Salt, crystal form and composition of AXL kinase inhibitor as well as preparation method and application of salt, crystal form and composition

Abstract

The invention relates to the technical field of medicines, and discloses a salt, a crystal form and a composition of an AXL kinase inhibitor as well as a preparation method and application of the salt, the crystal form and the composition of the AXL kinase inhibitor, and the salt is hydrochloride, sulfate, phosphate, mesylate, benzene sulfonate, p-toluenesulfonate, camphorsulfonate, maleate and oxalate. The crystalline form of the AXL kinase inhibitor salt is substantially pure. The basically pure AXL kinase inhibitor 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] This invention relates to the field of pharmaceutical technology, and more specifically, to a salt, crystal form, composition, preparation method, and application of an AXL kinase inhibitor. Background Technology

[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 bifibronectin repeat sequence in its extracellular domain, as well as a kinase domain of associated tyrosine residues in its cytoplasmic domain. TAM receptor tyrosine kinase-mediated cell signaling participates in processes such as cell growth, migration, aggregation, and apoptosis in various normal cells. The TAM family has two known ligands: GAS6 (growth arrest-specific 6) and protein S. Binding of Gas6 to AXL leads to receptor dimerization and AXL autophosphorylation. AXL is present in various organs and cells, including epithelial cell lines, mesenchymal and hematopoietic cells, and untransformed cells. AXL kinase inhibitors can block the interaction between the AXL ligand and phosphatidylserine (PtdSer) in the membrane. Therefore, new or improved agents that inhibit protein kinases such as AXL kinase can be used as drugs for the treatment and / or prevention of viral infectious diseases, such as drugs against Zika virus, coronavirus, novel coronavirus and hepatitis B virus.

[0003] Existing AXL kinase inhibitors suffer from drug resistance issues in the treatment of cancer and other diseases, and their pharmacokinetic properties and stability are insufficient, making it difficult to effectively inhibit AXL kinase activity. CN113912628B developed a new class of triazine compounds with excellent inhibitory activity and kinase selectivity, capable of effectively regulating AXL kinase activity, exhibiting good pharmacokinetic properties and liver microsomal stability, and showing virtually no inhibition or induction of CPY450 enzymes. This patent discloses a series of AXL kinase inhibitors, among which Example 25 discloses 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-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide, with the following structural formula: Without sufficient characterization of the crystal form, the crystal state of the compound cannot be known; nor is the information on the salts of the compound disclosed.

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

[0005] Different salts and solid forms of a drug active ingredient may have different properties. The changes in properties of different salts and solid forms can provide improved formulations, for example, being easy to synthesize or process, enhancing dissolution rate, or improving stability and shelf life. The property changes caused by different salts or solid forms can also improve the final dosage form, for example, if such changes can increase exposure, bioavailability, or extend the half-life. Different salts and solid forms of a drug active ingredient can also produce polymorphs or other crystal forms, thus providing more opportunities to evaluate the property changes of a solid active drug ingredient. Therefore, in pharmaceutical R & D, developing different salts and crystal forms of a drug is of great significance.

[0006] Therefore, there is an urgent need to develop a salt, crystal form, composition of an AXL kinase inhibitor, and its preparation method and application, which is of great significance. Summary of the Invention

[0007] In order to find a solid form with better drug properties, the present invention provides a salt, crystal form, composition of an AXL kinase inhibitor, and its preparation method and application, 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 formulation. Its preparation process is safe, has good repeatability, and strong operability, which is very beneficial to industrial production and subsequent product development.

[0008] In the first aspect, the present invention provides a salt shown in formula (B), which is a pharmaceutically acceptable acid addition salt of an AXL kinase inhibitor:

[0009]

[0010] Wherein, M is an inorganic acid or an organic acid; 0 < x ≤ 4, and x is a real number.

[0011] Wherein, x is selected from 0.5, 1, 2, 3, 4, etc.

[0012] In some embodiments, the AXL kinase inhibitor is 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-hexahydropyrazolo[1,5-a]pyridine-3-carboxamide (structure shown in Formula (A)).

[0013] In some embodiments, the salt represented by formula (B) is an inorganic acid salt or an organic acid salt.

[0014] In some embodiments, the inorganic acid salt is selected from at least one of hydrochloride, sulfate, bisulfate, nitrate, hydrobromide, hydroiodate, borate, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydrogen phosphate, dihydrogen phosphate, perchlorate, persulfate, hemisulfate, bisulfate, thiocyanate, phosphate, pyrophosphate, or metaphosphate.

[0015] In some embodiments, the organic acid salt is selected from citrate, methanesulfonate, oxalate, tartrate, L-tartrate, formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, ethanesulfonate, propanesulfonate, 4-nitrobenzene, benzenesulfonate, p-toluenesulfonate, malate, propynate, 2-butynate, 2-hydroxyethanesulfonate, vinyl acetate, fumarate, hydroxyethylsulfonate, maleate, lactate, lactobionate, salicylate, galactobionate, glucono-dimethylolpropionate, mandelate, 1 2-Ethylene disulfonate, 2-naphthalene sulfonate, trifluoroacetate, trifluoromethanesulfonate, adipate, octanoate, sebacic acid, butyne-1,4-diacidate, hexyne-1,6-diacidate, glycolate, alginate, ascorbate, isoascorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 2-(4-hydroxybenzoyl)benzoate, acetoacetate, chlorobenzoate, camphorate, itaconic acid, camphor sulfonate, L-camphor sulfonate, methylbenzoate, dinitrobenzoic acid Salts, aminosulfonates, lacturonates, galacturonates, cyclopentylpropionate, dodecyl sulfate, acrylates, cyclopentanepropionate, glyceryl phosphates, methoxybenzoates, digluconate, gluconate, heptate, hexanoate, trimethylacetate, glucuronate, laurate, phthalates, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pyrate, pectinate, phthalates, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2 -At least one of the following: naphthate, 3-phenylpropionate, isobutyrate, neopentanoate, picrate, stearate, 2,2-dichloroacetate, acylated amino acid salt, alginate, 4-acetaminobenzenesulfonate, caprylate, cholate, caprylate, nonanoate, cyclolatate, cysteine ​​hydrochloride, sorbate, glycine hydrochloride, naphthalene disulfonate, xylene sulfonate, dicysteine ​​hydrochloride, undecanoate, polyethylene sulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyethylene sulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or pentanoate.

[0016] In some embodiments, the inorganic acid is selected from at least one of hydrochloric acid, sulfuric acid, hydrogen sulfate, nitric acid, hydrobromic acid, hydroiodic acid, boric acid, carbonic acid, bicarbonate, sulfurous acid, hydrogen sulfite, pyrosulfuric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, perchloric acid, persulfate, hemisulfuric acid, disulfuric acid, thiocyanate, phosphoric acid, pyrophosphoric acid, or metaphosphoric acid.

[0017] In some embodiments, the organic acid is selected from citric acid, methanesulfonic acid, oxalic acid, tartaric acid, L-tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, malonic acid, succinic acid, pyruvic acid, ethanesulfonic acid, propanesulfonic acid, 4-nitrobenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, propynic acid, 2-butynic acid, 2-hydroxyethanesulfonic acid, vinylacetic acid, fumaric acid, hydroxyethylsulfonic acid, maleic acid, lactic acid, lactobionic acid, salicylic acid, galactobionic acid, glucoheponic acid, mandelic acid, 1,2 - Ethyl disulfonic acid, 2-naphthalenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, adipic acid, octanoic acid, sebacic acid, butyn-1,4-diic acid, hexyn-1,6-diic acid, glycolic acid, alginic acid, ascorbic acid, isoascorbic acid, aspartic acid, L-aspartic acid, glutamic acid, L-glutamic acid, 2-phenoxybenzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, acetoacetic acid, chlorobenzoic acid, camphoric acid, itaconic acid, camphor sulfonic acid, L-camphor sulfonic acid, methylbenzoic acid, dinitro Benzoic acid, sulfamic acid, lacturonic acid, galacturonic acid, cyclopentylpropionic acid, dodecyl sulfate, acrylic acid, cyclopentanepropionic acid, glycerophosphate, methoxybenzoic acid, digluconic acid, gluconic acid, heptanoic acid, hexanoic acid, trimethylacetic acid, glucuronic acid, lauric acid, phthalic acid, phenylacetic acid, lauryl sulfate, 2-acetoxybenzoic acid, nicotinic acid, cinnamic acid, oleic acid, palmitic acid, pyric acid, pectic acid, phthalic acid, glutaric acid, hydroxymaleic acid, hydroxybenzoic acid, phenylacetic acid, 3-hydroxy At least one of the following: -2-naphthoic acid, 3-phenylpropionic acid, isobutyric acid, neopentanoic acid, picric acid, stearic acid, 2,2-dichloroacetic acid, acylated amino acids, alginic acid, 4-acetaminophensulfonic acid, capric acid, cholic acid, caprylic acid, nonanoic acid, cycloladenic acid, cysteine, sorbic acid, glycine, naphthalene disulfonic acid, xylenesulfonic acid, dicysteine, undecanoic acid, polyvinylsulfonic acid, sulfosalicylic acid, phenylbutyric acid, 4-hydroxybutyric acid, polyvinyl sulfate, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, or pentanoic acid.

[0018] In some embodiments, the salt represented by formula (B) is the hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate, or oxalate of the AXL kinase inhibitor represented by formula (A).

[0019] The AXL kinase inhibitor shown in formula (A) is...

[0020] In a second aspect, the present invention provides a crystalline form of the AXL kinase inhibitor mesylate of formula (A): including mesylate crystalline form I and mesylate crystalline form II.

[0021] In this invention, the AXL kinase inhibitor shown in formula (A) is...

[0022] In some embodiments, the crystal form of the AXL kinase inhibitor mesylate shown in formula (A) is substantially pure.

[0023] In some embodiments, in the AXL kinase inhibitor mesylate of formula (A), the molar ratio of the AXL kinase inhibitor of formula (A) to mesylate is 1.0:1.0.

[0024] In some embodiments, the AXL kinase inhibitor mesylate of formula (A) 1 HNMR spectra have basically the following characteristics: Figure 27 shown 1 HNMR spectrum.

[0025] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.18°, 10.42°, 12.76°, 15.76°, and 21.00°, wherein the error of the 2θ angle is ±0.2°.

[0026] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.18°, 8.32°, 10.42°, 12.76°, 13.96°, 14.36°, 15.76°, 16.78°, 17.56°, 18.26°, 21.00°, and 25.88°, wherein the error of the 2θ angle is ±0.2°.

[0027] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form I shown in formula (A) has substantially the following characteristics: Figure 56 The X-ray powder diffraction pattern shown is shown.

[0028] In some embodiments, the AXL kinase inhibitor mesylate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 253.44℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0029] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor mesylate crystal form I shown in formula (A) has substantially the following characteristics: Figure 25 The differential scanning calorimetry (DSC) spectrum is shown.

[0030] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form II shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 10.32°, 12.42°, 17.42°, 20.54°, 21.06°, 23.34°, and 23.78°, wherein the error of the 2θ angle is ±0.2°.

[0031] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form II shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 10.32°, 12.42°, 13.76°, 15.70°, 16.28°, 17.42°, 18.32°, 19.18°, 20.54°, 21.06°, 22.19°, 2 2.52°, 22.87°, 23.34°, 23.78°, 24.52°, 25.14°, 26.12°, 26.46°, 26.92°, 27.98°, 30.28°, 31.66°, 33.38°, 34.32°, 37.58°, 38.50°, 42.68°, 44.43°, where the error of the 2θ angle is ±0.2°.

[0032] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor mesylate crystal form II shown in formula (A) has substantially the following characteristics: Figure 57 The X-ray powder diffraction pattern shown is shown.

[0033] In some embodiments, the AXL kinase inhibitor mesylate crystal form II shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 213.80℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0034] In some embodiments, the AXL kinase inhibitor mesylate crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetry spectrum has characteristic absorption peaks at approximately 213.80 °C ± 2 °C and 263.14 °C ± 2 °C.

[0035] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor mesylate crystal form II shown in formula (A) has substantially the following characteristics: Figure 28 The differential scanning calorimetry (DSC) spectrum is shown.

[0036] Thirdly, the present invention provides a crystalline form of the AXL kinase inhibitor p-toluenesulfonate as shown in formula (A): including p-toluenesulfonate crystalline form I.

[0037] In some embodiments, the crystal form of the AXL kinase inhibitor p-toluenesulfonate shown in Formula (A) is substantially pure.

[0038] In some embodiments, in the AXL kinase inhibitor p-toluenesulfonate shown in Formula (A), the molar ratio of the AXL kinase inhibitor shown in Formula (A) to p-toluenesulfonate is 1.0:1.0.

[0039] In some embodiments, the AXL kinase inhibitor of formula (A) is used to treat toluenesulfonate. 1 HNMR spectra have basically the following characteristics: Figure 37 shown 1 HNMR spectrum.

[0040] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor p-toluenesulfonate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.16°, 10.20°, 11.68°, 16.38°, 20.88°, 21.30°, wherein the error of the 2θ angle is ±0.2°.

[0041] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor p-toluenesulfonate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.16°, 10.20°, 11.68°, 15.16°, 16.38°, 20.01°, 20.88°, 21.30°, 23.40°, 24.76°, 25.92°, 28.22°, 28.94°, 30.13°, 30.96°, 33.20°, 36.76°, 38.56°, 38.90°, and 41.21°, wherein the error of the 2θ angle is ±0.2°.

[0042] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor of formula (A) for toluenesulfonate crystal form I has substantially the same characteristics as... Figure 58 The X-ray powder diffraction pattern shown is shown.

[0043] In some embodiments, the AXL kinase inhibitor p-toluenesulfonate crystal form I shown in formula (A) was determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum showed a characteristic absorption peak at approximately 277.44℃ ± 2℃ when the temperature was increased at a rate of 10℃ / min.

[0044] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor of formula (A) against tosylate crystal form I has essentially the same characteristics as... Figure 35 The differential scanning calorimetry (DSC) spectrum is shown.

[0045] Fourthly, the present invention provides a crystalline form of the AXL kinase inhibitor benzenesulfonate of formula (A): comprising benzenesulfonate crystalline form I.

[0046] In some embodiments, the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) is substantially pure.

[0047] In some embodiments, in the benzenesulfonate of the AXL kinase inhibitor shown in formula (A), the molar ratio of the AXL kinase inhibitor shown in formula (A) to benzenesulfonate is 1.0:1.0.

[0048] In some embodiments, the AXL kinase inhibitor benzyl sulfonate shown in formula (A) 1 HNMR spectra have basically the following characteristics: Figure 33 shown 1 HNMR spectrum.

[0049] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 10.30°, 12.18°, 17.12°, 20.80°, 22.34°, 24.56°, and 25.74°, wherein the error of the 2θ angle is ±0.2°.

[0050] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.11°, 10.30°, 12.18°, 14.86°, 15.22°, 15.72°, 17.12°, 18.70°, 19.18°, 20.18°, 20.80°, 22.34°, 22.86°, 24.56°, 25.74°, 26.16°, 29.91°, 30.20°, 31.74°, 34.37°, 38.46°, 40.80°, 42.89°, 43.09°, and 44.05°, wherein the error of the 2θ angle is ±0.2°.

[0051] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) has substantially the following characteristics: Figure 61 The X-ray powder diffraction pattern shown is shown.

[0052] In some embodiments, the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 252.26℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0053] In some embodiments, the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetry spectrum has characteristic absorption peaks at approximately 206.58 °C ± 2 °C and 252.26 °C ± 2 °C.

[0054] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor benzenesulfonate crystal form I shown in formula (A) has substantially the following characteristics: Figure 31 The differential scanning calorimetry (DSC) spectrum is shown.

[0055] Fifthly, the present invention provides a crystalline form of the AXL kinase inhibitor hydrochloride shown in formula (A): including hydrochloride crystalline form I and hydrochloride crystalline form II.

[0056] In some embodiments, the crystal form of the AXL kinase inhibitor hydrochloride shown in Formula (A) is substantially pure.

[0057] In some embodiments, the molar ratio of the AXL kinase inhibitor shown in Formula (A) to the hydrochloride is 1.0:1.0.

[0058] In some embodiments, the AXL kinase inhibitor hydrochloride of formula (A) 1 HNMR spectra have basically the following characteristics: Figure 13 shown 1 HNMR spectrum.

[0059] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.50°, 11.16°, 13.44°, 20.54°, 21.46°, and 23.34°, wherein the error of the 2θ angle is ±0.2°.

[0060] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 5.50°, 8.64°, 11.16°, 13.44°, 14.04°, 15.34°, 16.94°, 18.10°, 18.84°, 20.54°, 21.46°, 21.96°, 23.34°, 24.26°, 25.24°, 25.80°, 26.46°, 27.28°, 28.54°, 31.06°, 34.34°, 35.38°, and 40.22°, wherein the error of the 2θ angle is ±0.2°.

[0061] In some embodiments, the X-ray powder diffraction pattern of crystal form I of the AXL kinase inhibitor hydrochloride shown in formula (A) has substantially the following characteristics: Figure 42 The X-ray powder diffraction pattern shown is shown.

[0062] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 184.98℃±2℃ when the temperature is increased at a rate of 10℃ / min.

[0063] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 96.20 °C ± 2 °C and 184.98 °C ± 2 °C.

[0064] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 45.36 °C ± 2 °C, 96.20 °C ± 2 °C, and 184.98 °C ± 2 °C.

[0065] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) was determined by differential scanning calorimetry (DSC). When the temperature was increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum showed characteristic absorption peaks at approximately 45.36 °C ± 2 °C, 96.20 °C ± 2 °C, 137.80 °C ± 2 °C, and 184.98 °C ± 2 °C.

[0066] In some embodiments, the differential scanning calorimetry spectrum of AXL kinase inhibitor hydrochloride crystal form I shown in formula (A) has substantially the following characteristics: Figure 11 The differential scanning calorimetry (DSC) spectrum is shown.

[0067] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor hydrochloride crystal form II shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 6.06°, 11.16°, 16.90°, 17.40°, 21.32°, and 22.94°, wherein the error of the 2θ angle is ±0.2°.

[0068] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor hydrochloride crystal form II shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 6.06°, 10.52°, 11.16°, 12.06°, 15.24°, 15.38°, 16.90°, 17.40°, 19.42°, 19.68°, 20.38°, 21.32°, 22.20°, 22.94°, 26.00°, 26.48°, 27.60°, 28.48°, 29.90°, 31.09°, 33.29°, 34.18°, 35.46°, 36.66°, 40.78°, and 40.94°, wherein the error of the 2θ angle is ±0.2°.

[0069] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor hydrochloride crystal form II shown in formula (A) has substantially the following characteristics: Figure 43 The X-ray powder diffraction pattern shown is shown.

[0070] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 263.45℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0071] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 123.86 °C ± 2 °C and 263.45 °C ± 2 °C.

[0072] In some embodiments, the AXL kinase inhibitor hydrochloride crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 123.86 °C ± 2 °C, 203.26 °C ± 2 °C, and 263.45 °C ± 2 °C.

[0073] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor hydrochloride crystal form II shown in formula (A) has substantially the following characteristics: Figure 14 The differential scanning calorimetry (DSC) spectrum is shown.

[0074] In a sixth aspect, the present invention provides a crystalline form of the AXL kinase inhibitor sulfate of formula (A): comprising sulfate crystalline form I.

[0075] In some embodiments, the crystal form I of the AXL kinase inhibitor sulfate shown in formula (A) is substantially pure.

[0076] In some embodiments, in the AXL kinase inhibitor sulfate shown in Formula (A), the molar ratio of the AXL kinase inhibitor shown in Formula (A) to sulfuric acid is 1.0:1.0.

[0077] In some embodiments, the AXL kinase inhibitor sulfate shown in formula (A) 1 HNMR spectra have basically the following characteristics: Figure 19 shown 1 HNMR spectrum.

[0078] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor sulfate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 11.40°, 16.64°, 22.66°, 22.92°, wherein the error of the 2θ angle is ±0.2°.

[0079] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor sulfate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 11.40°, 14.31°, 16.23°, 16.64°, 20.71°, 22.66°, 22.92°, 26.10°, and 26.26°, wherein the error of the 2θ angle is ±0.2°.

[0080] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor sulfate crystal form I shown in formula (A) has substantially the following characteristics: Figure 39 The X-ray powder diffraction pattern shown is shown.

[0081] In some embodiments, the AXL kinase inhibitor sulfate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 294.46℃±2℃ when the temperature is increased at a rate of 10℃ / min.

[0082] In some embodiments, the AXL kinase inhibitor sulfate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 189.17 °C ± 2 °C and 294.46 °C ± 2 °C.

[0083] In some embodiments, the AXL kinase inhibitor sulfate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 45.22 °C ± 2 °C, 189.17 °C ± 2 °C, and 294.46 °C ± 2 °C.

[0084] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor sulfate crystal form I shown in formula (A) has substantially the following characteristics: Figure 17 The differential scanning calorimetry (DSC) spectrum is shown.

[0085] In a seventh aspect, the present invention provides a crystalline form of an AXL kinase inhibitor phosphate as shown in formula (A): comprising phosphate crystalline form I.

[0086] In some embodiments, the AXL kinase inhibitor phosphate crystal form I shown in formula (A) is substantially pure.

[0087] In some embodiments, in the AXL kinase inhibitor phosphate shown in Formula (A), the molar ratio of the AXL kinase inhibitor to phosphate is 1.0:1.0.

[0088] In some embodiments, the AXL kinase inhibitor phosphate of formula (A) 1 HNMR spectra have basically the following characteristics: Figure 23 shown 1 HNMR spectrum.

[0089] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor phosphate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 4.06°, 15.60°, 16.76°, and 20.96°, wherein the error of the 2θ angle is ±0.2°.

[0090] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor phosphate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 4.06°, 11.46°, 13.65°, 15.60°, 16.76°, 20.96°, and 23.68°, wherein the error of the 2θ angle is ±0.2°.

[0091] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor phosphate crystal form I shown in formula (A) has substantially the following characteristics: Figure 38 The X-ray powder diffraction pattern shown is shown.

[0092] In some embodiments, the AXL kinase inhibitor phosphate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 242.60℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0093] In some embodiments, the AXL kinase inhibitor phosphate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 167.10 °C ± 2 °C and 242.60 °C ± 2 °C.

[0094] In some embodiments, the AXL kinase inhibitor phosphate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 112.43 °C ± 2 °C, 167.10 °C ± 2 °C, and 242.60 °C ± 2 °C.

[0095] In some embodiments, the differential scanning calorimetry (DSC) spectrum of the AXL kinase inhibitor phosphate crystal form I shown in formula (A) has substantially the following characteristics: Figure 21 The differential scanning calorimetry (DSC) spectrum is shown.

[0096] Eighthly, the present invention provides a crystalline form of maleate of the AXL kinase inhibitor shown in formula (A): comprising maleate crystalline form I and maleate crystalline form II.

[0097] In some embodiments, the maleate crystal form I and the maleate crystal form II of the AXL kinase inhibitor shown in Formula (A) are substantially pure.

[0098] In some embodiments, in the maleate of the AXL kinase inhibitor shown in formula (A), the molar ratio of the AXL kinase inhibitor shown in formula (A) to the maleate is 1.0:1.0.

[0099] In some embodiments, the maleate of the AXL kinase inhibitor shown in formula (A) 1 HNMR spectra have basically the following characteristics: Figure 47 shown 1 HNMR spectrum.

[0100] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form I of the AXL kinase inhibitor shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 4.22°, 8.48°, 11.90°, 12.76°, 13.32°, and 15.74°, wherein the error of the 2θ angle is ±0.2°.

[0101] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form I of the AXL kinase inhibitor shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 4.22°, 8.48°, 11.90°, 12.76°, 13.32°, 15.74°, 17.14°, 20.44°, 21.56°, 22.94°, 23.71°, 24.50°, 26.68°, 28.24°, 34.86°, 37.12°, and 38.52°, wherein the error of the 2θ angle is ±0.2°.

[0102] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form I of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 40 The X-ray powder diffraction pattern shown is shown.

[0103] In some embodiments, the maleate crystal form I of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 169.91℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0104] In some embodiments, the maleate crystal form I of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 169.91 °C ± 2 °C and 193.11 °C ± 2 °C.

[0105] In some embodiments, the maleate crystal form I of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 109.84 °C ± 2 °C, 169.91 °C ± 2 °C, and 193.11 °C ± 2 °C.

[0106] In some embodiments, the differential scanning calorimetry spectrum of maleate crystal form I of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 45 The differential scanning calorimetry (DSC) spectrum is shown.

[0107] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor maleate crystal form II shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 8.88°, 11.08°, 13.28°, 14.60°, 14.94°, and 15.54°, wherein the error of the 2θ angle is ±0.2°.

[0108] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor maleate crystal form II shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 4.40°, 6.57°, 8.88°, 11.08°, 13.28°, 14.60°, 14.94°, 15.54°, 17.02°, 18.15°, 18.94°, 19.76°, 20.49°, 21.68°, 22.52°, 25.14°, and 37.14°, wherein the error of the 2θ angle is ±0.2°.

[0109] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor maleate crystal form II shown in formula (A) has substantially the following characteristics: Figure 41 The X-ray powder diffraction pattern shown is shown.

[0110] In some embodiments, the maleate crystal form II of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 203.01℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0111] In some embodiments, the maleate crystal form II of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 203.01 °C ± 2 °C and 213.06 °C ± 2 °C.

[0112] In some embodiments, the maleate crystal form II of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 203.01 °C ± 2 °C, 213.06 °C ± 2 °C, and 237.62 °C ± 2 °C.

[0113] In some embodiments, the differential scanning calorimetry spectrum of maleate crystal form II of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 48 The differential scanning calorimetry (DSC) spectrum is shown.

[0114] In a ninth aspect, the present invention provides a crystal form of the AXL kinase inhibitor oxalate of formula (A): comprising oxalate crystal form I and oxalate crystal form II.

[0115] In some embodiments, the AXL kinase inhibitors oxalate crystal form I and oxalate crystal form II shown in Formula (A) are substantially pure.

[0116] In some embodiments, in the oxalate of the AXL kinase inhibitor shown in formula (A), the molar ratio of the AXL kinase inhibitor shown in formula (A) to the oxalate is 1.0:1.0.

[0117] In some embodiments, the AXL kinase inhibitor oxalate shown in formula (A) 1 HNMR spectra have basically the following characteristics: Figure 53 shown 1 HNMR spectrum.

[0118] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 9.80°, 14.86°, 19.66°, 20.08°, 20.94°, 21.16°, 23.74°, and 25.70°, wherein the error of the 2θ angle is ±0.2°.

[0119] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form I shown in formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 9.80°, 10.98°, 11.70°, 13.31°, 13.64°, 14.86°, 17.16°, 17.70°, 19.34°, 19.66°, 20.08°, 20.94°. The angles are 21.16°, 21.82°, 22.38°, 22.67°, 23.74°, 24.40°, 25.21°, 25.70°, 26.96°, 27.76°, 28.70°, 29.94°, 31.33°, 32.48°, 36.10°, 36.44°, 37.54°, and 39.76°, with an error of ±0.2° for the 2θ angle.

[0120] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form I shown in formula (A) has substantially the following characteristics: Figure 59 The X-ray powder diffraction pattern shown is shown.

[0121] In some embodiments, the AXL kinase inhibitor oxalate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 263.27℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0122] In some embodiments, the AXL kinase inhibitor oxalate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetry spectrum has characteristic absorption peaks at approximately 230.84 ± 2 °C and 263.27 ± 2 °C.

[0123] In some embodiments, the AXL kinase inhibitor oxalate crystal form I shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetry spectrum has characteristic absorption peaks at approximately 214.15 °C ± 2 °C, 230.84 ± 2 °C, and 263.27 °C ± 2 °C.

[0124] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor oxalate crystal form I shown in formula (A) has substantially the following characteristics: Figure 51 The differential scanning calorimetry (DSC) spectrum is shown.

[0125] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 3.92°, 11.22°, 14.12°, 16.78°, and 21.74°, wherein the error of the 2θ angle is ±0.2°.

[0126] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 3.92°, 5.58°, 8.71°, 11.22°, 14.12°, 14.96°, 16.78°, 18.78°, 19.77°, 20.80°, 21.74°, 23.36°, 25.22°, 25.62°, 28.78°, and 30.44°, wherein the error of the 2θ angle is ±0.2°.

[0127] In some embodiments, the X-ray powder diffraction pattern of the AXL kinase inhibitor oxalate crystal form II shown in formula (A) has substantially the following characteristics: Figure 60 The X-ray powder diffraction pattern shown is shown.

[0128] In some embodiments, the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC), and its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 262.79℃ ± 2℃ when the temperature is increased at a rate of 10℃ / min.

[0129] In some embodiments, the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetry spectrum has characteristic absorption peaks at approximately 42.28 °C ± 2 °C and 262.79 °C ± 2 °C.

[0130] In some embodiments, the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 42.28 °C ± 2 °C, 191.13 °C ± 2 °C, and 262.79 °C ± 2 °C.

[0131] In some embodiments, the AXL kinase inhibitor oxalate crystal form II shown in Formula (A) was determined by differential scanning calorimetry (DSC). When the temperature was increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum showed characteristic absorption peaks at approximately 42.28 °C ± 2 °C, 191.13 °C ± 2 °C, 206.24 °C ± 2 °C, and 262.79 °C ± 2 °C.

[0132] In some embodiments, the differential scanning calorimetry spectrum of the AXL kinase inhibitor oxalate crystal form II shown in formula (A) has substantially the following characteristics: Figure 54 The differential scanning calorimetry (DSC) spectrum is shown.

[0133] In a tenth aspect, the present invention provides a crystalline form of the free base of an AXL kinase inhibitor as shown in formula (A), comprising free base crystalline form I, free base crystalline form II, free base crystalline form III, free base crystalline form IV and free base crystalline form V:

[0134]

[0135] In some embodiments, the free base of the AXL kinase inhibitor shown in formula (A) is substantially pure.

[0136] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form V of the AXL kinase inhibitor shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 6.02°, 12.18°, 16.30°, 20.78°, 22.17°, and 25.86°, wherein the error of the 2θ angle is ±0.2°.

[0137] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form V of the AXL kinase inhibitor shown in Formula (A) has characteristic peaks at at least one or more of the following 2θ angles: 6.02°, 10.72°, 12.18°, 13.98°, 15.42°, 16.30°, 18.26°, 19.01°, 20.78°, 22.17°, 22.71°, 22.81°, 25.22°, 25.86°, and 32.00°, wherein the error of the 2θ angle is ±0.2°.

[0138] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form V of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0139] In some embodiments, the free base crystal form V of the AXL kinase inhibitor shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic peaks at approximately 67.61 °C ± 2 °C, 160.05 ± 2 °C, 187.30 ± 2 °C, and 257.55 ± 2 °C.

[0140] In some embodiments, the differential scanning calorimetry spectrum of the free base crystal form V of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 3 The differential scanning calorimetry (DSC) spectrum is shown.

[0141] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form I of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is numbered [Blank_DCM-MeOH-Water.RAW].

[0142] In some embodiments, the free base crystal form I of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has a characteristic absorption peak at approximately 266.57 °C ± 2 °C.

[0143] In some embodiments, the differential scanning calorimetry spectrum of the free base crystal form I of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 7 The differential scanning calorimetry spectrum shown is numbered FC2084_Blank_DCM-MeOH-Water.

[0144] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form II of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is numbered [Blank_DCM-MeOH-MeOH.RAW].

[0145] In some embodiments, the free base crystal form II of the AXL kinase inhibitor shown in formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 188.98 °C ± 2 °C and 264.94 °C ± 2 °C.

[0146] In some embodiments, the differential scanning calorimetry spectrum of the free base crystal form II of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 7 The differential scanning calorimetry spectrum shown is numbered FC2084_Blank_DCM-MeOH_MeOH.

[0147] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form III of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is numbered [Blank_THF-Water.RAW].

[0148] In some embodiments, the free base crystal form III of the AXL kinase inhibitor shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 175.18 °C ± 2 °C, 205.00 °C ± 2 °C, 233.84 °C ± 2 °C, 242.09 °C ± 2 °C, and 266.16 °C ± 2 °C.

[0149] In some embodiments, the differential scanning calorimetry spectrum of the free base crystal form III of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 7 The differential scanning calorimetry spectrum shown is numbered FC2084_Blank_THF-Water.

[0150] In some embodiments, the X-ray powder diffraction pattern of the free base crystal form IV of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown is numbered [Blank_THF-MeOH.RAW].

[0151] In some embodiments, the free base crystal form IV of the AXL kinase inhibitor shown in Formula (A) is determined by differential scanning calorimetry (DSC). When the temperature is increased at a rate of 10 °C / min, its differential scanning calorimetric analysis spectrum has characteristic absorption peaks at approximately 49.19 °C ± 2 °C, 206.58 °C ± 2 °C, 216.38 °C ± 2 °C, and 264.83 °C ± 2 °C.

[0152] In some embodiments, the differential scanning calorimetry spectrum of the free base crystal form IV of the AXL kinase inhibitor shown in formula (A) has substantially the following characteristics: Figure 7 The differential scanning calorimetry spectrum shown is numbered FC2084-Blank-THF-MeOH.

[0153] Eleventhly, this invention provides a method for preparing the acid addition salt of the AXL kinase inhibitor shown in formula (B) and its crystal form, or the crystal form of the free base of the AXL kinase inhibitor shown in formula (A). The preparation can be achieved through methods such as solution processing, grinding, hot melt extrusion, freeze drying, supercritical fluid processing, ultrasonic-assisted crystallization, and spray drying. In this embodiment of the invention, the preparation method is kept simple without affecting the drug's crystal form and efficacy. The method is as follows:

[0154] The AXL kinase inhibitor shown in formula (A) is dissolved in a solvent, and after adding a counterionic acid solution or antisolvent, the mixture is stirred and the solid is collected to obtain the product.

[0155] In some embodiments, the molar ratio of the AXL kinase inhibitor shown in formula (A) to the counterionic acid is 1:(0.55-1.1), preferably 1:0.55, 1:1, 1:1.05, or 1:1.1.

[0156] In some embodiments, the preparation of the counterion acid solution involves adding the counterion acid to a solvent to obtain a clear counterion acid solution.

[0157] In some embodiments, the counterionic acid is an inorganic acid or an organic acid.

[0158] In some embodiments, the inorganic acid is selected from at least one of the following: acid, sulfuric acid, hydrogen sulfate, nitric acid, hydrobromic acid, hydroiodic acid, boric acid, carbonic acid, bicarbonate, sulfurous acid, hydrogen sulfite, pyrosulfuric acid, monohydrogen phosphate, dihydrogen phosphate, perchloric acid, persulfuric acid, hemisulfuric acid, disulfuric acid, thiocyanate, phosphoric acid, pyrophosphoric acid, or metaphosphoric acid.

[0159] In some embodiments, the organic acid is selected from citric acid, methanesulfonic acid, oxalic acid, tartaric acid, L-tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, malonic acid, succinic acid, pyruvic acid, ethanesulfonic acid, propanesulfonic acid, 4-nitrobenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, propynic acid, 2-butynic acid, 2-hydroxyethanesulfonic acid, vinylacetic acid, fumaric acid, hydroxyethylsulfonic acid, maleic acid, lactic acid, lactobionic acid, salicylic acid, galactobionic acid, glucoheponic acid, mandelic acid, 1,2 - Ethyl disulfonic acid, 2-naphthalenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, adipic acid, octanoic acid, sebacic acid, butyn-1,4-diic acid, hexyn-1,6-diic acid, glycolic acid, alginic acid, ascorbic acid, isoascorbic acid, aspartic acid, L-aspartic acid, glutamic acid, L-glutamic acid, 2-phenoxybenzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, acetoacetic acid, chlorobenzoic acid, camphoric acid, itaconic acid, camphor sulfonic acid, L-camphor sulfonic acid, methylbenzoic acid, dinitro Benzoic acid, sulfamic acid, lacturonic acid, galacturonic acid, cyclopentylpropionic acid, dodecyl sulfate, acrylic acid, cyclopentanepropionic acid, glycerophosphate, methoxybenzoic acid, digluconic acid, gluconic acid, heptanoic acid, hexanoic acid, trimethylacetic acid, glucuronic acid, lauric acid, phthalic acid, phenylacetic acid, lauryl sulfate, 2-acetoxybenzoic acid, nicotinic acid, cinnamic acid, oleic acid, palmitic acid, pyric acid, pectic acid, phthalic acid, glutaric acid, hydroxymaleic acid, hydroxybenzoic acid, phenylacetic acid, 3-hydroxy At least one of the following: -2-naphthoic acid, 3-phenylpropionic acid, isobutyric acid, neopentanoic acid, picric acid, stearic acid, 2,2-dichloroacetic acid, acylated amino acids, alginic acid, 4-acetaminophensulfonic acid, capric acid, cholic acid, caprylic acid, nonanoic acid, cycloladenic acid, cysteine, sorbic acid, glycine, naphthalene disulfonic acid, xylenesulfonic acid, dicysteine, undecanoic acid, polyvinylsulfonic acid, sulfosalicylic acid, phenylbutyric acid, 4-hydroxybutyric acid, polyvinyl sulfate, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, or pentanoic acid.

[0160] In some embodiments, the solvent in the method is selected from solvents that have a certain solubility in the AXL kinase inhibitor shown in formula (A) and do not affect the stability of the AXL kinase inhibitor shown in formula (A). Preferably, the solvent is selected from one or more of water, alcohols, nitriles, ketones, esters, alkanes, aromatic hydrocarbons, and haloalkanes; 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, and 2-butanone. Preferably, the solvent is selected from at least one of a mixed solvent of dichloromethane and methanol (more preferably, the volume ratio of the two is 3:1), tetrahydrofuran, n-hexane, acetonitrile, and ethanol.

[0161] In some embodiments, in the method, the antisolvent is selected from solvents with low or almost insoluble solubility for the AXL kinase inhibitor shown in formula (A) and which have no effect on the stability of the AXL kinase inhibitor shown in formula (A). Preferably, the antisolvent is one or more selected from water, alcohols, nitriles, ketones, esters, alkanes, aromatic hydrocarbons, and haloalkanes; more preferably, the antisolvent is one or more selected from 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, and 2-butanone. Preferably, the solvent is selected from at least one of water or methanol.

[0162] In some embodiments, the stirring time is 1-20 hours; preferably, the stirring temperature is 10-40°C, more preferably 10°C, 15°C, 20°C, 30°C, or 40°C. Preferably, the stirring time is 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours.

[0163] In some embodiments, the solids are collected in the following ways: ① by centrifugation (12000 rpm, centrifugation for 10 min); ② by allowing the solvent in the solution to evaporate naturally at 10-40℃, with a settling time of 1-30 days; preferably, the heating temperature is 10℃, 20℃, 30℃, or 40℃; the settling 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, or 30 days; ③ by adding an anti-solvent to the solution, such as MTBE (methyl tert-butyl ether); multiple solid collection methods can also be combined for collection.

[0164] In a twelfth aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (B) as described herein, its crystal form or a combination thereof, and optionally pharmaceutically acceptable excipients.

[0165] In a thirteenth aspect, the present invention relates to the use of the salt of formula (B), its crystalline form, or a pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment, therapeutic, or relief of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer, viral infections, heart failure, cardiovascular diseases, myocardial fibrosis, pulmonary fibrosis, pathological structural remodeling of cardiac tissue, or other diseases in patients. The use includes administering to a patient an effective therapeutic dose of the salt of formula (B), its crystalline form, or a pharmaceutical composition thereof as described in the present invention.

[0166] Beneficial effects:

[0167] Compared to existing technologies, this invention conducts a salt type screening study, selecting a total of nine counterions, including hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, maleic acid, and oxalic acid. Experiments revealed that the free base of compound 1 can generate nine salt types: hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate, and oxalate. Considering the complex heat flow curves of hydrochloride, sulfate, phosphate, benzenesulfonate, maleate, and oxalate, and combining other physicochemical characterizations, methanesulfonate, p-toluenesulfonate, and camphorsulfonate, with their single melting point and slightly better solid crystallinity, were identified as candidate salt types.

[0168] A comprehensive comparison of the physicochemical properties, solubility, and short-term solid-state stability of the free base, methanesulfonate, and p-toluenesulfonate showed that methanesulfonate and p-toluenesulfonate improved the solubility of the free base, thus increasing the solubility of the compound in artificial gastric fluid and accelerating its chemical stability under 2-week conditions.

[0169] The nine crystal forms provided by this invention have good physicochemical stability, are simple to prepare, low in cost, and are easy to mass-produce, which is beneficial to the development of subsequent products. In particular, they are of great value for the future development of formulations of AXL kinase inhibitors as shown in formula (A). Attached Figure Description

[0170] Figure 1 The image shows the XRPD plot of the AXL kinase inhibitor shown in Formula (A) of Comparative Example 1.

[0171] Figure 2 The PLM diagram of the AXL kinase inhibitor shown in Formula (A) of Comparative Example 1 is shown.

[0172] Figure 3 The image shows the DSC plot of the AXL kinase inhibitor shown in Formula (A) of Comparative Example 1.

[0173] Figure 4 The TGA plot of the AXL kinase inhibitor shown in Comparative Example 1 (A) is shown.

[0174] Figure 5 The image shows the XRPD plot of the AXL kinase inhibitor heating experiment as shown in Comparative Example 1 (A).

[0175] Figure 6 This is an X-ray powder diffraction overlay of the free alkali and its crystal form in Example 1.

[0176] Figure 7 This is a differential scanning calorimetry (DSC) overlay of the free alkali and its crystal form in Example 1.

[0177] Figure 8The image shows the XRPD overlay of the AXL kinase inhibitor in the tetrahydrofuran system as shown in Formula (A) of Example 3, where curve [ENB201194-041-P1.RAW] is the XRPD curve of the free base.

[0178] Figure 9 The image shows the XRPD overlay of the AXL kinase inhibitor shown in Formula (A) of Example 4 in the salt form screening of the dichloromethane-methanol system, where the curve [ENB201194-041-P1.RAW] is the XRPD curve of the free base.

[0179] Figure 10 This is an XRPD overlay of the hydrochloride salt in Example 5.

[0180] Figure 11 This is a DSC diagram of hydrochloride crystal form I prepared in the tetrahydrofuran system in Example 5.

[0181] Figure 12 The TGA spectrum is shown for hydrochloride crystal form I prepared in the tetrahydrofuran system in Example 5.

[0182] Figure 13 The hydrochloride salt prepared in the tetrahydrofuran system in Example 5 1 HNMR image.

[0183] Figure 14 The image shows the DSC diagram of hydrochloride crystal form II prepared in the dichloromethane-methanol system in Example 5.

[0184] Figure 15 The TGA spectrum of hydrochloride crystal form II prepared in the dichloromethane-methanol system in Example 5 is shown.

[0185] Figure 16 This is an XRPD overlay image of sulfate in Example 5.

[0186] Figure 17 This is the DSC diagram of sulfate crystal form I in Example 5.

[0187] Figure 18 The TGA spectrum of sulfate crystal form I in Example 5 is shown.

[0188] Figure 19 For the sulfate in Example 5 1 HNMR image.

[0189] Figure 20 This is an XRPD overlay of the phosphate in Example 5.

[0190] Figure 21 This is the DSC diagram of phosphate crystal form I in Example 5.

[0191] Figure 22The TGA spectrum of phosphate crystal form I in Example 5 is shown.

[0192] Figure 23 For phosphate crystal form I in Example 5 1 HNMR image.

[0193] Figure 24 This is an XRPD overlay of the methanesulfonate in Example 5.

[0194] Figure 25 This is a DSC diagram of methanesulfonate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0195] Figure 26 The image shows the TGA spectrum of methanesulfonate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0196] Figure 27 The methanesulfonate prepared in the tetrahydrofuran system in Example 5 1 HNMR image.

[0197] Figure 28 The image shows the DSC diagram of methanesulfonate crystal form II prepared in the dichloromethane-methanol system in Example 5.

[0198] Figure 29 The TGA spectrum of methanesulfonate crystal form II prepared in the dichloromethane-methanol system in Example 5 is shown.

[0199] Figure 30 This is an XRPD overlay of benzenesulfonate in Example 5.

[0200] Figure 31 This is the DSC diagram of benzenesulfonate crystal form I in Example 5.

[0201] Figure 32 The TGA spectrum of benzenesulfonate crystal form I in Example 5 is shown.

[0202] Figure 33 For benzenesulfonate crystal form I in Example 5 1 HNMR image.

[0203] Figure 34 This is an XRPD overlay of p-toluenesulfonate in Example 5.

[0204] Figure 35 This is the DSC diagram of p-toluenesulfonate crystal form I in Example 5.

[0205] Figure 36 The TGA spectrum of p-toluenesulfonate crystal form I in Example 5 is shown.

[0206] Figure 37 p-Toluenesulfonate in Example 5 1HNMR image.

[0207] Figure 38 This is the XRPD image of phosphate crystal form I in Example 5.

[0208] Figure 39 This is the XRPD image of sulfate crystal form I in Example 5.

[0209] Figure 40 This is the XRPD image of maleate crystal form I in Example 5.

[0210] Figure 41 This is the XRPD image of maleate crystal form II in Example 5.

[0211] Figure 42 This is the XRPD image of hydrochloride crystal form I in Example 5.

[0212] Figure 43 This is the XRPD image of hydrochloride crystal form II in Example 5.

[0213] Figure 44 This is an XRPD overlay of maleate in Example 5.

[0214] Figure 45 This is a DSC diagram of maleate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0215] Figure 46 The image shows the TGA spectrum of maleate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0216] Figure 47 The maleate salt prepared in the tetrahydrofuran system in Example 5 1 HNMR image.

[0217] Figure 48 The image shows the DSC diagram of maleate crystal form II prepared in the dichloromethane-methanol system in Example 5.

[0218] Figure 49 The image shows the TGA spectrum of maleate crystal form II prepared in the dichloromethane-methanol system in Example 5.

[0219] Figure 50 This is an XRPD overlay of oxalate in Example 5.

[0220] Figure 51 This is a DSC diagram of oxalate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0221] Figure 52 The image shows the TGA spectrum of oxalate crystal form I prepared in the tetrahydrofuran system in Example 5.

[0222] Figure 53 The oxalate crystal form I prepared in the tetrahydrofuran system in Example 5 1 HNMR image.

[0223] Figure 54 The image shows the DSC diagram of oxalate crystal form II prepared in the dichloromethane-methanol system in Example 5.

[0224] Figure 55 The TGA spectrum of oxalate crystal form II prepared in the dichloromethane-methanol system in Example 5 is shown.

[0225] Figure 56 This is the XRPD image of methanesulfonate crystal form I in Example 5.

[0226] Figure 57 This is the XRPD diagram of methanesulfonate crystal form II in Example 5.

[0227] Figure 58 This is the XRPD image of p-toluenesulfonate crystal form I in Example 5.

[0228] Figure 59 This is the XRPD image of oxalate crystal form I in Example 5.

[0229] Figure 60 This is the XRPD image of oxalate crystal form II in Example 5.

[0230] Figure 61 This is the XRPD diagram of benzenesulfonate crystal form I in Example 5. Detailed Implementation

[0231] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0232] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0233] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0234] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," "furthermore," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Furthermore, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0235] In the following content, all figures disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction.

[0236] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0237] The terms “optional,” “optional,” or “optionally” refer to events or situations that may, but are not necessarily, occur as described below.

[0238] The term “characteristic peaks at least at one or more of the following 2θ angles” means that the minimum number of “multiple” locations is at least 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0239] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention in any way. Furthermore, descriptions of well-known structures and techniques are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and techniques have also been described in many publications.

[0240] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0241] In this invention, "room temperature" or "normal temperature" refers to 10-40°C, preferably 20-35°C, and more preferably 25°C.

[0242] The term "crystal form" refers to a unique, ordered arrangement and / or conformation of molecules in a compound's crystal lattice.

[0243] The term "substantially pure" means that a crystal form substantially does not contain one or more other crystal forms, and has 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 that the crystal form contains other crystal forms that constitute 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.

[0244] The term "substantially free of" one or more other crystal forms means that the content of other crystal forms is 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.

[0245] The term "basically as shown" in an X-ray powder diffraction pattern means that 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 appear in its pattern.

[0246] The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in an X-ray powder diffraction pattern is 100%.

[0247] The term "antisolvent" refers to a solvent that promotes a solution to a supersaturated state or crystallization. In some embodiments, the solubility of the compound represented by formula (B) in the antisolvent is 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.

[0248] When referring to data in a spectrum and / or figure, the term "peak" means a feature that a person skilled in the art would not attribute to background noise.

[0249] In some embodiments, pharmaceutical compositions comprising the crystal form described in this invention can be further formulated into various solid dosage forms for oral administration, including capsules, tablets, pills, powders, and granules. These formulations may also include excipients or carriers, such as sodium citrate, calcium phosphate, fillers, binders, humectants, disintegrants, blockers, absorption enhancers, wetting agents, absorbents, or lubricants, or mixtures thereof. The filler includes starch, lactose, sucrose, glucose, mannitol, silicic acid, or combinations thereof; the binder includes carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, or combinations thereof; the humectant includes glycerin; the disintegrant includes agar, calcium carbonate, potato starch or cassava starch, alginate, certain silicates and sodium carbonate, low-substituted hydroxypropyl cellulose, or combinations thereof; the inhibitor solution is such as paraffin wax; the absorption promoter is such as quaternary ammonium compounds; the humectant is such as cetyl alcohol and glyceryl monostearate; the absorbent is such as kaolin and bentonite; the lubricant is such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or combinations thereof.

[0250] The technical solution of the present invention will be illustrated below with examples. The scope of protection sought by the present invention includes, but is not limited to, the following embodiments.

[0251] Table 1. Explanation of Abbreviations

[0252]

[0253] Experimental reagents:

[0254] Methanol (MeOH), ethanol (EtOH), isopropanol (IPA), acetone (Acetone), 2-butanone (MEK), ethyl acetate (EA), dichloromethane (DCM), hydrochloric acid, and sulfuric acid were purchased from Runjie Chemical; acetonitrile (ACN) was purchased from Anhui Shilian; methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), and phosphoric acid were purchased from Aladdin; 2-methyltetrahydrofuran and n-heptane were purchased from General Reagent; 1,4-dioxane was purchased from HiPure Chem; DCM:MeOH (3:1) was a self-made reagent; methanesulfonic acid was purchased from ACROS; benzenesulfonic acid was purchased from J&K; p-toluenesulfonic acid, maleic acid, and oxalic acid were purchased from Inokai; camphorsulfonic acid was purchased from Adamas.

[0255] instrument:

[0256] Analytical balance, manufactured by Cetris, model CP225D; X-ray powder diffractometer (XRPD), manufactured by Shimadzu, Japan, model XRD-6000; Differential scanning calorimeter (DSC), manufactured by Mettler, model DSC3; Thermogravimetric analyzer (TGA), manufactured by Platinum Elmer, model Pyris1TGA; Polarizing microscope (PLM), manufactured by Shanghai Changfang Optical Instrument Co., Ltd., model XPV-203E; Thermostatic magnetic stirrer, manufactured by Shanghai Sile Instrument Co., Ltd., model B13-3; Ultrasonic cleaner, manufactured by Shanghai Keda, model SK8300BT; High-speed centrifuge, manufactured by Catcher Instruments, model H4-20K; High-performance liquid chromatograph, manufactured by Agilent, model Agilent 1260.

[0257] Relevant testing conditions:

[0258] X-ray powder diffraction (XRPD)

[0259] The equipment used was a Shimadzu XRD-6000, and the sample was scanned according to the following parameters: the X-ray source was a Cu-Kα target. 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° to 50°. The scanning speed is 5deg / min.

[0260] Thermogravimetric analysis (TGA)

[0261] Weigh approximately 5 mg of sample into a crucible, protect it with nitrogen, and heat it from 30 °C to 300 °C at a rate of 20 °C / min. Hold the temperature at 300 °C for 1 min.

[0262] Differential Scanning Calorimeter (DSC)

[0263] Weigh approximately 1–5 mg of powder sample and place it in a sealed aluminum crucible. Make a pinhole in the crucible lid. Under nitrogen protection, perform differential thermal scanning by heating from 30°C to 300°C or 350°C, and hold at 300°C or 350°C for 1 min. The heating rate is 20°C / min.

[0264] Polarizing microscope (PLM):

[0265] The sample is dispersed in a medium (silicone oil), observed using a 10× eyepiece and a 10× objective lens, and the image is recorded using a camera and computer system.

[0266] Comparative Example 1

[0267] The free alkali solid prepared in Example 25 of patent CN113912628B was physically characterized by XRPD, TGA, DSC and PLM, and is denoted as free alkali crystal form V.

[0268] XRPD results ( Figure 1 The diffraction peaks of the AXL kinase inhibitor shown in formula (A) are not obvious, suggesting a mixture of crystalline and amorphous forms, similar to PLM ( Figure 2 The results show that the phenomenon is consistent. (DSC results) Figure 3 The results show three distinct endothermic peaks (Endo. 67.61℃, Endo. 160.05℃, Endo. 257.55℃) and one exothermic peak (Exo. 187.30℃). (TGA results) Figure 4 The results showed a weight loss of 0.1686% from 21.55℃ to 120℃ and a weight loss of 0.3734% from 120℃ to 220℃. The sample was analyzed using TGA. Figure 5 Medium curve [ENB201194-041-P1.RAW]) heated to 120℃ ( Figure 5 Medium curve [ENB201194-041-P1_Heating-120C.RAW]), XRPD after heating ( Figure 5 No significant changes were observed. XRPD analysis of the sample after heating to 220℃ showed that the free alkali underwent crystallization. Figure 5 Medium curve [ENB201194-041-P1_Heating-220C.RAW]).

[0269] Example 1: Crystal form of free base

[0270] Dissolve 50 mg of the AXL kinase inhibitor (free base crystal form V) shown in formula (A) in 2.5 mL of solvent one, then add solvent two dropwise to the solution. Stir and mix at room temperature to obtain the free base crystal form. See Table 2 below for details:

[0271] Table 2: Corresponding Curve Information

[0272]

[0273] from Figure 6 and Figure 7 It can be seen that free alkali, when pulped with different solvents, yields four different crystal forms. Among them... Figure 7 The DSC curve FC2084_ENB201194-041-P1 represents the DCS curve of the free alkali solid before it is pulped with solvent.

[0274] Example 2: Solubility Test of Free Base

[0275] To select a suitable method for salt form screening, approximate solubility testing was performed on the free base. The method was as follows: approximately 4 mg of the AXL kinase inhibitor (free base crystal form V) as shown in formula (A) was weighed, and appropriate volumes of solvent were gradually added. The mixture was shaken, and dissolution was observed. The volume of completely dissolved solvent and the volume of solvent that did not completely dissolve previously were recorded. The total amount of solvent with very poor solubility added should not exceed 4 mL. The approximate solubility was calculated. The results are shown in Table 3 below.

[0276] Table 3 Solubility of free base in different solvents

[0277] solvent Solubility (mg / mL) solvent Solubility (mg / mL) dichloromethane 40.5～81.0 Isopropanol <1.0 Dichloromethane:methanol (3:1) 27.9～41.9 acetone <1.0 1,4-Dioxane 27.7～41.5 2-Butanone <1.0 Tetrahydrofuran 20.2～26.9 Ethyl acetate <1.0 2-Methyltetrahydrofuran 1.9～2.1 Methyl tert-butyl ether <1.0 Purified water <1.0 Acetonitrile <1.0 ethanol <1.0 n-Heptane <1.0 methanol <1.0

[0278] According to the results in Table 3, the AXL kinase inhibitor shown in formula (A) has high solubility in dichloromethane, tetrahydrofuran, 1,4-dioxane, and dichloromethane:methanol (3:1, V:V).

[0279] Example 3: Salt screening in a tetrahydrofuran system

[0280] Based on the solubility results of Example 2, the tetrahydrofuran system was selected for salt type screening. Approximately 50 mg of the AXL kinase inhibitor active pharmaceutical ingredient (free base crystal form V) as shown in formula (A) was weighed into each vial, and 2.5 mL of tetrahydrofuran was added. The mixture was stirred at room temperature to dissolve the compound. Then, the counterionic acid was slowly added dropwise to the reaction solution at a molar ratio of 1:1.05 (wherein the molar ratio of the AXL kinase inhibitor as shown in formula (A) is 1, i.e., API). Finally, the samples were magnetically stirred overnight (approximately 20 h) at room temperature. After stirring overnight, if the sample in the vial was a suspension with a large amount of solids, the solids were collected by centrifugation (12000 rpm, 10 min); if the sample in the vial was a clear solution or had a small amount of solids, the solvent was concentrated by nitrogen purging or natural evaporation, and the solids were collected. The collected solids were dried under reduced pressure at 40°C for at least 4 h, and the dried solids were analyzed by X-ray powder diffraction. The results are shown in […]. Figure 8See Table 4. If the XRPD plot of the dried solid does not match that of the initial free base, these dried solids are further characterized, including by DSC, TGA, etc.

[0281] Table 4 Summary of salt form screening for free bases in the tetrahydrofuran system

[0282]

[0283]

[0284]

[0285] Combine Table 4 and Figure 8 It can be seen that in the tetrahydrofuran system, the free base forms nine salts, namely hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate, and oxalate, and they all have relatively good crystal forms.

[0286] Example 4: Salt screening in a dichloromethane-methanol mixed solution system

[0287] Based on the solubility results of Example 2, a dichloromethane-methanol mixed solution system was selected for salt type screening.

[0288] Weigh approximately 50 mg of the AXL kinase inhibitor active pharmaceutical ingredient (free base crystal form V) as shown in formula (A) into each vial, add 2 mL of dichloromethane-methanol mixture (3:1, V:V), and stir at room temperature to dissolve the compound into a solution. Then, slowly add the counterion 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 shown in formula (A) is 1, i.e., API). Finally, magnetically stir the samples at room temperature overnight (approximately 20 h).

[0289] After stirring overnight, if the sample in the vial is a suspension with a large amount of solids, the solids are collected by centrifugation (12000 rpm, 10 min). If the sample in the vial is a clear solution or has a small amount of solids, the solvent is concentrated by nitrogen purging or natural evaporation, and the solids are collected. The collected solids are dried under reduced pressure at 40°C for at least 4 hours, and the dried solids are analyzed by X-ray powder diffraction. The results are shown below. Figure 9 See Table 5. If the XRPD plot of the dried solid does not match that of the initial free base, these dried solids are further characterized, including by DSC, TGA, etc.

[0290] Table 5 Summary of salt form screening for free base in dichloromethane-methanol system

[0291]

[0292]

[0293]

[0294] Combine Table 4 and Figure 9 It can be seen that in the dichloromethane-methanol system, the free base forms nine salts, namely hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate and oxalate, and they all have relatively good crystal forms.

[0295] Example 5: Screening of Salt Crystal Forms

[0296] Eight different salts prepared in Examples 3 and 4, and the free alkali crystal form prepared in Example 1, were compared using XPRD images, and further analyzed using DSC, TGA, and [other methods]. 1 HNMR characterization.

[0297] Table 5: The crystal forms corresponding to each curve in the attached figure are as follows:

[0298]

[0299]

[0300] like Figure 10 As shown, the XRPD diagrams of the crystal forms of hydrochloride in the tetrahydrofuran system and the dichloromethane-methanol system do not overlap and have characteristic peaks, indicating that two different crystal forms are formed, which are named hydrochloride crystal form I and hydrochloride crystal form II, respectively.

[0301] like Figure 11 As shown, the differential scanning calorimetry spectrum of the obtained hydrochloride crystal form I has characteristic absorption peaks at approximately 45.36℃, 96.20℃, 137.80℃, and 184.98℃.

[0302] like Figure 12 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained hydrochloride crystal form I showed only a 3.0534% weight loss before 130℃, indicating that the hydrochloride crystal form is a solvate and does not contain organic solvents.

[0303] like Figure 13 As shown, the obtained hydrochloride crystal form I 1 The HNMR results showed that the actual molar ratio of free base to hydrochloric acid was 1.0:1.0.

[0304] like Figure 14 As shown, the differential scanning calorimetry spectrum of the obtained hydrochloride crystal form I has characteristic absorption peaks at approximately 123.86℃, 203.26℃, and 263.45℃.

[0305] like Figure 15 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained hydrochloride crystal form II showed only a weight loss of 3.0816% before 120℃, indicating that the hydrochloride crystal form is a solvate and does not contain organic solvents.

[0306] like Figure 16 As shown, the sulfate prepared in both the THF system and the dichloromethane-methanol system has the same crystal form, which is a single crystal form.

[0307] like Figure 17 As shown, the differential scanning calorimetry spectrum of the obtained sulfate crystal form I has characteristic absorption peaks at approximately 45.22℃, 189.17℃, and 294.46℃.

[0308] like Figure 18 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained sulfate crystal form I showed only a 2.1441% weight loss before 140℃, indicating that the sulfate crystal form is a solvate and does not contain organic solvents.

[0309] like Figure 19 As shown, the obtained sulfate crystal form I 1 The HNMR results showed that the actual molar ratio of free base to sulfuric acid was 1.0:1.0.

[0310] like Figure 20 As shown, the phosphate prepared in both the THF system and the dichloromethane-methanol system has the same crystal form, which is a single crystal form.

[0311] like Figure 21 As shown, the differential scanning calorimetry spectrum of the obtained phosphate crystal form I has characteristic absorption peaks at approximately 112.43℃, 167.10℃, and 242.60℃.

[0312] like Figure 22 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained phosphate crystal form I showed only a weight loss of 1.1481% before 120℃, indicating that the phosphate crystal form is a solvate and does not contain organic solvents.

[0313] like Figure 23 As shown, the obtained phosphate crystal form I 1 According to the HNMR results, the actual molar ratio of free base to phosphoric acid is 1.0:1.0.

[0314] like Figure 24 As shown, the methanesulfonates prepared in the THF system and the dichloromethane-methanol system have different crystal forms. The methanesulfonate crystals prepared in the tetrahydrofuran system are designated as methanesulfonate crystal form I, and the methanesulfonate crystals prepared in the dichloromethane-methanol system are designated as methanesulfonate crystal form II.

[0315] like Figure 25As shown, the differential scanning calorimetry spectrum of the obtained methanesulfonate crystal form I has a characteristic absorption peak at approximately 253.44 °C.

[0316] like Figure 26 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained methanesulfonate crystal form I showed only a weight loss of 0.6829% before 120℃, indicating that the methanesulfonate crystal form is a solvate and does not contain organic solvents.

[0317] like Figure 27 As shown, the obtained methanesulfonate crystal form I 1 According to the HNMR results, the actual molar ratio of free base to methanesulfonic acid was 1.0:1.0.

[0318] like Figure 28 As shown, the differential scanning calorimetry spectrum of the obtained methanesulfonate crystal form II has characteristic absorption peaks at approximately 213.80 °C and 263.14 °C.

[0319] like Figure 29 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained methanesulfonate crystal form II showed only a weight loss of 0.0716% before 120℃, indicating that the methanesulfonate crystal form is a solvate and does not contain organic solvents.

[0320] like Figure 30 As shown, the benzenesulfonate prepared in both the THF system and the dichloromethane-methanol system has the same crystal form, which is a single crystal form.

[0321] like Figure 31 As shown, the differential scanning calorimetry spectrum of the obtained benzenesulfonate crystal form I has characteristic absorption peaks at approximately 206.58 °C and 252.26 °C.

[0322] like Figure 32 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained benzenesulfonate crystal form I showed only a weight loss of 1.1291% before 140℃, indicating that the benzenesulfonate crystal form is a solvate and does not contain organic solvents.

[0323] like Figure 33 As shown, the obtained benzenesulfonate crystal form I 1 According to the HNMR results, the actual molar ratio of free base to benzenesulfonic acid is 1.0:1.0.

[0324] like Figure 58 As shown, the p-toluenesulfonate prepared in both the THF system and the dichloromethane-methanol system has the same crystal form, which is a single crystal form.

[0325] like Figure 35 As shown, the differential scanning calorimetry spectrum of the obtained p-toluenesulfonate crystal form I has a characteristic absorption peak at approximately 277.44 °C.

[0326] like Figure 36As shown, the thermogravimetric analysis (TGA) spectrum of p-toluenesulfonate crystal form I showed only a weight loss of 0.5059% before 120℃, indicating that p-toluenesulfonate crystal form is a solvate and does not contain organic solvents.

[0327] like Figure 37 As shown, the obtained p-toluenesulfonate crystal form I 1 According to the HNMR results, the actual molar ratio of free base to p-toluenesulfonic acid was 1.0:1.0.

[0328] like Figure 44 As shown, the maleate crystals prepared in the THF system and the dichloromethane-methanol system have different crystal forms. The maleate crystals prepared in the tetrahydrofuran system are referred to as maleate crystal form I, and the maleate crystals prepared in the dichloromethane-methanol system are referred to as maleate crystal form II.

[0329] like Figure 45 As shown, the differential scanning calorimetry spectrum of the obtained maleate crystal form I has characteristic absorption peaks at approximately 109.84℃, 169.91℃, and 193.11℃.

[0330] like Figure 46 As shown, the thermogravimetric analysis (TGA) spectrum of maleate crystal form I showed only a weight loss of 1.3220% before 100℃, indicating that the maleate crystal form is a solvate and does not contain organic solvents.

[0331] like Figure 47 As shown, the obtained maleate crystal form I 1 The HNMR results showed that the actual molar ratio of free alkali to camphor sulfonic acid was 1.0:1.0.

[0332] like Figure 48 As shown, the differential scanning calorimetry spectrum of the obtained maleate crystal form II has characteristic absorption peaks at approximately 203.01℃, 213.06℃, and 237.62℃.

[0333] like Figure 49 As shown, the thermogravimetric analysis (TGA) spectrum of maleate crystal form II showed only a weight loss of 0.9788% before 190℃, indicating that the maleate crystal form is a solvate and does not contain organic solvents.

[0334] like Figure 50 As shown, the oxalate crystals prepared in the THF system and the dichloromethane-methanol system are of different crystal forms. The oxalate crystals prepared in the tetrahydrofuran system are oxalate crystal form I, and the oxalate crystals prepared in the dichloromethane-methanol system are oxalate crystal form II.

[0335] like Figure 51As shown, the differential scanning calorimetry spectrum of the obtained oxalate crystal form I has characteristic absorption peaks at approximately 214.15℃, 263.27℃, and 230.84℃.

[0336] like Figure 52 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained oxalate crystal form I showed only a weight loss of 0.4315% before 120℃, indicating that the oxalate crystal form is a solvate and does not contain organic solvents.

[0337] like Figure 53 As shown, the obtained oxalate crystal form I 1 The HNMR results showed that the actual molar ratio of free base to oxalic acid was 1.0:1.0.

[0338] like Figure 54 As shown, the differential scanning calorimetry spectrum of the obtained oxalate crystal form II has characteristic absorption peaks at approximately 42.28℃, 191.13℃, 206.24℃, and 262.79℃.

[0339] like Figure 55 As shown, the thermogravimetric analysis (TGA) spectrum of the obtained oxalate crystal form II showed only a 2.3877% weight loss before 120℃, indicating that the oxalate crystal form is a solvate and does not contain organic solvents.

[0340] The differential scanning calorimetry (DSC) spectrum of a certain crystal form in this invention exhibits multiple characteristic peaks, possibly due to residual solvent, corresponding to the weight loss observed in the TGA. The approximately 3% weight loss in the TGA spectrum of this invention is likely due to residual solvent or the hygroscopic nature of the salt itself. Further NMR verification confirmed the absence of water of crystallization or crystallization solvent.

[0341] Example 1: Solubility Test

[0342] Preparation of buffer solution:

[0343] Water: Laboratory-purified Milli-Q water.

[0344] SGF (artificial gastric juice): Add 2.0 g of sodium chloride and 7 mL of concentrated hydrochloric acid to 1000 mL of purified water, and mix thoroughly to obtain the solution (pH 1.2).

[0345] FaSSIF (simulated fasting intestinal fluid): (1) Buffer solution: Dissolve 0.42 g sodium hydroxide (NaOH), 3.95 g sodium dihydrogen phosphate (NaH2PO4·H2O), and 6.19 g sodium chloride (NaCl) in approximately 0.9 L of purified water. Adjust the pH to 6.5 with sodium hydroxide (1N) or hydrochloric acid (1N). Make up to 1 L with purified water at room temperature. (2) Add 2.24 g of FaSSIF / FeSSIF / FaSSGF powder to approximately 0.5 L of buffer solution. Stir until the powder is completely dissolved. Make up to 1 L with buffer solution at room temperature.

[0346] FeSSIF (simulated intestinal fluid during feeding): (1) Buffer solution: Dissolve 4.04 g sodium hydroxide (NaOH), 8.65 g glacial acetic acid, and 11.87 g sodium chloride (NaCl) in approximately 0.9 L of purified water. Adjust the pH to 5.0 with sodium hydroxide (1N) or hydrochloric acid (1N). Make up to 1 L with purified water at room temperature. (2) Add 11.20 g FaSSIF / FeSSIF / FaSSGF powder to approximately 0.5 L of buffer solution. Stir until the powder is completely dissolved. Make up to 1 L with buffer solution at room temperature.

[0347] FaSSIF / FeSSIF / FaSSGF powder is supplied by Bio-Relevant. For detailed instructions, please visit (https: / / biorelevant.com).

[0348] Test method: Weigh 15 mg of the AXL kinase inhibitor raw material (as shown in formula (A), or its mesylate or p-toluenesulfonate) into a 4 mL vial, add 3 mL of the test solvent, and disperse the sample evenly. Stir the sample on a magnetic stirrer at 37 °C for 24 hours. Take samples at 1 hour and 24 hours, centrifuge the sample at 12000 rpm for 10 min, and filter it through a 0.45 μm aqueous syringe filter membrane. Determine the concentration using HPLC.

[0349] Linearity: Accurately weigh approximately 10 mg of the AXL kinase inhibitor compound shown in formula (A) into a 200 mL volumetric flask. Dissolve and dilute to the mark with tetrahydrofuran:methanol (1:1, v:v), and mix well to obtain the mother liquor. Take an appropriate amount of the mother liquor and dilute it to 25 μg / mL, 10 μg / mL, 5 μg / mL, and 1 μg / mL with tetrahydrofuran:methanol (1:1, v:v), respectively, and inject for analysis. Plot a standard curve based on the peak area and corresponding concentration values.

[0350] Chromatographic conditions for solubility detection: Column: Agilent SB-C18 C18, 4.6*50mm, 1.8μm; Mobile phase: A: 0.05% TFA in water; B: 0.05% TFA in ACN; Injection volume: 1μL; Flow rate: 0.8ml / min; Run time: 10min; Detection wavelength: 214nm; Column temperature: 45℃; Diluent: Tetrahydrofuran / Methanol (1 / 1) (V / V); Gradient: 0–6min: B phase 0%; 6–7min: B phase 60%; 7–7.1min: B phase 100%; 7.1–10min: B phase 0%.

[0351] The results are shown in the table below:

[0352] Table 6. Solubility determination results of relevant salt types in different media (1h & 24h, 37℃)

[0353]

[0354]

[0355] *Note: All results above are calculated based on the concentration of free alkali.

[0356] A comprehensive comparison of the physicochemical properties and solubility of free base, methanesulfonate, and p-toluenesulfonate shows that both methanesulfonate and p-toluenesulfonate improve the solubility of free base.

[0357] Example 2: Salt-type chemical stability test

[0358] Test method: Weigh 5 mg of the AXL kinase inhibitor raw material (as shown in formula (A), or its hydrochloride, maleate, mesylate, or p-toluenesulfonate, into a 20 mL glass bottle. Place the bottle open in a 40℃ / 75% stability chamber. Remove the cap from the open sample and cover the bottle opening with aluminum foil with pinholes to avoid cross-contamination. Take samples at 2-week time points, dilute with 5 mL of diluent (tetrahydrofuran / methanol (1 / 1) (V / V)) until completely dissolved, and perform HPLC analysis according to the chromatographic conditions. The results are summarized in Table 7.

[0359] Chromatographic conditions for stability testing: Column: Agilent Eclipse Plus C18, 4.6*250mm, 5μm; Mobile phase: A: 0.05% TFA in water; B: 0.05% TFA in ACN; Injection volume: 1μL; Flow rate: 0.8ml / min; Run time: 28min; Detection wavelength: 214nm.

[0360] 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 min: B phase 100%; 20 min-28 min: B phase 0%.

[0361] Table 7 (A) shows the results of the salt-form chemical stability test of AXL kinase inhibitors.

[0362]

[0363]

[0364] Note: The reporting limit is 0.02%.

[0365] A comprehensive comparison of the short-term solid-state stability of free alkali and all salts shows that methanesulfonate and p-toluenesulfonate exhibit good chemical stability under accelerated 2-week conditions.

[0366] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A salt of formula (B), characterized in that, Pharmaceutically acceptable acid addition salts of AXL kinase inhibitors: where M is an inorganic acid or an organic acid; 0 < x ≤ 4, x is a real number; or x is selected from 0.5, 1, 2, 3, 4; Preferably, the inorganic acid is selected from at least one of hydrochloric acid, sulfuric acid, hydrogen sulfate, nitric acid, hydrobromic acid, hydroiodic acid, boric acid, carbonic acid, sulfurous acid, pyrosulfuric acid, monohydrogen phosphate, dihydrogen phosphate, perchloric acid, persulfuric acid, semi-sulfuric acid, dithionic acid, thiocyanic acid, phosphoric acid, pyrophosphoric acid or metaphosphoric acid; Alternatively, the organic acid is selected from at least one of citric acid, methanesulfonic acid, oxalic acid, tartaric acid, L-tartaric acid, formic acid, acetic acid, propionic acid, butyric acid, benzoic acid, malonic acid, succinic acid, pyruvic acid, ethanesulfonic acid, propanesulfonic acid, 4-nitrobenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, propiolic acid, 2-butynoic acid, 2-hydroxy-ethanesulfonic acid, vinylacetic acid, fumaric acid, 2-hydroxyethylsulfonic acid, maleic acid, lactic acid, lactobionic acid, salicylic acid, galactaric acid, glucoheptonic acid, mandelic acid, 1,2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, adipic acid, suberic acid, sebacic acid, butyne-1,4-dioic acid, hexyne-1,6-dioic acid, glycolic acid, alginic acid, ascorbic acid, isoascorbic acid, aspartic acid, L-aspartic acid, glutamic acid, L-glutamic acid, 2-phenoxybenzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, acetoacetic acid, chlorobenzoic acid, camphoric acid, itaconic acid, camphorsulfonic acid, levocamphorsulfonic acid, methylbenzoic acid, dinitrobenzoic acid, sulfamic acid, lactobionic acid, galacturonic acid, cyclopentanepropionic acid, dodecylsulfuric acid, acrylic acid, cyclopentanepropionic acid, glycerophosphoric acid, methoxybenzoic acid, digluconic acid, gluconic acid, heptanoic acid, hexanoic acid, trimethylacetic acid, glucuronic acid, lauric acid, phthalic acid, phenylacetic acid, laurylsulfuric acid, 2-acetoxybenzoic acid, nicotinic acid, cinnamic acid, oleic acid, palmitic acid, pamoic acid, pectic acid, phthalic acid, glutaric acid, hydroxymaleic acid, hydroxybenzoic acid, phenylacetic acid, 3-hydroxy-2-naphthoic acid, 3-phenylpropionic acid, isobutyric acid, pivalic acid, picric acid, stearic acid, 2,2-dichloroacetic acid, acylated amino acids, alginic acid, 4-acetamidobenzenesulfonic acid, capric acid, cholic acid, caprylic acid, pelargonic acid, cyclamic acid, cysteine acid, sorbic acid, glycine acid, naphthalenedisulfonic acid, xylenesulfonic acid, cystine diacid, undecanoic acid, polyvinylsulfonic acid, sulfosalicylic acid, phenylbutyric acid,  4-hydroxybutyric acid, polyvinylsulfuric acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid or valeric acid; Preferably, the salt represented by formula (B) is a hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate or oxalate of the AXL kinase inhibitor represented by formula (A); The AXL kinase inhibitor shown in formula (A) is...

2. A crystalline form of the salt shown in formula (B), characterized in that, It is the hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, maleate or oxalate crystal form of the AXL kinase inhibitor shown in formula (A), including methanesulfonate crystal form I, methanesulfonate crystal form II, p-toluenesulfonate crystal form I, hydrochloride crystal form I, hydrochloride crystal form II, sulfate crystal form I, phosphate crystal form I, benzenesulfonate crystal form I, maleate crystal form I, maleate crystal form II, oxalate crystal form I and oxalate crystal form II; Alternatively, the crystal form is substantially pure. The AXL kinase inhibitor shown in formula (A) is...

3. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of methanesulfonate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 5.18°, 10.42°, 12.76°, 15.76°, and 21.00°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of methanesulfonate crystal form I has essentially the X-ray powder diffraction pattern shown in Figure 56; or, the differential scanning calorimetry (DSC) analysis of methanesulfonate crystal form I shows a characteristic absorption peak at approximately 253.44℃ ± 2℃; or, the differential scanning calorimetry (DSC) analysis of methanesulfonate crystal form I has essentially the differential scanning calorimetry (DSC) analysis pattern shown in Figure 25. Alternatively, the X-ray powder diffraction pattern of the methanesulfonate crystal form II has characteristic peaks at at least one or more of the following 2θ angles: 10.32°, 12.42°, 17.42°, 20.54°, 21.06°, 23.34°, and 23.78°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the methanesulfonate crystal form II has an X-ray powder diffraction pattern substantially as shown in Figure 57; or, the methanesulfonate crystal form II, determined by differential scanning calorimetry, has a characteristic absorption peak at at least one of the following two 2θ angles: 213.80℃±2℃ and 263.14℃±2℃; or, the differential scanning calorimetry pattern of the methanesulfonate crystal form II has a differential scanning calorimetry pattern substantially as shown in Figure 28.

4. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 5.16°, 10.20°, 11.68°, 16.38°, 20.88°, 21.30°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 58. Alternatively, the crystal form I of the p-toluenesulfonate is determined by differential scanning calorimetry, and its differential scanning calorimetric spectrum has a characteristic absorption peak at approximately 277.44℃±2℃; or, the differential scanning calorimetric spectrum of the crystal form I of the p-toluenesulfonate has a differential scanning calorimetric spectrum substantially as shown in Figure 35.

5. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the benzenesulfonate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 10.30°, 12.18°, 17.12°, 20.80°, 22.34°, 24.56°, and 25.74°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the benzenesulfonate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 61; or, the benzenesulfonate crystal form I, determined by differential scanning calorimetry, has a characteristic absorption peak at at least one of approximately 206.58℃±2℃ and 252.26℃±2℃ in its differential scanning calorimetry analysis spectrum; or, the differential scanning calorimetry analysis spectrum of the benzenesulfonate crystal form I has a differential scanning calorimetry analysis spectrum substantially as shown in Figure 31.

6. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the hydrochloride crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 5.50°, 11.16°, 13.44°, 20.54°, 21.46°, and 23.34°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the hydrochloride crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 42. Alternatively, the hydrochloride crystal form I is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has a characteristic absorption peak at at least one of 45.36℃±2℃, 96.20℃±2℃, 137.80℃±2℃, and 184.98℃±2℃; or, the differential scanning calorimetry spectrum of the hydrochloride crystal form I has a differential scanning calorimetry spectrum substantially as shown in Figure 11. Alternatively, the X-ray powder diffraction pattern of the hydrochloride crystal form II has characteristic peaks at at least one or more of the following 2θ angles: 6.06°, 11.16°, 16.90°, 17.40°, 21.32°, and 22.94°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the hydrochloride crystal form II has an X-ray powder diffraction pattern substantially as shown in Figure 43; or, the differential scanning calorimetry (DSC) analysis spectrum of the hydrochloride crystal form II has a characteristic absorption peak at at least one of 123.86℃±2℃, 203.26℃±2℃, and 263.45℃±2℃; or, the differential scanning calorimetry (DSC) analysis spectrum of the hydrochloride crystal form II has a differential scanning calorimetry (DSC) analysis spectrum substantially as shown in Figure 14.

7. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the sulfate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 11.40°, 16.64°, 22.66°, 22.92°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the sulfate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 39. Alternatively, the sulfate crystal form I is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has a characteristic absorption peak at at least one of 45.22℃±2℃, 189.17℃±2℃, and 294.46℃±2℃; or, the differential scanning calorimetry spectrum of the sulfate crystal form I has a differential scanning calorimetry spectrum substantially as shown in Figure 17.

8. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of the phosphate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 4.06°, 15.60°, 16.76°, and 20.96°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of the phosphate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 38. Alternatively, the phosphate crystal form I is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has at least one characteristic absorption peak at 112.43℃±2℃, 167.10℃±2℃, and 242.60℃±2℃; or, the differential scanning calorimetry spectrum of the phosphate crystal form I has a differential scanning calorimetry spectrum substantially as shown in Figure 21.

9. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of maleate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 4.22°, 8.48°, 11.90°, 12.76°, 13.32°, and 15.74°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of maleate crystal form I has an X-ray powder diffraction pattern substantially as shown in Figure 40. Alternatively, the maleate crystal form I is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has a characteristic absorption peak at at least one of approximately 109.84℃±2℃, 169.91℃±2℃, and 193.11℃±2℃; or, the differential scanning calorimetry spectrum of the maleate crystal form I has a differential scanning calorimetry spectrum substantially as shown in Figure 45. Alternatively, the X-ray powder diffraction pattern of maleate crystal form II has characteristic peaks at at least one or more of the following 2θ angles: 8.88°, 11.08°, 13.28°, 14.60°, 14.94°, and 15.54°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of maleate crystal form II has essentially the X-ray powder diffraction pattern shown in Figure 41; or, the differential scanning calorimetry (DSC) analysis of maleate crystal form II, determined by differential scanning calorimetry (DSC), has characteristic absorption peaks at at least one of approximately 203.01℃±2℃, 213.06℃±2℃, and 237.62℃±2℃; or, the differential scanning calorimetry (DSC) analysis pattern of maleate crystal form II has essentially the differential scanning calorimetry (DSC) analysis pattern shown in Figure 48.

10. The crystal form according to claim 2, characterized in that, The X-ray powder diffraction pattern of oxalate crystal form I has characteristic peaks at at least one or more of the following 2θ angles: 9.80°, 14.86°, 19.66°, 20.08°, 20.94°, 21.16°, 23.74°, and 25.70°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of oxalate crystal form I has essentially the X-ray powder diffraction pattern shown in Figure 59; or, the differential scanning calorimetry (DSC) analysis of oxalate crystal form I shows characteristic absorption peaks at at least one of approximately 214.15℃±2℃, 230.84±2℃, and 263.27℃±2℃; or, the differential scanning calorimetry (DSC) analysis of oxalate crystal form I has essentially the differential scanning calorimetry (DSC) analysis pattern shown in Figure 51. Alternatively, the X-ray powder diffraction pattern of oxalate crystal form II has characteristic peaks at at least one or more of the following 2θ angles: 3.92°, 11.22°, 14.12°, 16.78°, and 21.74°, wherein the error of the 2θ angle is ±0.2°; or, the X-ray powder diffraction pattern of oxalate crystal form II has an X-ray powder diffraction pattern substantially as shown in Figure 60; or, the differential scanning calorimetry (DSC) analysis of oxalate crystal form II shows characteristic absorption peaks at at least one of approximately 42.28℃±2℃, 191.13℃±2℃, 206.24℃±2℃, and 262.79℃±2℃; or, the differential scanning calorimetry (DSC) analysis pattern of oxalate crystal form II has a differential scanning calorimetry (DSC) analysis pattern substantially as shown in Figure 54.

11. A crystalline form of the free base of an AXL kinase inhibitor of formula (A), characterized in that, Including free alkali crystal form I, free alkali crystal form II, free alkali crystal form III and free alkali crystal form IV: Alternatively, the free base of the AXL kinase inhibitor shown in formula (A) is substantially pure; Preferably, the X-ray powder diffraction patterns of the free alkali crystal form I, free alkali crystal form II, free alkali crystal form III, and free alkali crystal form IV all have X-ray powder diffraction patterns that are essentially as shown in Figure 6. Preferably, the differential scanning calorimetry (DSC) spectra of the free alkali crystal form I, free alkali crystal form II, free alkali crystal form III, and free alkali crystal form IV all have a DSC spectra that are essentially as shown in Figure 7. Preferably, the free alkali crystal form I is determined by differential scanning calorimetry, and its differential scanning calorimetry analysis spectrum has a characteristic absorption peak at approximately 266.57℃±2℃; Preferably, the free alkali crystal form II is determined by differential scanning calorimetry, and its differential scanning calorimetry analysis spectrum has at least one characteristic absorption peak at approximately 188.98℃±2℃ and 264.94℃±2℃; Preferably, the free alkali crystal form III is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has a characteristic absorption peak at at least one of the following: 175.18℃±2℃, 205.00℃±2℃, 233.84℃±2℃, 242.09℃±2℃, and 266.16℃±2℃. Preferably, the free alkali crystal form IV is determined by differential scanning calorimetry, and its differential scanning calorimetry spectrum has a characteristic absorption peak at at least one of the following: approximately 49.19℃±2℃, 206.58℃±2℃, 216.38℃±2℃, and 264.83℃±2℃.

12. A method for preparing the crystal form of the salt of formula (B) according to claim 1 or the salt of formula (B) according to any one of claims 2 to 10 or the free alkali crystal form according to claim 11, characterized in that, It is prepared by at least one of the following methods: 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: dissolve the AXL kinase inhibitor shown in formula (A) in a solvent, add a counterionic acid solution or antisolvent, stir the reaction, and collect the solid to obtain the product; wherein the AXL kinase inhibitor shown in formula (A) is... Preferably, the preparation of the counterion acid solution involves adding the counterion acid to a solvent to obtain a clear counterion acid solution. Preferably, the counterionic acid is an inorganic acid or an organic acid.

13. A pharmaceutical composition, characterized in that, It includes the crystal form of the salt of formula (B) as described in claim 1 or the crystal form of the salt of formula (B) as described in any one of claims 2 to 10, the crystal form of the free base as described in claim 11, or a combination thereof, and optional pharmaceutically acceptable excipients.

14. The use of the salt of formula (B) as claimed in claim 1 or the crystal form of the salt of formula (B) as claimed in any one of claims 2 to 10, the free base crystal form as claimed in claim 11, or the pharmaceutical composition as claimed in claim 13 in the preparation of a medicament for the prevention, treatment, therapy, or relief of 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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