Camphorsulfonate, crystal form, composition and preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, and discloses camphorsulfonate, a crystal form, a composition and a preparation method and application thereof, and the camphorsulfonate is AXL kinase inhibition camphorsulfonate. The crystal form of the camphorsulfonate is substantially pure. The basically pure AXL kinase inhibition camphorsulfonate crystal form disclosed by the invention has good performance and high bioavailability; therefore, the compound can be used for preparing medicines for treating and / or preventing proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancers, virus infectious diseases, heart failure, cardiovascular diseases or other diseases of mammals.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to a camphorsulfonic acid salt, a crystal form, a composition, a preparation method and application thereof. BACKGROUND

[0002] AXL is a membrane-bound receptor tyrosine kinase belonging to the TAM (Tyro3, AXL, Mer) family. It is characterized by its two immunoglobulin-like domains and a double fibronectin repeat sequence in its extracellular domain and an associated tyrosine kinase domain in its cytoplasmic domain. TAM receptor tyrosine kinase-mediated cell signaling is involved in processes such as cell growth, migration, aggregation and apoptosis in a variety of normal cells. There are two known ligands for the TAM family, GAS6 (growth arrest-specific 6) and protein S. Binding of Gas6 to AXL leads to receptor dimerization and AXL autophosphorylation. AXL is present in a variety of organs and cells, including epithelial cell lines, mesenchymal and hematopoietic origin, and non-transformed cells. AXL is present in a variety of organs and cells, including epithelial cell lines, mesenchymal and hematopoietic origin, and non-transformed cells. AXL kinase inhibitors can block the interaction between AXL ligands and phosphatidylserine (PtdSer) in the membrane. Therefore, new or improved agents that inhibit protein kinases such as AXL kinase can be used as drugs to treat and / or prevent viral infectious diseases, for example, as drugs against Zika virus, coronavirus, new coronavirus and hepatitis B virus.

[0003] Based on the existing AXL kinase inhibitors, there are problems of drug resistance in the treatment of cancer and other diseases, and insufficient pharmacokinetic properties and stability, which makes it difficult to effectively inhibit the activity of AXL kinase. CN113912628B develops a new class of triazine compounds, which has excellent inhibitory activity and kinase selectivity, can effectively regulate the activity of AXL kinase, has good pharmacokinetic properties and liver microsomal stability, and has no inhibition or induction on CYP450 enzyme. The patent discloses a series of AXL kinase inhibitors, wherein example 25 discloses the compound N-(4-(4-amino-7-(1-(2-fluoro-2-methylpropionyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-2-oxo-1-(pyridin-2-yl)-1,2,4,5,6,7-hexahydropyrrolo[1,5-a]pyridine-3-carboxamide, which has the structural formula: There is no sufficient characterization of the crystal form, and the crystal form of the compound cannot be known; and the salt of the compound is not disclosed.

[0004] CN119548503A discloses the use of an AXL inhibitor in the preparation of a drug for treating heart failure, mentioning that the structure shown in formula (A) can be used not only as an anticancer drug, but also as a drug for treating heart failure, has a protective effect in myocardial fibrosis and pulmonary fibrosis, and a therapeutic effect on pathological structural remodeling of heart tissue, and can be used for the treatment of clinical heart failure patients or combined drug use.

[0005] Different salts and solid forms of a pharmaceutically active ingredient can have different properties. Changes in properties due to different salts or solid forms can provide improved formulations, for example, ease of synthesis or handling, improved dissolution, or improved stability and shelf life. Changes in properties due to different salts or solid forms can also improve the final dosage form, for example, if the change improves exposure, bioavailability, or extends half-life. Different salts and solid forms of a pharmaceutically active ingredient can also produce polymorphs or other crystal forms, providing more opportunities to assess changes in properties of a solid active pharmaceutical ingredient. Therefore, developing different salts and crystal forms of a drug is of great significance in drug development.

[0006] Therefore, it is of great significance to develop a camphorsulfonic acid salt, crystal form, composition of an AXL kinase inhibitor, and a preparation method and application thereof. SUMMARY

[0007] In order to find a solid form with better drug properties, the present application provides a camphorsulfonic acid salt, crystal form, composition, and a preparation method and application thereof, so that the AXL kinase inhibitor has better chemical and physical properties, especially relatively high solubility, stability, bioavailability, and efficacy, and the physical properties are more conducive to the preparation. The preparation process is safe, reproducible, and operable, which is very conducive to industrial production and subsequent product development.

[0008] In a first aspect, the present application provides a salt represented by formula (B), which is an AXL kinase inhibitor camphorsulfonic acid salt: .

[0009] In some embodiments, the molar ratio of the AXL kinase inhibitor to camphorsulfonic acid in the AXL kinase inhibitor camphorsulfonic acid salt is 1.0:1.0.

[0010] In some embodiments, the AXL kinase inhibitor camphorsulfonic acid salt has 1 an HNMR spectrum substantially as shown in Figure 11 . 1 an HNMR spectrum substantially as shown in

[0011] In a second aspect, the present application provides a crystalline form of a salt of formula (B), which is a crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A), including camphorsulfonate Form I and camphorsulfonate Form II. .

[0012] In some embodiments, the crystalline form of a salt of formula (B) is substantially pure.

[0013] In some embodiments, the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) is substantially pure.

[0014] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has characteristic peaks at one or more of the following 2Θ angles: 17.24°, 19.74°, 20.78°, 24.16°, wherein the error in the 2Θ angles is ±0.2°.

[0015] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has characteristic peaks at one or more of the following 2Θ angles: 5.42°, 9.74°, 10.88°, 12.46°, 17.24°, 19.74°, 20.78°, 22.92°, 24.16°, 28.32°, 29.92°, 32.28°, wherein the error in the 2Θ angles is ±0.2°.

[0016] In some embodiments, the X-ray powder diffraction pattern of the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has an X-ray powder diffraction pattern substantially as shown in Figure 14 .

[0017] In some embodiments, the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has a differential scanning calorimetry profile substantially as shown in

[0018] In some embodiments, the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has a differential scanning calorimetry profile substantially as shown in

[0019] In some embodiments, the differential scanning calorimetry profile of the crystalline form of a salt of an AXL kinase inhibitor camphorsulfonate of formula (A) Form I has a differential scanning calorimetry profile substantially as shown in Figure 9 .

[0020] In some embodiments, the TGA pattern of the AXL kinase inhibitor camsylate Form I of Formula (A) has a TGA pattern substantially as shown in Figure 10

[0021] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor camsylate Form II of Formula (A) has at least one characteristic peak at one or more of the following 2Θ angles: 5.30°, 10.68°, 12.24°, 17.00°, 17.46°, 18.64°, wherein the error in the 2Θ angles is ±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor camsylate Form II of Formula (A) has at least one characteristic peak at one or more of the following 2Θ angles: 4.72°, 5.30°, 9.56°, 10.68°, 12.24°, 13.86°, 14.35°, 15.34°, 16.02°, 17.00°, 17.46°, 18.64°, 20.87°, 21.60°, 22.46°, 23.94°, 26.48°, 27.78°, 29.34°, 30.58°, 32.67°, 33.88°, 37.92°, 38.74°, 45.33°, wherein the error in the 2Θ angles is ±0.2°.

[0023] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor camsylate Form II of Formula (A) has a X-ray powder diffraction pattern substantially as shown in Figure 15

[0024] In some embodiments, the AXL kinase inhibitor camsylate Form II of Formula (A) has a differential scanning calorimetry (DSC) profile of about 217.84 °C ± 2 °C when heated at a rate of 10 °C / min.

[0025] In some embodiments, the AXL kinase inhibitor camsylate Form II of Formula (A) has a differential scanning calorimetry (DSC) profile of about 217.84 °C ± 2 °C, 251.14 °C ± 2 °C when heated at a rate of 10 °C / min.

[0026] In some embodiments, the differential scanning calorimetry profile of the AXL kinase inhibitor camsylate Form II of Formula (A) has a differential scanning calorimetry profile substantially as shown in Figure 12

[0027] ​​​In some embodiments, the TGA pattern of the AXL kinase inhibitor camsylate Form II of Formula (A) has a TGA pattern substantially as shown in Figure 13

[0028] In a third aspect, the present application provides a method for preparing an AXL kinase inhibitor acid addition salt of Formula (B) and its crystal form, which can be prepared by solution method, grinding method, hot melt extrusion method, freeze-drying method, supercritical fluid method, ultrasonic-assisted crystallization method, spray drying technology and the like. The present application embodiment is simple in principle without affecting the efficacy of the drug crystal form, and the method is as follows: The AXL kinase inhibitor of Formula (A) is dissolved in a solvent, and after adding an anti-ion acid solution or an anti-solvent and stirring, the solid is collected to obtain the product.

[0029] In some embodiments, the molar ratio of the AXL kinase inhibitor of Formula (A) to the anti-ion acid in the method is 1:(0.55-1.1), preferably 1:0.55, 1:1, 1:1.05, 1:1.1.

[0030] In some embodiments, the anti-ion acid solution is prepared by adding an anti-ion acid to a solvent to obtain a clear anti-ion acid solution.

[0031] In some embodiments, the anti-ion acid is camsylate.

[0032] In some embodiments, the solvent in the method is selected from a solvent in which the AXL kinase inhibitor of Formula (A) has a certain solubility and the stability of the AXL kinase inhibitor of Formula (A) is not affected. Preferably, the solvent is selected from one or more of water, alcohols, nitriles, ketones, esters, alkanes, aromatic hydrocarbons and halogenated alkanes; more preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, methyl tert-butyl ether, n-hexane, n-heptane, dichloromethane, 1,4 dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone. Preferably, the solvent is selected from at least one of dichloromethane and methanol mixed solvents (further preferably the volume ratio of the two is 3:1), tetrahydrofuran, n-hexane, acetonitrile, ethanol.

[0033] ​In some embodiments, the anti-solvent is selected from a solvent in which the AXL kinase inhibitor of formula (A) has little or no solubility and in which the stability of the AXL kinase inhibitor of formula (A) is not affected. Preferably, the anti-solvent is selected from one or more of water, alcohols, nitriles, ketones, esters, alkanes, aromatic hydrocarbons, and halogenated alkanes; more preferably, the anti-solvent is selected from one or more of water, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetonitrile, acetone, methyl tert-butyl ether, n-hexane, n-heptane, dichloromethane, 1,4 dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone. Preferably, the solvent is selected from at least one of water or methanol.

[0034] In some embodiments, the stirring time is 1-20 h; preferably, the temperature of the stirring is 10-40 °C, preferably 10 °C, 15 °C, 20 °C, 30 °C, 40 °C. Preferably, the stirring time is 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, or 20 h.

[0035] In some embodiments, the solid is collected by: ① centrifugation (12000 rpm, 10 min); ② the solution is left to evaporate the solvent at 10-40 °C for 1-30 days; preferably, the temperature of the heating is 10 °C, 20 °C, 30 °C, 40 °C; the standing time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days; ③ adding an anti-solvent to the solution, such as MTBE (methyl tert-butyl ether); or a combination of the above methods.

[0036] In a fourth aspect, the present application relates to a pharmaceutical composition comprising the salt of formula (B), the crystal form thereof, or the combination thereof, and optionally a pharmaceutically acceptable excipient.

[0037] In a fifth aspect, the present application relates to the use of the salt of formula (B), the crystal form thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for preventing, treating, curing, or alleviating a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, a transplant rejection, a cancer, a viral infectious disease, heart failure, a cardiovascular disease, myocardial fibrosis, pulmonary fibrosis, cardiac histopathological structural remodeling, or other diseases in a patient. The use comprises administering to the patient an effective therapeutic dose of the salt of formula (B), the crystal form thereof, or the pharmaceutical composition thereof.

[0038] Beneficial effects: Compared with the prior art, the present application carries out salt type screening research, selects camphorsulfonic acid as a counter ion, generates camphorsulfonic acid salt, and obtains camphorsulfonic acid salt with single melting point and good solid crystallinity.

[0039] Compared with the prior art, the present application carries out salt type screening research, selects camphorsulfonic acid as a counter ion, generates camphorsulfonic acid salt, and obtains camphorsulfonic acid salt with single melting point and good solid crystallinity.

[0040] The camphorsulfonic acid salt crystal form provided by the present application has good physical and chemical stability, a simple preparation method, low cost, is convenient for large-scale production, is conducive to subsequent product development, and has important value for the development of the preparation of the AXL kinase inhibitor shown in formula (A) in the future. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 The XRPD pattern of the AXL kinase inhibitor shown in formula (A) in Comparative Example 1.

[0042] Figure 2 The PLM pattern of the AXL kinase inhibitor shown in formula (A) in Comparative Example 1.

[0043] Figure 3 The DSC pattern of the AXL kinase inhibitor shown in formula (A) in Comparative Example 1.

[0044] Figure 4 The TGA pattern of the AXL kinase inhibitor shown in formula (A) in Comparative Example 1.

[0045] Figure 5 The XRPD pattern of the AXL kinase inhibitor shown in formula (A) in Comparative Example 1.

[0046] Figure 6 The X-ray powder diffraction superimposition of the free base and the crystal form thereof in Example 1.

[0047] Figure 7 The differential scanning calorimetric analysis superimposition of the free base and the crystal form thereof in Example 1.

[0048] Figure 8 The XRPD superimposition of the camphorsulfonic acid salt in Example 3.

[0049] Figure 9 The DSC pattern of the camphorsulfonic acid salt crystal form I prepared in the tetrahydrofuran system in Example 5.

[0050] Figure 10 The TGA spectrum of the camphorsulfonic acid salt crystal form I prepared in the tetrahydrofuran system in Example 5.

[0051] Figure 11 DSC pattern for camphorsulfonate Form I prepared in the tetrahydrofuran system in Example 5. 1 HNMR pattern.

[0052] Figure 12 DSC pattern for camphorsulfonate Form II prepared in the dichloromethane-methanol system in Example 5.

[0053] Figure 13 TGA pattern for camphorsulfonate Form II prepared in the dichloromethane-methanol system in Example 5.

[0054] Figure 14 XRPD pattern for camphorsulfonate Form I in Example 5.

[0055] Figure 15 XRPD pattern for camphorsulfonate Form II in Example 5. DETAILED DESCRIPTION

[0056] Certain embodiments of the application are now described in detail by referring to certain embodiments which are illustrated in the accompanying drawings. The application is intended to cover all alternatives, modifications, and equivalents thereof which are included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials equivalent to those described herein can be used in the practice of the present application. Nothing herein is intended to be for limiting the application as defined by the claims. For the purposes of the present application, the following terms and phrases are defined below.

[0057] It should be further understood that any of the features could be provided in combination in a single embodiment, even though that feature combination is not explicitly described or illustrated. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any appropriate subcombination.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0059] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", "further", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples without contradiction.

[0060] In the following, all the numbers disclosed herein are approximate, whether or not the word "approximately" or "about" is used in connection with such numbers. The value of each number can vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20% or more. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8%, N + / - 10%, N + / - 15%, or N + / - 20% is also disclosed, where "+" or "-" means plus or minus.

[0061] The term "and / or" should be understood to mean either one of the items or a combination of any two or more of the items in the alternatives.

[0062] The term "optional", "optionally", or "optional" means that the event or circumstance subsequently described can occur, but does not necessarily occur.

[0063] The term "at least one of the following 2θ angles having a characteristic peak" means that the minimum number of "multiple" is at least 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0064] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in combination with embodiments. The specific embodiments described herein are only used to explain the present invention and do not constitute any limitation on the present invention. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present disclosure. Such structures and technologies are also described in many publications.

[0065] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0066] In the present invention, "room temperature" or "normal temperature" means 10-40°C, preferably 20-35°C, and further preferably 25°C.

[0067] The term "crystal form" refers to one distinct ordered arrangement and / or conformation of molecules in the crystal lattice of a compound.

[0068] The term "substantially pure" refers to a crystal form that is substantially free of one or more other crystal forms, with a crystal form purity of at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or contains other crystal forms in less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0069] The term "substantially free of" one or more other crystal forms refers to the other crystal forms in less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight.

[0070] The term "X-ray powder diffraction pattern substantially as shown" refers to at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern appearing in the pattern.

[0071] The term "relative intensity" refers to the ratio of the intensity of a peak to the intensity of the first most intense peak in the X-ray powder diffraction pattern.

[0072] The term "anti-solvent" refers to a solvent that promotes the solution to reach an over-saturated state or crystallization. In some embodiments, the compound of formula (B) has a solubility in the anti-solvent of less than 0.001 g / L, or less than 0.01 g / L, or less than 0.1 g / L, or less than 0.2 g / L, or less than 0.3 g / L, or less than 0.4 g / L, or less than 0.5 g / L, or less than 0.6 g / L, or less than 0.8 g / L, or less than 1 g / L, or less than 2 g / L, or less than 3 g / L, or less than 4 g / L, or less than 5 g / L, or less than 6 g / L, or less than 7 g / L, or less than 8 g / L, or less than 9 g / L, or less than 10 g / L.

[0073] The term "peak" when referring to a pattern and / or data in a pattern refers to a feature that would not be attributed to background noise by one of skill in the art.

[0074] In certain embodiments, the pharmaceutical compositions comprising the crystalline form of the present application can be further prepared into various solid preparations of oral drugs, including capsules, tablets, pills, powders, and granules. These preparations can also include excipients or carriers, including sodium citrate, calcium phosphate, fillers, binders, humectants, disintegrants, retardants, absorption promoters, wetting agents, absorbents, or lubricants or mixtures thereof. Among them, the fillers include starch, lactose, sucrose, glucose, mannitol, silicic acid or a combination thereof; the binders include carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic or a combination thereof; the humectants include glycerol; the disintegrants include agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, low-substituted hydroxypropyl cellulose or a combination thereof; the retardant solution such as paraffin; the absorption promoters such as quaternary amine compounds; the wetting agents such as cetyl alcohol and glycerol monostearate; the absorbents such as white clay and bentonite; the lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or a combination thereof.

[0075] The technical solutions of the present application are illustrated below, and the scope of protection requested by the present application includes but is not limited to the following embodiments.

[0076] Table 1 Explanation of related abbreviations

[0077] Experimental reagents: Methanol (MeOH), ethanol (EtOH), isopropanol (IPA), acetone, 2-butanone (MEK), ethyl acetate (EA), dichloromethane (DCM), hydrochloric acid, sulfuric acid, purchased from Runjie Chemical; acetonitrile (ACN) purchased from Anhui Shililian; methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), phosphoric acid purchased from Aldrich; 2-methyltetrahydrofuran, n-heptane purchased from General Reagent; 1,4-dioxane purchased from HiPure Chem; DCM:MeOH (3:1) is a self-made reagent; camphor sulfonic acid purchased from Aldrich.

[0078] Instruments: Analytical balance, manufacturer: Sartorius, model: CP225D; X-ray powder diffractometer (XRPD), manufacturer: Shimadzu, model: XRD-6000; differential scanning calorimeter (DSC), manufacturer: Mettler, model: DSC3; thermal gravimetric analyzer (TGA), manufacturer: Platinum, model: Pyris 1 TGA; polarized light microscope (PLM), manufacturer: Shanghai Changfang Optical Instrument Co., Ltd., model: XPV-203E; constant temperature magnetic stirrer, manufacturer: Shanghai Sile Instrument Co., Ltd., model: B13-3; ultrasonic cleaner, manufacturer: Shanghai Keduo, model: SK8300BT; high-speed centrifuge, manufacturer: KeCheng instrument, model: H4-20K; high performance liquid chromatography, manufacturer: Agilent, model: Agilent 1260.

[0079] Related detection conditions: X-ray powder diffraction (XRPD) The equipment is Shimadzu XRD-6000, and the sample is scanned according to the following parameters: the ray source is Cu~Kα target (1.54056Å), the minimum operating voltage and current of the light tube are 40kV and 30mA respectively, and the 2-Theta value of the sample scanning range is from 2 o to 50 o . The scanning speed is 5 deg / min.

[0080] Thermal gravimetric analysis (TGA) About 5 mg of sample was weighed in a crucible, and nitrogen protection was carried out from 30℃ to 300℃, and the temperature rising rate was 20℃ / min, and 300℃ was kept for 1min.

[0081] Differential scanning calorimeter (DSC) About 1~5 mg of powder sample was weighed and placed in a closed aluminum crucible, and a pinhole was punched on the crucible cover. Nitrogen protection, differential heat scanning from 30℃ to 300℃ or 350℃, 300℃ or 350℃ kept for 1min. The temperature rising rate was 20℃ / min.

[0082] Polarized light microscope (PLM): The sample was dispersed in the medium (silicone oil), and 10× ocular lens, 10× objective lens was used to observe the sample, and camera computer system was used to record the image.

[0083] Comparative example 1 The free base solid prepared in example 25 of patent CN113912628B was physically characterized by XRPD, TGA, DSC and PLM, and was recorded as free base crystal form V.

[0084] The XRPD results (Figure 1) show that the diffraction peak of the AXL kinase inhibitor represented by formula (A) is not obvious, and it is speculated to be a mixture of crystalline and amorphous forms, which is consistent with the phenomenon shown by PLM (Figure 2). Figure 3 ) showed three obvious endothermic peaks (Endo.67.61℃, Endo.160.05℃, Onset 257.55℃) and one exothermic peak (Exo.187.30). TGA results (Figure 4) showed a 0.1686% weight loss from 21.55℃ to 120℃ and a 0.3734% weight loss from 120℃ to 220℃. Figure 5 Middle curve [ENB201194-041-P1.RAW]) heated to 120℃ ( Figure 5 The XRPD of the sample heated to 220°C showed that the free base crystals were transformed (Figure 5). Figure 5 Middle curve [ENB201194-041-P1_Heating-220C.RAW]).

[0085] Example 1 Crystalline form of free base Dissolve 50 mg of the AXL kinase inhibitor represented by formula (A) (free base crystal form V) in 2.5 mL of solvent 1, then add solvent 2 dropwise to the solution. Stir and slurry at room temperature to obtain the free base crystal form. The details are shown in Table 2 below: Table 2 Corresponding curves

[0086] from Figure 6 and Figure 7 It can be seen that four different crystal forms can be obtained by beating the free base with different solvents. Figure 7 The middle DSC curve FC2084_ENB201194-041-P1 represents the DSC curve of the free base solid before slurrying with solvent.

[0087] Example 2 Solubility test of free base To select an appropriate method for salt screening, the free base was subjected to an approximate solubility test. The test method involved weighing approximately 4 mg of the AXL kinase inhibitor of Formula (A) (free base Form V), gradually adding appropriate volumes of solvent, shaking, and observing for dissolution. The volume that completely dissolved and the volume of solvent that did not completely dissolve were recorded. For poorly soluble solvents, the total amount added did not exceed 4 mL. The approximate solubility was calculated. The results are shown in Table 3 below: Table 3 Solubility of free base in different solvents

[0088] According to the results of Table 3, the AXL kinase inhibitor of formula (A) has a large solubility in dichloromethane, tetrahydrofuran, 1,4-dioxane and dichloromethane:methanol (3:1, V:V).

[0089] Example 3 Salt screening in tetrahydrofuran system According to the solubility results of Example 2, the tetrahydrofuran system was selected for salt type screening. About 50 mg of AXL kinase inhibitor of formula (A) (free base crystal form V) was weighed into each vial, 2.5 mL of tetrahydrofuran was added, and the compound was dissolved by stirring at room temperature. Then the counterion acid was slowly added to the reaction solution at a molar ratio of 1:1.05 (wherein the molar ratio of the AXL kinase inhibitor of formula (A) is 1, that is, API), and finally, the samples were all magnetically stirred overnight (about 20 h) at room temperature. After stirring overnight, if the sample in the vial is a suspension and the amount of solid is large, centrifugation (12000 rpm, centrifugation for 10 min) is used to collect the solid; if the sample in the vial is a clear solution or the amount of solid is small, nitrogen blowing or natural evaporation is used to concentrate the solvent and collect the solid. The collected solid is vacuum dried at 40°C under reduced pressure for more than 4 h, and the dried solid is subjected to X-ray powder diffraction detection. The results are shown in Table 3. If the XRPD pattern of the dried solid is inconsistent with that of the starting free base, the dried solid is further characterized, including DSC, TGA, etc.

[0090] Table 4 Summary of salt type screening of free base in tetrahydrofuran system

[0091] In combination Figure 8 From Table 4, it can be seen that in the tetrahydrofuran system, the camphorsulfonic acid salt basically has a good crystal form.

[0092] Example 4 Salt screening in dichloromethane-methanol mixed solution system According to the solubility results of Example 2, the dichloromethane-methanol mixed solution system was selected for salt type screening.

[0093] About 50 mg of AXL kinase inhibitor of formula (A) (free base crystal form V) was weighed into each vial, 2 mL of dichloromethane-methanol mixed solution (3:1, V:V) was added, and the compound was dissolved into a solution state by stirring at room temperature. Then the counterion was slowly added to the reaction solution at a molar ratio of 1:1.05 or 1:0.55 (wherein the molar ratio of the AXL kinase inhibitor of formula (A) is 1, that is, API), and finally, the samples were all magnetically stirred overnight (about 20 h) at room temperature.

[0094] After stirring overnight, if the sample in the vial is a suspension and the amount of solid is large, centrifugation (12000 rpm, 10 min) is used to collect the solid; if the sample in the vial is a clear solution or the amount of solid is small, nitrogen blowing or natural evaporation is used to concentrate the solvent and collect the solid. The collected solid is dried under reduced pressure at 40°C for more than 4 hours, and the dried solid is subjected to X-ray powder diffraction detection. The results are shown in Table 4. Figure 8 and Table 4. If the XRPD pattern of the dried solid is inconsistent with that of the starting free base, the dried solid is further characterized, including DSC, TGA, etc.

[0095] Table 5 Summary of salt screening of free base in dichloromethane-methanol system

[0096] In combination Figure 8 and Table 5, it can be seen that in the dichloromethane-methanol system, the free base forms a camphorsulfonic acid salt, and basically has a good crystal form.

[0097] Example 5 Crystal form screening of salt The salts prepared in Examples 3 and 4, the free base crystal form prepared in Example 1, are subjected to XPRD pattern comparison, further DSC, TGA and 1 HNMR characterization.

[0098] Table 6 The crystal forms corresponding to the curves in the figures are as follows:

[0099] As shown in Figure 8 , the crystal forms of the camphorsulfonic acid salt prepared in THF system and dichloromethane-methanol system are different, the camphorsulfonic acid salt crystal prepared in tetrahydrofuran system is camphorsulfonic acid salt crystal form I, and the camphorsulfonic acid salt crystal prepared in dichloromethane-methanol system is camphorsulfonic acid salt crystal form II.

[0100] As shown in Figure 9 , the differential scanning calorimetric analysis spectrum of the obtained camphorsulfonic acid salt crystal form I has characteristic absorption peaks at about 154.15°C and 264.57°C.

[0101] As shown in Figure 10 , the thermal gravimetric analysis TGA spectrum of the obtained camphorsulfonic acid salt crystal form I has only 1.4986% weight loss before 120°C, indicating that the crystal form of the camphorsulfonic acid salt is a non-solvate and does not contain organic solvents.

[0102] As shown in Figure 11 , the infrared spectrum of the obtained camphorsulfonic acid salt crystal form I has characteristic absorption peaks at 1653.8 cm-1 and 1510.2 cm-1. 1HNMR results, the actual molar ratio of free base and camphorsulfonic acid is 1.0: 1.0.

[0103] As shown in Figure 12 The differential scanning calorimetry spectrum of the obtained camphorsulfonate crystal form II has characteristic absorption peaks at about 217.84℃, 251.14℃.

[0104] As shown in Figure 13 The thermogravimetric analysis TGA spectrum of the obtained camphorsulfonate crystal form II only has a weight loss of 0.0933% before 150℃, indicating that the crystal form of camphorsulfonate is a non-solvent compound and does not contain organic solvents.

[0105] The differential scanning calorimetry spectrum of the crystal form in the present application has multiple characteristic peaks, which may be caused by residual solvents and correspond to the weight loss of TGA. In the present application, the weight loss in the thermogravimetric analysis TGA spectrum is because there may be partial solvent residues or the salt itself is hygroscopic. Further verified by nuclear magnetic resonance, there is no crystalline water or crystalline solvent.

[0106] Effect implementation example 1 solubility test Preparation of buffer solution: Water: laboratory Milli-Q purified water.

[0107] SGF (artificial gastric juice): add 2.0 grams of sodium chloride and 7 milliliters of concentrated hydrochloric acid to 1000 milliliters of purified water, dissolve completely and mix evenly to obtain (pH 1.2).

[0108] FaSSIF (simulated fasted state intestinal fluid): (1) buffer solution: dissolve 0.42 g of sodium hydroxide (NaOH), 3.95 g of sodium dihydrogen phosphate (NaH2PO4·H2O) and 6.19 g of sodium chloride (NaCl) in about 0.9 L of purified water. Adjust the pH to 6.5 with sodium hydroxide (1N) or hydrochloric acid (1N). Constant volume to 1 liter at room temperature (2) add 2.24 g of FaSSIF / FeSSIF / FaSSGF powder to about 0.5 L of buffer solution. Stir until the powder is completely dissolved. Constant volume to the mark (1 liter) with buffer solution at room temperature.

[0109] FeSSIF (simulated fed state intestinal fluid): (1) buffer solution: dissolve 4.04 g of sodium hydroxide (NaOH), 8.65 g of glacial acetic acid and 11.87 g of sodium chloride (NaCl) in about 0.9 L of purified water. Adjust the pH to 5.0 with sodium hydroxide (1N) or hydrochloric acid (1N). Constant volume to 1 liter at room temperature (2) add 11.20 g of FaSSIF / FeSSIF / FaSSGF powder to about 0.5 L of buffer solution. Stir until the powder is completely dissolved. Constant volume to the mark (1 liter) with buffer solution at room temperature.

[0110] FaSSIF / FeSSIF / FaSSGF powders were provided by Bio-Relevant company, see (https: / / biorelevant.com) for details.

[0111] Test method: 15 mg of AXL kinase inhibitor of formula (A) or its camsylate salt was weighed in a 4 mL vial, 3 ml of the solvent to be tested was added, the sample was uniformly dispersed, and it was placed on a magnetic stirrer at 37 ℃ for 24 hours. Samples were taken at 1 hour and 24 hours, respectively, and centrifuged at 12000 rpm for 10 min, and filtered with a 0.45 µm water phase needle filter. The concentration was determined by HPLC.

[0112] Linearity: About 10 mg of AXL kinase inhibitor of formula (A) was weighed in a 200 ml volumetric flask, accurately weighed, and dissolved and diluted to the mark with tetrahydrofuran:methanol (1:1, v:v). Shake well to obtain the stock solution. Take an appropriate amount of the stock solution, and dilute to 25 μg / ml, 10 μg / ml, 5 μg / ml and 1 μg / ml with tetrahydrofuran:methanol (1:1, v:v), respectively, and analyze by sampling. According to the peak area and the corresponding concentration value, a standard curve is drawn.

[0113] Chromatographic conditions for solubility detection: Column: Agilent SB-C18 C18, 4.6*50 mm, 1.8 μm; mobile phase: A: 0.05% TFA in water B: 0.05% TFA in ACN; injection volume: 1 μL; flow rate: 0.8 ml / min; run time: 10 min; detection wavelength: 214 nm; column temperature: 45℃; diluent: tetrahydrofuran / methanol (1 / 1) (V / V); gradient: 0~6min: B phase is 0; 6-7min: B phase 60%; 7~7.1, B phase 100%,; 7.1-10min, B phase 0; The results are shown in Table 7 below: Table 7 Solubility determination results of related salt types in different media (1h & 24h, 37℃)

[0114] Note: The results measured above are calculated according to the concentration of free base.

[0115] Compared with the physicochemical properties and solubility of free base and camsylate salt, the camsylate salt can improve the solubility of the compound in artificial gastric juice.

[0116] Effect implementation example 2: Salt type chemical stability test Test method: 5 mg of AXL kinase inhibitor of formula (A) or its camphorsulfonic acid salt was weighed into a 20 mL glass bottle, and placed in a 40℃ / 75% stability chamber with open bottle. The open sample was removed from the bottle cap and covered with an aluminum foil with a pinhole to avoid cross contamination. At 2 weeks time point, the sample was diluted with 5 mL diluent (tetrahydrofuran / methanol (1 / 1) (V / V)) to make it completely dissolved, and then analyzed by HPLC according to the chromatographic conditions. The results are summarized in Table 8.

[0117] Chromatographic conditions for stability test: Column: Agilent Eclipse Plus C18, 4.6*250 mm, 5 μm; mobile phase: A: 0.05% TFA in water B: 0.05% TFA in ACN; injection volume: 1 μL; flow rate: 0.8 ml / min; run time: 28 min; detection wavelength: 214 nm; column temperature: 45℃; diluent: tetrahydrofuran / methanol (1 / 1) (V / V); gradient: 0~15 min: B phase 0; 15-20 min: B phase 60%; 20~20.11, B phase 100%,; 20.1-28 min, B phase 0; Table 8 Results of chemical stability test of AXL kinase inhibitor of formula (A) salt form

[0118] Note: The reporting limit is 0.02%.

[0119] Compared with the short-term solid state stability of free base and camphorsulfonic acid salt, the chemical stability of camphorsulfonic acid salt under accelerated 2 weeks condition is good.

[0120] The method of the present application has been described by preferred embodiments, and the related personnel can obviously make changes or appropriate changes and combinations to the method and application described herein within the content, spirit and scope of the present application, to realize and apply the present technical. The skilled in the art can refer to the content herein to realize the appropriate improvement of process parameters. It is particularly pointed out that all similar substitutions and changes are obvious to the skilled in the art, and they are considered to be included in the present application.

Claims

1. A salt represented by formula (B), characterized in that: Camphorsulfonate for AXL kinase inhibition: ； Alternatively, the molar ratio of the AXL kinase inhibitor to camphorsulfonic acid is 1.0:1.

0.

2. A crystalline form of a salt represented by formula (B), characterized in that: It is a crystalline form of the AXL kinase inhibitor camphorsulfonate, including camphorsulfonate crystalline form I and camphorsulfonate crystalline form II; or, the crystalline form is substantially pure, Alternatively, the X-ray powder diffraction pattern of the camphorsulfonate salt form I has characteristic peaks at at least one or more of the following 2θ angles: 17.24°, 19.74°, 20.78°, and 24.16°, wherein the error of the 2θ angle is ±0.2°; Alternatively, the X-ray powder diffraction pattern of the camphorsulfonate salt form II has characteristic peaks at at least one or more of the following 2θ angles: 5.30°, 10.68°, 12.24°, 17.00°, 17.46°, and 18.64°, wherein the error of the 2θ angle is ±0.2°.

3. The crystalline form according to claim 2, characterized in that The X-ray powder diffraction pattern of the camphorsulfonate salt form I has characteristic peaks at at least one or more of the following 2θ angles: 5.42°, 9.74°, 10.88°, 12.46°, 17.24°, 19.74°, 20.78°, 22.92°, 24.16°, 28.32°, 29.92°, and 32.28°, wherein the error of the 2θ angle is ±0.2°; Alternatively, the camphorsulfonate salt form I is determined by differential scanning calorimetry, and its differential scanning calorimetry analysis spectrum has at least one characteristic absorption peak at 154.15±2°C and 264.57±2°C.

4. The crystalline form according to claim 2, characterized in that The X-ray powder diffraction pattern of the camphorsulfonate salt form I has an X-ray powder diffraction pattern substantially as shown in FIG14 ; Alternatively, the differential scanning calorimetry analysis spectrum of the camphorsulfonate salt crystal form I has a differential scanning calorimetry analysis spectrum substantially as shown in FIG9 .

5. The crystalline form according to claim 2, characterized in that The X-ray powder diffraction pattern of the AXL kinase inhibitor camphorsulfonate salt crystal form II has characteristic peaks at at least one or more of the following 2θ angles: 4.72°, 5.30°, 9.56°, 10.68°, 12.24°, 13.86°, 14.35°, 15.34°, 16.02°, 17.00°, 17.46°, 18.64°, 20.87°, 21.60°, 22.46°, 23. .94°, 26.48°, 27.78°, 29.34°, 30.58°, 32.67°, 33.88°, 37.92°, 38.74°, and 45.33°, wherein the error of the 2θ angle is ±0.2°; or, the camphorsulfonate salt form II is determined by differential scanning calorimetry, and its differential scanning calorimetry analysis spectrum has at least one characteristic absorption peak at 217.84°C±2°C and 251.14°C±2°C.

6. The crystalline form according to claim 2, characterized in that The X-ray powder diffraction pattern of the camphorsulfonate salt form II has an X-ray powder diffraction pattern substantially as shown in FIG15 .

7. The crystalline form according to claim 2, characterized in that The differential scanning calorimetry analysis spectrum of the camphorsulfonate salt crystal form II has a differential scanning calorimetry analysis spectrum substantially as shown in FIG12 .

8. A method for preparing the crystalline form of the salt represented by formula (B) according to claim 1 or the salt represented by formula (B) according to any one of claims 2 to 7, characterized in that: Prepared by at least one method selected from the group consisting of solution method, grinding method, hot melt extrusion method, freeze drying method, supercritical fluid method, ultrasonic assisted crystallization method, and spray drying technology; Preferably, the method is as follows: dissolving the AXL kinase inhibitor represented by formula (A) in a solvent, adding a counterion acid solution or an antisolvent, stirring the reaction, and collecting the solid to obtain the product; wherein the AXL kinase inhibitor represented by formula (A) is ； Preferably, the counterion acid solution is prepared by adding the counterion acid to a solvent to obtain a clear counterion acid solution; Preferably, the counter ion acid is camphorsulfonic acid.

9. A pharmaceutical composition, characterized in that The invention comprises the salt represented by formula (B) according to claim 1 or the crystalline form of the salt represented by formula (B) according to any one of claims 2 to 7, and optional pharmaceutically acceptable excipients.

10. Use of the salt of formula (B) according to claim 1, or the crystalline form of the salt of formula (B) according to any one of claims 2 to 7, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing, treating, curing, or allergic reactions in patients with proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer, viral infectious diseases, heart failure, cardiovascular diseases, myocardial fibrosis, pulmonary fibrosis, pathological structural remodeling of cardiac tissue, or other diseases.

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