Pharmaceutically acceptable salt and crystalline form of tyrosine kinase inhibitor and preparation method therefor

Abstract

The present disclosure relates to a crystalline form of a pharmaceutically acceptable salt of a compound as shown in formula (I), and a preparation method therefor. The crystalline form of the pharmaceutically acceptable salt of the present disclosure can be used for preventing and / or treating tyrosine kinase mediated or dependent diseases or conditions.

Description

A pharmaceutically acceptable salt, crystalline form and preparation method of a tyrosine kinase inhibitor

[0001] The present disclosure claims priority to a Chinese patent application filed with the Patent Office of China on August 11, 2023, entitled “A pharmaceutically acceptable salt, a crystalline form and a method for preparing the same” and application number 202311008796.0. The entire contents of the above application are incorporated herein by reference. Technical Field

[0002] The present disclosure relates to a pharmaceutically acceptable salt, a crystalline form and a preparation method of a tyrosine kinase inhibitor. Specifically, a pharmaceutically acceptable salt, a crystalline form and a preparation method of a compound represented by formula (I) are provided. Background Art

[0003] Fms-like tyrosine kinase 3 (FLT3) is primarily expressed in normal myeloid and lymphoid cell precursors and is expressed in 70% to 90% of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. FLT3, a member of the protein tyrosine kinase (PTK) family, was independently discovered by the Rosnet and Matthews groups in 1991. FLT3 belongs to the protein tyrosine receptor III family and is composed of an extracellular domain containing five immunoglobulins, a transmembrane domain, a juxtamembrane fragment, and a cytoplasmic region. Numerous studies have shown that mutations and aberrant activation of the tyrosine kinase FLT3 are closely associated with the development and progression of AML (Marrin, C. et al. Blood, 2014, 124, 3).

[0004] Patent CN108727341A provides a compound shown in the following formula, which has been found to have strong inhibitory activity against FLT3.

[0005] Based on their chemical structure, salts vary in solubility, stability, hygroscopicity, and other aspects. Furthermore, it is impossible to confidently predict whether a compound will crystallize and under what conditions. The presence and quantity of polymorphic compounds are unpredictable. Different crystalline forms of a compound can have significant differences in solubility, stability, hygroscopicity, and other aspects, which in turn can affect the efficacy and safety of the drug. Therefore, there is a need to develop salts and solid crystalline forms of compounds whose properties make them suitable for the development of drug substances and drug products.

[0006] Summary of the Invention

[0007] The present disclosure provides pharmaceutically acceptable salts and crystal forms of the compound represented by formula (I), as well as preparation methods and applications. The pharmaceutically acceptable salts and crystal forms disclosed herein have good physical and chemical properties, including good crystallinity and a high melting point. The pharmaceutically acceptable salts and crystal forms disclosed herein also have excellent stability, solubility, and low hygroscopicity, and are of great value to the optimization and development of drugs.

[0008] The present disclosure provides a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from hydrochloride, hippurate, p-toluenesulfonate,

[0009] Preferably, the chemical ratio of the compound represented by formula (I) to the acid molecule or anion is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0010] Preferably, the chemical ratio of the compound represented by formula (I) to hydrochloric acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0011] Preferably, the chemical ratio of the compound represented by formula (I) to hippuric acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0012] Preferably, the chemical ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0013] The present disclosure provides a hydrochloride salt of a compound represented by formula (I).

[0014] The present disclosure provides a crystalline form A of the hydrochloride salt of a compound represented by formula (I),

[0015] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 16.306±0.2° and 25.691±0.2°, preferably at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 13.245±0.2°, 16.306±0.2° and 25.691±0.2°. .653±0.2°, 21.351±0.2°, 22.673±0.2°, 23.542±0.2° and 25.691±0.2°, more preferably at 7.472±0.2°, 8.163±0.2°, 10.310±0.2°, 12.608±0.2°, 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, Characteristic peaks are found at 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22.673±0.2°, 22.953±0.2°, 23.542±0.2°, 25.691±0.2° and 27.492±0.2°, and particularly preferably at 7.472±0.2°, 8.163±0.2°, 10.310±0.2°, 12.608±0.2°, 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, 16.306±0.2°, 17.017±0.2°, 1 There are characteristic peaks at 0.2°, 17.653±0.2°, 19.677±0.2°, 20.396±0.2°, 21.351±0.2°, 22.091±0.2°, 22.673±0.2°, 22.953±0.2°, 23.542±0.2°, 24.826±0.2°, 25.691±0.2°, 26.829±0.2°, 27.492±0.2°, 30.747±0.2° and 35.942±0.2°, and the most preferred X-ray powder diffraction pattern expressed in diffraction angle 2θ is shown in Figure 1.

[0016] The present disclosure provides a hippurate salt of a compound represented by formula (I).

[0017] The present disclosure provides a crystalline form A of a hippurate salt of a compound represented by formula (I),

[0018] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2° and 23.774±0.2°, preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 20.256±0.2°, 23.387±0.2° and 23.774±0.2°, more preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2° The peaks are preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 18.007±0.2°, 18.481±0.2°, 19.624±0.2°, 20.256±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2° and 24.622±0.2°, and the peaks are preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 13.028±0.2°, 13.378±0.2°, 14.2 70±0.2°, 14.867±0.2°, 16.625±0.2°, 17.210±0.2°, 18.007±0.2°, 18.481±0.2°, 19.260±0.2°, 19.624±0.2°, 20.256±0.2°, 21.189±0.2°, 21.530±0.2°, 21.876±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2°, 24.622±0.2°, 24.885±0.2°, 25.380±0.2°, 26.250±0.2°, 26.691±0.2°, 27.006± The present invention relates to an X-ray powder diffraction pattern of the present invention, wherein the X-ray powder diffraction pattern is as follows: 1.544±0.2°, 2.776±0.2°, 3.111±0.2°, 3.397±0.2°, 3.436±0.2°, 3.620±0.2°, 3.913±0.2°, 3.091±0.2°, 3.106±0.2°, 3.247±0.2°, 3.304±0.2°, 3.441±0.2°, 3.620±0.2°, 3.913±0.2°, 3.913±0.2°, 3.091±0.2°, 3.106±0.2°, 3.247±0.2°, 3.309±0.2°, 3.

[0019] The present disclosure provides a p-toluenesulfonate salt of a compound represented by formula (I).

[0020] The present disclosure provides a crystalline form A of a p-toluenesulfonate salt of a compound represented by formula (I),

[0021] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, and 17.048±0.2°, preferably at 7.089±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, 17.048±0.2°, 18.555±0.2°, 21.084±0.2°, 23.756±0.2°, and 26. .924±0.2°, more preferably at 7.089±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, 17.048±0.2°, 18.555±0.2°, 20.107±0.2°, 21.084±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 24.699±0.2°, 25.479±0.2° and 26. The characteristic peaks are preferably at 7.089±0.2°, 7.387±0.2°, 8.679±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 13.745±0.2°, 14.201±0.2°, 14.706±0.2°, 16.248±0.2°, 17.048±0.2°, 18.057±0.2°, 18.555±0.2°, 19.168±0.2°, 20.1 The present invention discloses an X-ray powder diffraction pattern having characteristic peaks at 07±0.2°, 21.084±0.2°, 22.506±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 24.699±0.2°, 25.479±0.2°, 26.366±0.2°, 26.924±0.2°, 27.631±0.2°, 28.568±0.2°, 30.192±0.2° and 31.599±0.2°, and the most preferred X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 5.

[0022] Effects of the Invention

[0023] The hydrochloride, hippurate, and p-toluenesulfonate salts of the compound of formula (I) provided herein have advantages in terms of physical and chemical properties, formulation processing performance, and bioavailability, such as advantages in at least one of melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability. In particular, the hippurate salt crystal form A has good overall performance and has significant advantages over other crystal forms in at least one of solubility, stability, and hygroscopicity. The salts and crystal forms described herein have good physical and chemical stability, and the crystal forms prepared from the same starting materials have a high yield. They also have significant advantages in terms of solubility, hygroscopicity, stability, mechanical stability, fluidity, compressibility, and adhesion, providing a new and better option for the development of tyrosine kinase inhibitor drugs, which is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1: XRPD pattern of hydrochloride form A of the compound represented by formula (I).

[0025] Figure 2: DSC / TGA data of hydrochloride form A of the compound represented by formula (I).

[0026] Figure 3: XRPD pattern of hippurate salt form A of the compound represented by formula (I).

[0027] Figure 4: DSC / TGA data of hippurate salt form A of the compound represented by formula (I).

[0028] Figure 5: XRPD pattern of Form A of the p-toluenesulfonate salt of the compound represented by formula (I).

[0029] Figure 6: DSC / TGA data of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).

[0030] Figure 7: DVS diagram of hydrochloride form A of the compound represented by formula (I).

[0031] Figure 8: DVS image of hippurate salt form A of the compound represented by formula (I).

[0032] Figure 9: DVS diagram of the p-toluenesulfonate crystalline form A of the compound represented by formula (I).

[0033] Figure 10: XRPD pattern of Form B of the hippurate salt of the compound represented by formula (I).

[0034] Figure 11: XRPD pattern of Form C of the hippurate salt of the compound represented by formula (I).

[0035] Figure 12: XRPD pattern of hippurate salt form D of the compound represented by formula (I).

[0036] Figure 13: XRPD pattern of hippurate salt form E of the compound represented by formula (I). DETAILED DESCRIPTION

[0037] To make the technical solutions and beneficial effects of the present disclosure more clearly understood, the following detailed description is provided by way of specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly illustrate the details of the local features. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0038] The present disclosure provides a pharmaceutically acceptable salt of a compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from hydrochloride, hippurate, p-toluenesulfonate,

[0039] Preferably, the chemical ratio of the compound represented by formula (I) to the acid molecule or anion is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0040] Preferably, the chemical ratio of the compound represented by formula (I) to hydrochloric acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0041] Preferably, the chemical ratio of the compound represented by formula (I) to hippuric acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0042] Preferably, the chemical ratio of the compound represented by formula (I) to p-toluenesulfonic acid is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1.

[0043] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), comprising the step of forming a salt with an acid.

[0044] In certain embodiments, the solvent used in the salt-forming reaction is selected from at least one of methanol, butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water.

[0045] In certain embodiments, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of evaporating the solvent or stirring for crystallization, filtering, drying, and the like.

[0046] The present disclosure provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salt.

[0047] The present disclosure also provides a pharmaceutical composition comprising the aforementioned pharmaceutically acceptable salt or the pharmaceutically acceptable salt prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0048] The present disclosure provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned pharmaceutically acceptable salt, or the pharmaceutically acceptable salt of the compound of formula (I) prepared by the aforementioned method, with a pharmaceutically acceptable carrier, diluent or excipient.

[0049] The present disclosure provides a pharmaceutically acceptable salt of a compound of the preceding formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or use of the composition prepared by the aforementioned method in preparing a medicament for preventing and / or treating a disease or condition mediated or dependent on tyrosine kinase, preferably in preparing a medicament for preventing and / or treating a disease or condition mediated or dependent on FLT3 or a mutant thereof; preferably, the tyrosine kinase-mediated or dependent disease or condition is selected from cancer, preferably acute myeloid leukemia.

[0050] The present disclosure provides a hydrochloride salt of a compound represented by formula (I).

[0051] The present disclosure provides a crystalline form A of the hydrochloride salt of a compound represented by formula (I),

[0052] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 16.306±0.2° and 25.691±0.2°, preferably at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 13.245±0.2°, 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22.673±0.2°, 23.542±0.2° and 25.691±0.2°, more preferably at 7.472±0.2° , 15.181±0.2°, 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22.673±0.2°, 22.953±0.2°, 23.542±0.2°, 25.691±0.2° and 27.492±0.2°, and particularly preferably at 7.472±0.2°, 8.163±0.2°, 10.310±0.2°, 12.608±0.2°, 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22.673±0.2°, 22.953±0.2°, 23.542±0.2°, 25.691±0.2° and 27.492±0.2°. 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, 16.306±0.2°, 17.017±0.2°, 17.653±0.2°, 19.677±0.2°, 20.396±0.2°, 21.351±0.2°, 22.091±0.2°, 22.673±0.2° , 22.953±0.2°, 23.542±0.2°, 24.826±0.2°, 25.691±0.2°, 26.829±0.2°, 27.492±0.2°, 30.747±0.2° and 35.942±0.2°, and the most preferred X-ray powder diffraction pattern expressed in diffraction angle 2θ is shown in Figure 1.

[0053] The present disclosure provides a method for preparing a crystalline form A of the hydrochloride salt of a compound represented by formula (I), comprising the steps of: mixing the compound represented by formula (I), hydrochloric acid and solvent 1, and reacting to obtain crystals.

[0054] In certain embodiments, the solvent 1 is selected from isopropyl alcohol.

[0055] In certain embodiments, the preparation method disclosed herein further comprises steps such as centrifugation, washing or drying.

[0056] The present disclosure provides a hippurate salt of a compound represented by formula (I).

[0057] The present disclosure provides a crystalline form A of a hippurate salt of a compound represented by formula (I),

[0058] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2° and 23.774±0.2°, preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 20.256±0.2°, 23.387±0.2° and 23.774±0.2°, more preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2° The peaks are preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 18.007±0.2°, 18.481±0.2°, 19.624±0.2°, 20.256±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2° and 24.622±0.2°, and the peaks are preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 13.028±0.2°, 13.378±0.2°, 14.2 70±0.2°, 14.867±0.2°, 16.625±0.2°, 17.210±0.2°, 18.007±0.2°, 18.481±0.2°, 19.260±0.2°, 19.624±0.2°, 20.256±0.2°, 21.189±0.2°, 21.530±0.2°, 21.876±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2°, 24.622±0.2°, 24.885±0.2°, 25.380±0.2°, 26.250±0.2°, 26.691±0.2°, 27.006± The present invention relates to an X-ray powder diffraction pattern of the present invention, wherein the X-ray powder diffraction pattern is as follows: 1.544±0.2°, 2.776±0.2°, 3.111±0.2°, 3.397±0.2°, 3.436±0.2°, 3.620±0.2°, 3.913±0.2°, 3.091±0.2°, 3.106±0.2°, 3.247±0.2°, 3.304±0.2°, 3.441±0.2°, 3.620±0.2°, 3.913±0.2°, 3.913±0.2°, 3.091±0.2°, 3.106±0.2°, 3.247±0.2°, 3.309±0.2°, 3.

[0059] The present disclosure provides a method for preparing crystalline form A of a hippurate salt of a compound represented by formula (I), characterized in that the method comprises the steps of: mixing the compound represented by formula (I), hippuric acid and solvent 2, and crystallizing after the reaction.

[0060] In certain embodiments, the solvent 2 is preferably selected from tetrahydrofuran.

[0061] In certain embodiments, the preparation method disclosed herein further comprises steps such as centrifugation, washing or drying.

[0062] The present disclosure provides a p-toluenesulfonate salt of a compound represented by formula (I).

[0063] The present disclosure provides a crystalline form A of a p-toluenesulfonate salt of a compound represented by formula (I),

[0064] The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, and 17.048±0.2°, preferably at 7.089±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, 17.048±0.2°, 18.555±0.2°, 21.084±0.2°, 23.756±0.2°, and 26. .924±0.2°, more preferably at 7.089±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, 17.048±0.2°, 18.555±0.2°, 20.107±0.2°, 21.084±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 24.699±0.2°, 25.479±0.2° and 26. The characteristic peaks are preferably at 7.089±0.2°, 7.387±0.2°, 8.679±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 13.745±0.2°, 14.201±0.2°, 14.706±0.2°, 16.248±0.2°, 17.048±0.2°, 18.057±0.2°, 18.555±0.2°, 19.168±0.2°, 20.1 The present invention discloses an X-ray powder diffraction pattern having characteristic peaks at 07±0.2°, 21.084±0.2°, 22.506±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 24.699±0.2°, 25.479±0.2°, 26.366±0.2°, 26.924±0.2°, 27.631±0.2°, 28.568±0.2°, 30.192±0.2° and 31.599±0.2°, and the most preferred X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 5.

[0065] The present disclosure provides a method for preparing a crystalline form A of a p-toluenesulfonic acid salt of a compound represented by formula (I), characterized in that the method comprises the steps of: mixing the compound represented by formula (I), p-toluenesulfonic acid and a solvent 3, and reacting to obtain crystals.

[0066] In certain embodiments, the solvent 3 is preferably selected from butanone.

[0067] In certain embodiments, the preparation method disclosed herein further comprises steps such as centrifugation, washing or drying.

[0068] The present disclosure further provides a pharmaceutical composition prepared from the crystalline form A of the hydrochloride salt of the compound represented by the aforementioned formula (I), the crystalline form A of the hippurate salt of the compound represented by the aforementioned formula (I), or the crystalline form A of the p-toluenesulfonate salt of the compound represented by the aforementioned formula (I).

[0069] The present disclosure further provides a pharmaceutical composition containing Form A of the hydrochloride salt of the compound represented by the aforementioned formula (I) or Form A of the hippurate salt of the compound represented by the aforementioned formula (I) or Form A of the p-toluenesulfonate salt of the compound represented by the aforementioned formula (I) and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[0070] The present disclosure further provides a method for preparing a pharmaceutical composition, comprising the step of mixing the crystalline form A of the hydrochloride salt of the compound represented by the aforementioned formula (I) or the crystalline form A of the hippurate salt of the compound represented by the aforementioned formula (I) or the crystalline form A of the p-toluenesulfonate salt of the compound represented by the aforementioned formula (I) with a pharmaceutically acceptable carrier, diluent or excipient.

[0071] The present disclosure further provides a crystalline form A of the hydrochloride salt of the compound represented by the aforementioned formula (I), or the crystalline form A of the hippurate salt of the compound represented by the aforementioned formula (I), or the crystalline form A of the p-toluenesulfonate salt of the compound represented by the aforementioned formula (I), or the aforementioned composition, or the use of the composition prepared by the aforementioned method in the preparation of a drug for preventing and / or treating tyrosine kinase-mediated or dependent diseases or conditions.

[0072] In certain embodiments, the crystalline form A of the hydrochloride salt of the compound represented by the aforementioned formula (I) or the crystalline form A of the hippurate salt of the compound represented by the aforementioned formula (I) or the crystalline form A of the p-toluenesulfonate salt of the compound represented by the aforementioned formula (I), or the aforementioned composition, or the composition prepared by the aforementioned method is used in the preparation of a drug for preventing and / or treating diseases or conditions mediated or dependent on FLT3 or its mutants.

[0073] In certain embodiments, the tyrosine kinase-mediated or -dependent disease or condition is selected from cancer.

[0074] In certain embodiments, the cancer is selected from acute myeloid leukemia.

[0075] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.2 (including the case where the number exceeding 1 decimal place is rounded off), which can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, - 0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0076] The precipitation methods disclosed herein include, but are not limited to, stirring, cooling, volatilization, beating, and precipitation.

[0077] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2020 edition of the Chinese Pharmacopoeia,

[0078] Deliquescent: Absorbs sufficient water to form a liquid;

[0079] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0080] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0081] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0082] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0083] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0084] The drying temperature in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and the drying can be performed under normal pressure or reduced pressure.

[0085] A "pharmaceutical composition" refers to a composition comprising one or more pharmaceutically acceptable salts of the compounds of Formula (I) described herein, or crystalline forms thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0086] The method of the present invention is described below by means of specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples. The implementation conditions adopted in the examples can be further adjusted according to specific requirements. The implementation conditions not specified are generally the conditions in routine experiments.

[0087] The abbreviations used in this disclosure are explained as follows:

[0088] XRPD: X-ray powder diffraction

[0089] DSC: Differential Scanning Calorimetry

[0090] TGA: Thermogravimetric analysis

[0091] DVS: Dynamic Water Sorption

[0092] Instruments and methods used to collect data:

[0093] XRPD

[0094] X-ray powder diffraction data of the sample were collected under ambient conditions using a Bruker D2 X-ray powder diffractometer with an X-ray emitter power of 300 W. The sample stage had no background signal, the step rate was 0.15 s / step, the total number of steps was 1837, the step length was 2θ = 0.02°, the voltage was 30 kV, and the current was 10 mA. The X-ray tube used a Cu target (Kα) with a Kα2 / Kα1 intensity ratio of

[0095] DSC

[0096] Thermal data for the samples were collected using a TA Discovery 2500 Series Differential Scanning Calorimeter (DSC). Several milligrams of sample were weighed into a Tzero aluminum pan, sealed with a Tzero seal lid. Heating was performed under N2 protection with an N2 flow rate of 50 mL / min and a heating rate of 10°C / min.

[0097] TGA

[0098] Thermogravimetric data were collected using a TA Discovery 550 series thermogravimetric analyzer. Several milligrams of sample were placed in a crucible and heated from room temperature to the target temperature under N2 protection at a flow rate of 60 mL / min and a heating rate of 10°C / min.

[0099] DVS

[0100] Hygroscopicity data for the sample was collected at 25°C using an ADVENTURE series dynamic vapor sorption instrument (DVS) under N2 protection. The sample size was ~30 mg. The crystal form was tested as follows:

[0101] Anhydrous crystal type:

[0102] 1) The first relative humidity increase process: 0% RH to 90% RH, the rate is 10% RH / stage; 90% RH to 95% RH, the rate is 5% RH / stage;

[0103] 2) Relative humidity reduction process: 95% RH to 90% RH, the rate is 5% RH / stage; 90% RH to 0% RH, the rate is 10% RH / stage;

[0104] Hydrate:

[0105] 1) The first relative humidity increase process: the room humidity is increased to 90% RH at a rate of 10% RH / stage; from 90% RH to 95% RH, the rate is 5% RH / stage;

[0106] 2) Relative humidity reduction process: 95% RH to 90% RH, the rate is 5% RH / stage; 90% RH to 0% RH or room humidity, the rate is 10% RH / stage;

[0107] The second relative humidity increase process: 0% RH to 90% RH, the rate is 10% RH / stage; 90% RH to 95% RH, the rate is 5% RH / stage.

[0108] The compound represented by formula (I) disclosed in the present invention can be prepared according to existing technologies, for example, according to the method described in CN108727341A.

[0109] Example 1: Screening of salt forms of the compound represented by formula (I)

[0110] According to the rough solubility and pKa (basicity 4.9 and 6.9, calculated by ACD Labs) of the compound represented by formula (I), 22 acids were selected and 100 salt type screening experiments were set up through reactive crystallization in different molar ratios and four solvent systems. The specific experimental steps are divided into two types. When the ligand is solid, first weigh the corresponding mass of the ligand, then weigh ~20 mg of the compound represented by formula (I) into an HPLC vial, and then add about 0.3 mL of the corresponding solvent and stir magnetically at room temperature. When the ligand is liquid, weigh ~20 mg of the compound represented by formula (I) into an HPLC vial, first add 0.3 mL of the corresponding solvent, then add the corresponding volume of the ligand to the vial, and stir magnetically at room temperature. After stirring for 2 days, the solid was separated by centrifugation, dried in vacuo at 30°C overnight, and the dried solid was collected for characterization.

[0111] Based on the characterization results, a total of 23 new crystal forms / salt forms were discovered, designated as corresponding ligand acid salts A to C. The salt form screening results are shown in Table 1. The characterization results of the new crystal forms / salt forms are summarized in Table 2.

[0112] Table 1: Summary of screening results of salt forms of compounds represented by formula (I)

[0113] *: According to HPLC purity and 1 H NMR data suggested that degradation had occurred.

[0114] Table 2: Summary of characterization data of new crystal forms / salt forms of the compound represented by formula (I)

[0115] The temperature in [] is the end point temperature of TGA integration, and the starting point is room temperature;

[0116] *: The purity is significantly lower than that of the starting sample (99.58 area%). It is speculated that partial degradation may have occurred.

[0117] Based on the basic solid-state property results, hydrochloride form A, hippurate form A and p-toluenesulfonate form A were recommended as the preferred salt forms. The selection criteria included but were not limited to: 1) high crystallinity, 2) simple DSC thermal signal, 3) ligand safety, and 4) ligand commonality.

[0118] Example 2: Preparation of Form A of the Hydrochloride Salt of the Compound Represented by Formula (I)

[0119] Weigh 450.77 mg of the compound of formula (I) into a 20-mL glass vial and add 5 mL of isopropanol. After magnetic stirring at room temperature (~20°C) for 5 minutes, a uniform suspension was formed. At an acid / base molar ratio of 1.05:1, 0.1 mL of concentrated hydrochloric acid was added to a 4-mL glass vial and diluted with 2.5 mL of isopropanol. The diluted acid solution was slowly dripped into the suspension of the compound of formula (I) using a dropper. 4.5 mL of isopropanol was added for rinsing, and the suspension was magnetically stirred at room temperature for 2 days. The sample was filtered and vacuum-dried at 30°C for 1 day to collect 390 mg of product, with a yield of approximately 79%. X-ray powder diffraction analysis confirmed that the product was Form A of the hydrochloride salt of the compound of formula (I). The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 3. The DSC / TGA spectrum is shown in Figure 2.

[0120] Table 3: XRPD diffraction peak data of Form A of the hydrochloride salt of the compound represented by formula (I)

[0121] Example 3: Preparation of Form A of the Hippurate Salt of the Compound of Formula (I)

[0122] 5.043 g of the compound represented by formula (I) was weighed into a 250-mL reaction flask, 70 mL of THF was added, and magnetic stirring (120 rpm / min) was performed at room temperature (~20°C) to form a suspension. 2.369 g of hippuric acid was weighed and added to approximately 40 mL of THF at an acid / base molar ratio of 1.05:1 to form a uniform suspension. The hippuric acid suspension was slowly dripped into the suspension of the compound represented by formula (I) using a dropper, and 30 mL of THF was added as a rinse solution. The mixture was magnetically stirred at room temperature for 1 day. The sample was filtered and vacuum-dried at 50°C for 2 days to collect 5.98 g of product, with a yield of approximately 81%. X-ray powder diffraction analysis showed that the product was Form A of the hippurate salt of the compound represented by formula (I). The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 4. The DSC / TGA spectrum is shown in Figure 4.

[0123] Table 4: XRPD diffraction peak data of Form A of the hippurate salt of the compound represented by formula (I)

[0124] Example 4: Preparation of Form A of the p-toluenesulfonate salt of the compound represented by formula (I)

[0125] Weigh 398.69 mg of the compound of formula (I) into a 20-mL glass vial and add 5 mL of butanone. After magnetic stirring at room temperature (~20°C) for 5 minutes, a uniform suspension was formed. At an acid / base molar ratio of 1.05:1, weigh 225.74 mg of p-toluenesulfonic acid into a 20-mL glass vial and dissolve it with 3 mL of butanone. The dissolved acid solution was slowly dripped into the suspension of the compound of formula (I) using a dropper. Rinse with 4 mL of butanone and magnetically stir at room temperature for 2 days. The sample was filtered and vacuum-dried at 30°C overnight to collect 430 mg of product, with a yield of approximately 69%. X-ray powder diffraction analysis confirmed that the product was Form A of the p-toluenesulfonate salt of the compound of formula (I). The XRPD spectrum is shown in Figure 5 , and the positions of its characteristic peaks are shown in Table 5 . The DSC / TGA spectrum is shown in Figure 6 .

[0126] Table 5: XRPD diffraction peak data of Form A of the p-toluenesulfonate salt of the compound represented by formula (I)

[0127] Example 5: Solubility of the Crystalline Salt of the Compound Represented by Formula (I)

[0128] SGF (simulated artificial gastric fluid) and FeSSIF (simulated fed intestinal fluid) are bio-relevant media that can better reflect the impact of the gastrointestinal physiological environment on drug release. The solubility tested in such media is closer to the solubility in the human body environment.

[0129] Approximately 30 mg of the starting material (calculated as the compound of formula (I)) was added to 3 mL of water and two biological solvents (SGF and FeSSIF), respectively, and shaken at 37°C (100 rpm). 1 mL samples were taken at 1, 4, and 24 hours, centrifuged for 1 minute, and the supernatant / clarified solution was filtered and used for solubility testing (HPLC) and pH analysis. The results are shown in Table 6.

[0130] Table 6: Dynamic solubility of the crystalline form of the salt of the compound represented by formula (I) in different solvents Solubility unit: mg / mL;

[0131] The hydrochloride salt form A was observed to change in crystal form in water, and the p-toluenesulfonate salt form A was observed to change in crystal form in FeSSIF.

[0132] Example 6: Hygroscopicity of the Crystalline Salt of the Compound Represented by Formula (I)

[0133] As shown in FIG7 , the weight change of hydrochloride crystal form A during the adsorption / desorption process from 0% RH to 95% RH is relatively uniform, and the weight gain at 80% RH is 8.8% (compared to the starting point of 30% RH), indicating that hydrochloride crystal form A is hygroscopic.

[0134] Form A hippurate was subjected to DVS testing starting at 60% RH (room humidity) and ending at 95% RH. The results (Figure 8) show that Form A hippurate gained 0.7% weight at 80% RH (compared to the starting point of 60% RH). In the desorption curve, the sample's weight changed slowly from 10% RH to 95% RH, indicating that Form A hippurate is slightly hygroscopic.

[0135] Figure 9 shows that Form A, the p-toluenesulfonate salt, experiences relatively slow weight changes during adsorption / desorption from 10% RH to 80% RH, while experiencing rapid weight loss / gain at RH <10%. The sample gained 1.4% at 80% RH (compared to the starting point of 50% RH), and rapidly gained 2.8% from 80% RH to 95% RH, indicating that Form A, the p-toluenesulfonate salt, is slightly hygroscopic.

[0136] Example 7: Stability of the Crystalline Form of the Salt of the Compound Represented by Formula (I)

[0137] To evaluate the physicochemical stability of the preferred salt forms (hydrochloride form A, hippurate form A, and p-toluenesulfonate form A), hydrochloride form A, hippurate form A, and p-toluenesulfonate form A were exposed to the air at 25°C / 60% RH, 40°C / 75% RH, and 60°C, and samples stored for one and two weeks were subjected to HPLC and XRPD analysis, respectively.

[0138] The results showed that there was no crystalline change in hippurate Form A and p-toluenesulfonate Form A; the crystallinity of hydrochloride Form A was significantly reduced at 25°C / 60% RH and 40°C / 75% RH; the purity of p-toluenesulfonate Form A and hippurate Form A did not change significantly.

[0139] Table 7: Evaluation results of the solid-state stability of the salt of the compound represented by formula (I)

[0140] Example 8: Crystal Screening of Hippurate Salt of the Compound Represented by Formula (I)

[0141] A total of 95 polymorph screening experiments were designed using hippurate form A as the starting material. The methods included: antisolvent addition, gas-solid diffusion, gas-liquid diffusion, slow evaporation, polymer induction, room temperature / 50°C slurrying, cyclic heating and cooling (50-5°C), slow cooling, and grinding. Based on the characterization results, a total of five new polymorphs were discovered, designated as forms A to E. Hippurate forms B to E had poor crystalline stability under room temperature and humidity, but easily converted to hippurate form A after drying under room temperature and humidity, indicating that hippurate form A has better stability.

[0142] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations of the claims. Various modifications and variations may be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments merely illustrate several implementations of the present invention and do not limit the scope of protection of the patent of this invention.

Claims

1. A pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from hydrochloride, hippurate, p-toluenesulfonate, 2. The pharmaceutically acceptable salt according to claim 1, characterized in that The chemical ratio of the compound represented by formula (I) to the acid molecule or anion is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:

1.

3. The pharmaceutically acceptable salt according to claim 1 or 2, which is hippurate.

4. A method for preparing a pharmaceutically acceptable salt according to any one of claims 1 to 3, comprising: The step of forming a salt of the compound of formula (1) with an acid.

5. The method according to claim 4, characterized in that The solvent used in the salt-forming reaction is selected from at least one of methanol, butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water.

6. Form A of the hydrochloride of the compound represented by formula (I), It is characterized in that The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 16.306±0.2° and 25.691±0.2°, preferably at 7.472±0.2°, 8.163±0.2°, 12.608±0.2°, 13.245±0.2°, 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22 .673±0.2°, 23.542±0.2° and 25.691±0.2°, more preferably at 7.472±0.2°, 8.163±0.2°, 10.310±0.2°, 12.608±0.2°, 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, 16.306±0.2°, 17.653±0.2°, 21.351±0.2°, 22.673±0.2° , 22.953±0.2°, 23.542±0.2°, 25.691±0.2° and 27.492±0.2°, and particularly preferably at 7.472±0.2°, 8.163±0.2°, 10.310±0.2°, 12.608±0.2°, 13.245±0.2°, 13.839±0.2°, 15.181±0.2°, 16.306±0.2°, 17.017±0.2°, 17.653±0.2° 0.2°, 19.677±0.2°, 20.396±0.2°, 21.351±0.2°, 22.091±0.2°, 22.673±0.2°, 22.953±0.2°, 23.542±0.2°, 24.826±0.2°, 25.691±0.2°, 26.829±0.2°, 27.492±0.2°, 30.747±0.2° and 35.942±0.2°, and the most preferred is the diffraction The X-ray powder diffraction pattern expressed in 2θ degrees is shown in FIG1 .

7. Form A of hippurate of the compound represented by formula (I), It is characterized in that The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2° and 23.774±0.2°, preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 20.256±0.2°, 23.387±0.2° and 23.774±0.2°, more preferably at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 20.256±0.2°, 23.387±0.2° and 23.774±0.2°. The invention also has characteristic peaks at 0.2°, 10.051±0.2°, 12.578±0.2°, 14.867±0.2°, 16.625±0.2°, 18.007±0.2°, 18.481±0.2°, 19.624±0.2°, 20.256±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2° and 24.622±0.2°, and it is particularly preferred that the peaks are at 6.655±0.2°, 7.083±0.2°, 9.169±0.2°, 10.051±0.2°, 12.578±0.2°, 13.028±0.2°, 13.378±0.2°, 14.2 70±0.2°, 14.867±0.2°, 16.625±0.2°, 17.210±0.2°, 18.007±0.2°, 18.481±0.2°, 19.260±0.2°, 19.624±0.2°, 20.256±0.2°, 21.189±0.2°, 21.530±0.2°, 21.876±0.2°, 22.486±0.2°, 23.387±0.2°, 23.774±0.2°, 24.622±0.2°, 24.885±0.2°, 25.380±0.2°, 26.250±0.2°, 26.691±0.2°, 27.006±0.2° 38.233±0.2°, 39.716±0.2°, 31.704±0.2°, 32.571±0.2°, 33.533±0.2°, 34.172±0.2°, 34.939±0.2°, 35.508±0.2°, 36.268±0.2°, 36.596±0.2°, and 38.233±0.2° have characteristic peaks, and the most preferred X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 3.

8. Form A of the p-toluenesulfonate of the compound represented by formula (I), It is characterized in that The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, and 17.048±0.2°, preferably at 7.089±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, and 17.048±0.2°. There are characteristic peaks at 6.248±0.2°, 17.048±0.2°, 18.555±0.2°, 21.084±0.2°, 23.756±0.2° and 26.924±0.2°, more preferably at 7.089±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 16.248±0.2°, 17.048±0.2°, 18.555±0.2°, 20.107±0.2°, 21.084±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 24.699±0.2°, 25.479±0.2°, and 26.924±0.2 °, especially preferably at 7.089±0.2°, 7.387±0.2°, 8.679±0.2°, 9.555±0.2°, 11.153±0.2°, 12.095±0.2°, 12.649±0.2°, 13.745±0.2°, 14.201±0.2°, 14.706±0.2°, 16. 248±0.2°, 17.048±0.2°, 18.057±0.2°, 18.555±0.2°, 19.168±0.2°, 20.107±0.2°, 21.084±0.2°, 22.506±0.2°, 22.957±0.2°, 23.756±0.2°, 24.420±0.2°, 2 There are characteristic peaks at 4.699±0.2°, 25.479±0.2°, 26.366±0.2°, 26.924±0.2°, 27.631±0.2°, 28.568±0.2°, 30.192±0.2° and 31.599±0.2°, and the most preferred X-ray powder diffraction pattern expressed in diffraction angle 2θ is shown in Figure 5.

9. The method for preparing the crystalline form A of the hydrochloride of the compound represented by formula (I) according to claim 6, characterized in that: The method comprises the steps of: mixing a compound represented by formula (I), hydrochloric acid and a solvent 1, and crystallizing after reaction; the solvent 1 is preferably selected from isopropanol.

10. The method for preparing the crystalline form A of the hippurate salt of the compound represented by formula (I) according to claim 7, characterized in that: The method comprises the steps of: mixing the compound represented by formula (I), hippuric acid and solvent 2, and crystallizing after reaction; the solvent 2 is preferably tetrahydrofuran.

11. A method for preparing the crystalline form A of the p-toluenesulfonate of the compound represented by formula (I) according to claim 8, characterized in that: The method comprises the steps of: mixing a compound represented by formula (I), p-toluenesulfonic acid and a solvent 3, and crystallizing after reaction; the solvent 3 is preferably selected from butanone.

12. A pharmaceutical composition prepared from the crystalline form A of the hydrochloride salt of the compound of formula (I) according to claim 6, the crystalline form A of the hippurate salt of the compound of formula (I) according to claim 7, or the crystalline form A of the p-toluenesulfonate salt of the compound of formula (I) according to claim 8.

13. A pharmaceutical composition comprising the crystalline form A of the hydrochloride salt of the compound represented by formula (I) according to claim 6, the crystalline form A of the hippurate salt of the compound represented by formula (I) according to claim 7, or the crystalline form A of the p-toluenesulfonate salt of the compound represented by formula (I) according to claim 8, and a pharmaceutically acceptable carrier, diluent or excipient.

14. A method for preparing a pharmaceutical composition, comprising the step of mixing the hydrochloride form A of the compound of formula (I) according to claim 6, the hippurate form A of the compound of formula (I) according to claim 7, or the p-toluenesulfonate form A of the compound of formula (I) according to claim 8 with a pharmaceutically acceptable carrier, diluent or excipient.

15. Use of the hydrochloride form A of the compound of formula (I) according to claim 6, the hippurate form A of the compound of formula (I) according to claim 7, or the p-toluenesulfonate form A of the compound of formula (I) according to claim 8, or the composition according to claim 12 or 13, or the composition prepared by the method according to claim 14 in the preparation of a medicament for preventing and / or treating a disease or condition mediated or dependent on tyrosine kinase, preferably in the preparation of a medicament for preventing and / or treating a disease or condition mediated or dependent on FLT3 or its mutants; Preferably, the tyrosine kinase-mediated or -dependent disease or disorder is selected from cancer, preferably acute myeloid leukemia.

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