Polymorphs of macrocyclic fxia inhibitor compounds, preparation method therefor, and medical use thereof

Abstract

The present invention belongs to the technical field of chemical drugs, and provides a series of polymorphs of macrocyclic FXIa inhibitor compounds. The present invention further relates to pharmaceutical compositions containing the polymorphs of the compounds and a use of the compounds in a medicament for treating thromboembolism and other diseases.

Description

Polymorphisms of macrocyclic FXIa inhibitor compounds, their preparation methods and pharmaceutical uses Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology and provides a series of polymorphs of macrocyclic FXIa inhibitor compounds. This invention also relates to pharmaceutical compositions comprising these polymorphs and the use of the polymorphs in medicaments for treating diseases such as thromboembolism. Background Technology

[0002] Globally, cardiovascular and cerebrovascular diseases such as cerebrovascular disease, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis claim nearly 12 million lives each year, accounting for almost a quarter of the world's total deaths and becoming the number one threat to human health. In China, more than 2.6 million people die from cardiovascular diseases annually, and 75% of survivors are disabled, with more than 40% suffering severe disabilities. Thrombosis caused by cardiovascular and cerebrovascular diseases, diabetes, and their complications has become an urgent problem that needs to be addressed.

[0003] The human blood clotting process consists of an intrinsic pathway, an extrinsic pathway, and a common pathway (Annu. Rev. Med. 2011. 62: 41–57). It is a chain reaction in which multiple zymogens are sequentially activated, and the process is continuously strengthened and amplified. The coagulation cascade is initiated by the intrinsic pathway (also known as the contact activation pathway) and the extrinsic pathway (also known as the tissue factor pathway) to generate FXa, which then passes through the common pathway to generate thrombin (FIIa), and finally forms fibrin.

[0004] The endogenous pathway refers to the activation of factor XII to form XIa-VIIIa-Ca. 2+ The process of β-PL complex activation and factor X activation involves the release of tissue factor (TF) into TF-VIIa-Ca from the extrinsic coagulation pathway. 2+ The process involves the formation and activation of factor X. The common pathway refers to the merging of two pathways after factor Xa formation, activating prothrombin and ultimately generating fibrin. FXI is essential for maintaining the intrinsic pathway and plays a crucial role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback-activate FXI, and the activated FXI (FXIa) further promotes the production of large amounts of thrombin, thus amplifying the coagulation cascade. Therefore, FXI antagonists have been widely developed for the treatment of various types of thrombosis.

[0005] Traditional anticoagulants, such as warfarin, heparin, and low molecular weight heparin (LMWH), as well as newer drugs launched in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), have all shown good efficacy in reducing thrombus formation and occupy a large share of the cardiovascular and cerebrovascular market due to their significant effectiveness. However, their side effects are becoming increasingly significant, among which "bleeding risk" is one of the most prominent and serious problems (N Engl J Med 1991; 325:153-8, Blood. 2003; 101:4783-4788).

[0006] Studies have found that inhibiting FXIa can effectively suppress thrombus formation in thrombosis models, but its effect is negligible in more severe thrombosis cases (Blood. 2010; 116(19):3981-3989). Clinical statistics show that increasing FXIa levels increases the incidence of VTE (Blood 2009; 114:2878-2883), while those with severe FXIa deficiency have a reduced risk of DVT (Thromb Haemost 2011; 105:269–273).

[0007] As an emerging target for inhibiting thrombosis, patent applications for compounds with FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017 / 023992, and WO2018041122.

[0008] In its earlier application PCT / CN2024 / 102166, the applicant filed a patent application for a series of macrocyclic FXIa inhibitor compounds, including compound A as shown in the following formula:

[0009] This invention provides polymorphs of macrocyclic FXIa inhibitor compounds of formula (I), which improve their physicochemical properties and facilitate their application. This invention is introduced in PCT / CN2024 / 102166. Summary of the Invention

[0010] This invention provides a polymorph of a macrocyclic FXIa inhibitor compound, its preparation method, and its application in medicine.

[0011] Specifically,

[0012] This invention first provides polymorphs of macrocyclic FXIa inhibitor compounds.

[0013] in:

[0014] The polymorph is crystal form A, which has the strongest characteristic absorption peak at 16.51° in the X-ray diffraction pattern, represented by a 2θ angle, with an error of ±0.2°.

[0015] As a preferred embodiment of the present invention, the crystal form, represented by a 2θ angle in the X-ray diffraction pattern, further exhibits characteristic peaks at 9.86°, 18.04°, 20.35°, 24.20°, and 24.79°, with an error of ±0.2°.

[0016] As a preferred embodiment of the present invention, the crystal form, represented by a 2θ angle in the X-ray diffraction pattern, further exhibits characteristic peaks at 5.34°, 10.47°, 13.64°, 14.27°, 14.68°, 15.94°, 18.82°, 19.66°, 21.13°, 21.83°, 22.40°, 24.05°, 25.09°, 25.66°, 27.65°, 29.38°, 29.79°, 31.11°, and 33.35°, with an error of ±0.2°.

[0017] As a preferred embodiment of the present invention, the X-ray diffraction pattern of the crystal form is shown in Figure 1 or Figure 3.

[0018] As a preferred embodiment of the present invention, the DSC spectrum of the crystal form has a maximum absorption peak at 261.2℃±3℃.

[0019] As a preferred embodiment of the present invention, the DSC spectrum of the crystal form is shown in Figure 2 or Figure 4.

[0020] The present invention further provides a pharmaceutical composition comprising a polymorph of the aforementioned macrocyclic FXIa inhibitor compound and one or more pharmaceutically acceptable carriers.

[0021] The present invention further provides the use of the macrocyclic FXIa inhibitor compound in polymorphism, or the pharmaceutical composition thereof, in the preparation of a medicament for treating FXIa-related diseases.

[0022] As a preferred embodiment of the present invention, the method is selected from the use of drugs for treating thrombosis-related diseases.

[0023] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0024] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, and transdermal penetration enhancers. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0025] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0026] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0027] The term "treatment" refers to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0028] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0029] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0030] The compounds of this invention have significant inhibitory activity against human FXIa and significant anticoagulant activity against human plasma.

[0031] The preferred compounds of this invention have good oral absorption and high absolute bioavailability and exposure.

[0032] The compounds of this invention have a relatively weak inhibitory effect on chymotrypsin and coagulation factor FIIa, but exhibit good selectivity.

[0033] Crystal form A of the present invention exhibits better stability. Attached Figure Description

[0034] Figure 1. XRPD spectrum of crystal form A in Example 8.

[0035] Figure 2, DSC spectrum of crystal form A in Example 8.

[0036] Figure 3, XRPD spectrum of crystal form A in Example 9.

[0037] Figure 4, DSC spectrum of crystal form A in Example 9. Detailed Implementation

[0038] The present invention will now be described in further detail with reference to the embodiments and accompanying drawings, but the implementation of the invention is not limited thereto.

[0039] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-III NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl₃) as the solvents and tetramethylsilane (TMS) as the internal standard.

[0040] MS measurements were performed using an ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).

[0041] High-performance liquid chromatography (HPLC) analysis was performed using a Thermo U3000 HPLC DAD high-performance liquid chromatograph.

[0042] The CombiFlash rapid preparation system uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).

[0043] Thin-layer chromatography silica gel plates are Yantai Yinlong HSGF254 or GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.17mm to 0.23mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0044] Silica gel column chromatography generally uses 100-200 mesh silica gel from Rushan Shangbang as the carrier.

[0045] Unless otherwise stated, the crystal form and amorphous form of this invention were detected using the following equipment and conditions: X-ray powder diffraction (XRPD). The XRPD patterns were acquired on an X-ray powder diffractometer manufactured by PANalytacal, and the scanning parameters are shown in the table below:

[0046] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed. The TGA and DSC images were acquired using a Netzsch TG 209F3 thermogravimetric analyzer and a DSC 200F3 differential scanning calorimeter, respectively. The test parameters are shown in the table below:

[0047] Example 1

[0048] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridin-1(6H)-yl)-2 5 ,2 6 -Difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazole-2(1,3)-benzenenonanaphthalene-8-one (I)

[0049] The specific synthesis route is as follows:

[0050] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)one (100 mg, 0.325 mmol) was dissolved in dry, anhydrous 1,4-dioxane (10 mL), and then bis(trimethylsilyl)aminolithium (1 mol / L tetrahydrofuran solution, 0.325 mL, 0.325 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then (7R)-2 5 ,2 6 -Difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1H-9-aza-1(5,4)-pyrazole-2(1,3)-benzoza-3-yl-4-nitrobenzenesulfonate (170 mg, 0.325 mmol) was reacted at 70°C for 16 hours.

[0051] After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature. A saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). This was then purified by preparative high-performance liquid chromatography to give 19.7 mg of a white amorphous solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridin-1(6H)-yl)-2 5 ,2 6 -Difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazolazole-2(1,3)-benzenenonanaphthyl-8-one (yield: 9.7%). LC-MS: RT = 1.95 min, [M+H] + =627.98.

[0052] 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.74(s,1H),8.48(s,1H),7.89(d,J=2.3Hz,1 H),7.82(dd,J=8.5,2.4Hz,1H),7.75(d,J=8.5Hz,1H),7.54-7.45(m,2H),7.45-7. 37(m,1H),6.40(s,1H),5.52(d,J=12.6Hz,1H),2.47-2.30(m,2H),1.95-1.82(m,1 H),1.82-1.69(m,1H),1.45-1.33(m,1H),1.17-1.02(m,2H),0.94(d,J=6.7Hz,3H).

[0053] Example 2: Detection of the bioactivity of the compound of the present invention against human coagulation factor XIa using optical absorption method.

[0054] 1. Experimental materials

[0055] Enzyme: Human Factor XIa (ENZYME RESEARCH, catalog number HFXIa 1111a)

[0056] Substrate: S-2366 TM(CHROMOGENIX, part number 82109039)

[0057] Buffer solution: 145mM NaCl, 5mM KCl, 1mg / mL PEG 8000, 30mM HEPES, pH 7.4.

[0058] 2. Experimental Procedure

[0059] The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0.00128 μM. 98 μL (77.7 ng / mL) of FXIa enzyme solution was added to each well of a 96-well plate. 98 μL of buffer was added to the blank wells instead. Then, 2 μL of the compound at different concentrations was added. DMSO was used instead of DMSO in the blank and control wells. The mixture was shaken and incubated at 37°C for 20 min.

[0060] Finally, 100 μL of 800 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0061] 3 Data Processing

[0062] Curve fitting was performed using GraphPad Prism software to calculate IC. 50 value.

[0063] Example 3: Determination of the in vitro anticoagulant effect of the compounds of the present invention on human plasma

[0064] 1. Experimental materials

[0065] aPTT batch number 220106600, calcium chloride batch number 210305600, and needle washing solution batch number 211101300: manufactured by Shenzhen Mindray Bio-Medical Electronics Co., Ltd. Human mixed plasma, from healthy individuals, blood was collected using disposable intravenous blood collection tubes, using disposable human venous blood collection containers (batch number 211108) from Liuyang Sanli Medical Technology Development Co., Ltd., with a sodium citrate ratio of 9:1. Human blood was collected at room temperature, centrifuged at 3000 rpm for 10 minutes, and the supernatant was collected for later use (batch number 20220606).

[0066] 2. Experimental Procedure

[0067] The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 0.29, 0.59, 1.17, 2.34, 4.69, 9.38, 18.75, and 37.50 μM. 99 μL of human mixed plasma was added to each 1.5 ml centrifuge tube, followed by 1 μL of the compound at different concentrations. 1 μL of DMSO was added to the blank wells. The mixture was repeatedly inverted by hand to mix thoroughly. After centrifugation using a handheld centrifuge, the samples were incubated in a 37°C water bath for 10 min to mix. aPTT was then detected using a fully automated coagulation analyzer according to the pre-set program.

[0068] 3. Data Processing

[0069] Curve fitting was performed using Graphad Prism software, and EC1.5× was calculated.

[0070] The results of Examples 2 and 3 are shown in Table 1:

[0071] Table 1:

[0072] Conclusion: The compounds of this invention have significant inhibitory activity against human FXIa and significant anticoagulant activity against human plasma.

[0073] Example 4: Pharmacokinetic Experiment

[0074] 1. Reagents and Instruments

[0075] Polyethylene glycol 400 (batch number GORKREUT, Saen Chemical Technology (Shanghai) Co., Ltd.), DMSO (batch number 20200319, Guangdong Guanghua Technology Co., Ltd.), physiological saline (batch number C20052604, Jiangxi Kelun Pharmaceutical Co., Ltd.). LC-MS instruments (Thermo Fisher Ultimate 3000 UPLC, TSQ QUANTUM ULTRA triple quadrupole mass spectrometer, AB SCIEX 5500 QTARP).

[0076] 2. Laboratory animals

[0077] SD rats: male, 180-250g, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0078] 3. Formulation preparation

[0079] Accurately weigh the sample powder, dissolve it completely in DMSO, add PEG-400, vortex and sonicate to mix, then add physiological saline and vortex and sonicate to make 0.5 mg / mL (DMSO:PEG-400:NS=5:60:35, V / V / V). Administer 10 mL / kg by gavage or 0.5 mL / kg by intravenous administration.

[0080] 4. Blood sample collection

[0081] After intravenous or gavage administration to rats, 200 μL of venous blood was collected at 5 min (no blood was collected after gavage), 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h and placed in heparinized EP tubes. The tubes were centrifuged at 12,000 rpm for 2 min, and the plasma was frozen at -80℃ for later analysis.

[0082] 5. Biological Analysis

[0083] Accurately weigh a certain amount of the test sample and dissolve it in DMSO to a concentration of 1 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the stock solution and dilute it with acetonitrile to prepare a series of standard solutions. Accurately pipette 20 μL of each of the above standard solutions and add 180 μL of blank plasma. Vortex to mix, preparing plasma samples equivalent to concentrations of 1, 3, 10, 30, 100, 300, 1000, 3000, and 5000 ng / mL. Perform dual-sample analysis for each concentration to establish a standard curve. Take 20 μL of plasma and add 200 μL of acetonitrile solution containing propranolol (5 ng / mL) as an internal standard. Vortex to mix and centrifuge at 4000 rpm for 5 min. Analyze the supernatant by LC-MS. The LC-MS detection conditions are as follows:

[0084] Chromatographic column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1mm, 1.8μm.

[0085] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution is shown in Table 2 below:

[0086] Table 2

[0087] 6. Data Processing

[0088] After LC-MS was used to detect the blood drug concentration, the pharmacokinetic parameters of the beagle dogs after administration were calculated using WinNonlin 6.1 software and a non-compartmental model. The results are shown in Table 3 below.

[0089] Table 3: Pharmacokinetic parameters of the compounds of this invention in dogs (IV and PO administration)

[0090] As shown in Table 3, the preferred compound of this invention has better oral absorption, higher absolute bioavailability and exposure, and is superior to the control compound.

[0091] Example 5: Detection of the bioactivity of the compound of the present invention against human coagulation factor chymotrypsin by absorption spectrophotometry

[0092] 1. Experimental materials

[0093] Enzyme: α-Chymotrypsin (Sigma, catalog number C8946)

[0094] Substrate: S-2586 TM (Boatman Biotechnology, Product No. B2586)

[0095] Buffer solution: 0.05M HEPES; 0.145M NaCl; 5mM KCl and 0.1% PEG 8000, pH 7.4

[0096] 2. Experimental Procedure

[0097] The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 100, 33.33, 11.11, 3.704, 1.235, 0.412, 0.137, and 0.046 μM. 29.4 μL (20 nM) of chymotrypsin enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells, followed by 0.6 μL of the compound at different concentrations. DMSO was used instead of DMSO in the blank and control wells. The mixture was shaken and incubated at 37°C for 30 min.

[0098] Finally, 30 μL of substrate at a concentration of 200 μM was added to each well, and the absorbance was measured at 405 nm.

[0099] 3. Data Processing

[0100] Curve fitting was performed using GraphPad Prism software to calculate IC. 50 Values ​​are shown in Table 4.

[0101] Table 4. Inhibitory effects of compounds on hymotrypsin

[0102] Experimental conclusion: The compound of this invention has a relatively weak inhibitory effect on chymotrypsin, suggesting that the compound has better selectivity for chymotrypsin.

[0103] Example 6: Detection of the bioactivity of the compound of the present invention against human coagulation factor Trypsin by absorption spectrophotometry

[0104] 1. Experimental materials

[0105] Enzyme: Human Trypsin (Sigma, catalog number T6424)

[0106] Substrate: S-2222 TM (CHROMOGENIX, part number 82031639)

[0107] Buffer solution: 0.1M sodium phosphate; 0.2M NaCl and 0.5% PEG 8000, pH 7.4

[0108] 2. Experimental steps:

[0109] The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 10000, 3333, 1111, 370.4, 123.5, 41.2, 13.7, and 4.6 μM. 29.4 μL (0.8 nM) of Trypsin enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells instead. 0.6 μL of different concentrations of the compound was added to each well. DMSO was used instead of DMSO in the blank and control wells. The mixture was shaken and incubated at 37°C for 30 min.

[0110] Finally, 30 μL of substrate at a concentration of 40 μM was added to each well, and the absorbance was measured at 405 nm.

[0111] 3. Data Processing

[0112] Curve fitting was performed using GraphPad Prism software to calculate IC. 50 Values ​​are shown in Table 5.

[0113] Table 5. Inhibitory effects of compounds on Trypsin

[0114] Experimental conclusion: The inhibitory effect of the compound of this invention on Trypsin is relatively weak, suggesting that the compound has better selectivity for Trypsin.

[0115] Example 7: Detection of the bioactivity of the compound of the present invention against human coagulation factor FIIa by absorption spectrophotometry

[0116] 1. Experimental materials

[0117] Enzyme: Human FIIa (Enzyme Research Laboratories, Catalog No. HT 1002a)

[0118] Substrate: S-2366 TM (CHROMOGENIX, part number 82109039)

[0119] Buffer solution: 0.1M sodium phosphate; 0.2M NaCl and 0.5% PEG 8000, pH 7.4

[0120] 2. Experimental Procedure

[0121] The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 10000, 3333, 1111, 370.4, 123.5, 1.2, 13.7, and 4.6 μM. 29.4 μL (4 nM) of FIIa enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells. 0.6 μL of different concentrations of the compound was added to each well. DMSO was used instead of blank and control wells. The mixture was shaken and incubated at 37°C for 30 min.

[0122] Finally, 30 μL of substrate at a concentration of 200 μM was added to each well, and the absorbance was measured at 405 nm.

[0123] 3. Data Processing

[0124] Curve fitting was performed using GraphPad Prism software to calculate IC. 50 Values ​​are shown in Table 6.

[0125] Table 6. Inhibitory effects of compounds on coagulation factor FIIa

[0126] Experimental conclusion: The compound of this invention has a relatively weak inhibitory effect on coagulation factor FIIa, suggesting that the compound has better selectivity for coagulation factor FIIa.

[0127] The structural formula of the reference compound is as follows:

[0128] Example 8: Preparation method of crystal form A

[0129] Add 60g of crude compound 1 from Example 1 to a reaction flask, add 300ml of ethanol, heat to 60°C to dissolve, then add 450ml of n-heptane and continue stirring for 1 day, filter, and dry the solid under vacuum at 40°C for 1 day.

[0130] The X-ray diffraction pattern of the obtained crystal form is shown in Figure 1, and the DSC pattern is shown in Figure 2.

[0131] Example 9: Preparation method of crystal form A

[0132] 200 mg of the crude compound 1 from Example 1 was dissolved in 4.5 ml of acetone, and then 20 ml of isopropyl ether was added. The mixture was stirred at room temperature for 6 h, then filtered, and the solid was dried under vacuum at 50 °C for 1 day.

[0133] The X-ray diffraction pattern of the obtained crystal form is shown in Figure 3, and the DSC pattern is shown in Figure 4.

[0134] The X-ray diffraction data of crystal form A in Examples 8 and 9 are as follows:

[0135] Table 7: X-ray diffraction data of crystal form A of the compound sample of the present invention

[0136] Where No. = serial number, Rel.Int.[%] = Relative Intensity, Pos.[°2θ] = Position[ 。 2Theta], with an error of ±0.2°. Rel.Int. = Relative Intensity only represents the approximate intensity of the characteristic peak and should not be used as a limitation on a specific crystal form.

[0137] In summary, based on the XRD spectra and characteristic peak data in Figures 1 and 3, the strongest characteristic absorption peak is located at 16.51°, represented by a 2θ angle, with an error of ±0.2° and a relative absorption intensity of 100%.

[0138] Furthermore, the crystal form also has characteristic peaks at 9.86°, 18.04°, 20.35°, 24.20°, and 24.79°, with an error of ±0.2° and a relative absorption intensity greater than 50%.

[0139] Furthermore, the described crystal form also exhibits characteristic peaks at 5.34°, 10.47°, 13.64°, 14.27°, 14.68°, 15.94°, 18.82°, 19.66°, 21.13°, 21.83°, 22.40°, 24.05°, 25.09°, 25.66°, 27.65°, 29.38°, 29.79°, 31.11°, and 33.35°, with an error of ±0.2° and a relative absorption intensity greater than 10%. These peaks allow for more detailed differentiation between other substances representing this crystal form. Other weak absorption peaks may vary significantly due to experimental errors; therefore, for those skilled in the art, these other absorption peaks are unnecessary for characterizing this crystal form.

[0140] Example 10: Stability study of the compound sample of the present invention

[0141] The experimental conditions and results are as follows:

[0142] 10.1 Stability (bare sample): (Conditions: 92.5% ± 5% RH):

[0143] Table 8

[0144] 10.2 Stability (Sealing): (Conditions: 40℃±2℃, 75%±5%RH):

[0145] Table 9

[0146] As can be seen from the above results, the polymorph of the present invention, crystal form A, exhibits better stability.

[0147] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A polymorph of a macrocyclic FXIa inhibitor compound, characterized in that, The compound is shown in formula (I): Wherein: the polymorph is crystal form A, and the crystal form has the strongest characteristic absorption peak at 16.51° in the X-ray diffraction pattern, represented by the 2θ angle, with an error of ±0.2°.

2. The polymorph of the macrocyclic FXIa inhibitor compound according to claim 1, wherein the polymorph, represented by an angle of 2θ in the X-ray diffraction pattern, further exhibits characteristic peaks at 9.86°, 18.04°, 20.35°, 24.20°, and 24.79° with an error of ±0.2°.

3. The polymorph of the macrocyclic FXIa inhibitor compound according to claim 2, wherein the polymorph, represented by a 2θ angle in the X-ray diffraction pattern, further exhibits characteristic peaks at 5.34°, 10.47°, 13.64°, 14.27°, 14.68°, 15.94°, 18.82°, 19.66°, 21.13°, 21.83°, 22.40°, 24.05°, 25.09°, 25.66°, 27.65°, 29.38°, 29.79°, 31.11°, and 33.35°, with an error of ±0.2°.

4. The polymorphism of the macrocyclic FXIa inhibitor compound according to any one of claims 1-3, characterized in that, The X-ray diffraction pattern of the crystal form is shown in Figure 1 or Figure 3.

5. The polymorph of the macrocyclic FXIa inhibitor compound according to any one of claims 1-4, characterized in that, The DSC spectrum of the crystal form shows a maximum absorption peak at 261.2℃±3℃.

6. The polymorphism of the macrocyclic FXIa inhibitor compound according to any one of claims 5, characterized in that, The DSC spectrum of the crystal form is shown in Figure 2 or Figure 4.

7. A pharmaceutical composition, characterized in that, It includes the polymorph of the macrocyclic FXIa inhibitor compound as described in any one of claims 1-6, and one or more pharmaceutically acceptable carriers.

8. The use of the polymorph of the macrocyclic FXIa inhibitor compound according to any one of claims 1-6, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating FXIa-related diseases.

9. The use according to claim 8, characterized in that, Selected from the uses of drugs for treating thrombosis-related diseases.

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