WO2021139717A1 - 氘代噻吩并吡啶类化合物 - Google Patents

氘代噻吩并吡啶类化合物 Download PDF

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WO2021139717A1
WO2021139717A1 PCT/CN2021/070646 CN2021070646W WO2021139717A1 WO 2021139717 A1 WO2021139717 A1 WO 2021139717A1 CN 2021070646 W CN2021070646 W CN 2021070646W WO 2021139717 A1 WO2021139717 A1 WO 2021139717A1
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compound
present
acid
pharmaceutically acceptable
acceptable salt
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PCT/CN2021/070646
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English (en)
French (fr)
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付志飞
罗妙荣
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202180008603.4A priority Critical patent/CN114945576B/zh
Priority to US17/790,985 priority patent/US20230094146A1/en
Priority to EP21738457.7A priority patent/EP4089095A4/en
Priority to JP2022542061A priority patent/JP7434575B2/ja
Publication of WO2021139717A1 publication Critical patent/WO2021139717A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a series of deuterated thienopyridine compounds, in particular to compounds represented by formula (I) and pharmaceutically acceptable salts thereof.
  • the present invention is a multi-receptor tyrosine kinase inhibitor (tyrosinekinasesinhibitor), which targets RET, MET, VEGFR-1, -2, -3, KIT, TRKB, FLT-3, AXL, TIE-2 and the like.
  • Tyrosine kinases play a very important role in the occurrence and development of tumors.
  • the research and development of drugs with tyrosine kinases as the target has become a hot spot in the research of anti-tumor drugs in the world.
  • Tyrosinase inhibitors can achieve anti-tumor effects by inhibiting the damage and repair of tumor cells, stagnating cell division in G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis.
  • the present invention relates to compounds that inhibit the activity of protein tyrosine kinases.
  • Tyrosine kinases can be divided into growth factor receptor (such as EGFR, PDGFR, FGFR and erbB2) or non-receptor (such as c-src and bcr-abl) kinases.
  • Receptor tyrosine kinases include about 20 different industry families.
  • Non-receptor tyrosine kinases include many subfamilies. These tyrosine kinases have different biological activities.
  • Receptor tyrosine kinases are huge enzymes that are transmembrane and have extracellular binding regions for growth factors, transmembrane regions, and intracellular groups that function as kinases that phosphorylate specific tyrosine residues in proteins. , And therefore affect cell proliferation. Improper or inappropriate protein kinase activity can produce disease states associated with these inappropriate kinase activity.
  • Sitravatinib developed by Mirati is a kind of the above-mentioned kinase inhibitor. Its structure is as Formula II. It has shown good efficacy in clinical practice. However, due to its insufficient stability in humans and higher dosages, more research and development is needed. Stable and more reliable alternative drugs, with lower doses, to achieve the same or better curative effect.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 Each is independently selected from H and D, and one of them must be selected from D.
  • R 1 , R 2 and R 3 are independently selected from H and D, and other variables are as defined in the present invention.
  • R 4 and R 5 are independently selected from H and D, and other variables are as defined in the present invention.
  • R 6 and R 7 are independently selected from H and D, and other variables are as defined in the present invention.
  • R 8 and R 9 are independently selected from H and D, and other variables are as defined in the present invention.
  • R 10 is selected from H and D, and other variables are as defined in the present invention.
  • R 11 is selected from H and D, and other variables are as defined in the present invention.
  • R 12 is selected from H and D, and other variables are as defined in the present invention.
  • R 13 is selected from H and D, and other variables are as defined in the present invention.
  • R 14 , R 15 , R 16 and R 17 are independently selected from H and D, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are as defined in the present invention.
  • the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the application of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of medicines for diseases related to tyrosine kinase.
  • the compound of the present invention has a good inhibitory effect on Axl, c-Kit, Mer, DDR2, VEGFR1, VEGFR2, VEGFR3, TrkA and FLT3, and has good liver microsomal metabolic stability and better pharmacokinetic properties.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • D in the present invention represents deuterium ( 2 H).
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
  • SXRD single crystal X-ray diffraction
  • the cultivated single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • Step 1 Synthesis of compound 001-03
  • reaction solution was concentrated to dryness, ethyl acetate (100 mL) and water (100 mL) were added to dissolve and dilute, the organic phase was separated, washed with water (100 mL), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • the crude product was separated by silica gel column chromatography (120 g flash column, content of ethyl acetate in petroleum ether: 0-100%) to obtain compound 001-04.
  • Step 8 Synthesis of compound 001
  • compound 002-06 (799.09 mg, 4.71 mmol, 3.0 eq) and tetrahydrofuran (8 mL) were added to a 100 mL three-necked flask. After cooling to -78°C, n-butyllithium (2.5M, 1.88mL, 3.0eq) was added dropwise.
  • Buffer conditions 20mM hydroxyethylpiperazine ethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM ethylene glycol diaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene lauryl ether ( Brij35), 0.02mg/ml BSA, 0.1mM Na 3 VO 4 , 2mM dithiothreitol (DTT), 1% DMSO.
  • Hepes 20mM hydroxyethylpiperazine ethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM ethylene glycol diaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene lauryl ether ( Brij35), 0.02mg/ml BSA, 0.1mM Na 3 VO 4 , 2mM dithiothreitol
  • Test procedure Dissolve the substrate in the newly prepared buffer, add the tested kinase to it and mix gently. Using acoustic technology (Echo 550), the DMSO solution with the test compound dissolved in the above mixed reaction solution was added and incubated at room temperature for 20 minutes. The compound concentration in the reaction solution was 3 ⁇ M, 1 ⁇ M, 0.333 ⁇ M, 0.111 ⁇ M, 0.0370 ⁇ M, 0.0123 ⁇ M, 4.12nM, 1.37nM, 0.457nM, 0.152nM. After 15 minutes of incubation, 33 P-ATP (activity 0.01 ⁇ Ci/ ⁇ L, Km concentration) was added to start the reaction. After the reaction was carried out at room temperature for 120 minutes, the radioactivity was detected by the filter binding method.
  • Echo 550 acoustic technology
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with that of the blank group (only containing DMSO).
  • the IC 50 value is obtained by curve fitting with Prism4 software (GraphPad). The experimental results are shown in Table 1.
  • the compound of the present invention shows good inhibitory activity on Axl, c-Kit, Mer, DDR2, VEGFR1, VEGFR2, VEGFR3, TrkA, FLT3.
  • mice were purchased from Corning, Xenotech or BioIVT, and stored in a refrigerator at -80°C.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • Control compounds testosterone, diclofenac, propafenone.
  • Working concentration preparation 100% acetonitrile diluted to 100 ⁇ M (organic phase content: 99% ACN, 1% DMSO).
  • microsomal working solution live microsomal protein concentration of 0.56 mg/mL
  • the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 ⁇ M
  • the concentration of liver microsomes is 0.5mg/mL
  • the final concentration of DMSO and acetonitrile in the reaction system are 0.01% (v/v) and 0.99% (v/v), respectively.
  • stop solution containing 200 ng/mL tolbutamide and 200 ng/mL labetalol to the sample wells of each stop plate.
  • Acetonitrile solution After incubating for an appropriate time (such as 5, 10, 20, 30, and 60 minutes), add 180 ⁇ L of stop solution (containing 200 ng/mL tolbutamide and 200 ng/mL labetalol to the sample wells of each stop plate). Acetonitrile solution), and then take out 60 ⁇ L sample from the T60 incubation plate to stop the reaction.
  • the rodent pharmacokinetic characteristics of the compounds after oral administration were tested in a standard protocol.
  • the candidate compounds were prepared into clear solutions and administered to rats orally.
  • the solvent is 10% NMP/40% PEG400/50%. Collect whole blood samples within 24 hours (0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24h), and add all blood samples to plastic centrifuge tubes pre-labeled with 0.5M K2-EDTA anticoagulant.
  • C max peak concentration
  • T max peak time
  • AUC 0-last area under the plasma concentration-time curve from the zero time point to the last detectable concentration time point.
  • the pharmacokinetic index of the compound of the present invention is good in rats, and the exposure of compound 001 is better than that of the reference compound sitravatinib.

Abstract

氘代噻吩并吡啶类化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

氘代噻吩并吡啶类化合物
本发明主张如下优先权：
申请号：CN202010015514.X，申请日：2020年01月07日；
申请号：CN202010323048.1，申请日：2020年04月22日；
申请号：CN202010389596.4，申请日：2020年05月08日。
技术领域
本发明涉及一系列氘代噻吩并吡啶类化合物，具体涉及了式(I)所示化合物及其药学上可接受的盐。
背景技术
本发明是一种多受体酪氨酸激酶抑制剂(tyrosinekinasesinhibitor)，靶向RET、MET、VEGFR-1，-2，-3、KIT、TRKB、FLT-3、AXL、TIE-2等。酪氨酸激酶在肿瘤的发生、发展过程中起着非常重要的作用，以酪氨酸激酶为靶点进行药物研发己成为国际上抗肿瘤药物研究的热点。酪氨酸酶抑制剂通过抑制肿瘤细胞的损伤修复、使细胞***阳滞在G1期、诱导和维持细胞凋亡、抗新生血管形成等多途径实现抗肿瘤效果。
本发明涉及抑制蛋白酪氨酸激酶活性的化合物。酪氨酸激酶可分为生长因子受体(如EGFR、PDGFR、FGFR和erbB2)或非受体(如c-src和bcr-abl)激酶。受体型酪氨酸激酶包括约20个不同的业家族。非受体型酪氨酸激酶包括许多亚家族。这些酪氨酸激酶具有不同的生物活性。受体酪氨酸激酶是巨大的酶，其跨膜且具有对于生长因子的细胞外结合区域、跨膜区域、和功能为在蛋白质中磷酸化特定酪氨酸残基的激酶的细胞内基团，且因此影响细胞增殖。不当或不适合的蛋白激酶活性能够产生与这些不当激酶活性相关的疾病状态。
Mirati公司研发的Sitravatinib是一款上述的激酶抑制剂，结构如式II，已在临床中展现出良好的药效，但由于其在人体中的稳定性不够，给药剂量较高，需要研发更稳定、更可靠的替代药物，以更低的给药剂量，实现同等或更好的疗效。
Figure PCTCN2021070646-appb-000001
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021070646-appb-000002
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17分别独立地选自H和D，且其中必有一个选自D。
在本发明的一些方案中，上述R 1、R 2和R 3分别独立地选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 4、R 5分别独立地选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 6和R 7分别独立地选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 8和R 9分别独立地选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 10选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 11选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 12选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 13选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述R 14、R 15、R 16和R 17分别独立选自H和D，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2021070646-appb-000003
其中，R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17如本发明所定义。
本发明提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2021070646-appb-000004
本发明还提供了上述化合物或其药学上可接受的盐在制备与酪氨酸激酶相关疾病的药物中的应用。
技术效果
本发明化合物对Axl、c-Kit、Mer、DDR2、VEGFR1、VEGFR2、VEGFR3、TrkA和FLT3具有较好的抑制作用，具有较好的肝微粒体代谢稳定性和较优的药代动力学性质。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过 敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，本发明所述D代表氘( 2H)。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位 点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021070646-appb-000005
直形虚线键
Figure PCTCN2021070646-appb-000006
或波浪线
Figure PCTCN2021070646-appb-000007
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021070646-appb-000008
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021070646-appb-000009
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2021070646-appb-000010
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021070646-appb-000011
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021070646-appb-000012
仍包括
Figure PCTCN2021070646-appb-000013
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021070646-appb-000014
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021070646-appb-000015
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2021070646-appb-000016
合成路线：
Figure PCTCN2021070646-appb-000017
Figure PCTCN2021070646-appb-000018
步骤1：化合物001-03的合成
将化合物001-01(20g,107.52mmol,1eq)和化合物001-02(7.88g,129.03mmol,7.80mL,1.2eq)溶于二氯甲烷(200mL)中，在20℃加入醋酸硼氢化钠(29.63g,139.78mmol,1.3eq)，继续反应1.5小时，浓缩干得化合物001-03。
LCMS:MS(ESI)m/z:231.1[M+1] +。
步骤2：化合物001-04的合成
将化合物001-03(24.85g,107.53mmol,1eq)溶于二氯甲烷(200mL)加入三乙胺(38.08g,376.37mmol,52.39mL,3.5eq)，接着加入二碳酸二叔丁酯(28.16g,129.04mmol,29.64mL,1.2eq)，在20℃反应1小时。将反应液浓缩干，加入乙酸乙酯(100mL)和水(100mL)溶解稀释，分出有机相，水洗(100mL)，饱和氯化钠溶液洗(100mL)，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(120g快速柱，乙酸乙酯在石油醚的含量:0-100％)分离得化合物001-04。
LCMS:MS(ESI)m/z:331.1[M+1] +；
1H NMR(400MHz,CDCl 3)δ1.45(br s,9H),3.27-3.41(m,2H),3.73(br s,2H),4.46(br s,2H),7.47(br s,2H),8.27(br s,1H)。
步骤3：化合物001-05的合成
将化合物001-04(22g,66.42mmol,1eq)溶于四氢呋喃(250mL)和二甲基甲酰胺(44mL)中，接着加入碳酸铯(32.46g,99.64mmol,1.5eq)，然后加入氘代碘甲烷(14.44g,99.64mmol,6.20mL,1.5eq)，在35℃反应63小时。将反应液趁热过滤，浓缩。粗品经硅胶柱层析(120g快速柱，乙酸乙酯在石油醚的含量:0-30％)分离得化合物001-05。
LCMS:MS(ESI)m/z:348.1[M+1] +。
步骤4：化合物001-07的合成
将化合物001-06(10.39g,61.28mmol,2eq)溶于四氢呋喃(150mL)中，干冰乙醇浴降温至-78℃，接着缓慢滴加正丁基锂(2.5M,24.51mL,2eq)，滴毕继续搅拌0.5小时，接着加入氯化锌(2M,30.64mL,2eq)，然后移至20℃反应1小时，再加入化合物001-05(10.67g,30.64mmol,1eq)和四三苯基膦钯(1.06g,919.17μmol,0.03eq)的四氢呋喃(100mL)，移至70℃反应1小时。往反应液中加入 饱和碳酸氢钠溶液(20mL)，接着加入乙酸乙酯(100mL)，分出有机相，饱和氯化钠溶液(150mL)洗，无水硫酸钠干燥，浓缩。粗品经硅胶柱层析(120g快速柱，乙酸乙酯在石油醚的含量:0-80％)分离得化合物001-07。LCMS:MS(ESI)m/z:437.0[M+1] +；
1H NMR(400MHz,CDCl 3)δ1.49(br d,J＝19.58Hz,9H),3.23-3.72(m,4H),4.59(br s,2H),7.29(d,J＝5.02Hz,1H),7.62-7.80(m,1H),7.86(d,J＝8.28Hz,1H),7.99(s,1H),8.52-8.62(m,2H)。
步骤5：化合物001-09的合成
将化合物001-08(719.04mg,4.58mmol,2eq)和化合物001-07(1g,2.29mmol,1eq)溶于氯苯(5mL)中，接着加入二异丙基乙胺(739.43mg,5.72mmol,996.53μL,2.5eq)，在140℃反应40小时。将反应液浓缩。粗品经硅胶柱层析(乙酸乙酯在石油醚的含量:0-60％)分离得化合物001-09。
LCMS:MS(ESI)m/z:558.2[M+1] +；
1H NMR(400MHz,CDCl 3)δ1.48(br d,J＝13.55Hz,9H),3.27-3.61(m,4H),4.58(br s,2H),6.71(d,J＝5.27Hz,1H),7.35(t,J＝8.28Hz,1H),7.62-7.76(m,1H),7.86(d,J＝8.03Hz,1H),8.01(s,1H),8.09-8.22(m,2H),8.53(s,1H),8.61(d,J＝5.27Hz,1H)。
步骤6：化合物001-10的合成
将化合物001-09(200mg,358.68μmol,1eq)溶于乙醇(4mL)和水(2mL)中，接着加入铁粉(60.09mg,1.08mmol,3eq)和氯化铵(19.19mg,358.68μmol,1eq)，在70℃反应3小时。将反应液趁热滤去不溶物，母液浓缩，接着用二氯甲烷(20mL)溶解，加入无水硫酸钠，滤去不溶物，浓缩得化合物001-10。
LCMS:MS(ESI)m/z:528.2[M+1] +。
步骤7：化合物001-12的合成
将化合物001-10(176mg,333.57μmol,1eq)，化合物001-11(96.79mg,433.64μmol,1.3eq)溶于二氯甲烷(4mL)中，接着加入二异丙基乙胺(86.22mg,667.14μmol,116.20μL,2eq)和O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(177.57mg,467.00μmol,1.4eq)，在39℃反应6小时。往反应液中加入水(20mL)，分出有机相，有机相用饱和碳酸氢钠溶液(30mL)洗，饱和氯化钠溶液(30mL)洗，浓缩。粗品经硅胶柱层析(4g快速柱，甲醇在二氯甲烷的含量:0-6％)分离得化合物001-12。
LCMS:MS(ESI)m/z:733.3[M+1] +。
步骤8：化合物001的合成
将化合物001-12(196mg,267.46μmol,1eq)溶于二氯甲烷(5mL)中，接着加入三氟乙酸(3.08g,27.01mmol,2mL,100.99eq)，在20℃反应1小时，将反应液浓缩干。粗品经高效液相色谱分离(柱子:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:22％-52％,8min)得目标化合物001的三氟乙酸盐。
LCMS:MS(ESI)m/z:633.2[M+1] +；
1H NMR(400MHz,CD 3OD)δ1.66(m,4H),3.33(br s,2H),3.66-3.74(m,2H),4.37(s,2H),6.88(d,J＝5.77Hz,1H),7.03-7.13(m,2H),7.40-7.50(m,2H),7.53-7.60(m,2H),7.90(dd,J＝12.67,2.13Hz,1H),8.10(dd,J＝8.16,2.13Hz,1H),8.22-8.30(m,2H),8.62(br d,J＝5.52Hz,1H),8.76(d,J＝1.51Hz,1H)。
实施例2
Figure PCTCN2021070646-appb-000019
合成路线：
Figure PCTCN2021070646-appb-000020
步骤1：化合物002-02的合成
在100mL的瓶中加入002-01(18g,80.64mmol,1eq)，氘代甲醇(50mL)，氘代硼氢化钠(9.76 g,258.04mmol,3.2eq)，在25℃下搅拌2小时。反应液体加入饱和氯化铵(50mL)，后加入乙酸乙酯(100mL)萃取，萃取三次滤液合并浓缩后，用饱和食盐水(100mL×3)洗涤，浓缩得到化合物002-2。
LCMS:MS(ESI)m/z:197.9[M+1] +。
步骤2：化合物002-03的合成
在100mL瓶中加入化合物002-2(5.1g,25.86mmol,1eq)，乙醇(20mL)，钯碳(500mg,10％纯度,1.00eq)，氢气抽换气三次，在15psi压力，40℃下加热搅拌48小时。过滤除去钯碳，反应液浓缩得到化合物002-03。
1H NMR(400MHz,CD 3OD)δppm 2.76(s,2H)。
步骤3：化合物002-04的合成
在100mL的瓶中加入002-03(1.26g,19.97mmol,2.80mL,1.0eq)，001-01(3.71g,19.97mmol,1eq)，1,2-二氯乙烷(2mL)。搅拌20分钟后加入醋酸硼氢化钠(4.87g,22.97mmol,1.15eq)在25℃下搅拌16小时，得到化合物002-04的溶液，未分离直接下一步。
LCMS:MS(ESI)m/z:232.9[M+1] +。
步骤4：化合物002-05的合成
在上一步化合物002-04的溶液中加入三乙胺(12.11g,119.69mmol,16.66mL,6.0eq)，二碳酸二叔丁酯(13.06g,59.85mmol,13.75mL,3.0eq)在25℃下搅拌3小时。反应液体旋干，柱层析(20-100％乙酸乙酯在石油醚中)得到化合物002-05。
LCMS:MS(ESI)m/z:333.1[M+1] +。
步骤5：化合物002-06的合成
在0℃氮气氛围下加入化合物002-05(1.5g,4.50mmol,1eq)，N,N-二甲基甲酰胺(10mL)，氢化钠(235.88mg,5.90mmol,60％含量,1.31eq)，搅拌30分钟，后加入氘代碘甲烷(1.28g,9.00mmol,560.48μL,2.0eq)在25℃下搅拌2小时。反应液体加入饱和氯化铵，后加入乙酸乙酯(20mL×3)萃取，合并有机相，浓缩。柱层析(20-100％乙酸乙酯在石油醚中)得到化合物002-06。
LCMS:MS(ESI)m/z:350.1[M+1] +。
步骤6：化合物002-07的合成
氮气氛围中在100mL三颈瓶中加入化合物002-06(799.09mg,4.71mmol,3.0eq)，四氢呋喃(8mL)。冷却到-78℃下后滴加正丁基锂(2.5M,1.88mL,3.0eq)。搅拌30分钟后加入二氯化锌的2-甲基四氢呋喃溶液(2M,2.36mL,3.0eq)，缓慢升温至25℃，搅拌1小时后加入四三苯基膦钯(181.45mg,157.03μmol,0.1eq)，化合物001-06(550mg,1.57mmol,1eq)的四氢呋喃(8mL)溶剂。后在70℃下加入回流1小时。反应液加入饱和氯化铵(10mL)，后加入乙酸乙酯(10mL×3)萃取，合并有机相，浓缩。柱层析(0-50％二氯甲烷在乙酸乙酯中)得到化合物002-07。
LCMS:MS(ESI)m/z:439.0[M+1] +。
步骤7：化合物002-08的合成
在50mL的瓶中加入化合物002-07(474mg,1.08mmol,1eq)，氯苯(5mL)，二异丙基胺(348.88mg,2.70mmol,470.19μL,2.5eq)和化合物001-08(339.26mg,2.16mmol,2.0eq)，在140℃下搅拌72小时。浓缩反应液，柱层析(二氯甲烷:乙酸乙酯＝20％-100％)得到化合物002-08。
LCMS:MS(ESI)m/z:560.1[M+1] +。
步骤8：化合物002-09的合成
在10mL的瓶中加入化合物002-08(160mg,285.91μmol,1eq)，氯化铵固体(15.29mg,285.91μmol,1eq)，铁粉(79.83mg,1.43mmol,5.0eq)，乙醇(4mL)和水(2mL)，在70℃下搅拌3小时。过滤除去固体，浓缩反应液体，用5mL二氯甲烷洗涤，后加入二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥半小时，过滤，浓缩，得到粗产品化合物002-09。
LCMS:MS(ESI)m/z:530.1[M+1] +。
步骤9：化合物002-10的合成
在10mL的瓶中加入化合物002-09(151mg,285.10μmol,1.0eq)，化合物001-11(76.36mg,342.12μmol,1.2eq)，二异丙基乙胺(151mg,285.10μmol,1.0eq)，二氯甲烷(3mL)和O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(162.61mg,427.65μmol,1.5eq)，在40℃下搅拌3小时。将反应液浓缩，加入3mL甲醇HPLC分离。柱子:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:50％-80％,7min。得到化合物002-10。
LCMS:MS(ESI)m/z:735.3[M+1] +。
步骤10：化合物002的合成
在50mL的瓶中加入化合物002-10(70mg,95.26μmol,1eq)，甲醇(0.2mL)，氯化氢/二氧六环(4M,23.82μL,1eq)，在25℃下搅拌16小时。反应液直接高效液相色谱分离，分离条件：柱子:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:20％-40％,7min得到产物002的盐酸盐。
LCMS:MS(ESI)m/z:635.2[M+1] +；
1H NMR(400MHz,CD 3OD)δppm 1.67(s,4H),3.08(s,2H),4.15(s,2H),6.68(d,J＝5.52Hz,1H),7.09(t,J＝8.78Hz,2H),7.34-7.50(m,2H),7.58(dd,J＝8.91,4.89Hz,2H),7.87(dd,J＝12.67,2.13Hz,1H),8.01(br d,J＝8.03Hz,1H),8.07-8.27(m,2H),8.47-8.57(m,1H),8.68(s,1H)。
生物测试数据：
实验例1：激酶体外抑制活性评价
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对Axl、c-Kit、Mer、DDR2、VEGFR1、VEGFR2、VEGFR3、TrkA、FLT3的抑制能力。
缓冲液条件：20mM羟乙基哌嗪乙硫磺酸(Hepes)(pH 7.5),10mM MgCl 2,1mM乙二醇双氨乙基醚四乙酸(EGTA),0.02％聚氧乙烯十二烷醚(Brij35),0.02mg/ml BSA,0.1mM Na 3VO 4,2mM二硫苏糖醇(DTT),1％DMSO。
化合物处理：将测试化合物溶于100％DMSO中并由Integra Viaflo Assist用DMSO连续稀释至特定浓度。
试验步骤：将底物溶解在新配制的缓冲液中，向其中加入受测激酶并轻轻混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中，并在室温下孵育20分钟。反应液中化合物浓度为3μM,1μM,0.333μM,0.111μM,0.0370μM,0.0123μM,4.12nM,1.37nM,0.457nM,0.152nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μL，Km浓度)开始反应。反应在室温下进行120分钟后，通过过滤器结合方法检测放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC 50值，实验结果如表1所示。
表1：本发明化合物体外筛选试验结果
Figure PCTCN2021070646-appb-000021
结论：本发明化合物对Axl、c-Kit、Mer、DDR2、VEGFR1、VEGFR2、VEGFR3、TrkA、FLT3都展现出较好的抑制活性。
实验例2：体外肝微粒体代谢稳定性评价
1.材料
1.1肝微粒体
SD大鼠、小鼠、比格犬、食蟹猴和人微粒体购买于Corning、Xenotech或BioIVT，储存于-80℃冰箱。
1.2还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：Chem-impex international，货号：00616。
1.3对照化合物：睾酮，双氯芬酸，普罗帕酮。
2.实验步骤
2.1工作液的配制
储备液：10mM DMSO溶液。
工作浓度配制：100％乙腈稀释到100μM(有机相含量：99％ACN，1％DMSO)。
2.2实验步骤
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL甲糖宁和200ng/mL拉贝洛尔的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μLNADPH再生体系工作液启动反应。在空白板中只添加54μL微粒体工作液、6μL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。
孵育适当时间(如5、10、20、30和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。
所有样品板摇匀并在3220×g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。
3.液相色谱串联质谱分析
所有样品进样分析。
实验结果如表2所示。
表2：本发明化合物体外肝微粒代谢稳定性试验结果
Figure PCTCN2021070646-appb-000022
注：CL int(liver)：肝固有清除率。
结论：本发明化合物对比文献化合物sitravatinib都展现出更好的稳定性。
实验例3：化合物药代动力学评价
实验目的：
测试本发明化合物在大鼠体内药代动力学性质
实验材料：
SD大鼠(雄性)
实验操作：
以标准方案测试化合物口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予大鼠口服给药。溶媒为10％NMP/40％PEG400/50％。收集24小时内(0.0833，0.25、0.5、1、2、4、6、8、24h)的全血样品，所有血样均加入预先加好0.5M K2-EDTA抗凝剂标记好的塑料离心管。血样采集后，4℃，3000xg离心10分钟吸取上清血浆，迅速置于干冰中，保持-20℃或更低温度，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
实验结果：
表3：大鼠药代动力学测试结果
Figure PCTCN2021070646-appb-000023
注：C max：峰浓度；T max：达峰时间；AUC 0-last：从零时间点到最后一个可检测到浓度时间点的血浆浓度-时间曲线下面积。
结论：本发明化合物大鼠药代动力学指标良好，001化合物的暴露量优于参考化合物sitravatinib。

Claims (12)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021070646-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17分别独立地选自H和D，且其中必有一个选自D。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1、R 2和R 3分别独立地选自H和D。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 4和R 5分别独立地选自H和D。
  4. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 6和R 7分别独立地选自H和D。
  5. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 8和R 9分别独立地选自H和D。
  6. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 10选自H和D。
  7. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 11选自H和D。
  8. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 12选自H和D。
  9. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 13选自H和D。
  10. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 14、R 15、R 16和R 17分别独立选自H和D。
  11. 下式所示化合物或其药学上可接受的盐，
    Figure PCTCN2021070646-appb-100002
    Figure PCTCN2021070646-appb-100003
  12. 根据权利要求1～11任意一项所述的化合物或其药学上可接受的盐在制备与酪氨酸激酶相关疾病的药物中的应用。
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