WO2020125747A1 - Crystal form and amorphous form of mek inhibitor and applications thereof - Google Patents

Crystal form and amorphous form of mek inhibitor and applications thereof Download PDF

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WO2020125747A1
WO2020125747A1 PCT/CN2019/126948 CN2019126948W WO2020125747A1 WO 2020125747 A1 WO2020125747 A1 WO 2020125747A1 CN 2019126948 W CN2019126948 W CN 2019126948W WO 2020125747 A1 WO2020125747 A1 WO 2020125747A1
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crystal form
pattern
compound
whose
formula
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PCT/CN2019/126948
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Chinese (zh)
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毛庆华
吴家虎
姚婷
吴成德
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基石药业（苏州）有限公司
拓石药业（上海）有限公司
基石药业
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Priority to CN201980069331.1A priority Critical patent/CN112912380B/en
Publication of WO2020125747A1 publication Critical patent/WO2020125747A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the invention relates to a polymorphic form, an amorphous form of a compound of formula (I) as a MEK inhibitor, and a preparation method and application thereof.
  • MAPK pathway exists in a series of cellular processes such as cell proliferation, differentiation, apoptosis and stress response.
  • MAPK pathways There are currently four known MAPK pathways: ERK1/2, JNK, p38 and ERK5.
  • ERK1/2 ERK1/2
  • JNK p38
  • ERK5 ERK5
  • Ras/Raf kinase pathway One of the most important and well-known MAPK pathways.
  • the pathway is first activated by extracellular growth factors (ie PDGF or EGF, etc.) and transmembrane receptors (ie PDGFR or EGFR or ErbB2, etc.) to activate the receptors, and activated receptors through guanylate exchange factors (such as SOS)
  • extracellular growth factors ie PDGF or EGF, etc.
  • transmembrane receptors ie PDGFR or EGFR or ErbB2, etc.
  • guanylate exchange factors such as SOS
  • the Ras in the membrane is combined with GTP and activated; the activated Ras further indirectly phosphorylates and activates Raf (MAPKKK in this pathway); then, the activated Raf is at the two serines of MEK1/2 (MAPKK in this pathway) Phosphorylation of residues (MEK1 corresponds to S218 and S222; MEK2 corresponds to S222 and S226) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431).
  • ERK Phosphorylated ERK dimerizes and moves into the nucleus and accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). ERK in the nucleus involves many cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and migration, and mRNA processing and translation (Ahn et al., Molecular Cell, 2000, 6, 1343 -1354).
  • the RAF-MEK-ERK pathway can transmit the proliferation and anti-apoptotic signals emitted by growth factors and oncogenic factors, thereby promoting cell growth, development and transfer; if the genes involved in the pathway are mutated or growth factors, downstream signaling proteins or protein kinases Overexpression will lead to uncontrolled cell proliferation and eventually tumor formation.
  • mutations in cancer cells cause overexpression of growth factors, which leads to the continuous activation of the internal MAPK pathway; or the inactivation of the activated Ras complex due to mutations can also cause the continuous activation of the MAPK pathway; recently, People have identified bRaf mutations in more than 60% of melanomas (Davies, H. et al., Nature, 2002, 417, 949-954).
  • MAPK pathway is central to cell proliferation and differentiation, inhibiting this pathway will be beneficial for the treatment of a variety of hyperproliferative diseases, and MEK in this pathway downstream of Ras and Raf has become a key role in this pathway.
  • MEK the only known substrates that can be phosphorylated and activated by MEK are MAPK, namely ERK1 and ERK2. This strict selectivity and the unique ability of its bifunctional kinase make it an attractive drug target. Potential and extensive therapeutic applications, such as malignant and benign hyperproliferative diseases, immunoregulation and inflammation.
  • sorafenib (Bay 43-9006) approved by the FDA in December 2005 is a non-specific inhibitor of silk/threonine and tyrosine kinases, and its targets include Raf, MEK, VEGFR2/3, and Flt-3 , PDGFR, c-Kit, etc.
  • B-Raf-specific inhibitors such as dabrafenib (GSK21 18436) and vemurafenib (PLX4032) have good clinical effects, but the duration is short, and clinical studies have found that long-term treatment of B-Raf inhibitors will lead to patient acquisition Drug resistance.
  • Trametinib (GSK-1 120212), which specifically inhibits the MEK1/2 inhibitor, was approved by the FDA in May 2013 and was approved in January 2014 to be combined with dabrafenib for the treatment of advanced melanoma; it specifically inhibits the MEK1/2 inhibitor cobimetinib It was approved by the FDA in 2015 for use in combination with vemurafenib for melanoma treatment. In 2016, Binimetinib applied to the FDA for registration for the treatment of N-RAS mutant melanoma. In addition, Selumetinib, refametinibd and other MEK1/2 inhibitors are in clinical stage.
  • the present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.31 ⁇ 0.2°, 15.45 ⁇ 0.2°, and 18.96 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of Form A above has characteristic diffraction peaks at the following 2 ⁇ angles: 12.31 ⁇ 0.2°, 13.08 ⁇ 0.2°, 15.45 ⁇ 0.2°, 18.96 ⁇ 0.2°, 21.63 ⁇ 0.2 °, 24.47 ⁇ 0.2°, 27.17 ⁇ 0.2° and 28.73 ⁇ 0.2°.
  • the XRPD pattern of the above crystalline form A is shown in FIG. 1.
  • Table 1 XRPD pattern analysis data of crystal form A
  • the differential scanning calorimetry curve (DSC) of Form A above has a starting point for an endothermic peak at 188.10 ⁇ 3°C.
  • the DSC pattern of Form A above is shown in FIG. 2.
  • thermogravimetric analysis curve (TGA) of Form A above has a weight loss of 0.3606% at 197.79 ⁇ 3°C.
  • the TGA pattern of the above crystalline form A is shown in FIG. 3.
  • the invention also provides Form B of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 6.25 ⁇ 0.2°, 12.43 ⁇ 0.2° and 21.89 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of Form B above has characteristic diffraction peaks at the following 2 ⁇ angles: 6.25 ⁇ 0.2°, 12.43 ⁇ 0.2°, 18.74 ⁇ 0.2°, 21.89 ⁇ 0.2°, 23.46 ⁇ 0.2 °, 24.99 ⁇ 0.2°, 29.75 ⁇ 0.2° and 31.44 ⁇ 0.2°.
  • the XRPD pattern of the above crystalline form B is shown in FIG. 4.
  • the differential scanning calorimetry curve (DSC) of the above crystalline form B has a starting point of an endothermic peak at 171.21 ⁇ 3°C.
  • the DSC pattern of the above crystal form B is shown in FIG. 5.
  • thermogravimetric analysis curve (TGA) of the above crystalline form B has a weight loss of 0.4681% at 180.52 ⁇ 3°C.
  • the TGA pattern of the above B crystal form is shown in FIG. 6.
  • the invention also provides Form C of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.55 ⁇ 0.2°, 18.79 ⁇ 0.2°, and 25.10 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the above C form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.33 ⁇ 0.2°, 12.55 ⁇ 0.2°, 15.22 ⁇ 0.2°, 17.68 ⁇ 0.2°, 18.79 ⁇ 0.2 °, 20.07 ⁇ 0.2°, 25.10 ⁇ 0.2° and 26.76 ⁇ 0.2°.
  • the differential scanning calorimetry curve (DSC) of Form C above has a starting point of an endothermic peak at 168.06 ⁇ 3°C.
  • the DSC pattern of the above C form is shown in FIG. 8.
  • thermogravimetric analysis curve (TGA) of the above C crystal form has a weight loss of 0.7482% at 176.32 ⁇ 3°C.
  • the TGA pattern of the above C crystal form is shown in FIG. 9.
  • the present invention also provides the crystal form D of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 18.94 ⁇ 0.2°, 24.83 ⁇ 0.2°, and 26.15 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of Form D above has characteristic diffraction peaks at the following 2 ⁇ angles: 12.45 ⁇ 0.2°, 14.86 ⁇ 0.2°, 17.13 ⁇ 0.2°, 18.41 ⁇ 0.2°, 18.94 ⁇ 0.2 °, 22.83 ⁇ 0.2°, 24.83 ⁇ 0.2° and 26.15 ⁇ 0.2°.
  • the XRPD pattern of the above D form is shown in FIG. 10.
  • the differential scanning calorimetry curve (DSC) of Form D above has a starting point for an endothermic peak at 163.80 ⁇ 3°C.
  • the DSC pattern of the above D form is shown in FIG. 11.
  • thermogravimetric analysis curve (TGA) of the above D crystal form has a weight loss of 0.9987% at 121.34 ⁇ 3°C; and a weight loss of 1.1087% at 174.58°C.
  • the TGA pattern of the above D crystal form is shown in FIG. 12.
  • the present invention also provides the crystal form E of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 22.81 ⁇ 0.2°, 24.93 ⁇ 0.2°, and 25.82 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the above E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 12.41 ⁇ 0.2°, 15.02 ⁇ 0.2°, 17.48 ⁇ 0.2°, 18.69 ⁇ 0.2°, 22.81 ⁇ 0.2 °, 23.61 ⁇ 0.2°, 24.93 ⁇ 0.2° and 25.82 ⁇ 0.2°.
  • the XRPD pattern of the above E crystal form is shown in FIG. 13.
  • the differential scanning calorimetry curve (DSC) of the above E crystal form has a starting point of an endothermic peak at 167.83 ⁇ 3°C.
  • the DSC pattern of the above E crystal form is shown in FIG. 14.
  • thermogravimetric analysis curve (TGA) of the above E crystal form has a weight loss of 0.6462% at 99.83 ⁇ 3°C; a weight loss of 0.73118% at 176.84 ⁇ 3°C.
  • the TGA pattern of the above E crystal form is shown in FIG. 15.
  • the present invention also provides an amorphous compound of formula (I), and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 16.
  • the present invention also provides a method for preparing the compound B crystal form of formula (I), which includes:
  • the alcohol solvent includes ethanol.
  • the invention also provides an amorphous preparation method of the compound of formula (I), including:
  • the solvent is selected from acetone, tetrahydrofuran and acetonitrile.
  • the present invention also provides the use of the above-mentioned Form A, Form B, Form C, Form D or Form E in the preparation of a medicament for treating MEK-related disorders.
  • the invention also provides the application of the above-mentioned amorphous form in the preparation of a medicament for treating MEK-related disorders.
  • the amorphous and various crystal forms in the present invention have stable properties, weak hygroscopicity, are suitable for long-term storage, and are suitable for medicine preparation.
  • Compounds of formula (I) in various dosage groups can effectively inhibit the growth of HT-29 tumors.
  • the intermediate 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 the combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO 3 H stands for ethanesulfonic acid; MeSO 3 H stands for methanesulfonic acid; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate; THF stands for tetrahydrofuran; EA stands for ethyl acetate; DMAP stands for 4-dimethylaminopyridine; DCM stands for dichloromethane; DIPEA stands for N,N-diisopropylethylamine; Pd( dppf) Cl 2.
  • CH 2 Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichlor
  • Light tube Cu, K-Alpha,
  • Light tube voltage 40kV
  • light tube current 40mA
  • Anti-scattering slit 7.10mm
  • DSC Differential Scanning Calorimeter
  • Test conditions at 50mL / min N 2 conditions at / min heating rate 10 °C, the sample was heated from 30 deg.] C to 300 °C.
  • Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test conditions Under 25mL/min N2, heat the sample from room temperature to 300°C at a heating rate of 10°C/min.
  • Hygroscopic classification ⁇ W% deliquescence Absorb enough water to form liquid Very hygroscopic ⁇ W% ⁇ 15% Hygroscopic 15%> ⁇ W% ⁇ 2% Slightly hygroscopic 2%> ⁇ W% ⁇ 0.2%
  • ⁇ W% represents the hygroscopic weight gain of the tested product at 25 ⁇ 1°C and 80 ⁇ 2%RH
  • Figure 16 Amorphous XRPD pattern of the compound of formula (I);
  • Figure 17 Amorphous DVS spectrum of the compound of formula (I).
  • Step 1 Synthesis of compound BA-2.
  • step 1
  • reaction solution was filtered through celite to remove insoluble materials, and the filtrate was spin-dried to obtain a crude product.
  • the crude product (101.85 g) of the compound of formula (I) was added to ethanol (1.13 L) and beaten at 22° C. for 16 hours. After filtration, the filter cake was washed with ethanol (500 mL*3) and dried under vacuum at 40° C. for 20 hours to obtain Form B of the compound of formula (I).
  • Form B (80.92 g) of the compound of formula (I) and acetone (250.00 mL) were added to a 1 L reaction flask in sequence, and stirred for 15 minutes until the solid was completely dissolved. Concentrate to dryness under reduced pressure and continue to concentrate for 30 minutes. The solid was collected into a crystallizing dish and crushed into powder and fine particles, and vacuum dried at 95-100° C.
  • Amorphous 10 to 15 mg of the compound of formula (I) is placed in the DVS sample pan for testing.
  • the compound of formula (I) has an amorphous weight gain of 1.577% at 25°C and 80% RH, which is slightly hygroscopic.
  • the compound of formula (I) is amorphous and has good stability.
  • the reference solution STD-1 (day 0 S1 sample) was diluted 2000-fold and recorded as LOQ (limit of detection).
  • the compound of formula (I) is amorphous and has good stability.
  • Example 8 In vivo pharmacodynamic study of compound of formula (I) amorphous in human colon cancer HT-29 cell subcutaneous xenograft tumor BALB/c nude mouse model
  • mice purchased from Beijing Vital Lihua Experimental Animal Technology Co., Ltd., female, 6-8 weeks, 70 mice (excluding the group of remaining mice). Animals were housed in IVC (Independent Air Supply System) cages (5 per cage) in SPF animal houses. The rats were kept in a special pathogen-free environment and in a single ventilated cage (4 per cage). All cages, bedding and drinking water are sterilized before use. Cages, feed and drinking water are changed twice a week. All animals have free access to standard certified commercial laboratory diets.
  • IVC Independent Air Supply System
  • TGI (%) [(1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group))/(average tumor at the end of treatment in the solvent control group Volume-average tumor volume at the beginning of treatment in the solvent control group)] ⁇ 100%.
  • the c.p value is calculated based on the relative tumor volume.
  • Compounds of formula (I) in various dosage groups can effectively inhibit the growth of HT-29 tumors.

Abstract

Disclosed are a polymorph and an amorphous form of a compound of formula (I) as a MEK inhibitor and preparation methods and applications thereof.

Description

一种MEK抑制剂的晶型、无定形及其应用Crystal form, amorphous form and application of MEK inhibitor
本申请主张如下优先权：This application claims the following priority:
CN201811573858.1，申请日：2018.12.21。CN201811573858.1, application date: December 21, 2018.
技术领域Technical field
本发明涉及到一种作为MEK抑制剂的式(Ⅰ)化合物的多晶型、无定形及其制备方法和应用。The invention relates to a polymorphic form, an amorphous form of a compound of formula (I) as a MEK inhibitor, and a preparation method and application thereof.
背景技术Background technique
MAPK通路存在于细胞增殖，分化，凋亡与应激反应等一系列细胞进程中。目前已知的MAPK通路有四条：ERK1/2，JNK，p38与ERK5。其中最重要且最广为人知的MAPK通路之一，是Ras/Raf激酶通路。该通路首先由细胞外生长因子(即PDGF或EGF等)与跨膜受体(即PDGFR或EGFR或ErbB2等)结合，活化受体，而活化的受体通过鸟苷酸交换因子(如SOS)使膜内的Ras与GTP结合并活化；被激活的Ras进一步间接磷酸化并活化Raf(此通路中的MAPKKK)；然后，活化的Raf在MEK1/2(此通路中的MAPKK)的两个丝氨酸残基上进行磷酸化(MEK1对应S218与S222；MEK2对应S222与S226)(Ahn et al.，Methods in Enzymology，2001，332，417-431)。磷酸化的ERK二聚后移向细胞核内并积聚(Khokhlatchev et al.，Cell，1998，93，605-615)。在细胞核内的ERK涉及到许多细胞功能，包括但不限于核转运，信号转导，DNA修复，核小体组装与迁移以及mRNA加工与翻译(Ahn et al.，Molecular Cell，2000，6，1343-1354)。MAPK pathway exists in a series of cellular processes such as cell proliferation, differentiation, apoptosis and stress response. There are currently four known MAPK pathways: ERK1/2, JNK, p38 and ERK5. One of the most important and well-known MAPK pathways is the Ras/Raf kinase pathway. The pathway is first activated by extracellular growth factors (ie PDGF or EGF, etc.) and transmembrane receptors (ie PDGFR or EGFR or ErbB2, etc.) to activate the receptors, and activated receptors through guanylate exchange factors (such as SOS) The Ras in the membrane is combined with GTP and activated; the activated Ras further indirectly phosphorylates and activates Raf (MAPKKK in this pathway); then, the activated Raf is at the two serines of MEK1/2 (MAPKK in this pathway) Phosphorylation of residues (MEK1 corresponds to S218 and S222; MEK2 corresponds to S222 and S226) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and moves into the nucleus and accumulates (Khokhlatchev et al., Cell, 1998, 93, 605-615). ERK in the nucleus involves many cellular functions, including but not limited to nuclear transport, signal transduction, DNA repair, nucleosome assembly and migration, and mRNA processing and translation (Ahn et al., Molecular Cell, 2000, 6, 1343 -1354).
RAF-MEK-ERK通路能传导由生长因子与致癌因子发出的增殖与抗凋亡信号，从而促进细胞的生长，发展与转移；若通路涉及的基因发生突变或生长因子、下游信号蛋白或蛋白激酶过表达，将会导致细胞增殖失控并最终导致肿瘤形成。举例来说，癌细胞突变引起生长因子过表达，从而导致其内部的MAPK通路的持续激活；或因突变导致激活的Ras复合物的无法去活化，同样也会造成MAPK通路的持续激活；近来，人们已从超过60％的黑素瘤中识别出bRaf变异(Davies，H.et al.，Nature，2002，417，949-954)。这些bRaf变异导致了自发活化的MAPK级联的产生。人们在胰腺癌，结肠癌，肺癌，卵巢癌与肾癌等原发性肿瘤样本与细胞系的研究中，也观察到了MAPK通路的自发性或者过度活化现象(Hoshino，R.et al.，Oncogene，1999，18，813-822)。因此，由于基因突变引起的MAPK通路过度活化与癌症之间有很强的相关性。The RAF-MEK-ERK pathway can transmit the proliferation and anti-apoptotic signals emitted by growth factors and oncogenic factors, thereby promoting cell growth, development and transfer; if the genes involved in the pathway are mutated or growth factors, downstream signaling proteins or protein kinases Overexpression will lead to uncontrolled cell proliferation and eventually tumor formation. For example, mutations in cancer cells cause overexpression of growth factors, which leads to the continuous activation of the internal MAPK pathway; or the inactivation of the activated Ras complex due to mutations can also cause the continuous activation of the MAPK pathway; recently, People have identified bRaf mutations in more than 60% of melanomas (Davies, H. et al., Nature, 2002, 417, 949-954). These bRaf mutations lead to the generation of spontaneously activated MAPK cascades. Spontaneous or excessive activation of the MAPK pathway has also been observed in studies of primary tumor samples and cell lines such as pancreatic cancer, colon cancer, lung cancer, ovarian cancer, and renal cancer (Hoshino, R. et al., Oncogene , 1999, 18, 813-822). Therefore, there is a strong correlation between excessive activation of the MAPK pathway due to gene mutations and cancer.
因为MAPK通路处于细胞增殖与分化中的中枢位置，抑制该通路将有利于治疗多种过度增殖疾病，而该通路中处于Ras与Raf下游的MEK则成为了该通路中的关键角色。此外，目前已知可由MEK磷酸化并激活的底物仅有MAPK，即ERK1与ERK2，这种严格的选择性及其双功能激酶独特能力，使其成为了很具吸引力的药物靶标，具有潜在而广泛的治疗应用，比如，恶性与良性过度增殖疾病，免疫调节与炎症。Because the MAPK pathway is central to cell proliferation and differentiation, inhibiting this pathway will be beneficial for the treatment of a variety of hyperproliferative diseases, and MEK in this pathway downstream of Ras and Raf has become a key role in this pathway. In addition, the only known substrates that can be phosphorylated and activated by MEK are MAPK, namely ERK1 and ERK2. This strict selectivity and the unique ability of its bifunctional kinase make it an attractive drug target. Potential and extensive therapeutic applications, such as malignant and benign hyperproliferative diseases, immunoregulation and inflammation.
针对MAPK信号通路，目前已有多个Raf和MEK抑制剂处于临床和上市阶段。如05年12月FDA批准上市的sorafenib(Bay 43-9006)，是非特异性的丝/苏氨酸和酪氨酸激酶抑制剂，其作用靶点包含Raf，MEK，VEGFR2/3，Flt-3，PDGFR，c-Kit等。B-Raf特异性抑制剂如dabrafenib(GSK21 18436)和vemurafenib(PLX4032)均有良好的临床效果，但持续时间较短，且临床研究发现，B-Raf抑制剂的长期治疗会导致 患者产生获得性耐药性。因此，临床上常将MEK抑制剂与B-Raf抑制剂联用。特异性抑制MEK1/2抑制剂Trametinib(GSK-1 120212)已于2013年5月经FDA批准上市，并于2014年1月获批与dabrafenib联合治疗晚期黑色素瘤；特异性抑制MEK1/2抑制剂cobimetinib于2015年被FDA批准用于和vemurafenib联合用药，用于黑色素瘤治疗。Binimetinib在2016年，向FDA申请注册用于N-RAS突变的的黑色素瘤治疗。此外，还有Selumetinib，refametinibd等MEK1/2抑制剂处于临床阶段。In response to the MAPK signaling pathway, several Raf and MEK inhibitors are currently in clinical and marketing stages. For example, sorafenib (Bay 43-9006) approved by the FDA in December 2005 is a non-specific inhibitor of silk/threonine and tyrosine kinases, and its targets include Raf, MEK, VEGFR2/3, and Flt-3 , PDGFR, c-Kit, etc. B-Raf-specific inhibitors such as dabrafenib (GSK21 18436) and vemurafenib (PLX4032) have good clinical effects, but the duration is short, and clinical studies have found that long-term treatment of B-Raf inhibitors will lead to patient acquisition Drug resistance. Therefore, clinically often combined with MEK inhibitors and B-Raf inhibitors. Trametinib (GSK-1 120212), which specifically inhibits the MEK1/2 inhibitor, was approved by the FDA in May 2013 and was approved in January 2014 to be combined with dabrafenib for the treatment of advanced melanoma; it specifically inhibits the MEK1/2 inhibitor cobimetinib It was approved by the FDA in 2015 for use in combination with vemurafenib for melanoma treatment. In 2016, Binimetinib applied to the FDA for registration for the treatment of N-RAS mutant melanoma. In addition, Selumetinib, refametinibd and other MEK1/2 inhibitors are in clinical stage.
目前公开了一系列的MEK抑制剂的专利申请，其中包括WO2007/096259，WO2010/003022和WO2012/162293，WO2014/169843，WO2015/058589等。A series of patent applications for MEK inhibitors are currently disclosed, including WO2007/096259, WO2010/003022 and WO2012/162293, WO2014/169843, WO2015/058589, etc.
发明内容Summary of the invention
本发明提供了式(Ⅰ)化合物的A晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.31±0.2°、15.45±0.2°和18.96±0.2°。The present invention provides Form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 12.31±0.2°, 15.45±0.2°, and 18.96±0.2°.
Figure PCTCN2019126948-appb-000001
Figure PCTCN2019126948-appb-000001
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.31±0.2°、13.08±0.2°、15.45±0.2°、18.96±0.2°、21.63±0.2°、24.47±0.2°、27.17±0.2°和28.73±0.2°。In some aspects of the present invention, the X-ray powder diffraction pattern of Form A above has characteristic diffraction peaks at the following 2θ angles: 12.31±0.2°, 13.08±0.2°, 15.45±0.2°, 18.96±0.2°, 21.63±0.2 °, 24.47±0.2°, 27.17±0.2° and 28.73±0.2°.
本发明的一些方案中，上述A晶型的XRPD图谱如图1所示。In some solutions of the present invention, the XRPD pattern of the above crystalline form A is shown in FIG. 1.
本发明的一些方案中，上述A晶型的的XRPD图谱解析数据如表1所示：In some solutions of the present invention, the XRPD pattern analysis data of the above Form A is shown in Table 1:
表1：A晶型的XRPD图谱解析数据Table 1: XRPD pattern analysis data of crystal form A
Figure PCTCN2019126948-appb-000002
Figure PCTCN2019126948-appb-000002
Figure PCTCN2019126948-appb-000003
Figure PCTCN2019126948-appb-000003
本发明的一些方案中，上述A晶型的差示扫描量热曲线(DSC)在188.10±3℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve (DSC) of Form A above has a starting point for an endothermic peak at 188.10±3°C.
本发明的一些方案中，上述A晶型的DSC图谱如图2所示。In some aspects of the present invention, the DSC pattern of Form A above is shown in FIG. 2.
本发明的一些方案中，上述A晶型的热重分析曲线(TGA)在197.79±3℃时失重达0.3606％。In some aspects of the present invention, the thermogravimetric analysis curve (TGA) of Form A above has a weight loss of 0.3606% at 197.79±3°C.
本发明的一些方案中，上述A晶型的TGA图谱如图3所示。In some solutions of the present invention, the TGA pattern of the above crystalline form A is shown in FIG. 3.
本发明还提供了式(Ⅰ)化合物的B晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.25±0.2°、12.43±0.2°和21.89±0.2°。The invention also provides Form B of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 6.25±0.2°, 12.43±0.2° and 21.89±0.2°.
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.25±0.2°、12.43±0.2°、18.74±0.2°、21.89±0.2°、23.46±0.2°、24.99±0.2°、29.75±0.2°和31.44±0.2°。In some aspects of the present invention, the X-ray powder diffraction pattern of Form B above has characteristic diffraction peaks at the following 2θ angles: 6.25±0.2°, 12.43±0.2°, 18.74±0.2°, 21.89±0.2°, 23.46±0.2 °, 24.99±0.2°, 29.75±0.2° and 31.44±0.2°.
本发明的一些方案中，上述B晶型的XRPD图谱如图4所示。In some solutions of the present invention, the XRPD pattern of the above crystalline form B is shown in FIG. 4.
本发明的一些方案中，上述B晶型的的XRPD图谱解析数据如表2所示：In some solutions of the present invention, the XRPD pattern analysis data of the above crystalline form B are shown in Table 2:
表2：B晶型的XRPD图谱解析数据Table 2: XRPD pattern analysis data of crystal form B
Figure PCTCN2019126948-appb-000004
Figure PCTCN2019126948-appb-000004
本发明的一些方案中，上述B晶型的差示扫描量热曲线(DSC)在171.21±3℃处具有吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve (DSC) of the above crystalline form B has a starting point of an endothermic peak at 171.21±3°C.
本发明的一些方案中，上述B晶型的DSC图谱如图5所示。In some aspects of the present invention, the DSC pattern of the above crystal form B is shown in FIG. 5.
本发明的一些方案中，上述B晶型的热重分析曲线(TGA)在180.52±3℃时失重达0.4681％。In some solutions of the present invention, the thermogravimetric analysis curve (TGA) of the above crystalline form B has a weight loss of 0.4681% at 180.52±3°C.
本发明的一些方案中，上述B晶型的TGA图谱如图6所示。In some solutions of the present invention, the TGA pattern of the above B crystal form is shown in FIG. 6.
本发明还提供了式(Ⅰ)化合物的C晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.55±0.2°、18.79±0.2°和25.10±0.2°。The invention also provides Form C of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 12.55±0.2°, 18.79±0.2°, and 25.10±0.2°.
本发明的一些方案中，上述C晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.33±0.2°、12.55±0.2°、15.22±0.2°、17.68±0.2°、18.79±0.2°、20.07±0.2°、25.10±0.2°和26.76±0.2°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above C form has characteristic diffraction peaks at the following 2θ angles: 6.33±0.2°, 12.55±0.2°, 15.22±0.2°, 17.68±0.2°, 18.79±0.2 °, 20.07±0.2°, 25.10±0.2° and 26.76±0.2°.
本发明的一些方案中，上述C晶型的XRPD图谱如图7所示。In some solutions of the present invention, the XRPD pattern of the above C form is shown in FIG. 7.
本发明的一些方案中，上述C晶型的的XRPD图谱解析数据如表3所示：In some solutions of the present invention, the XRPD pattern analysis data of the above C crystal form are shown in Table 3:
表3：C晶型的XRPD图谱解析数据Table 3: XRPD pattern analysis data of crystal form C
Figure PCTCN2019126948-appb-000005
Figure PCTCN2019126948-appb-000005
本发明的一些方案中，上述C晶型的差示扫描量热曲线(DSC)在168.06±3℃处具有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve (DSC) of Form C above has a starting point of an endothermic peak at 168.06±3°C.
本发明的一些方案中，上述C晶型的DSC图谱如图8所示。In some aspects of the present invention, the DSC pattern of the above C form is shown in FIG. 8.
本发明的一些方案中，上述C晶型的热重分析曲线(TGA)在176.32±3℃时失重达0.7482％。In some solutions of the present invention, the thermogravimetric analysis curve (TGA) of the above C crystal form has a weight loss of 0.7482% at 176.32±3°C.
本发明的一些方案中，上述C晶型的TGA图谱如图9所示。In some solutions of the present invention, the TGA pattern of the above C crystal form is shown in FIG. 9.
本发明还提供了式(Ⅰ)化合物的D晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：18.94±0.2°、24.83±0.2°和26.15±0.2°。The present invention also provides the crystal form D of the compound of formula (I) whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 18.94±0.2°, 24.83±0.2°, and 26.15±0.2°.
本发明的一些方案中，上述D晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.45±0.2°、14.86±0.2°、17.13±0.2°、18.41±0.2°、18.94±0.2°、22.83±0.2°、24.83±0.2°和26.15±0.2°。In some aspects of the present invention, the X-ray powder diffraction pattern of Form D above has characteristic diffraction peaks at the following 2θ angles: 12.45±0.2°, 14.86±0.2°, 17.13±0.2°, 18.41±0.2°, 18.94±0.2 °, 22.83±0.2°, 24.83±0.2° and 26.15±0.2°.
本发明的一些方案中，上述D晶型的XRPD图谱如图10所示。In some aspects of the present invention, the XRPD pattern of the above D form is shown in FIG. 10.
本发明的一些方案中，上述D晶型的的XRPD图谱解析数据如表4所示：In some solutions of the present invention, the XRPD pattern analysis data of the above D form is shown in Table 4:
表4：D晶型的XRPD图谱解析数据Table 4: XRPD pattern analysis data of crystal form D
Figure PCTCN2019126948-appb-000006
Figure PCTCN2019126948-appb-000006
本发明的一些方案中，上述D晶型的差示扫描量热曲线(DSC)在163.80±3℃处具有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve (DSC) of Form D above has a starting point for an endothermic peak at 163.80±3°C.
本发明的一些方案中，上述D晶型的DSC图谱如图11所示。In some aspects of the present invention, the DSC pattern of the above D form is shown in FIG. 11.
本发明的一些方案中，上述D晶型的热重分析曲线(TGA)在121.34±3℃时失重达0.9987％；在174.58℃时失重达1.1087％。In some solutions of the present invention, the thermogravimetric analysis curve (TGA) of the above D crystal form has a weight loss of 0.9987% at 121.34±3°C; and a weight loss of 1.1087% at 174.58°C.
本发明的一些方案中，上述D晶型的TGA图谱如图12所示。In some solutions of the present invention, the TGA pattern of the above D crystal form is shown in FIG. 12.
本发明还提供了式(Ⅰ)化合物的E晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：22.81±0.2°、24.93±0.2°和25.82±0.2°。The present invention also provides the crystal form E of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2θ angles: 22.81±0.2°, 24.93±0.2°, and 25.82±0.2°.
本发明的一些方案中，上述E晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.41±0.2°、15.02±0.2°、17.48±0.2°、18.69±0.2°、22.81±0.2°、23.61±0.2°、24.93±0.2°和25.82±0.2°。In some aspects of the present invention, the X-ray powder diffraction pattern of the above E crystal form has characteristic diffraction peaks at the following 2θ angles: 12.41±0.2°, 15.02±0.2°, 17.48±0.2°, 18.69±0.2°, 22.81±0.2 °, 23.61±0.2°, 24.93±0.2° and 25.82±0.2°.
本发明的一些方案中，上述E晶型的XRPD图谱如图13所示。In some aspects of the present invention, the XRPD pattern of the above E crystal form is shown in FIG. 13.
本发明的一些方案中，上述E晶型的的XRPD图谱解析数据如表5所示：In some solutions of the present invention, the XRPD pattern analysis data of the above E crystal form is shown in Table 5:
表5：E晶型的XRPD图谱解析数据Table 5: XRPD pattern analysis data of crystal E
Figure PCTCN2019126948-appb-000007
Figure PCTCN2019126948-appb-000007
本发明的一些方案中，上述E晶型的差示扫描量热曲线(DSC)在167.83±3℃处具有一个吸热峰的起始点。In some aspects of the present invention, the differential scanning calorimetry curve (DSC) of the above E crystal form has a starting point of an endothermic peak at 167.83±3°C.
本发明的一些方案中，上述E晶型的DSC图谱如图14所示。In some aspects of the present invention, the DSC pattern of the above E crystal form is shown in FIG. 14.
本发明的一些方案中，上述E晶型的热重分析曲线(TGA)在99.83±3℃时失重达0.6462％；在176.84±3℃时失重达0.73118％。In some solutions of the present invention, the thermogravimetric analysis curve (TGA) of the above E crystal form has a weight loss of 0.6462% at 99.83±3°C; a weight loss of 0.73118% at 176.84±3°C.
本发明的一些方案中，上述E晶型的TGA图谱如图15所示。In some solutions of the present invention, the TGA pattern of the above E crystal form is shown in FIG. 15.
本发明还提供了式(Ⅰ)化合物的无定形，其X射线粉末衍射(XRPD)图谱如图16所示。The present invention also provides an amorphous compound of formula (I), and its X-ray powder diffraction (XRPD) pattern is shown in FIG. 16.
本发明还提供式(I)化合物B晶型的制备方法，包括：The present invention also provides a method for preparing the compound B crystal form of formula (I), which includes:
(a)将式(I)化合物加入醇类溶剂中使其成悬浊液；(a) The compound of formula (I) is added to an alcoholic solvent to make it into a suspension;
(b)悬浊液25～60℃下搅拌8～120小时；(b) The suspension is stirred at 25 to 60°C for 8 to 120 hours;
(c)离心后干燥8～16小时；(c) Dry for 8 to 16 hours after centrifugation;
本发明的一些方案中，上述醇类溶剂包含乙醇。In some embodiments of the present invention, the alcohol solvent includes ethanol.
本发明还提供式(I)化合物无定形的制备方法，包括：The invention also provides an amorphous preparation method of the compound of formula (I), including:
(a)将式(I)化合物加入溶剂或者混合溶剂中溶解；(a) The compound of formula (I) is added to a solvent or mixed solvent to dissolve;
(b)将溶液旋干，或者喷雾干燥，或者冻干等。(b) Spin-dry the solution, or spray-dry it, or freeze-dry it.
其中，所述溶剂选自丙酮、四氢呋喃和乙腈。Wherein, the solvent is selected from acetone, tetrahydrofuran and acetonitrile.
本发明还提供了上述A晶型、B晶型、C晶型、D晶型或E晶型在制备治疗MEK相关病症的药物上的应用。The present invention also provides the use of the above-mentioned Form A, Form B, Form C, Form D or Form E in the preparation of a medicament for treating MEK-related disorders.
本发明还提供了上述无定形在制备治疗MEK相关病症的药物上的应用。The invention also provides the application of the above-mentioned amorphous form in the preparation of a medicament for treating MEK-related disorders.
技术效果Technical effect
本发明中的无定形及各晶型，性质稳定，吸湿性弱，适宜长期保存，适于成药。式(I)化合物无定形各个剂量组均可有效抑制HT-29肿瘤生长。The amorphous and various crystal forms in the present invention have stable properties, weak hygroscopicity, are suitable for long-term storage, and are suitable for medicine preparation. Compounds of formula (I) in various dosage groups can effectively inhibit the growth of HT-29 tumors.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术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。当本文出现商品名时，旨在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.
本发明的中间体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。The intermediate 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 the combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
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。The chemical reaction of the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the reagents and materials required. In order to obtain the compound of the present invention, it is sometimes necessary for a person skilled in the art to modify or select a synthesis step or a reaction scheme based on existing embodiments.
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。The present invention will be specifically described below through examples, which are not meant to limit the present invention.
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。All solvents used in the present invention are commercially available and can be used without further purification.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO 3H代表乙磺酸；MeSO 3H代表甲磺酸；THF代表四氢呋喃；EtOAc代表乙酸乙酯；THF代表四氢呋喃；EA代表乙酸乙酯；DMAP代表4-二甲氨基吡啶；DCM代表二氯甲烷；DIPEA代表N,N-二异丙基乙胺；Pd(dppf)Cl 2.CH 2Cl 2代表[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物。 The solvent used in the present invention is commercially available. The present invention uses the following abbreviations: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO 3 H stands for ethanesulfonic acid; MeSO 3 H stands for methanesulfonic acid; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate; THF stands for tetrahydrofuran; EA stands for ethyl acetate; DMAP stands for 4-dimethylaminopyridine; DCM stands for dichloromethane; DIPEA stands for N,N-diisopropylethylamine; Pd( dppf) Cl 2. CH 2 Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex.
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法Powder X-ray diffraction (X-ray powder diffractometer, XRPD) method of the present invention
仪器型号：Bruker D8 advance X射线粉末衍射仪(XRPD)Instrument model: Bruker D8 advance X-ray powder diffractometer (XRPD)
测试条件：Test Conditions:
光管：Cu,K-Alpha，
Figure PCTCN2019126948-appb-000008
Light tube: Cu, K-Alpha,
Figure PCTCN2019126948-appb-000008
光管电压：40kV，光管电流：40mALight tube voltage: 40kV, light tube current: 40mA
散射狭缝：0.60mmScattering slit: 0.60mm
探测器狭缝：10.50mmDetector slit: 10.50mm
反散射狭缝：7.10mmAnti-scattering slit: 7.10mm
扫描范围：4-40degScanning range: 4-40deg
步长：0.02degStep size: 0.02deg
速率：0.1SRate: 0.1S
样品盘转速：15rpmSample tray speed: 15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法Differential Scanning Calorimeter (DSC) method of the present invention
仪器型号：TA Q2000差示扫描量热仪(DSC)Instrument model: TA Q2000 Differential Scanning Calorimeter (DSC)
测试条件：在50mL/min N 2条件下，以10℃/min升温速率，加热样品从30℃到300℃。 Test conditions: at 50mL / min N 2 conditions at / min heating rate 10 ℃, the sample was heated from 30 deg.] C to 300 ℃.
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
仪器型号：TA Q5000热重分析仪(TGA)Instrument Model: TA Q5000 Thermogravimetric Analyzer (TGA)
测试条件：在25mL/min N2条件下，以10℃/min升温速率加热样品从室温到300℃。Test conditions: Under 25mL/min N2, heat the sample from room temperature to 300°C at a heating rate of 10°C/min.
本发明动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法Dynamic Vapor Sorption (DVS) method of the present invention
将样品10mg～15mg置动态水蒸气吸附仪(DVS)样品盘内测定。 Place 10 mg to 15 mg of the sample in the sample tray of a dynamic water vapor adsorption instrument (DVS).
仪器型号：SMS DVS Advantage动态蒸汽吸附仪Instrument model: SMS DVS Advantage dynamic steam adsorption instrument
测试条件：温度：25℃Test condition: temperature: 25℃
平衡dm/dt：0.01％/min：(时间：10min最大180min)Balance dm/dt: 0.01%/min: (time: 10min, max 180min)
干燥：0％RH，120minDrying: 0%RH, 120min
RH(％)测量梯度：10％RH (%) measurement gradient: 10%
RH(％)测量梯度范围：0％～90％～0％RH(%) measurement gradient range: 0%～90%～0%
引湿性评价分类如下：The classification of hygroscopicity is as follows:
吸湿性分类Hygroscopic classification ΔW％ΔW%
潮解deliquescence 吸收足量水分形成液体Absorb enough water to form liquid
极具吸湿性Very hygroscopic ΔW％≥15％ΔW%≥15%
有吸湿性Hygroscopic 15％>ΔW％≥2％15%>ΔW%≥2%
略有吸湿性Slightly hygroscopic 2％>ΔW％≥0.2％2%>ΔW%≥0.2%
无或几乎无吸湿性No or almost no hygroscopicity ΔW％<0.2％ΔW%<0.2%
ΔW％表示受试品在25±1℃和80±2％RH下的吸湿增重ΔW% represents the hygroscopic weight gain of the tested product at 25±1℃ and 80±2%RH
附图说明BRIEF DESCRIPTION
图1：式(I)化合物A晶型的XRPD图谱；Figure 1: XRPD pattern of compound A crystal form of formula (I);
图2：式(I)化合物A晶型的DSC谱图；Figure 2: DSC spectrum of compound A of formula (I);
图3：式(I)化合物A晶型的TGA谱图；Figure 3: TGA spectrum of compound A crystal form of formula (I);
图4：式(I)化合物B晶型的XRPD图谱；Figure 4: XRPD pattern of compound B crystal form of formula (I);
图5：式(I)化合物B晶型的DSC谱图；Figure 5: DSC spectrum of compound B crystal form of formula (I);
图6：式(I)化合物B晶型的TGA谱图；Figure 6: TGA spectrum of compound B crystal form of formula (I);
图7：式(I)化合物C晶型的XRPD图谱；Figure 7: XRPD pattern of compound C crystal form of formula (I);
图8：式(I)化合物C晶型的DSC谱图；Figure 8: DSC spectrum of compound C crystal form of formula (I);
图9：式(I)化合物C晶型的TGA谱图；Figure 9: TGA spectrum of compound C crystal form of formula (I);
图10：式(I)化合物D晶型的XRPD图谱；Figure 10: XRPD pattern of compound D crystal form of formula (I);
图11：式(I)化合物D晶型的DSC谱图；Figure 11: DSC spectrum of compound D of formula (I);
图12：式(I)化合物D晶型的TGA谱图；Figure 12: TGA spectrum of compound D of formula (I);
图13：式(I)化合物E晶型的XRPD图谱；Figure 13: XRPD pattern of the crystal form E of the compound of formula (I);
图14：式(I)化合物E晶型的DSC谱图；Figure 14: DSC spectrum of compound E crystal form of formula (I);
图15：式(I)化合物E晶型的TGA谱图；Figure 15: TGA spectrum of the crystal form E of the compound of formula (I);
图16：式(I)化合物无定形的XRPD图谱；Figure 16: Amorphous XRPD pattern of the compound of formula (I);
图17：式(I)化合物无定形的DVS谱图。Figure 17: Amorphous DVS spectrum of the compound of formula (I).
具体实施方式detailed description
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。In order to better understand the content of the present invention, the following further description will be made in conjunction with specific embodiments, but the specific implementation manner is not a limitation to the content of the present invention.
中间体AIntermediate A
Figure PCTCN2019126948-appb-000009
Figure PCTCN2019126948-appb-000009
合成路线：synthetic route:
Figure PCTCN2019126948-appb-000010
Figure PCTCN2019126948-appb-000010
步骤1：化合物BA-2的合成。Step 1: Synthesis of compound BA-2.
将化合物A-1(249.70g，1.98mol，1.00eq)溶于水(500.00mL)中，于60～80℃下加入环丙胺(113.04g，1.98mol，1.00eq)。升温至100℃，搅拌反应6小时后，有沉淀生成。反应完毕后，反应液冷却至室温。加入甲醇(100mL)，搅拌30分钟。过滤收集滤饼，用乙酸乙酯(50mL*3)洗涤，旋干得到化合物A-2。MS m/z：205.0[M+H] + Compound A-1 (249.70 g, 1.98 mol, 1.00 eq) was dissolved in water (500.00 mL), and cyclopropylamine (113.04 g, 1.98 mol, 1.00 eq) was added at 60 to 80°C. After raising the temperature to 100°C and stirring the reaction for 6 hours, a precipitate formed. After the reaction was completed, the reaction solution was cooled to room temperature. Methanol (100 mL) was added and stirred for 30 minutes. The filter cake was collected by filtration, washed with ethyl acetate (50 mL*3), and spin-dried to obtain compound A-2. MS m/z: 205.0[M+H] +
步骤2：化合物A-3的合成。Step 2: Synthesis of compound A-3.
将化合物A-2(31.85g，192.81mmol，1.00eq)与甲基丙二酸(33.59g，192.81mmol，1.00eq，)混合于二苯醚(180.00mL)中，在氮气保护下升温至220-230℃，搅拌反应6小时。反应完毕后，反应液冷却后加入石油醚(1L)稀释，收集滤饼，用石油醚(50mL*3)洗涤，旋干后，用二氯甲烷(500mL)搅拌30分钟，过滤并用二氯甲烷(50mL*3)洗涤，合并有机相旋干得粗品，经柱色谱(DCM/EA＝1/1)纯化，得到目标化合物A-3。 1H NMR(400MHz，CDCl 3-d)δ12.85(s，1H)，6.25(s，1H)，2.91-2.89(m，1H)，2.60(s，3H)，1.99(s，3H)，1.37-1.35(m，2H)，1.00-0.99(m，2H)。MS m/z:247.9[M+H] + Compound A-2 (31.85g, 192.81mmol, 1.00eq) and methylmalonic acid (33.59g, 192.81mmol, 1.00eq,) were mixed in diphenyl ether (180.00mL), and heated to 220 under nitrogen protection At -230°C, the reaction was stirred for 6 hours. After the reaction was completed, the reaction solution was cooled and diluted with petroleum ether (1L). The filter cake was collected and washed with petroleum ether (50mL*3). After spin-drying, it was stirred with dichloromethane (500mL) for 30 minutes, filtered and filtered with dichloromethane (50mL*3) washed, combined organic phase was spin-dried to obtain crude product, and purified by column chromatography (DCM/EA=1/1) to obtain the target compound A-3. 1 H NMR (400 MHz, CDCl 3 -d) δ 12.85 (s, 1H), 6.25 (s, 1H), 2.91-2.89 (m, 1H), 2.60 (s, 3H), 1.99 (s, 3H), 1.37-1.35 (m, 2H), 1.00-0.99 (m, 2H). MS m/z:247.9[M+H] +
步骤3：化合物A-4的合成。Step 3: Synthesis of compound A-4.
将化合物A-3(4.83g，19.53mmol，1.00eq)，三乙胺(3.95g，39.06mmol，2.00eq)和DMAP(47.72mg，390.60μmol，0.02eq)溶于二氯甲烷(120.00mL)中，于15℃下加入4-甲基苯磺酰氯(3.72g，19.53mmol，1.00eq)。15℃下搅拌反应16小时。反应完毕后，反应液依次用水(50mL)与饱和的氯化钠溶液(50mL)洗涤，经过无水硫酸钠干燥，旋干得到粗品。粗品经柱色谱(DCM，DCM/EA＝5/1)纯化，得到目标化合物A-4。 1H NMR(400MHz，CDCl 3-d)δ7.96-7.94(m，2H)，7.41-7.39(m，2H)，6.07(s，1H)，2.85(s，1H)，2.54(m，3H)，2.49(s，3H)，1.67(s，3H)，1.32-1.30(m，2H)，0.87-0.86(m，2H). Compound A-3 (4.83g, 19.53mmol, 1.00eq), triethylamine (3.95g, 39.06mmol, 2.00eq) and DMAP (47.72mg, 390.60μmol, 0.02eq) were dissolved in dichloromethane (120.00mL) In, 4-methylbenzenesulfonyl chloride (3.72 g, 19.53 mmol, 1.00 eq) was added at 15°C. The reaction was stirred at 15°C for 16 hours. After the reaction was completed, the reaction solution was washed with water (50 mL) and saturated sodium chloride solution (50 mL) in this order, dried over anhydrous sodium sulfate, and vortexed to obtain a crude product. The crude product was purified by column chromatography (DCM, DCM/EA=5/1) to obtain the target compound A-4. 1 H NMR (400 MHz, CDCl 3 -d) δ 7.96-7.94 (m, 2H), 7.41-7.39 (m, 2H), 6.07 (s, 1H), 2.85 (s, 1H), 2.54 (m, 3H ), 2.49 (s, 3H), 1.67 (s, 3H), 1.32-1.30 (m, 2H), 0.87-0.86 (m, 2H).
步骤4：化合物A-5的合成。Step 4: Synthesis of compound A-5.
将化合物A-4(6.97g，17.36mmol，1.00eq)溶于乙腈(25.00mL)和二氯甲烷(25.00mL)中，分批加入N-溴代琥珀酰亚胺(4.63g，26.04mmol，1.50eq)。15℃下搅拌反应1小时。反应完毕后，将反应液旋干得到粗品。粗品经乙腈(50mL)打浆30分钟，过滤并用乙腈(10mL*3)洗涤，收集滤饼，旋干得到目标化合物A-5。 1H NMR(400MHz，CDCl 3-d)δ7.92-7.90(m，2H)，7.40-7.38(m，2H)，2.95(m，1H)，2.75(s，3H)，2.47(s，3H)，1.64(s，3H)，1.40-1.30(m，2H)，0.87-0.85(m，2H)。MS m/z：481.9[M+H] + Compound A-4 (6.97 g, 17.36 mmol, 1.00 eq) was dissolved in acetonitrile (25.00 mL) and dichloromethane (25.00 mL), and N-bromosuccinimide (4.63 g, 26.04 mmol, 1.50eq). The reaction was stirred at 15°C for 1 hour. After the reaction is completed, the reaction solution is spin-dried to obtain a crude product. The crude product was slurried with acetonitrile (50 mL) for 30 minutes, filtered and washed with acetonitrile (10 mL*3). The filter cake was collected and spin-dried to obtain the target compound A-5. 1 H NMR (400 MHz, CDCl 3 -d) δ 7.92-7.90 (m, 2H), 7.40-7.38 (m, 2H), 2.95 (m, 1H), 2.75 (s, 3H), 2.47 (s, 3H ), 1.64 (s, 3H), 1.40-1.30 (m, 2H), 0.87-0.85 (m, 2H). MS m/z: 481.9[M+H] +
步骤5：化合物A的合成。Step 5: Synthesis of Compound A.
将化合物A-5(5.30g，11.03mmol，1.00eq)与邻氟苯胺(5.30g，47.65mmol，4.32eq)溶于乙醇(120.00mL)中，升温至85℃搅拌反应16小时。反应完毕后，反应液冷却后，过滤并用乙醇(30mL*3)洗涤，收集滤饼，旋干后得到目标化合物A。 1H NMR(400MHz，CDCl 3-d)δ11.01(s，1H)，7.12-7.10(m，3H)，7.03-7.01(m，1H)，2.97(s，3H)，1.61(m，3H)，1.38-1.36(t，3H)，0.91-0.90(t，3H)。MS m/z：420.8[M+H] + Compound A-5 (5.30 g, 11.03 mmol, 1.00 eq) and o-fluoroaniline (5.30 g, 47.65 mmol, 4.32 eq) were dissolved in ethanol (120.00 mL), and the temperature was raised to 85° C. and the reaction was stirred for 16 hours. After the reaction was completed, after the reaction solution was cooled, it was filtered and washed with ethanol (30 mL*3), and the filter cake was collected and spin-dried to obtain the target compound A. 1 H NMR (400 MHz, CDCl 3 -d) δ 11.01 (s, 1H), 7.12-7.10 (m, 3H), 7.03-7.01 (m, 1H), 2.97 (s, 3H), 1.61 (m, 3H ), 1.38-1.36 (t, 3H), 0.91-0.90 (t, 3H). MS m/z: 420.8[M+H] +
中间体BIntermediate B
Figure PCTCN2019126948-appb-000011
Figure PCTCN2019126948-appb-000011
合成路线：synthetic route:
Figure PCTCN2019126948-appb-000012
Figure PCTCN2019126948-appb-000012
步骤1：化合物B-2的合成。Step 1: Synthesis of compound B-2.
将化合物B-1(5.00g，26.87mmol，1.00eq)溶于吡啶(100.00mL)中，于0℃氮气保护下加入甲烷磺酰氯(11.87g，103.62mmol，3.86eq)。升温至60℃搅拌反应1小时。反应完毕后，旋除溶剂。残留物溶于二氯甲烷(100mL)，加入盐酸(1M，100mL)洗涤，再加入饱和的碳酸氢钠溶液(100mL)洗涤。有机相经无水硫酸钠干燥，过滤，旋干得粗品。粗品经柱色谱(PE/EA＝10/1-2/1)纯化得化合物B-2。 1H NMR(400MHz，CDCl 3-d)δ7.47(d，J＝8.0Hz，1H)，7.43(d，J＝8.0Hz，1H)，7.10(t，J＝8.0H，1H)，6.39(s，1H)，3.03(s，3H)，2.45(s，3H)。MS m/z：264.0[M+H] + Compound B-1 (5.00 g, 26.87 mmol, 1.00 eq) was dissolved in pyridine (100.00 mL), and methanesulfonyl chloride (11.87 g, 103.62 mmol, 3.86 eq) was added under nitrogen protection at 0°C. The temperature was raised to 60°C and the reaction was stirred for 1 hour. After the reaction is completed, the solvent is removed. The residue was dissolved in methylene chloride (100 mL), washed with hydrochloric acid (1M, 100 mL), and then washed with saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was purified by column chromatography (PE/EA=10/1-2/1) to obtain compound B-2. 1 H NMR (400 MHz, CDCl 3 -d) δ 7.47 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.10 (t, J=8.0H, 1H), 6.39 (s, 1H), 3.03 (s, 3H), 2.45 (s, 3H). MS m/z: 264.0[M+H] +
步骤2：化合物B的合成。Step 2: Synthesis of compound B.
将化合物B-2(3.00g，11.36mmol，1.00eq)和频哪醇硼酯(4.33g，17.04mmol，1.50eq)溶于二氧六环 (60.00mL)中，于20℃氮气保护下加入Pd(dppf)Cl 2.CH 2Cl 2(927.51mg，1.14mmol，0.10eq)和醋酸钾(3.34g，34.08mmol，3.00eq)，升温至85℃搅拌反应3小时。反应完毕后，冷却到室温，加入水(100mL)，用二氯甲烷(100mL*2)萃取。收集有机相，经饱和氯化钠溶液(100mL)洗涤，经无水硫酸钠干燥，过滤，旋干得粗品。粗品经制备TLC(PE/EA＝1/1)纯化，得到化合物BB-9。 1H NMR(400MHz，CDCl 3-d)δ7.70-7.65(m，1H)，7.61-7.56(m，1H)，7.25(t，J＝7.6Hz，1H)，6.29(s，1H)，3.00(s，3H)，2.55(s，3H)，1.37(s，12H)。MS m/z：311.9[M+H] + Compound B-2 (3.00 g, 11.36 mmol, 1.00 eq) and pinacol borate (4.33 g, 17.04 mmol, 1.50 eq) were dissolved in dioxane (60.00 mL) and added under nitrogen at 20°C Pd(dppf)Cl 2 .CH 2 Cl 2 (927.51 mg, 1.14 mmol, 0.10 eq) and potassium acetate (3.34 g, 34.08 mmol, 3.00 eq) were heated to 85° C. and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and extracted with dichloromethane (100 mL*2). The organic phase was collected, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. The crude product was purified by preparative TLC (PE/EA=1/1) to obtain compound BB-9. 1 H NMR (400 MHz, CDCl 3 -d) δ 7.70-7.65 (m, 1H), 7.61-7.56 (m, 1H), 7.25 (t, J=7.6 Hz, 1H), 6.29 (s, 1H), 3.00 (s, 3H), 2.55 (s, 3H), 1.37 (s, 12H). MS m/z: 311.9[M+H] +
实施例1：式(I)化合物的制备Example 1: Preparation of compound of formula (I)
Figure PCTCN2019126948-appb-000013
Figure PCTCN2019126948-appb-000013
步骤1：step 1:
将化合物A(2g,6.43mmol)与化合物B(2.16g,5.14mmol)溶于二氧六环(30mL)与水(15mL)的混合溶剂中，于氮气保护下加入2-双环己基膦-2′,6′-二甲氧基联苯(S-Phos)(527.94mg,1.29mmol)磷酸钾(2.73g,12.86mmol)以及Pd(dppf)Cl 2.CH 2Cl 2(525.1mg,643.0μmol)。反应升至100℃搅拌12小时。LCMS显示底物已消耗完目标产物已生成。反应液经硅藻土滤除不溶物，滤液旋干得粗品。粗品用硅胶柱色谱(石油醚：乙酸乙酯＝5:1至1：1)分离纯化得到化合物C。 1H NMR(400MHz,CDCl 3)δppm 11.13(s,1H),7.53(d,J＝8.4Hz,1H),7.31(t,J＝8.0Hz,1H),7.09-7.11(m,3H),6.97-7.02(m,2H),6.29-6.37(m,1H),3.12(s,3H),2.91-2.99(m,1H),2.56(s,3H),2.30(s,3H),2.09(s,3H),0.91-0.97(m,3H)。LCMS(ESI):m/z:524.1[M+1] +。 Dissolve compound A (2g, 6.43mmol) and compound B (2.16g, 5.14mmol) in a mixed solvent of dioxane (30mL) and water (15mL), add 2-biscyclohexylphosphine-2 under the protection of nitrogen ',6'-dimethoxybiphenyl (S-Phos) (527.94 mg, 1.29 mmol) potassium phosphate (2.73 g, 12.86 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (525.1 mg, 643.0 μmol ). The reaction was raised to 100°C and stirred for 12 hours. LCMS showed that the substrate had been consumed and the target product had been formed. The reaction solution was filtered through celite to remove insoluble materials, and the filtrate was spin-dried to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1 to 1:1) to obtain compound C. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 11.13 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.09-7.11 (m, 3H), 6.97-7.02(m, 2H), 6.29-6.37(m, 1H), 3.12(s, 3H), 2.91-2.99(m, 1H), 2.56(s, 3H), 2.30(s, 3H), 2.09( s, 3H), 0.91-0.97 (m, 3H). LCMS (ESI): m/z: 524.1 [M+1] + .
步骤2：Step 2:
将化合物C(800mg,1.53mmol)溶于N,N-二甲基甲酰胺(8mL)，于0℃氮气保护下加入三氟乙酸(6.16g,4.00mL)与N-碘代琥珀酰亚胺(688.44mg,3.06mmol)。反应于20℃搅拌12小时。LCMS显示底物有剩余，目标产物已生成。反应液用饱和碳酸氢钠水溶液(30mL)与饱和硫代硫酸钠水溶液(10mL)淬灭。混合液用二氯甲烷(30mL*2)萃取，有机相依次用水(20mL)，饱和氯化钠水溶液(30mL)洗涤。有机相经无水硫酸钠干燥后滤除固体旋干得粗品。粗品用制备高效液相色谱分离纯化得到化合物D。 1H  NMR(400MHz,CDCl 3)δppm 11.11(s,1H),7.54(d,J＝7.6Hz,1H),7.46(dd,J＝9.6Hz,1.6Hz,1H),7.41(d,J＝8.4Hz,1H),6.99(d,J＝7.2Hz,1H),6.70(t,J＝8.4Hz,1H),6.23(s,1H),3.12(s,3H),2.91-2.98(m,1H),2.30(s,3H),2.08(s,3H),1.59(s,3H),1.38(td,J＝7.2Hz,2.8Hz,2H),0.95(q,J＝4.0Hz,2H)。LCMS(ESI):m/z:650.1[M+1] +。 Compound C (800 mg, 1.53 mmol) was dissolved in N,N-dimethylformamide (8 mL), and trifluoroacetic acid (6.16 g, 4.00 mL) and N-iodosuccinimide were added under nitrogen protection at 0°C. (688.44mg, 3.06mmol). The reaction was stirred at 20°C for 12 hours. LCMS showed that the substrate remained and the target product had been formed. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (30 mL) and saturated aqueous sodium thiosulfate solution (10 mL). The mixture was extracted with dichloromethane (30 mL*2), and the organic phase was washed successively with water (20 mL) and saturated aqueous sodium chloride solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, and the solid was filtered off and spin-dried to obtain a crude product. The crude product was separated and purified by preparative high performance liquid chromatography to obtain compound D. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 11.11 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.46 (dd, J=9.6 Hz, 1.6 Hz, 1H), 7.41 (d, J= 8.4Hz, 1H), 6.99(d, J=7.2Hz, 1H), 6.70(t, J=8.4Hz, 1H), 6.23(s, 1H), 3.12(s, 3H), 2.91-2.98(m, 1H), 2.30(s, 3H), 2.08(s, 3H), 1.59(s, 3H), 1.38(td, J=7.2Hz, 2.8Hz, 2H), 0.95(q, J=4.0Hz, 2H) . LCMS (ESI): m/z: 650.1 [M+1] + .
步骤3：Step 3:
将化合物D(1.44g,2.22mmol)送手性SFC分离纯化(分离条件：色谱柱：OJ(250mm x 50mm,10um)；流动相：A：二氧化碳,B：乙醇+0.1％氨水；洗脱梯度：起始B：35％,结束B：35％；流速：200mL/min。)。馏分在45℃下减压浓缩干，得到式(I)化合物。 1H NMR(400MHz,DMSO-d 6)δppm 11.29(s,1H),9.19(s,1H),7.71(dd,J＝10.0Hz,J＝1.6Hz,1H),7.51(d,J＝8.0Hz,1H),7.38(d,J＝7.2Hz,1H),7.31(t,J＝8.0Hz,1H),7.10(d,J＝7.6Hz,1H),6.87(t,J＝8.4Hz,1H),3.06-3.01(m,1H),3.00(s,3H),2.22(s,3H),2.05(s,3H),1.43(s,3H),1.25-1.13(m,2H),0.97-0.83(m,2H)。LCMS(ESI):m/z:650.0[M+1] +。 Compound D (1.44g, 2.22mmol) was sent to chiral SFC for separation and purification (separation conditions: chromatographic column: OJ (250mm x 50mm, 10um); mobile phase: A: carbon dioxide, B: ethanol + 0.1% ammonia; elution gradient : Start B: 35%, End B: 35%; Flow rate: 200 mL/min.). The fraction was concentrated and dried under reduced pressure at 45°C to obtain the compound of formula (I). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.29 (s, 1H), 9.19 (s, 1H), 7.71 (dd, J=10.0 Hz, J=1.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.38 (d, J = 7.2Hz, 1H), 7.31 (t, J = 8.0Hz, 1H), 7.10 (d, J = 7.6Hz, 1H), 6.87 (t, J = 8.4Hz, 1H), 3.06-3.01(m, 1H), 3.00(s, 3H), 2.22(s, 3H), 2.05(s, 3H), 1.43(s, 3H), 1.25-1.13(m, 2H), 0.97 -0.83(m,2H). LCMS (ESI): m/z: 650.0 [M+1] + .
实施例2：式(I)化合物各晶型的制备Example 2: Preparation of various crystal forms of the compound of formula (I)
称量如表6中重量的式(I)化合物于2.0mL样品瓶中，加入一定体积表6中的溶剂，制备不同单一溶剂和混合溶剂的悬浊液(为保证溶液浑浊，且能搅动，采取多次补加化合物或溶剂方式进行)。混悬液在40℃条件下持续振摇2天后，离心后将残留固体放入真空干燥箱，在40℃条件下真空干燥过夜去除残留溶剂。干燥之后的样品用XRPD检测。实验结果如表6所示：Weigh the compound of formula (I) as shown in Table 6 into a 2.0 mL sample bottle, add a certain volume of the solvent in Table 6 to prepare a suspension of different single solvents and mixed solvents (to ensure that the solution is turbid and can be stirred, Take multiple times to add compounds or solvents). After the suspension was continuously shaken at 40°C for 2 days, the residual solid was placed in a vacuum drying oven after centrifugation, and the residual solvent was removed by vacuum drying at 40°C overnight. The samples after drying were detected by XRPD. The experimental results are shown in Table 6:
表6：化合物晶型筛选实验结果Table 6: Experimental results of compound crystal form screening
Figure PCTCN2019126948-appb-000014
Figure PCTCN2019126948-appb-000014
实施例3：式(I)化合物无定形的制备Example 3: Amorphous preparation of compound of formula (I)
称量如表7中重量的式(I)化合物于2.0mL样品瓶中，加入一定体积表7中的溶剂，制备不同单一溶剂和混合溶剂的悬浊液(为保证溶液浑浊，且能搅动，采取多次补加化合物或溶剂方式进行)。混悬液在40℃条件下持续振摇2天后，离心后将残留固体放入真空干燥箱，在40℃条件下真空干燥过夜去除残留溶 剂。干燥之后的样品用XRPD检测。实验结果如表7所示：Weigh the compound of formula (I) as shown in Table 7 into a 2.0 mL sample bottle, add a certain volume of the solvent in Table 7 to prepare a suspension of different single solvents and mixed solvents (to ensure that the solution is turbid and can be stirred, Take multiple times to add compounds or solvents). After the suspension was continuously shaken at 40°C for 2 days, the residual solid was placed in a vacuum drying oven after centrifugation, and the residual solvent was removed by vacuum drying at 40°C overnight. The samples after drying were detected by XRPD. The experimental results are shown in Table 7:
表7：化合物无定形筛选实验结果Table 7: Compound amorphous screening results
Figure PCTCN2019126948-appb-000015
Figure PCTCN2019126948-appb-000015
将式(I)化合物的粗品(101.85g)加入乙醇(1.13L)中于22℃打浆16小时。过滤，滤饼用乙醇(500mL*3)洗涤，并于40℃真空干燥20小时，得到式(I)化合物的B晶型。将式(I)化合物的B晶型(80.92g)和丙酮(250.00mL)依次加入1L反应瓶，搅拌15分钟至固体完全溶解。减压浓缩至干后继续浓缩30分钟。收集固体至结晶皿碾碎为粉末和细小颗粒，于95～100℃、P≤-0.085MPa真空干燥48小时，得到式(I)化合物无定形。 1H NMR(400MHz,DMSO-d 6)δppm 11.31(s,1H),9.21(s,1H),7.72(dd,J＝10.0Hz,1.8Hz,1H),7.52(d,J＝8.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.33(t,J＝7.3Hz,1H),7.11(d,J＝6.5Hz,1H),6.88(t,J＝8.7Hz,1H),3.07～3.04(m,1H),3.02(s,3H),2.24(s,3H),2.07(s,3H),1.45(s,3H),1.24～1.20(m,2H),0.96～0.90(m,2H)。 The crude product (101.85 g) of the compound of formula (I) was added to ethanol (1.13 L) and beaten at 22° C. for 16 hours. After filtration, the filter cake was washed with ethanol (500 mL*3) and dried under vacuum at 40° C. for 20 hours to obtain Form B of the compound of formula (I). Form B (80.92 g) of the compound of formula (I) and acetone (250.00 mL) were added to a 1 L reaction flask in sequence, and stirred for 15 minutes until the solid was completely dissolved. Concentrate to dryness under reduced pressure and continue to concentrate for 30 minutes. The solid was collected into a crystallizing dish and crushed into powder and fine particles, and vacuum dried at 95-100° C. and P≦−0.085 MPa for 48 hours to obtain the amorphous compound of formula (I). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.31 (s, 1H), 9.21 (s, 1H), 7.72 (dd, J = 10.0 Hz, 1.8 Hz, 1 H), 7.52 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 7.6Hz, 1H), 7.33 (t, J = 7.3Hz, 1H), 7.11 (d, J = 6.5Hz, 1H), 6.88 (t, J = 8.7Hz, 1H) , 3.07～3.04(m, 1H), 3.02(s, 3H), 2.24(s, 3H), 2.07(s, 3H), 1.45(s, 3H), 1.24～1.20(m, 2H), 0.96～0.90 (m, 2H).
实施例4：式(I)化合物无定形的吸湿性研究Example 4: Study on the amorphous hygroscopicity of the compound of formula (I)
实验材料：Experimental Materials:
SMS DVS Advantage动态蒸汽吸附仪SMSDVSAdvantage dynamic steam adsorption instrument
实验方法：experimental method:
取式(I)化合物无定形10～15mg置于DVS样品盘内进行测试。 Amorphous 10 to 15 mg of the compound of formula (I) is placed in the DVS sample pan for testing.
实验结果：Experimental results:
式(I)化合物无定形的DVS谱图如图17所示，△W＝1.577％。The amorphous DVS spectrum of the compound of formula (I) is shown in FIG. 17, ΔW=1.577%.
实验结论：Experimental results:
式(I)化合物无定形在25℃和80％RH下的吸湿增重为1.577％，略有吸湿性。The compound of formula (I) has an amorphous weight gain of 1.577% at 25°C and 80% RH, which is slightly hygroscopic.
实施例5：式(I)化合物无定形的长期固体稳定性试验Example 5: Long-term solid stability test of amorphous compound of formula (I)
1.5g样品分别装入双层LDPE袋，每层LDPE袋分别扎扣密封，再将LDPE袋子放入铝箔袋中并热封，分别放入40℃/75％RH(6包)条件下考察。试验结果见下表8所示：The 1.5g samples were put into double-layer LDPE bags, and each layer of LDPE bags were buckled and sealed separately. Then the LDPE bags were placed in aluminum foil bags and heat-sealed. They were placed under 40°C/75%RH (6 bags) for inspection. The test results are shown in Table 8 below:
表8：式(I)化合物无定形的固体稳定性试验结果Table 8: Test results of amorphous solid stability of compound of formula (I)
Figure PCTCN2019126948-appb-000016
Figure PCTCN2019126948-appb-000016
结论：式(I)化合物无定形具有良好的稳定性。Conclusion: The compound of formula (I) is amorphous and has good stability.
实施例6：式(I)化合物B晶型的稳定性试验Example 6: Stability test of compound B crystal form of formula (I)
准确称重式(I)化合物B晶型约10mg置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为正式供试样品，放置于加速试验条件下(40℃/75％RH和60℃/75％RH)，其样品为完全暴露放样，用铝箔纸盖上，扎上小孔。试验在15天，1月取样分析，分析方法见表9，实验结果见表10。Accurately weigh about 10mg of compound B of formula (I) in a dry and clean glass bottle and spread it into a thin layer as a formal test sample, placed under accelerated test conditions (40℃/75%RH and 60 ℃/75%RH), the sample is completely exposed and placed, covered with aluminum foil paper and pierced with small holes. The test is conducted in 15 days and sampled and analyzed in January. The analysis method is shown in Table 9, and the test results are shown in Table 10.
稀释剂及流动相的制备Preparation of diluent and mobile phase
稀释剂：乙腈：水(20:10)作为稀释剂Thinner: acetonitrile: water (20:10) as thinner
如：取100mL纯水和200mL纯乙腈相混合于玻璃瓶中，超声脱气10min，冷至室温。For example: mix 100mL of pure water and 200mL of pure acetonitrile in a glass bottle, degas by ultrasound for 10min, and cool to room temperature.
流动相A：0.04％TFA水溶液Mobile phase A: 0.04% TFA in water
如：量取0.4mL磷酸加入到4000mL水中，超声10分钟，混匀，放冷至室温，作为流动相A。For example: measure 0.4mL of phosphoric acid into 4000mL of water, sonicate for 10 minutes, mix well, let cool to room temperature, as mobile phase A.
流动相B：乙腈Mobile phase B: Acetonitrile
取乙腈作为流动相B。Take acetonitrile as mobile phase B.
对照品溶液的制备(0.8mg/mL)Preparation of reference solution (0.8mg/mL)
0天的样品S1.S2，加入稀释剂12.5mL，超声5min，混合均匀,后标记为STD-1和STD-2。At day 0, the samples S1.S2 were added with diluent 12.5mL, ultrasonically mixed for 5min, and mixed evenly. They were labeled STD-1 and STD-2.
灵敏度样品溶液的制备Preparation of sensitivity sample solution
取对照品溶液STD-1(0天的S1样品)稀释2000倍，记作LOQ(检测限)。The reference solution STD-1 (day 0 S1 sample) was diluted 2000-fold and recorded as LOQ (limit of detection).
样品溶液的制备(0.8mg/mL)Preparation of sample solution (0.8mg/mL)
于冰箱取出样品，恢复至室温后加入12.5mL稀释剂溶解，超声5min，混合均匀。待***稳定后进液相。Remove the sample in the refrigerator, add 12.5mL of diluent to dissolve after returning to room temperature, sonicate for 5min, and mix well. Enter the liquid phase after the system is stable.
表9：高效液相色谱分析方法Table 9: High-performance liquid chromatography analysis method
Figure PCTCN2019126948-appb-000017
Figure PCTCN2019126948-appb-000017
Figure PCTCN2019126948-appb-000018
Figure PCTCN2019126948-appb-000018
表10：式(I)化合物B晶型的稳定性结果Table 10: Stability results of the crystalline form of compound B of formula (I)
Figure PCTCN2019126948-appb-000019
Figure PCTCN2019126948-appb-000019
注：“-”表示未检测到。Note: "-" means not detected.
结论：式(I)化合物B晶型具有较好的稳定性。Conclusion: Compound B of formula (I) has better stability.
实施例7：式(I)化合物无定形的稳定性试验Example 7: Amorphous stability test of compound of formula (I)
各称取式(I)化合物无定形约2g置于干燥洁净的玻璃瓶中，摊成薄薄一层，作为正式供试样品，放置于加速试验条件下(40℃/75％RH和60℃/75％RH)，其样品为完全暴露放样，用铝箔纸盖上，扎上小孔。试验在3月取样分析，分析方法参见B晶型的分析方法，结果见表11。Weigh about 2g of each compound of formula (I) in a dry and clean glass bottle and spread it into a thin layer as a formal test sample and place it under accelerated test conditions (40℃/75%RH and 60℃) /75%RH), the sample is completely exposed and lofted, covered with aluminum foil paper and pierced with small holes. The test was sampled and analyzed in March. For the analysis method, please refer to the analysis method of Form B. The results are shown in Table 11.
表11：式(I)化合物无定形的稳定性结果Table 11: Amorphous stability results of compounds of formula (I)
Figure PCTCN2019126948-appb-000020
Figure PCTCN2019126948-appb-000020
结论：式(I)化合物无定形具有良好的稳定性。Conclusion: The compound of formula (I) is amorphous and has good stability.
实施例8：式(I)化合物无定形在人结肠癌HT-29细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究Example 8: In vivo pharmacodynamic study of compound of formula (I) amorphous in human colon cancer HT-29 cell subcutaneous xenograft tumor BALB/c nude mouse model
实验材料：Experimental Materials:
购自北京维通利华实验动物技术有限公司的BALB/c裸小鼠，雌性，6～8周，70只(不包含分组剩余鼠)。动物在SPF级动物房以IVC(独立送风***)笼具饲养(每笼5只)。将鼠保持在一个特殊的无病原体的环境中，且在单个通风笼中(4只每笼)。所有笼具、垫料及饮水在使用前均灭菌。笼具、饲料及饮水每周更换两次。所有的动物都可以自由获取标准认证的商业实验室饮食。BALB/c nude mice purchased from Beijing Vital Lihua Experimental Animal Technology Co., Ltd., female, 6-8 weeks, 70 mice (excluding the group of remaining mice). Animals were housed in IVC (Independent Air Supply System) cages (5 per cage) in SPF animal houses. The rats were kept in a special pathogen-free environment and in a single ventilated cage (4 per cage). All cages, bedding and drinking water are sterilized before use. Cages, feed and drinking water are changed twice a week. All animals have free access to standard certified commercial laboratory diets.
实验方法：experimental method:
动物到达后在实验环境饲养10天后方开始实验。将0.1mL(5×10 6个)HT-29细胞皮下接种于每只裸小鼠的右后背。肿瘤平均体积达到165mm 3时开始根据肿瘤体积随机分组给药。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 After the animals arrived, they were reared in the experimental environment for 10 days before starting the experiment. 0.1 mL (5×10 6 cells) of HT-29 cells were subcutaneously inoculated on the right back of each nude mouse. When the average tumor volume reached 165 mm 3 , the drug was randomly divided into groups according to the tumor volume. The diameter of the tumor was measured with vernier calipers twice a week. The calculation formula of tumor volume is: V=0.5a×b 2 , a and b represent the long and short diameters of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×100％。The antitumor efficacy of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group))/(average tumor at the end of treatment in the solvent control group Volume-average tumor volume at the beginning of treatment in the solvent control group)]×100%.
各组间比较用one-way ANOVA进行分析，如果F值有显著性差异，应用Games-Howell法进行检验。如果F值无显著性差异，应用Tukey法进行分析。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。One-way ANOVA was used for comparison between the groups. If the F value was significantly different, the Games-Howell method was used for testing. If there is no significant difference in F value, Tukey method is used for analysis. Use SPSS 17.0 for all data analysis. p<0.05 is considered to be a significant difference.
实验结果：见表12所示。Experimental results: see Table 12.
表12：药效学测试结果Table 12: Pharmacodynamic test results
Figure PCTCN2019126948-appb-000021
Figure PCTCN2019126948-appb-000021
注：Note:
a.平均值±SEM。a. Mean ± SEM.
b.肿瘤生长抑制由T RTV/C RTV和TGI(TGI(％)＝[1-(T 25RTV-T 0RTV)/(V 25RTV-V 0RTV)]×100)计算。 b. Tumor growth inhibition is calculated from T RTV /C RTV and TGI (TGI (%)=[1-(T 25RTV -T 0RTV )/(V 25RTV -V 0RTV )]×100).
c.p值根据相对肿瘤体积计算。The c.p value is calculated based on the relative tumor volume.
实验结论：Experimental results:
式(I)化合物无定形各个剂量组均可有效抑制HT-29肿瘤生长。Compounds of formula (I) in various dosage groups can effectively inhibit the growth of HT-29 tumors.

Claims (41)

  1. 式(Ⅰ)化合物的A晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.31±0.2°、15.45±0.2°和18.96±0.2°。The crystalline form A of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at the following 2θ angles: 12.31±0.2°, 15.45±0.2°, and 18.96±0.2°.
    Figure PCTCN2019126948-appb-100001
    Figure PCTCN2019126948-appb-100001
  2. 根据权利要求1所述的A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：12.31±0.2°、13.08±0.2°、15.45±0.2°、18.96±0.2°、21.63±0.2°、24.47±0.2°、27.17±0.2°和28.73±0.2°。The crystal form A according to claim 1, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.31±0.2°, 13.08±0.2°, 15.45±0.2°, 18.96±0.2°, 21.63±0.2 °, 24.47±0.2°, 27.17±0.2° and 28.73±0.2°.
  3. 根据权利要求2所述的A晶型，其XRPD图谱如图1所示。The crystal form A according to claim 2 whose XRPD pattern is shown in FIG. 1.
  4. 根据权利要求1～3任意一项所述的A晶型，其差示扫描量热曲线(DSC)在188.10±3℃处具有吸热峰的起始点。The crystal form A according to any one of claims 1 to 3, whose differential scanning calorimetry curve (DSC) has an onset of endothermic peak at 188.10±3°C.
  5. 根据权利要求4所述的A晶型，其DSC图谱如图2所示。The crystalline pattern of Form A according to claim 4 is shown in FIG. 2.
  6. 根据权利要求1～3任意一项所述的A晶型，其热重分析曲线(TGA)在197.79±3℃时失重达0.3606％。The crystal form A according to any one of claims 1 to 3, whose thermogravimetric analysis curve (TGA) has a weight loss of 0.3606% at 197.79±3°C.
  7. 根据权利要求6所述的A晶型，其TGA图谱如图3所示。The crystal form A according to claim 6, whose TGA pattern is shown in FIG. 3.
  8. 式(Ⅰ)化合物的B晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：6.25±0.2°、12.43±0.2°和21.89±0.2°。The crystalline form B of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at the following 2θ angles: 6.25±0.2°, 12.43±0.2°, and 21.89±0.2°.
  9. 根据权利要求8所述的B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：6.25±0.2°、12.43±0.2°、18.74±0.2°、21.89±0.2°、23.46±0.2°、24.99±0.2°、29.75±0.2°和31.44±0.2°。The crystal form B according to claim 8, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.25±0.2°, 12.43±0.2°, 18.74±0.2°, 21.89±0.2°, 23.46±0.2 °, 24.99±0.2°, 29.75±0.2° and 31.44±0.2°.
  10. 根据权利要求9所述的B晶型，其XRPD图谱如图4所示。The crystal form B according to claim 9 whose XRPD pattern is shown in FIG. 4.
  11. 根据权利要求8～10任意一项所述的B晶型，其差示扫描量热曲线(DSC)在171.21±3℃处具有吸热峰的起始点。The crystal form B according to any one of claims 8 to 10, whose differential scanning calorimetry curve (DSC) has an onset point of an endothermic peak at 171.21±3°C.
  12. 根据权利要求11所述的B晶型，其DSC图谱如图5所示。The crystal form B according to claim 11, whose DSC pattern is shown in Fig. 5.
  13. 根据权利要求8～10任意一项所述的B晶型，其热重分析曲线(TGA)在180.52±3℃时失重达0.4681％。The crystal form B according to any one of claims 8 to 10, whose thermogravimetric analysis curve (TGA) has a weight loss of 0.4681% at 180.52±3°C.
  14. 根据权利要求13所述的B晶型，其TGA图谱如图6所示。The B crystal form according to claim 13, whose TGA pattern is shown in FIG. 6.
  15. 式(Ⅰ)化合物的C晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：12.55±0.2°、18.79±0.2°和25.10±0.2°。The crystalline form C of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at the following 2θ angles: 12.55±0.2°, 18.79±0.2°, and 25.10±0.2°.
  16. 根据权利要求15所述的C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：6.33±0.2°、12.55±0.2°、15.22±0.2°、17.68±0.2°、18.79±0.2°、20.07±0.2°、25.10±0.2°和26.76±0.2°。The C crystal form according to claim 15, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.33±0.2°, 12.55±0.2°, 15.22±0.2°, 17.68±0.2°, 18.79±0.2 °, 20.07±0.2°, 25.10±0.2° and 26.76±0.2°.
  17. 根据权利要求16所述的C晶型，其XRPD图谱如图7所示。The C crystal form according to claim 16, whose XRPD pattern is shown in FIG. 7.
  18. 根据权利要求15～17任意一项所述的C晶型，其差示扫描量热曲线(DSC)在168.06±3℃处具有吸热峰的起始点。The crystal form C according to any one of claims 15 to 17, whose differential scanning calorimetry curve (DSC) has an onset point of an endothermic peak at 168.06±3°C.
  19. 根据权利要求18所述的C晶型，其DSC图谱如图8所示。The C crystal form according to claim 18, the DSC pattern of which is shown in FIG. 8.
  20. 根据权利要求15～17任意一项所述的C晶型，其热重分析曲线(TGA)在176.32±3℃时失重达0.7482％。The crystal form C according to any one of claims 15 to 17, whose thermogravimetric analysis curve (TGA) has a weight loss of 0.7482% at 176.32±3°C.
  21. 根据权利要求20所述的C晶型，其TGA图谱如图9所示。The C crystal form according to claim 20, the TGA pattern of which is shown in FIG.
  22. 式(Ⅰ)化合物的D晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：18.94±0.2°、24.83±0.2°和26.15±0.2°。The crystalline form D of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at the following 2θ angles: 18.94±0.2°, 24.83±0.2°, and 26.15±0.2°.
  23. 根据权利要求22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：12.45±0.2°、14.86±0.2°、17.13±0.2°、18.41±0.2°、18.94±0.2°、22.83±0.2°、24.83±0.2°和26.15±0.2°。The crystal form D according to claim 22, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.45±0.2°, 14.86±0.2°, 17.13±0.2°, 18.41±0.2°, 18.94±0.2 °, 22.83±0.2°, 24.83±0.2° and 26.15±0.2°.
  24. 根据权利要求23所述的D晶型，其XRPD图谱如图10所示。The D crystal form according to claim 23, whose XRPD pattern is shown in FIG. 10.
  25. 根据权利要求22～24任意一项所述的D晶型，其差示扫描量热曲线(DSC)在163.80±3℃处具有一个吸热峰的起始点。The crystal form D according to any one of claims 22 to 24, whose differential scanning calorimetry curve (DSC) has a starting point of an endothermic peak at 163.80±3°C.
  26. 根据权利要求25所述的D晶型，其DSC图谱如图11所示。The crystal form D according to claim 25, the DSC pattern of which is shown in FIG.
  27. 根据权利要求22～24任意一项所述的D晶型，其热重分析曲线(TGA)在121.34±3℃时失重达0.9987％；在174.58℃时失重达1.1087％。The crystal form D according to any one of claims 22 to 24, whose thermogravimetric analysis curve (TGA) has a weight loss of 0.9987% at 121.34±3°C; and a weight loss of 1.1087% at 174.58°C.
  28. 根据权利要求27所述的D晶型，其TGA图谱如图12所示。The D form according to claim 27, the TGA pattern of which is shown in FIG.
  29. 式(Ⅰ)化合物的E晶型，其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰：22.81±0.2°、24.93±0.2°和25.82±0.2°。The E form of the compound of formula (I) has an X-ray powder diffraction (XRPD) pattern with characteristic diffraction peaks at the following 2θ angles: 22.81±0.2°, 24.93±0.2°, and 25.82±0.2°.
  30. 根据权利要求29所述的E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：12.41±0.2°、15.02±0.2°、17.48±0.2°、18.69±0.2°、22.81±0.2°、23.61±0.2°、24.93±0.2°和25.82±0.2°。The E crystal form according to claim 29, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.41±0.2°, 15.02±0.2°, 17.48±0.2°, 18.69±0.2°, 22.81±0.2 °, 23.61±0.2°, 24.93±0.2° and 25.82±0.2°.
  31. 根据权利要求30所述的E晶型，其XRPD图谱如图13所示。The E crystal form according to claim 30, whose XRPD pattern is shown in FIG. 13.
  32. 根据权利要求29～31任意一项所述的E晶型，其差示扫描量热曲线(DSC)在167.83±3℃处具有一个吸热峰的起始点。The E crystal form according to any one of claims 29 to 31, whose differential scanning calorimetry curve (DSC) has a starting point of an endothermic peak at 167.83±3°C.
  33. 根据权利要求32所述的E晶型，其DSC图谱如图14所示。The E crystal form according to claim 32, the DSC pattern of which is shown in FIG.
  34. 根据权利要求29～31任意一项所述的E晶型，其热重分析曲线(TGA)在99.83±3℃时失重达0.6462％；在176.84±3℃时失重达0.73118％。The E crystal form according to any one of claims 29 to 31, whose thermogravimetric analysis curve (TGA) has a weight loss of 0.6462% at 99.83±3°C; a weight loss of 0.73118% at 176.84±3°C.
  35. 根据权利要求34所述的E晶型，其TGA图谱如图15所示。The E crystal form according to claim 34, whose TGA pattern is shown in FIG. 15.
  36. 式(I)化合物的无定形，其X射线粉末衍射(XRPD)图谱如图16所示。The amorphous X-ray powder diffraction (XRPD) pattern of the compound of formula (I) is shown in FIG. 16.
  37. 式(I)化合物B晶型的制备方法，包括：The preparation method of compound B crystal form of formula (I) includes:
    (a)将式(I)化合物加入醇类溶剂中使其成悬浊液；(a) The compound of formula (I) is added to an alcoholic solvent to make it into a suspension;
    (b)悬浊液25～60℃下搅拌8～120小时；(b) The suspension is stirred at 25 to 60°C for 8 to 120 hours;
    (c)离心后干燥8～16小时。(c) Dry for 8 to 16 hours after centrifugation.
  38. 根据权利要求37所述的制备方法，其中，所述醇类溶剂包含乙醇。The production method according to claim 37, wherein the alcohol solvent contains ethanol.
  39. 式(I)化合物无定形的制备方法，包括：The amorphous preparation method of the compound of formula (I) includes:
    (a)将式(I)化合物加入溶剂或者混合溶剂中溶解；(a) The compound of formula (I) is added to a solvent or mixed solvent to dissolve;
    (b)将溶液旋干、喷雾干燥或者冻干。(b) Spin-dry, spray-dry or freeze-dry the solution.
    其中，所述的溶剂选自丙酮、四氢呋喃和乙腈。Wherein, the solvent is selected from acetone, tetrahydrofuran and acetonitrile.
  40. 式(I)化合物的A晶型、B晶型、C晶型、D晶型或E晶型在制备治疗MEK相关病症的药物上的应用。The use of the crystalline form A, B, C, D or E of the compound of formula (I) in the preparation of a medicament for the treatment of MEK-related disorders.
  41. 式(I)化合物的无定形在制备治疗MEK相关病症的药物上的应用。The use of the amorphous form of the compound of formula (I) in the preparation of a medicament for the treatment of MEK-related disorders.
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