WO2021063276A1 - 大环类衍生物及其制备方法和用途 - Google Patents

大环类衍生物及其制备方法和用途 Download PDF

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WO2021063276A1
WO2021063276A1 PCT/CN2020/117985 CN2020117985W WO2021063276A1 WO 2021063276 A1 WO2021063276 A1 WO 2021063276A1 CN 2020117985 W CN2020117985 W CN 2020117985W WO 2021063276 A1 WO2021063276 A1 WO 2021063276A1
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cancer
compound
pharmaceutically acceptable
tautomers
stereoisomers
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PCT/CN2020/117985
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English (en)
French (fr)
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陈友喜
毛文涛
龚亮
向清
赵雯雯
胡泰山
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202080063779.5A priority Critical patent/CN114423762B/zh
Publication of WO2021063276A1 publication Critical patent/WO2021063276A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a new macrocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an inhibitor of SRC, MET and/or CSF-1R kinase.
  • Protein kinases are key regulators of cell growth, proliferation and survival. In recent years, research on anticancer drugs targeting protein kinases has been in full swing. Although the good effects of these inhibitors have brought hope to cancer patients, protein The drug resistance caused by the unidirectional inhibition of kinases also follows. Therefore, some researchers have begun to pay attention to multi-target inhibitors, hoping to solve the increasingly prominent problem of drug resistance.
  • c-Met also known as MET or hepatocyte growth factor receptor (HGFR) plays an important role in the human body as a tyrosine kinase, among which hepatocyte growth factor is the high affinity of c-Met in the human body Of natural ligands.
  • c-Met is generally expressed in epithelial cell tissues, and there are multiple activation mechanisms, such as overexpression, gene amplification, gene mutation, and autologous or paralogous HGF activation.
  • the c-Met protein is a heterodimer composed of a 50kDa extracellular a subunit and a 145kDa transmembrane catalytic ⁇ subunit connected by disulfide bonds. It contains three functional domains.
  • HGF interacts with c-Met cells.
  • the subunits of the outer region bind to catalyze the phosphorylation of Tyrl234 and Tyr1235 in the catalytic domain of the receptor tyrosine kinase intracellular domain to activate c-Met kinase, and then combine with the downstream signal SH2 (Srchomology 2) to produce a variety of cells Internal signal transduction.
  • SH2 Session 2
  • HGF/c-Met signaling pathway is involved in embryonic development, wound healing and tissue regeneration.
  • c-Met RNA is expressed at a low level, which only rises briefly after tissue injury, and then returns to normal levels.
  • HGF/c-Met in tumor cells, such as human ovarian cancer, nasopharyngeal carcinoma, uterine cancer, gastric cancer, non-small cell lung cancer, kidney cancer and other cancer cells.
  • High expression of c-Met is observed After blocking the abnormally activated HGF/c-Met signaling pathway in tumor cells, tumor cells will have cell morphology changes, such as slowed proliferation, reduced tumor formation rate, and decreased invasion ability, so the overexpression of c-Met It is closely related to the formation and prognosis of a variety of tumors.
  • c-Src protein As a non-receptor tyrosine kinase, c-Src protein is also called SRC. It consists of 6 parts, namely N-terminal myristoylation sequence, SH2 domain, SH3 domain, single sequence, kinase domain, and C-terminal. Regulatory domains, these parts play different biological roles.
  • the N-terminal myristoyl group anchored on the inner side of the plasma membrane can make the c-Src protein closer to the cytokine receptor; the SH2 domain consisting of about 100 amino acid residues specifically recognizes short peptides containing phosphotyrosine, After it is combined with it, the signal is transduced and transmitted; the SH3 domain is composed of about 50 amino acid residues, which mediates the connection between proteins, and binds to the target protein through proline and hydrophobic amino acid residues.
  • c-Src plays an important role in maintaining the normal physiological functions of the body. In normal cells and tissues, c-Src exists in an inactive form. Tyrosine 530 (Tyr530) binds to the SH2 domain, and the proline linking region is associated with SH3. The domains bind to maintain the inactive state of c-Src.
  • c-Src is not only highly expressed, but also continuously activated in tumor cells or interstitium, resulting in The occurrence and development of tumors.
  • increased SRC kinase activity was detected, including breast cancer, lung cancer, pancreatic cancer, gastric cancer, ovarian cancer, bladder cancer, head and neck cancer, esophageal cancer, black pigment tumor, Kaposi’s sarcoma, lymphoproliferative Diseases etc.
  • c-Src is a key downstream converter driven by c-Met.
  • inhibition of c-Src enhances the sensitivity of cells to c-Met inhibitors, so dual inhibition of c-Met and c-Src kinase activity can be used as tumor targeting Treatment strategy.
  • Colony stimulating factor-1 is also known as macrophage colony stimulating factor. Its receptor (CSF-1R) is encoded by the c-fms proto-oncogene. CSF-1R is a single unit consisting of 972 amino acid residues. Chain transmembrane glycoproteins belong to tyrosine kinase receptors and are expressed in monocytes, macrophages and the precursors of bone marrow cells, trophoblasts and choriocarcinoma cells. CSF-1R has five immunoglobulin-like domains in the extracellular part that binds to the ligand, and a single transmembrane domain and a split kinase domain in the intracellular part.
  • CSF-1R and CSF-1 can induce receptor dimerization, resulting in conformational changes, which leads to phosphorylation of tyrosine residues in intracellular domains. Most of these phosphorylated residues can attract effector molecules and activate a series of signal transduction pathways such as macrophage survival, proliferation, and differentiation.
  • CSF-1 and its receptor are closely related to the occurrence and metastasis of a variety of malignant tumors. For example, CSF can be detected in breast cancer, ovarian cancer, nasopharyngeal cancer, colorectal cancer, pancreatic cancer, and Hodgkin’s lymphoma. Co-expression of -1R and CSF-1.
  • HGF/MET Abnormal activation of the HGF/MET pathway caused by Mf7 mutation, gene amplification and translocation, HGF paracrine or autocrine upregulation has been found in a variety of tumors.
  • Abnormal HGF/MET signaling not only leads to cancer, but can also coordinate drug resistance.
  • SRC is a key downstream converter of MET, and it is also involved in the formation, metastasis and drug resistance of malignant tumors.
  • CSF-1R plays a role in tumor-associated macrophage regulation, tumor progression, and angiogenesis. Therefore, multi-target inhibition of MET, SRC and/or CSF-1R can be used as an effective strategy to treat tumors, effectively targeting abnormal HGF/MET signal transduction, and at the same time targeting tumor internal signal transduction and tumor microenvironment.
  • the present invention provides a new type of macrocyclic compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R 1 is selected from a hydrogen atom or an amino group
  • R 2 to R 8 are the same or different, and are each independently selected from a hydrogen atom or a deuterium atom.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention provides a pharmaceutical composition containing an effective dose of the compound of general formula (I) or its stereoisomers, tautomers or its pharmaceutically acceptable Salts, and pharmaceutically acceptable carriers, excipients, or combinations thereof.
  • the present invention provides a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition for preparing SRC, MET and/or CSF-1R Use in inhibitors.
  • the present invention provides a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in preparation and treatment of SRC, MET and/or CSF -1R-mediated diseases, wherein the diseases mediated by SRC, MET and/or CSF-1R are preferably cancers; wherein the cancers are preferably gastric cancer, colon cancer, kidney cancer, liver cancer , Lung cancer, glioblastoma or head and neck tumors.
  • the present invention provides a use of a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of drugs for the treatment of cancer, wherein
  • the cancer is preferably gastric cancer, colon cancer, kidney cancer, liver cancer, lung cancer, glioblastoma or head and neck tumors.
  • Amino refers to -NH 2 .
  • “Pharmaceutically acceptable salts” refer to certain salts of the above compounds that can maintain the original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration of the biological body, which is conducive to the absorption of the active ingredient and thus the biological activity.
  • the mass spectrum is measured by an LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • DMSO-d 6 Deuterated dimethyl sulfoxide.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • a silica gel column chromatography eluent system wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; the volume ratio of the solvent is based on the compound
  • the polarity is different, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.
  • AKZONOBEL Kromasil 250 ⁇ 21.2mm ID, 5 ⁇ m, 20mL/min
  • fluidity A 0.05% TFA+H 2 O
  • fluidity B CH 3 CN
  • Test Example 1 Test of inhibitory activity of the compound of the present invention on Src/Met/CSF-1R kinase
  • the following method is used to determine the degree of inhibition of recombinant human Src/Met/CSF-1R kinase activity by the compounds of the present invention under in vitro conditions.
  • This method uses Cisbio's KinEASE-TK tyrosine kinase kit (Cat. No. 62TK0PEB), the principle of this kit is based on time-resolved fluorescence energy resonance transfer (TF-FRET), by measuring SRC/MET/CSF-1R kinase-mediated biotinylated peptide substrate
  • TF-FRET time-resolved fluorescence energy resonance transfer
  • the degree of phosphorylation of the compound reflects the inhibitory strength of the compound on the SRC/MET/CSF-1R kinase activity.
  • Recombinant human SRC/MET/CSF-1R proteins were purchased from SignalChem Company (catalog numbers are MET#M52-18G-10, SRC#S19-18G-10, CSF-1R#R14-11
  • test compound is first dissolved in DMSO to prepare a storage solution, and then the compound dilution buffer (Src: HEPES 50mM, MgCl 2 5mM, Na 3 VO 4 0.1mM, DTT 1mM, 0.01% BSA ;Met and CSF-1R: HEPES 50mM, MgCl 2 5mM, MnCl 2 1mM, Na 3 VO 4 0.1mM, DTT 1mM, 0.01% BSA) for gradient dilution, the final concentration range of the test compound in the reaction system is 1000nM ⁇ 0.004nM.
  • ATP Km concentration of Src/Met/CSF-1R protein using a gradiently diluted ATP solution (Sangong Bioengineering (Shanghai) Co., Ltd., A600311), and set it as the corresponding kinase reaction system based on the Km value obtained ATP concentration.
  • the reaction is carried out in a 384-well microtiter plate. First, add the compound and a certain amount of the corresponding SRC/MET/CSF-1R protein to the well, and incubate at room temperature for 5-10 minutes, and then add ATP solution and biological solution to the reaction solution. Vegetarian peptide substrate solution, and incubate with shaking at room temperature for 40-60 minutes.
  • Table 1 The IC 50 value of the compound of the present invention for inhibiting SRC/MET/CSF-1R kinase activity
  • the compound 1 of the present invention has a significant inhibitory effect on SRC, MET and CSF-1R kinase, and its inhibitory activity on MET kinase is significantly better than SRC and CSF-1R.
  • Test Example 2 The pharmacokinetic study of the compound of the present invention in ICR mice
  • the LC/MS/MS method was used to determine the intravenous or intragastric administration of TPX-0022 and the compound of the present invention in mice, and to determine the drug concentration in plasma at different times to study the compound of the present invention in mice Pharmacokinetic characteristics in vivo.
  • ICR mice male, 18, 28.8-37.0g, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Animal quality certificate number: 190927043.
  • Oral gavage group Weigh an appropriate amount of medicine, add an appropriate amount of carboxymethyl cellulose sodium (CMC-Na, containing 0.5% Tween 80), vortex and sonicate to prepare a 0.5 mg/mL suspension;
  • CMC-Na carboxymethyl cellulose sodium
  • ICR mice Eighteen ICR mice were divided into 2 groups evenly. After fasting overnight, they were administered intravenously (dose 1mg/kg, dose volume 5mL/kg) and intragastrically (dose 5mg/kg, given The drug volume is 10mL/kg), and eat 4 hours after the administration.
  • 80 ⁇ L of blood was collected from the orbit at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours before and after administration, and EDTA-K2 was used for anticoagulation.
  • the blood samples were collected on ice and centrifuged to separate the plasma (centrifugation conditions: 1500g, 10 minutes).
  • the collected plasma was stored at -40 ⁇ -20°C before analysis.
  • LC-MS/MS was used to determine the content of test compounds in mouse plasma after intravenous injection and intragastric administration of different compounds.
  • Example 1 of the present invention Compared with TPX-0022, the compound of Example 1 of the present invention has significantly increased Cmax, good pharmacokinetic absorption, long half-life, low clearance rate, significantly improved bioavailability, and better pharmacokinetic properties.
  • TPX-0022 is prepared according to the method disclosed in patent application WO2019023417, and its specific structure is as follows:

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Abstract

本发明涉及大环类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式（I）所示的大环类衍生物、其制备方法及其可药用的盐，以及它们作为治疗剂，特别是SRC、MET和/或CSF-1R抑制剂的用途，其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

大环类衍生物及其制备方法和用途 技术领域
本发明涉及一种新的大环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为SRC、MET和/或CSF-1R激酶抑制剂的用途。
背景技术
蛋白激酶是细胞生长，增殖和存活的关键调节因子，近年来，对靶向蛋白激酶的抗癌药物的研究进行地如火如荼，虽然这类抑制剂的良好效果给肿瘤患者带来了希望，但是蛋白激酶的单向抑制产生的耐药性也随之而来，因此，一些研究者开始关注多靶点抑制剂，希望以此来解决日益突出的耐药性问题。
c-Met，也称为MET或者肝细胞生长因子受体(HGFR)，作为一种酪氨酸激酶在人体中发挥着重要作用，其中肝细胞生长因子是人体内c-Met的高亲和性的天然配体。c-Met一般在上皮细胞组织表达，存在多种激活机制，如过表达、基因扩增、基因变异、自源性或旁源性的HGF激活等。c-Met蛋白是由50kDa的细胞外a亚基和145kDa的跨膜催化β亚基通过二硫键相连的异二聚体，它包含有三个功能不同的结构域，HGF通过与c-Met胞外区的亚基结合，催化受体酪氨酸激酶胞内区催化结构域的Tyrl234和Tyr1235的磷酸化来激活c-Met激酶，进而与下游信号SH2(Src homology 2)结合，产生多种胞内信号转导。正常情况下，HGF/c-Met信号通路参与胚胎发育、伤口愈合和组织再生等，在正常细胞中，c-Met的RNA低水平表达，仅在组织损伤后短暂上升，随即又恢复正常水平。相反，肿瘤细胞中则存在HGF/c-Met的过度表达，例如人卵巢癌、鼻咽癌、子宫癌、胃癌、非小细胞肺癌、肾癌等癌症细胞中会观察到c-Met的高表达，将肿瘤细胞中异常活化HGF/c-Met信号通路阻断后，肿瘤细胞会出现细胞形态改变，如增殖减缓、成瘤率降低、侵袭能力下降等一系列变化，因此c-Met的过度表达和多种肿瘤的形成及预后密切相关。
c-Src蛋白作为一种非受体型酪氨酸激酶，也称为SRC，由6个部分构成，分别是N端豆蔻酰化序列、SH2域、SH3域、单一序列、激酶域、C端调节域，这些部分发挥着不同的生物学作用。在质膜内侧锚定的N端豆蔻酰基，可使c-Src蛋白更接近细胞因子受体；由约100个氨基酸残基组成的SH2域，通过特异性识别含有磷酸酪氨酸的短肽，并与之结合后将信号进行转导传递；由约50个氨基酸残基组成SH3域，可介导蛋白之间的连接，通过脯氨酸及疏水氨基酸残基与靶蛋白结合，在细胞骨架的重组及c-Src蛋白的转运方面具有重要意义；激酶域的两个磷酸化位点Y416和Y527调控激酶自身的生物学活性；C端负调节区的是c-Src蛋白的特征区，v-Src蛋白即无此调节区。c-Src对维持机体正常生理功能具有重要作用，在正常细胞和组织中，c-Src以非活性形式存在，酪氨酸530位点(Tyr530)与SH2域结合，脯氨酸链接区与SH3域结合以维持c-Src的非活化状态。正常情况下，它的活化是短暂且被精确调控的，而在许多肿瘤细胞中由于失去了精确的负性调控，c-Src 不仅高表达，而且在肿瘤细胞或者间质中持续活化，因而导致肿瘤的发生和发展。在一些肿瘤中，检测到SRC激酶活性增加，包括乳腺癌、肺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、头颈部癌、食道癌、黒色素瘤、卡波济氏肉瘤、淋巴增生性疾病等。c-Src是c-Met驱动的关键下游转换器，同时抑制c-Src增强了细胞对c-Met抑制剂的敏感性，因此c-Met和c-Src激酶活性的双重抑制可以作为肿瘤靶向治疗的策略。
集落刺激因子-1(CSF-1)又称巨噬细胞集落刺激因子，其受体(CSF-1R)由c-fms原癌基因编码的，CSF-1R是由972个氨基酸残基组成的单链跨膜糖蛋白，属于酪氨酸激酶受体，在单核细胞、巨噬细胞及骨髓细胞的前体、胎膜滋养层和绒毛膜瘤细胞中表达。CSF-1R在细胞外与配体结合部分有5个免疫球蛋白样结构域，细胞内部分中有单个跨膜结构域和分裂激酶结构域。CSF-1R与CSF-1结合可诱导受体二聚化，产生构象变化，从而导致细胞内结构域中酪氨酸残基磷酸化。这些磷酸化残基大部分可吸引效应分子，激活巨噬细胞存活、增殖、分化等一系列信号传导途径。CSF-1及其受体与多种恶性肿瘤的发生和转移密切相关，如在乳腺癌、卵巢癌、鼻咽癌、结直肠癌、胰腺癌以及霍奇金淋巴瘤等肿瘤中能够检测到CSF-1R和CSF-1的共表达。
在多种肿瘤中发现Mf7突变、基因扩增和易位、HGF旁分泌或自分泌上调等导致的HGF/MET途径的异常激活，异常的HGF/MET信号传导不仅导致癌症，也可以协同耐药性的产生，SRC是MET的一个关键下游转换器，它也参与恶性肿瘤的形成、转移和耐药性。在肿瘤微环境中，CSF-1R在肿瘤相关巨噬细胞调节、肿瘤进展和血管生成中发挥作用。因此，MET、SRC和/或CSF-1R的多靶点抑制可以作为治疗肿瘤的有效策略，有效地靶向异常的HGF/MET信号传导，同时靶向肿瘤内在信号传导和肿瘤微环境。
目前已经公开了一系列的SRC、MET和/或CSF-1R多靶点抑制剂专利申请，其中包括WO2019023417等，同时TPX-0022作为MET、SRC和CSF-1R的多靶点抑制剂，目前已经进入临床一期，产生显著的肿瘤生长抑制的同时并没有带来体重减轻等明显的副反应，具有良好的成药性和临床前安全性，有待进一步开发，因而，其它的SRC、MET和/或CSF-1R多靶点抑制剂的开发具有很大的前景和必要性，以解决尚未满足的临床需求。
发明内容
针对上述的技术问题，本发明提供一种通式(I)所示的一类新的大环类化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2020117985-appb-000001
其中：
L 1选自化学键或者-C(＝O)-；优选为化学键；
R 1选自氢原子或氨基；
R 2～R 8相同或不同，各自独立地选自氢原子或氘原子。
本发明的优选方案，一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中L 1选自化学键。
本发明的优选方案，一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 1选自氢原子。
本发明的优选方案，一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 2～R 8选自氢原子。
本发明的典型化合物包括，但不限于：
Figure PCTCN2020117985-appb-000002
或其立体异构体、互变异构体或其可药用的盐。
更进一步，本发明提供了一种药物组合物，所述的药物组合物含有有效剂量的通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备SRC、MET和/或CSF-1R抑制剂中的用途。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗由SRC、MET和/或CSF-1R介导的疾病的药物中的用途，其中所述的由SRC、MET和/或CSF-1R介导的疾病优选为癌症；其中所述的癌症优选为胃癌、结肠癌、肾癌、肝癌、肺癌、胶质母细胞瘤或头颈部肿瘤。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物在制备治疗癌症的药物中的用途，其中所述的癌症优选为胃癌、结肠癌、肾癌、肝癌、肺癌、胶质母细胞瘤或头颈部肿瘤。
发明的详细说明
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
“氨基”指-NH 2。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，有利于活性成分的吸收进而发挥生物活性。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实施例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH&Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD 3OD：氘代甲醇。
CDCl 3：氘代氯仿。
DMSO-d 6：氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用硅胶柱层析洗脱剂体系，其中洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。对化合物制备HPLC分离，具体条件如下：AKZONOBEL Kromasil，250×21.2mm I.D.，5μm，20mL/min；流动性A：0.05％TFA+H 2O，流动性B：CH 3CN，设置不同流动相的配比梯度洗脱。
实施例1
(11R)-2-ethyl-6-fluoro-11-methyl-14-oxo-10-oxa-2,13,17,21,22-pentaazatetracyclo[13.5.2..0 4,9.0 18,22]docosa-1(21),4,6,8,15,17,19-heptaene-5-carbonitrile
(11R)-2-乙基-6-氟-11-甲基-14-氧代-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-5-腈
Figure PCTCN2020117985-appb-000003
第一步
2-溴-3-氟-6-羟基苯甲醛
将2-溴-3-氟苯甲醛1a(8g,40mmol)、2-氨基-4-氯苯甲酸(3.4g,20mmol)、1-氟-2,4,6-三甲基吡啶三氟甲磺酸盐(17g,60mmol)、醋酸钯(898mg,4mmol)和对甲苯磺酸(13.8g,80mmol)加到50mL的醋酸中，室温搅拌10分钟，加热至120℃，反应24小时。反应结束后，冷却至室温，硅藻土过滤，以50mL乙酸乙酯洗涤，滤液减压浓缩，得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂：A体系)，得到2-溴-3-氟-6-羟基苯甲醛1b(5g)。
1H NMR(400MHz,DMSO-d6)δppm 11.77(s,1H),10.33(s,1H),7.26-7.32(dd,J＝8.0Hz,J＝16.0Hz,1H),6.92-6.96(dd,J＝4.0Hz,J＝12.0Hz,1H).
第二步
(S)-(2-(3-溴-4-氟-2-甲酰基苯氧基)丙基)氨基甲酸叔丁酯
将2-溴-3-氟-6-羟基苯甲醛1b(219mg,1mmol)、(R)-5-甲基-1,2,3-恶噻唑烷-3-甲酸叔 丁酯2,2-二氧化物1c(261mg,1.1mmol)和碳酸钾(414mg,3mmol)加到5mL的N,N-二甲基甲酰胺，室温反应3小时。反应结束后，向反应液中加水10mL，用乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂：A体系)，得到(S)-(2-(3-溴-4-氟-2-甲酰基苯氧基)丙基)氨基甲酸叔丁酯1d(376mg)。
MS m/z(ESI):397.9[M+Na]
第三步
(S)-(2-(3-溴-2-((乙基氨基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯
将(S)-(2-(3-溴-4-氟-2-甲酰基苯氧基)丙基)氨基甲酸叔丁酯1d(376mg,1mmol)和乙胺(90mg,2mmol)加到5mL的甲醇中，室温反应30分钟，再加入硼氢化钠(76mg,2mmol)，室温反应2小时。反应结束后，向反应液中加水10mL，用乙酸乙酯萃取(15mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂：A体系)，得到(S)-(2-(3-溴-2-((乙基氨基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯1e(290mg)。
MS m/z(ESI):404.9[M+H]
第四步
(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸乙酯
将(S)-(2-(3-溴-2-((乙基氨基)甲基)-4-氟苯氧基)丙基)氨基甲酸叔丁酯1e(240mg,0.592mmol)、6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯1f(133mg,0.592mmol)和氟化钾(172mg,2.96mmol)加到5mL的二甲基亚砜中，加热至120℃，反应过夜。反应结束后，冷却至室温，向反应液中加水10mL，用乙酸乙酯萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂：A体系)，得到(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸乙酯1g(175mg)。
MS m/z(ESI):593.9[M+H]
第五步
(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸
将(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸乙酯1g(175mg,0.29mmol)和氢氧化锂一水合物(98mg,2.32mmol)加到2.5mL的混合溶液(V 四氢呋喃:V 乙醇:V 水＝2:2:1)中，加热至75℃，反应5小时。反应结束后，冷却至室温，向反应液中加入乙酸乙酯10mL，以10％的柠檬酸水溶液洗涤，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸的粗品1h(164mg)，产物未经纯化， 直接进行下一步反应。
MS m/z(ESI):566.3[M+H]
第六步
(S)-6-((6-((1-氨基丙-2-基)氧基)-2-溴-3-氟苄基)(乙基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸
将(S)-6-((2-溴-6-((1-((叔丁氧基羰基)氨基)丙-2-基)氧基)-3-氟苄基)(乙基)氨基)咪唑[1,2]-b]哒嗪-3-甲酸的粗品1h(164mg,0.29mmol)加到3mL的二氯甲烷中，再加入4M的盐酸/二氧六环溶液0.5mL。室温下反应3小时。反应结束后，反应液减压浓缩，得到(S)-6-((6-((1-氨基丙-2-基)氧基)-2-溴-3-氟苄基)(乙基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸的粗品1i(135mg)，产物未经纯化，直接进行下一步反应。
MS m/z(ESI):466.3[M+H]
第七步
(11R)-5-溴-2-乙基-6-氟-11-甲基-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-14-酮
将(S)-6-((6-((1-氨基丙-2-基)氧基)-2-溴-3-氟苄基)(乙基)氨基)咪唑并[1,2-b]哒嗪-3-甲酸1i(135mg,0.29mmol)、五氟苯基二苯基磷酸酯(134mg,0.35mmol)和N,N-二异丙基乙胺(0.4mL,2.32mmol)溶于6mL的混合溶液中(V 二氯甲烷:V N,N-二甲基甲酰胺＝1:1)，室温下反应16小时。反应结束后，向反应液中加水10mL，用二氯甲烷萃取(10mL×3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物通过硅胶柱层析进一步分离纯化(洗脱剂：B体系)，得到(11R)-5-溴-2-乙基-6-氟-11-甲基-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-14-酮1j(65mg)。
MS m/z(ESI):447.9[M+H]
第八步
(11R)-2-乙基-6-氟-11-甲基-14-氧代-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-5-腈
氩气保护下，将(11R)-5-溴-2-乙基-6-氟-11-甲基-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-14-酮1j(130mg,0.29mmol)、氰化锌(170mg,1.45mmol)、锌(2mg,0.029mmol)、1,1'-双二苯基膦二茂铁(80mg,0.145mmol)和三(二亚苄基丙酮)二钯(53mg,0.058mmol)加到5mL的N,N-二甲基乙酰胺中，加热至130℃，反应3小时。反应结束后，冷却至室温，硅藻土过滤，以20mL乙酸乙酯洗涤，滤液依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的残留物制备液相分离(AKZONOBEL Kromasil，250×21.2mm I.D.，5μm，20mL/min；流动性A：0.05％TFA+H 2O，流动性B：CH 3CN)，得到(11R)-2-乙基-6-氟-11-甲基-14-氧代-10-氧杂-2,13,17,21,22-五氮杂四环[13.5.2.0 4,9.0 18,22]二十二烷-1(21),4,6,8,15,17,19-庚烯-5-腈1(25mg)。
MS m/z(ESI):395.0[M+H]
1H NMR(400MHz,CDCl 3)δppm 9.68(s,1H),8.46(s,1H),8.20(s,1H),7.26-7.31(m,1H), 7.10-7.12(m,2H),5.58-5.64(m,1H),3.86-4.62(m,5H),3.39-3.41(m,1H),1.54-1.61(m,3H),1.30-1.35(m,3H).
生物学评价
测试例1本发明化合物对Src/Met/CSF-1R激酶抑制活性的测试
以下方法用于测定本发明化合物在体外条件下对重组人源Src/Met/CSF-1R激酶活性的抑制程度。本方法使用Cisbio公司的
Figure PCTCN2020117985-appb-000004
KinEASE-TK酪氨酸激酶试剂盒(货号62TK0PEB)，该试剂盒原理基于时间分辨荧光能量共振转移(TF-FRET)，通过测定SRC/MET/CSF-1R激酶介导的生物素化的多肽底物的磷酸化程度来反映化合物对SRC/MET/CSF-1R激酶活性的抑制强弱。详细实验操作可参考试剂盒说明书。重组人源SRC/MET/CSF-1R蛋白均购自SignalChem公司(货号分别为MET#M52-18G-10，SRC#S19-18G-10，CSF-1R#R14-11G-10)
将实验流程简述如下：受试化合物首先溶解于DMSO中制备为贮存液，随后以配置化合物稀释缓冲液(Src：HEPES 50mM，MgCl 25mM，Na 3VO 40.1mM，DTT 1mM，0.01％BSA；Met和CSF-1R：HEPES 50mM，MgCl 25mM，MnCl 2 1mM，Na 3VO 40.1mM，DTT 1mM，0.01％BSA)进行梯度稀释，受试化合物在反应体系中的终浓度范围为1000nM～0.004nM。使用梯度稀释的ATP溶液(生工生物工程(上海)股份有限公司，A600311)的测定Src/Met/CSF-1R蛋白的ATP Km值浓度，依据获得的Km值，设定为相应激酶反应体系中ATP浓度。反应在384孔微孔板中进行，首先向孔中加入化合物和一定量的对应SRC/MET/CSF-1R蛋白，并在室温下孵育5-10分钟，随后向反应液中加入ATP溶液和生物素化的多肽底物溶液，并在室温下振荡孵育40-60分钟。然后向反应中加入偶联有铕系元素化合物的抗磷酸化酪氨酸抗体和偶联有修饰化的别藻蓝蛋白XL665的链酶亲和素，并在室温下继续振荡孵育1小时。孵育结束后，在酶标仪以TF-FRET模式上测定各孔在激发波长为304nm，发射波长为620nM和665nM的荧光强度值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析，或得化合物的IC 50值，见表1。
表1本发明化合物对SRC/MET/CSF-1R激酶活性抑制的IC 50值
Figure PCTCN2020117985-appb-000005
从表1可以看出，本发明化合物1对SRC、MET和CSF-1R激酶具有显著的抑制作用，且对MET激酶的抑制活性显著优于SRC和CSF-1R。
测试例2、本发明化合物ICR小鼠药代动力学研究
1、实验目的
以ICR小鼠为受试动物，采用LC/MS/MS法测定小鼠静脉注射或灌胃给予TPX-0022 和本发明化合物，测定其不同时刻血浆中的药物浓度，研究本发明化合物在小鼠体内的药代动力学特征。
2、实验方案
2.1实验药品与动物
TPX-0022和实施例1化合物；
ICR小鼠，雄性，18只，28.8～37.0g，购买于北京维通利华实验动物技术有限公司。动物质量合格证号：1909270043。
2.2药物配制
静脉注射组：称取适量药物，加入DMA:30％Solutol HS-15:Saline＝10:10:80(v/v/v)，配置最终配置浓度为0.2mg/mL；
口服灌胃组：称取适量药物，加入适量羧甲基纤维素钠(CMC-Na，含0.5％Tween 80)中，涡旋振荡、超声制备0.5mg/mL悬浮液；
2.3给药
ICR小鼠18只，平均分为2组，禁食过夜后分别静脉注射给药(给药剂量1mg/kg，给药体积5mL/kg)和灌胃给药(给药剂量5mg/kg，给药体积10mL/kg)，给药4小时后进食。
3、操作
于给药前和给药后0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时经眼眶采血80μL，EDTA-K2抗凝。血液样本采集后置于冰上，离心分离血浆(离心条件：1500g，10分钟)。收集的血浆分析前存放于–40～–20℃。
用LC-MS/MS测定不同化合物静脉注射和灌胃给药后小鼠血浆中待测化合物含量。
4、药代动力学参数结果
本发明的化合物和阳性对照TPX-0022的药代动力学参数如下表所示。
Figure PCTCN2020117985-appb-000006
备注：N/A表示无相关结果
结论：本发明实施例1化合物与TPX-0022相比，Cmax明显增加，药代吸收良好，半衰期长，清除率低，生物利用度明显提高，具有较好的药代动力学性质。
TPX-0022是根据专利申请WO2019023417公开的方法制备而得，具体结构如下：
Figure PCTCN2020117985-appb-000007

Claims (9)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2020117985-appb-100001
    其中：
    L 1选自化学键或者-C(＝O)-；优选为化学键；
    R 1选自氢原子或氨基；
    R 2～R 8相同或不同，各自独立地选自氢原子或氘原子。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中L 1选自化学键。
  3. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 1选自氢原子。
  4. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 2～R 8选自氢原子。
  5. 根据权利要求1～4中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物选自：
    Figure PCTCN2020117985-appb-100002
  6. 一种药物组合物，所述的药物组合物含有有效剂量的根据权利要求1～5中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
  7. 根据权利要求1～5中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求6所述的药物组合物在制备SRC、MET和/或CSF-1R抑制剂中的用途。
  8. 根据权利要求1～5中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求6所述的药物组合物在制备治疗由SRC、MET和/或CSF-1R介导的疾病的药物中的用途，其中所述的由SRC、MET和/或CSF-1R介导的疾病优选为癌症；其中所述的癌症优选为胃癌、结肠癌、肾癌、肝癌、肺癌、胶质母细胞瘤或头颈部肿瘤。
  9. 根据权利要求1～5中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求6所述的药物组合物在制备治疗癌症的药物中的用途，其中所述的癌症优选为胃癌、结肠癌、肾癌、肝癌、肺癌、胶质母细胞瘤或头颈部肿瘤。
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