WO2022022735A1 - 成纤维细胞生长因子受体抑制剂的晶型及其制备方法 - Google Patents

成纤维细胞生长因子受体抑制剂的晶型及其制备方法 Download PDF

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WO2022022735A1
WO2022022735A1 PCT/CN2021/110008 CN2021110008W WO2022022735A1 WO 2022022735 A1 WO2022022735 A1 WO 2022022735A1 CN 2021110008 W CN2021110008 W CN 2021110008W WO 2022022735 A1 WO2022022735 A1 WO 2022022735A1
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cancer
crystal form
formula
preparation
compound
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PCT/CN2021/110008
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French (fr)
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吴永谦
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药捷安康(南京)科技股份有限公司
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Priority to KR1020237006892A priority Critical patent/KR20230044483A/ko
Priority to JP2023506334A priority patent/JP2023535836A/ja
Priority to AU2021317820A priority patent/AU2021317820A1/en
Priority to US18/007,421 priority patent/US20240043408A1/en
Priority to EP21850254.0A priority patent/EP4190775A1/en
Publication of WO2022022735A1 publication Critical patent/WO2022022735A1/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
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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 belongs to the technical field of medicine, and in particular relates to a crystal form of a fibroblast growth factor receptor inhibitor and a preparation method thereof.
  • Fibroblast growth factor receptor is an important member of the tyrosine kinase receptor family.
  • FGFR contains four members, namely FGFR-1, FGFR-2, FGFR-3 and FGFR. -4. Most of them are single-chain glycoprotein molecules with a molecular mass ranging from 110 to 150kd, and their structure is divided into extracellular region, transmembrane region and intracellular region.
  • FGFR binds to its ligand fibroblast growth factor (FGF), FGFR dimerizes and phosphorylates itself, and activates downstream signaling pathways, such as JAK/STAT pathway, phospholipase The C pathway, phosphoinositide-3-kinase PI3K, and MAPK signaling pathways play important roles in tumor growth and angiogenesis.
  • FGF ligand fibroblast growth factor
  • FGFR dimerizes and phosphorylates itself, and activates downstream signaling pathways, such as JAK/STAT pathway, phospholipase The C pathway, phosphoinositide-3-kinase PI3K, and MAPK signaling pathways play important roles in tumor growth and angiogenesis.
  • the abnormally high expression of FGFR is closely related to the occurrence and development of various tumors, such as lung cancer, liver cancer, glioma, rhabdomyosarcoma and melanoma.
  • the compound represented by the following formula (I) 1-((2S,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl ) Amino)-2-(hydroxymethyl)pyrrolidin)-1-propyl-2-en-1-one is an inhibitor of FGFR, and its preparation method is described in WO2018040885A1 to obtain a pale yellow solid, which is amorphous , the XRPD analysis is shown in Figure 2.
  • the compound has good inhibitory activity on FGFR, and has clinical application potential for treating or preventing related diseases mediated by FGF/FGFR.
  • the study of crystal form is very important. Compared with other forms, the crystal form of a compound is very different in terms of stability and related substances.
  • the present inventors conducted research on the compound of formula (I) in order to obtain the crystalline form of the compound.
  • the purpose of the present invention is to provide a crystal form of the compound of formula (I) and a preparation method thereof.
  • the present invention provides crystal form I of the compound represented by formula (I):
  • the crystalline form I of the compound of formula (I) exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1 when irradiated with Cu-K ⁇ .
  • the present invention also provides the preparation method of the crystal form I of the compound represented by formula (I):
  • the single or mixed solvent is selected from methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, methyl
  • the single or mixed solvent is selected from: methanol, ethanol, ethyl acetate, acetonitrile , tetrahydrofuran, isopropanol, methyl tert-butyl ether, acetone, toluene, dichloromethane, isopropanol/water, ethanol/water.
  • the fresh crystal form of Form I is stored at 105°C for 3 days, 5 days, or 10 days, or at 60°C for 10 days, 20 days, After 30 days, no spoilage impurities are produced.
  • the mixed solvent is a mixture of water and isopropanol, methanol, and ethanol, and the volume ratio is 1:1 to 5, preferably 1:1.5 to 4, and more preferably 1 :3.
  • the temperature rise refers to the temperature rising to not lower than 35°C, preferably 40 to 100°C.
  • the cooling refers to that the temperature is lowered to lower than 40° C., preferably to room temperature.
  • the room temperature refers to the natural indoor temperature, usually 15 to 25°C.
  • the amount of the single or mixed solvent used is 4-40 times the volume of the compound of formula (I).
  • the single or mixed solvent is selected from: methanol, ethanol, ethyl acetate, acetonitrile, tetrahydrofuran, isopropanol, methyl tert-butyl ether, acetone, toluene, dichloromethane , isopropanol/water, ethanol/water, preferably, the solvent and crystallization conditions are as follows: ethanol/water (3/1: 80°C ⁇ 40°C ⁇ 80°C ⁇ room temperature), methanol (cooled from 70°C to room temperature), Ethyl acetate (cooled from 80°C to room temperature), ethanol (cooled from 90°C to room temperature), acetonitrile (cooled from 90°C to room temperature), tetrahydrofuran (cooled from 80°C to room temperature), isopropanol (cooled from 90°C to room temperature), isopropanol/water (4:6: cooled from 90 °C to room temperature), methyl tert
  • the present invention also provides a pharmaceutical composition comprising crystal form I of the compound represented by formula (I) and one or more second therapeutically active agents.
  • the present invention also provides a pharmaceutical preparation containing crystal form I of the compound represented by formula (I).
  • the pharmaceutical formulation may comprise one or more pharmaceutically acceptable carriers.
  • the pharmaceutical carrier of the present invention can be one or more solid or liquid fillers suitable for human use.
  • the pharmaceutically acceptable carrier preferably has sufficient purity and sufficiently low toxicity, and is compatible with the compounds provided by the present invention without significantly reducing their efficacy.
  • the pharmaceutical carrier can be a filler, binder, disintegrant, lubricant, aqueous or non-aqueous solvent, and the like.
  • the pharmaceutical preparation of the present invention can be prepared into any pharmaceutically acceptable dosage form, and the "therapeutically effective amount" of the aforementioned compound of formula (I) crystal form I can be administered in any suitable manner, such as oral, parenteral , rectal or pulmonary administration to a patient or subject in need of such treatment.
  • oral administration it can be made into tablets, capsules, pills, granules and the like.
  • parenteral administration it can be prepared into injection solution, sterile powder for injection and the like.
  • the present invention also provides the use of the crystal form I of the compound represented by formula (I), or the pharmaceutical preparation or pharmaceutical composition containing the crystal form I in the preparation of a medicine for the treatment or prevention of related diseases mediated by FGF/FGFR; preferably , the related diseases mediated by FGF/FGFR are related diseases caused by changes in the FGFR signaling pathway; specifically, the related diseases caused by the changes in the FGFR signaling pathway are cancers; the cancers are solid tumors and hematological tumors; the Cancers include gallbladder cancer, bile duct cancer, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal cancer, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, Liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ
  • the present invention also provides the use of crystal form I of the compound represented by formula (I), or a pharmaceutical preparation or pharmaceutical composition containing crystal form I in the treatment or prevention of related diseases mediated by FGF/FGFR.
  • the present invention also provides a method of treating or preventing related diseases mediated by FGF/FGFR, the method comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned crystalline form I of formula (I), or containing crystalline form I pharmaceutical preparations or pharmaceutical compositions.
  • the “room temperature” in the present invention refers to the natural indoor temperature, which is usually 15°C to 25°C.
  • the "double volume” in the present invention refers to the volume (mL) of the solvent required to dissolve 1 g of the substance. For example, if the solvent required to dissolve 1 g of the compound of formula (I) is 20 mL, it is called 20 times the volume.
  • a “therapeutically effective amount” as used herein refers to an amount of the aforementioned compound or a pharmaceutically acceptable salt, stereoisomer, composition or pharmaceutical preparation thereof that can at least alleviate the symptoms of the patient's condition when administered to a patient.
  • the actual amount encompassing a "therapeutically effective amount” will vary depending on a variety of circumstances, including but not limited to the particular condition being treated, the severity of the condition, the patient's physical and medical condition, and the route of administration. A skilled medical practitioner can readily determine appropriate amounts using methods known in the medical art.
  • the "destroyed impurities" in the present invention refer to the newly added peaks in the liquid chromatography of the sample after the stability test compared to the liquid chromatography of the sample at day 0.
  • the expression “heating up and then cooling down, or repeating the “heating up and then cooling down” process 1-2 times” refers to carrying out the “heating up and then cooling down” process once, or carrying out the “heating up and then cooling down” process 2-3 times.
  • the crystal form I according to technical scheme 1 is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction represented by 2 ⁇ angle is further at 11.5 ⁇ 0.2°, 12.9 ⁇ 0.2°, 22.4 ⁇ 0.2° There are characteristic peaks.
  • the crystal form I according to technical scheme 4 is characterized in that, using Cu-K ⁇ radiation, X-ray powder diffraction represented by 2 ⁇ angle, at 5.2 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.5 ⁇ 0.2°, There are characteristic peaks at 12.9 ⁇ 0.2°, 13.9 ⁇ 0.2°, 16.0 ⁇ 0.2°, 16.4 ⁇ 0.2°, 18.9 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.4 ⁇ 0.2°, 24.4 ⁇ 0.2°, and 26.1 ⁇ 0.2°.
  • Described single or mixed solvent is selected from: methanol, ethanol, isopropanol, toluene, acetone, tetrahydrofuran, dichloromethane, dichloroethane, ethyl acetate, acetonitrile, methyl tert-butyl ether, 2-methyl A mixture of one or more of tetrahydrofuran, dimethyl sulfoxide and water; preferably, the single or mixed solvent is selected from: methanol, ethanol, ethyl acetate, acetonitrile, tetrahydrofuran, isopropanol, methyl tertiary Butyl ether, acetone, toluene, dichloromethane, isopropanol/water, ethanol/water.
  • a pharmaceutical composition comprising the crystal form I according to any one of technical solutions 1-5, and one or more second therapeutically active agents.
  • crystal form 1 described in any one of technical solutions 1-5 or the pharmaceutical composition described in technical solution 7 or the pharmaceutical preparation described in technical solution 8 are prepared for treatment or prevention of related diseases mediated by FGF/FGFR. Use in medicine.
  • the related disease is selected from gallbladder cancer, bile duct cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer Cancer, breast duct cancer, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system Cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non- Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma, myelodysplastic syndrome
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of the compound of formula (I), Form I.
  • Figure 2 is an XRPD pattern of an amorphous sample of Compound (I).
  • Figure 3 is a high-performance liquid chromatogram of amorphous 0-day related substances.
  • Figure 4 is a high-performance liquid chromatogram of related substances in amorphous form at 105°C for 10 days.
  • Figure 5 is a high-performance liquid chromatogram of amorphous related substances at 60°C for 30 days.
  • Step 1 Synthesis of 1-tert-butyl 2-methyl(2S,4S)-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1,2-dicarboxylate
  • the starting material 1-(tert-butyl)2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (10.5g, 36.8mmol, 1.0eq) was dissolved in dichloromethane In methane (100 mL), triethylamine (11.7 g, 115.8 mmol, 3.0 eq) was added, the reaction was stirred at room temperature for 0.5 h, cooled to 0 °C in an ice bath, and chloroformic acid dissolved in dichloromethane was slowly added dropwise with a constant pressure dropping funnel Benzyl ester (7.9g, 46.3mmol, 1.2eq) was gradually warmed to room temperature and reacted overnight.
  • Step 2 Synthesis of (2S,4S)-4-((((benzyloxy)carbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Lithium aluminum hydride (0.7 g, 19.0 mmol, 2.0 eq) was dissolved in anhydrous tetrahydrofuran (20 mL) at 0 °C, and the reaction was stirred for half an hour, and 1-tert-butyl 2-methyl (2S) was slowly added dropwise.
  • Step 3 Synthesis of (2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester
  • Step 5 ((2S,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)quinazoline)-2-amino)pyrrolidine)-2- Synthesis of methanol hydrochloride
  • reaction solution was directly concentrated to obtain a yellow solid ((2S,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline)-2-amino)pyrrole alkane)-2-methanol hydrochloride (180.0 mg crude, yield: 100%).
  • Step 6 1-((2S,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-2- Synthesis of (Hydroxymethyl)pyrrolidin)-1-propyl-2-en-1-one
  • the starting material ((2S,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline)-2-amino)pyrrolidine)-2-methanol
  • the hydrochloride (160.0 mg, 0.35 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10.0 mL), triethylamine (106.0 mg, 1.1 mmol, 3.0 eq) was added, the reaction was stirred at room temperature for half an hour, cooled to 0 °C, and slowly dropped Acryloyl chloride (38.0 mg, 0.42 mmol, 1.2 eq) was added and the temperature was gradually raised to room temperature for 1 hour. TLC monitored the reaction to complete.
  • Example 3-14 The XRPD pattern of the crystal form prepared in Example 3-14 is similar to that in FIG. 1 , so the crystal form I was also prepared in Example 3-14.
  • the crystal form I of the present invention is placed at 105°C for 10 days and at 60°C for 30 days. There is no obvious change in properties, related substances and forms, and the sample has good stability.
  • Amorphous at day 0 HPLC analysis is shown in Figure 3.
  • the amorphous form was placed at 105°C for 10 days, and the related substances produced 7 destroyed impurities.
  • the retention times of the impurities were 14.315min, 25.015min, 30.414min, 34.129min, 34.788min, 35.581min, and 36.476min respectively.
  • the HPLC analysis is shown in Figure 4. shown.
  • the amorphous form was placed at 60°C for 30 days, and the related substances produced 2 destroyed impurities.
  • the retention times of the impurities were 35.146min and 35.714min respectively.
  • the HPLC analysis is shown in Figure 5.
  • SNU-16 is abnormal FGFR cells in gastric cancer
  • Test substance Compound (I) amorphous, crystal form I
  • Test equipment use Espire multi-function microplate reader.
  • the crystalline form I of the present invention has good inhibitory activity on cells with abnormal FGFR of SNU-16, indicating that the compounds of the present invention can be used to treat cancers mediated by abnormal FGF/FGFR, such as gastric cancer.

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Abstract

本发明属于医药技术领域，具体涉及式（I）所示的成纤维细胞生长因子受体抑制剂的晶型及其制备方法。

Description

成纤维细胞生长因子受体抑制剂的晶型及其制备方法 技术领域
本发明属于医药技术领域，具体涉及成纤维细胞生长因子受体抑制剂的晶型及其制备方法。
背景技术
成纤维细胞生长因子受体(fibroblast growth factor receptor,FGFR)是属于酪氨酸激酶受体家族中的重要一员，FGFR包含4个成员，即FGFR-1、FGFR-2、FGFR-3和FGFR-4。它们多为单链的糖蛋白分子，分子质量在110至150kd，结构分为胞外区，跨膜区和胞内区组成。在正常生理条件下，FGFR与其配体成纤维细胞生长因子(fibroblast growth factor，FGF)结合，FGFR发生二聚体化以及自身的磷酸化，激活下游的信号通路，如JAK/STAT通路、磷脂酶C通路、磷酸酰肌醇-3-激酶PI3K以及MAPK信号通路，以上信号通路在肿瘤生长和血管发生过程中发挥着重要的作用。FGFR的异常高表达，与多种肿瘤，如肺癌、肝癌、脑胶质瘤、横纹肌肉瘤以及黑色素瘤的发生发展密切相关。
下式(I)所示的化合物1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮是FGFR的抑制剂，在WO2018040885A1中记载了其制备方法，得淡黄色固体，为无定型，XRPD分析如图2所示。该化合物对FGFR具有较好的抑制活性，具有治疗或者预防由FGF/FGFR介导的相关疾病的临床应用潜力。
Figure PCTCN2021110008-appb-000001
在药物的研发过程中，晶型的研究非常重要，化合物的晶体形式相对于其他形态，在稳定性，有关物质等方面有很大不同。本发明人对式(I)化合物进行了研究，以期得到该化合物的晶型。
发明内容
本发明的目的是，提供式(I)化合物的晶型及其制备方法。
本发明提供式(I)所示化合物的晶型I：
式(I)所示化合物1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮的晶型，为晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.2±0.2°、10.5±0.2°、13.9±0.2°、16.0±0.2°、20.9±0.2°、24.4±0.2°、26.1±0.2°处有特征峰，
Figure PCTCN2021110008-appb-000002
在本发明的一种实施方式中，式(I)所示化合物的晶型I，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，除上文所述的特征峰外，还在11.5±0.2°、12.9±0.2°、22.4±0.2°处有特征峰。
在本发明的一种实施方式中，式(I)所示化合物的晶型I，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，除上文所述的特征峰外，还在16.4±0.2°、18.9±0.2°处有特征峰。
在本发明的一种实施方式中，式(I)所示化合物的晶型I，使用Cu-Kα辐射时显示出基本上如图1所示的X-射线粉末衍射图。
本发明还提供式(I)所示化合物的晶型I的制备方法：
将式(I)化合物溶于单一或混合溶剂，升温然后降温，或者重复“升温然后降温”过程1-2次得到晶型I；
在本发明的一种实施方式中，所述的单一或混合溶剂选自：甲醇、乙醇、异丙醇、甲苯、丙酮、四氢呋喃、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、甲基叔丁基醚、2-甲基四氢呋喃、二甲基亚砜、水中的一种或几种的混合；优选地，所述的单一或混合溶剂选自：甲醇、乙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醇、甲基叔丁基醚、丙酮、甲苯、二氯甲烷、异丙醇/水、乙醇/水。
在本发明的一种实施方式中，所述晶型I的新鲜晶型在105℃条件下，存储3天、5天、或10天后，或在60℃条件下，存储10天、20天、30天后，不会产生破坏杂质。
在本发明的一种实施方式中，所述的混合溶剂为水分别与异丙醇、甲醇、乙醇的混合，体积比为1:1至5，优选为1:1.5至4，更优选为1:3。
在本发明的一种实施方式中，所述的升温是指温度升高至不低于35℃，优选为40至100℃。
在本发明的一种实施方式中，所述的降温是指温度降至低于40℃，优选降至室温。所述室温，是指室内自然温度，通常指15至25℃。
在本发明的一种实施方式中，所述单一或混合溶剂的用量是式(I)化合物的4-40倍体积。
在本发明的一种实施方式中，所述的单一或混合溶剂选自：甲醇、乙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醇、甲基叔丁基醚、丙酮、甲苯、二氯甲烷、异丙醇/水、乙醇/水，优选地，溶剂与结晶条件如下：乙醇/水(3/1：80℃→40℃→80℃→室温)、甲醇(自70℃冷却至室温)、乙酸乙酯(自80℃冷却至室温)、乙醇(自90℃冷却至室温)、乙腈(自90℃冷却至室温)、四氢呋喃(自80℃冷却至室温)、异丙醇(自90℃冷却至室温)、异丙醇/水(4:6：自90℃冷却至室温)、甲基叔丁基醚(自50℃冷却至室温)、丙酮(自70℃冷却至室温)、甲苯(自100℃冷却至室温)、二氯甲烷(自40℃冷却至室温)、乙醇/水(8:2：自90℃冷却至室温)。
本发明还提供了含有式(I)所示化合物晶型I，及一种或多种第二治疗活性剂的药物组合物。
本发明还提供了含有式(I)所示化合物晶型I的药物制剂。
在发明的一些实施方式中，药物制剂可以包含一种或多种药用载体。
本发明所述的药用载体可以是一种或多种适合于人使用的固体或液体填料。所述药用载体优选具有足够的纯度和足够低的毒性，并且与本发明提供的化合物具有相容性且不明显减低其药效。例如，药用载体可以为填充剂、粘合剂、崩解剂、润滑剂、水性溶剂或非水性溶剂等。
本发明所述的药物制剂，可以制成药学上可接受的任意剂型，将“治疗有效量”的前述式(I)化合物晶型I，以任何合适的给药方式，例如通过口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，可以制成片剂、胶囊剂、丸剂、颗粒剂等。用于肠胃外给药时，可以制成注射液、注射用无菌粉末等。
本发明还提供了式(I)所示化合物晶型I，或含有晶型I的药物制剂或药物组合物在制备治疗或者预防由FGF/FGFR介导的相关疾病的 药物中的用途；优选地，所述由FGF/FGFR介导的相关疾病是FGFR信号通路改变导致的相关疾病；具体地，所述FGFR信号通路改变导致的相关疾病为癌症；所述癌症为实体瘤和血液瘤；所述的癌症包括胆囊癌、胆管癌、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，骨髓增生异常综合症。
本发明还提供了式(I)所示化合物晶型I，或含有晶型I的药物制剂或药物组合物在治疗或者预防由FGF/FGFR介导的相关疾病中的用途。
本发明还提供了一种治疗或预防由FGF/FGFR介导的相关疾病的方法，该方法包括向有需要的患者给药治疗有效量的前述式(I)晶型I，或含有晶型I的药物制剂或药物组合物。
发明详述
本发明所述的“室温”是指室内自然温度，通常为15℃至25℃。
本发明所述的“倍体积”是指溶解1g物质所需要的溶剂的体积(mL)，例如，溶解1g式(I)化合物所需要的溶剂为20mL，则称为20倍体积。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物或其药学上可接受的盐、立体异构体、组合物或药物制剂的量。包含“治疗有效量”的实际量会根据多种情况而变化，多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
本发明所述“破坏杂质”是指稳定性测试后样品的液相色谱相比0天时样品的液相色谱新增的峰。
在本发明中，表述“升温然后降温，或者重复‘升温然后降温’过程1-2次”是指进行‘升温然后降温’过程一次，或者进行‘升温然后降温’过程2-3次。
本发明还涉及以下技术方案：
1.式(I)所示化合物1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮的晶型，为晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.2±0.2°、10.5±0.2°、13.9±0.2°、16.0±0.2°、20.9±0.2°、24.4±0.2°、26.1±0.2°处有特征峰，
Figure PCTCN2021110008-appb-000003
2.如技术方案1所述的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在11.5±0.2°、12.9±0.2°、22.4±0.2°处有特征峰。
3.如技术方案2所述的晶型I，使用Cu-Kα辐射时显示出基本上如图1所示的X-射线粉末衍射图。
4.式(I)所示化合物1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮的晶型，为晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.2±0.2°、10.5±0.2°、13.9±0.2°、16.0±0.2°、16.4±0.2°、24.4±0.2°、26.1±0.2°处有特征峰，
Figure PCTCN2021110008-appb-000004
5.如技术方案4所述的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.2±0.2°、10.5±0.2°、11.5±0.2°、12.9±0.2°、13.9±0.2°、16.0±0.2°、16.4±0.2°、18.9±0.2°、20.9±0.2°、22.4±0.2°、24.4±0.2°、26.1±0.2°处有特征峰。
6.如技术方案1-5中任一项所述的晶型I的制备方法，
将式(I)化合物溶于单一或混合溶剂，升温然后降温，或者重复“升温然后降温”过程1-2次得到晶型I；
所述的单一或混合溶剂选自：甲醇、乙醇、异丙醇、甲苯、丙酮、 四氢呋喃、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、甲基叔丁基醚、2-甲基四氢呋喃、二甲基亚砜、水中的一种或几种的混合；优选地，所述的单一或混合溶剂选自：甲醇、乙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醇、甲基叔丁基醚、丙酮、甲苯、二氯甲烷、异丙醇/水、乙醇/水。
7.含有技术方案1-5任一项所述的晶型I，及一种或多种第二治疗活性剂的药物组合物。
8.含有技术方案1-5任一项所述的晶型I的药物制剂，其特征在于包含一种或多种药用载体。
9.技术方案1-5任一项所述的晶型I或技术方案7所述的药物组合物或技术方案8所述的药物制剂在制备治疗或者预防由FGF/FGFR介导的相关疾病的药物中的用途。
10.如技术方案9所述的用途，所述的相关疾病是FGFR信号通路改变导致的相关疾病。
11.如技术方案9-10中任一项所述的用途，所述的相关疾病是癌症。
12.如技术方案9-11中任一项所述的用途，所述的相关疾病是实体瘤和血液瘤。
13.如技术方案9-12中任一项所述的用途，所述的相关疾病选自胆囊癌、胆管癌、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，骨髓增生异常综合症，或其组合。
附图说明
图1是式(I)化合物晶型I的X-射线粉末衍射(XRPD)图谱。
图2是化合物(I)无定型样品的XRPD图。
图3是无定型0天有关物质高效液相色谱图。
图4是无定型105℃10天有关物质高效液相色谱图。
图5是无定型60℃30天有关物质高效液相色谱图。
具体实施方式
以下通过具体实施方式对本发明的上述内容作进一步的详细说明，但不应该理解为本发明上述主题的范围仅限于以下实施例。凡是基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1式(I)化合物的制备
步骤1：1-叔丁基2-甲基(2S,4S)-4-(((苄氧基)羰基)氨基)吡咯烷-1,2-二甲酸酯的合成
Figure PCTCN2021110008-appb-000005
将原料1-(叔丁基)2-甲基(2S,4S)-4-氨基吡咯烷-1,2-二甲酸酯盐酸盐(10.5g,36.8mmol,1.0eq)溶解在二氯甲烷(100mL)中，加入三乙胺(11.7g,115.8mmol,3.0eq)，室温搅拌反应0.5h，冰浴降温至0℃，用恒压滴液漏斗缓慢滴加二氯甲烷溶解的氯甲酸苄酯(7.9g,46.3mmol,1.2eq)，逐渐升温至室温反应过夜，TLC监测反应完全，向反应液中加入饱和碳酸氢钠溶液(100mL)分液，水相二氯甲烷(50mL×2)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析(200-300目硅胶,PE:EA＝10:1～3:1)得无色油状物1-叔丁基2-甲基(2S,4S)-4-(((苄氧基)羰基)氨基)吡咯烷-1,2-二甲酸酯(3.6g,收率24.7％)。
步骤2：(2S,4S)-4-((((苄氧基)羰基)氨基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯的合成
Figure PCTCN2021110008-appb-000006
将氢化铝锂(0.7g,19.0mmol,2.0eq)在0℃条件下溶于无水四氢呋喃(20mL)中，搅拌反应半小时，缓慢滴加溶有1-叔丁基2-甲基(2S,4S)-4-(((苄氧基)羰基)氨基)吡咯烷-1,2-二甲酸酯(3.6g,9.5mmol,1.0eq)的四氢呋喃溶液，逐渐升温至室温反应2小时，TLC检测反应完全，将反应液降温至0℃，向反应液中缓慢滴加水(0.7mL)和10％的 氢氧化钠溶液(0.7mL)，补加水(2.1mL)，搅拌半小时，将反应液过滤，滤液浓缩，粗品经硅胶柱层析(200-300目,PE:EA＝10:1～2:1)得无色油状物(2S,4S)-4-((((苄氧基)羰基)氨基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(1.05g,收率30.0％)。
步骤3：(2S,4S)-4-氨基-2-(羟甲基)吡咯烷-1-羧酸叔丁酯的合成
Figure PCTCN2021110008-appb-000007
将(2S,4S)-4-((((苄氧基)羰基)氨基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(250mg，0.71mmol，1.0eq)溶解在甲醇(5.0mL)中，加入钯碳(75.2mg,7.2mmoL,0.01eq)。置换氢气4次，室温搅拌反应过夜，TLC监测反应完全，将反应液垫上硅藻土抽滤，滤液浓缩得无色透明油状物(2S,4S)-4-氨基-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(123.0mg,收率80.2％)。
步骤4：(2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉)-2-氨基)-2-(羟甲基)吡咯烷-1-甲酸叔丁酯的合成
Figure PCTCN2021110008-appb-000008
将原料(2S,4S)-4-氨基-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(123.0mg，0.57mmol，1.0eq)和2-氯-6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉(231.5mg,0.63mmol,1.1eq)溶解在N-甲基吡咯烷酮(4.0mL)中，加入N,N-二异丙基乙胺(147.3mg,1.14mmoL,2.0eq)，逐渐升温至110℃，搅拌反应5小时，TLC监测反应完全，将反应液降温至室温，向反应液中加入20mL冰水，搅拌10分钟，过滤，滤饼少量冰水洗涤后二氯甲烷(10mL)溶解，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析(200-300目,DCM:MeOH＝100:1～50:1)得淡棕色固体(2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(113.0mg,收率36.1％)。
步骤5：((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉)-2-氨基)吡咯烷)-2-甲醇盐酸盐的合成
Figure PCTCN2021110008-appb-000009
将原料(2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(113.0mg,0.21mmol,1.0eq)溶解在乙醇(5.0mL)中，冰浴降温至0℃，加入氯化氢乙醇溶液(5.0mL)，逐渐升温至室温反应过夜，TLC监测反应完全。将反应液直接浓缩得到黄色固体((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉)-2-氨基)吡咯烷)-2-甲醇盐酸盐(180.0mg粗品，收率:以100％计)。
步骤6：1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮的合成
Figure PCTCN2021110008-appb-000010
将原料((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉)-2-氨基)吡咯烷)-2-甲醇盐酸盐(160.0mg,0.35mmol,1.0eq)溶解在四氢呋喃(10.0mL)中，加入三乙胺(106.0mg,1.1mmol,3.0eq)，室温搅拌反应半小时，降温至0℃，缓慢滴加丙烯酰氯(38.0mg,0.42mmol,1.2eq)逐步升温至室温反应1小时，TLC监测反应完全，向反应液中加入饱和碳酸氢钠溶液(15mL)，加入乙酸乙酯(8mL)，分液，水相乙酸乙酯萃取(8mL×2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，粗品硅胶柱层析(200-300目硅胶,DCM:MeOH＝100:1～50:1)得淡黄色固体1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷-1-基)丙基-2-烯-1-酮(75.0mg,收率42.5％)。
1H NMR(400MHz,DMSO)δ(ppm):9.18(s,1H),7.89(s,1H),7.80(s,1H),7.55(d,1H),7.52(d,1H),7.00(s,1H),6.60-6.71(m,1H),6.16(d,1H),5.67(d,1H),5.09(s,1H),4.55(m,1H),4.12-4.20(m,2H),4.03(s,6H),3.97(m,1H),3.74(m,1H),3.52(m,1H),1.98(m,2H)。
分子式：C 24H 24Cl 2N 4O 4分子量：503.39LC-MS(Pos,m/z)＝505.40[M+H +]。
实施例2式(I)化合物晶型I的制备
取4.8g式(I)化合物加入到20mL乙醇：水＝3:1溶液中，加热至 80℃，3小时后关闭加热，冷却至40℃左右时，有固体析出，再次加热至80℃，有大量固体析出，加热2.5小时后关闭加热，冷至室温，过滤干燥得晶型I。XRPD分析如图1所示。X-射线粉末衍射图谱如下图中所示，其中主要参数如下：
2θ角(°) 强度(％)
5.2 66.9
10.5 93.1
11.5 13.8
12.9 10.3
13.9 100
16.0 51
16.4 39.3
18.9 13.1
20.9 25.5
22.4 12.4
24.4 36.6
26.1 37.2
实施例3式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，加热至70℃，加入甲醇2mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例4式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，80℃下加入乙酸乙酯3mL，加热1小时关闭加热，冷却至室温析出晶型I。
实施例5式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，90℃下加入乙醇3mL，加热1小时后关闭加热，冷却至室温析出晶型I。
实施例6式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，90℃下加入乙腈4mL，加热1小时后关闭加热，冷却至室温析出晶型I。
实施例7式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，80℃下加入四氢呋喃3mL，加热半小时后关闭加热，冷却至室温干燥得晶型I。
实施例8式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，90℃下加入异丙醇3mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例9式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，90℃下加入异丙醇：水＝4:6共10mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例10式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，50℃下加入甲基叔丁基醚10mL，加热半小时不溶，关闭加热，冷却至室温过滤得晶型I。
实施例11式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，70℃下加入丙酮2mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例12式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，100℃下加入甲苯3mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例13式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，40℃下加入二氯甲烷2mL，加热半小时后关闭加热，冷却至室温干燥得晶型I。
实施例14式(I)化合物晶型I的制备
取300mg式(I)化合物加入到反应瓶中，90℃下加入乙醇：水＝8:2共5mL，加热半小时后关闭加热，冷却至室温析出晶型I。
实施例3-14制备得到的晶型XRPD图与图1相近，因此实施例3-14也制备得到晶型I。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。
实验例1：本发明晶型I的稳定性测试
方法：取晶型I样品适量置于称量瓶中，分别开口放置在60℃、RH92.5％、RH75％、光照(≥4500±500Lux)条件下，于第0、4、10天取样，考察性状、纯度变化。
结果：
表1影响因素检测结果
Figure PCTCN2021110008-appb-000011
结论：本发明晶型I各影响因素条件下放置10天，性状及纯度未见明显变化，样品稳定性良好。
实验例2：无定型和晶型I稳定性测试
方法：取晶型I样品适量，置于称量瓶中，放置在105℃条件下，分别于3天、5天、10天取样；放置在60℃条件下，分别于10天、20天、30天取样，考察性状、有关物质和型态的变化。
取化合物(I)无定型样品适量，置于称量瓶中，放置在105℃条件下，分别于3天、5天、10天取样；放置在60℃条件下，分别于10天、20天、30天取样，考察性状、有关物质的变化。
结果如下：
表2：晶型I稳定性有关物质检测结果
Figure PCTCN2021110008-appb-000012
表3：晶型I稳定性性状和XRPD检测结果
Figure PCTCN2021110008-appb-000013
表4：无定型稳定性有关物质和性状检测结果
Figure PCTCN2021110008-appb-000014
结论：本发明晶型I在105℃条件下放置10天以及在60℃条件下放置30天，性状、有关物质和型态均无明显变化，样品稳定性良好。无定型在0天时，HPLC分析如图3所示。无定型在105℃条件下放置10天，有关物质产生7个破坏杂质，杂质保留时间分别为14.315min、25.015min、30.414min、34.129min、34.788min、35.581min、36.476min，HPLC分析如图4所示。无定型在60℃条件下放置30天，有关物质产生2个破坏杂质，杂质保留时间分别为35.146min，35.714min，HPLC分析如图5所示。
实验例3：细胞活性测试
SNU-16为胃癌FGFR异常细胞
测试物：化合物(I)无定型、晶型I
测试仪器：使用Espire多功能酶标仪。
试验方法：
将SNU-16细胞接种于96孔板中贴壁培养过夜后，加入不同浓度的化合物(12个剂量组，3倍DMSO系列稀释)使终浓度为0.17-30000nM，其中DMSO终含量均为5‰。阴性对照孔为含有5‰DMSO的培养基。37℃，5％CO2，95％湿度孵育72h后待测。每孔加入30μL Cell titer-Glo试剂，室温孵育30min后，Espire读取终数据。
测试结果如下表5所示
表5：细胞的抑制活性(IC 50)
化合物 SNU-16细胞的抑制活性(nM)
无定型 11
晶型I 9.5
由上表可见，本发明晶型I对SNU-16的FGFR异常的细胞具有良好的抑制活性，说明本发明化合物可以用来治疗由FGF/FGFR异常介导的癌症如胃癌。

Claims (8)

  1. 式(I)所示化合物1-((2S,4S)-4-((6-(2,6-二氯-3,5-二甲氧基苯基)喹唑啉-2-基)氨基)-2-(羟甲基)吡咯烷)-1-丙基-2-烯-1-酮的晶型，为晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.2±0.2°、10.5±0.2°、13.9±0.2°、16.0±0.2°、20.9±0.2°、24.4±0.2°、26.1±0.2°处有特征峰，
    Figure PCTCN2021110008-appb-100001
  2. 如权利要求1所述的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在11.5±0.2°、12.9±0.2°、22.4±0.2°处有特征峰。
  3. 如权利要求2所述的晶型I，使用Cu-Kα辐射时显示出基本上如图1所示的X-射线粉末衍射图。
  4. 如权利要求1所述的晶型I的制备方法，
    将式(I)化合物溶于单一或混合溶剂，升温然后降温，或者重复“升温然后降温”过程1-2次得到晶型I；
    所述的单一或混合溶剂选自：甲醇、乙醇、异丙醇、甲苯、丙酮、四氢呋喃、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、甲基叔丁基醚、2-甲基四氢呋喃、二甲基亚砜、水中的一种或几种的混合；优选地，所述的单一或混合溶剂选自：甲醇、乙醇、乙酸乙酯、乙腈、四氢呋喃、异丙醇、甲基叔丁基醚、丙酮、甲苯、二氯甲烷、异丙醇/水、乙醇/水。
  5. 含有权利要求1-3任一项所述的晶型I，及一种或多种第二治疗活性剂的药物组合物。
  6. 含有权利要求1-3任一项所述的晶型I的药物制剂，其特征在于包含一种或多种药用载体。
  7. 权利要求1-3任一项所述的晶型I或权利要求5所述的药物组合物或权利要求6所述的药物制剂在制备治疗或者预防由FGF/FGFR介导的相关疾病的药物中的用途。
  8. 如权利要求7所述的用途，所述由FGF/FGFR介导的相关疾病是指FGFR信号通路改变导致的相关疾病；优选为癌症；更优选地，所述癌症为实体瘤和血液瘤；进一步优选地所述的癌症包括胆囊癌、胆管癌、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、前列腺癌、甲状腺癌、女性生殖系统癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤，骨髓增生异常综合症。
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