WO2023185869A1 - Crystalline form of fumarate of pyrroloheterocyclic derivative and preparation method therefor - Google Patents

Crystalline form of fumarate of pyrroloheterocyclic derivative and preparation method therefor Download PDF

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WO2023185869A1
WO2023185869A1 PCT/CN2023/084452 CN2023084452W WO2023185869A1 WO 2023185869 A1 WO2023185869 A1 WO 2023185869A1 CN 2023084452 W CN2023084452 W CN 2023084452W WO 2023185869 A1 WO2023185869 A1 WO 2023185869A1
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formula
compound represented
cancer
crystal form
fumarate salt
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French (fr)
Chinese (zh)
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周先强
杨俊然
尤凌峰
冯君
杜振兴
王捷
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023185869A1 publication Critical patent/WO2023185869A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to a new crystal form of fumarate salt of a pyrroloheterocyclic derivative and a preparation method thereof, and belongs to the field of pharmaceuticals.
  • Mitogen-activated protein kinase plays an extremely important role in the signal transduction pathway, and extracellular signal regulated kinase (ERK) is a member of the MAPK family.
  • ERK extracellular signal regulated kinase
  • RAS-RAF-MEK-ERK step exogenous stimulation signals are transmitted to ERK, and the activated ERK is transferred into the nucleus to regulate the activity of transcription factors, thereby regulating biological functions such as cell proliferation, differentiation, and apoptosis, or through phosphorylation
  • Cytoskeletal components in the cytoplasm participate in the regulation of cell morphology and the redistribution of the cytoskeleton.
  • RAS and RAF gene mutations cause continuous activation of the MAPK-ERK signaling pathway, promoting malignant transformation and abnormal proliferation of cells, and ultimately the formation of tumors (Roberts PJ et al., Oncogene, 2007, 26(22), 3291-3310).
  • the combination of MEK inhibitors and B-RAF inhibitors can further improve the effect of B-RAF inhibitors on inhibiting tumor growth, and can significantly improve the disease-free progression and overall survival rates of melanoma patients carrying BRAF V600E and V600K mutations (Frederick DT et al. , Clinical Cancer Research, 2013.19(5), 1225-1231).
  • B-RAF/MEK inhibitors can inhibit tumors, their efficacy is short-lived.
  • B-RAF/MEK inhibitors not only inhibit tumor growth, but also regulate the immune microenvironment of tumors.
  • B-RAF/MEK inhibitors can enhance the expression of tumor-specific antigens, improve the recognition and killing of tumors by antigen-specific T cells, and promote the migration and infiltration of immune cells.
  • the expression of PD-L1 in tumor tissues was enhanced, and when combined with antibodies against checkpoint molecules (such as PD-1 antibodies, CTLA4 antibodies), it showed superior efficacy.
  • checkpoint molecules such as PD-1 antibodies, CTLA4 antibodies
  • BioMed Valley Discoveries’ BVD-523 is in the second clinical phase
  • Merck’s MK-8353 and Astex’s Astex-029 are in the first clinical phase.
  • Relevant patents include WO1999061440A1, WO2001056557A2, WO2001056993A2, WO2001057022A2, WO2002022601A1, WO2012118850A1, WO2013018733A1, WO2014179154A2, WO2015 103133A1, WO2016192063A1, WO2017180817A1, WO2018049127A1.
  • the present disclosure provides a V crystal form of the fumarate salt of the compound represented by formula (I), the fumarate salt of the compound represented by formula (I), wherein the compound represented by formula (I) and fumaric acid
  • the molar ratio of the salt is 2:1, and its X-ray powder diffraction spectrum has characteristic peaks at 2 ⁇ angles of 13.763, 14.493, 17.975, 19.549, and 25.502.
  • the V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at 2 ⁇ angle of 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, 23.299, 23.711 There are characteristic peaks at , 25.502 and 26.448.
  • the V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at the 2 ⁇ angle of 7.756, 8.278, 11.684, 12.703, 13.763, 14.493, 15.305, 16.740, 17.975 There are characteristic peaks at , 19.549, 21.221, 22.519, 23.299, 23.711, 24.132, 25.502, 26.448, 27.356, 29.725, 30.822, and 36.057.
  • the present disclosure provides the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • Another aspect of the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) Dissolving the compound represented by formula (I) and fumaric acid in an organic In the solvent, 2) crystallizes out, wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, acetonitrile, ethanol, isopropanol, Ethyl acetate, tetrahydrofuran, acetone or mixtures thereof.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I).
  • the step of dissolving the compound represented by formula (I) and fumaric acid in an organic solvent is Operate under heating conditions, the temperature can be selected from 30-120°C, such as 35-80°C, such as 40-60°C, specifically it can be selected from 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C , 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I).
  • the crystallization step is completed under heating conditions, and the temperature can be selected from 30-120°C. example Such as 35-80°C, such as 40-60°C, specifically it can be selected from 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85 °C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from the group consisting of 20: 1-2:1, for example 10:1-2:1.
  • the crystallization step time is greater than 1.5 hours, such as greater than 3 hours, such as greater than 7 hours, For example, it is greater than 15 hours, for example, it is greater than 24 hours.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), and the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, Tetrahydrofuran, acetonitrile, acetone or mixtures thereof, preferably methanol.
  • the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) adding the compound represented by formula (I) and fumaric acid in Dissolve in an organic solvent under heating conditions, 2) crystallize under heating conditions, the temperature of step 1) and step 2) is selected from 30-120°C, optionally the same or different, wherein the compound represented by formula (I)
  • the molar ratio to fumaric acid is selected from 10:1-2:1, the time of step 2) is greater than 1.5 hours, and the organic solvent is methanol, ethanol, isopropyl alcohol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or mixtures thereof.
  • the method for preparing the crystalline forms described in the present disclosure further includes filtration, washing or drying steps.
  • the present disclosure provides a composition prepared from the V crystal form of the fumarate salt of the compound represented by formula (I).
  • composition contains the following components: i) the V crystal form of the fumarate salt of the compound represented by formula (I); and ii) one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Another aspect of the present disclosure provides a preparation method of the above-mentioned pharmaceutical composition, including the following steps: Mix the ingredients.
  • the present disclosure also provides the V crystal form of the fumarate salt of the compound represented by formula (I), or the composition prepared by the aforementioned method in the preparation of drugs for the treatment or prevention of cancer, inflammation, or other proliferative diseases.
  • the cancer is selected from the group consisting of melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, and bladder cancer , prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumors, myeloma, astrocytoma and glioma.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20, which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01 , 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • Crystallization as described in this disclosure includes, but is not limited to, stirring crystallization, beating crystallization and volatilization crystallization.
  • the drying temperature mentioned in the publication is generally 25°C to 100°C, preferably 40°C to 70°C. Drying can be done under normal pressure or under reduced pressure.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
  • HPLC High-performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a Bruker D8 Discovery X-ray diffractometer. Specific collection information: Cu anode (40kV, 40mA), Cu-K ⁇ ray Scanning mode: ⁇ /2 ⁇ , scanning range (2 ⁇ range): 5 ⁇ 50°.
  • DSC is differential scanning calorimetry: the measurement is performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding chart (mostly 25-300 or 25-350°C), nitrogen purge speed 50mL/min.
  • TGA thermogravimetric analysis: the METTLER TOLEDO TGA2 thermogravimetric analyzer is used for detection, with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding chart (mostly 25-300°C), and the nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: the detection uses SMS DVS Advantage. At 25°C, the humidity changes from 50%-95%-0%-95%-50% in steps of 10% (the last step is 5%) (specific range of humidity Subject to the corresponding chart, most methods of use are listed here), and the judgment standard is that dm/dt is not greater than 0.002%.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: In the methylene chloride/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • Ion chromatography Thermo Scientific Dionex Intergrion ion chromatograph and chromatographic column DionexIonPacTM AS11-HC (4 ⁇ m, 4*250cm) were used for detection.
  • Example 1 (Preparation method of Example 10 in WO2020200069A1)
  • compound 1e (4.0g, 8.51mmol) was dissolved in 50mL of 1,4-dioxane, and 4,4,4',4',5,5,5',5'- were added in sequence Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.24g, 12.76mmol), potassium acetate (3.34g, 34.04mmol) and [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (1.24g, 1.70mmol), stirred at 90°C for 2 hours. Cool, filter through diatomaceous earth, concentrate the filtrate, and purify by column chromatography with eluent system C to obtain the title compound If (2.0 g), yield: 45%.
  • compound 1f (98.6 mg, 0.19 mmol), pre-prepared 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine 1i, [1,1′ - Bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.02 mmol), cesium carbonate (124 mg, 0.2 mmol) mixture was suspended in 20 mL of 1,4-dioxane and 4 mL of water, heated to The reaction was stirred at 80°C for 14 hours.
  • Dissolve compound 1j (100 mg, 0.17 mmol) in 20 mL of methylene chloride, add 1 mL of trifluoroacetic acid dropwise, complete the addition, and stir for 4 hours. Adjust the pH to 7 with saturated sodium bicarbonate, extract with dichloromethane (20 mL ⁇ 2), combine the organic phases, concentrate under reduced pressure, and purify with column chromatography using eluent system A to obtain the title compound 1 (15 mg), yield: 18%. The product was tested by X-ray powder diffraction and found to be amorphous. Type, XRPD spectrum is shown in Figure 1.
  • the TGA spectrum is shown in Figure 4.
  • the weight loss is 0.44% at 25°C-140°C, and the weight loss is 8.46% at 140°C-270°C.
  • the DVS spectrum is shown in Figure 5. Under normal storage conditions (i.e. 25°C humidity 60%), the water absorption is approximately 0.18%; under accelerated test conditions (i.e. humidity 70%), the water absorption is approximately 0.23%; under extreme conditions (i.e. humidity 90%) %), water absorption is about 0.44%. During the humidity change process from 0% to 95%, the desorption process and adsorption process of the sample basically coincided; the X-ray powder diffraction comparison before and after DVS showed that the crystal form did not change before and after DVS (see Figure 6).
  • the fumarate V crystal form of the compound represented by formula (I) was placed flat in the open and examined under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). Regarding the stability of the sample, the sampling inspection period is 30 days.
  • the fumarate V crystal form of the compound represented by formula (I) was placed at 25°C, 60% RH and 40°C, 75% RH to examine its stability.
  • the long-term/accelerated stability experiment shows that the physical and chemical properties of the fumarate V crystal form of the compound represented by formula (I) are good when placed under long-term accelerated stability conditions for 6 months.
  • Embodiment 5 preparation of ⁇ crystal form of hydrobromide salt of compound represented by formula (I)
  • Embodiment 6 preparation of ⁇ crystal form of hydrobromide salt of compound represented by formula (I)
  • hydrobromide ⁇ crystal form of the compound represented by formula (I) and the hydrobromide beta crystal form of the compound represented by formula (I) are placed flat in the open, and the stability of the samples under high temperature (40°C, 60°C) conditions is investigated. nature, the sampling inspection period is 30 days.
  • Example 8 the hydrobromide ⁇ crystal form of the compound represented by formula (I), the hydrobromide beta crystal form of the compound represented by formula (I), and the fumarate V crystal form of the compound represented by formula (I) in physiological media dispersion phenomenon
  • Excessive fumarate crystal form V of the compound represented by formula (I) and hydrobromide ⁇ and ⁇ crystal form samples (target concentration approximately 5 mg/ml) of the compound represented by formula (I) were placed in FaSSGF, FeSSIF, and FaSSIF physiological systems respectively.
  • the relevant media were equilibrated at 37°C and 120rpm for 1h and 24h, and the observed phenomena are shown in Table 8.
  • the fumarate crystal form V of the compound represented by formula (I) has good dispersion behavior in physiological media.

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Abstract

The present disclosure relates to a crystalline form of a fumarate of a pyrroloheterocyclic derivative and a preparation method therefor. Specifically, the present disclosure relates to a crystalline form V of a fumarate of a compound represented by formula (I) and a preparation method therefor. The crystalline form V of the fumarate of the compound of formula (I) provided by the present disclosure has good stability, and can be better used for clinical treatment.

Description

一种吡咯并杂环类衍生物的富马酸盐的晶型及其制备方法A kind of crystal form of fumarate of pyrroloheterocyclic derivatives and preparation method thereof
本申请要求申请日为2022/3/28的中国专利申请202210311269.6的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202210311269.6 with a filing date of 2022/3/28. This application cites the full text of the above-mentioned Chinese patent application.
技术领域Technical field
本公开涉及一种新的吡咯并杂环类衍生物的富马酸盐的晶型及其制备方法，属于制药领域。The present disclosure relates to a new crystal form of fumarate salt of a pyrroloheterocyclic derivative and a preparation method thereof, and belongs to the field of pharmaceuticals.
背景技术Background technique
正常细胞的增殖、分化、代谢、凋亡受到体内细胞信号转导通路的严格调节。丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)在信号转导通路中起着极为重要的作用，胞外信号调节激酶(extracellular signal regulated kinase，ERK)是MAPK家族的一员。通过RAS-RAF-MEK-ERK步骤，外源的刺激信号被传递给ERK，活化后的ERK转移进入细胞核，调节转录因子活性，从而调节细胞的增殖分化凋亡等生物学功能，或者通过磷酸化胞浆中细胞骨架成分参与细胞形态的调节及细胞骨架的重新分布。The proliferation, differentiation, metabolism, and apoptosis of normal cells are strictly regulated by cell signal transduction pathways in the body. Mitogen-activated protein kinase (MAPK) plays an extremely important role in the signal transduction pathway, and extracellular signal regulated kinase (ERK) is a member of the MAPK family. Through the RAS-RAF-MEK-ERK step, exogenous stimulation signals are transmitted to ERK, and the activated ERK is transferred into the nucleus to regulate the activity of transcription factors, thereby regulating biological functions such as cell proliferation, differentiation, and apoptosis, or through phosphorylation Cytoskeletal components in the cytoplasm participate in the regulation of cell morphology and the redistribution of the cytoskeleton.
RAS和RAF基因突变造成MAPK-ERK信号通路的持续激活，促使细胞恶性转化、异常增殖，最终产生肿瘤(Roberts PJ等，Oncogene，2007，26(22)，3291-3310)。MEK抑制剂跟B-RAF抑制剂联用可以进一步提高B-RAF抑制剂抑制肿瘤生长的效果，可以显著提高携带BRAFV600E和V600K突变的黑色素瘤病人的无病进展期和总体生存率(Frederick DT等，Clinical Cancer Research，2013.19(5)，1225-1231)。虽然B-RAF/MEK抑制剂联用可以起到抑制肿瘤的效果，但是他们的疗效是短暂的，在2-18个月内绝大多数患者会产生耐药，肿瘤会进一步恶化。B-RAF/MEK抑制剂耐药性的产生机制非常复杂，大多与ERK信号通路的重新激活有着直接关系(Smalley I等， Cancer Discovery，2018，8(2)，140-142)。所以，开发新的ERK抑制剂，不仅对MAPK信号通路产生突变的病人有效，对于B-RAF/MEK抑制剂产生耐药的病人也同样有效。RAS and RAF gene mutations cause continuous activation of the MAPK-ERK signaling pathway, promoting malignant transformation and abnormal proliferation of cells, and ultimately the formation of tumors (Roberts PJ et al., Oncogene, 2007, 26(22), 3291-3310). The combination of MEK inhibitors and B-RAF inhibitors can further improve the effect of B-RAF inhibitors on inhibiting tumor growth, and can significantly improve the disease-free progression and overall survival rates of melanoma patients carrying BRAF V600E and V600K mutations (Frederick DT et al. , Clinical Cancer Research, 2013.19(5), 1225-1231). Although the combination of B-RAF/MEK inhibitors can inhibit tumors, their efficacy is short-lived. Within 2-18 months, the vast majority of patients will develop drug resistance and the tumors will further worsen. The mechanisms of resistance to B-RAF/MEK inhibitors are very complex, and most of them are directly related to the reactivation of the ERK signaling pathway (Smalley I et al., Cancer Discovery, 2018, 8(2), 140-142). Therefore, the development of new ERK inhibitors is not only effective for patients with mutations in the MAPK signaling pathway, but also for patients with resistance to B-RAF/MEK inhibitors.
B-RAF/MEK抑制剂在抑制肿瘤生长的同时，对肿瘤的免疫微环境起到了调控作用。B-RAF/MEK抑制剂可以增强肿瘤特异性抗原的表达，提高抗原特异性T细胞对肿瘤的识别和杀伤，促进免疫细胞的迁移和浸润。动物模型中，经过B-RAF/MEK抑制剂处理后，肿瘤组织中PD-L1表达增强，与检查点(checkpoint)分子的抗体(例如PD-1抗体、CTLA4抗体)联用时，更显示出优于B-RAF/MEK抑制剂单用时的抑制肿瘤生长的效果(Boni A等，Cancer Research，2010，70(13)，5213-5219)。研究表明，ERK抑制剂与B-RAF/MEK抑制剂类似，与检查点抗体联用可以起到调节肿瘤微环境的作用，提高细胞毒性T细胞的功能，达到抑制肿瘤生长的效果。B-RAF/MEK inhibitors not only inhibit tumor growth, but also regulate the immune microenvironment of tumors. B-RAF/MEK inhibitors can enhance the expression of tumor-specific antigens, improve the recognition and killing of tumors by antigen-specific T cells, and promote the migration and infiltration of immune cells. In animal models, after treatment with B-RAF/MEK inhibitors, the expression of PD-L1 in tumor tissues was enhanced, and when combined with antibodies against checkpoint molecules (such as PD-1 antibodies, CTLA4 antibodies), it showed superior efficacy. The effect of inhibiting tumor growth when B-RAF/MEK inhibitor is used alone (Boni A et al., Cancer Research, 2010, 70(13), 5213-5219). Studies have shown that ERK inhibitors are similar to B-RAF/MEK inhibitors, and combined with checkpoint antibodies can regulate the tumor microenvironment, improve the function of cytotoxic T cells, and achieve the effect of inhibiting tumor growth.
目前已有多个化合物被开发。其中BioMed Valley Discoveries公司的BVD-523在临床二期，默克公司的MK-8353以及Astex的Astex-029在临床一期。相关的专利有WO1999061440A1、WO2001056557A2、WO2001056993A2、WO2001057022A2、WO2002022601A1、WO2012118850A1、WO2013018733A1、WO2014179154A2、WO2015103133A1、WO2016192063A1、WO2017180817A1、WO2018049127A1。Several compounds have been developed so far. Among them, BioMed Valley Discoveries’ BVD-523 is in the second clinical phase, Merck’s MK-8353 and Astex’s Astex-029 are in the first clinical phase. Relevant patents include WO1999061440A1, WO2001056557A2, WO2001056993A2, WO2001057022A2, WO2002022601A1, WO2012118850A1, WO2013018733A1, WO2014179154A2, WO2015 103133A1, WO2016192063A1, WO2017180817A1, WO2018049127A1.
发明内容Contents of the invention
本公开提供一种式(I)所示化合物的富马酸盐的V晶型，所述的式(I)所示化合物的富马酸盐，其中式(I)所示化合物与富马酸盐的摩尔比例为2∶1，其X-射线粉末衍射谱图在2θ角为13.763、14.493、17.975、19.549、25.502处有特征峰，
The present disclosure provides a V crystal form of the fumarate salt of the compound represented by formula (I), the fumarate salt of the compound represented by formula (I), wherein the compound represented by formula (I) and fumaric acid The molar ratio of the salt is 2:1, and its X-ray powder diffraction spectrum has characteristic peaks at 2θ angles of 13.763, 14.493, 17.975, 19.549, and 25.502.
本公开提供的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图在2θ角为11.684、12.703、13.763、14.493、16.740、17.975、19.549、23.299、23.711、25.502、26.448处有特征峰。The V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at 2θ angle of 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, 23.299, 23.711 There are characteristic peaks at , 25.502 and 26.448.
本公开提供的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图在2θ角为7.756、8.278、11.684、12.703、13.763、14.493、15.305、16.740、17.975、19.549、21.221、22.519、23.299、23.711、24.132、25.502、26.448、27.356、29.725、30.822、36.057处有特征峰。The V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure has an X-ray powder diffraction spectrum at the 2θ angle of 7.756, 8.278, 11.684, 12.703, 13.763, 14.493, 15.305, 16.740, 17.975 There are characteristic peaks at , 19.549, 21.221, 22.519, 23.299, 23.711, 24.132, 25.502, 26.448, 27.356, 29.725, 30.822, and 36.057.
本公开提供的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图如图2所示。The X-ray powder diffraction spectrum of the fumarate salt form V of the compound represented by formula (I) provided by the present disclosure is shown in Figure 2.
本公开提供的式(I)所示化合物的富马酸盐的V晶型，其中，所述2θ角度的误差范围为±0.2。The present disclosure provides the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the error range of the 2θ angle is ±0.2.
本共开另一方面提供一种制备式(I)所示化合物的富马酸盐的V晶型的方法，包括以下步骤：1)将式(I)所示化合物与富马酸溶于有机溶剂中，2)结晶析出，其中式(I)所示化合物与富马酸的摩尔比选自10∶1-2∶1，所述的有机溶剂选自甲醇、乙腈、乙醇、异丙醇、乙酸乙酯、四氢呋喃、丙酮或其混合物。Another aspect of the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) Dissolving the compound represented by formula (I) and fumaric acid in an organic In the solvent, 2) crystallizes out, wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, acetonitrile, ethanol, isopropanol, Ethyl acetate, tetrahydrofuran, acetone or mixtures thereof.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，将式(I)所示化合物与富马酸溶于有机溶剂的步骤在加热条件下操作，温度可选自30-120℃，例如35-80℃，例如40-60℃，具体可选自30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃。In an optional embodiment, the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I). The step of dissolving the compound represented by formula (I) and fumaric acid in an organic solvent is Operate under heating conditions, the temperature can be selected from 30-120℃, such as 35-80℃, such as 40-60℃, specifically it can be selected from 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃ , 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，结晶析出的步骤在加热条件下完成，温度可选自30-120℃，例 如35-80℃，例如40-60℃，具体可选自30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃。In an optional embodiment, the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I). The crystallization step is completed under heating conditions, and the temperature can be selected from 30-120°C. example Such as 35-80℃, such as 40-60℃, specifically it can be selected from 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85 ℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，其中式(I)所示化合物与富马酸的摩尔比选自20∶1-2∶1，例如10∶1-2∶1。In an optional embodiment, the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from the group consisting of 20: 1-2:1, for example 10:1-2:1.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，结晶析出的步骤时间大于1.5小时，例如大于3小时，例如大于7小时，例如大于15小时，例如大于24小时。In an optional embodiment, in the method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I) provided by the present disclosure, the crystallization step time is greater than 1.5 hours, such as greater than 3 hours, such as greater than 7 hours, For example, it is greater than 15 hours, for example, it is greater than 24 hours.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，所述的有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、乙腈、丙酮或其混合物，优选甲醇。In an optional embodiment, the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), and the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, Tetrahydrofuran, acetonitrile, acetone or mixtures thereof, preferably methanol.
可选的实施方案中，本公开提供的制备式(I)所示化合物的富马酸盐的V晶型的方法，包括以下步骤：1)将式(I)所示化合物与富马酸在加热条件下溶于有机溶剂中，2)在加热条件下结晶析出，所述步骤1)与步骤2)的温度选自30-120℃，任选相同或者不同，其中式(I)所示化合物与富马酸的摩尔比选自10∶1-2∶1，所述步骤2)的时间大于1.5小时，所述有机溶剂为甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、乙腈、丙酮或其混合物。In an optional embodiment, the present disclosure provides a method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I), including the following steps: 1) adding the compound represented by formula (I) and fumaric acid in Dissolve in an organic solvent under heating conditions, 2) crystallize under heating conditions, the temperature of step 1) and step 2) is selected from 30-120°C, optionally the same or different, wherein the compound represented by formula (I) The molar ratio to fumaric acid is selected from 10:1-2:1, the time of step 2) is greater than 1.5 hours, and the organic solvent is methanol, ethanol, isopropyl alcohol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or mixtures thereof.
在某些实施方式中，本公开所述的晶型的制备方法还包括过滤、洗涤或干燥步骤。In certain embodiments, the method for preparing the crystalline forms described in the present disclosure further includes filtration, washing or drying steps.
另一方面，本公开提供一种由所述的式(I)所示化合物的富马酸盐的V晶型制备得到的组合物。On the other hand, the present disclosure provides a composition prepared from the V crystal form of the fumarate salt of the compound represented by formula (I).
本公开另一方面条提供一种药物组合物。其包含如下组分：i)式(I)所示化合物的富马酸盐的V晶型；和ii)一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure provides a pharmaceutical composition. It contains the following components: i) the V crystal form of the fumarate salt of the compound represented by formula (I); and ii) one or more pharmaceutically acceptable carriers, diluents or excipients.
本公开另一方面提供一种上述药物组合物的制备方法，包括下述步骤： 将所述组分混合。Another aspect of the present disclosure provides a preparation method of the above-mentioned pharmaceutical composition, including the following steps: Mix the ingredients.
本公开还提供了前述的式(I)所示化合物的富马酸盐的V晶型、或由前述方法制备得到的组合物在制备治疗或预防癌症、炎症、或其它增殖性疾病的药物中的用途，优选癌症；所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌、鼻咽癌、结肠直肠癌、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤，星形细胞瘤和胶质瘤。The present disclosure also provides the V crystal form of the fumarate salt of the compound represented by formula (I), or the composition prepared by the aforementioned method in the preparation of drugs for the treatment or prevention of cancer, inflammation, or other proliferative diseases. Use, preferably cancer; the cancer is selected from the group consisting of melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, breast cancer, and bladder cancer , prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumors, myeloma, astrocytoma and glioma.
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20，可以为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20, which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01 , 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
本公开所述的“结晶析出”包括但不限于搅拌结晶、打浆结晶和挥发结晶。"Crystallization" as described in this disclosure includes, but is not limited to, stirring crystallization, beating crystallization and volatilization crystallization.
公开中所述干燥温度一般为25℃-100℃，优选40℃-70℃，可以常压干燥，也可以减压干燥。The drying temperature mentioned in the publication is generally 25°C to 100°C, preferably 40°C to 70°C. Drying can be done under normal pressure or under reduced pressure.
附图说明Description of drawings
图1.式(I)所示化合物的无定型的XRPD谱图；Figure 1. Amorphous XRPD spectrum of the compound represented by formula (I);
图2.式(I)所示化合物的富马酸盐V晶型的XRPD谱图；Figure 2. XRPD spectrum of fumarate crystal form V of the compound represented by formula (I);
图3.式(I)所示化合物的富马酸盐V晶型的DSC谱图；Figure 3. DSC spectrum of fumarate crystal form V of the compound represented by formula (I);
图4.式(I)所示化合物的富马酸盐V晶型的TGA谱图；Figure 4. TGA spectrum of fumarate crystal form V of the compound represented by formula (I);
图5.式(I)所示化合物的富马酸盐V晶型的DVS谱图；Figure 5. DVS spectrum of fumarate crystal form V of the compound represented by formula (I);
图6.式(I)所示化合物的富马酸盐V晶型的DVS前后的XRPD谱图；Figure 6. XRPD spectra before and after DVS of the fumarate V crystal form of the compound represented by formula (I);
图7.式(I)所示化合物的氢溴酸盐α晶型的XRPD谱图；Figure 7. XRPD spectrum of the hydrobromide α crystal form of the compound represented by formula (I);
图8.式(I)所示化合物的氢溴酸盐β晶型的XRPD谱图。 Figure 8. XRPD spectrum of the hydrobromide beta crystal form of the compound represented by formula (I).
具体实施方式Detailed ways
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。The present invention will be explained in more detail below with reference to examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the essence and scope of the present invention.
实验所用仪器的测试条件：Test conditions of the instruments used in the experiment:
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M. The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). , the internal standard is tetramethylsilane (TMS).
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).
waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)
THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q Exactive)
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。High-performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-pressure liquid chromatograph.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
手性制备使用Shimadzu LC-20AP制备型色谱仪。Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
XRPD为X射线粉末衍射检测：测定使用Bruker D8 Discovery型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα射线 扫描方式：θ/2θ，扫描范围(2θ范围)：5～50°。XRPD is X-ray powder diffraction detection: the measurement is carried out using a Bruker D8 Discovery X-ray diffractometer. Specific collection information: Cu anode (40kV, 40mA), Cu-Kα ray Scanning mode: θ/2θ, scanning range (2θ range): 5～50°.
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或 25-350℃)，氮气吹扫速度50mL/min。DSC is differential scanning calorimetry: the measurement is performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min. The specific temperature range refers to the corresponding chart (mostly 25-300 or 25-350℃), nitrogen purge speed 50mL/min.
TGA为热重分析：检测采用METTLER TOLEDO TGA2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度50mL/min。TGA is thermogravimetric analysis: the METTLER TOLEDO TGA2 thermogravimetric analyzer is used for detection, with a heating rate of 10°C/min. The specific temperature range refers to the corresponding chart (mostly 25-300°C), and the nitrogen purge rate is 50mL/min.
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.002％。DVS is dynamic moisture adsorption: the detection uses SMS DVS Advantage. At 25℃, the humidity changes from 50%-95%-0%-95%-50% in steps of 10% (the last step is 5%) (specific range of humidity Subject to the corresponding chart, most methods of use are listed here), and the judgment standard is that dm/dt is not greater than 0.002%.
实施例中无特殊说明，溶液是指水溶液。There is no special explanation in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The reaction progress in the embodiment is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: In the methylene chloride/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
离子色谱：检测采用Thermo Scientific Dionex Intergrion离子色谱仪，色谱柱DionexIonPacTM AS11-HC(4μm，4*250cm)进行检测。Ion chromatography: Thermo Scientific Dionex Intergrion ion chromatograph and chromatographic column DionexIonPacTM AS11-HC (4μm, 4*250cm) were used for detection.
实施例1、(WO2020200069A1中实施例10的制备方法)Example 1, (Preparation method of Example 10 in WO2020200069A1)
实施例1Example 1
(S)-2-(1-(3-氯苯基)-2-羟乙基)-6-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1，2-二氢-3H-吡咯并[1，2-c]咪唑-3-酮1
(S)-2-(1-(3-chlorophenyl)-2-hydroxyethyl)-6-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidine-4 -yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one 1
第一步first step
(S)-2-((叔丁基二甲基硅烷基)氧基)-1-(3-氯苯基)乙胺1b(S)-2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethylamine 1b
将(S)-2-氨基-2-(3-氯苯基)乙醇1a(4g，23.3mmol，上海毕得医药科技有限公司)，咪唑(3.2g，46.6mmol)溶于80mL二氯甲烷中，冰浴下加入叔丁基二甲基氯硅烷(5.2g，35mmol)，搅拌反应14小时。加水，二氯甲烷萃取(80mL×3)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物1b(6.5g)，产率：97％。Dissolve (S)-2-amino-2-(3-chlorophenyl)ethanol 1a (4g, 23.3mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) and imidazole (3.2g, 46.6mmol) in 80mL dichloromethane , add tert-butyldimethylsilyl chloride (5.2g, 35mmol) under ice bath, and stir for 14 hours. Add water and extract with dichloromethane (80mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system C to obtain the title compound 1b (6.5g), yield: 97% .
MS m/z(ESI)：286.1[M+1]MS m/z(ESI): 286.1[M+1]
第二步Step 2
(S)-N-((4-溴-1H-吡咯-2-基)甲基)-2-((叔丁基二甲基硅烷基)氧基)-1-(3-氯苯基)乙胺1d (S)-N-((4-bromo-1H-pyrrol-2-yl)methyl)-2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl) Ethylamine 1d
将4-溴-1H-吡咯-2-甲醛1c(2.37g，13.62mmol，上海毕得)，化合物1b(3.9g，13.64mmol)搅拌反应3小时。加100mL甲醇稀释，降温至0℃，加入硼氢化钠(516mg，13.64mmol)搅拌反应2小时。加水，反应液减压浓缩，加水，乙酸乙酯萃取(40mL×3)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物1d(4.8g)，产率：79％。4-Bromo-1H-pyrrole-2-carboxaldehyde 1c (2.37g, 13.62mmol, Shanghai Bide) and compound 1b (3.9g, 13.64mmol) were stirred and reacted for 3 hours. Add 100 mL of methanol to dilute, cool to 0°C, add sodium borohydride (516 mg, 13.64 mmol) and stir for 2 hours. Water was added, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system C to obtain the title compound 1d (4.8g), yield: 79% .
MS m/z(ESI)：444.2[M+1]MS m/z(ESI): 444.2[M+1]
第三步third step
(S)-6-溴-2-(2-((叔丁基二甲基硅烷基)氧基)-1-(3-氯苯基)乙基)-1H-吡咯并[1，2-c]咪唑-3(2H)-酮1e(S)-6-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl)-1H-pyrrolo[1,2- c]imidazole-3(2H)-one 1e
将化合物1d(4.8g，10.81mmol)溶于100mL四氢呋喃中，冰浴下加入N，N′-羰基二咪唑(2.45g，15.11mmol)搅拌0.5小时，加入氢化钠(60％，621mg，16.22umol)室温搅拌反应14小时。加饱和氯化铵。反应液减压浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物1e(4.0g)，产率：78％。Dissolve compound 1d (4.8g, 10.81mmol) in 100mL tetrahydrofuran, add N,N'-carbonyldiimidazole (2.45g, 15.11mmol) under ice bath and stir for 0.5 hours, add sodium hydride (60%, 621mg, 16.22umol) ) and stir the reaction at room temperature for 14 hours. Add saturated ammonium chloride. The reaction solution was concentrated under reduced pressure, and purified by column chromatography using eluent system C to obtain the title compound 1e (4.0 g), yield: 78%.
MS m/z(ESI)：469.1[M+1]MS m/z(ESI): 469.1[M+1]
第四步the fourth step
(S)-2-(2-((叔丁基二甲基硅烷基)氧基)-1-(3-氯苯基)乙基)-6-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)-1H-吡咯并[1，2-c]咪唑-3(2H)-酮1f(S)-2-(2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl)-6-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[1,2-c]imidazole-3(2H)-one 1f
在氩气氛下，将化合物1e(4.0g，8.51mmol)溶于50mL 1，4-二氧六环中，依次加入4，4，4’，4’，5，5，5’，5’-八甲基-2，2’-二(1，3，2-二氧硼杂环戊烷)(3.24g，12.76mmol)，乙酸钾(3.34g，34.04mmol)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(1.24g，1.70mmol)，在90℃搅拌2小时。冷却，通过硅藻土过滤，将滤液浓缩，用柱层析以洗脱剂体系C纯化得到标题化合物1f(2.0g)，产率：45％。Under an argon atmosphere, compound 1e (4.0g, 8.51mmol) was dissolved in 50mL of 1,4-dioxane, and 4,4,4',4',5,5,5',5'- were added in sequence Octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.24g, 12.76mmol), potassium acetate (3.34g, 34.04mmol) and [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (1.24g, 1.70mmol), stirred at 90°C for 2 hours. Cool, filter through diatomaceous earth, concentrate the filtrate, and purify by column chromatography with eluent system C to obtain the title compound If (2.0 g), yield: 45%.
MS m/z(ESI)：517.2[M+1]MS m/z(ESI): 517.2[M+1]
第五步 the fifth step
4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺1i4-Chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine 1i
将N-(1-甲基-1H-吡唑-5-基)甲酰胺1h(324.82mg，2.60mmol，采用专利申请“WO2017/80979”公开的方法制备而得)，溶于15mL N，N-二甲基甲酰胺中，0℃下加入氢化钠(60％，311.47mg，7.79mmol)，搅拌反应0.5小时，加入4-氯-2-(甲基磺酰基)嘧啶1g(500mg，2.60mm0l)，继续反应2小时。加水20mL，乙酸乙酯萃取(20mL×3)，合并有机相减压浓缩，用薄层色谱法以展开剂体系C纯化所得残余物，得到标题化合物1i(270mg)，产率：49.6％。Dissolve N-(1-methyl-1H-pyrazol-5-yl)carboxamide 1h (324.82mg, 2.60mmol, prepared by the method disclosed in the patent application "WO2017/80979") in 15mL N, N -In dimethylformamide, add sodium hydride (60%, 311.47mg, 7.79mmol) at 0°C, stir and react for 0.5 hours, add 1g of 4-chloro-2-(methylsulfonyl)pyrimidine (500mg, 2.60mmol) ) and continue the reaction for 2 hours. Add 20 mL of water, extract with ethyl acetate (20 mL × 3), combine the organic phases and concentrate under reduced pressure, and purify the residue obtained by thin layer chromatography using developer system C to obtain the title compound 1i (270 mg), yield: 49.6%.
MS m/z(ESI)：210.3[M+1]MS m/z(ESI): 210.3[M+1]
第六步Step 6
(S)-2-(2-((叔丁基二甲基硅烷基)氧基)-1-(3-氯苯基)乙基)-6-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1，2-二氢-3H-吡咯并[1，2-c]咪唑-3(2H)-酮1j(S)-2-(2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethyl)-6-(2-((1-methyl-1H) -pyrazol-5-yl)amino)pyrimidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3(2H)-one 1j
在氩气氛下，将化合物1f(98.6mg，0.19mmol)，预制4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺1i，[1，1′-双(二苯基膦基)二茂铁]二氯化钯(28mg，0.02mmol)，碳酸铯(124mg，0.2mmol)混合物悬浮于20mL 1，4-二氧六环和4mL水中，加热至80℃搅拌反应14小时。冷却，通过硅藻土过滤，收集滤液，乙酸乙酯萃取(20mL×3)，合并有机相，减压浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物1j(100mg)，产率：92％。Under an argon atmosphere, compound 1f (98.6 mg, 0.19 mmol), pre-prepared 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyrimidin-2-amine 1i, [1,1′ - Bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 0.02 mmol), cesium carbonate (124 mg, 0.2 mmol) mixture was suspended in 20 mL of 1,4-dioxane and 4 mL of water, heated to The reaction was stirred at 80°C for 14 hours. Cool, filter through diatomaceous earth, collect the filtrate, extract with ethyl acetate (20 mL × 3), combine the organic phases, concentrate under reduced pressure, and purify with column chromatography using eluent system A to obtain the title compound 1j (100 mg), yield :92%.
MS m/z(ESI)：564.3[M+1]MS m/z(ESI): 564.3[M+1]
第七步Step 7
(S)-2-(1-(3-氯苯基)-2-羟乙基)-6-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1，2-二氢-3H-吡咯并[1，2-c]咪唑-3-酮1(S)-2-(1-(3-chlorophenyl)-2-hydroxyethyl)-6-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidine-4 -yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one 1
将化合物1j(100mg，0.17mmol)溶于20mL二氯甲烷中，滴加1mL三氟乙酸，加毕，搅拌反应4小时。用饱和碳酸氢钠调pH至7，二氯甲烷萃取(20mL×2)，合并有机相，减压浓缩，用柱层析以洗脱剂体系A纯化得到标题化合物1(15mg)，产率：18％。产品经X-射线粉末衍射检测，为无定 型，XRPD谱图如图1。Dissolve compound 1j (100 mg, 0.17 mmol) in 20 mL of methylene chloride, add 1 mL of trifluoroacetic acid dropwise, complete the addition, and stir for 4 hours. Adjust the pH to 7 with saturated sodium bicarbonate, extract with dichloromethane (20 mL × 2), combine the organic phases, concentrate under reduced pressure, and purify with column chromatography using eluent system A to obtain the title compound 1 (15 mg), yield: 18%. The product was tested by X-ray powder diffraction and found to be amorphous. Type, XRPD spectrum is shown in Figure 1.
MS m/z(ESI)：450.1[M+1]MS m/z(ESI): 450.1[M+1]
1H NMR(400MHz，CDCl3)：δ8.33(d，1H)，7.72(s，1H)，7.48(d，1H)，7.41-7.33(m，3H)，7.28-7.24(m，1H)，7.18(s，1H)，6.92(d，1H)，6.51(s，1H)，6.32(d，1H)，5.17(dd，1H)，4.46(d，1H)，4.32(dd，1H)，4.27-4.17(m，3H)，3.82(s，3H)。1H NMR (400MHz, CDCl 3 ): δ8.33 (d, 1H), 7.72 (s, 1H), 7.48 (d, 1H), 7.41-7.33 (m, 3H), 7.28-7.24 (m, 1H), 7.18(s, 1H), 6.92(d, 1H), 6.51(s, 1H), 6.32(d, 1H), 5.17(dd, 1H), 4.46(d, 1H), 4.32(dd, 1H), 4.27 -4.17 (m, 3H), 3.82 (s, 3H).
实施例2、式(I)所示化合物富马酸盐V晶型的制备Example 2. Preparation of fumarate crystal form V of the compound represented by formula (I)
将0.5g化合物和64mg富马酸50℃溶于2mL无水甲醇中，降温至37℃，保温3h，降至室温反应过夜，抽滤，干燥得固体0.328g，经离子色谱检测，富马酸含量为11.36％，故式(I)所示化合物与富马酸的摩尔比为2∶1；经X-射线粉末衍射检测，该产物为晶型V，XRPD谱图如图2，具体峰位置见表1.Dissolve 0.5g of the compound and 64mg of fumaric acid in 2mL of anhydrous methanol at 50°C, cool to 37°C, keep incubated for 3 hours, lower to room temperature for overnight reaction, filter with suction, and dry to obtain 0.328g of solid. After ion chromatography detection, fumaric acid The content is 11.36%, so the molar ratio of the compound represented by formula (I) to fumaric acid is 2:1; after X-ray powder diffraction detection, the product is crystal form V. The XRPD spectrum is shown in Figure 2, with specific peak positions. See Table 1.
表1.式(I)所示化合物富马酸盐V晶型峰位置

Table 1. Peak position of fumarate crystal form V of the compound represented by formula (I)

DSC谱图如图3，吸热峰峰值为153.63℃；The DSC spectrum is shown in Figure 3, the endothermic peak is 153.63°C;
TGA谱图如图4，25℃-140℃失重0.44％，140℃-270℃，失重8.46％。The TGA spectrum is shown in Figure 4. The weight loss is 0.44% at 25°C-140°C, and the weight loss is 8.46% at 140°C-270°C.
DVS谱图如图5，在正常储存条件(即25℃湿度60％)，吸水约为0.18％；在加速试验条件(即湿度70％)，吸水约为0.23％；在极端条件(即湿度90％)，吸水约为0.44％。在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合；DVS前后X-射线粉末衍射对比图显示DVS前后晶型未发生转变(见图6)。The DVS spectrum is shown in Figure 5. Under normal storage conditions (i.e. 25°C humidity 60%), the water absorption is approximately 0.18%; under accelerated test conditions (i.e. humidity 70%), the water absorption is approximately 0.23%; under extreme conditions (i.e. humidity 90%) %), water absorption is about 0.44%. During the humidity change process from 0% to 95%, the desorption process and adsorption process of the sample basically coincided; the X-ray powder diffraction comparison before and after DVS showed that the crystal form did not change before and after DVS (see Figure 6).
实施例3、影响因素稳定性研究Example 3. Study on the stability of influencing factors
式(I)所示化合物富马酸盐V晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 92.5％)条件下样品的稳定性，取样考察期为30天。The fumarate V crystal form of the compound represented by formula (I) was placed flat in the open and examined under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%). Regarding the stability of the sample, the sampling inspection period is 30 days.
表2.式(I)所示化合物富马酸盐V晶型影响因素稳定性

Table 2. Factors affecting the stability of fumarate V crystal form of the compound represented by formula (I)

结论：影响因素实验表明：在高温40℃和60℃、高湿75％和92.5％条件下，式(I)所示化合物富马酸盐V晶型具有好的物理、化学稳定性。Conclusion: Experiments on influencing factors show that the fumarate V crystal form of the compound represented by formula (I) has good physical and chemical stability under the conditions of high temperature 40°C and 60°C and high humidity 75% and 92.5%.
实施例4、长期/加速稳定性研究Example 4. Long-term/accelerated stability study
将式(I)所示化合物富马酸盐V晶型，分别放置25℃，60％RH和40℃，75％RH条件考察其稳定性The fumarate V crystal form of the compound represented by formula (I) was placed at 25°C, 60% RH and 40°C, 75% RH to examine its stability.
表3.式(I)所示化合物富马酸盐V晶型长期/加速稳定性研究

Table 3. Study on the long-term/accelerated stability of fumarate crystal form V of the compound represented by formula (I)

长期/加速稳定性实验显示：式(I)所示化合物富马酸盐V晶型长期加速稳定性条件下放置6个月的物理化学性质稳定性良好。The long-term/accelerated stability experiment shows that the physical and chemical properties of the fumarate V crystal form of the compound represented by formula (I) are good when placed under long-term accelerated stability conditions for 6 months.
实施例5、式(I)所示化合物氢溴酸盐的α晶型的制备Embodiment 5, preparation of α crystal form of hydrobromide salt of compound represented by formula (I)
称量100mg式(I)所示化合物游离碱，加入7ul氢溴酸与5ml乙腈，50℃/800rpm搅拌2-36h，抽滤，40℃烘干1h，产物经离子色谱检测，溴离子含量为7.6％。说明该盐中式(I)所示化合物与氢溴酸的摩尔比为2∶1，将该产物定义为晶型α，XRPD谱图如图7，峰位置如表4所示。Weigh 100 mg of the free base of the compound represented by formula (I), add 7 ul of hydrobromic acid and 5 ml of acetonitrile, stir at 50°C/800rpm for 2-36 hours, filter with suction, and dry at 40°C for 1 hour. The product is detected by ion chromatography and the bromide ion content is 7.6%. It is shown that the molar ratio of the compound represented by formula (I) to hydrobromic acid in the salt is 2:1, and the product is defined as crystal form α. The XRPD spectrum is shown in Figure 7, and the peak positions are shown in Table 4.
表4.式(I)所示化合物氢溴酸盐α晶型峰位置

Table 4. Peak position of hydrobromide α crystal form of the compound represented by formula (I)

实施例6、式(I)所示化合物氢溴酸盐的β晶型的制备Embodiment 6, preparation of β crystal form of hydrobromide salt of compound represented by formula (I)
称量100mg式(I)所示化合物游离碱，加入14ul氢溴酸与5ml乙腈，50℃/800rpm搅拌2h，抽滤，40℃烘干1h，产物经离子色谱检测，溴离子含量为14.3％。说明该盐中式(I)所示化合物与氢溴酸的摩尔比为1∶1，将该产物定义为晶型β，XRPD谱图如图8，峰位置如表5所示。Weigh 100 mg of the free base of the compound represented by formula (I), add 14 ul of hydrobromic acid and 5 ml of acetonitrile, stir at 50°C/800rpm for 2 hours, filter with suction, and dry at 40°C for 1 hour. The product is detected by ion chromatography and the bromide ion content is 14.3%. . It is shown that the molar ratio of the compound represented by formula (I) and hydrobromic acid in the salt is 1:1, and the product is defined as crystal form β. The XRPD spectrum is shown in Figure 8, and the peak positions are shown in Table 5.
表5.式(I)所示化合物氢溴酸盐β晶型峰位置

Table 5. Peak position of hydrobromide β crystal form of the compound represented by formula (I)

实施例7、影响因素稳定性研究Example 7. Study on the stability of influencing factors
式(I)所示化合物氢溴酸盐α晶型、式(I)所示化合物氢溴酸盐β晶型敞口平摊放置，考察在高温(40℃、60℃)条件下样品的稳定性，取样考察期为30天。The hydrobromide α crystal form of the compound represented by formula (I) and the hydrobromide beta crystal form of the compound represented by formula (I) are placed flat in the open, and the stability of the samples under high temperature (40°C, 60°C) conditions is investigated. nature, the sampling inspection period is 30 days.
表6.式(I)所示化合物氢溴酸盐α晶型影响因素稳定性数据
Table 6. Stability data of factors affecting the α crystal form of hydrobromide of the compound represented by formula (I)
表7.式(I)所示化合物氢溴酸盐β晶型影响因素稳定性数据

Table 7. Stability data of factors affecting the beta crystal form of hydrobromide of the compound represented by formula (I)

结论：式(I)所示化合物氢溴酸盐α晶型及式(I)所示化合物氢溴酸β晶型在60℃放置时不稳定。Conclusion: The hydrobromide α crystal form of the compound represented by formula (I) and the hydrobromide β crystal form of the compound represented by formula (I) are unstable when placed at 60°C.
实施例8、式(I)所示化合物氢溴酸盐α晶型、式(I)所示化合物氢溴酸β晶型、式(I)所示化合物富马酸盐V晶型生理介质中分散现象Example 8, the hydrobromide α crystal form of the compound represented by formula (I), the hydrobromide beta crystal form of the compound represented by formula (I), and the fumarate V crystal form of the compound represented by formula (I) in physiological media dispersion phenomenon
过量式(I)所示化合物富马酸盐V晶型和式(I)所示化合物氢溴酸盐α、β晶型样品(目标浓度约5mg/ml)分别放于FaSSGF、FeSSIF、FaSSIF生理相关介质，在37℃、120rpm平衡1h、24h，观察现象如表8所示。Excessive fumarate crystal form V of the compound represented by formula (I) and hydrobromide α and β crystal form samples (target concentration approximately 5 mg/ml) of the compound represented by formula (I) were placed in FaSSGF, FeSSIF, and FaSSIF physiological systems respectively. The relevant media were equilibrated at 37°C and 120rpm for 1h and 24h, and the observed phenomena are shown in Table 8.
表8.氢溴酸盐α晶型、氢溴酸β晶型、富马酸盐V晶型分散现象
Table 8. Dispersion phenomena of hydrobromide α crystal form, hydrobromide β crystal form, and fumarate crystal form V
结果：式(I)所示化合物富马酸盐V晶型在生理介质中分散行为较好。 Results: The fumarate crystal form V of the compound represented by formula (I) has good dispersion behavior in physiological media.

Claims (10)

  1. 一种式(I)所示化合物的富马酸盐的V晶型，所述的式(I)所示化合物的富马酸盐，其中式(I)所示化合物与富马酸盐的摩尔比例为2∶1，其X-射线粉末衍射谱图在2θ角为13.763、14.493、17.975、19.549、25.502处有特征峰，
    A V crystal form of the fumarate salt of the compound represented by formula (I), the fumarate salt of the compound represented by formula (I), wherein the mole of the compound represented by formula (I) and the fumarate salt The ratio is 2:1, and its X-ray powder diffraction spectrum has characteristic peaks at 2θ angles of 13.763, 14.493, 17.975, 19.549, and 25.502.
  2. 根据权利要求1所述的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图在2θ角为11.684、12.703、13.763、14.493、16.740、17.975、19.549、23.299、23.711、25.502、26.448处有特征峰。According to the V crystal form of the fumarate salt of the compound represented by formula (I) according to claim 1, its X-ray powder diffraction spectrum at the 2θ angle is 11.684, 12.703, 13.763, 14.493, 16.740, 17.975, 19.549, There are characteristic peaks at 23.299, 23.711, 25.502, and 26.448.
  3. 根据权利要求1所述的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图在2θ角为7.756、8.278、11.684、12.703、13.763、14.493、15.305、16.740、17.975、19.549、21.221、22.519、23.299、23.711、24.132、25.502、26.448、27.356、29.725、30.822、36.057处有特征峰。According to the V crystal form of the fumarate salt of the compound represented by formula (I) according to claim 1, its X-ray powder diffraction spectrum at the 2θ angle is 7.756, 8.278, 11.684, 12.703, 13.763, 14.493, 15.305, There are characteristic peaks at 16.740, 17.975, 19.549, 21.221, 22.519, 23.299, 23.711, 24.132, 25.502, 26.448, 27.356, 29.725, 30.822, and 36.057.
  4. 根据权利要求1所述的式(I)所示化合物的富马酸盐的V晶型，其X-射线粉末衍射谱图如图2所示。The V crystal form of the fumarate salt of the compound represented by formula (I) according to claim 1 has an X-ray powder diffraction spectrum as shown in Figure 2.
  5. 根据权利要求1-4任一项所述的式(I)所示化合物的富马酸盐的V晶型，其中，所述2θ角度的误差范围为±0.2。The V crystal form of the fumarate salt of the compound represented by formula (I) according to any one of claims 1 to 4, wherein the error range of the 2θ angle is ±0.2.
  6. 一种制备权利要求1-5任一项所述的式(I)所示化合物的富马酸盐的V晶型的方法，包括以下步骤：1)将式(I)所示化合物与富马酸溶于有机溶剂中，2)结晶析出，其中式(I)所示化合物与富马酸的摩尔比选自10∶1-2∶1，所述的有机溶剂选自甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、乙腈、丙酮或其混合物，优选甲醇。A method for preparing the V crystal form of the fumarate salt of the compound represented by formula (I) according to any one of claims 1 to 5, comprising the following steps: 1) combining the compound represented by formula (I) with fumarate The acid is dissolved in an organic solvent, and 2) crystallization is precipitated, wherein the molar ratio of the compound represented by formula (I) to fumaric acid is selected from 10:1-2:1, and the organic solvent is selected from methanol, ethanol, isopropyl Alcohol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone or mixtures thereof, preferably methanol.
  7. 一种由根据权利要求1-5任一项所述的式(I)所示化合物的V晶型制 备得到的组合物。A preparation made from the V crystal form of the compound represented by formula (I) according to any one of claims 1-5 Prepare the composition.
  8. 一种药物组合物，其包含如下组分：A pharmaceutical composition comprising the following components:
    i)根据权利要求1-5任一项所述的式(I)所示化合物的富马酸盐的V晶型；和i) Form V of the fumarate salt of the compound represented by formula (I) according to any one of claims 1 to 5; and
    ii)一种或多种药学上可接受的载体、稀释剂或赋形剂。ii) One or more pharmaceutically acceptable carriers, diluents or excipients.
  9. 一种制备根据权利要8所述的药物组合物的方法，包括下述步骤：将所述组分混合。A method of preparing the pharmaceutical composition according to claim 8, comprising the step of mixing the components.
  10. 根据权利要求1-5任一项所述的式(I)所示化合物的富马酸盐的V晶型、或根据权利要求7-8任一项所述的组合物在制备治疗或预防癌症、炎症、或其它增殖性疾病的药物中的用途，优选癌症；所述的癌症选自黑色素瘤、肝癌、肾癌、肺癌、鼻咽癌、结肠直肠癌、结肠癌、直肠癌、胰腺癌、宫颈癌、卵巢癌、乳腺癌、膀胱癌、前列腺癌、白血病、头颈鳞状细胞癌、子宫颈癌、甲状腺癌、淋巴瘤、肉瘤、成神经细胞瘤、脑瘤、骨髓瘤，星形细胞瘤和胶质瘤。 The V crystal form of the fumarate salt of the compound represented by formula (I) according to any one of claims 1 to 5, or the composition according to any one of claims 7 to 8 in the preparation, treatment or prevention of cancer , inflammation, or other proliferative diseases, preferably cancer; the cancer is selected from melanoma, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, colon cancer, rectal cancer, pancreatic cancer, Cervical cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, leukemia, head and neck squamous cell carcinoma, cervical cancer, thyroid cancer, lymphoma, sarcoma, neuroblastoma, brain tumor, myeloma, astrocytoma and glioma.
PCT/CN2023/084452 2022-03-28 2023-03-28 Crystalline form of fumarate of pyrroloheterocyclic derivative and preparation method therefor WO2023185869A1 (en)

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