EA044623B1 - CRYSTAL FORMS OF THE COMPOUND - Google Patents

Description

Field of technology

The present invention relates to the field of pharmaceuticals and provides new crystalline forms, solvates and crystalline forms thereof of the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl )ethyl)amino)pyrimidine-5-carbonitrile and pharmaceutical compositions containing them, as well as methods for their preparation and their use.

State of the art

PI _3K (phosphatidylinositol 3-kinase) is a family of lipid kinases, and disruption of the PI3K-mediated signal transduction pathway is believed to play critical roles in the initiation and development of a variety of malignancies. Dysregulation and hyperactivation of the PI3K/AKT pathway have been found in cancer cells. PI ₃ Kδ is also involved in mammalian immune system functions, including signaling from B cells, T cells, mast cells, dendritic cells, neutrophils, NK cells and monocytes/phagocytes. Studies have shown that PI3K inhibition, including selective inhibition of PI3K5 activity, is suitable for the treatment of autoimmune diseases or inflammatory diseases such as: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis and asthma. In addition, inhibition of PI3K, including selective inhibition of PI3K5 activity, is also suitable for the treatment of cancer, in particular hematological malignancies such as lymphoma, leukemia and multiple myeloma.

Suitable compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile according to the present invention with chemical structure Formula A is capable of effectively inhibiting PI3K, in particular it has PI3K5 inhibitory activity. Thus, the compound is suitable for the treatment of diseases susceptible to inhibition of PI3K activity, for example for the treatment of autoimmune diseases, inflammatory diseases and cancer.

NH ₂ formula A

The phenomenon that a compound can exist as two or more crystal structures is known as polymorphism. Many compounds can exist in various polymorphic crystals and also in solid amorphous form. However, until polymorphism of a compound is discovered, it is very difficult to predict (1) whether a particular compound will exhibit polymorphism, (2) how such unknown polymorphs can be produced, and (3) what are the properties, such as stability, of such unknown polymorphs. See, for example, J. Bernstein Polymorphism in Molecular Crystals, Oxford University Press, (2002).

Because the properties of a solid depend on both the structure and the nature of the compound itself, different solid forms of a compound can and often do exhibit different physical and chemical properties, as well as different biopharmaceutical properties. Differences in chemical properties can be determined, analyzed and compared through a number of analytical methods. These differences can ultimately be used to differentiate different solid forms. In addition, differences in physical properties such as solubility and biopharmaceutical properties such as bioavailability are also important when describing the solid state of a pharmaceutical compound. Likewise, when developing a pharmaceutical compound, such as a compound of Formula A, new crystalline and amorphous forms of the pharmaceutical compound are also important.

The compound (S)-4-amino-6-(( 1 -(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin-5 carbonitrile and its preparation are described in the application for patent WO 2016045591 A1.

The essence of the invention

Short description

As a result of extensive research and search, the present inventors have discovered that the compound of formula A (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl) ethyl)amino)pyrimidine-5-carbonitrile can exist in various crystalline forms (i.e. polymorphs) and can form solvates with some solvents. The inventors of the present invention have conducted extensive studies on polymorphs of the compound of formula A and have, as a result, obtained and characterized crystalline forms that meet the requirements for pharmaceutical use. Based on these studies, the present invention provides various crystalline forms of the compound of formula A and its solvates and crystalline forms thereof, which are designated as Form I, Form IV, Form V, Form VI and Form VIII, respectively.

In one aspect, the polymorphs of the compound of formula A or solvates thereof according to the present invention have good crystallinity and good stability and are non-hygroscopic.

First, the present invention provides crystalline Form I (S)-4-amino-6((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine -5-carbonitrile, that is, Form I of the compound of formula A.

Secondly, the present invention provides crystalline Form IV of (S)-4-amino6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin- 5-carbonitrile, that is, Form IV of the compound of formula A.

Also provided according to the present invention is crystalline form V (S)-4-amino-6-((1(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin-5- carbonitrile, that is, Form V of the compound of formula A.

In addition, according to the present invention there are provided solvates of (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile , which are the acetone solvate and aqueous isopropanol solvate of the compound of formula A.

In addition, according to the present invention there are provided solvates of (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile , which are the monoacetone solvate and the aqueous isopropanol solvate (containing 3 molecules of water and 0.5 molecules of isopropanol) of the compound of formula A.

In addition, according to the present invention, there is provided a monoacetone solvate of (S)-4-amino-6((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin-5 -carbonitrile, which is Form VI of the compound of formula A.

In addition, according to the present invention, there is provided an aqueous isopropanol solvate (containing 3 molecules of water and 0.5 molecules of isopropanol) (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b] pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile, which is Form VIII of the compound of formula A.

In another aspect, the present invention provides methods for preparing crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) that are reproducible and easy to implement. .

In yet another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of one or more crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII), and the remainder an amount of at least one pharmaceutically acceptable carrier.

The present invention also provides a method of treating diseases susceptible to inhibition of PI3K activity, comprising administering to a subject in need thereof an effective amount of one or more crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI or Form VIII) according to the present invention.

The present invention also provides the use of crystalline forms of a compound of formula A, solvates of a compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI or Form VIII) for the preparation of a medicament for the treatment of diseases susceptible to inhibition of activity PI3K. In some embodiments, said diseases susceptible to inhibition of PI3K activity are selected from autoimmune diseases, inflammatory diseases, and cancer (preferably hematologic malignancies). In some embodiments, said autoimmune diseases or inflammatory diseases are selected from systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis, and asthma. In some embodiments, said cancer is selected from a lymphoma (such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, small cell lymphocytic lymphoma, marginal zone lymphoma, Burkitt's lymphoma, B-cell lymphoma, T-cell lymphoma, NK cell lymphoma, and diffuse large B-cell lymphoma), leukemia (such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia and chronic myelogenous leukemia), multiple myeloma and Waldenström's macroglobulinemia.

Brief description of drawings

In fig. 1 shows a powder X-ray diffraction pattern of Form I of a compound of formula A, where the x-axis (X-axis) represents the diffraction angle 2 theta, and the ordinate (Y-axis) represents the diffraction intensity (%).

In fig. 2 shows a differential scanning calorimetry (DSC) profile for Form I of a compound of formula A, where the x-axis (X-axis) represents temperature (°C) and the y-axis (Y-axis) represents heat flux (mW).

In fig. Figure 3 shows a thermogravimetric (TG) profile for Form I of a compound of formula A, where the x-axis (X-axis) represents the temperature (°C) and the y-axis (Y-axis) represents the mass in percent (%).

- 2 044623

In fig. Figure 4 shows a powder X-ray diffraction pattern of Form IV of a compound of formula A, where the x-axis (X-axis) represents the diffraction angle of 2 theta, and the ordinate (Y-axis) represents the diffraction intensity (%).

In fig. 5 shows a differential scanning calorimetry (DSC) profile for Form IV of a compound of formula A, where the x-axis (X-axis) represents temperature (°C) and the y-axis (Y-axis) represents heat flux (mW).

In fig. 6 shows a thermogravimetric (TG) profile for Form IV of a compound of formula A, where the x-axis (X-axis) represents the temperature (°C) and the y-axis (Y-axis) represents the mass in percent (%).

In fig. Figure 7 shows a powder X-ray diffraction pattern of Form V of a compound of formula A, where the x-axis (X-axis) represents the diffraction angle of 2 theta, and the ordinate (Y-axis) represents the diffraction intensity (%).

In fig. 8 shows a differential scanning calorimetry (DSC) profile for Form V of a compound of formula A, where the x-axis (X-axis) represents temperature (°C) and the y-axis (Y-axis) represents heat flux (mW).

In fig. 9 shows a thermogravimetric (TG) profile for Form V of a compound of formula A, where the x-axis (X-axis) represents the temperature (°C) and the y-axis (Y-axis) represents the mass in percent (%).

In fig. 10 shows a powder X-ray diffraction pattern of Form VI of a monoacetone solvate of a compound of formula A, where the x-axis (X-axis) represents the diffraction angle of 2 theta, and the ordinate (Y-axis) represents the diffraction intensity (%).

In fig. 11 shows a differential scanning calorimetry (DSC) profile for Form VI of the monoacetone solvate of compound of formula A, where the x-axis (X-axis) represents temperature (°C) and the y-axis (Y-axis) represents heat flux (mW).

In fig. 12 shows the thermogravimetric (TG) profile for Form VI of the monoacetone solvate of the compound of formula A, where the x-axis (X-axis) represents the temperature (°C) and the y-axis (Y-axis) represents the mass in percent (%).

In fig. 13 shows a powder X-ray diffraction pattern of Form VIII of an aqueous isopropanol solvate of the compound of formula A, where the x-axis (X-axis) represents the diffraction angle of 2 theta, and the ordinate (Y-axis) represents the diffraction intensity (%).

In fig. 14 shows a differential scanning calorimetry (DSC) profile for Form VIII of the aqueous isopropanol solvate of compound of formula A, where the x-axis (X-axis) represents temperature (°C) and the y-axis (Y-axis) represents heat flux (mW).

In fig. 15 shows the thermogravimetric (TG) profile for Form VIII of the aqueous isopropanol solvate of compound of formula A, where the x-axis (X-axis) represents the temperature (°C) and the y-axis (Y-axis) represents the mass in percent (%).

In fig. 16 shows an isothermal dynamic vapor sorption (DVS) curve of Form I of a compound of formula A, where the x-axis (X-axis) represents the relative humidity (%) and the y-axis (Y-axis) represents the percentage change in mass (%).

In fig. 17 shows an isothermal dynamic vapor sorption (DVS) curve for Form IV of a compound of formula A, where the x-axis (X-axis) represents the relative humidity (%) and the ordinate (Y-axis) represents the percentage change in mass (%).

In fig. 18 shows an isothermal dynamic vapor sorption (DVS) curve for Form V of a compound of formula A, where the x-axis (X-axis) represents the relative humidity (%) and the ordinate (Y-axis) represents the percentage change in mass (%).

Definitions

Unless otherwise specified, the following abbreviations or terms used in this application (including the description and claims) have the meanings given below. It should be noted that in the present specification and claims, the indefinite and definite forms of the singular include plural entities unless expressly stated otherwise.

The term crystalline forms according to the present invention as used herein refers to crystalline forms of Form I, Form IV, Form V, Form VI or Form VIII of a compound of formula A or solvates thereof or any mixture thereof. As used herein, the terms form, crystalline form, and polymorph may be used interchangeably.

The term compound of formula A or (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin7-yl)ethyl)amino)pyrimidine-5-carbonitrile as used herein refers to a compound having the following chemical structure of formula A (also called compound A):

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Formula A.

The term C _1-6 alkanol as used herein refers to a fully saturated straight or branched alkyl alcohol containing 1, 2, 3, 4, 5 or 6 carbon atoms. Examples include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, nbutanol, isobutanol, tert-butanol, n-pentanol, isopentanol, n-hexanol and the like.

The term C5-8 straight or branched alkane as used herein refers to a fully saturated straight or branched hydrocarbon containing 5, 6, 7 or 8 carbon atoms. Examples include, but are not limited to, n-pentane, n-hexane, nheptane, n-octane and the like.

The term approximately as used herein refers to a deviation from a specified numerical value of no more than ±10%.

The term substantially free of other forms as used herein means that the content of said other forms is less than 50%, preferably less than 40%, preferably less than 30%, preferably less than 20%, preferably less than 10%, preferably less than 5%, preferably less than 1 % by weight based on the total weight of the forms.

The term solution as used herein means a mixture of one or more solutes in one or more solvents for a particular application. A solution includes both homogeneous and heterogeneous mixtures, such as slurries or other suspension mixtures containing insoluble (undissolved) material.

The term organic solvent as used herein broadly means any suitable organic solvent for the particular application disclosed herein.

The term dissolution solvent as used herein refers to any suitable organic solvent that is capable of dissolving, in whole or in part, solutes under suitable conditions, such as a suitable amount and a suitable temperature, for example, room temperature or elevated temperature.

The term dissolution-inhibiting solvent as used herein refers to any suitable organic solvent in which the substance has less solubility than in the dissolution solvent.

The term effective amount of a compound of formula A and its crystalline forms, solvates and crystalline forms thereof means an amount that is effective to alleviate or provide regression of diseases susceptible to inhibition of PI ₃ K activity, such as autoimmune diseases, inflammatory diseases and cancer (preferably hematological malignancies disease), when administered to an individual, which may be a human, animal or the like, wherein diseases susceptible to inhibition of PI3K activity, such as autoimmune diseases, inflammatory diseases and cancer (preferably hematological malignancies) include, but are not limited to, , systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis, asthma, lymphoma (such as Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, small cell lymphocytic lymphoma, marginal zone lymphoma, Ber lymphoma kitta, B-cell lymphoma, T-cell lymphoma, NK cell lymphoma and diffuse large B-cell lymphoma), leukemia (such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia and chronic myelogenous leukemia), multiple myeloma and Waldenström's macroglobulinemia. The effective amount may vary depending on various factors such as the compound, the condition of the disease being treated, the severity of the disease being treated, the age and health status of the individual, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and so on.

The term individual or subject as used herein means mammals and non-mammals. The term mammals means any member of the class mammals, including, but not limited to, humans; non-human primates such as chimpanzees and other species of monkeys and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; pets such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds and the like. The term individual or subject does not designate a specific age or gender.

Detailed Description of the Present Invention

The present invention provides new crystalline forms, solvates and crystalline forms thereof of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino )pyrimidine-5-carbonitrile.

The crystalline forms of the present invention have good crystallinity and good stability and are non-hygroscopic. The crystalline forms of the present invention are characterized by good reproducibility and can provide reproducible production in high yield; Moreover, they are stable in conventional formulations, and therefore can be conveniently used for the preparation of formulations and treatment of diseases. In addition, the crystalline forms of the present invention have high purity and lower residual solvent content, which meets the quality requirements of bulk medicinal products, such as the requirements of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Q3A) Guideline Q3A.

A person skilled in the art can verify the above advantages of the crystalline forms according to the present invention in accordance with the methods of analysis disclosed in the pharmacopoeias and their modifications or conventional methods known in the art.

As described herein, crystalline forms of the present invention can be identified using one or more solid state analysis techniques. For example, the crystalline forms of the present invention may be identified using one or more methods, for example, X-ray powder diffractometry, single crystal lattice parameters, Fourier transform infrared spectroscopy, differential scanning calorimetry analysis data and/or thermogravimetric curve. Moreover, if the result of identification or analysis by one of these methods corresponds to the result for the forms according to the present invention, this does not mean that the result obtained using any other methods corresponds to the result for the forms according to the present invention.

As described herein, new crystalline forms can be identified according to powder X-ray diffractometry data. However, it is known in the art that peak intensities and/or measured peak angles determined from a powder X-ray diffraction pattern may vary depending on different experimental conditions, for example, different diffraction analysis conditions and/or orientation preference effects or the like. In addition, the measured 2θ value may have an error of approximately ±0.2 2θ due to differences in the accuracy of the instruments. However, it is known that, compared to peak positions, relative peak intensity values are more dependent on certain properties of the samples being tested, such as the size of the crystals in the sample, the effect of crystal orientation, and the purity of the analytes. Therefore, peak intensity deviations of about ±20% or more may be observed. However, despite experimental errors, instrument errors, orientation preferences, and the like, one skilled in the art can obtain information from the PXD data presented herein that is sufficient to identify Form I and any other crystalline forms of the present invention.

Form I.

The present invention provides Form I of the compound of formula A.

In some embodiments, Form I of the compound of formula A can be identified according to powder x-ray diffraction data. In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form I of a compound of formula A include values of 6.8, 10.0, 16.5, 20.1, and 22.6 degrees, where each of the measured 2θ values has the error is approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form I of the compound of Formula A include values of 6.8, 10.0, 13.7, 14.4, 15.3, 16.5, 20.1, 21.3 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form I of a compound of Formula A include values of 6.8, 8.0, 10.0, 12.1, 13.7, 14.4, 15.0, 15.3, 16.5, 18.7, 20.1, 21.3 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form I of the compound of Formula A include values of 6.8, 7.6, 8.0, 10.0, 12.1, 12.6, 13.7, 14.4, 15.0, 15.3, 16.2, 16.5, 17.0, 18.7, 20.1, 21.3 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the diffraction pattern

- 5 044623 powder X-ray diffraction of Form I of compounds of formula A include values 6.8, 7.6, 8.0,

10.0, 12.1, 12.6, 13.7, 14.4, 15.0, 15.3, 16.2, 16.5, 17.0, 17.9, 18.7, 20, 1, 21.3, 22.6, 23.1, 25.4, 26.1 and 29.0 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, Form I of the compound of Formula A has the diffraction pattern shown in FIG. 1.

In some embodiments, Form I of the compound of formula A can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form I of the compound of formula A has a DSC curve shown in FIG. 2. In the DSC profile, the endothermic peak of Form I of the compound of formula A is located at approximately 261.2-262.1°C.

In some embodiments, Form I of a compound of Formula A can be characterized by thermogravimetric analysis (TGA). In some embodiments, Form I of the compound of Formula A has a TGA curve shown in FIG. 3, which indicates that Form I is an anhydrous substance or a pure crystal.

In some embodiments, Form I of the compound of Formula A is substantially free of the other crystalline forms described herein. For example, the content by weight of Form I of the compound of formula A is at least 99%, at least 95%, at least 90%, or even less than 80%. In addition, the content by weight of Form I of the compound of formula A is at least 70% or at least 60%. In addition, the content by weight of Form I of the compound of formula A is at least 50%.

Methods for obtaining Form I.

Method A.

The present invention relates to a process for preparing Form I of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent to dissolve and heat the mixture to reflux to obtain a solution; for example, said at least one dissolution solvent is selected from ethyl acetate, tetrahydrofuran, 1,4dioxane, butanone, toluene, dichloromethane, a mixture of ethanol and acetic acid, a mixture of ethyl acetate and acetone, a mixture of ethyl acetate and isopropanol, or a mixture of butanone and ethanol;

(2) cooling the solution obtained in step (1) until a solid precipitates;

(3) isolating to obtain solid Form I the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, the at least one dissolution solvent is selected from ethyl acetate, tetrahydrofuran, 1,4-dioxane, butanone, toluene, and dichloromethane.

In some embodiments, said at least one dissolution solvent is selected from ethanol/acetic acid (about 25/4 v/v), ethyl acetate/acetone (about 7/3 to about 3/7 v/v) .), ethyl acetate/isopropanol mixtures (about 7/3 to about 3/7 v/v), butanone/ethanol mixtures (about 1/1 to about 1/4 v/v), and the like.

In some embodiments, said cooling of the solution may be accomplished by slow cooling while stirring, for example, stirring at a moderate speed, for example, at a speed in the range of 50 to 200 rpm.

In some embodiments, said cooling of the solution may be accomplished by natural cooling or controlled temperature cooling to room temperature or lower, such as 25-30°C, 20-25°C, 5-10°C, and the like.

In some embodiments, the drying temperature and drying time may be determined in a conventional manner by one skilled in the art so as to ensure sufficient drying and retention of the desired crystalline properties of the solid. In some embodiments, the drying temperature is 55-60°C, such as 55°C, 58°C, or 60°C. In some embodiments, the drying time is 1-24 hours, such as 1 hour, 1.5 hours, 2 hours, or 16 hours.

Method B.

The present invention provides another method for preparing Form I of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of tetrahydrofuran and water, and heating the mixture to boiling under reflux to obtain the first solution; for example, said at least one dissolution solvent is selected from one or more of the following: ethyl acetate, 1,4-dioxane, ethanol and tetrahydrofuran;

(2) adding at least one dissolution-inhibiting solvent to said first solution to form a second solution and then cooling the second solution until a solid precipitates; or, alternatively, first cooling said first solution and then adding at least one anti-dissolution solvent until the solid precipitates

- 6 044623 substances; wherein, if said dissolution solvent in step (1) is ethanol, the dissolution preventing solvent is not water;

(3) isolating to obtain solid Form I the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, the tetrahydrofuran and water are mixed in a suitable ratio. In some embodiments, the volume ratio of tetrahydrofuran to water is about 4/1.

In some embodiments, said dissolution-inhibiting solvent is selected from water, a C5-8 straight or branched alkane (such as n-heptane), and isopropyl ether.

In some embodiments, the volume ratio of the at least one dissolution solvent or solvent mixture consisting of tetrahydrofuran and water to the at least one anti-dissolution solvent is in the range of from about 1/3 to about 6/1, for example , 1/2.7, 1/1.33, 1/1, 1.2/1, 5.4/1.

Method C.

The present invention provides another method for preparing Form I of a compound of formula A, comprising:

(1) suspending the solid form of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile in solvent; for example, said solvent is selected from one or more of the following: ethyl acetate, toluene, tetrahydrofuran and ethanol;

(2) stirring the suspension obtained in step (1), wherein if said solvent in step (1) is ethanol, the stirring time must be at least 24 hours;

(3) isolating to obtain solid Form I the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solid form of the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile , used in step (1) may be in the form of any forms, such as a single crystalline form or an amorphous form, for example, Form IV or Form V, or mixtures of two or more crystalline forms or an amorphous form.

In some embodiments, in said step (1), the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin- The 5-carbonitrile is not completely dissolved in the suspension system, meaning some of the compound remains as a solid.

In some embodiments, said solvent is selected from one or more of ethyl acetate and toluene.

In some embodiments, heat may be applied to stir the suspension in step (2), and the heating temperature does not exceed the boiling point of the solvent system, such as when refluxing.

It should be understood that Form I of the compound of Formula A can be prepared by one or more of the methods described above.

Form IV.

The present invention provides Form IV of the compound of formula A.

In some embodiments, Form IV of a compound of formula A can be identified according to powder x-ray diffraction data. In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form IV of a compound of formula A include values of 4.6, 9.2, 15.5, 17.8, and 19.0 degrees, where each of the measured 2θ values has the error is approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form IV of a compound of Formula A include values of 4.6, 9.2, 11.5, 12.0, 13.2, 15.5, 16.0, 17.8, 19.0 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form IV of a compound of Formula A include values of 4.6, 9.2, 9.7, 11.3, 11.5, 12.0, 13.2, 13.8, 14.7, 15.5, 16.0, 17.8, 19.0, 22.3 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ) .

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form IV of a compound of Formula A include values of 4.6, 7.2, 8.2, 9.2, 9.7, 11.3, 11.5, 12.0, 13.2, 13.8, 14.4, 14.7, 15.5, 16.0, 16.5, 17.8, 19.0, 22.3 and 22.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form IV of a compound of Formula A include values of 4.6, 7.2, 8.2, 9.2, 9.7, 11.3, 11.5, 12.0, 13.2, 13.8, 14.4, 14.7, 15.5, 16.0, 16.5, 17.8, 18.2, 19.0, 19.5, 21, 1, 21.6, 22.3, 22.6 and 23.6 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

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In some embodiments, Form IV of the compound of Formula A has the diffraction pattern shown in FIG. 4.

In some embodiments, Form IV of a compound of Formula A can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form IV of the compound of formula A has a DSC curve shown in FIG. 5. In the DSC profile, the endothermic peak of Form IV of the compound of formula A is located at approximately 261.8-263.8°C.

In some embodiments, Form IV of a compound of Formula A can be characterized by thermogravimetric analysis (TGA). In some embodiments, Form IV of the compound of Formula A has a TGA curve shown in FIG. 6, which indicates that Form IV is an anhydrous substance or pure crystal.

In some embodiments, Form IV of the compound of Formula A is substantially free of the other crystalline forms described herein. For example, the content by weight of Form IV of the compound of formula A is at least 99%, at least 95%, at least 90%, or even less than 80%. In addition, the content by weight of Form IV of the compound of formula A is at least 70% or at least 60%. In addition, the content by weight of Form IV of the compound of formula A is at least 50%.

Methods for obtaining Form IV.

Method A.

The present invention relates to a process for preparing Form IV of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of a water-miscible organic solvent and water, and heating the mixture to boiling under reflux to obtain a solution; for example, said at least one dissolution solvent is selected from C ₁ . ₆ αlkanol, a mixture of isopropanol and acetic acid or a mixture of methanol and acetic acid; said water-miscible organic solvent is selected from C ₁ . ₆ alkanol, provided that said water-miscible organic solvent is not tert-butanol;

(2) cooling the solution obtained in step (1) until a solid precipitates;

(3) isolating to obtain solid Form IV the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said C ₁ . ₆ The alkanol is selected from methanol, ethanol, isopropanol and n-butanol. In some embodiments, said C ₁ . ₆ The alkanol is selected from methanol, ethanol and isopropanol. In some embodiments, said C ₁ . ₆ alkanol is selected from ethanol.

In some embodiments, said water-miscible organic solvent is selected from ethanol, isopropanol, and n-butanol.

In some embodiments, the percentage volumetric content of said water-miscible organic solvent in said solvent mixture is no more than about 95%, such as 95%, 90%, 80%, 70%, and the like.

In some embodiments, the at least one dissolution solvent is selected from isopropanol/acetic acid (about 22/1 v/v), methanol/acetic acid (about 25/3 v/v), and the like .

In some embodiments, said cooling of the solution may be accomplished by slow cooling while stirring, for example, stirring at a moderate speed, for example, at a speed in the range of 50 to 200 rpm. In some embodiments, stirring is applied after cooling, and the stirring time is preferably no more than 24 hours.

In some embodiments, said cooling of the solution may be accomplished by natural cooling or cooling at a controlled temperature (eg, a cooling rate of 0.2°C/min, 0.5°C/min, 2°C/min, and the like) to room temperature or lower temperature such as 20-25°C, 0-5°C and the like.

In some embodiments, the drying temperature and drying time may be determined in a conventional manner by one skilled in the art so as to ensure sufficient drying and retention of the desired crystalline properties of the solid. In some embodiments, the drying temperature is 50-60°C, such as 55°C. In some embodiments, the drying time is 1-24 hours, such as 1.5 hours, 2 hours, 5 hours, or 17 hours.

Method B.

The present invention provides another method for preparing Form IV of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of a water-miscible organic solvent and water, and heating the mixture to boiling under reflux to obtain the first solution; For example,

- 8 044623 said at least one solvent for dissolution is selected from methanol, ethanol, isopropanol or a mixture of 1,4-dioxane and ethanol; said water-miscible organic solvent is selected from C ₁ . ₆ alkanol or a mixture of tetrahydrofuran and ethanol;

(2) adding at least one dissolution-inhibiting solvent to said first solution to form a second solution and then cooling the second solution until a solid precipitates; or, alternatively, first cooling said first solution and then adding at least one anti-dissolution solvent until a solid precipitates;

(3) isolating to obtain solid Form IV the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said at least one dissolution solvent is selected from 1,4-dioxane/ethanol (about 1/5 v/v) and the like.

In some embodiments, said water-miscible organic solvent is selected from C ₁ . ₆ α-alkanols such as methanol, ethanol and isopropanol. In some embodiments, the percentage volumetric content of said water-miscible organic solvent in said solvent mixture of water-miscible organic solvent and water is no more than about 95%, such as 95%, 80%, 70%, and the like .

In some embodiments, said water-miscible organic solvent and water are mixed in a suitable ratio. In some embodiments, the volume ratio of the water-miscible organic solvent to water is from about 6/1 to 4/1, such as in a methanol/water mixture (about 16/3 v/v), a tetrahydrofuran/ethanol/water mixture ( about 1/99/25, about 5/95/25, or about 10/90/25 v/v).

In some embodiments, said dissolution-preventing solvent is selected from water.

In some embodiments, the volume ratio of the at least one dissolution solvent or solvent mixture consisting of a water-miscible organic solvent and water to the at least one anti-dissolution solvent is in the range of from about 1/3 to about 2 /1, for example, 1/2.1, 1/1.4, 1/1, 1.36/1.

In some embodiments, said dissolution-inhibiting solvent may be added in one portion or added in multiple portions.

Method C.

The present invention provides another method for preparing Form IV of a compound of formula A, comprising:

(1) suspending the solid form of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile in solvent; wherein said solvent is selected from C ₁ . ₆ α-alkanol, water or a solvent mixture consisting of a water-miscible organic solvent (such as one selected from methanol, ethanol and isopropanol) and water;

(2) stirring the suspension obtained in step (1), wherein if said solvent in step (1) is ethanol, the stirring time should be less than 24 hours;

(3) isolating to obtain solid Form IV the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solid form of the compound (S)-4-amino-6-((1-(3-chloro6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile , used in step (1) may be in the form of any forms, for example, a single crystalline form or an amorphous form such as Form I, Form IV, Form V, Form VI or Form VIII, or a mixture of two or more crystalline forms or an amorphous form .

In some embodiments, in said step (1), the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin- The 5-carbonitrile is not completely dissolved in the suspension system, meaning some of the compound remains as a solid.

In some embodiments, said C ₁ . ₆ The alkanol is selected from methanol, ethanol and isopropanol.

In some embodiments, said water-miscible organic solvent is selected from methanol. In some embodiments, the percentage volumetric content of said water-miscible organic solvent in said solvent mixture is less than about 25%, such as 10%.

In some embodiments, heat may be applied in step (2) while stirring the suspension, and the heating temperature does not exceed the boiling point of the solvent system, for example, 60-70°C, 70-80°C, 75-85°C, and the like. Said heating may cause the solid in the suspension system to be converted to Form IV of the compound of formula A.

It should be understood that Form IV of the compound of Formula A can be prepared by one or more of the methods described above.

- 9 044623

Form V.

The present invention provides Form V of the compound of formula A.

In some embodiments, Form V of a compound of formula A can be identified according to powder x-ray diffraction data. In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form V of a compound of formula A include values of 7.3, 11.6, 14.6, 19.3 and 23.4 degrees, where each of the measured 2θ values has the error is approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form V of a compound of formula A include values of 4.6, 7.3, 8.9, 11.6, 13.5, 14.6, 15.5, 18.0, 19.3 and 23.4 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form V of a compound of formula A include values of 4.6, 7.3, 8.9, 10.0, 11.2, 11.6, 13.5, 14.6, 15.5, 16.0, 18.0, 19.3, 20.0 and 23.4 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form V of a compound of formula A include values of 4.6, 7.3, 8.9, 10.0, 11.2, 11.6, 13.5, 14.6, 15.5, 16.0, 18.0, 19.3, 20.0, 22.7, 23.4, 25.1, 26.0 and 27.2 degrees, where each of the measured values 2θ has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form V of a compound of formula A include values of 4.6, 7.3, 8.9, 10.0, 11.2, 11.6, 13.5, 14.6, 15.5, 16.0, 17.7, 18.0, 19.3, 20.0, 22.7, 23.4, 24.0, 25.1, 26.0, 27, 2, 28.4 and 29.7 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, Form V of the compound of formula A has the diffraction pattern shown in FIG. 7.

In some embodiments, Form V of a compound of formula A can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form V of the compound of formula A has a DSC curve shown in FIG. 8. In the DSC profile, the endothermic peak of Form V of the compound of formula A is located at approximately 261.4-262.4°C.

In some embodiments, Form V of a compound of Formula A can be characterized by thermogravimetric analysis (TGA). In some embodiments, Form V of the compound of formula A has a TGA curve shown in FIG. 9, which indicates that Form V is an anhydrous substance or pure crystal.

In some embodiments, Form V of the compound of Formula A is substantially free of the other crystalline forms described herein. For example, the content by weight of Form V of the compound of formula A is at least 99%, at least 95%, at least 90%, or even less than 80%. In addition, the content by weight of Form V of the compound of formula A is at least 70% or at least 60%. In addition, the content by weight of Form V of the compound of formula A is at least 50%.

Methods for obtaining form V.

Method A.

The present invention relates to a process for preparing Form V of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of acetonitrile and water, and heating the mixture to boiling under reflux to obtain a solution; for example, said at least one dissolution solvent is selected from acetonitrile, a mixture of acetonitrile and acetic acid, a mixture of acetonitrile and ethyl acetate, a mixture of acetonitrile and butanone, a mixture of acetonitrile and tetrahydrofuran, or a mixture of acetone and ethanol;

(2) cooling the solution obtained in step (1) until a solid precipitates;

(3) isolating to obtain solid Form V the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, the at least one dissolution solvent is selected from acetonitrile.

In some embodiments, said solvent mixture of acetonitrile and water has a volume percentage of said acetonitrile in said solvent mixture of 90%.

In some embodiments, the at least one dissolution solvent is selected from acetonitrile/acetic acid (about 14/1 v/v), acetonitrile/ethyl acetate (about 7/3 v/v), acetonitrile/ethyl acetate (about 7/3 v/v), butanone (approximately 1/1 v/v), acetonit-10 044623 ril/tetrahydrofuran mixtures (approximately 7/3 v/v), acetone/ethanol mixtures (approximately 1/4 v/v), etc. similar.

In some embodiments, said cooling of the solution may be accomplished by slow cooling while stirring, for example, stirring at a moderate speed, for example, at a speed in the range of 50 to 200 rpm.

In some embodiments, said cooling of the solution may be accomplished by natural cooling or controlled temperature cooling to room temperature or lower, such as 20-25°C, (-10)-(-5)°C, and the like.

In some embodiments, the drying temperature and drying time may be determined in a conventional manner by one skilled in the art so as to ensure sufficient drying and retention of the desired crystalline properties of the solid. In some embodiments, the drying temperature is 50-60°C, such as 50°C or 60°C. In some embodiments, the drying time is 1-24 hours, such as 1 hour or 16 hours.

Method B.

The present invention provides another method for preparing Form V of a compound of formula A, comprising:

(1) suspending the solid form of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile in acetonitrile;

(2) stirring the suspension obtained in step (1);

(3) isolating to obtain solid Form V the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solid form of the compound (S)-4-amino-6-((1-(3-chloro6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile . used in step (1) may be in any form, for example, a single crystalline form or an amorphous form such as Form I, Form IV or Form V, or a mixture of two or more crystalline forms or an amorphous form.

In some embodiments, in said step (1), the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin- The 5-carbonitrile is not completely dissolved in the suspension system, meaning some of the compound remains as a solid.

In some embodiments, heat may be applied in step (2) while stirring the suspension, and the heating temperature does not exceed the boiling point of the solvent system, for example, 70-80°C.

It should be understood that Form V of the compound of Formula A can be prepared by one or more of the methods described above.

Acetone solvate.

The present invention also provides an acetone solvate of the compound of formula A.

In some embodiments, the acetone solvate of the compound of formula A is a monoacetone solvate.

In some embodiments, the monoacetone solvate of the compound of Formula A is Form VI.

In some embodiments, Form VI monoacetone solvate of the compound of formula A can be characterized by powder x-ray diffractometry. The characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VI include values of 8.6, 10.4, 12.0, 15.0 and 19.7 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VI monoacetone solvate of the compound of formula A include values of 6.9, 8.6, 9.8, 10.4, 12.0, 13.4, 15, 0, 19.7, 20.6, 23.8 and 29.8 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VI monoacetone solvate of the compound of formula A include values of 6.9, 8.6, 9.8, 10.4, 12.0, 13.4, 15, 0, 15.8, 16.8, 18.0, 19.7, 20.6, 23.3, 23.8, 26.2 and 29.8 degrees, where each of the measured 2θ values has an error of approximately ±0 .2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VI monoacetone solvate of the compound of formula A include values of 6.9, 8.6, 9.8, 10.4, 12.0, 13.4, 15, 0, 15.8, 16.8, 18.0, 19.4, 19.7, 20.6, 21.0, 22.5, 23.0, 23.3, 23.8, 25.0, 26.2 and 29.8 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VI monoacetone solvate of the compound of Formula A include values of 6.9, 8.6, 9.0, 9.8, 10.4, 12.0, 13, 4, 15.0, 15.8, 16.2, 16.8, 17.3, 18.0, 18.2, 18.9, 19.4, 19.7, 20.6, 21.0, 21.6, 22.5, 23.0, 23.3, 23.8, 24.5, 25.0, 26.2 and 29.8 degrees, where each of the measured values

- 11 044623

2θ has an error of approximately ±0.2 degrees (2θ).

In some embodiments, Form VI monoacetone solvate of the compound of formula A has the diffraction pattern shown in FIG. 10.

In some embodiments, Form VI monoacetone solvate of the compound of formula A can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form VI monoacetone solvate of the compound of formula A has a DSC curve shown in FIG. 11. In the DSC profile, the endothermic peaks of Form VI monoacetone solvate of the compound of formula A are at about 97.3-106.0°C and about 262.3-265.0°C.

In some embodiments, Form VI monoacetone solvate of the compound of Formula A can be characterized by thermogravimetric analysis (TGA). In some embodiments, Form VI monoacetone solvate of the compound of formula A has a TGA curve shown in FIG. 12, which indicates that Form VI is a solvate. The result of subsequent analysis by gas chromatography (GC) shows that the indicated form contains 1 molecule of acetone. Form VI is a monoacetone solvate.

In some embodiments, Form VI monoacetone solvate of the compound of Formula A is substantially free of the other crystalline forms described herein. For example, the content by weight of Form VI monoacetone solvate of the compound of formula A is at least 99%, at least 95%, at least 90%, or even less than 80%. In addition, the content by weight of Form VI monoacetone solvate of the compound of formula A is at least 70% or at least 60%. In addition, the content by weight of Form VI monoacetone solvate of the compound of formula A is at least 50%.

Methods for obtaining Form VI.

Method A.

The present invention relates to a process for preparing Form VI of a compound of formula A, comprising:

(1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of acetone and water, and heating the mixture to boiling under reflux to obtain a solution; wherein said at least one solvent for dissolution is selected from acetone or a solvent mixture consisting of acetone and isopropanol;

(2) cooling the solution obtained in step (1) until a solid precipitates;

(3) isolating to obtain solid Form VI the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solvent mixture of acetone and water has a volume percentage of said acetone in said solvent mixture of 95% or 75%.

In some embodiments, said acetone and isopropanol are mixed in a suitable ratio. In some embodiments, the volume ratio of acetone to isopropanol is about 7/3.

In some embodiments, said cooling of the solution may be accomplished by natural cooling or controlled temperature cooling to room temperature or lower, such as 25-30°C, 20-25°C, 0-5°C, and the like.

In some embodiments, the drying temperature and drying time may be determined in a conventional manner by one skilled in the art so as to ensure sufficient drying and retention of the desired crystalline properties of the solid. In some embodiments, the drying conditions are air drying for 30 minutes.

Method B.

The present invention provides another method for preparing Form VI of the compound of formula A, comprising:

(1) suspending the solid form of the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile in acetone or a solvent mixture consisting of acetone and water;

(2) stirring the suspension obtained in step (1);

(3) isolating to obtain solid Form VI the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solid form of the compound (S)-4-amino-6-((1-(3-chloro6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile , used in step (1) may be in the form of any forms, for example, a single crystalline form or an amorphous form such as Form I or Form V, or a mixture of two or more crystalline forms or an amorphous form.

In some embodiments, in said step (1), the compound (S)-4-amino-6-((1-(3-chloro-6phenylimidazo[1,2-b]pyridazin-7-yl)ethyl)amino)pyrimidin- 5-carbonitrile is not completely dissolved in

- 12 044623 suspension system, that is, part of the compound remains as a solid.

In some embodiments, said acetone and water are mixed in a suitable ratio.

In some embodiments, the volume ratio of acetone to water is about 3/1.

In some embodiments, in said step (2), the mixing time of the suspension is at least 48 hours, for example 6 days.

It should be understood that Form VI of the compound of Formula A can be prepared by one or more of the methods described above.

Aqueous isopropanol solvate.

The present invention also provides an aqueous isopropanol solvate of the compound of formula A.

In some embodiments, the aqueous isopropanol solvate of the compound of Formula A contains 3 molecules of water and 0.5 molecules of isopropanol.

In some embodiments, the aqueous isopropanol solvate (containing 3 molecules of water and 0.5 molecules of isopropanol) of the compound of Formula A is Form VIII.

In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of formula A can be characterized by powder x-ray diffractometry. The characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VIII include values of 7.0, 8.3, 11.4, 15.3 and 23.1 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VIII aqueous isopropanol solvate of the compound of Formula A include values of 7.0, 8.3, 9.8, 10.7, 11.4, 15.3, 15.7, 22.4 and 23.1 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VIII aqueous isopropanol solvate of the compound of Formula A include values of 7.0, 8.3, 9.8, 10.7, 11.4, 13.3, 14.2, 15.3, 15.7, 17.7, 22.4, 23.1, 25.4 and 26.9 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ) .

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VIII aqueous isopropanol solvate of the compound of Formula A include values of 7.0, 8.3, 9.8, 10.7, 11.4, 13.3, 13.8, 14.2, 15.3, 15.7, 17.7, 19.0, 19.4, 20.3, 22.4, 23.1, 23.5, 25.4 and 26, 9 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, the characteristic diffraction angles (2θ) in the X-ray powder diffraction pattern of Form VIII aqueous isopropanol solvate of the compound of Formula A include values of 7.0, 8.3, 9.8, 10.7, 11.4, 13.3, 13.8, 14.2, 15.3, 15.7, 17.7, 19.0, 19.4, 19.6, 20.3, 21.4, 22.4, 23.1, 23, 5, 24.0, 25.0, 25.4, 26.9 and 27.2 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ).

In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of formula A has the diffraction pattern shown in FIG. 13.

In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of formula A can be characterized using differential scanning calorimetry (DSC). In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of Formula A has the DSC curve shown in FIG. 14. In the DSC profile, the endothermic peaks of Form VIII of the aqueous isopropanol solvate of the compound of formula A are at about 64.181.7°C and about 261.5-262.2°C.

In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of Formula A can be characterized by thermogravimetric analysis (TGA). In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of formula A has a TGA curve shown in FIG. 15, which indicates that Form VIII is a solvate. The results of subsequent determination of water content by the Karl-Fischer (KF) method and analysis by gas chromatography (GC) show that the indicated form contains 3 molecules of water and 0.5 molecules of isopropanol. Form VIII is a water-isopropanol solvate containing 3 molecules of water and 0.5 molecules of isopropanol.

In some embodiments, Form VIII of the aqueous isopropanol solvate of the compound of formula A is substantially free of the other crystalline forms described herein. For example, the content by weight of Form VIII of the aqueous isopropanol solvate of the compound of formula A is at least 99%, at least 95%, at least 90%, or even less than 80%. In addition, the content by weight of Form VIII of the aqueous isopropanol solvate of the compound of formula A is at least 70% or at least 60%. In addition, the content by weight of Form VIII of the aqueous isopropanol solvate of the compound of formula A is at least 50%.

- 13 044623

Methods for obtaining Form VIII.

The present invention relates to a process for preparing Form VIII of a compound of formula A, comprising:

(1) mixing the compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile with a mixture of solvents consisting of isopropanol and water, and heating the mixture to boiling under reflux to obtain a solution;

(2) cooling the solution obtained in step (1) until a solid precipitates and then stirring the mixture (preferably for at least 72 hours);

(3) isolating to obtain solid Form VIII the compound of formula A;

(4) optionally, drying the solid obtained in step (3).

In some embodiments, said solvent mixture of isopropanol and water has a volume percentage of said isopropanol in said solvent mixture of 70%.

In some embodiments, the drying temperature and drying time may be determined in a conventional manner by one skilled in the art so as to ensure sufficient drying and retention of the desired crystalline properties of the solid. In some embodiments, the drying conditions are air drying for 50-100 minutes.

Features of each embodiment of the methods described above for preparing crystalline forms of the compound of Formula A or solvates thereof can be optionally combined. Each embodiment derived from such arbitrary combinations is included within the scope of the present invention to the same extent as if those embodiments derived from such arbitrary combinations were specifically and independently listed herein.

Pharmaceutical compositions and methods of treatment.

Crystalline forms of the compound of formula A, solvates of the compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI and Form VIII) are suitable for the treatment of diseases such as autoimmune diseases, inflammatory diseases and cancer. The cancer is preferably a hematological malignancy. Autoimmune diseases, inflammatory diseases and cancer include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis, asthma, lymphoma (such as Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, follicular lymphoma, small cell lymphocytic lymphoma, marginal zone lymphoma, Burkitt lymphoma, B-cell lymphoma, T-cell lymphoma, NK cell lymphoma and diffuse large B-cell lymphoma), leukemia (such as chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia and chronic myelogenous leukemia), multiple myeloma and Waldenström's macroglobulinemia.

The present invention provides a method of treating diseases susceptible to inhibition of PI3K activity, comprising administering active pharmaceutical ingredients containing a compound of formula A or one or more crystalline forms of a compound of formula A, solvates of a compound of formula A and crystalline forms thereof (e.g. Form I, Form IV , Form V, Form VI or Form VIII).

In some embodiments, the method of treatment targets at least one of the diseases susceptible to inhibition of PI3K activity, such as autoimmune diseases, inflammatory diseases, and cancer (preferably a hematologic malignancy). An effective amount of a pharmaceutical composition according to the present invention is administered to a subject in need thereof, wherein said pharmaceutical composition contains at least one pharmaceutically acceptable carrier and one or more crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (e.g., Form I, Form IV, Form V, Form VI or Form VIII).

An administered amount of at least one active pharmaceutical ingredient selected from crystalline forms of a compound of formula A, solvates of a compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI or Form VIII) providing the desired biological effect, may depend on a number of factors, such as the intended use, route of administration and the clinical condition of the patient. The daily dose may, for example, be in the range of 0.01 mg to 3 g/day (eg, 0.05 mg to 2 g/day, even 100 mg to 1 g/day). Unit dose formulations that can be administered orally include, for example, tablets or capsules.

For the treatment of the above conditions, at least one active pharmaceutical ingredient selected from crystalline forms of a compound of formula A, solvates of a compound of formula A, and crystalline forms thereof may be administered by itself, but will typically be administered in the form of a pharmaceutical composition prepared with using one or more pharmaceutically acceptable carriers or excipients.

Typical carriers or excipients should be compatible with the other ingredients of the composition and should not cause harmful effects on the health of the patient. The carrier or excipient may be solid or liquid or both, and may be included together with crystalline forms of the compound of formula A, solvates of the compound of formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI and/or Form VIII) into a pharmaceutical composition or unit dosage form (eg, tablet, capsule), which may contain from 0.05% to 95% by weight of crystalline forms of a compound of formula A, solvates of a compound of formula A, or crystalline forms thereof. The pharmaceutical compositions described herein can be prepared using known methods for preparing pharmaceuticals, such as methods involving admixture with pharmaceutically acceptable carriers and/or excipients and diluents.

In some embodiments, at least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) may be combined with at least one component, such as a carrier and/or an excipient and/or a diluent, which may be selected from sweeteners, flavoring agents, coloring agents, dyes and emulsifiers.

In some embodiments, crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) are not converted when formulated with one or more pharmaceutically acceptable carriers and/or auxiliaries and/or diluents. In other embodiments, crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, or Form VIII) can be converted, in whole or in part, into one or more other crystalline forms forms or amorphous form or in non-solid form when formulated together with one or more pharmaceutically acceptable carriers and/or excipients and/or diluents. In some embodiments, Form I or other crystalline forms described herein may be dissolved when included in a pharmaceutical composition. Accordingly, in such cases, upon dissolution, Form I or other crystalline forms cease to exist as their respective forms in the pharmaceutical composition.

In some embodiments, at least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) is formulated as suitable dosage form.

The pharmaceutical compositions described herein may be in dosage forms suitable for oral and intraoral (eg, sublingual) administration. The appropriate route of administration may depend not only on the individual condition and the severity of the condition being treated, but also on the nature of the particular forms of the active pharmaceutical ingredient selected from crystalline forms of the compound of formula A, solvates of the compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI and Form VIII) used to obtain a pharmaceutical composition.

Suitable pharmaceutical compositions for oral administration prepared from at least one active pharmaceutical ingredient selected from crystalline forms of a compound of formula A, solvates of a compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI and Form VIII ), may be in the form of unit dosage forms such as capsules, sachets and tablets, including lozenges, each of which is formulated together with a specified amount of at least one active pharmaceutical ingredient described herein; and in forms selected from powders, granules, solutions, suspensions in an aqueous or non-aqueous liquid, and oil-in-water and water-in-oil emulsions. These compositions, as already mentioned, can be prepared using any suitable methods for the preparation of pharmaceuticals, such as methods comprising the step of combining at least one active pharmaceutical ingredient selected from crystalline forms of a compound of formula A, solvates of a compound of formula A and their crystalline forms (such as Form I, Form IV, Form V, Form VI and Form VIII), and a carrier and/or excipient and/or diluent (which may consist of one or more added ingredients). The compositions can generally be prepared by uniformly and homogeneously mixing at least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII), with liquid or highly dispersed solid carriers, after which the product can be shaped.

At least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) may also be administered in combination with one

- 15 044623 or more other active ingredients (such as in therapy with a synergistic effect).

When administered as a combination, the active ingredients may be formulated as separate compositions that are administered simultaneously or sequentially at different times (e.g., administered sequentially in any order) through the same or different routes of administration, or the active ingredients may be administered at the same pharmaceutical composition.

In some embodiments, at least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) may be administered in combination with one or more other active ingredients with a known therapeutic effect, for example used to treat diseases susceptible to inhibition of PI3K activity, such as autoimmune diseases, inflammatory diseases and cancer (preferably hematological malignancies).

As used herein, the phrase combination defines the combined use of at least one active pharmaceutical ingredient selected from crystalline forms of a compound of Formula A, solvates of a compound of Formula A, and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI, and Form VIII) , with one or more other active ingredients, for example, combination use in the treatment of autoimmune diseases or inflammatory diseases (for example, in combination with immunosuppressives, steroids), combination use in the treatment of cancer, in particular hematological malignancies (for example, in combination with inhibitors BTK, SYK inhibitors, JAK inhibitors, Bcl-2 inhibitors, anti-CD20 monoclonal antibodies, lenalidomide). Examples of BTK inhibitors include, but are not limited to, ibrutinib, ACP-196 (acalabrutinib), CC-292 (spebrutinib), ONO-4059 (tirabrutinib), BGB-3111, and GDC-0853. Examples of SYK inhibitors include, but are not limited to, GS-9973 (entospletinib) and HMPL-523. Examples of JAK inhibitors include, but are not limited to, ruxolitinib. Examples of Bcl-2 inhibitors include, but are not limited to, venetoclax (ABT-199), ABT-263 (navitoclax), and BCL201 (S55746). Examples of anti-CD20 monoclonal antibodies include, but are not limited to, rituximab, ofatumumab, and obinutuzumab.

Examples of immunosuppressants include, but are not limited to, corticoids (eg, fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide, or budesonide), disease-modifying agents (eg, antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine , metronidazole or Dpenicillamine), non-steroidal anti-inflammatory drugs (eg, acetaminophen, aspirin, sodium salicylate, sodium cromoglycate, magnesium salicylate, choline-magnesium salicylate, salicyl salicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, piroxicam , indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, meclofenamate sodium, mefenamic acid, nabumetone, oxaprozin, phenylbutylnitrone (PBN), sulindac or tolmetin), COX-2 inhibitors, cytokine synthesis/release inhibitors (eg, anti-cytokine antibodies, anti-receptor antibodies cytokines and the like).

Examples of steroids include, but are not limited to, glucocorticoids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, mometasone furoate and the like.

In addition, at least one active pharmaceutical ingredient selected from the crystalline forms, solvates and crystalline forms thereof according to the present invention can also be used in combination with other antitumor agents. As used herein, the term antineoplastic agent refers to any agent suitable for treating cancer. Examples of an antitumor agent include, but are not limited to: a radiotherapeutic agent, an immunotherapeutic agent, DNA-damaging chemotherapeutic agents, and chemotherapeutic agents that interfere with cell replication.

DNA damaging chemotherapeutic agents include, but are not limited to, topoisomerase I inhibitors (eg, irinotecan, topotecan, camptothecin and their analogs or metabolites, and adriacin); topoisomerase II inhibitors (eg, etoposide, teniposide, mitoxantrone, idarubicin and daunorubicin); alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin, and cyclophosphamide); DNA intercalators (eg, cisplatin, oxaliplatin and carboplatin); DNA intercalators and free radical sources such as bleomycin; and nucleoside mimetics (eg, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that interfere with cell replication include, but are not limited to: paclitaxel, docetaxel and related analogs; vincristine, vinblastine and related analogues; thalidomide and related analogues (eg, CC-5013 and CC-4047); protein tyrosine kinase inhibitors (eg, imatinib mesylate and gefitinib); proteasome inhibitors (eg

- 16 044623 bortezomib); NF-kappa B inhibitors, including kappa B kinase I inhibitors; antibodies that bind to proteins overexpressed in cancers and thereby inhibit cell replication (eg, trastuzumab, rituximab, cetuximab and bevacizumab); and other inhibitors of proteins or enzymes that have been found to be up-regulated, overexpressed or activated in cancer and the inhibition of which can inhibit cell replication.

In addition, the methods described herein are not limited to the sequence of administration; one or more other active ingredients may be administered simultaneously, before or after administration of the at least one active pharmaceutical ingredient. The at least one active pharmaceutical ingredient in the combination described above is selected from crystalline forms of the compound of formula A, solvates of the compound of formula A and crystalline forms thereof (such as Form I, Form IV, Form V, Form VI and Form VIII).

The following are non-limiting examples.

Experiments.

Compound (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]πpyridazin-7-yl)ethyl)amino)pyrumidine-5-carbonitrile as a crude substance, used in accordance with the examples were prepared in accordance with WO 2016045591 A1.

All reagents, with the exception of intermediates, used in accordance with this disclosure are commercially available. The names of all compounds, except the reagents, were obtained using ChemDraw Professional 16.0.

Unless otherwise stated, X-ray powder diffraction patterns were obtained using a Bruker D8 ADVANCE X-ray diffractometer, Germany (target: Cu; voltage: 40 kV; electric current: 40 mA; scan speed: 4 degrees/min; step size: 0.02 degrees; scanning range: 3-45 degrees).

Unless otherwise stated, differential scanning calorimetry (DSC) was performed using a NETZSCH DSC 204F1, Germany (purge gas: nitrogen; flow rate: 2060 ml-min ^-1 ; heating rate: 5-10°C/min; temperature range: from 30°C to 300°C). Sample analysis was performed in aluminum cuvettes with pierced lids. Indium was used to calibrate the temperature. Alternatively, DSC was performed using a Q2000 differential scanning calorimeter from TA, USA.

Unless otherwise stated, thermogravimetric (TG) data were obtained using a NETZSCH TGA 209F1 instrument, Germany (purge gas: nitrogen; heating rate: 10°C/min); or were obtained using a Q500 thermogravimetric analyzer from TA, USA.

Example 1 Preparation of Form I of the compound of formula A.

0.86 g of the compound of formula A was dissolved in 28 ml of ethyl acetate with heating and stirring. The solution was then cooled to room temperature and stirred for 17 hours at moderate speed. The precipitate was then filtered and dried at 60°C under vacuum for 1.5 hours to obtain 0.53 g of solid.

The resulting powder sample was Form I of the compound of formula A, the powder x-ray diffraction pattern of which is shown in FIG. 1. Selected in FIG. peaks (2θ) have the following values: 6.8, 7.6, 8.0, 10.0, 12.1, 12.6, 13.7, 14.4, 15.0, 15.3, 16. 2, 16.5, 17.0, 17.9, 18.7, 20.1, 21.3, 22.6, 23.1, 25.4, 26.1, and 29.0 degrees, where each of the measured values, 2θ has an error of approximately ±0.2 degrees (2θ), with characteristic peaks (2θ) found at 6.8, 10.0, 16.5, 20.1 and 22.6 degrees. The DSC result is shown in Fig. 2, which shows that the endothermic peak of Form I is at approximately 261.2-262.1°C.

Example 2 Preparation of Form I of the compound of formula A.

A suitable amount of a compound of formula A was suspended in a suitable amount of solvents, respectively given in table. 1. The suspensions were heated to the temperatures given in table. 1, to ensure dissolution. Then the solutions were cooled to 20-25°C. The precipitates were then filtered to obtain each sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Table 1

Amount of compound of formula A/solvent Solvent Heating temperature 150 mg/1.2 ml 1,4-dioxane 80-85 °C 150 mg/1.5 ml tetrahydrofuran 60-70 °C 80 mg/1.16 l ethanol/acetic acid (volume ratio 25/4) 75-80 °C

Example 3 Preparation of Form I of the compound of formula A.

A suitable amount of a compound of formula A was suspended in a suitable amount of solvents, respectively given in table. 2. The suspensions were heated to the temperatures given in

- 17 044623 table. 2, to ensure dissolution. The solutions were then cooled to 20-25°C and stirred for a certain period of time at moderate speed. The precipitates were then filtered to obtain each sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

table 2

Amount of compound of formula A/solvent 100 mg/3.2 ml Solvent ethyl acetate/acetone (volume ratio 7/3) Heating temperature 50-60 °C Mixing time 17 o'clock 100 mg/3.7 ml ethyl acetate/acetone (volume ratio 1/1) 50-60 °C 17 o'clock 100 mg/4 ml ethyl acetate/acetone (volume ratio 3/7) 50-60 °C 17 o'clock 100 mg/3.4 ml ethyl acetate/isopropanol 70-80 °C 17 o'clock (volume ratio 3/7) ethyl acetate/isopropanol 70-80 °C 100 mg/2.3 ml 17 o'clock (volume ratio 1/1) ethyl acetate/isopropanol (volume ratio 7/3) 70-80 °C 100 mg/2.4 ml 17 o'clock 110 mg/2 ml butanone 70-80 °C 17 o'clock 90 mg/2 ml butanone/ethanol (volume ratio 1/1) 70-80 °C 17 o'clock 80 mg/2.2 ml butanone/ethanol (volume ratio 1/4) 75-85 °C 18 hours

Example 4 Preparation of Form I of the compound of formula A.

0.55 g of the compound of formula A was suspended in 15.5 ml of ethyl acetate and heated to 70-80°C to ensure dissolution. The solution was then cooled to 5-10°C and stirred for 1 hour at moderate speed. The precipitate was then filtered and dried at 55°C under vacuum for 16 hours to obtain 0.36 g of sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 5 Preparation of Form I of the compound of formula A.

2.4 g of compound of formula A was suspended in 265 ml of toluene and heated to 100-110°C to ensure dissolution. Then the solution was cooled to 20-25°C. The precipitate was then filtered and dried at 55°C under vacuum for 16 hours to obtain 2.19 g of sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 6 Preparation of Form I of the compound of formula A.

130 mg of compound of formula A was suspended in 20 ml of dichloromethane and heated to gentle reflux to ensure dissolution. The solution was stirred at reflux for 1 hour and then cooled to 20-25°C. A small amount of solid precipitate has formed. 5 ml of dichloromethane was added and stirring was continued for 4 hours. A solid sample was obtained by filtration. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 7 Preparation of Form I of the compound of formula A.

100 mg of the compound of formula A was suspended in 2 ml of a solvent mixture (tetrahydrofuran/water, volume ratio 4/1) and heated to 60-70°C to ensure dissolution. The solution was cooled to 25-30°C and after 1 hour no solid precipitation had occurred. Then 2 ml of water was added and stirred for 18 hours. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 8 Preparation of Form I of the compound of formula A.

1.08 g of compound of formula A was suspended in 37 ml of ethyl acetate and heated to 70-80°C to ensure dissolution. Then the solution was cooled to 25-30°C and stirred for 2 hours. Then the precipitate was filtered and dried at 58°C under vacuum for 2 hours to obtain the first portion of the sample. Then 100 ml of isopropyl ether was added to the filtrate and stirred for 17 hours. The precipitate was then filtered again and dried at 58°C under vacuum for 2 hours to obtain a second portion of the sample. As a result of the measurement, both X-ray powder diffraction patterns of the obtained two portions of the samples corresponded to the diffraction pattern of Form I of the compound of formula A obtained in Example 1.

- 18 044623

Example 9 Preparation of Form I of the compound of formula A.

120 mg of compound of formula A was suspended in 4.5 ml of ethanol, heated to 75-85°C to ensure dissolution and filtered while hot. Then 6 ml of n-heptane was added to the filtrate. The solution was cooled to 25-30°C and stirred for 16 hours. Then the precipitate was filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 10 Preparation of Form I of the compound of formula A.

110 mg of compound of formula A was suspended in 1.2 ml of 1,4-dioxane and heated to 80-85°C to ensure dissolution. 1 ml of n-heptane was added. The solution was then cooled to 20-25°C and stirred for 18 hours. The precipitate was then filtered and dried at 55°C under vacuum for 4 hours to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 11 Preparation of Form I of the compound of formula A.

0.52 g of the compound of formula A was suspended in 27 ml of ethyl acetate, heated to 75-85°C to ensure dissolution and filtered while hot to remove small amounts of insoluble matter. The filtrate was then reheated to 75-85°C to ensure dissolution of all solids and 5 ml of n-heptane was added. The mixture was then cooled to 20-25°C and stirred for 17 hours. The precipitate was then filtered and dried at 55°C under vacuum for 2 hours to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 12 Preparation of Form I of the compound of formula A.

The solid forms of the compound of Formula A (a mixture of Form IV and Form V) were suspended in ethyl acetate and toluene, respectively, and heated to reflux. Solid forms of the compound of Formula A (a mixture of Form IV and Form V) were then added until the solids were present in excess in each system. The resulting suspensions were stirred at reflux for 2 hours, cooled to 20-25°C and left for 18 hours. The solids were then filtered to obtain each sample, respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 13 Preparation of Form I of the compound of formula A.

The solid form of the compound of Formula A (a mixture of Form IV and Form V) was suspended in 0.7 ml of tetrahydrofuran and heated to reflux. Solid forms of the compound of Formula A (a mixture of Form IV and Form V) were then added until the solids were present in excess in the system. The resulting suspension was stirred at reflux for 2 hours and left for 10 minutes. Then, 0.5 ml of the supernatant was transferred to another vial, and the tetrahydrofuran was removed from the vial by purging with nitrogen, followed by drying at 60 °C under vacuum for 1 h to obtain a solid sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Example 14 Preparation of Form I of the compound of formula A.

A suitable amount of solid forms of the compound of formula A (the forms being those given in Table 3) was suspended in a suitable amount of solvents, respectively given in the table. 3. The suspensions were stirred at 25-30°C for a certain period of time and filtered to obtain each solid sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form I of the compound of formula A obtained in accordance with Example 1.

Table 3

Amount of solid form of compound of formula A/solvent Form of compound of formula A Solvent Mixing time 40 mg/1 ml Form IV ethanol 8 days 160 mg/2.5 ml form V ethyl acetate 20 days 160 mg/2.5 ml form V toluene 20 days

Example 15 Preparation of Form IV of the compound of formula A.

3.59 g of compound of formula A was dissolved in 100 ml of 90% ethanol by heating to 70-80°C. The solution was then slowly cooled to room temperature and stirred at moderate speed. The precipitate was then collected by filtration and dried to obtain 1.64 g of solid.

The resulting solid sample was Form IV of the compound of formula A, the powder x-ray diffraction pattern of which is shown in FIG. 4. Selected

- 19 044623 in Fig. peaks (2Θ) have the following values: 4.6, 7.2, 8.2, 9.2, 9.7, 11.3, 11.5, 12.0, 13.2, 13.8, 14, 4, 14.7, 15.5, 16.0, 16.5, 17.8, 18.2, 19.0, 19.5, 21.1, 21.6, 22.3, 22.6 and 23.6 degrees, where each of the measured 2Θ values has an error of approximately ±0.2 degrees (2Θ), with the characteristic peaks (2Θ) being at 4.6, 9.2, 15.5, 17.8 and 19. 0 degrees. The DSC result is shown in Fig. 5, which shows that the endothermic peak of Form IV is at approximately 261.8-263.8°C. Example 16 Preparation of Form IV of the Compound of Formula A 81.2 mg of the compound of Formula A was dissolved in 3 ml of ethanol at reflux and stirred for 20 minutes. After heating ceased, the solution was naturally cooled to 20-25°C and stirred for 1 hour at moderate speed. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 17 Preparation of Form IV of the compound of formula A.

81.4 mg of the compound of formula A was dissolved in 2.2 ml of 95% ethanol at reflux and stirred for 30 minutes. After heating ceased, the solution was naturally cooled to 20-25°C and stirred for 1 hour at moderate speed. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 18 Preparation of Form IV of the compound of formula A.

A suitable amount of compound of formula A was dissolved in various solvents under appropriate heating conditions. Each resulting solution was then accordingly cooled to a certain temperature and stirred for a certain period of time at a moderate speed. The precipitates were then filtered to obtain each sample respectively (the specific conditions were as shown in Table 4). As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Table 4

Amount of compound of formula A/solvent Solvent Heating conditions Cooling conditions, temperature and stirring time 80 mg/3.5 ml 71.6 mg/6 ml 80 mg/3.66 ml ethanol isopropanol isopropanol/acetic acid (volume ratio 175/8) reflux reflux 75-85 °C Natural cooling to 20-25 °C, stirring for 17 hours Cooling to 20-25 °C in 2-3 hours, stirring for 1 hour Natural cooling to 20-25 °C, stirring for 18 hours 80 mg/1.12 ml methanol/acetic acid (volume ratio 25/3) 60-70 °C Natural cooling to 20-25 °C, stirring for 18 hours

Example 19 Preparation of Form IV of the compound of formula A.

A suitable amount of compound of formula A was dissolved in various solvents under appropriate heating conditions. Each resulting solution was then accordingly cooled to a certain temperature and stirred for a certain period of time at a moderate speed. The precipitates were then filtered and dried to obtain each sample respectively (the specific conditions were those given in Table 5). As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

- 20 044623

Table 5

Amount of compound of formula A/solvent Solvent Heating conditions Cooling conditions, temperature and stirring time Drying conditions 10.26 g/120 ml 80% ethanol reflux Cooling to 0-5 °C at 0.2 °C ^min'1 , stirring for 12 hours Drying at 55 °C under vacuum for 5 hours 100 mg/4.5 ml methanol reflux Natural cooling to 20-25 °C, stirring for 4 hours Drying at 55 °C under vacuum for 2 hours 1.01 g/21 ml 95% isopropanol 80-85 °C Cooling to 2025 °C, stirring for 18 hours; additional cooling to 0-5 °C, stirring for 6 hours Drying at 55 °C under vacuum for 17 hours 0.4 g/6.2 ml 90% isopropanol 75-85 °C Cooling to 0-5 °C, stirring for 2 hours Drying at 55 °C under vacuum for 17 hours 0.5 g/6.2 ml 80% isopropanol 75-85 °C Cooling to 0-5 °C, stirring for 2 hours Drying at 55 °C under vacuum for 17 hours 1.02 g/11.5 ml 70% isopropanol 80-85 °C Cooling to 2025 °C, stirring for 18 hours; additional cooling to 0-5 °C, stirring for 6 hours Drying at 55 °C under vacuum for 17 hours 0.71 g/6 ml 90% nbutanol 90-100 °C Cooling to 0-5 °C, stirring for 2 hours Drying at 55 °C under vacuum for 17 hours

Example 20 Preparation of Form IV of the compound of formula A.

100 mg of compound of formula A was dissolved in a solvent mixture of methanol/water (8.0 ml/1.5 ml) at 60-65°C and kept at 60-65°C for 30 minutes. The solution was then cooled to 20-25°C and only a small amount of precipitated solid formed. Then 7 ml of water was added to the mixture and stirring was continued for 17 hours. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 21 Preparation of Form IV of the compound of formula A.

0.99 g of compound of formula A was dissolved in 24 ml of 95% ethanol at 75-85°C, 40 ml of water was added and the mixture was kept at 75-85°C for 30 minutes. Then the mixture was cooled to 20-25°C, another 10 ml of water was added and stirred for 1 hour. Then the mixture was further cooled to 0-5°C and stirred for 2 hours. Then the precipitate was filtered and dried at 55°C under vacuum for 1.5 hours to obtain 0.80 g of sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 22 Preparation of Form IV of the compound of formula A.

6.05 g of compound of formula A were dissolved in 90 ml of 80% ethanol while heating to reflux. The solution was cooled to 70°C at a cooling rate of 0.5°C/min, and no solid precipitation occurred; 90 ml of water was slowly added to the solution over 80 min, and a large amount of precipitated solid formed. The mixture was stirred at 70°C for 100 min; cooled to 60°C at a cooling rate of 0.5°C/min and stirred for 2 hours; then the mixture was cooled to 50°C at a cooling rate of 0.5°C/min and stirred for 2 hours; and then the mixture was cooled to 0°C at a cooling rate of 0.2°C/min and stirred for 5.5 hours. Then the mixture was stirred at 0-5°C for another 5 hours. Then the precipitate was filtered off and dried at room temperature for 3 days and further dried at 55°C under vacuum for 2 hours to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 23 Preparation of Form IV of the compound of formula A.

5.04 g of a compound of formula A was dissolved in 65 ml of 70% isopropanol while heating to boiling with

- 21 044623 reflux condenser. 90 ml of water was quickly added to the solution. Then the solution was cooled to 2025°C at a rate of 2°C/min and stirred for 5 hours. Then the precipitate was filtered and dried at

55°C under vacuum for 16 hours to obtain 4.96 g of sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 24 Preparation of Form IV of the compound of formula A.

190 mg of the compound of formula A were dissolved in 3.3 ml of a solvent mixture (1,4-dioxane/ethanol, volume ratio 1/5) at 80-85°C. 6 ml of water was added to the solution, cooled to 20-25°C and stirred for 18 hours. Then the precipitate was filtered and dried at 55°C under vacuum for 4 hours to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 25 Preparation of Form IV of the compound of formula A.

g of compound of formula A was dissolved in 60 ml of a solvent mixture (tetrahydrofuran/ethanol/water, volume ratios were 1/99/25, 5/95/25 and 10/90/25, respectively) at 80-85°C, respectively. and stirred at 80-85°C for 30 minutes. The solutions were then cooled to 60°C at a rate of 0.5°C/min, respectively, and stirred at 60°C for 1.5 hours. 60 ml of water was added dropwise to the solutions (addition time was 1 hour), respectively. The mixture was stirred at 60°C for 1 hour after adding water; cooled to 25°C at a rate of 0.5°C/min, respectively, and stirred for 17.5 hours; cooled to 0°C at a rate of 0.5°C/min, respectively, and stirred for 2 hours. Then the solids were filtered, washed with 5 ml of 40% ethanol and dried at 55°C under vacuum for 18 hours to obtain, respectively, for each sample. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 26 Preparation of Form IV of the compound of formula A.

120 mg of solid compound of formula A (Form I) was suspended in 4 ml of water at 7585°C for 1 hour. The suspension was then cooled to 20-25°C and stirred for 3 hours. 0.8 ml of ethanol was added to the mixture and Stirring was continued for 16 hours. The solid was then filtered to obtain the product. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 27 Preparation of Form IV of the compound of formula A.

Suitable amounts of solvents given in table. 6 were placed in appropriate flasks at 20-25° C. and solid forms of the compound of formula A (a mixture of Form IV and Form V) were added until solids were present in excess in the solutions. Then the mixtures were heated to the appropriate temperatures given in table. 6, and the solid forms of the compound of Formula A (a mixture of Form IV and Form V) were added until the solids were present in excess in each system. Then the mixtures were stirred at the temperatures given in the table. 6, over 2 hours, cooled to 20-25°C and left for 18 hours, respectively. The solids were then filtered to obtain each sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Table 6

Solvent Temperature methanol 60-70 °C 10% methanol 60-70 °C ethanol 70-80 °C isopropanol 75-85 °C

Example 28 Preparation of Form IV of the compound of Formula A.

A suitable amount of solid forms of the compound of formula A (the forms are those given in Table 7) was suspended in a suitable amount of water, respectively. The suspensions were then stirred at specified temperatures for a specified period of time and filtered to obtain each solid sample respectively (specific conditions were as given in Table 7). As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

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Table 7

Amount of solid form of compound of formula A/water Form of compound of formula A Temperature Mixing time 40 mg/2 ml Form VI 20-25 °C 4 days 30 mg/1 ml Form I 25-30 °C 8 days 30 mg/1 ml Form IV 25-30 °C 8 days 30 mg/1 ml form V 25-30 °C 8 days 200 mg/5 ml Form VIII 20-25 °C 1 day

Example 29 Preparation of Form IV of the compound of formula A.

A suitable amount of the solid form of the compound of Formula A (Form VI) was heated at 120° C. under vacuum for 3 hours to obtain a sample. Alternatively, a suitable amount of the solid form of the compound of formula A (Form VI) was dried under vacuum, first at 50°C for 0.5 hours, then at 55°C for 4 hours and finally at 120°C for 0 .5 hours to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form IV of the compound of formula A obtained in accordance with Example 15.

Example 30 Preparation of Form V of the compound of formula A.

0.83 g of the compound of formula A was suspended in 85 ml of acetonitrile and heated to 70-80° C. to ensure dissolution. The solution was then cooled to 20-25°C and stirred for 17 hours at moderate speed. The precipitate was then filtered and dried at 60°C under vacuum for 1 hour to obtain 0.62 g of solid.

The resulting powder sample was Form V of the compound of formula A, the powder x-ray diffraction pattern of which is shown in FIG. 7. The peaks (20) selected in the figure have the following values: 4.6, 7.3, 8.9, 10.0, 11.2, 11.6, 13.5, 14.6, 15.5, 16 ,0, 17.7, 18.0, 19.3, 20.0, 22.7, 23.4, 24.0, 25.1, 26.0, 27.2, 28.4 and 29.7 degrees, where each of the measured values 20 has an error of approximately ±0.2 degrees (20), with the characteristic peaks (20) being at 7.3, 11.6, 14.6, 19.3 and 23.4 degrees. The DSC result is shown in Fig. 8, which shows that the endothermic peak of Form V is at approximately 261.4-262.4°C.

Example 31 Preparation of Form V of the compound of formula A.

700 mg of the compound of formula A was suspended in a mixture of acetonitrile/acetic acid (20 ml/1.4 ml) and heated to 75-80°C to ensure dissolution. Then the solution was cooled to 20-25°C and stirred for 1 hour at moderate speed. The precipitate was then filtered and dried at 55°C under vacuum for 1 hour to obtain 300 mg of solid. As a result of the measurement, the X-ray powder diffraction pattern of the obtained sample corresponded to the diffraction pattern of Form V of the compound of formula A obtained in accordance with Example 30.

Example 32 Preparation of Form V of the compound of formula A.

g of compound of formula A was suspended in 50 ml of 90% acetonitrile and heated to 70-80°C to ensure dissolution. Then the solution was cooled to 20-25°C and stirred for 15 hours at moderate speed; then further cooled to -10 - -5°C and stirred for 3 hours at moderate speed. The precipitate was then filtered and dried at 60° C. under vacuum for 16 hours to obtain 0.72 g of solid. As a result of the measurement, the X-ray powder diffraction pattern of the obtained sample corresponded to the diffraction pattern of Form V of the compound of formula A obtained in accordance with Example 30.

Example 33 Preparation of Form V of the compound of formula A.

A suitable amount of a compound of formula A was suspended in a suitable amount of solvents, respectively given in table. 8. The suspensions were heated to the temperatures given in table. 8, to ensure dissolution. The solutions were then cooled to 20-25°C and stirred for a certain period of time at moderate speed. The precipitates were then filtered to obtain each sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form V of the compound of formula A obtained in accordance with Example 30.

Table 8

Amount of compound of formula A/solvent Solvent Heating temperature Mixing time 80 mg/2.36 ml acetonitrile/acetic acid (volume ratio 55/4) 75-80 °C 18 hours 80 mg/3.2 ml acetone/ethanol (volume ratio 1/4) 55-60°С 17 o'clock

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90 mg/6 ml ethyl acetate/acetonitrile (volume ratio 3/7) 70-80°С 17 o'clock 110 mg/6 ml butanone/acetonitrile (volume ratio 1/1) 70-80°С 17 o'clock 90 mg/3.8 ml tetrahydrofuran/acetonitrile (volume ratio 3/7) 60-70°С 17 o'clock

Example 34 Preparation of Form V of the compound of formula A.

The solid form of the compound of Formula A (a mixture of Form IV and Form V) was suspended in an appropriate amount of acetonitrile and heated to reflux. Solid forms of the compound of Formula A (a mixture of Form IV and Form V) were then added until the solids were present in excess in the system. The resulting suspension was stirred at reflux for 2 hours, cooled to 20-25°C and left for 18 hours. The solid was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the obtained sample corresponded to the diffraction pattern of Form V of the compound of formula A obtained in accordance with Example 30.

Example 35 Preparation of Form V of the compound of formula A.

160 mg of a sample of Form I of the compound of Formula A and 180 mg of a sample of Form IV of the compound of Formula A were mixed with 8 ml of acetonitrile, respectively, stirred at 70-80°C for 4 hours and then cooled to 22-28°C and stirred for 7 days. An additional 3 ml of acetonitrile was added to each mixture, respectively. The mixtures were reheated to 70-80°C and stirred for 4 hours; then cooled to 22-28°C and stirred for 16 hours. The solids were then filtered and dried at 50°C under vacuum for 30 minutes to obtain each sample respectively. As a result of the measurement, the X-ray powder diffraction pattern of each of the obtained samples corresponded to the diffraction pattern of Form V of the compound of formula A obtained in accordance with Example 30.

Example 36 Preparation of Form VI of the compound of formula A.

g of compound of formula A was suspended in 130 ml of acetone and heated to 55-60°C to ensure dissolution. The solution was then cooled to 25-30°C and stirring continued for approximately 18 hours. The precipitate was then filtered off and air dried for 30 minutes to obtain 2.15 g of product. Acetone content (gas chromatography, GC): 10.86%.

The resulting powder sample was Form VI of the compound of Formula A, the powder X-ray diffraction pattern of which is shown in FIG. 10. Selected in FIG. peaks (2Θ) have the following values: 6.9, 8.6, 9.0, 9.8, 10.4, 12.0, 13.4, 15.0, 15.8, 16.2, 16, 8, 17.3, 18.0, 18.2, 18.9, 19.4, 19.7, 20.6, 21.0, 21.6, 22.5, 23.0, 23.3, 23.8, 24.5, 25.0, 26.2 and 29.8 degrees, where each of the measured 2Θ values has an error of approximately ±0.2 degrees (2θ), with the characteristic peaks (2Θ) being at 8. 6, 10.4, 12.0, 15.0 and 19.7 degrees. The DSC result is shown in Fig. 11, which shows that the endothermic peaks of Form VI are at about 97.3-106.0°C and about 262.3-265.0°C.

Example 37 Preparation of Form VI of the compound of formula A.

The compound of formula A was dissolved in 2.5 ml of 95% acetone to saturation at 40-45°C and filtered while hot to remove insoluble substances. The filtrate was then cooled to 20-25°C and stirring continued for 2 hours. The precipitate was then filtered to obtain the product. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form VI of the compound of formula A obtained in accordance with Example 36.

Example 38 Preparation of Form VI of the compound of formula A.

mg of compound of formula A was suspended in 3.7 ml of acetone, heated to 50-60°C to ensure dissolution and stirred for 30 minutes. The mixture was then filtered. The solution was then quickly cooled to 0-5°C using an ice bath and stirred for another 1 hour. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form VI of the compound of formula A obtained in accordance with Example 36.

Example 39 Preparation of Form VI of the compound of formula A.

mg of compound of formula A was suspended in 8 ml of acetone/isopropanol solvent mixture (volume ratio 7/3) and heated to 50-60°C to ensure dissolution. Then the heating was stopped, and the solution was subjected to natural cooling to 20-25°C. The precipitate was then filtered to obtain a sample. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form VI of the compound of formula A obtained in accordance with Example 36.

Example 40 Preparation of Form VI of the compound of formula A.

700 mg of the compound of formula A was suspended in 20 ml of acetone/water solvent mixture (volume ratio 3/1), heated to 50-60° C. to ensure dissolution and filtered while hot. The filtrate was then cooled to 20-25°C and stirred for another 1 hour; then cooled to 0-5°C and stirred for 30 minutes. A small amount of the sample was then filtered to obtain the first portion of the sample. Then 30 ml of water was added to the remaining mixture and stirring was continued at 20-25°C for 17 hours. The precipitate was then filtered to obtain a second portion of the sample. As a result of the measurements, the powder X-ray diffraction patterns of the resulting two portions of the samples corresponded to the diffraction pattern of Form VI of the compound of formula A obtained in accordance with Example 36.

Example 41 Preparation of Form VI of the compound of formula A.

mg of the solid form of the compound of formula A (a mixture of Form I and Form V) was suspended in 0.9 ml of acetone/water solvent mixture (volume ratio 3/1), stirred at 25-30°C for 6 days and filtered to obtain a solid . As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form VI of the compound of formula A obtained in accordance with Example 36.

Example 42 Preparation of Form VIII of the compound of formula A.

.2 g of compound of formula A was mixed with 130 ml of 70% isopropanol, heated to reflux to ensure dissolution and stirred at 75-80°C for 30 minutes. The solution was then cooled to 45-55°C and stirred for another 2 hours; further cooled to 23-30°C and stirred for approximately 6 days. The precipitate was then filtered and air dried for 100 min to obtain the product. Water content (WC): 10.8%; isopropanol content (gas chromatography, GC): 6.8%.

The resulting powder sample was Form VIII of the compound of formula A, the powder x-ray diffraction pattern of which is shown in FIG. 13. Selected in FIG. peaks (2θ) have the following values: 7.0, 8.3, 9.8, 10.7, 11.4, 13.3, 13.8, 14.2, 15.3, 15.7, 17. 7, 19.0, 19.4, 19.6, 20.3, 21.4, 22.4, 2z.1, 23.5, 24.0, 25.0, 25.4, 26.9 and 27.2 degrees, where each of the measured 2θ values has an error of approximately ±0.2 degrees (2θ), with the characteristic peaks (2θ) being at 7.0, 8.3, 11.4, 15.3 and 23. 1 degree. The DSC result is shown in Fig. 14, which shows that the endothermic peaks of Form VIII are at about 64.1-81.7°C and about 261.5-262.2°C.

Example 43 Preparation of Form VIII of the compound of formula A.

A 3.9 g sample of Form IV of the compound of Formula A was suspended in 50 ml of 70% isopropanol and stirred at room temperature for 3 days to obtain the first portion of sample for analysis. The suspension was stirred for another 3 days. 10 ml of 70% isopropanol was added to the suspension and stirring was continued for 2 days. The solid was then collected by filtration and dried at room temperature in air for 50 minutes to obtain a second portion of the sample. As a result of the measurement, both X-ray powder diffraction patterns of the obtained two portions of the samples corresponded to the diffraction pattern of Form VIII of the compound of formula A obtained in accordance with Example 42.

Example 44 Preparation of Form VIII of the compound of formula A.

A 200 mg sample of Form IV of the compound of Formula A was suspended in 4 ml of 90% isopropanol. The mixture was stirred at 20-25°C for 4 days and filtered to obtain a solid. As a result of the measurement, the X-ray powder diffraction pattern of the resulting sample corresponded to the diffraction pattern of Form VIII of the compound of formula A obtained in accordance with Example 42.

Example 45 Stability of Form I, Form IV and Form V under high temperature, high humidity and light conditions.

Method of Determination: Test samples of Form I, Form IV and Form V of the compound of formula A were placed on appropriate uncovered culture dishes and placed in hermetically sealed, clean containers. The containers were placed under 60°C temperature, 25°C temperature and 92.5% ± 5% relative humidity and 4500 lux ± 500 lux illumination, respectively, for 10 days. Samples were then collected, the purity and crystalline form of the samples were examined, and the results of the study were compared. The results are presented in table. 9.

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Table 9

Analysis conditions High temperature (60°C) High humidity (RH 92.5%) Illumination (4500 lux) Sampling time 0 day 5 days 10 days 5 days 10 days 5 days 10 days Form I I I I I I I Chemical purity (%) 99.76 99.63 99.63 99.65 99.60 99.61 99.45 Form IV IV IV IV IV IV IV Chemical purity (%) 99.27 99.57 99.68 99.68 99.68 99.59 99.55 Form V V V V V V V Chemical purity (%) 99.70 99.88 99.87 99.88 99.87 99.85 99.81

Conclusion: the data presented in table. 9 show that the chemical purity and crystalline form of Form I, Form IV and Form V of the compound of Formula A remained unchanged after exposure to high temperature, high humidity and light conditions for 10 days, indicating that Form I, Form IV and Form V are stable.

Example 46 Stability of Form IV mixed with excipients.

Method of determination: 50 mg of samples of Form IV of the compound of formula A were mixed with 200 mg of excipients starch and microcrystalline cellulose, respectively. The mixtures were used as assay samples and placed on appropriate uncapped culture dishes and placed in sealed, clean containers. The containers were then placed under 60°C temperature, 25°C temperature and 92.5% ± 5% relative humidity and 4500 lux ± 500 lux illumination, respectively, for 30 days. Then samples were taken, the change in the crystalline shape of the samples was studied, and the results of the study were compared. The results are presented in table. 10.

Table 10

Material under study Analysis time Analysis conditions Analysis result Form Form IV Mixture containing starch 0 day Form IV 30 days High temperature (60°C) Form IV High humidity (RH 92.5%) Form IV Illumination (4500 lux) Form IV Blend containing microcrystalline cellulose 0 day Form IV 30 days High temperature (60°C) Form IV High humidity (RH 92.5%) Form IV Illumination (4500 lux) Form IV

Conclusion: the data presented in table. 10 show that mixtures of Form IV of the compound of Formula A with starch or microcrystalline cellulose were stable under high temperature, high humidity and light conditions, indicating that Form IV is stable under the assay conditions.

Example 47 Solubility of Form I, Form IV and Form V in various buffers.

Method of determination: Excess samples of Form I, Form IV and Form V of the compound of formula A were suspended in appropriate buffers of different pH. Saturation of the system was carried out by shaking for a certain period of time at 37°C in a water bath with a constant temperature. The system was then filtered and the filtrate was used to determine the solubility of the samples. The solubility of each form is presented in table. 11. Buffers with different pH were prepared in accordance with the requirements of the United States Pharmacopoeia (USP40-NF35).

Table 11

Buffer pH value Solubility (mg/ml) Form I* Form IV** Shape V** pH 1.2 10.78 8.56 9.64 pH 2.1 0.8 0.5 0.58 pH 4.5 0.04 0.02 0.02 pH 6.8 0.03 0.02 0.02

*: shaken at 37°C in a water bath for 0.5 hours, **: shaken at 37°C in a water bath for 2 hours

Conclusion: the data presented in table. 11 show that in the studied buffers the form

Claims (11)

I, Form IV and Form V of the compounds of formula A have good solubility. Example 48 Hygroscopicity of Form I, Form IV and Form V. Method of Determination: Test samples of Form I, Form IV and Form V of the compound of formula A were placed in the appropriate sample cups of a dynamic vapor sorption apparatus (DVS-INTRINSIC). The increase in sample mass due to moisture absorption was then determined at a relative humidity of 0-95% at 25°C. The results are presented in Fig. 16, fig. 17 and fig. 18. Conclusion: the curves in Fig. 16, fig. 17 and fig. 18 show that Form I, Form IV and Form V of the compound of formula A are non-hygroscopic. It should be understood that the examples and embodiments described herein are provided for purposes of interpretation only and, with that in mind, various improvements or modifications may be suggested to those skilled in the art that are within the spirit and scope of this application and the scope of the appended claims. inventions. All publications, patents and patent applications referenced herein are incorporated herein by reference for all purposes. CLAIM 1. A crystalline form of a compound of formula A, wherein the compound of formula A is (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl )amino)pyrimidine-5carbonitrile, wherein said form is Form IV, wherein the X-ray powder diffraction pattern of Form IV contains the following diffraction angles (2θ): 4.6, 9.2, 15.5, 17.8 and 19.0 degrees , where each of the measured 2θ values has an error of ±0.2 degrees (2θ). 2. A crystalline form of a compound of formula A, wherein the compound of formula A is (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7-yl)ethyl )amino)pyrimidine-5-carbonitrile, wherein said form is Form V, wherein the X-ray powder diffraction pattern of Form V contains the following diffraction angles (2θ): 7.3, 11.6, 14.6, 19.3 and 23, 4 degrees, where each of the measured 2θ values has an error of ±0.2 degrees (2θ). 3. The form according to claim 1, wherein said form is Form IV, wherein the X-ray powder diffraction pattern of Form IV contains the following diffraction angles (2θ): 4.6, 9.2, 11.5, 12.0, 13.2 , 15.5, 16.0, 17.8, 19.0 and 22.6 degrees, where each of the measured 2θ values has an error of ±0.2 degrees (2θ). 4. The form according to claim 2, wherein said form is Form V, wherein the X-ray powder diffraction pattern of Form V contains the following diffraction angles (2θ): 4.6, 7.3, 8.9, 11.6, 13.5 , 14.6, 15.5, 18.0, 19.3 and 23.4 degrees, where each of the measured 2θ values has an error of ±0.2 degrees (2θ). 5. The form according to any one of claims 1 to 4, in which the content of other crystalline forms of (S)-4-amino-6((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7- yl)ethyl)amino)pyrimidine-5-carbonitrile is less than 40%, preferably less than 30%, preferably less than 20%, preferably less than 10%, preferably less than 5% or preferably less than 1% by weight. 6. A pharmaceutical composition containing an effective amount of one or both crystalline forms according to any one of claims 1 to 5 and pharmaceutically acceptable carriers. 7. Use of a crystalline form according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of a disease associated with PI3K activity, wherein said disease associated with PI3K activity is selected from an autoimmune disease, an inflammatory disease and cancer. 8. A method of treating a disease associated with PI3K activity, comprising administering to a subject in need thereof an effective amount of a crystalline form according to any one of claims 1 to 5, wherein said disease associated with PI3K activity is selected from an autoimmune disease, an inflammatory disease, and cancer. 9. Use of a crystalline form according to any one of claims 1 to 5 for the treatment of a disease associated with PI3K activity, said disease associated with PI3K activity selected from an autoimmune disease, an inflammatory disease and cancer. 10. Use according to claim 9, wherein said autoimmune disease and inflammatory disease is selected from systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis, asthma, and cancer is selected from lymphoma, leukemia, multiple myeloma and Waldenström's macroglobulinemia. 11. A method for obtaining a crystalline form according to claim 1 or 3, wherein said form is Form IV, comprising: (1) mixing a (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazin-7yl)ethyl)amino)pyrimidine-5-carbonitrile compound of at least with one solvent for dissolution or with a solvent mixture consisting of a water-miscible organic solvent and water, and heating the mixture to boiling under reflux to obtain a solution; wherein at least one solvent for dissolution is selected from C ₁ . ₆ alkanol, a mixture of isopropanol and acetic acid and -