WO2023197978A1 - Fgfr4选择性抑制剂化合物的晶型及其制备方法和用途 - Google Patents

Fgfr4选择性抑制剂化合物的晶型及其制备方法和用途 Download PDF

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WO2023197978A1
WO2023197978A1 PCT/CN2023/087201 CN2023087201W WO2023197978A1 WO 2023197978 A1 WO2023197978 A1 WO 2023197978A1 CN 2023087201 W CN2023087201 W CN 2023087201W WO 2023197978 A1 WO2023197978 A1 WO 2023197978A1
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compound
formula
crystal form
preparation
present
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PCT/CN2023/087201
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French (fr)
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郑剑锋
施珍娟
苏笛
龚永祥
钟金清
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浙江海正药业股份有限公司
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D403/02—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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to the field of chemical pharmaceuticals, and more specifically to N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)) New crystal form of pyrimidin-4-yl)amino)-5-(4-ethyl-4,7-diazaspiro[2.5]octane-7-yl)phenyl)acrylamide diethylsulfonate, Its preparation method and its medicinal use.
  • PCT/CN2017/085135 reports a new class of pyrimidine derivatives, which are FGFR4 pathway inhibitors.
  • a large amount of evidence shows that there are FGFR4 gene amplification mutations in lung cancer, ovarian cancer, prostate cancer, liver cancer, and cholangiocarcinoma.
  • FGFR4 selective inhibitors have the advantage of less toxicity than other FGFR inhibitors (Brow, AP et al (2005), Toxocol. Pathol., 449-455).
  • Current research on FGFR4 selective inhibitors in anti-cancer, especially anti-liver cancer is far from sufficient. There is a need to research and develop new FGFR4 inhibitors.
  • PCT/CN2017/085135 discloses that the chemical name is N-(2-((6-(3-(2,6-dichloro-3,5-dimethoxyphenyl))-1-methylureido)pyrimidine
  • one of the objects of the present invention is to overcome at least one of the above-mentioned shortcomings in the prior art and provide a new compound form.
  • the present invention provides a crystal form A of the compound of formula (I) with good chemical and physical stability,
  • the crystal form has excellent properties in terms of physical and chemical stability, water solubility, bioavailability and hygroscopicity; and the preparation method of the crystal form of the present invention is simple to operate and easy to industrialize.
  • the X-ray powder diffraction (XRD) pattern of the crystal form A of the compound of formula (I) according to the present invention has characteristic peaks at the following diffraction angles 2 ⁇ : 6.6 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.6 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.3 ⁇ 0.2°, 20.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, and 26.9 ⁇ 0.2°.
  • the crystal form A of the compound of formula (I) according to the present invention also has characteristic peaks at the following diffraction angles 2 ⁇ : 22.1 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.8 ⁇ 0.2°, 28.2 ⁇ 0.2° and 29.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form A of the compound of formula (I) according to the present invention further has characteristic peaks at the following 2 ⁇ : 7.2 ⁇ 0.2°, 10.2 ⁇ 0.2°, 13.4 ⁇ 0.2°, 19.1 ⁇ 0.2°, 24.6 ⁇ 0.2°, 25.0 ⁇ 0.2° and 30.9 ⁇ 0.2°.
  • the crystal form A of the compound of formula (I) according to the present invention has substantially the same X-ray powder as shown in Figure 1 Diffraction spectrum.
  • the X-ray powder diffraction pattern has 2 ⁇ and relative intensity data as shown in Table 1 below:
  • the crystal form A of the compound of formula (I) according to the present invention has substantially the same DSC spectrum as shown in Figure 2, and its melting point is 188°C.
  • the crystal form A of the compound of formula (I) according to the present invention has substantially the same TGA spectrum as shown in Figure 3.
  • Another object of the present invention is to provide a method for preparing crystal form A of the compound of formula (I), which method includes the following steps:
  • the suspension of the compound of formula (I) refers to the suspension of the compound of formula (I) in the following solvents: alcohol, ketone, ester, ether, alkane, water or a mixture thereof.
  • the solid-liquid ratio (g/mL) of the suspension is 1:3-40.
  • the present invention also relates to a pharmaceutical composition containing a compound of Formula (I), Form A, which pharmaceutical composition contains a therapeutically effective amount of a compound of Formula (I), Form A, and one or more pharmaceutically acceptable carriers.
  • the present invention also relates to the use of crystalline form A of the compound of formula (I) or a pharmaceutical composition containing crystalline form A of the compound of formula (I) in the preparation of medicaments for treating tumors.
  • the tumor is preferably selected from the group consisting of non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer and cholangiocarcinoma, more preferably selected from the group consisting of liver cancer and cholangiocarcinoma.
  • the present invention also relates to a method for treating tumors, which includes administering crystal form A of the compound of formula (I) of the present invention or a pharmaceutical composition containing crystal form A of the compound of formula (I) to a subject in need thereof.
  • the tumor is preferably selected from the group consisting of non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer and cholangiocarcinoma, more preferably selected from the group consisting of liver cancer and cholangiocarcinoma.
  • the inventor of the present invention has discovered the crystal form A of the compound of formula (I) after extensive research. Its crystallization process is simple, easy to operate, has little pollution, has high yield, and can realize industrial production; the crystal form drug of the present invention also has product purity. High, excellent physical and chemical properties, good chemical stability, good water solubility, high bioavailability and low hygroscopicity.
  • Figure 1 is the X-ray powder diffraction pattern of crystal form A of the compound of formula (I) obtained in Example 1.
  • Figure 2 is a DSC spectrum of crystal form A of the compound of formula (I) obtained in Example 1.
  • Figure 3 is a TGA spectrum of crystal form A of the compound of formula (I) obtained in Example 1.
  • the solvent used in the present invention is not particularly limited, and commercially available conventional solvents can be used.
  • the ethanol can be commercially available ethanol, including industrial ethanol, anhydrous ethanol, and the like.
  • the stirring method includes magnetic stirring and mechanical stirring, and the stirring speed is 50-300rpm/min, preferably 100-200rpm/min.
  • the X-ray powder diffraction instrument and test conditions involved in the present invention are: X-ray diffraction instrument model Rigaku D/max-2200Cu target; operating method: scanning speed 4°/min, scanning step width 0.01°.
  • the DSC model involved in the present invention is: NETZSCH DSC200 F3 Jaia; the test conditions are a heating rate of 10°C/min and a temperature range of 25 to 250°C.
  • thermogravimetric analyzer TGA
  • test conditions TGA model is PerkinElmer TGA400
  • test conditions are a heating rate of 10°C/min and a temperature range of 30-250°C.
  • the crude compound of formula (I) can be used as the raw material for preparing crystal form A.
  • the raw material can be prepared by reacting the compound of formula (II) with ethanesulfonic acid.
  • the specific preparation is as follows: take the free base compound of formula (II) ( 1000mg, 1.5mmol) into the reaction bottle, add 25ml acetone and 1.25ml water, stir evenly, add ethanesulfonic acid (0.39g, 3.3mmol), stir and dissolve at room temperature, the reaction solution is concentrated to remove acetone, filtered, dried, and the formula is ( 1.2g of amorphous solid of compound I), yield 90%.
  • the X-ray powder diffraction pattern of this crystal is shown in Figure 1, the DSC pattern is shown in Figure 2, and the TGA pattern is shown in Figure 3. It is named as the compound of formula (I) crystal form A in the present invention.
  • the crystal form A obtained in Examples 2-6 has the same XRD, DSC and TGA patterns as the crystal form A obtained in Example 1.
  • the amorphous form is prone to slow degradation at room temperature and rapid degradation under high temperature and light conditions. Especially under long-term lighting conditions, its appearance and purity are basically destroyed, while its crystal form can be well preserved under normal temperature, high temperature and lighting conditions. The difference is obvious.
  • the amorphous form has crystallization phenomenon after grinding, indicating that it is prone to the risk of crystallization during the grinding process or granulation process of the preparation.
  • the ICR mice in group A were given a single intragastric administration of 75 mg ⁇ kg-1 amorphous ethanesulfonate preparation, and the ICR mice in group B were given a single intragastric administration of 75 mg ⁇ kg-1 ethanesulfonate crystals.
  • Type A drug preparation before administration and 0.25, 0.5, 1, 2, 4, 8, 10, 12 and 24 hours after administration, collect 0.15 mL of blood from the fundus venous plexus and place it in an anticoagulant tube containing EDTA-K2 middle.
  • amorphous forms generally have higher energy due to their unstable form and generally have significantly better bioavailability than crystalline forms.
  • the crystalline form A has similar pharmacokinetic parameters to the amorphous form and shows basically the same bioequivalence. This result is unexpected.

Abstract

本发明涉及式(I)化合物的晶型A以及其制备方法和用途。所述晶型A在物理化学稳定性、水溶性、生物利用度和加工适应性方面均具有优异的性质。

Description

FGFR4选择性抑制剂化合物的晶型及其制备方法和用途
本申请要求于2022年04月14日提交到中国国家知识产权局、申请号为202210393796.6、发明名称为“FGFR4选择性抑制剂化合物的晶型及其制备方法和用途”的中国专利申请的优先权,其全部内容均通过引用结合在本申请中。
技术领域
本发明涉及化学制药领域，更具体地涉及N-(2-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)-5-(4-乙基-4,7-二氮杂螺[2.5]辛烷-7-基)苯基)丙烯酰胺二乙磺酸盐的新晶型、其制备方法以及其医药用途。
技术背景
PCT/CN2017/085135报道了一类新的嘧啶类衍生物，这类化合物是FGFR4途径抑制剂。大量的证据表明，肺癌、卵巢癌、前列腺癌、肝癌和胆管癌等中有FGFR4的基因扩增突变。FGFR4选择性抑制剂，相对于其他FGFR抑制剂具有毒性小的优势(Brow,AP et al(2005),Toxocol.Pathol.,449-455)。考虑到目前可用药物的安全性和有效性缺陷，尤其是考虑到FGFR4选择性抑制剂的应用潜力，目前对于FGFR4选择性抑制剂在抗癌尤其是抗肝癌等方面的研究是远远不够的，有必要研究和开发新的FGFR4抑制剂。
PCT/CN2017/085135公开了化学名称为N-(2-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)-5-(4-乙基-4,7-二氮杂螺[2.5]辛烷-7-基)苯基)丙烯酰胺的式(II)游离碱化合物，其结构如下所示：
体外细胞活性检测发现，式(II)化合物对肝癌细胞Hep3B具有良好的抑制活性，IC50值为0.019μM，具有良好的开发前景。但是在式(II)化合物的成药性研究过程中，本发明的发明人发现，式(II)化合物的常见可药用盐在理化性质和成药性方面均不能令人满意，包括在生物利用度、水溶性、引湿性等方面。因此，有必要深入研究找到适合药用的新形式，以满足药物开发的需要。
发明内容
考虑到现有技术的缺点，本发明的目的之一在于克服现有技术中的上述至少一个缺点，提供一种新的化合物形式。为此，本发明提供了一种化学和物理稳定性均较好的式(I)化合物的晶型A，
所述晶型在物理及化学稳定性、水溶性、生物利用度和引湿性方面具有优异的性质；且本发明晶型的制备方法操作简便，易于工业化生产法。
本发明所述的式(I)化合物晶型A的X-射线粉末衍射(XRD)图在以下衍射角2θ处有特征峰：6.6±0.2°、14.6±0.2°、16.4±0.2°、17.6±0.2°、19.6±0.2°、20.3±0.2°、20.8±0.2°、23.0±0.2°、和26.9±0.2°。优选地，本发明所述的式(I)化合物晶型A还在以下衍射角2θ处具有特征峰：22.1±0.2°、23.3±0.2°、25.8±0.2°、28.2±0.2°和29.8±0.2°。
更优选地，本发明所述的式(I)化合物晶型A的X-射线粉末衍射图进一步在以下2θ处有特征峰：7.2±0.2°、10.2±0.2°、13.4±0.2°、19.1±0.2°、24.6±0.2°、25.0±0.2°和30.9±0.2°。
优选地，本发明所述的式(I)化合物晶型A具有如图1所示的基本相同的X-射线粉末 衍射谱图。
在一个实施方案中，所述X-射线粉末衍射谱图具有如下表1所示的2θ和相对强度数据：
表1
优选地，本发明所述的式(I)化合物晶型A具有如图2所示的基本相同的DSC谱图，其熔点为188℃。
优选地，本发明所述的式(I)化合物晶型A具有如图3所示的基本相同的TGA谱图。
本发明的另一目的在于提供一种制备式(I)化合物晶型A的方法，该方法包括以下步骤:
提供式(I)化合物的混悬液，在10-40℃下搅拌4-12h，过滤，得式(I)化合物晶型A。
作为优选，其中式(I)化合物的混悬液是指式(I)化合物在以下溶剂中的混悬液：醇、酮、酯、醚、烷烃、水或其混合物。
作为优选，所述混悬液的固液比(g/mL)为1:3-40。
作为优选，在上述制备方法中，在过滤之后还有干燥步骤。
本发明还涉及含有式(I)化合物晶型A的药物组合物，所述药物组合物包含治疗有效量的式(I)化合物晶型A，以及一种或多种药学上可接受的载体。
本发明还涉及式(I)化合物晶型A或含有式(I)化合物晶型A的药物组合物在制备用于治疗肿瘤的药物中的用途。所述肿瘤优选选自非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌和胆管癌，更优选选自肝癌和胆管癌。
相应地，本发明还涉及一种治疗肿瘤的方法，包括向有此需要的对象给予本发明的式(I)化合物晶型A或含有式(I)化合物晶型A的药物组合物。所述肿瘤优选选自非小细胞肺癌、胃癌、多发性骨髓瘤、肝癌和胆管癌，更优选选自肝癌和胆管癌。
本发明的发明人经过大量研究发现了式(I)化合物的晶型A，其结晶工艺简单、便于操作、污染小、收率高、可实现工业化生产；本发明的晶型药物同时具备产品纯度高、理化性质优异、化学稳定性良好、水溶性好、生物利用度高和引湿性小的优点。
附图说明
图1为实施例1所得式(I)化合物晶型A的X-射线粉末衍射图谱。
图2为实施例1所得式(I)化合物晶型A的DSC图谱。
图3为实施例1所得式(I)化合物晶型A的TGA图谱。
具体实施方式
下列实施例用于进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
本发明实施例中的式(I)化合物粗品均采用自制得到。
本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂，例如所述乙醇可以是市售乙醇，包括工业乙醇、无水乙醇等。
除非另有说明，本发明方法中所述的“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50-300rpm/min，优选100-200rpm/min。
本发明所涉及的X-射线粉末衍射仪器及测试条件为:X-衍射仪器型号Rigaku D/max-2200Cu靶；操作方法:扫描速度4°/min，扫描步宽0.01°。
本发明所涉及的DSC型号为：NETZSCH DSC200 F3 Jaia；测试条件为升温速率10℃/min，温度范围：25～250℃。
本发明所涉及的热重分析仪(TGA)及测试条件为：TGA型号为PerkinElmer TGA400；测试条件为升温速率10℃/min，温度范围为30-250℃。
本发明涉及的式(I)化合物HPLC的纯度检测条件为：色谱柱：Waters，XBridge C18 4.6×150mm，3.5μm；流动相A:缓冲液:乙腈＝70:30，流动相B:缓冲液:乙腈＝35:35，缓冲液:称取9.13g三水合磷酸氢二钾于2000mL纯水中，磷酸调节PH至8.0；检测波长:234nm；流速:1.0mL/min；柱温:25℃；进样量:10μL。
梯度洗脱条件
应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意欲的保护范围并不局限于该数字本身，本领域技术人员能够理解，它们包含了那些已被本领域广为接 受的可允许误差范围，例如实验误差、测量误差、统计误差和随机误差等等，而这些误差范围均包含在本发明的范围之内。
原料制备实施例：
本发明方法中可使用式(I)化合物粗品作为晶型A的制备原料，所述原料可由式(II)化合物与乙磺酸反应制得，具体制备如下：取式(II)游离碱化合物(1000mg,1.5mmol)投入反应瓶，加入25ml丙酮和1.25ml水，搅拌均匀，加入乙磺酸(0.39g，3.3mmol)，室温下搅拌溶解，反应液浓缩除去丙酮，过滤，干燥，得式(I)化合物的无定型固体1.2g，收率90％。
实施例1 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至10mL甲醇中形成混悬液，升温至30℃搅拌12h，过滤，40℃真空干燥，得0.95g晶体，HPLC检测纯度为99.64％。
该晶体的X-射线粉末衍射图谱详见图1，DSC图谱见图2，TGA图谱见图,3，在本发明中将其命名为式(I)化合物晶型A。
实施例2 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至3mL水中形成混悬液，10℃搅拌4h，过滤，40℃真空干燥，得0.65g晶体，HPLC检测纯度为99.60％。经测X-射线粉末衍射图谱(XRD)，确认为式(I)化合物晶型A。
实施例3 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至10mL丙酮中形成混悬液，20℃搅拌8h，过滤，40℃真空干燥，得0.94g晶体，HPLC检测纯度为99.53％。经测X-射线粉末衍射图谱(XRD)，确认为式(I)化合物晶型A。
实施例4 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至30mL乙酸乙酯中形成混悬液，25℃搅拌6h，过滤，40℃真空干燥，得0.93g晶体，HPLC检测纯度为99.57％。经测X-射线粉末衍射图谱(XRD)，确认为式(I)化合物晶型A。
实施例5 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至20mL异丙醚中形成混悬液，15℃搅拌8h，过滤，40℃真空干燥，得0.96g晶体，HPLC检测纯度为99.47％。经测X-射线粉末衍射图谱(XRD)，确认为式(I)化合物晶型A。
实施例6 式(I)化合物晶型A的制备
将式(I)化合物粗品1.0g加至40mL正庚烷中形成混悬液，40℃搅拌4h，过滤，40℃真空干燥，得0.95g晶体，HPLC检测纯度为99.48％。经测X-射线粉末衍射图谱(XRD)，确认为式(I)化合物晶型A。
经测试，实施例2-6所得晶型A具有与实施例1所得晶型A相同的XRD、DSC和TGA图。
效果实施例1
水中溶解度对比实验：分别取式I化合物无定型和晶型A、式II化合物(游离碱)进行25℃水中溶解度测试，具体结果如下：
由上述结果可知，式I化合物的水中溶解度大大优于式II游离碱化合物，说明其成盐后水溶性得到极大改善，达到了成盐所预期的效果，且无定型盐和结晶态盐的水中溶解度较为接近。
效果实施例2
稳定性实验：将式I化合物无定型和晶型A分别在25℃、40℃和光照4500LX条件下放置30天，结果如下:



从上述稳定性结果可知，无定型在常温下易缓慢降解，在高温和光照条件下快速降解， 尤其在长时间光照条件下其外观和纯度基本都已破坏，而其晶型在常温、高温及光照条件下均能良好保存，其差距是显而易见的。
效果实施例3
研磨实验：将无定型和晶型A分别研磨5min、加乙醇研磨至干和加水研磨至干后测其XRD，其结果如下：
从研磨结果看，无定型在研磨后出现转晶现象，说明其在制剂粉碎过程中或制粒过程中容易出现转晶风险。
效果实施例4
药代动力学实验
实验当天，A组ICR小鼠单次灌胃给予75mg·kg-1的乙磺酸盐无定型给药制剂，B组ICR小鼠单次灌胃给予75mg·kg-1的乙磺酸盐晶型A给药制剂，于给药前及给药后0.25、0.5、1、2、4、8、10、12和24h，由眼底静脉丛采血0.15mL，置于含EDTA-K2的抗凝管中。
采用Pharsight Phoenix 7.0中的非房室模型计算相应的药代动力学参数，结果见下表。
本领域众所周知的是，无定型形式通常因其处于不稳定形式而具有较高的能量，并通常具有比晶体形式显著更好的生物利用度。然而，由上述结果可知，晶型A具有和无定型相似的药代动力学参数，表现出基本相同的生物等效性，这一结果是出乎意料的。

Claims (8)

  1. 一种式(I)化合物晶型A，其特征在于，其X-射线粉末衍射图在以下衍射角2θ处具有特征峰：6.6±0.2°、14.6±0.2°、16.4±0.2°、17.6±0.2°、19.6±0.2°、20.3±0.2°、20.8±0.2°、23.0±0.2°和26.9±0.2°
  2. 根据权利要求1所述的式(I)化合物晶型A，其X-射线粉末衍射图还在以下衍射角2θ处具有特征峰：22.1±0.2°、23.3±0.2°、25.8±0.2°、28.2±0.2°和29.8±0.2°。
  3. 根据权利要求2所述的式(I)化合物晶型A，其X-射线粉末衍射图进一步在以下衍射角2θ处具有特征峰：7.2±0.2°、10.2±0.2°、13.4±0.2°、19.1±0.2°、24.6±0.2°、25.0±0.2°和30.9±0.2°。
  4. 根据权利要求1-3中任一项所述的式(I)化合物晶型A，其中所述晶型A具有如图1所示的X-射线粉末衍射谱图。
  5. 根据权利要求1-4中任一项所述的式(I)化合物晶型A，其熔点为188℃；优选地，其DSC谱图如图2所示。
  6. 根据权利要求1-5中任一项所述的式(I)化合物晶型A，其TGA谱图如图3所示。
  7. 一种药物组合物，其含有权利要求1-6任何一项所述的式(I)化合物晶型A。
  8. 根据权利要求1-6中任一项所述的式(I)化合物晶型A或权利要求7所述的药物组合在制备用于治疗癌症的药物中的用途。
PCT/CN2023/087201 2022-04-14 2023-04-10 Fgfr4选择性抑制剂化合物的晶型及其制备方法和用途 WO2023197978A1 (zh)

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