WO2021023195A1 - 吡嗪-2（1h）-酮类化合物的d晶型及其制备方法 - Google Patents

吡嗪-2（1h）-酮类化合物的d晶型及其制备方法 Download PDF

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WO2021023195A1
WO2021023195A1 PCT/CN2020/106901 CN2020106901W WO2021023195A1 WO 2021023195 A1 WO2021023195 A1 WO 2021023195A1 CN 2020106901 W CN2020106901 W CN 2020106901W WO 2021023195 A1 WO2021023195 A1 WO 2021023195A1
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compound
crystal form
formula
preparation
present
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PCT/CN2020/106901
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French (fr)
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陈志亮
罗志毅
庄毅超
林锦霞
高龙辉
付志飞
罗妙荣
张杨
黎健
陈曙辉
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漳州片仔癀药业股份有限公司
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Priority to CN202080054561.3A priority Critical patent/CN114269723B/zh
Priority to JP2022507756A priority patent/JP7200437B2/ja
Priority to ES20850461T priority patent/ES2968388T3/es
Priority to US17/633,299 priority patent/US11597722B2/en
Priority to EP20850461.3A priority patent/EP4011869B1/en
Publication of WO2021023195A1 publication Critical patent/WO2021023195A1/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
    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention relates to a crystal form of a pyrazine-2(1H)-one compound and a preparation method thereof, in particular to a preparation method of a compound of formula (II) and a crystal form thereof.
  • Fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signal transduction. Its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), and is composed of extracellular immunoglobulin ( Ig)-like domain, hydrophobic transmembrane domain and intracellular part including tyrosine kinase domain. Fibroblast growth factor (FGF) through these receptors (FGFR) plays an important role in many physiological regulation processes such as cell proliferation, cell differentiation, cell migration and angiogenesis.
  • FGF fibroblast growth factor
  • FGF signaling pathway high expression, gene amplification, gene mutation, chromosomal reorganization, etc.
  • pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target, attracting extensive research and development interest.
  • the present invention provides crystal form D of the compound of formula (II), and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.42 ⁇ 0.20°, 26.28 ⁇ 0.20°, 27.72 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form D of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.42 ⁇ 0.20°, 10.92 ⁇ 0.20°, 14.60 ⁇ 0.20°, 20.08 ⁇ 0.20°, 23.19 ⁇ 0.20°, 24.11 ⁇ 0.20°, 26.28 ⁇ 0.20°, 27.72 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form D of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.42 ⁇ 0.20°, 10.92 ⁇ 0.20°, 14.60 ⁇ 0.20°, 19.31 ⁇ 0.20°, 20.08 ⁇ 0.20°, 23.19 ⁇ 0.20°, 24.11 ⁇ 0.20°, 24.92 ⁇ 0.20°, 26.28 ⁇ 0.20°, 27.08 ⁇ 0.20°, 27.72 ⁇ 0.20°, 29.29 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystal form D of the compound of formula (II) has characteristic diffraction peaks at the following 2 ⁇ angles: 9.42°, 10.92°, 14.60°, 16.61°, 19.31°, 20.08 °, 23.19°, 24.11°, 24.92°, 26.28°, 27.08°, 27.72°, 29.29°, 30.39°, 33.92°, 38.33°.
  • the XRPD pattern of the crystal form D of the compound of formula (II) is shown in FIG. 1.
  • the XRPD pattern analysis data of the crystal form D of the compound of formula (II) is shown in Table 1.
  • the crystalline form D of the compound of formula (II) above has a differential scanning calorimetry curve with the starting point of the endothermic peak at 179.1°C ⁇ 2.0°C and the endothermic peak at 247.1°C ⁇ 2.0°C The starting point of the peak.
  • the DSC chart of the crystal form D of the compound of formula (II) is shown in FIG. 2.
  • thermogravimetric analysis curve of the D crystal form of the compound of formula (II) has a weight loss of 7.11% at 190.0°C ⁇ 3.0°C, a weight loss of 12.10% at 250.0°C ⁇ 3.0°C, and a weight loss of 12.10% at 290.0°C ⁇ 3.0°C. Weightlessness reached 14.12%.
  • the crystal form D of the compound of formula (II) above has a TGA pattern as shown in FIG. 3.
  • the present invention also provides the application of the above-mentioned compound D crystal form of formula (II) in the preparation of drugs for treating diseases related to FGFR.
  • the crystal form of compound D of formula (II) has good stability and is easy to prepare medicine. According to the experimental examples of the trifluoroacetate salt of compound of formula (I), it can be seen that the crystal form of compound of formula (II) has better performance against wild-type FGFR. Inhibitory activity, and the selectivity of FGFR2, 3 to FGFR1, 4 is higher. The mouse pharmacokinetic index of the crystal form of compound D of formula (II) is good.
  • the trifluoroacetate salt of the compound of formula (I) shows good inhibitory activity against wild-type FGFR, and FGFR2, 3 has high selectivity to FGFR1, 4.
  • the trifluoroacetate salt of the compound of formula (I) has a good pharmacokinetic index in mice.
  • 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.
  • eq stands for equivalent or equivalent
  • PE petroleum ether
  • DMSO dimethyl sulfoxide
  • MeOH stands for methanol
  • TFA trifluoroacetic acid
  • the solvent used in the present invention can be obtained commercially, and the commercially available compound adopts the supplier's catalog name.
  • the solvents can be mixed first and then added to the reaction solution; or each single solvent can be added to the reaction solution in sequence and mixed in the reaction system.
  • Light tube voltage 40kV
  • light tube current 40mA
  • the method is: 25°C-300 or 350°C, 10°C/min.
  • Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of the D crystal form of compound of formula (II).
  • Figure 2 is a DSC spectrum of the crystal form D of compound of formula (II).
  • Figure 3 is a TGA spectrum of the crystal form D of compound of formula (II).
  • compound BB-2-1 (2.0g, 18.77mmol, 2.17mL, 1eq, HCl) was dissolved in chlorobenzene (15.0mL), and compound BB-2-2 (8.3g , 65.69mmol, 5.8mL, 3.5eq), the mixture was slowly heated to 90°C and stirred for 16 hours.
  • Water (30.0 mL) and ethyl acetate (30.0 mL) were added to the reaction system, and the layers were separated while standing, while the aqueous phase was extracted three times with ethyl acetate (20.0 mL, 20.0 mL, 20.0 mL).
  • compound 4 250mg, 890.61 ⁇ mol, 1eq was dissolved in a mixed solvent of acetonitrile (20.0mL) and dichloromethane (5.0mL), and sulfonyl chloride (84mg, 623.43 ⁇ mol, 62.33 ⁇ L, 0.7 eq) in acetonitrile (2.5 mL), and the mixture was stirred at 0°C for 10 minutes.
  • Methanol 5.0 mL was added to the reaction solution to quench the reaction, and it was concentrated to dryness under reduced pressure.
  • the compound of formula (I) (44.4 g, 94.89 mmol, 1 eq) was dissolved in tetrahydrofuran (450 mL), and then an ethyl acetate solution of hydrogen chloride (4M, 94.89 mL, 4 eq) was added dropwise, and the mixture was stirred at 25° C. for 3 hrs. The reaction liquid was filtered to obtain a yellow solid, and the oil pump was pulled dry. The compound of formula (II) is obtained.
  • the compound of formula (II) (0.4g, 793.07umol, 1eq) was added to acetonitrile (6mL), stirred at 50°C for 60hrs, and filtered. The filter cake was dried in a vacuum drying oven at 50° C. for 3.5 hrs to obtain the D crystal form of the compound of formula (II).
  • the 33 P isotope-labeled kinase activity test (Reaction Biology Corp) was used to determine the IC 50 value to evaluate the inhibitory ability of the test compound on human FGFR1 and FGFR4.
  • Buffer conditions 20mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (Hepes) (pH 7.5), 10mM MgCl 2 , 1mM ethylene glycol-bis-(2-aminoethyl ether)tetraacetic acid (EGTA), 0.02% polyoxyethylene lauryl ether (Brij35), 0.02mg/ml bovine serum albumin (BSA), 0.1mM sodium vanadate (Na 3 VO 4 ), 2mM dithiothreitol (DTT), 1% DMSO.
  • test compound was dissolved in DMSO to prepare a 10 mM solution for use. Dissolve the substrate in the newly prepared buffer, add the test kinase to it and mix well. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above-mentioned mixed reaction solution.
  • the compound concentration in the reaction solution is 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.370 ⁇ M, 0.123 ⁇ M, 41.2nM, 13.7nM, 4.57nM, 1.52nM, 0.508nM, or 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1nM , 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM.
  • 33 P-ATP activity 0.01 ⁇ Ci/ ⁇ L, the corresponding concentration is listed in Table 2 was added to start the reaction.
  • FGFR1, FGFR4 and its substrate supplier's product number, batch number and concentration information in the reaction solution are listed in Table 2.
  • the reaction liquid was spotted on P81 ion exchange filter paper (Whatman#3698-915). After washing the filter paper repeatedly with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (only DMSO).
  • the IC 50 value is obtained by curve fitting with Prism4 software (GraphPad). The experimental results are shown in Table 3.
  • Table 2 Information about kinases, substrates and ATP in in vitro tests.
  • the trifluoroacetate salt of the compound of formula (I) exhibits good inhibitory activity against wild-type FGFR, and FGFR2, 3 have high selectivity to FGFR1, 4.
  • CD-1 mouse male
  • vehicle (0.5% (w/v) methylcellulose 0.5% (v/v) Tween 80 aqueous solution)
  • compound 0027 trifluoroacetate.
  • the solvent is 0.5% (w/v) methyl cellulose 0.5% (v/v) Tween 80 aqueous solution, and it is prepared according to the following procedure:
  • Animals in groups 1 and 2 were given 5 mg/mL and 30 mg/mL compound by single gavage, and the administration volume was 10 mL/kg.
  • the acceptable error of the collection time point is the time point within 1 hour of administration ⁇ 1 minute, and the other time point is the theoretical time ⁇ 5%.

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Abstract

公开了一种吡嗪-2(1H)-酮类化合物的晶型及其制备方法，具体公开了式(II)化合物及其晶型的制备方法。

Description

吡嗪-2(1H)-酮类化合物的D晶型及其制备方法
本申请主张如下优先权：
CN201910731106.1，2019年8月8日；
CN201911059942.6，2019年11月1日。
技术领域
本发明涉及一种吡嗪-2(1H)-酮类化合物的晶型及其制备方法，具体涉及式(ⅠI)化合物及其晶型的制备方法。
背景技术
成纤维细胞生长因子受体(FGFR)是成纤维细胞生长因子(FGF)信号传导的受体，其家族由四个成员(FGFR1、FGFR2、FGFR3、FGFR4)组成，为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞内部分所组成的糖蛋白。成纤维细胞生长因子(FGF)通过这些受体(FGFR)在细胞增殖、细胞分化、细胞迁移和血管生成等许多生理学调节过程中发挥重要作用。有许多证据将FGF信号通路异常(高表达、基因扩增、基因突变、染色体重组等)与肿瘤细胞增殖、迁移、入侵和血管形成等许多病理过程直接相关联。因此，FGFR成为了一类重要治疗靶点，吸引了广泛的研发兴趣。
发明内容
本发明提供了式(II)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、26.28±0.20°、27.72±0.20°。
Figure PCTCN2020106901-appb-000001
本发明的一些方案中，上述式(II)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、10.92±0.20°、14.60±0.20°、20.08±0.20°、23.19±0.20°、24.11±0.20°、26.28±0.20°、27.72±0.20°。
本发明的一些方案中，上述式(II)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、10.92±0.20°、14.60±0.20°、19.31±0.20°、20.08±0.20°、23.19±0.20°、24.11±0.20°、24.92±0.20°、26.28±0.20°、27.08±0.20°、27.72±0.20°、29.29±0.20°。
本发明的一些方案中，上述式(II)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42°、10.92°、14.60°、16.61°、19.31°、20.08°、23.19°、24.11°、24.92°、26.28°、27.08°、27.72°、29.29°、30.39°、33.92°、38.33°。
本发明的一些方案中，上述式(II)化合物的D晶型，其XRPD图谱如图1所示。
本发明的一些方案中，上述式(II)化合物的D晶型，其XRPD图谱解析数据如表1所示。
表1：式(II)化合物的D晶型XRPD图谱解析数据
Figure PCTCN2020106901-appb-000002
本发明的一些方案中，上述式(II)化合物的D晶型，其差示扫描量热曲线在179.1℃±2.0℃处具有吸热峰的起始点，在247.1℃±2.0℃处具有吸热峰的起始点。
本发明的一些方案中，上述式(II)化合物的D晶型，其DSC图谱如图2所示。
本发明的一些方案中，上述式(II)化合物的D晶型，热重分析曲线在190.0℃±3.0℃失重达7.11％，在250.0℃±3.0℃失重达12.10％，在290.0℃±3.0℃失重达14.12％。
本发明的一些方案中，上述式(II)化合物的D晶型，其TGA图谱如图3所示。
本发明还提供了上述式(II)化合物D晶型在制备治疗与FGFR相关疾病的药物中的应用。
技术效果
式(II)化合物D晶型稳定性好，易于成药，根据式(I)化合物的三氟乙酸盐的实验例可知，式(II)化合物D晶型对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。式(II)化合物D晶型的小鼠药代动力学指标良好。
式(I)化合物的三氟乙酸盐对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。式(I)化合物的三氟乙酸盐小鼠药代动力学指标良好。
定义和说明
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。
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。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明采用下述缩略词：eq代表当量、等量；PE代表石油醚；DMSO代表二甲亚砜；MeOH代表甲醇；TFA代表三氟乙酸。
本发明所使用的溶剂可经市售获得，市售化合物采用供应商目录名称。将混合溶剂加入到反应液中时，可以先将各个溶剂混合，然后加入到反应液中；或依次向反应液中加入各个单一溶剂，在反应体系中混合。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020106901-appb-000003
软件命名，市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,k2,
Figure PCTCN2020106901-appb-000004
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
取样品(0.5～1mg)置于DSC铝锅内进行测试，方法为：25℃–300或350℃，10℃/min。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到300度或失重20％。
附图说明
图1为式(II)化合物D晶型的Cu-Kα辐射的XRPD谱图。
图2为式(II)化合物D晶型的DSC谱图。
图3为式(II)化合物D晶型的TGA谱图。
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：式(I)化合物及其三氟乙酸盐的制备的合成
Figure PCTCN2020106901-appb-000005
Figure PCTCN2020106901-appb-000006
步骤1：化合物BB-1-3的合成
将化合物BB-1-2(2.0g,11.49mmol,1eq)和化合物BB-1-1(2.6g,11.49mmol,1eq)溶解到水(6.0mL)和二氧六环(25.0mL)中，然后再加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(841mg,1.15mmol,0.1eq)和碳酸钾(4.8g,34.48mmol,3eq)，在氮气保护下加热至100℃反应16小时。将所得反应液抽滤旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:0-0:1)纯化得到化合物BB-1-3。
MS(ESI)m/z:190.0[M+H] +。
步骤2：化合物BB-1的合成
将化合物BB-1-3(0.5g,2.64mmol,1eq)和吡啶(209mg,2.64mmol,213.28μL,1eq)加入到氯仿(20.0mL)中，冷却至0℃然后再加入溴素(422mg,2.64mmol,136.22μL,1eq)。在室温28℃下反应18小时。将反应物用硫代硫酸钠(1.0mL)淬灭，然后抽滤，将滤液浓缩，粗品使用快速硅胶柱层析法纯化(石油醚：乙酸乙酯＝1:0-1:1)。得到化合物BB-1。MS(ESI)m/z:267.9[M+H] +。
1H NMR(400MHz,CD 3OD)δ:8.12(s,1H)7.90(s,1H)3.86(s,3H)2.43(s,3H)。
步骤3：化合物2的合成
在氮气的保护下，将化合物BB-2-1(2.0g,18.77mmol,2.17mL,1eq,HCl)溶解到氯苯(15.0mL)中，25℃滴加化合物BB-2-2(8.3g,65.69mmol,5.8mL,3.5eq)，混合物在缓慢升温至90℃搅拌16小时。向反应体系中加入水(30.0mL)和乙酸乙酯(30.0mL)，静置分层，同时水相用乙酸乙酯(20.0mL，20.0mL，20.0mL)萃取三次。合并有机相，用饱和氯化钠溶液(30.0mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。粗品经柱层析(石油醚：乙酸乙酯＝1:0-2:1)分离纯化，得到化合物2。MS(ESI)m/z:178.7[M+1] +。
1H NMR(400MHz,CDCl 3)δ:7.26(s,1H),3.61(s,3H)。
步骤4：化合物4的合成
在微波管中，在氮气的保护下，将化合物2(0.2g,1.12mmol,1eq)和化合物3(213mg,1.17mmol,1.05eq)溶解到二氧六环(1.5mL)和水(1.5mL)的混合溶液中，加入四三苯基磷钯(65mg,55.86μmol,0.05eq)、碳酸钠(130mg,1.23mmol,1.1eq)，混合物在120℃微波搅拌30分钟。直接浓缩反应液。粗品经柱层析(石油醚：乙酸乙酯＝1:0-0:1)(TLC检测石油醚：乙酸乙酯＝1:1)分离，得到化合物4。MS(ESI)m/z:281.0[M+1] +。
1H NMR(400MHz,CDCl 3)δ:7.64(d,2H),7.28(s,1H),6.59(t,1H),3.86(s,6H),3.61(s,3H)。
步骤5：化合物0027-1的合成
在氮气的保护下，将化合物4(250mg,890.61μmol,1eq)溶解到乙腈(20.0mL)和二氯甲烷(5.0mL)的混合溶剂中，0℃缓慢滴加磺酰氯(84mg,623.43μmol,62.33μL,0.7eq)的乙腈(2.5mL)溶液，混合物在0℃搅拌10分钟。向反应液中加入甲醇(5.0mL)淬灭反应，并减压浓缩干。粗品经柱层析(石油醚：乙酸乙酯＝1:0-1:1)(TLC检测石油醚：乙酸乙酯＝1:1)分离，得到化合物0027-1。MS(ESI)m/z:314.9[M+H] +。
步骤6：式(I)化合物的合成
在三口瓶中，将化合物0027-1(59mg,186.49μmol,1eq),双联嚬哪醇硼酸酯(52mg,205.14μmol,1.1eq)，醋酸钯(5mg,20.51μmol,0.11eq)和2-二环己基磷-2,4,6-三异丙基联苯(20mg,41.03μmol,0.22eq)，乙酸钾(60mg,615.42μmol,3.3eq)加入到二氧六环(4.0mL)溶液中，用氮气置换反应体系中的空气，并在氮气的饱和下，升温至100℃回流搅拌30分钟,降至25℃，加入化合物BB-1(50mg,186.49μmol,1eq)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯的二氯甲烷络合物(15mg,18.65μmol,0.1eq)，碳酸钾(77mg,559.47μmol,3eq)，二氧六环(4.0mL)和水(2.0mL)，用氮气置换反应体系中的空气，并在氮气的饱和下，升温至100℃回流搅拌8小时。直接浓缩反应液。将得到的粗品，用高效液相色谱分离纯化(色谱柱:Boston Green ODS150×30mm 5μm；流动相:[水(0.1％TFA)-ACN]；B％:30％-60％,8min)得到式(I)化合物的三氟乙酸盐。MS(ESI)m/z:468.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ:8.79(s,1H),8.09(m,2H),6.76(m,2H),3.93(s,3H),3.89(s,3H),3.84(s,3H),3.80(s,3H),2.54(s,3H)。该盐溶于二氯甲烷，加饱和碳酸钠洗，有机相用无水硫酸钠干燥，过滤，滤液旋干得式(I)化合物。 1H NMR(400MHz,CDCl 3)δ:8.51(s,1H),8.15(s,1H),6.71(d,J＝2.8Hz,1H),6.63(d,J＝2.8Hz,1H),6.43(brs,2H),3.94(s,3H),3.92(s,3H),3.84(s,3H),3.79(s,3H),2.55(s,3H)。
实施例2：式(II)化合物的制备
Figure PCTCN2020106901-appb-000007
将式(I)化合物(44.4g,94.89mmol,1eq)溶于四氢呋喃(450mL)中，随后滴加氯化氢(4M,94.89mL,4eq)的乙酸乙酯溶液，在25℃搅拌3hrs。将反应液过滤得黄色固体，油泵拉干。得式(II)化合物。 1H NMR(400MHz,DMSO)δ:8.71(s,1H),8.18(s,2H),6.82(d,J＝2.8Hz,1H),6.75(d,J＝2.8Hz,1H)3.91(s,3H),3.81(s,3H),3.80(s,3H),3.71(s,3H),2.44(s,3H).
实施例3：式(II)化合物的D晶型的制备
将式(II)化合物(0.4g,793.07umol,1eq)加入到乙腈(6mL)中，在50℃搅拌60hrs，过滤。滤饼在50℃的真空干燥箱烘干3.5hrs得到式(II)化合物的D晶型。
实验例1：野生型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人FGFR1、FGFR4的抑制能力。
缓冲液条件：20mM 4-(2-羟乙基)-1-哌嗪乙磺酸(Hepes)(pH 7.5),10mM MgCl 2,1mM乙二醇-双-(2-氨基乙醚)四乙酸(EGTA),0.02％聚氧乙烯月桂醚(Brij35),0.02mg/ml牛血清白蛋白(BSA),0.1mM钒酸钠(Na 3VO 4),2mM二硫苏糖醇(DTT),1％DMSO。
实验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测激酶并混合均匀。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。反应液中化合物浓度为10μM,3.33μM,1.11μM,0.370μM,0.123μM,41.2nM,13.7nM,4.57nM,1.52nM,0.508nM，或为10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μL，相应浓度列在表2中)开始反应。FGFR1、FGFR4和其底物的供应商货号、批号以及在反应液中的浓度信息列在表2中。反应在室温下进行120分钟后，将反应液点在P81离子交换滤纸(Whatman#3698-915)上。用0.75％磷酸溶液反复清洗滤纸后，测定滤纸上残留的磷酸化底物的放射性。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3所示。
表2：体外测试中激酶、底物和ATP的相关信息。
激酶 供应商 Cat# Lot# ATP浓度(μM)
FGFR1 Invitrogen PV3146 28427Q 5
FGFR2 Invitrogen PV3368 31517I 5
FGFR3 Invitrogen PV3145 28459R 30
FGFR4 Invitrogen P3054 26967J 2.5
Figure PCTCN2020106901-appb-000008
表3：本发明化合物体外筛选试验结果
Figure PCTCN2020106901-appb-000009
结论：式(I)化合物的三氟乙酸盐对野生型FGFR都展现出较好的抑制活性，且FGFR2、3对FGFR1、4的选择性较高。
实验例2：化合物药代动力学评价
实验目的：测试化合物在小鼠体内药代动力学
实验材料：
CD-1小鼠(雄性)、溶媒(0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液)、化合物0027的三氟乙酸盐。
1、给药制剂的配制：
溶媒为0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液，并根据以下程序进行配制：
a.加入约50％体积的纯化水于合适的容器中，并加热到约60℃至70℃。
b.当水温到达指定值范围时，关掉加热器。缓慢加入所需量的甲基纤维素于上述容器中并不断搅拌。
c.4℃持续搅拌直到目测为澄清溶液。
d.加入所需体积吐温80至上述溶液中。持续搅拌至目测吐温80均匀分散，且为澄清溶液。
e.用适量纯水将上述溶液定容到最终体积。
f.持续搅拌直至均一溶液形成。
灌胃给药制剂的配制：
a.称取适量的供试品放入玻璃瓶内；
b.加入70％体积的溶媒(0.5％(w/v)甲基纤维素0.5％(v/v)吐温80水溶液)；
c.搅拌制剂直至目视均一，需要的时候水浴超声；
e.补足剩余体积的0.5％甲基纤维素+0.5％吐温80，搅拌均一。
2、给药
第1、2组动物分别通过单次灌胃给予5mg/mL,30mg/mL的化合物，给药体积为10mL/kg。
在给药前称量动物体重，根据体重计算给药体积。
3、样品采集和处理
通过隐静脉采血方式在规定的时间采集(0.25、0.5、1、2、4、6、8、24h)全血样品(30μL)，并在试验记录中记录实际采血时间。采集时间点可接受的误差为给药1小时内时间点±1分钟，其他时间点的为理论时间±5％。
所有血样立即转移至贴有标签的含K2-EDTA的商品化离心管中。血样采集后，4℃，3200转/分钟离心10分钟吸取上清血浆，迅速至于干冰中，保持-20℃或更低温度，用于LC-MS/MS分析。并计算药代参数，实验结果：见表4。
表4药代动力学测试结果
Figure PCTCN2020106901-appb-000010
ND代表:未确定
结论：式(I)化合物的三氟乙酸盐小鼠药代动力学指标良好。

Claims (10)

  1. 式(II)化合物的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、26.28±0.20°、27.72±0.20°。
    Figure PCTCN2020106901-appb-100001
  2. 根据权利要求1所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、10.92±0.20°、14.60±0.20°、20.08±0.20°、23.19±0.20°、24.11±0.20°、26.28±0.20°、27.72±0.20°。
  3. 根据权利要求2所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42±0.20°、10.92±0.20°、14.60±0.20°、19.31±0.20°、20.08±0.20°、23.19±0.20°、24.11±0.20°、24.92±0.20°、26.28±0.20°、27.08±0.20°、27.72±0.20°、29.29±0.20°。
  4. 根据权利要求3所述的D晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：9.42°、10.92°、14.60°、16.61°、19.31°、20.08°、23.19°、24.11°、24.92°、26.28°、27.08°、27.72°、29.29°、30.39°、33.92°、38.33°。
  5. 根据权利要求4所述的D晶型，其XRPD图谱如图1所示。
  6. 根据权利要求1～5任意一项所述的D晶型，其差示扫描量热曲线在179.1℃±2.0℃处具有吸热峰的起始点，在247.1℃±2.0℃处具有吸热峰的起始点。
  7. 根据权利要求6所述的D晶型，其DSC图谱如图2所示。
  8. 根据权利要求1～5任意一项所述的D晶型，热重分析曲线在190.0℃±3.0℃失重达7.11％，在250.0℃±3.0℃失重达12.10％，在290.0℃±3.0℃失重达14.12％。
  9. 根据权利要求8所述的D晶型，其TGA图谱如图3所示。
  10. 根据权利要求1～9任意一项所述的式(II)化合物的D晶型在制备治疗与FGFR相关疾病的药物中的应用。
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