Salts of compounds and their crystal forms

Abstract

This invention belongs to the field of pharmaceutical science and provides pharmaceutically acceptable salts of the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholino-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine, their crystal forms, solvates and crystal forms, pharmaceutical compositions thereof, their preparation methods and applications.

Description

[0001] This application is a divisional application of Chinese Patent Application 201880052524.1, filed on August 22, 2018, with a priority date of August 22, 2017, entitled "Salts of Compounds and Crystal Forms Thereof". Technical Field

[0002] This invention belongs to the field of pharmaceutical science and provides pharmaceutically acceptable salts of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, as well as their crystal forms, solvates and crystal forms, pharmaceutical compositions thereof, preparation methods thereof, and applications thereof. Background Technology

[0003] Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase that plays an important role in immune receptors and integrin-mediated signaling in many cells, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, platelets, and osteoclasts.

[0004] Syk is essential for B-cell activation mediated by B-cell receptor signaling. Upon binding to phosphorylated B-cell receptors, Syk is activated, initiating the B-cell receptor signaling pathway, which mediates various biological effects. This pathway, in turn, depends on the developmental stage of the B cell. The intensity and duration of B-cell receptor signaling must be strictly regulated. Abnormal B-cell receptor signaling pathways can lead to dysregulation of B-cell activation or the formation of pathological autoantibodies, resulting in multiple autoimmune or inflammatory diseases. Mice deficient in Syk exhibit impaired B-cell maturation, reduced immunoglobulin production, weakened T-cell-independent immune responses, and significantly diminished calcium ion signaling induced by B-cell receptor activation.

[0005] Extensive evidence suggests that B cells and the humoral immune system play crucial roles in the pathogenesis of autoimmune and inflammatory diseases. Autoantibodies and the immune complexes they produce are involved in the pathological processes of these diseases. Pathological responses to these antibodies depend on the activation of the Syk-mediated signaling pathway via the Fc receptor. Given Syk's role in B cell activation and in the Fc signaling pathway, inhibiting Syk can suppress B cell-mediated pathological activities, including autoantibody production. Therefore, inhibiting intracellular Syk enzyme activity can suppress autoantibody production, thereby potentially therapeutically addressing autoimmune diseases.

[0006] Therefore, inhibiting Syk activity can be used to treat autoimmune and inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, multiple sclerosis, idiopathic thrombocytopenic purpura, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, and asthma. Furthermore, Syk has been reported to mediate a ligand-independent signaling pathway mediated by B cell receptors, which is also a known important signaling pathway for B cell survival. Therefore, inhibiting Syk activity can be used to treat cancer, particularly hematologic malignancies such as lymphoma, leukemia, and multiple myeloma.

[0007] The compound of this invention, (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, exhibits effective inhibition of Syk kinase activity. Therefore, it can be used to treat diseases that respond to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancer.

[0008] The phenomenon that a compound can exist in two or more crystal structures is called polymorphism. Many compounds can exist in multiple crystal forms, as well as in amorphous solid forms. Before the discovery of polymorphism in a compound, it is difficult to predict (1) whether a particular compound exhibits polymorphism; (2) how to obtain these unknown polymorphs; and (3) what the properties of these polymorphs will be, such as their stability. See J. Bernstein "Polymorphism in Molecular Crystals", Oxford University Press, (2002).

[0009] Salt formation does not alter the biological activity of a compound, but it can change its physicochemical properties, such as solubility, stability, crystallinity, and polymorphism. However, it is impossible to predict which specific properties will be changed or to what extent. Furthermore, it is unpredictable whether a compound or its salts with acids / bases will form crystals or amorphous forms, what type of crystals will form, how a particular crystal will form, and whether the formed crystals will possess certain specific properties.

[0010] Because the properties of solids depend on their structure and the nature of the compound itself, different solid forms of compounds often exhibit different physical and chemical properties, as well as different biopharmaceutical properties. Differences in chemical properties can be determined, analyzed, and compared using various analytical techniques, and these differences can ultimately be used to distinguish these different solid forms. Differences in physical properties such as solubility and biopharmaceutical properties such as bioavailability are also important in describing the solid forms of drug compounds. Similarly, in the development of drug compounds, such as (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholino-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, the salt, novel crystal form, and amorphous morphology of the drug compound are also important.

[0011] Patent application WO2012167733A1 discloses the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine and its preparation method. Summary of the Invention

[0012] Overview

[0013] Through extensive research, we discovered that the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine can be prepared into various pharmaceutically acceptable salts, the chemical structures of which are shown in Formula A. Our results indicate that the solubility of Formula A salts relative to their free base is significantly increased, which is beneficial for improving the pharmacokinetic characteristics of the compound and enhancing its bioavailability in vivo. We also found that Formula A salts can exist in different crystalline forms (i.e., polymorphs) and can form solvates with certain solvents. We conducted extensive research on the polymorphisms of Formula A salts, identifying and preparing crystalline forms that meet pharmaceutical requirements. Based on these studies, the present invention provides various crystal forms of pharmaceutically acceptable salts of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, their solvates and their crystal forms, which are designated as crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III, respectively.

[0014]

[0015] Where n is 0.5 or 1;

[0016] M is a pharmaceutically acceptable acid molecule.

[0017] On the one hand, the present invention provides a polymorph of salt of formula A or its solvates, which has the characteristics of good crystallinity, high solubility and good stability.

[0018] First, the present invention provides a pharmaceutically acceptable salt of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine.

[0019] Secondly, the present invention provides a pharmaceutically acceptable salt of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine as shown in Formula A, namely, the salt of Formula A.

[0020] Furthermore, the present invention provides pharmaceutically acceptable salts of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine as shown in Formula A, namely acetate, p-toluenesulfonate and malate.

[0021] Furthermore, the present invention provides pharmaceutically acceptable salts of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine as shown in Formula A, namely, an acetate, a pair of toluenesulfonates, an malate, and a hemimalate.

[0022] Furthermore, the present invention provides an AI-type crystal of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine acetate, namely, the crystal form AI of the salt of formula A (where n is 1 and M is acetic acid).

[0023] Furthermore, the present invention provides a BI-type crystal of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate, namely, the crystal form BI of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0024] Furthermore, the present invention provides a B-II type crystal of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate, namely, the crystal form B-II of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0025] Furthermore, the present invention provides a solvate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate, which is a hydrate of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0026] Furthermore, the present invention provides a hydrate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate, which is a hemihydrate of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0027] Furthermore, the present invention provides a hydrate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate, which is a hemihydrate of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid), which is crystal form B-III.

[0028] Furthermore, the present invention provides a CI-type crystal of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate, namely, the crystal form CI of the salt of formula A (where n is 1 and M is malic acid).

[0029] Furthermore, the present invention provides a solvate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate, which is a hydrate of the salt of formula A (wherein n is 0.5 and M is malic acid).

[0030] Furthermore, the present invention provides hydrates of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate, which are hydrates and monohydrates of the salt of formula A (where n is 0.5 and M is malic acid) containing 0.75 molecules of water.

[0031] Furthermore, the present invention provides a hydrate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine malate, which is a hydrate of formula A (wherein n is 0.5 and M is malic acid) containing 0.75 molecules of water, and is in crystal form C-II.

[0032] Furthermore, the present invention provides a hydrate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate, which is a monohydrate of the salt of formula A (wherein n is 0.5 and M is malic acid), and is in crystal form C-III.

[0033] On the other hand, the present invention provides methods for preparing salts of formula A or solvates thereof, or crystal forms of salts of formula A or solvates thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III), which are reproducible and easy to operate.

[0034] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of one or more of a salt of formula A or a solvate thereof or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III), and the balance being at least one pharmaceutically acceptable carrier.

[0035] The present invention also provides a method for treating diseases that respond to inhibition of Syk kinase activity. The method comprises administering to an individual in need an effective amount of one or more salts of formula A or solvates thereof, or crystal forms of salts of formula A or solvates thereof, such as crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, or crystal form C-III.

[0036] The present invention also provides the use of a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (such as crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II or crystal form C-III) for the preparation of a medicament for the treatment of diseases that respond to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases and cancers (preferably hematologic malignancies), such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, lymphomas (such as B-cell lymphoma, T-cell lymphoma), leukemias (such as chronic lymphocytic leukemia, acute lymphoblastic leukemia and acute myeloid leukemia) and multiple myeloma. Attached Figure Description

[0037] Figure 1 The powder X-ray diffraction pattern of crystal form AI of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0038] Figure 2 The differential scanning calorimetry (DSC) plot of salt A with crystal form AI is shown, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing heat flow.

[0039] Figure 3 Thermogravimetric analysis plot of crystal form AI of salt A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing weight percentage.

[0040] Figure 4 The powder X-ray diffraction pattern of crystal form BI of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0041] Figure 5 The differential scanning calorimeter of crystal form BI of salt A is represented by the horizontal axis (X-axis) which is temperature and the vertical axis (Y-axis) which is heat flow.

[0042] Figure 6 Thermogravimetric analysis plot of crystal form BI of salt A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing weight percentage.

[0043] Figure 7 The powder X-ray diffraction pattern of crystal form B-II of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0044] Figure 8 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plots of crystal form B-II of salt A are shown, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing heat flow and weight percentage.

[0045] Figure 9 The powder X-ray diffraction pattern of crystal form B-III of the hemihydrate of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0046] Figure 10 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) plots of crystal form B-III of the hemihydrate of salt A are shown. The horizontal axis (X-axis) represents temperature, and the vertical axis (Y-axis) represents heat flow and weight percentage.

[0047] Figure 11 The powder X-ray diffraction pattern of crystal form CI of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0048] Figure 12 The differential scanning calorimetry (DSC) plot of crystal form CI of salt A is shown, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing heat flow.

[0049] Figure 13Thermogravimetric analysis plot of crystal form CI of salt A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing weight percentage.

[0050] Figure 14 The powder X-ray diffraction pattern of crystal form C-II of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0051] Figure 15 Differential scanning calorimetry (DSC) plot of crystal form C-II of salt hydrate of formula A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing heat flux.

[0052] Figure 16 Thermogravimetric analysis diagram of crystal form C-II of salt hydrate of formula A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing weight percentage.

[0053] Figure 17 The powder X-ray diffraction pattern of crystal form C-III of the monohydrate of salt A is shown. The horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

[0054] Figure 18 The differential scanning calorimetry (DSC) plot of the monohydrate of salt A, crystal form C-III, is shown with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing heat flow.

[0055] Figure 19 Thermogravimetric analysis plot of crystal form C-III of the monohydrate of salt A, with the horizontal axis (X-axis) representing temperature and the vertical axis (Y-axis) representing weight percentage. Detailed Implementation

[0056] definition

[0057] Unless otherwise stated, the following abbreviations or terms used in this application (including the specification and claims) have the definitions given below. It should be noted that the singular forms used in this specification and appended claims also include the plural forms, unless the context clearly indicates otherwise.

[0058] As used herein, “crystal form” refers to the crystalline form of the salt of formula A or its solvates, crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II or crystal form C-III, or a mixture of several of these forms. “crystal form”, “crystalline form” and “polymorph” are used interchangeably herein.

[0059] As used in this article, "salt of formula A" refers to a salt having the following chemical structure (also called salt A):

[0060]

[0061] Where n is 0.5 or 1;

[0062] M is a pharmaceutically acceptable acid molecule.

[0063] The "C" used in this article 1-6 "Alkyl alcohol" refers to a fully saturated straight-chain or branched alkyl alcohol having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, and n-hexanol.

[0064] As used in this article, "haloalkanes with fewer than three carbon atoms" refers to fully saturated hydrocarbons having one or two carbon atoms that are substituted by one or more halogen atoms selected from F, Cl, Br, or I. Examples include dichloromethane, trichloromethane, carbon tetrachloride, and 1,2-dichloroethane.

[0065] The term “approximately” as used in this article means a deviation from a specific given value by no more than ±10%.

[0066] As used in this article, "basically does not contain other crystal forms" means that the content of other crystal forms is less than 50% by weight of the total weight of the crystal form, preferably less than 40%, preferably less than 30%, preferably less than 20%, preferably less than 10%, preferably less than 5%, and preferably less than 1%.

[0067] As used herein, “solution” refers to a mixture of one or more solutes in one or more solvents for a specific purpose. A solution includes both homogeneous mixtures and multiphase mixtures, such as pulping solutions or other suspensions containing insoluble substances.

[0068] As used in this article, “organic solvent” refers to any appropriate organic solvent used for any purpose described herein.

[0069] As used in this article, “solvent” refers to any suitable organic solvent that can partially or completely dissolve the solute under appropriate conditions, such as appropriate amount and appropriate temperature, such as room temperature or heating.

[0070] The term "anti-dissolution solvent" as used in this article refers to any suitable organic solvent in which the substance is less soluble than in the dissolving solvent.

[0071] The term "pharmaceutically acceptable salts" as used in this article includes, but is not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, phosphorous acid, sulfuric acid, sulfurous acid, and nitric acid, and salts formed with organic acids such as malate, maleate, mandelate, fumarate, tartrate, succinate, citrate, aspartate, glutamate, 2-hydroxy-2-phenylpropionate, gluconate, lactate, camphor sulfonate, methanesulfonate, ethanesulfonate, naphthalene sulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, β-hydroxybutyrate, benzoate, salicylates, and alkyl carboxylates such as acetate, propionate, stearate, and HOOC-(CH2)n-COOH (where n is 0-4).

[0072] The "effective amount" of Formula A salt, its crystal form, solvate, and crystal form refers to the amount applied to an individual that can effectively reduce or improve diseases that respond to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancers (preferably hematologic malignancies). The recipient can be a human or an animal subject. Diseases that respond to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancers (preferably hematologic malignancies), can include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, lymphomas (such as B-cell lymphoma and T-cell lymphoma), leukemias (such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia), and multiple myeloma. The "effective dose" will vary depending on a variety of factors, including the compound, the disease state being treated, the severity of the disease, the individual's age and related health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0073] As used herein, “individual” refers to both mammals and non-mammals. Mammals include any member of the mammal class, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals 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. The term “individual” does not indicate a specific age or sex. Invention Details

[0075] The present invention provides pharmaceutically acceptable salts of the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine, as well as their crystal forms, solvates, and crystal forms.

[0076] The crystal form provided by this invention possesses excellent crystallinity, high solubility, and good stability. The crystal form of this invention exhibits good reproducibility, enabling repetitive scale-up production; moreover, it is stable in common formulations, thus facilitating formulation manufacturing and use in treating diseases. Furthermore, the crystal form of this invention has high purity and low solvent residue, meeting the quality requirements of active pharmaceutical ingredients, such as ICH Q3A requirements.

[0077] Those skilled in the art can verify the above advantages of the crystal form of the present invention based on the test methods disclosed in the pharmacopoeia, their variations, or conventional methods in the art.

[0078] As described herein, the crystal form of the present invention can be identified by one or more solid-state analysis methods. For example, the crystal form of the present invention can be identified by one or more methods, such as powder X-ray diffraction, lattice parameters of single crystals, Fourier transform infrared spectroscopy, differential scanning calorimetry data, and / or thermogravimetric analysis. Furthermore, if the identification analysis result of one method is consistent with the crystal form of the present invention, it does not mean that the identification result of any other method is consistent with the crystal form of the present invention.

[0079] As described herein, novel crystal forms can be identified using powder X-ray diffraction (PXRD). However, those skilled in the art will know that the peak intensities and / or peak characteristics of PXRD can vary depending on experimental conditions, such as different diffraction test conditions and / or preferred orientations. Furthermore, due to differences in the precision of different instruments, the measured 2θ values ​​may have an error of approximately ±0.2 2θ. However, it is known that the relative intensity of a peak depends more on certain properties of the sample being measured than on its position, such as the size of the crystals in the sample, the orientation effect of crystallization, and the purity of the material being analyzed; therefore, peak intensity deviations of approximately ±20% or greater are possible. Nevertheless, despite the presence of experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information from the XRPD data provided herein to identify crystal form AI and various other crystal forms of this invention.

[0080] Crystalline AI

[0081] The present invention provides a crystal form AI of salt of formula A (where n is 1 and M is acetic acid).

[0082] In some embodiments, the crystalline form AI of formula A salt can be identified by X-ray powder diffraction. In some embodiments, the characteristic diffraction angles (2θ) of the crystalline form AI of formula A salt by powder X-ray diffraction include 6.2, 9.4, 16.3, 17.2, and 19.0 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0083] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form AI of salt of formula A include 6.2, 9.4, 10.8, 16.3, 17.2, 19.0, 20.1, 21.7, 24.6 and 29.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0084] In some implementations, the characteristic diffraction angles (2θ) of the powder X-ray diffraction of the crystalline AI include 6.2, 9.4, 10.8, 12.1, 15.8, 16.3, 17.2, 19.0, 20.1, 21.7, 22.7, 24.6, 25.4, and 29.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0085] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form AI of salt of formula A include 6.2, 9.4, 10.8, 12.1, 14.1, 15.8, 16.3, 17.2, 19.0, 19.3, 20.1, 21.1, 21.7, 22.2, 22.7, 24.6, 25.4, and 29.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0086] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form AI of salt of formula A include 6.2, 9.4, 10.8, 12.1, 14.1, 15.8, 16.3, 17.2, 19.0, 19.3, 20.1, 21.1, 21.7, 22.2, 22.7, 24.6, 25.4, 26.8, 27.2, 27.5, 29.2, 30.6, and 31.8 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0087] In some implementations, the crystal form AI of salt A has such Figure 1 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form AI of the A salt from the XRPD data provided herein.

[0088] In some embodiments, the crystal form AI of salt A can be identified using differential scanning calorimetry. In some embodiments, the crystal form AI of salt A has the following characteristics: Figure 2 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peaks of the crystal form AI of salt A are at approximately 162.8–179.6 °C and 217.0–219.4 °C.

[0089] In some embodiments, the crystal form AI of formula A salt can be identified using thermogravimetric analysis. In some embodiments, the crystal form AI of formula A salt has the following characteristics: Figure 3The thermogravimetric analysis curve shown indicates a weight loss of approximately 10.96% between 100-170℃, which is due to the loss of acetic acid upon heating. This crystalline form of AI is either anhydrous or a pure crystal.

[0090] In some implementations, the Al crystal form of the salt of formula A substantially does not contain any of the other crystal forms described herein. For example, the Al crystal form of the salt of formula A has a weight content of at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the Al crystal form of the salt of formula A has a weight content of at least 70%, or at least 60%. Or even further, the Al crystal form of the salt of formula A has a weight content of at least 50%.

[0091] Preparation method of crystalline AI

[0092] Method A

[0093] This article relates to a method for preparing the crystal form AI of salt A, including:

[0094] (1) Reacting compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine with acetic acid to form a salt, and stirring the formed salt in at least one dissolving solvent or in a mixed solvent consisting of a water-miscible organic solvent and water;

[0095] (2) The crystalline form of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine acetate was isolated and obtained as Al solid.

[0096] (3) Optionally, dry the solid obtained in step (2).

[0097] In some embodiments, the molar ratio of the acetic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.5:1. In some embodiments, the molar ratio is about 2:1. In some embodiments, the molar ratio is about 3:1. In some embodiments, the molar ratio is about 10:1. In some embodiments, the molar ratio is about 25:1.

[0098] In some embodiments, the volume (mL) of the dissolving solvent or mixed solvent in step (1) is not less than about 10 mL / g (volume-to-mass ratio), for example 13 mL / g, 18 mL / g, 23 mL / g, 24 mL / g, 25 mL / g, 31 mL / g, 35 mL / g, 90 mL / g, or 100 mL / g.

[0099] In some embodiments, the dissolving solvent is selected from C 1-6 Alkyl alcohols, tetrahydrofuran, dioxane, halogenated alkanes with fewer than three carbon atoms, acetone, butanone, and acetonitrile. In some embodiments, the dissolving solvent is selected from methanol, ethanol, isopropanol, tert-butanol, dioxane, acetone, and acetonitrile. In some embodiments, the dissolving solvent is selected from ethanol, isopropanol, and dioxane.

[0100] In some embodiments, the water-miscible organic solvent accounts for less than about 95% of the volume of the mixed solvent.

[0101] In some embodiments, the water-miscible organic solvent is selected from acetone, C... 1-6 Alkyl alcohols (e.g., methanol, ethanol, isopropanol), dioxane, and acetonitrile. In some embodiments, the water-miscible organic solvent is selected from acetone, ethanol, and dioxane.

[0102] In some embodiments, the water-miscible organic solvent and water are mixed in an appropriate ratio. In some embodiments, the volume ratio of the water-miscible organic solvent to water is from about 15:1 to 3:1, for example, ethanol / water (volume ratio about 11.6:1), acetone / water (volume ratio about 11:1), dioxane / water (volume ratio about 8:1).

[0103] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system, for example, about 40-50 degrees Celsius, about 60-70 degrees Celsius and about 80-85 degrees Celsius.

[0104] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature or lower, such as about 20-25 degrees Celsius, about 5-10 degrees Celsius and about 0-5 degrees Celsius.

[0105] In some embodiments, in step (1), the formed salt is stirred for 1-120 hours, for example at least 1 hour, at least 2 hours, at least 12 hours, at least 17 hours, at least 24 hours, at least 72 hours, or at least 120 hours.

[0106] In some embodiments, the drying temperature and drying time in step (3) are appropriate to ensure that the solid is sufficiently dried and retains the desired crystal properties. In some embodiments, the drying temperature is 55 degrees Celsius. In some embodiments, the drying temperature is 60 degrees Celsius.

[0107] Method B

[0108] This article relates to another method for preparing the crystal form AI of salt of formula A, including:

[0109] (1) The compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine and acetic acid are added to an appropriate amount of at least one dissolving solvent or a mixed solvent consisting of a water-miscible organic solvent and water to react and form a salt, thus obtaining the first solution;

[0110] (2) Add at least one anti-dissolution solvent to the first solution to obtain the second solution;

[0111] (3) The crystalline form of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine acetate was isolated and obtained as Al solid.

[0112] (4) Optionally, dry the solid obtained in step (3).

[0113] In some embodiments, the dissolving solvent is selected from C 1-6 Alkyl alcohols (such as ethanol and isopropanol) and dichloromethane.

[0114] In some embodiments, the water-miscible organic solvent is selected from C 1-6 Alkyl alcohols (e.g., methanol, ethanol, isopropanol), dioxane, acetone, and acetonitrile. In some embodiments, the water-miscible organic solvent is selected from ethanol, wherein ethanol constitutes not less than about 50% by volume of the mixed solvent, for example, 86.4% or 95%.

[0115] In some embodiments, the anti-dissolution solvent is selected from acetone, isopropyl ether, and methyl tert-butyl ether.

[0116] In some embodiments, the volume ratio of the dissolving solvent or mixed solvent to the anti-dissolving solvent is from about 1:2 to about 30:1, for example 1:2.3, 3.2:1, 4:1, 27.5:1.

[0117] In some implementations, in step (1), stirring is performed and heating may be performed simultaneously. The heating temperature should not be higher than the boiling point of the solvent system, for example, about 40-50 degrees Celsius, about 60-64 degrees Celsius, and about 80 degrees Celsius.

[0118] Crystal form BI

[0119] The present invention provides a crystal form BI of salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0120] In some embodiments, the crystal form BI of salt of formula A can be identified by X-ray powder diffraction. In some embodiments, the characteristic diffraction angles (2θ) of the powder X-ray diffraction of crystal form BI of salt of formula A include 4.9, 5.5, 9.6, 14.4, 16.4 and 19.8 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0121] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form BI of salt of formula A include 4.9, 5.5, 9.6, 14.4, 15.9, 16.4, 17.3, 18.4, 19.3 and 19.8 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0122] In some implementations, the characteristic diffraction angles (2θ) of the powder X-ray diffraction of crystal form BI include 4.9, 5.5, 6.8, 9.6, 10.1, 14.4, 14.8, 15.9, 16.4, 17.3, 18.4, 19.3, 19.8, 22.5, and 23.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0123] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form BI of salt of formula A include 4.9, 5.5, 6.8, 9.6, 10.1, 14.4, 14.8, 15.9, 16.4, 17.3, 18.4, 19.3, 19.8, 20.7, 21.4, 22.5, 23.2, 25.0, 26.1, 27.0, and 29.0 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0124] In some implementations, the crystal form BI of salt of formula A has the following characteristics: Figure 4The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form BI of the A salt from the XRPD data provided herein.

[0125] In some embodiments, the crystal form BI of salt A can be identified using differential scanning calorimetry. In some embodiments, the crystal form BI of salt A has the following characteristics: Figure 5 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peak of crystal form BI of salt A is located at approximately 205.7–209.6 °C.

[0126] In some embodiments, the crystal form BI of the salt of formula A can be identified by thermogravimetric analysis. In some embodiments, the crystal form BI of the salt of formula A has the following characteristics: Figure 6 The thermogravimetric analysis curves shown indicate that the BI crystal form is anhydrous or a pure crystal.

[0127] In some embodiments, the crystal form BI of the salt of formula A substantially does not contain any of the other crystal forms described herein. For example, the salt of formula A has a crystal form BI weight content of at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the salt of formula A has a crystal form BI weight content of at least 70%, or at least 60%. Or even further, the salt of formula A has a crystal form BI weight content of at least 50%.

[0128] Preparation method of crystalline BI

[0129] Method A

[0130] This article relates to a method for preparing crystal form BI of salt of formula A, including:

[0131] (1) The compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine was reacted with p-toluenesulfonic acid to form a salt, and the salt was stirred in a mixed solvent consisting of a water-miscible organic solvent and water.

[0132] (2) The crystalline form BI solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine p-toluenesulfonate was obtained by separation;

[0133] (3) Optionally, dry the solid obtained in step (2).

[0134] In some embodiments, the molar ratio of the p-toluenesulfonic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.1:1.

[0135] In some embodiments, the volume (mL) of the mixed solvent in step (1) to the weight (g) of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine is not less than about 10 mL / g (volume-to-mass ratio), for example 25 mL / g, 32 mL / g, 33.5 mL / g, 37 mL / g, 42 mL / g, 52 mL / g.

[0136] In some embodiments, the water-miscible organic solvent accounts for less than about 96% of the volume of the mixed solvent.

[0137] In some embodiments, the water-miscible organic solvent is selected from C 1-6 Alkyl alcohols (e.g., ethanol, isopropanol) and acetone. In some embodiments, the water-miscible organic solvent is selected from ethanol and isopropanol.

[0138] In some embodiments, the water-miscible organic solvent and water are mixed in an appropriate ratio. In some embodiments, the volume ratio of the water-miscible organic solvent to water is from about 22:1 to 4:1, for example, ethanol / water (volume ratio of about 4.3:1, about 7.7:1 or about 13:1), isopropanol / water (volume ratio of about 4.3:1 or about 17.4:1), acetone / water (volume ratio of about 22:1).

[0139] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system, for example, about 50-60 degrees Celsius and about 80-90 degrees Celsius.

[0140] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature or a lower temperature, such as about 15-20 degrees Celsius.

[0141] In some implementations, in step (1), the formed salt is stirred for 1-120 hours, for example at least 3 hours, at least 16 hours, or at least 72 hours.

[0142] In some embodiments, the drying temperature and drying time in step (3) are appropriate to ensure that the solid is sufficiently dried and retains the desired crystal properties. In some embodiments, the drying temperature is room temperature. In some embodiments, the drying temperature is 60 degrees Celsius.

[0143] Method B

[0144] This article relates to another method for preparing crystal form BI of salt of formula A, including:

[0145] Crystal form B-II of salt of formula A is stirred in about 95% ethanol at a temperature of about 10-30°C, for example at room temperature, to obtain crystal form BI.

[0146] In some implementations, the stirring time is 4 days.

[0147] Crystal form B-II

[0148] The present invention provides crystal form B-II of salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0149] In some embodiments, crystal form B-II of salt of formula A can be identified by X-ray powder diffraction. In some embodiments, the characteristic diffraction angles (2θ) of crystal form B-II of salt of formula A by powder X-ray diffraction include 5.1, 6.0, 10.2, 17.1, and 19.1 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0150] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form B-II of salt of formula A include 5.1, 6.0, 9.5, 10.2, 14.8, 15.8, 17.1, 19.1 and 22.4 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0151] In some embodiments, the characteristic diffraction angles (2θ) of powder X-ray diffraction for crystal form B-II include 5.1, 6.0, 9.5, 10.2, 14.3, 14.8, 15.8, 17.1, 19.1, 20.2, 20.8, 22.4, and 26.0 degrees, with the measured 2θ values ​​having an error of approximately ±0.22θ.

[0152] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form B-II of salt of formula A include 5.1, 6.0, 9.5, 10.2, 14.3, 14.8, 15.3, 15.8, 17.1, 17.9, 19.1, 19.7, 20.2, 20.8, 22.4, 23.4, 26.0, and 27.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0153] In some embodiments, the crystal form B-II of salt of formula A has the following characteristics: Figure 7 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form B-II of the A salt from the XRPD data provided herein.

[0154] In some embodiments, the crystal form B-II of the salt of formula A can be identified using differential scanning calorimetry. In some embodiments, the crystal form B-II of the salt of formula A has the following characteristics: Figure 8 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peak of crystal form B-II of salt A is located at approximately 203.0–211.4 °C.

[0155] In some embodiments, the crystal form B-II of the salt of formula A can be identified by thermogravimetric analysis. In some embodiments, the crystal form B-II of the salt of formula A has the following characteristics: Figure 8 The thermogravimetric analysis curves shown indicate that crystal form B-II is an anhydrous or pure crystal.

[0156] In some embodiments, the crystal form B-II of the salt of formula A substantially does not contain any of the other crystal forms described herein. For example, the weight content of crystal form B-II of the salt of formula A is at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the weight content of crystal form B-II of the salt of formula A is at least 70%, or at least 60%. Or even further, the weight content of crystal form B-II of the salt of formula A is at least 50%.

[0157] Preparation method of crystal form B-II

[0158] This article relates to a method for preparing crystal form B-II of salt of formula A, including:

[0159] (1) The compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine was reacted with p-toluenesulfonic acid to form a salt, and the formed salt was stirred in a mixed solvent consisting of methanol and water.

[0160] (2) The crystal form B-II solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine p-toluenesulfonate was isolated;

[0161] (3) Optionally, dry the solid obtained in step (2).

[0162] In some embodiments, the molar ratio of the p-toluenesulfonic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.1:1.

[0163] In some embodiments, the volume (mL) of the mixed solvent in step (1) to the weight (g) of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyridino[3,4-b]pyrazine-5-amine is not less than about 10 mL / g (volume-to-mass ratio), for example about 32 mL / g.

[0164] In some implementations, the volume ratio of methanol to water in step (1) is approximately 13:1.

[0165] In some implementations, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system.

[0166] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature.

[0167] In some implementations, in step (1), the formed salt is stirred for 1-120 hours, for example at least 72 hours.

[0168] Hydrate (crystal form B-III)

[0169] The present invention also provides a hydrate of a salt of formula A (where n is 1 and M is p-toluenesulfonic acid).

[0170] In some embodiments, the hydrate of salt of formula A (where n is 1 and M is p-toluenesulfonic acid) is a hemihydrate.

[0171] In some embodiments, the hemihydrate of the salt of formula A (where n is 1 and M is p-toluenesulfonic acid) is crystal form B-III.

[0172] In some embodiments, the crystal form B-III of the hemihydrate of formula A salt can be identified by X-ray powder diffraction. The characteristic diffraction angles (2θ) of crystal form B-III by powder X-ray diffraction include 5.3, 5.9, 10.7, 13.6, and 15.6 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0173] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form B-III of the hemihydrate of formula A salt include 5.3, 5.9, 9.9, 10.7, 11.8, 13.6, 14.9, 15.6 and 17.6 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0174] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form B-III of the hemihydrate of formula A salt include 5.3, 5.9, 9.9, 10.7, 11.8, 13.6, 14.9, 15.6, 16.0, 17.6, 20.0, and 22.8 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0175] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of crystal form B-III of the hemihydrate of formula A salt include 5.3, 5.9, 9.9, 10.7, 11.8, 13.6, 14.9, 15.6, 16.0, 17.6, 18.9, 20.0, 21.6, 22.8, 25.0, and 27.0 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0176] In some embodiments, the crystal form B-III of the hemihydrate of formula A salt has the following characteristics: Figure 9 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form B-III of the hemihydrate of the A salt from the XRPD data provided herein.

[0177] In some embodiments, the crystal form B-III of the hemihydrate of formula A salt can be identified using differential scanning calorimetry. In some embodiments, the crystal form B-III of the hemihydrate of formula A salt has the following characteristics: Figure 10 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the crystal form B-III of the hemihydrate of salt A has an exothermic peak at approximately 168.1–172.5 °C and a distinct endothermic peak at approximately 199.6–208.3 °C.

[0178] In some embodiments, the crystal form B-III of the hemihydrate of formula A salt can be identified by thermogravimetric analysis. In some embodiments, the crystal form B-III of the hemihydrate of formula A salt has the following characteristics: Figure 10 The thermogravimetric analysis curves shown in the figure indicate that crystal form B-III is a hemihydrate.

[0179] In some embodiments, the crystal form B-III of the hemihydrate of formula A salt substantially does not contain any of the other crystal forms described herein. For example, the weight content of crystal form B-III of the hemihydrate of formula A salt is at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the weight content of crystal form B-III of the hemihydrate of formula A salt is at least 70%, or at least 60%. Or even further, the weight content of crystal form B-III of the hemihydrate of formula A salt is at least 50%.

[0180] Preparation method of crystal form B-III

[0181] Method A

[0182] This article relates to a method for preparing crystal form B-III of the hydrate of salt of formula A, including:

[0183] (1) The compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine was reacted with p-toluenesulfonic acid to form a salt, and the salt was stirred in water.

[0184] (2) The crystal form B-III solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine p-toluenesulfonate was isolated;

[0185] (3) Optionally, dry the solid obtained in step (2).

[0186] In some embodiments, the molar ratio of the p-toluenesulfonic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.1:1.

[0187] In some embodiments, the volume (mL) of water in step (1) is about 54 mL / g (volume-to-mass ratio) of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyridino[3,4-b]pyrazine-5-amine.

[0188] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should be appropriate, for example, about 80-85 degrees Celsius.

[0189] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature.

[0190] Method B

[0191] This article relates to another method for preparing crystal form B-III of the hydrate of salt of formula A, including:

[0192] The crystal form BI of salt of formula A is stirred in water at a temperature of about 10-30°C, for example at room temperature. The solid is collected by filtration and optionally dried to obtain crystal form B-III.

[0193] In some implementations, the stirring time is 4 days.

[0194] In some embodiments, the drying is vacuum drying. In some embodiments, the drying temperature and drying time are appropriate to ensure that the solid is sufficiently dried and retains the desired crystal properties. In some embodiments, the drying temperature is 60 degrees Celsius. In some embodiments, the drying time is 2 hours.

[0195] Crystal form CI

[0196] The present invention provides a crystal form CI of salt of formula A (where n is 1 and M is malic acid).

[0197] In some embodiments, the crystal form CI of salt of formula A can be identified by X-ray powder diffraction. In some embodiments, the characteristic diffraction angles (2θ) of the crystal form CI of salt of formula A by powder X-ray diffraction include 8.6, 14.3, 15.5, 19.5, and 22.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0198] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form CI of salt of formula A include 8.6, 10.8, 14.3, 15.5, 16.4, 17.7, 18.4, 19.5, 22.2 and 23.8 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0199] In some embodiments, the characteristic diffraction angles (2θ) of the powder X-ray diffraction of the crystal form CI include 8.6, 10.8, 14.3, 15.5, 16.4, 17.2, 17.7, 18.4, 19.5, 20.9, 22.2, 22.6, 23.8, 29.2, 29.8, and 30.7 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0200] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form CI of salt of formula A include 8.6, 10.8, 11.8, 13.5, 14.3, 15.5, 16.4, 17.2, 17.7, 18.1, 18.4, 19.5, 20.9, 22.2, 22.6, 23.8, 25.8, 26.7, 27.8, 29.2, 29.8, and 30.7 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0201] In some embodiments, the crystal form CI of salt of formula A has such Figure 11 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form CI of the A salt from the XRPD data provided herein.

[0202] In some embodiments, the crystal form CI of salt A can be identified using differential scanning calorimetry. In some embodiments, the crystal form CI of salt A has the following characteristics: Figure 12 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peak of crystal form CI of salt A is located at approximately 211.1–214.9 °C.

[0203] In some embodiments, the crystal form CI of the salt of formula A can be identified by thermogravimetric analysis. In some embodiments, the crystal form CI of the salt of formula A has the following characteristics: Figure 13 The thermogravimetric analysis curves shown indicate that the crystal form CI is anhydrous or a pure crystal.

[0204] In some embodiments, the crystal form CI of the salt of formula A substantially does not contain any of the other crystal forms described herein. For example, the weight content of crystal form CI of the salt of formula A is at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the weight content of crystal form CI of the salt of formula A is at least 70%, or at least 60%. Or even further, the weight content of crystal form CI of the salt of formula A is at least 50%.

[0205] Preparation method of crystalline CI

[0206] This article relates to a method for preparing the crystal form CI of salt of formula A, including:

[0207] (1) Reacting compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine with malic acid to form a salt, and stirring the formed salt in at least one dissolving solvent or in a mixed solvent consisting of a water-miscible organic solvent and water;

[0208] (2) The crystalline form CI solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate was isolated and obtained;

[0209] (3) Optionally, dry the solid obtained in step (2).

[0210] In some embodiments, the molar ratio of the malic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.1:1. In some embodiments, the molar ratio is about 1.5:1.

[0211] In some embodiments, the volume (mL) of the dissolving solvent or mixed solvent in step (1) is not less than about 30 mL / g (volume-to-mass ratio), for example 38 mL / g, 53 mL / g, 67 mL / g, 86 mL / g, or 135 mL / g.

[0212] In some embodiments, the dissolving solvent is selected from C 1-6 Alkyl alcohols (e.g., methanol, ethanol, isopropanol) and tetrahydrofuran. In some embodiments, the dissolving solvent is selected from ethanol.

[0213] In some embodiments, the water-miscible organic solvent is selected from C 1-6 Alkyl alcohols (such as methanol, ethanol, isopropanol) and tetrahydrofuran.

[0214] In some embodiments, the water-miscible organic solvent and water are mixed in an appropriate ratio. In some embodiments, the volume ratio of the water-miscible organic solvent to water is from about 12:1 to 1:1, for example, ethanol / water (volume ratio about 1.5:1), methanol / water (volume ratio about 1.5:1), isopropanol / water (volume ratio about 1.4:1), tetrahydrofuran / water (volume ratio about 12:1).

[0215] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system, for example, about 40-50 degrees Celsius, about 60-70 degrees Celsius and about 75-85 degrees Celsius.

[0216] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature or a lower temperature, such as about 15-20 degrees Celsius.

[0217] In some embodiments, in step (1), the formed salt is stirred for 1-120 hours, for example at least 12 hours, at least 14 hours, at least 20 hours, or at least 72 hours.

[0218] In some embodiments, the drying temperature and drying time in step (3) are appropriate to ensure that the solid is sufficiently dried and retains the desired crystal properties. In some embodiments, the drying temperature is 60 degrees Celsius.

[0219] Hydrate (Crystal form C-II)

[0220] The present invention also provides a hydrate of a salt of formula A (where n is 0.5 and M is malic acid).

[0221] In some embodiments, the hydrate of salt of formula A (where n is 0.5 and M is malic acid) contains 0.75 molecules of water.

[0222] In some embodiments, the hydrate of salt of formula A (where n is 0.5 and M is malic acid) containing 0.75 molecules of water is crystal form C-II.

[0223] In some embodiments, the crystal form C-II of the hydrate of formula A salt can be identified by X-ray powder diffraction. The characteristic diffraction angles (2θ) of crystal form C-II by powder X-ray diffraction include 11.3, 11.6, 17.0, 20.0, 21.6, and 23.1 degrees, and the measured 2θ values ​​have an error of approximately ±0.2 2θ.

[0224] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-II of the hydrate of formula A salt include 5.3, 9.5, 10.0, 11.3, 11.6, 17.0, 20.0, 21.6, 23.1, 26.9 and 28.3 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0225] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-II of the hydrate of formula A salt include 5.3, 9.5, 10.0, 10.6, 11.3, 11.6, 12.4, 12.8, 17.0, 20.0, 21.6, 23.1, 24.9, 26.4, 26.9 and 28.3 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0226] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-II of the hydrate of formula A salt include 5.3, 9.5, 10.0, 10.6, 11.3, 11.6, 12.4, 12.8, 13.6, 15.9, 17.0, 18.4, 20.0, 20.9, 21.6, 23.1, 24.9, 26.4, 26.9, and 28.3 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0227] In some embodiments, the crystal form C-II of the hydrate of formula A salt has the following characteristics: Figure 14 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form C-II of the hydrate of the A salt from the XRPD data provided herein.

[0228] In some embodiments, the crystal form C-II of the hydrate of formula A salt can be identified using differential scanning calorimetry. In some embodiments, the crystal form C-II of the hydrate of formula A salt has the following characteristics: Figure 15 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peaks of crystal form C-II of the hydrate of formula A salt are at approximately 70.2–90.4 °C and approximately 202.6–215.0 °C.

[0229] In some embodiments, the crystal form C-II of the hydrate of formula A salt can be identified by thermogravimetric analysis. In some embodiments, the crystal form C-II of the hydrate of formula A salt has the following characteristics: Figure 16 The thermogravimetric analysis curves shown in the figure indicate a weight loss of 2.61% around 30-90℃, suggesting that this crystal form C-II is a hydrate containing 0.75 molecules of water.

[0230] In some embodiments, the hydrate of formula A contains essentially no other crystal forms C-II as described herein. For example, the hydrate of formula A has a C-II weight content of at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the hydrate of formula A has a C-II weight content of at least 70%, or at least 60%. Or even further, the hydrate of formula A has a C-II weight content of at least 50%.

[0231] Preparation method of crystal form C-II

[0232] This article relates to a method for preparing the C-II crystal form of the hydrate of salt of formula A, including:

[0233] (1) The compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine was reacted with malic acid to form a salt, and the salt was stirred in a mixed solvent consisting of acetonitrile and water.

[0234] (2) The crystalline form C-II solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate was isolated and obtained;

[0235] (3) Optionally, dry the solid obtained in step (2).

[0236] In some embodiments, the molar ratio of the malic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.1:1.

[0237] In some embodiments, the volume (mL) of the mixed solvent in step (1) is about 88 mL / g (volume-to-mass ratio) of the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyridino[3,4-b]pyrazine-5-amine.

[0238] In some embodiments, the volume ratio of water to acetonitrile in step (1) is not less than about 6:1. In some embodiments, the volume ratio is about 6:1.

[0239] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system, for example, about 80-85 degrees Celsius.

[0240] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature.

[0241] In some implementations, in step (1), the formed salt is stirred for 1-120 hours, for example at least 18 hours.

[0242] Hydrate (Crystal form C-III)

[0243] The present invention also provides a hydrate of a salt of formula A (where n is 0.5 and M is malic acid).

[0244] In some implementations, the hydrate of salt of formula A (where n is 0.5 and M is malic acid) is a monohydrate.

[0245] In some implementations, the monohydrate of salt of formula A (where n is 0.5 and M is malic acid) is of crystal form C-III.

[0246] In some embodiments, the crystal form C-III of the monohydrate of formula A salt can be identified by X-ray powder diffraction. The characteristic diffraction angles (2θ) of crystal form C-III by powder X-ray diffraction include 5.3, 10.6, 17.0, 17.9, and 25.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0247] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-III of the monohydrate of formula A salt include 5.3, 10.6, 12.8, 17.0, 17.9, 20.3, 21.7, 22.5 and 25.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0248] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-III of the monohydrate of formula A salt include 5.3, 10.6, 11.8, 12.8, 16.0, 17.0, 17.9, 18.9, 20.3, 21.7, 22.5 and 25.2 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0249] In some embodiments, the characteristic powder X-ray diffraction angles (2θ) of the crystal form C-III of the monohydrate of formula A salt include 5.3, 10.6, 11.8, 12.8, 16.0, 17.0, 17.9, 18.6, 18.9, 20.3, 21.7, 22.5, 23.1, 25.2, 25.6, and 27.4 degrees, with the measured 2θ values ​​having an error of approximately ±0.2 2θ.

[0250] In some embodiments, the crystal form C-III of the monohydrate of formula A salt has the following characteristics: Figure 17 The diffraction pattern is shown. Despite experimental errors, instrumental errors, and preferred orientations, those skilled in the art can obtain sufficient information about the crystal form C-III of the monohydrate of the A salt from the XRPD data provided herein.

[0251] In some embodiments, the crystal form C-III of the monohydrate of formula A can be identified using differential scanning calorimetry. In some embodiments, the crystal form C-III of the monohydrate of formula A has the following characteristics: Figure 18 The differential scanning calorimetry (DSC) curves are shown. In the DSC spectrum, the endothermic peaks of crystal form C-III of the monohydrate of formula A salt are at approximately 69.9–88.5 °C and approximately 201.6–206.7 °C.

[0252] In some embodiments, the crystal form C-III of the monohydrate of formula A can be identified by thermogravimetric analysis. In some embodiments, the crystal form C-III of the monohydrate of formula A has the following characteristics: Figure 19 The thermogravimetric analysis curves shown in the figure indicate a weight loss of 3.2% around 30-90℃, suggesting that this crystal form C-III is a monohydrate.

[0253] In some embodiments, the monohydrate of formula A contains essentially no other crystal forms C-III as described herein. For example, the monohydrate of formula A has a C-III weight content of at least 99%, at least 95%, at least 90%, or even lower than 80%. Alternatively, the monohydrate of formula A has a C-III weight content of at least 70%, or at least 60%. Or even further, the monohydrate of formula A has a C-III weight content of at least 50%.

[0254] Preparation method of crystal form C-III

[0255] This article relates to a method for preparing the C-III crystal form of the hydrate of salt of formula A, including:

[0256] (1) The compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine was reacted with malic acid to form a salt, and the salt was stirred in a mixed solvent consisting of ethanol and water.

[0257] (2) The crystalline form C-III solid of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine malate was isolated and obtained;

[0258] (3) Optionally, dry the solid obtained in step (2).

[0259] In some embodiments, the molar ratio of the malic acid to the compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine is not less than about 1:1. In some embodiments, the molar ratio is about 1.5:1.

[0260] In some embodiments, the volume (mL) of the mixed solvent in step (1) is about 55 mL / g (volume-to-mass ratio) of the compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyridino[3,4-b]pyrazine-5-amine.

[0261] In some embodiments, the volume ratio of water to ethanol in step (1) is not less than about 4:1. In some embodiments, the volume ratio is about 4:1.

[0262] In some embodiments, in step (1), the salt formation is carried out under heating and / or stirring, and the heating temperature should not be higher than the boiling point of the solvent system, for example, about 80 degrees Celsius.

[0263] In some embodiments, in step (1), the formed salt is stirred under cooling, preferably natural cooling, for example, cooling to room temperature or a lower temperature, such as about 15-20 degrees Celsius.

[0264] In some implementations, in step (1), the formed salt is stirred for 1-120 hours, for example at least 12 hours.

[0265] Features in the various embodiments of the preparation methods relating to the crystal forms of salts of formula A or their solvates can be arbitrarily combined with each other, and the various combinations thereof are included within the scope of the present invention, as if these combinations were specifically and individually listed herein.

[0266] Pharmaceutical compositions and treatment methods

[0267] Salts of Formula A or solvates thereof, or crystal forms of salts of Formula A or solvates thereof (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, and C-III), may be used to treat diseases such as autoimmune diseases, inflammatory diseases, and cancers. The cancers are preferably hematologic malignancies. The autoimmune diseases, inflammatory diseases, and cancers include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, lymphomas (such as B-cell lymphoma and T-cell lymphoma), leukemias (such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia), and multiple myeloma.

[0268] This article provides a method for treating diseases that respond to inhibition of Syk kinase activity, including administration of an active pharmaceutical ingredient formed from a salt of formula A, or a salt of formula A or a solvate thereof of the present invention, or a crystal form of a salt of formula A or a solvate thereof such as crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II or crystal form C-III.

[0269] In some embodiments, this treatment method targets at least one disease that responds to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancer (preferably hematologic malignancies). Treatment is performed by administering an effective amount of the pharmaceutical composition of the invention to an individual in need, the pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and one or more of a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, or crystal form C-III).

[0270] The dosage of at least one active pharmaceutical ingredient selected from a salt of formula A, or a crystal form of formula A, or a solvate of formula A, or a crystal form thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, or crystal form C-III) to achieve the intended physiological effect depends on a variety of factors, such as the purpose of use, the route of administration, and the patient's clinical condition. Daily doses may range, for example, from 0.01 mg to 3 g daily (e.g., from 0.05 mg to 2 g daily, or even from 100 mg to 1 g daily). Unit-dose formulations that can be administered orally include, for example, tablets or capsules.

[0271] To achieve the therapeutic objectives mentioned above, at least one active pharmaceutical ingredient selected from the salt of formula A or its solvates or crystal forms of the salt of formula A or its solvates may be administered in the form of the compound itself, but they are usually used in the form of a pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients.

[0272] Representative carriers or excipients should be compatible with other components in the composition and should not harm the patient's health. The carriers or excipients can be solid or liquid, or both, and they form a pharmaceutical composition or unit dosage form (e.g., tablets, capsules) with a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and / or crystal form C-III), which may contain 0.05% to 95% by weight of a salt of formula A. The pharmaceutical compositions described in this invention can be prepared by known pharmaceutical preparation methods, such as methods involving mixing with pharmaceutically acceptable carriers and / or excipients and diluents.

[0273] In some instances, at least one active pharmaceutical ingredient selected from the salt of formula A or its solvates, or crystal forms of the salt of formula A or its solvates (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III), may be combined with at least one component, such as a carrier and / or excipient and / or diluent, which may be selected from sweeteners, flavoring agents, coloring agents, dyes and emulsifiers.

[0274] In some instances, the salt of formula A or its solvates, or the crystal forms of the salt of formula A or its solvates (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, and C-III), do not transform when formulated with one or more pharmaceutically acceptable carriers and / or excipients and / or diluents. In other instances, the salt of formula A or its solvates, or the crystal forms of the salt of formula A or its solvates (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, or C-III), may transform, wholly or partially, into one or more crystal forms, including transformation into a non-solid form, when formulated with one or more pharmaceutically acceptable carriers and / or excipients and / or diluents. In some instances, the crystal form AI or other crystal forms of the present invention can be dissolved when formulated into a pharmaceutical composition. Therefore, in these instances of "dissolution," the crystal form AI or other crystal forms are no longer present in their respective crystal forms in the pharmaceutical composition.

[0275] In some instances, at least one active pharmaceutical ingredient selected from the salt of formula A or its solvates or crystal forms of the salt of formula A or its solvates (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III) is formulated into a suitable formulation for administration.

[0276] The pharmaceutical compositions described in this invention may be dosage forms suitable for oral and oral (e.g., sublingual) administration, and the appropriate administration method may depend on the condition and severity of the treatment in each case, as well as the nature of the specific form in which the active pharmaceutical ingredient selected from the salt of formula A or its solvates or crystal forms of the salt of formula A or its solvates (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, and C-III) is used in the preparation of the pharmaceutical composition.

[0277] Suitable pharmaceutical compositions for oral administration may also be in the form of unit dosage forms, such as capsules, pods, and tablets, including suckable tablets, each of which is quantitatively prepared from at least one active pharmaceutical ingredient of formula A or its solvates or crystal forms (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, and C-III). The formulation may also be selected from powders, granules, solutions, suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions, and water-in-oil emulsions. These compositions can also be prepared by any applicable pharmaceutical preparation method as described above, for example, methods comprising the steps of: mixing at least one active pharmaceutical ingredient selected from a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, and crystal form C-III), with a carrier and / or excipients and / or diluents (which may consist of one or more additives). These compositions are typically prepared by uniformly and homogeneously mixing at least one active pharmaceutical ingredient selected from a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, and crystal form C-III) with a liquid or finely segmented solid carrier, the product being shaped accordingly.

[0278] At least one active pharmaceutical ingredient selected from the salt of formula A or its solvates, or crystal forms of the salt of formula A or its solvates (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, and crystal form C-III), may also be used in combination with one or more other active ingredients (e.g., in synergistic therapy). When used in combination, the active ingredients may be separate compositions for simultaneous administration via the same or different routes of administration or for separate administration at different times (e.g., sequential administration in any order), or they may be administered together in the same pharmaceutical composition.

[0279] In some instances, at least one active pharmaceutical ingredient selected from the salt of formula A or its solvates, or crystal forms of the salt of formula A or its solvates (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II and crystal form C-III), may be administered concurrently with one or more other active ingredients known to have therapeutic effects, such as for the treatment of diseases that respond to inhibition of Syk kinase activity, such as autoimmune diseases, inflammatory diseases and cancers (preferably hematologic malignancies).

[0280] The term "combination use" as used herein defines the use of at least one active pharmaceutical ingredient selected from the salt of formula A or its solvates, or crystal forms of the salt of formula A or its solvates (e.g., crystal forms AI, BI, B-II, B-III, CI, C-II, and C-III), in combination with one or more other active ingredients, such as in the treatment of autoimmune or inflammatory diseases (e.g., in combination with antiimmunotherapy agents or steroids), or in antitumor methods (e.g., in combination with BTK inhibitors, PI3Kδ inhibitors, Bcl-2 inhibitors, or 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 PI3Kδ inhibitors include, but are not limited to, ederalipix (Idelalisib), IPI-145 (Duvelisib), TGR-1202 (Umbralisib), GS-9820 (Acalisib), and INCB-050465. Examples of Bcl-2 inhibitors include, but are not limited to, venetoclax (ABT-199) and ABT-263 (Navitoclax). Here, "anti-tumor method" can refer to any method aimed at treating cancer (including hematologic malignancies). Examples of anti-tumor methods include, but are not limited to, chemotherapy, radiotherapy, targeted therapy, and immunotherapy.

[0281] Examples of anti-immunotherapy agents include, but are not limited to, corticosteroids (such as fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide, or budesonide), disease modifiers (such as antimalarial drugs, methotrexate, sulfamethoxazole salicylate, masalazine, imidazoline, 6-mercaptopurine, metronidazole, and D-penicillamine), and nonsteroidal anti-inflammatory drugs (such as acetaminophen, aspirin, sodium salicylate, dextromethorphan, magnesium salicylate, and magnesium choline salicylate). Disalicylic acid, ibuprofen, naproxen, diclofenac, difluorophenylsalicylic acid, etodoxacin, fenofibrate calcium, flurbiprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenac conjugate base, meclofenac sodium, meclofenac, naproxen, oxapazine, butylphenyl nitrone, sulindac, or toluidine pyridine acetate), COX-2 inhibitors, cytokine synthesis / release inhibitors (such as anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.).

[0282] Therefore, the methods described herein are not limited to the order of administration, and one or more other active ingredients may be administered simultaneously, before, or after administration. In the combinations described above, at least one pharmaceutical active ingredient is derived from a salt of formula A or a solvate thereof, or a crystal form of a salt of formula A or a solvate thereof (e.g., crystal form AI, crystal form BI, crystal form B-II, crystal form B-III, crystal form CI, crystal form C-II, and crystal form C-III).

[0283] The following are non-restrictive examples.

[0284] Experimental Section

[0285] The compound (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine used in the examples was prepared according to WO2012167733A1.

[0286] All reagents used in this invention (except intermediates) were commercially available. The names of all compounds (except reagents) were generated using ChemBioDraw Ultra 16.0 software.

[0287] Unless otherwise noted, powder X-ray diffraction spectroscopy was performed using a Bruker D8 ADVANCE (target: Cu, voltage: 40 kV, current: 40 mA, scan rate: 4 degrees / minute, step size: 0.02 degrees, measurement range: 3-45 degrees).

[0288] Unless otherwise noted, differential scanning calorimetry (DSC) measurements were performed using a Netzsch DSC 204F1 instrument (purge gas: nitrogen, flow rate: 20-60 mL / min). -1 Heating rate: 5-10℃ / minute, measurement range: 30℃→300℃) The sample measurement used a perforated aluminum disc and indium was used for temperature correction.

[0289] Unless otherwise noted, thermogravimetric analysis was performed using a TGA 209F1 thermometer from Netzsch GmbH, Germany (purge gas: nitrogen, heating rate: 10°C / min).

[0290] Figure 8 and Figure 10 Differential scanning calorimetry and thermogravimetric analysis were performed using a DSC Q2000 and a TG Q500 from TA Instruments, Inc., respectively.

[0291] Example 1: Preparation of the crystal form AI of salt of formula A

[0292] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of ethanol and heated to slight reflux with stirring. 0.315 mL of 1 M aqueous acetic acid solution was added, and the solution became clear. Heating was then stopped. The mixture was stirred at room temperature for 5 days, filtered, and dried to give 71.52 mg of a yellow solid.

[0293] 1 H NMR (400 MHz, cdcl3) δ 8.88 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9Hz, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.53 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.07 (t, J = 5.6 Hz, 1H), 4.06 – 3.94 (m, 4H), 3.89 (tdd, J = 6.6, 3.9, 2.4Hz, 1H), 3.70 (dtd, J = 10.9, 6.9, 4.5 Hz, 2H), 3.11 (dd, J = 12.3, 2.0 Hz,2H), 2.93 (dd, J = 10.4, 3.0 Hz, 2H), 2.85 (d, J = 1.7 Hz, 3H), 2.83 – 2.75(m, 2H), 2.74 – 2.63 (m, 1H), 2.05 (s, 2H), 2.02 (d, J = 13.9 Hz, 2H), 1.97 –1.83 (m, 2H).

[0294] The obtained powder sample is of crystal form AI of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 1 As shown. The peaks selected are as follows: 6.2, 9.4, 10.8, 12.1, 14.1, 15.8, 16.3, 17.2, 19.0, 19.3, 20.1, 21.1, 21.7, 22.2, 22.7, 24.6, 25.4, 26.8, 27.2, 27.5, 29.2, 30.6, and 31.8 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 6.2, 9.4, 16.3, 17.2, and 19.0 degrees. The DSC test results are as follows. Figure 2 As shown, the crystalline AI exhibits distinct endothermic peaks at approximately 162.8–179.6 °C and approximately 217.0–219.4 °C.

[0295] Example 2: Preparation of the crystal form AI of salt of formula A

[0296] Glacial acetic acid (0.124 mL, 2.1 mmol) and (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) were added to 2 mL of ethanol. The mixture was heated to dissolve with stirring, and then heating was stopped. 0.5 mL of isopropyl ether was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried to obtain 60 mg of a yellow solid. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the Al salt of formula A obtained in Example 1.

[0297] Example 3: Preparation of the crystal form AI of salt of formula A

[0298] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was mixed with 0.5 mL of 1 M aqueous acetic acid solution in 5 mL of 95% ethanol. The mixture was heated to dissolve with stirring, and the temperature was lowered to room temperature. Then, 0.2 mL of isopropyl ether was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried to obtain 20 mg of a yellow solid. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0299] Example 4: Preparation of the crystal form AI of salt of formula A

[0300] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was added to 4 mL of ethanol and heated to 50-55 °C with stirring. 3 mL of glacial acetic acid was added to obtain a clear solution. 9 mL of methyl tert-butyl ether was added dropwise, and the solution was kept at 50-55 °C for 30 minutes, then cooled to 20-25 °C and stirred for 17 hours. The solution was filtered and dried under vacuum at 55 °C for 5 hours to obtain 0.98 g of product, yield: 87%, purity: 99.55%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0301] Example 5: Preparation of the crystal form AI of salt of formula A

[0302] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (4.0 g, 8.29 mmol) was added to a mixed solvent of 16 mL ethanol and 10 mL water. The mixture was heated to 70-75 °C with stirring, and 1.42 mL glacial acetic acid was added to obtain a clear solution. 100 mL ethanol was slowly added to the solution, and the mixture was kept at 70-75 °C for 30 minutes with stirring, then slowly cooled to 0-5 °C. The precipitated solid was filtered, and the product was dried under vacuum at 55 °C for 17 hours to obtain 3.8 g of product, with a yield of 84% and a purity of 99.77%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0303] Example 6: Preparation of the crystal form AI of salt of formula A

[0304] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was added to 4 mL of isopropanol and heated to 50-55 °C with stirring. 3 mL of glacial acetic acid was added to obtain a clear solution. 9 mL of methyl tert-butyl ether was added dropwise, and the solution was kept at 50-55 °C for 30 minutes, then cooled to 20-25 °C and stirred for 17 hours. The solution was filtered and dried under vacuum at 55 °C for 5 hours to obtain 0.99 g of product, yield: 88%, purity: 99.54%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0305] Example 7: Preparation of the crystal form AI of salt of formula A

[0306] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 4 mL of isopropanol and heated to 80 °C with stirring. 0.32 mL of 1 M aqueous acetic acid solution was added to obtain a clear solution. After cooling to room temperature, the solution was stirred overnight, filtered, and dried to obtain 40 mg of solid. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the Al salt of formula A obtained in Example 1.

[0307] Example 8: Preparation of the crystal form AI of salt of formula A

[0308] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was suspended in 10 mL of isopropanol and heated to 80-85 °C. 3.11 mL of 1 M aqueous acetic acid solution was added to obtain a clear solution. 10 mL of isopropanol was added to the solution, and the reaction mixture was cooled to room temperature and stirred overnight. The solid was collected by filtration, the filter cake was washed with isopropanol, and dried under vacuum at 60 °C for 2 hours to obtain 880 mg of product with a purity of 99.2%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0309] Example 9: Preparation of the crystal form AI of salt of formula A

[0310] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of acetonitrile and heated to slight reflux with stirring. 0.315 mL of 1M aqueous acetic acid solution was added, and the solution became clear. Heating was stopped, and the mixture was stirred overnight at room temperature. 1 mL of acetonitrile was added, and stirring continued for 5 days. The mixture was filtered and dried to obtain 38.54 mg of a yellow solid. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0311] Example 10: Preparation of the crystal form AI of salt of formula A

[0312] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 4.5 mL of acetonitrile and heated to 80-85 °C. 0.2 mL of 1 M aqueous acetic acid solution and 0.1 mL of water were added to obtain a clear solution. The reaction system was then cooled to room temperature and stirred overnight. The solid was collected by filtration and dried to obtain 39.4 mg of the product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0313] Example 11: Preparation of the crystal form AI of salt of formula A

[0314] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of acetone and heated to slight reflux. 0.315 mL of 1 M aqueous acetic acid solution was added to obtain a clear solution, and heating was stopped. The reaction system was stirred overnight at room temperature, and the product precipitated. Stirring was continued at room temperature for 5 days. The solid was collected by filtration and dried at room temperature to obtain 76.04 mg of product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0315] Example 12: Preparation of the crystal form AI of salt of formula A

[0316] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was dissolved in 3 mL of glacial acetic acid at 60-64 °C. 18 mL of tert-butanol was added dropwise, and the mixture was stirred for 30 minutes after the addition was complete. The mixture was then cooled to 20-25 °C and stirred for 17 hours. The solid was collected by filtration and dried under vacuum at 60 °C for 6 hours to obtain 1.04 g of product. The yield was 92%, and the purity was 98.74%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0317] Example 13: Preparation of the crystal form AI of salt of formula A

[0318] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was suspended in a mixed solvent consisting of 6 mL of dioxane and 2 mL of water. The mixture was heated to 45-50 °C with stirring, and 0.36 mL of glacial acetic acid was added to obtain a clear solution. 10 mL of dioxane was added to the solution at 50-55 °C. The reaction system was cooled to 20-25 °C and stirred for 2 hours. The solid was collected by filtration and dried under vacuum at 55 °C to obtain 0.7 g of product, yield: 62%, purity: 99.83%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0319] Example 14: Preparation of the crystal form AI of salt of formula A

[0320] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was dissolved in 3 mL of glacial acetic acid at 40-50 °C. 35 mL of dioxane was added dropwise. After the addition was complete, the reaction mixture was cooled to 20-25 °C and stirred for 1 hour. The temperature was then further reduced to 5-10 °C and stirred for another hour. The solid was collected by filtration and dried under vacuum at 55 °C for 17 hours to obtain 0.23 g of the product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0321] Example 15: Preparation of the crystal form AI of salt of formula A

[0322] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (0.5 g, 1.04 mmol) was dissolved in 9.5 mL of dichloromethane at 40-45 °C. 0.12 mL of glacial acetic acid was added with stirring, followed by 3 mL of methyl tert-butyl ether. The mixture was kept at 40-45 °C with stirring for 10 minutes, then cooled to 20-25 °C and stirred for another 17 hours. The solid was collected by filtration and dried under vacuum at 55 °C for 4 hours to obtain 0.5 g of product with a purity of 99.56%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0323] Example 16: Preparation of the crystal form AI of salt of formula A

[0324] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 1 mL of methanol, heated to 70 °C, and 0.2 mL of 1 M aqueous acetic acid solution was added to obtain a clear solution. The reaction system was cooled to room temperature and stirred overnight. The solid was collected by filtration and dried to obtain 30.2 mg of product. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the Al sample of salt A obtained in Example 1.

[0325] Example 17: Preparation of the crystal form AI of salt of formula A

[0326] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.5 g, 3.11 mmol) and glacial acetic acid (0.37 g) were suspended in a mixed solvent consisting of 6 mL of acetone and 3 mL of water. The mixture was heated to 50 °C and stirred at this temperature for 20 minutes. Then, 27 mL of acetone was slowly added, and the mixture was heated to 60 °C and stirred for 2 hours. The mixture was then allowed to cool naturally to room temperature and stirred overnight. The solid was collected by filtration and dried to obtain 1.4 g of product with a purity of 99.72%. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form AI of salt A obtained in Example 1.

[0327] Example 18: Preparation of crystal form BI of salt of formula A

[0328] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was suspended in a mixed solvent consisting of 30 mL of isopropanol and 4.6 mL of water. The mixture was heated to 80-85 °C with stirring, and 2.3 mL of 1 M p-toluenesulfonic acid aqueous solution was added. After the reaction mixture was dissolved, the temperature was lowered to 15-20 °C, and stirring was continued for 16 hours. The solid was collected by filtration and dried to give 1.06 g of product.

[0329] 1H NMR (400 MHz, dmso) δ 8.03 – 7.99 (m, J = 2.0 Hz, 1H), 7.76 – 7.73(m, J = 2.0 Hz, 1H), 7.18 – 7.11 (m, J = 8.4 Hz, 2H), 7.06 – 6.99 (m, J = 6.0Hz, 1H), 6.58 – 6.55 (m, 1H), 6.47 – 6.42 (m, 2H), 6.41 – 6.36 (m, J = 8.4Hz, 2H), 6.10 – 6.05 (m, J = 7.8 Hz, 2H), 3.13 – 3.04 (m, 1H), 3.04 – 2.96(m, J = 12.5, 3.2 Hz, 1H), 2.83 – 2.64 (m, 7H), 2.18 – 2.11 (m, J = 12.2 Hz, 1H), 2.08 – 1.96 (m, J = 12.5, 8.7 Hz, 1H), 1.89 (s, 3H), 1.86 – 1.78 (m, J =12.0, 9.6 Hz, 3H), 1.74 – 1.66 (m, J = 12.0 Hz, 1H), 1.25 (s, 3H), 0.94 –0.85 (m, J = 12.6 Hz, 2H), 0.77 – 0.64 (m, 2H).

[0330] The obtained powder sample is of crystal form BI of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 4 As shown. The peaks selected are as follows: 4.9, 5.5, 6.8, 9.6, 10.1, 14.4, 14.8, 15.9, 16.4, 17.3, 18.4, 19.3, 19.8, 20.7, 21.4, 22.5, 23.2, 25.0, 26.1, 27.0, and 29.0 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 4.9, 5.5, 9.6, 14.4, 16.4, and 19.8 degrees. The DSC test results are as follows. Figure 5 As shown, the endothermic peak of crystalline BI is approximately 205.7-209.6℃.

[0331] Example 19: Preparation of crystal form BI of salt of formula A

[0332] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 1.5 mL of 95% ethanol at 80 °C. 0.11 mL of 1 M p-toluenesulfonic acid aqueous solution was added to obtain a clear solution. The reaction system was cooled to 15-20 °C and stirred for 3 hours. The solution was filtered and dried to obtain the product. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form BI sample of salt A obtained in Example 18.

[0333] Example 20: Preparation of crystal form BI of salt of formula A

[0334] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of ethanol and heated to slight reflux with stirring. 0.23 mL of 1 M p-toluenesulfonic acid aqueous solution was added, and the solution became clear. Heating was stopped, and an oily substance precipitated. 2 mL of ethanol was added, and stirring continued at room temperature for 3 days. The mixture was filtered and dried to obtain 124.36 mg of solid. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form BI sample of salt A obtained in Example 18.

[0335] Example 21: Preparation of crystal form BI of salt of formula A

[0336] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in a mixed solvent consisting of 2 mL of ethanol and 0.23 mL of water. The solution was heated to 80-90 °C, and 0.23 mL of 1 M p-toluenesulfonic acid aqueous solution was added to obtain a clear solution. The solution was cooled to room temperature and stirred for 16 hours. The solid was collected by filtration and dried at room temperature to obtain 85 mg of product. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form BI sample of salt A obtained in Example 18.

[0337] Example 22: Preparation of crystal form BI of salt of formula A

[0338] Approximately 50 mg of crystal form B-II of salt A was suspended in approximately 0.5 mL of 95% ethanol and stirred at 20°C for 4 days. The solid was then collected by filtration to obtain the product. The X-ray powder diffraction pattern of the obtained sample was consistent with that of crystal form BI of salt A obtained in Example 18.

[0339] Example 23: Preparation of crystal form BI of salt of formula A

[0340] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of isopropanol and heated to slight reflux with stirring. 0.23 mL of 1 M p-toluenesulfonic acid aqueous solution was added, and the solution became clear. Heating was stopped, and an oily substance precipitated. 3 mL of isopropanol was added, and stirring continued at room temperature for 3 days. The mixture was filtered and dried to obtain 131.92 mg of solid. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form BI sample of salt A obtained in Example 18.

[0341] Example 24: Preparation of crystal form BI of salt of formula A

[0342] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of acetone and heated to slight reflux with stirring. 0.23 mL of 1 M p-toluenesulfonic acid aqueous solution was added, and the solution became clear. Heating was stopped, and an oily substance precipitated. 4 mL of acetone was added, and stirring continued at room temperature for 3 days. The mixture was filtered and dried to obtain 94.77 mg of solid. The X-ray powder diffraction pattern of the obtained sample was consistent with that of the crystal form BI sample of salt A obtained in Example 18.

[0343] Example 25: Preparation of crystal form B-II of salt of formula A

[0344] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (100 mg, 0.21 mmol) was suspended in 1 mL of methanol and heated to slight reflux with stirring. 0.23 mL of 1 M p-toluenesulfonic acid aqueous solution was added. The solution became clear, and heating was stopped to precipitate an oily substance. 2 mL of methanol was added, and stirring was continued at room temperature for 3 days. The mixture was filtered and dried to obtain 71.66 mg of solid.

[0345] 1H NMR (400 MHz, cdcl3) δ 8.88 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 1.9Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H),7.31 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.95 (t, J = 6.0 Hz, 1H),4.21 – 4.12 (m, 1H), 4.04 – 3.88 (m, 6H), 3.47 (dd, J = 42.8, 12.1 Hz, 2H),3.12 – 3.03 (m, 1H), 2.98 (t, J = 11.8 Hz, 1H), 2.83 (s, 3H), 2.80 – 2.75 (m,2H), 2.71 – 2.62 (m, 1H), 2.28 (s, 3H), 1.98 (d, J = 12.4 Hz, 2H), 1.92 –1.84 (m, 2H).

[0346] The obtained powder sample is crystal form B-II of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 7 As shown. The peaks selected are as follows: 5.1, 6.0, 9.5, 10.2, 14.3, 14.8, 15.3, 15.8, 17.1, 17.9, 19.1, 19.7, 20.2, 20.8, 22.4, 23.4, 26.0, and 27.2 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 5.1, 6.0, 10.2, 17.1, and 19.1 degrees. The DSC test results are as follows. Figure 8 As shown, the endothermic peak of crystal form B-II is at approximately 203.0-211.4℃.

[0347] Example 26: Preparation of crystal form B-III of salt of formula A

[0348] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 2.5 mL of water at 80-85 °C. 0.11 mL of 1 M p-toluenesulfonic acid aqueous solution was added to obtain a clear solution. The solution was stirred and cooled to room temperature, a precipitate was formed, filtered, and dried to obtain a solid.

[0349] The obtained powder sample is crystal form B-III of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 9 As shown. The peaks selected are as follows: 5.3, 5.9, 9.9, 10.7, 11.8, 13.6, 14.9, 15.6, 16.0, 17.6, 18.9, 20.0, 21.6, 22.8, 25.0, and 27.0 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 5.3, 5.9, 10.7, 13.6, and 15.6 degrees. The DSC test results are as follows. Figure 10 As shown, crystal form B-III exhibits an exothermic peak at approximately 168.1–172.5 °C and a distinct endothermic peak at approximately 199.6–208.3 °C.

[0350] Example 27: Preparation of crystal form B-III of salt of formula A

[0351] Approximately 50 mg of crystal form BI of salt A was suspended in 0.5 mL of water and stirred at room temperature for 4 days. The solid was collected by filtration and dried under vacuum at 60°C for 2 hours to obtain the product. The X-ray powder diffraction pattern of the obtained sample was consistent with that of crystal form B-III of salt A obtained in Example 26.

[0352] Example 28: Preparation of the crystal form CI of salt of formula A

[0353] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (96.5 mg, 0.2 mmol) was suspended in 3 mL of isopropanol and heated to 80-85 °C with stirring. 0.3 mL of 1 M aqueous malic acid solution and 1.8 mL of water were added, and the reaction mixture became a clear solution. The mixture was cooled to room temperature and stirred overnight. The solid was collected by filtration and dried to give 97.7 mg of the product.

[0354] 1H NMR (400 MHz, dmso) δ 9.03 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.98 (t, J = 6.1 Hz, 1H), 7.58 (s, 1H),7.41 (d, J = 8.4 Hz, 2H), 4.07 – 3.94 (m, 3H), 3.91 (dd, J = 9.8, 4.2 Hz,1H), 3.78 – 3.61 (m, 8H), 3.07 – 2.66 (m, 14H), 2.33 (dd, J = 15.6, 4.2 Hz,1H), 1.93 (d, J = 13.2 Hz, 2H), 1.74 (dt, J = 12.5, 8.9 Hz, 2H).

[0355] The obtained powder sample is of crystal form CI of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 11 As shown. The peaks selected are as follows: 8.6, 10.8, 11.8, 13.5, 14.3, 15.5, 16.4, 17.2, 17.7, 18.1, 18.4, 19.5, 20.9, 22.2, 22.6, 23.8, 25.8, 26.7, 27.8, 29.2, 29.8, and 30.7 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 8.6, 14.3, 15.5, 19.5, and 22.2 degrees. The DSC test results are as follows. Figure 12 As shown, the endothermic peak of crystalline CI is approximately 211.1–214.9 °C.

[0356] Example 29: Preparation of the crystal form CI of salt of formula A

[0357] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol) was suspended in 20 mL of ethanol and heated to 80 °C. 3.1 mL of 1 M malic acid aqueous solution was added, followed by 12 mL of water, resulting in a clear solution. Then, 3 mL of ethanol was added, and the reaction mixture was cooled to 15-20 °C and stirred for 14 hours. The solution was filtered and dried under vacuum at 60 °C for 2 hours to obtain 1.03 g of product with a purity of 99.7%. X-ray powder diffraction patterns of the obtained sample were consistent with those of the crystal form CI of salt A obtained in Example 28.

[0358] Example 30: Preparation of the crystal form CI of salt of formula A

[0359] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (96.5 mg, 0.2 mmol) was mixed with 7 mL of tetrahydrofuran, 0.7 mL of water, and 0.3 mL of 1M malic acid aqueous solution and heated to dissolve, yielding a clear solution. The reaction system was then cooled to 15-20°C, and 5 mL of tetrahydrofuran was added. Stirring continued for 3 days, followed by filtration and drying to obtain 87.9 mg of the product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form CI sample of salt A obtained in Example 28.

[0360] Example 31: Preparation of the crystal form CI of salt of formula A

[0361] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (96.5 mg, 0.2 mmol) was mixed with 5 mL of methanol, 3 mL of water, and 0.3 mL of 1 M malic acid aqueous solution and heated to 75-80 °C to obtain a clear solution. The reaction system was then slowly cooled to 15-20 °C with stirring, filtered, and dried to obtain 104 mg of the product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form CI sample of salt A obtained in Example 28.

[0362] Example 32: Preparation of the crystal form CI of salt of formula A

[0363] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol) was suspended in 3 mL of ethanol. 14.8 mg of malic acid, suspended in 0.2 mL of ethanol, was added to the mixture. The reaction mixture was kept at 40 °C and stirred for 20 hours. After stirring, the mixture was cooled to room temperature, filtered, and dried to obtain approximately 40 mg of the product. The X-ray powder diffraction pattern of the obtained sample was consistent with the crystal form CI of salt A obtained in Example 28.

[0364] Example 33: Preparation of crystal form C-II of salt of formula A

[0365] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (48 mg, 0.1 mmol), 3.5 mL of water, 0.6 mL of acetonitrile, and 0.11 mL of 1 M aqueous malic acid solution were mixed and heated to 80-85 °C with stirring to dissolve. The reaction mixture was then cooled to room temperature and stirred for 18 hours. After filtration and drying, 35.2 mg of the product was obtained.

[0366] 1 H NMR (400 MHz, dmso) δ 9.02 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.89 (t, J = 6.0 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 3.89 (d, J = 9.1 Hz, 2H), 3.84 (dd, J = 10.8, 3.4Hz, 1H), 3.80 – 3.63 (m, 5H), 3.56 (dd, J = 23.4, 11.8 Hz, 2H), 3.08 (d, J =12.7 Hz, 1H), 2.92 (d, J = 2.1 Hz, 4H), 2.85 (dd, J = 12.2, 9.8 Hz, 5H), 2.70 (dt, J = 22.5, 11.2 Hz, 3H), 2.46 (d, J = 10.8 Hz, 1H), 2.31 (dd, J = 15.6, 3.4 Hz, 1H), 1.93 (d, J = 12.9 Hz, 2H), 1.74 (dt, J = 12.2, 8.5 Hz, 2H).

[0367] The obtained powder sample is of crystal form C-II of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 14 As shown. The peaks selected are as follows: 5.3, 9.5, 10.0, 10.6, 11.3, 11.6, 12.4, 12.8, 13.6, 15.9, 17.0, 18.4, 20.0, 20.9, 21.6, 23.1, 24.9, 26.4, 26.9, and 28.3 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 11.3, 11.6, 17.0, 20.0, 21.6, and 23.1 degrees. The DSC test results are as follows. Figure 15 As shown, the endothermic peaks of crystal form C-II are at approximately 70.2–90.4 °C and approximately 202.6–215.0 °C.

[0368] Example 34: Preparation of crystal form C-III of salt of formula A

[0369] (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine (1.0 g, 2.1 mmol), 11 mL of ethanol, 41 mL of water, and 3.1 mL of 1 M aqueous malic acid solution were mixed and heated to 80 °C to dissolve. The reaction mixture was then slowly cooled to 15-20 °C and stirred overnight. The solid was collected by filtration and dried to give 0.94 g of product with a purity of 99.7%.

[0370] 1 H NMR (400 MHz, dmso) δ 9.02 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.0Hz, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.90 (t, J = 5.9 Hz, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 3.90 (d, J = 8.9 Hz, 2H), 3.84 (dd, J = 10.7, 3.4Hz, 1H), 3.80 – 3.65 (m, 5H), 3.62 – 3.54 (m, 2H), 3.10 (d, J = 11.8 Hz, 2H),2.98 – 2.79 (m, 7H), 2.78 – 2.65 (m, 2H), 2.46 (d, J = 10.7 Hz, 1H), 2.31 (dd, J = 15.6, 3.4 Hz, 1H), 1.92 (d, J = 12.8 Hz, 2H), 1.74 (qd, J = 12.6, 4.0 Hz, 2H).

[0371] The obtained powder sample is of crystal form C-III of salt of formula A, and its powder X-ray diffraction pattern is as follows. Figure 17 As shown. The peaks selected are as follows: 5.3, 10.6, 11.8, 12.8, 16.0, 17.0, 17.9, 18.6, 18.9, 20.3, 21.7, 22.5, 23.1, 25.2, 25.6, and 27.4 degrees, with an error of ±0.2 degrees (2θ) for each different angle. The characteristic peaks are 5.3, 10.6, 17.0, 17.9, and 25.2 degrees. The DSC test results are as follows. Figure 18 As shown, the endothermic peaks of crystal form C-III are at approximately 69.9–88.5 °C and approximately 201.6–206.7 °C.

[0372] Example 35: Stability test of salt of formula A

[0373] Determination method: Test samples of salt A with crystal forms AI, BI, CI and C-III were placed in petri dishes, with the openings exposed, and placed in sealed clean containers. They were placed at 60℃ for 10 days, at an illumination of 4500 lx ± 500 lx for 10 days, and at 25℃ and a relative humidity of 92.5% ± 5% for 10 days. Samples were taken on the 5th and 10th days to investigate the purity (analyzed by HPLC) and crystal form (analyzed by X-ray powder diffraction). The results were compared. The experimental results of various salts and their crystal forms are shown in Tables 1, 2, 3 and 4.

[0374] Table 1: Experimental results on the stability of the A-salt crystal form AI

[0375]

[0376] Table 2: Experimental results of the stability of the A-salt crystal form BI

[0377]

[0378] Table 3: Experimental results on the stability of the A-salt crystal form CI

[0379]

[0380] Table 4: Stability test results of salt crystal form C-III of Formula A

[0381]

[0382] Conclusion: The data in Tables 1, 2, 3 and 4 show that the chemical purity and crystal form of the A salts AI, BI, CI and C-III did not change after being placed under high temperature, light, or high humidity for 10 days, indicating that the A salts AI, BI, CI and C-III are stable.

[0383] Example 36: Solubility test of salt of formula A

[0384] (1) Determination of the solubility of Formula A salt (acetate, crystalline form AI): Appropriate amounts of Formula A salt (acetate, crystalline form AI) and its free base (compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine) sample were added to various solvents respectively. The mixtures were stirred at a certain temperature for 4 hours, excess solid was filtered off, and the solubility of the clear filtrate was determined. The experimental results are shown in Table 5.

[0385] Table 5

[0386]

[0387] Conclusion: The data in Table 5 show that the solubility of salt A (acetate, crystal form AI) in water is significantly increased compared with its free base.

[0388] (2) Determination of the rough solubility of salt A: The salt of formula A to be roughly soluble was weighed beforehand and added to a test tube. Pure water was then added dropwise to the test tube, and the amount of water added each time was recorded. After each addition of water, the test tube was shaken for 5 minutes until the solid was completely dissolved. The rough solubility of the compound was then calculated based on the weighed mass of the compound and the total amount of water added. The calculation results are shown in Table 6.

[0389] Table 6

[0390]

[0391] Conclusion: The data in Table 6, combined with the data in Table 5, show that the solubility of salt A in water is increased to varying degrees compared with its free base. The solubility of acetate is increased particularly significantly, followed by p-toluenesulfonate and malate.

[0392] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations therein will be suggested to those skilled in the art, and these are included within the spirit and scope of this application and the appended claims. All publications, patents and patent applications referenced herein are incorporated herein by reference and used for all purposes.

Claims

1. Acetate of (S)-7-(4-(1-(methylsulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine.

2. The acetate of claim 1, wherein the salt is an acetate.

3. The acetate as described in claim 1 or 2, wherein it is in the crystalline form Al, characterized in that, Characteristic peaks are observed at the following 2θ angles in the powder X-ray diffraction pattern: 6.2, 9.4, 16.3, 17.2, and 19.0 degrees, with each 2θ value having an error of approximately ±0.2°.

4. The acetate as described in claim 1 or 2, wherein it is in the crystalline form Al, characterized in that, Characteristic peaks are observed at the following 2θ angles in the powder X-ray diffraction pattern: 6.2, 9.4, 10.8, 16.3, 17.2, 19.0, 20.1, 21.7, 24.6, and 29.2 degrees. The measured 2θ values ​​have an error of approximately ±0.2 2θ.

5. The acetate as described in claim 1 or 2, wherein it is in the crystalline form Al, characterized in that, Characteristic peaks are observed at the following 2θ angles in the powder X-ray diffraction pattern: 6.2, 9.4, 10.8, 12.1, 15.8, 16.3, 17.2, 19.0, 20.1, 21.7, 22.7, 24.6, 25.4, and 29.2 degrees. The measured 2θ values ​​have an error of approximately ±0.2 2θ.

6. A pharmaceutical composition comprising an effective amount of one or more acetates as described in any one of claims 1 to 5, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising an effective amount of any one of claims 3 to 5 acetate, and a pharmaceutically acceptable carrier.

8. Use of the acetate according to any one of claims 1 to 5 in the preparation of a medicament for the treatment of diseases associated with Syk kinase activity, such as autoimmune diseases, inflammatory diseases, and cancers (preferably hematologic malignancies), said autoimmune diseases, inflammatory diseases, and cancers being selected, for example, from systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, IgA nephropathy, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, asthma, lymphomas (such as B-cell lymphoma, T-cell lymphoma), leukemias (such as chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia), and multiple myeloma.

9. A method for preparing the acetate according to any one of claims 3 to 5, wherein the acetate is crystalline Al, comprising: (1) reacting compound (S)-7-(4-(l-(methylsulfonyl)-piperidin-4-yl)phenyl)-N- (morpholin-2-ylmethyl)pyrido[3,4-b]pyrazin-5-amine with acetic acid to form a salt, and isolating the salt formed in at least one dissolving solvent (e.g., C 1-6 alkyl alcohol, tetrahydrofuran, dioxane, halogenated alkane of less than three carbon atoms, acetone, butanone, or acetonitrile) or in a mixed solvent consisting of a water-miscible organic solvent (e.g., acetone, C 1-6 alkyl alcohol such as methanol, ethanol, or isopropanol, dioxane, or acetonitrile) and water; (2) The crystalline form of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine acetate was isolated and obtained as Al solid. (3) Optionally, dry the solid obtained in step (2).

10. A method for preparing the acetate according to any one of claims 3 to 5, wherein the acetate is crystalline Al, comprising: (1) Compound (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyridino[3,4-b]pyrazin-5-amine was added to an appropriate amount of at least one dissolving solvent (e.g., C) with acetic acid. 1-6 Alkyl alcohols such as ethanol or isopropanol, or dichloromethane) or water-miscible organic solvents (e.g., C45) 1-6 In a mixed solvent consisting of alkyl alcohols (such as methanol, ethanol, isopropanol, dioxane, acetone, or acetonitrile) and water, the first solution is obtained by reacting the alkyl alcohols to form a salt. (2) Add at least one anti-dissolving solvent (e.g., acetone, isopropyl ether or methyl tert-butyl ether) to the first solution to obtain the second solution; (3) The crystalline form of (S)-7-(4-(1-(methanesulfonyl)-piperidin-4-yl)phenyl)-N-(morpholin-2-ylmethyl)pyrido[3,4-b]pyrazine-5-amine acetate was isolated and obtained as Al solid. (4) Optionally, dry the solid obtained in step (3).

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