷基、烷氧基、(CH 2) mNR 7R 8中的一种或几种； R 4 is selected from one or more of hydrogen atom, hydroxyl, alkyl, alkoxy, (CH 2 ) m NR 7 R 8 ;
    R 5和R 6分别选自氢、甲基、或者R 5和R 6形成环丙烷； R 5 and R 6 are respectively selected from hydrogen, methyl, or R 5 and R 6 form cyclopropane;
    R 7和R 8分别选自氢、烷基、环烷基及杂环烷基一种或几种； R 7 and R 8 are respectively selected from one or more of hydrogen, alkyl, cycloalkyl and heterocycloalkyl;
    R 7和R 8形成一个4-7元杂环烷基，其中4-7元杂环内含有一个或多个N、O、S原子，且4-7元杂环上被一个或多个烷基取代； R 7 and R 8 form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocyclic ring contains one or more N, O, S atoms, and the 4-7 membered heterocyclic ring is surrounded by one or more alkanes base substitution;
    X选自C原子或N原子；X is selected from C atom or N atom;
    Y选自C原子或N原子；Y is selected from C atom or N atom;
    Z选自CONH、NHCO、SO 2NH或NHSO 2； Z is selected from CONH, NHCO, SO2NH or NHSO2 ;
    n是0或1；n is 0 or 1;
    m是1-6。m is 1-6.
  2. 根据权利要求1所述的6-位取代的吲哚酮衍生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，其特征在于，The 6-substituted indolinone derivative or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate according to claim 1, characterized in that,
    所述的6-位取代的吲哚酮衍生物选自：The 6-substituted indolinone derivatives are selected from:
    (S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐；(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride;
    (R,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-2-甲酰胺盐酸盐；(R,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-2-carboxamide hydrochloride;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-4-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-4-carboxamide hydrochloride;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-2-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-2-carboxamide hydrochloride;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)哌啶-3-甲酰胺盐酸盐；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)piperidine-3-carboxamide hydrochloride;
    (S,Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)吡咯烷-3-甲酰胺盐酸盐；(S,Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methanol Base)-2,4-dimethyl-1H-pyrrol-3-yl)pyrrolidine-3-carboxamide hydrochloride;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(吡咯烷-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(pyrrolidin-1-yl)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(哌啶-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(piperidin-1-yl)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(4-甲基哌嗪-1-基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(4-methylpiperazin-1-yl)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二乙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(diethylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(二甲氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(dimethylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(乙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(ethylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(丙氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(propylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(叔丁氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(tert-butylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-(环戊氨基)丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-(cyclopentylamino)propionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-3-吗啉基丙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-3-morpholinopropionamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(吡咯烷-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(pyrrolidin-1-yl)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(哌啶-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(piperidin-1-yl)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(二乙氨基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(diethylamino)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-吗啉基乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-morpholinoacetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(环戊氨基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-Dimethyl-1H-pyrrol-3-yl)-2-(cyclopentylamino)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)-2-(4-甲基哌嗪-1-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene )methyl)-2,4-dimethyl-1H-pyrrol-3-yl)-2-(4-methylpiperazin-1-yl)acetamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -N-(2-(diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-5-氟-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-5-fluoro-2-oxindole-3-ylidene )methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((6-(3-(5-甲基异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((6-(3-(5-methylisoxazol-3-yl)ureido )-2-oxindole-3-ylidene)methyl)-1H-pyrrole-3-carboxamide;
    (Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3-(三氟甲基)异恶唑-5-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxido-6-(3-(3-(trifluoromethyl)isoxane Azol-5-yl)ureido)indol-3-ylidene)methyl)-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)ureido)-2-oxindole-3-ylidene )methyl)-N-(2-(diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(4-氯-3-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(三氟甲基)吡啶-3-基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxygen-6-(3-(trifluoromethyl)pyridin-3-yl ) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(4-(叔丁基)-3-氯苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(4-(tert-butyl)-3-chlorophenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-( 2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(4-(叔丁基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(4-(tert-butyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N-(2-(di Ethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(3-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(2-氯-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(2-Chloro-4-(trifluoromethyl)phenyl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-N-(2-(二乙氨基)乙基)-5-((6-(3-(3-甲氧基-4-(三氟甲基)苯基)脲基)-2-氧化吲哚-3-亚基)甲 基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-5-((6-(3-(3-methoxy-4-(trifluoromethyl)phenyl)ureido)-2 -oxindole-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-N-(2-(二乙氨基)乙基)-2,4-二甲基-5-((2-氧化-6-(3-(3,4,5-三甲氧基苯基)脲基)吲哚-3-亚基)甲基)-1H-吡咯-3-甲酰胺；(Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(3-(3,4,5-trimethoxybenzene base) ureido) indole-3-ylidene) methyl)-1H-pyrrole-3-carboxamide;
    (Z)-N-(5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-基)乙酰胺；(Z)-N-(5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl) -2,4-dimethyl-1H-pyrrol-3-yl)acetamide;
    (Z)-N 1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
    (Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N,2,4-三甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-N, 2,4-Trimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxamide;
    (Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸甲酯；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid methyl ester;
    (Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid;
    (Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene) -2-oxindol-6-yl)urea;
    (Z)-1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
    (Z)-N 1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-甲氧基-4-(三氟甲基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-methoxy-4-(trifluoromethane base) phenyl) urea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(叔丁基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(tert-butyl)phenyl)urea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)-1-甲基-1H-吡唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)-1-methyl -1H-pyrazol-5-yl)urea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-(tert-butyl)isoxazole-5 - base) urea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(3-氯-4-(三氟甲基)苯基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(3-chloro-4-(trifluoromethyl) Phenyl) urea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-(哌啶-4-基)苯基)脲盐酸盐；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-(piperidin-4-yl)phenyl ) urea hydrochloride;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(4-((4,4-二甲基哌啶-1-基)甲基)苯基脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(4-((4,4-dimethylpiper (pyridin-1-yl)methyl)phenylurea;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-5-氟-2-氧化吲哚-6-基)-3-(3-(叔丁基)异恶唑-5-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-5-fluoro-2-oxindol-6-yl)-3-(3-(tert-butyl)iso oxazol-5-yl) urea;
    (Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(5-氟-3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(5-fluoro-3-((4-methyl-1H-imidazol-5-yl)methylene )-2-oxindol-6-yl)urea;
    (Z)-1-(3-(叔丁基)异恶唑-5-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(3-(tert-butyl)isoxazol-5-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Oxydolin-6-yl) urea;
    (Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Piperazin-1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide;
    (Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) -3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)malonamide;
    (Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺；(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((4-((2-(diethylamino)ethyl)carbamoyl)-3 ,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide;
    (Z)-N-(5-(叔丁基)异恶唑-3-基)-N-(3-((3,5-二甲基-4-(2-(4-甲基哌啶-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)环丙烷-1,1-二甲酰胺；(Z)-N-(5-(tert-butyl)isoxazol-3-yl)-N-(3-((3,5-dimethyl-4-(2-(4-methylpiperidine -1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)cyclopropane-1,1-dicarboxamide;
    (Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((3,5-二甲基-4-(2-(4-甲基哌嗪-1-基)乙酰氨基)-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((3,5-dimethyl-4-(2-(4-methyl Piperazin-1-yl)acetylamino)-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide;
    (Z)-N 1-(5-(叔丁基)异恶唑-3-基)-N 3-(3-((4-((2-(二乙氨基)乙基)氨基甲酰基)-3,5-二甲基-1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-2,2-二甲基丙二酰胺； (Z)-N 1 -(5-(tert-butyl)isoxazol-3-yl)-N 3 -(3-((4-((2-(diethylamino)ethyl)carbamoyl) -3,5-Dimethyl-1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-2,2-dimethylmalonamide;
    (Z)-5-((6-(3-(5-(叔丁基)异恶唑-3-基)脲基)-2-氧化吲哚-3-亚基)甲基)-2,4-二甲基-1H-吡咯-3-甲酸乙酯；(Z)-5-((6-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)-2-oxindole-3-ylidene)methyl)-2, 4-Dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester;
    (Z)-1-(3-((1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-imidazol-5-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
    (Z)-1-(5-(叔丁基)异恶唑-3-基)-3-(3-((4-甲基-1H-咪唑-5-基)亚甲基)-2-氧化吲哚-6-基)脲；(Z)-1-(5-(tert-butyl)isoxazol-3-yl)-3-(3-((4-methyl-1H-imidazol-5-yl)methylene)-2- Oxydolin-6-yl) urea;
    (Z)-1-(3-((1H-咪唑-2-基)亚甲基)-2-氧化吲哚-6-基)-3-(5-(叔丁基)异恶唑-3-基)脲；(Z)-1-(3-((1H-imidazol-2-yl)methylene)-2-oxindol-6-yl)-3-(5-(tert-butyl)isoxazole-3 - base) urea;
    (Z)-N 1-(3-((1H-吡咯-2-基)亚甲基)-2-氧化吲哚-6-基)-N 3-(5-(叔丁基)异恶唑-3-基)丙二酰胺； (Z)-N 1 -(3-((1H-pyrrol-2-yl)methylene)-2-oxindol-6-yl)-N 3 -(5-(tert-butyl)isoxazole -3-yl) malonamide;
    (Z)-5-((6-(3-(3-(叔丁基)异恶唑-5-基)脲基)-2-氧化吲哚-3-亚基)甲基)-N-(2-(二乙氨基)乙基-2,4-二甲基-1H-吡咯-3-甲酰胺。(Z)-5-((6-(3-(3-(tert-butyl)isoxazol-5-yl)ureido)-2-oxindole-3-ylidene)methyl)-N- (2-(Diethylamino)ethyl-2,4-dimethyl-1H-pyrrole-3-carboxamide.
  3. 根据权利要求1所述的6-位取代的吲哚酮衍生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，其特征在于，所述异构体选自对映异构体、非对映异构体、几何异构体或立体异构体中的一种或者几种。The 6-substituted indolinone derivative or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate according to claim 1, wherein the isomer One or more selected from enantiomers, diastereoisomers, geometric isomers or stereoisomers.
  4. 如根据权利要求1-3所述的6-位取代的吲哚酮衍生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的制备方法。The preparation method of the 6-substituted indolinone derivative or its pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate according to claims 1-3.
  5. 一种药物组合物，包括如权利要求1-3中任一权利要求中所述的6-位取代的吲哚酮衍生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。A pharmaceutical composition, comprising the 6-substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs thereof as described in any one of claims 1-3 Forms or solvates.
  6. 如权利要求1-3中任一项所述的6-位取代的吲哚酮衍生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在制备酪氨酸激酶抑制剂中的用途。6-position substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof in the preparation of tyrosine as described in any one of claims 1-3 Use in acid kinase inhibitors.
  7. 如权利要求1-3中任一项所述的6-位取代的吲哚酮衍生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在制备肿瘤相关巨噬细胞免疫调节剂中的用途，包括在治疗恶性肿瘤、炎症性疾病、骨疾病和神经性疾病中的用途。6-position substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates as claimed in any one of claims 1-3 in the preparation of tumor-related Uses in macrophage immunomodulators include uses in the treatment of malignant tumors, inflammatory diseases, bone diseases and neurological diseases.
  8. 如权利要求1-3中任一项所述的6-位取代的吲哚酮衍生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，或根据权利要求5所述的药物组合物在制备用于治疗或预防多种恶性肿瘤免疫治疗药物中的用途。6-substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof as claimed in any one of claims 1-3, or according to the claims Use of the pharmaceutical composition described in claim 5 in the preparation of immunotherapeutic drugs for treating or preventing various malignant tumors.
  9. 如权利要求8中任一项所述的6-位取代的吲哚酮衍生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与其他靶向抗肿瘤药物、免疫检查点抑制剂等免疫治疗药物联合用于治疗多种恶性肿瘤的用途。6-substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates as claimed in any one of claim 8 and other targeted anti-tumor Drugs, immune checkpoint inhibitors and other immunotherapy drugs are used in combination to treat a variety of malignant tumors.
  10. 如权利要求1-3中任一项所述的6-位取代的吲哚酮衍生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，或根据权利要求5所述的药物组合物，或与免疫检查点抑制剂联用使用在制备用于治疗结直肠癌的药物中的用途。6-substituted indolinone derivatives or pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates thereof as claimed in any one of claims 1-3, or according to the claims The pharmaceutical composition described in claim 5, or its use in combination with an immune checkpoint inhibitor in the preparation of a drug for treating colorectal cancer.
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